Endophthalmitis in Clinical Practice [2nd ed. 2023] 3031351835, 9783031351839

Citation preview

In Clinical Practice

Harry W. Flynn Jr. · Nidhi Relhan Batra · Stephen G. Schwartz · Prashanth G. Iyer · Lyubomyr Lytvynchuk · Andrzej Grzybowski

Endophthalmitis in Clinical Practice Second Edition

In Clinical Practice

Taking a practical approach to clinical medicine, this series of smaller reference books is designed for the trainee physician, primary care physician, nurse practitioner and other general medical professionals to understand each topic covered. The coverage is comprehensive but concise and is designed to act as a primary reference tool for subjects across the field of medicine.

Harry W. Flynn Jr. Nidhi Relhan Batra Stephen G. Schwartz Prashanth G. Iyer Lyubomyr Lytvynchuk Andrzej Grzybowski

Endophthalmitis in Clinical Practice Second Edition

Harry W. Flynn Jr. Department of Ophthalmology Bascom Palmer Eye Institute, University of Miami Miller School of Medicine Miami, FL, USA

Nidhi Relhan Batra Department of Ophthalmology, Bascom Palmer Eye Institute University of Miami Miller School of Medicine Miami, FL, USA

Stephen G. Schwartz Department of Ophthalmology Bascom Palmer Eye Institute, University of Miami Miller School of Medicine Naples, FL, USA

Prashanth G. Iyer Department of Ophthalmology Bascom Palmer Eye Institute, University of Miami Miller School of Medicine Miami, FL, USA

Lyubomyr Lytvynchuk Department of Ophthalmology Justus-Liebig-University Giessen, Eye Clinic, University Hospital Giessen and Marburg GmbH Giessen, Germany

Andrzej Grzybowski Foundation for Ophthalmology Development Institute for Research in Ophthalmology Mickiewicza, Poznań, Poland

ISSN 2199-6652     ISSN 2199-6660 (electronic) In Clinical Practice ISBN 978-3-031-35183-9    ISBN 978-3-031-35184-6 (eBook) https://doi.org/10.1007/978-3-031-35184-6 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Foreword

Over the past few decades, we have a better understanding of the pathophysiology of intraocular infections through clinical and microbiological studies, and we can initiate more prompt diagnosis and treatment to improve outcomes in the management of endophthalmitis. It is amazing to witness the changes in the differential diagnoses and management of endophthalmitis in recent years. With the increases in invasive ophthalmic procedures, there is a need for a concise, up-to-date reference on clinical endophthalmitis which includes options for antimicrobial therapy and the role of pars plana vitrectomy. This book, entitled Endophthalmitis in Clinical Practice, meets the need very well. Multiple chapters in the book are dedicated to specific subtopics in endophthalmitis management. The background section includes historical information as well as details on the Endophthalmitis Vitrectomy Study (EVS), as well as controversies in the use of intracameral antibiotics during cataract surgery. This follows a discussion on the various etiologies of endophthalmitis and includes initial treatment strategies in each subgroup. As part of diagnostic evaluation, sections include imaging for documentation of clinical features, echographic characteristics, and complications affecting visual outcomes. Management of more difficult cases may require retreatment after initial antimicrobials and uncommonly may require removal of the capsular bag and the intraocular lens (IOL) in specific cases. Illustrations of pre- and posttreatment cases are shown from the authors’ clinical practice. v

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Foreword

Pars plana vitrectomy is often considered in more rapidly advancing cases, especially in endophthalmitis after cataract surgery in patients presenting with light perception visual acuity. The use of vitrectomy may be limited by corneal or media opacities, but small-gauge vitrectomy approaches may allow a simpler approach to core vitrectomy without the need for conjunctival dissection or suture placement. Antimicrobial therapy is then discussed. This includes initial broad coverage of both Gram-positive and Gram-­ negative bacteria. Likewise, antifungal agents including amphotericin B and voriconazole can be utilized in suspected or confirmed endophthalmitis caused by fungi. Alternative agents for resistant organisms are reviewed and the tailoring of treatment for subsequent management. The use of intravitreal injections for retinal diseases has become the leading ophthalmic procedure in the United States. In these patients, endophthalmitis can occur from solution contamination as well as from the injection procedure itself. These cases generally present early after injection and frequently involve oropharyngeal flora from contamination of the needle or the ocular surface during drug delivery. Streptococcus as well as other Gram-positive organisms in these cases may have a more advanced clinical presentation with poor visual and anatomic outcomes. This text will undoubtedly prove to be a valuable asset for clinical ophthalmologists as well as retinal specialists. The abundant clinical illustrations, concise tables, and reference material enhance its readability. With the exception of the EVS, there are no major randomized clinical trials on which to base definitive recommendations. Rather, the authors utilize published case series and their own experience to provide guidelines regarding the prompt and efficient management of endophthalmitis. Bascom Palmer Eye Institute Miami, FL, USA

Richard K. Forster,

Conflict of Interest

Funding/Grant Support—This work was supported in part by National Institutes of Health center core grant P30EY014801 and by unrestricted grant from the Institute for Research in Ophthalmology, Foundation for Ophthalmology Development, Poznan, Poland. Financial Disclosures Dr. Harry W. Flynn Jr.—None Dr. Nidhi Relhan Batra—None Dr. Prashanth Iyer—None Dr. Lyubomyr Lytvynchuk—None Dr. Stephen G.  Schwartz discloses personal fees from Alimera, Bausch + Lomb, and Welch Allyn within the past 3 years. Dr. Andrzej Grzybowski reports grants from Alcon, Bausch&Lomb, Zeiss, Teleon, J&J, CooperVision, Hoya; lectures honoraria from Thea, Polpharma, Viatris; member of Advisory Boards: Nevakar, GoCheckKids, and Thea; all outside the submitted work.

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Endophthalmitis

Endophthalmitis is characterized by marked inflammation of intraocular fluids and tissues. Infectious endophthalmitis may be categorized by the apparent cause of the infection, including the onset of symptoms, the degree of inflammation, and other factors. The classification helps to plan further management and helps in predicting the treatment outcomes. Endophthalmitis may be exogenous (caused by inoculation of microorganisms from the external environment) or endogenous (caused by hematogenous spread from other parts of the body). All categories of endophthalmitis are associated with variable degrees of marked intraocular inflammation, typically with hypopyon, in addition to visual loss, redness, and pain. The diagnosis, treatment, and prophylaxis of endophthalmitis have been discussed in this book. 1. Classification of Endophthalmitis 2. Differential Diagnosis of Endophthalmitis 3. Making the Diagnosis of Endophthalmitis 4. Endophthalmitis Categories 5. Antimicrobial Treatment 6. Endophthalmitis Prophylaxis 7. Endophthalmitis and Retinal Detachment 8. Antibiotic Stewardship 9. Outcomes (Anatomical and Functional) and Complications of Treatment 10. Endophthalmitis: Miscellaneous Categories

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How to Use This Book

Endophthalmitis remains an uncommon but serious cause of visual loss. Early diagnosis and treatment may restore useful vision for many patients. However, visual outcomes may be poor despite prompt and appropriate therapy in other patients. This book is intended to be a practical guide to the clinical management of patients with endophthalmitis. The guidelines included in this book are based on the current peer-reviewed literature, as well as the authors’ experience and opinions. Summary statements from published studies are adapted for inclusion in the current text. These adaptations are used to ensure that the exact message is conveyed since rephrasing of sentences may change the original message. The Endophthalmitis Vitrectomy Study (EVS) was a randomized clinical trial that has provided high-level evidence for endophthalmitis associated with cataract surgery or secondary intraocular lens (IOL) surgery between 1991 and 1994. However, many patients with endophthalmitis from other causes have a different spectrum of microbial etiologies, a different set of clinical features, and a different visual prognosis. The best available evidence for these patients consists of clinical case series and individual case reports. This book provides guidance for an overall approach to the diagnosis and management of endophthalmitis, but the broad guidelines do not always apply to an individual patient, and treatment has to be individualized. The ultimate judgment regarding the care of an individual patient must be made by the treating physician, incorporating the specific clinical features, systemic risk factors, the microorganisms involved, and the wishes of the patient. xi

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How to Use This Book

This book is not intended to be an all-inclusive document nor a medical-legal resource. It is intended to provide practical guidelines in the care of patients with endophthalmitis.

Contents

1 Endophthalmitis:  Classification and Most Frequently Reported Organisms ���������������������������������   1 2 Differential  Diagnosis of Endophthalmitis�����������������  21 Toxic Anterior Segment Syndrome ���������������������������   22 Retained Lens Fragments �������������������������������������������   25 Flare-Up of Pre-existing Uveitis���������������������������������   27 Vitreous Hemorrhage �������������������������������������������������   28 Retinoblastoma�������������������������������������������������������������   32 Uveal Melanoma ���������������������������������������������������������   33 Intravitreal Triamcinolone Acetonide�����������������������   34 Viral Retinitis ���������������������������������������������������������������   36 Noninfectious Inflammation from Intravitreal Injections�����������������������������������������������������������������������   38 Brolucizumab-Related Intraocular Inflammation���   40 Drug-Associated Uveitis (a Rare Cause of Pseudoendophthalmitis)�����������������������������������������   42 3 Diagnosis  of Endophthalmitis: Clinical Presentation, Pathology, Microbiology, and Echography �������������������������������������������������������������  45 Clinical Presentations���������������������������������������������������   45 Microbiology�����������������������������������������������������������������   48 How to Perform TAP and Inject ���������������������������   48 Intravitreal Antimicrobial Injection�����������������������   51 Results of Anterior Chamber TAP Versus Vitreous TAP �����������������������������������������������   52 Culture Media�����������������������������������������������������������   54 Other Testing�������������������������������������������������������������   57 Echography�������������������������������������������������������������������   59 xiii

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4 Acute-Onset  Endophthalmitis: Clinical Categories, Incidence Rates, ­Signs/Symptoms, Risk Factors, Microbiology, Treatment, and Follow-Up �����������������������������  61 Acute-Onset Post-Operative Endophthalmitis Following Cataract Surgery�����������������������������������������   61 Incidence�������������������������������������������������������������������   61 Signs/Symptoms �������������������������������������������������������   61 Risk Factors���������������������������������������������������������������   62 Microbial Isolates�����������������������������������������������������   63 Initial Management of Acute-Onset Post-Operative Endophthalmitis ���������������������������   64 Intravitreal antimicrobials �������������������������������������   66 Follow-Up Management of Acute-Onset Post-­Operative Endophthalmitis ���������������������������   67 Acute-Onset Endophthalmitis Following Pars Plana Vitrectomy ���������������������������������������������������������   70 Incidence�������������������������������������������������������������������   70 Signs/Symptoms �������������������������������������������������������   70 Risk Factors �������������������������������������������������������������   70 Microbial Isolates�����������������������������������������������������   71 Endophthalmitis after Pars Plana Vitrectomy for Vitreous Floaters �����������������������������������������������   71 Initial Management of Acute-Onset Endophthalmitis Following Vitrectomy�����������������   73 Follow-Up Management in Patients with Acute-­Onset Endophthalmitis Following Vitrectomy�����������������������������������������������������������������   73 Post-Traumatic Endophthalmitis �������������������������������   75 Incidence�������������������������������������������������������������������   75 Signs/Symptoms �������������������������������������������������������   75 Risk Factors���������������������������������������������������������������   75 Microbial Isolates�����������������������������������������������������   77 Initial Management of Post-Traumatic Endophthalmitis�������������������������������������������������������   79 Follow-Up Management in Patients with Post-­Traumatic Endophthalmitis ���������������������������   80

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Endophthalmitis Associated with Intravitreal Injection�������������������������������������������������������������������������   83 Incidence�������������������������������������������������������������������   83 Signs/Symptoms of Endophthalmitis after Intravitreal Injections�����������������������������������������������   84 Risk Factors���������������������������������������������������������������   85 Microbial Isolates�����������������������������������������������������   86 Initial Management of Endophthalmitis Associated with Intravitreal Injection�������������������   86 Follow-Up Management in Patients with Endophthalmitis Associated with Intravitreal Injection���������������������������������������������������������������������   86 Additional Discussion Points �������������������������������������   91 Vitreous TAP Versus AC TAP/Paracentesis���������   91 Controversies in Care ���������������������������������������������   92 Systemic Immunosuppressives and the Risk of Post-Cataract Surgery Endophthalmitis�����������   93 5 D  elayed-Onset (Chronic) Endophthalmitis and Miscellaneous Categories: Incidence Rates, Signs/Symptoms, Risk Factors, Microbiology, Treatment, and Follow-Up��������������������������������������������  95 Delayed-Onset (Chronic) Post-Operative Endophthalmitis Following Cataract Surgery�����������   95 Incidence�������������������������������������������������������������������   96 Signs/Symptoms �������������������������������������������������������   96 Risk Factors���������������������������������������������������������������   96 Microbial Isolates�����������������������������������������������������   98 Initial Management of Delayed-Onset Endophthalmitis�������������������������������������������������������   99 Follow-Up Management in Patients with Delayed-­Onset Post-Operative Endophthalmitis������������������������������������������������������� 100 Two to Three Days after Initial Treatment����������� 101 Conjunctival Filtering Bleb: Associated Infection and Endophthalmitis���������������������������������������������������  102 Incidence of Bleb-Associated Endophthalmitis���  102

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Signs/Symptoms �������������������������������������������������������  103 Risk Factors���������������������������������������������������������������  104 Microbial Isolates�����������������������������������������������������  104 Initial Management of Conjunctival Filtering Bleb-­Associated Endophthalmitis�������������������������  105 Follow-Up Management in Patients with Conjunctival Filtering Bleb-Associated Infection or Endophthalmitis���������������������������������  105 Endophthalmitis Associated with Glaucoma Drainage Devices�����������������������������������������������������  108 Incidence�������������������������������������������������������������������  109 Signs/Symptoms �������������������������������������������������������  109 Risk Factors���������������������������������������������������������������  109 Microbiology�������������������������������������������������������������  110 Initial Management of Glaucoma Drainage Device-Associated Endophthalmitis���������������������  110 Follow-Up Management in Patients with Endophthalmitis Associated with Glaucoma Drainage Devices�����������������������������������������������������  110 Delayed-Onset Endophthalmitis Associated with Keratitis�����������������������������������������������������������������  112 Incidence�������������������������������������������������������������������  112 Signs/Symptoms �������������������������������������������������������  112 Risk Factors for Keratitis that May Lead to Endophthalmitis���������������������������������������������������  113 Microbial Isolates�����������������������������������������������������  113 Initial Management of Endophthalmitis Associated with Keratitis�����������������������������������������  114 Follow-Up Management in Patients with Endophthalmitis Associated with Keratitis�����������  114 The Role of Corneal Collagenous Cross-­Linking (CXL) in the Treatment of Keratitis and Corneal Ulcers�����������������������������������������������������������������������������  115 The Role of Photodynamic Therapy in Advanced Keratitis with Threat of Endophthalmitis�����������������  117 Endophthalmitis after Pterygium Removal �������������  118 Endophthalmitis After Strabismus Surgery �������������  119 Endophthalmitis Post-Suture Removal���������������������  120 Endophthalmitis after Blepharoplasty ���������������������  121

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6 Endogenous  Endophthalmitis: Incidence Rates, Signs/Symptoms, Risk Factors, Microbiology, Treatment, and Follow-Up�������������������������������������������� 125 Endogenous Fungal Endophthalmitis�����������������������  125 Incidence�������������������������������������������������������������������  125 Signs/Symptoms �������������������������������������������������������  126 Risk Factors���������������������������������������������������������������  126 Malignancy ���������������������������������������������������������������  126 Microbial Isolates�����������������������������������������������������  126 Initial Management of Endogenous Fungal Endophthalmitis�������������������������������������������������������  127 Follow-Up Management in Patients with Endogenous Fungal Endophthalmitis�������������������  128 Screening of Endogenous Candida Endophthalmitis in the Hospital Setting�������������������  132 Endogenous Bacterial Endophthalmitis�������������������  133 Incidence�������������������������������������������������������������������  133 Signs/Symptoms �������������������������������������������������������  133 Risk Factors���������������������������������������������������������������  133 Malignancy ���������������������������������������������������������������  134 Microbial Isolates�����������������������������������������������������  134 Initial Management of Endogenous Bacterial Endophthalmitis�������������������������������������������������������  134 Follow-Up Management in Patients with Endogenous Bacterial Endophthalmitis���������������  134 7 Pars  Plana Vitrectomy for the Management of Endophthalmitis: Endophthalmitis Vitrectomy Study and Beyond����������������������������������������������������������� 139 Endophthalmitis Vitrectomy Study���������������������������  139 Early Vitrectomy for Endophthalmitis (beyond the EVS)�����������������������������������������������������  145 Endophthalmitis in Phakic Eyes�����������������������������  146 Endoscopic Vitrectomy for Endophthalmitis�������  147 8 A  ntimicrobial Treatment, Resistance, and Alternatives��������������������������������������������������������������������� 149 Antimicrobial Routes���������������������������������������������������  149 Summary of Antimicrobial Dosages �������������������������  151 Preparation of Antimicrobials �����������������������������������  153

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Preparation of Intravitreal Antimicrobials�����������  153 Preparation of Subconjunctival Antibiotics ���������  155 Preparation of Fortified Topical Antimicrobials�����������������������������������������������������������  156 Adverse Effects of Antimicrobials�����������������������������  157 Antimicrobial Resistance and Alternatives �������������  160 Data on Antimicrobial Resistance�������������������������  160 Pharmacokinetics and Pharmacodynamics of Antimicrobials ���������������������������������������������������������  164 9 Endophthalmitis Prophylaxis��������������������������������������� 167 Antisepsis����������������������������������������������������������������������  167 Topical Antibiotics�������������������������������������������������������  170 Topical Antibiotics: Literature �����������������������������������  171 Systemic Antibiotics�������������������������������������������������  174 Endophthalmitis Prophylaxis for Specific Case Scenarios �������������������������������������������������������������  176 Endophthalmitis Prophylaxis for Cataract Surgery�������������������������������������������������������  176 Corneal Wound Closure ���������������������������������������������  179 Endophthalmitis Prophylaxis for Intravitreal Injections�����������������������������������������������������������������������  185 Endophthalmitis Prophylaxis for Open Globe Injuries���������������������������������������������������������������������������  187 10 Retinal  Detachment (RD) and Endophthalmitis������� 189 Frequency: Retinal Detachment in Endophthalmitis�����������������������������������������������������������  189 Visual Outcomes: Retinal Detachment in Endophthalmitis�������������������������������������������������������  190 Presentation: Retinal Detachment in Endophthalmitis�������������������������������������������������������  190 Risk Factors Associated with Poor Visual Outcomes in Eyes with RD and Endophthalmitis���������������������������������������������������  190 Role of Silicone Oil in Endophthalmitis Patients �������������������������������������������������������������������������  191 Hyperoleon�������������������������������������������������������������������  191

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Antimicrobial Properties of Silicone Oil���������������  191 Literature: Silicone Oil in Endophthalmitis and Rhegmatogenous Retinal Detachment�����������������  192 11 Antibiotic Stewardship ������������������������������������������������� 197 12 Outcomes  (Anatomic and Functional) and Treatment-Related Complications �����������������������201 Treatment Outcomes of Acute-Onset Post-­Operative Endophthalmitis Following Cataract Surgery����������������������������������������������������������� 201 Outcomes as Reported by the EVS�����������������������  202 Lalwani et al. 2008���������������������������������������������������  202 Yannuzzi et al. 2016�������������������������������������������������  203 Treatment Outcomes of Delayed-Onset Post­Operative Endophthalmitis Following Cataract Surgery���������������������������������������������������������������������������  205 Clark et al �����������������������������������������������������������������  205 Shirodkar et al. (2012)���������������������������������������������  206 Treatment Outcomes of Endophthalmitis after Pars Plana Vitrectomy�������������������������������������������������  208 Treatment Outcomes of Endophthalmitis Following Glaucoma Surgery�������������������������������������  210 Conjunctival Filtering Bleb-Associated Infection and Endophthalmitis�������������������������������  210 Endophthalmitis Associated with Glaucoma Drainage Devices�����������������������������������������������������  212 Treatment Outcomes of Post-Traumatic Endophthalmitis�����������������������������������������������������������  213 Colyer et al. (Ophthalmology 2007) ���������������������  213 Mieler et al. (Ophthalmology 1990)�����������������������  214 Banker et al. (OSLI Retina, 2017)�������������������������  215 Treatment Outcomes of Endogenous Endophthalmitis�����������������������������������������������������������  216 Schiedler et al. (2004) ���������������������������������������������  216 Lingappan et al. (2012) �������������������������������������������  217 Sridhar et al. (2013)�������������������������������������������������  217 Treatment Outcomes of Endophthalmitis Associated with Intravitreal Injection�����������������������  219

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Goldberg et al. (Ophthalmology 2013)�����������������  219 Gregori et al. (Retina 2015) �����������������������������������  220 Yannuzzi et al. (OSLI-Retina 2018)�����������������������  220 Complications Associated with Endophthalmitis Prophylaxis/Treatment�������������������������������������������������  221

Chapter 1 Endophthalmitis: Classification and Most Frequently Reported Organisms 1. Post-operative endophthalmitis • Following cataract surgery: Acute-onset post-operative endophthalmitis • Coagulase (−) Staphylococci, Staphylococcus aureus, Streptococcus, Gram-negative bacteria • Following cataract surgery: Delayed-onset post-­ operative endophthalmitis • Cutibacterium acnes, coagulase (−) Staphylococci, fungi • Following glaucoma surgery: Conjunctival filtering bleb-associated infection and endophthalmitis • Streptococcus species, Haemophilus influenzae, Staphylococcus species • Following glaucoma surgery: Endophthalmitis associated with glaucoma drainage devices • Following elective corneal transplant 2. Post-traumatic endophthalmitis Bacillus species (30–40%), Staphylococcus species, Cutibacterium acnes, Pseudomonas, and Streptococcus species. 3. Endogenous Endophthalmitis Candida species, Staphylococcus aureus, Gram-negative bacteria (Klebsiella), Aspergillus. © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 H. W. Flynn Jr. et al., Endophthalmitis in Clinical Practice, In Clinical Practice, https://doi.org/10.1007/978-3-031-35184-6_1

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Chapter 1.  Endophthalmitis: Classification and Most…

4. Endophthalmitis Associated with Keratitis Pseudomonas, Staphylococcus/Streptococcus species, Fusarium, Paecilomyces, Candida. 5. Endophthalmitis Associated with Intravitreal Injection Staphylococcus/Streptococcus species, Abiotrophia defectiva(Figs. 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, 1.12,1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21, 1.22, 1.23, 1.24, and 1.25).

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Figure 1.1  Acute-onset endophthalmitis. A 78-year-old male patient with acute-onset post-operative endophthalmitis following cataract surgery. (a) The patient presented with conjunctival congestion, mild corneal edema, hypopyon, hazy view to the posterior segment, and hand motions (HM) visual acuity. Patient underwent vitreous tap and intraocular antibiotics (vancomycin and ceftazidime). The vitreous culture was positive for Staphylococcus epidermidis resistant to all fluoroquinolones and sensitive to vancomycin. (b) At 8-month follow-­up, the patient regained best corrected visual acuity of 20/30

Chapter 1.  Endophthalmitis: Classification and Most…

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Figure 1.2  Acute-onset endophthalmitis. A 68-year-old male patient with acute-onset post-operative endophthalmitis following cataract surgery. (a) The patient presented with conjunctival congestion, mild corneal edema, hypopyon, and hand motions (HM) visual acuity. The patient underwent vitreous tap and intraocular antibiotics and was culture positive for methicillin-resistant Staphylococcus aureus (MRSA) resistant to all fluoroquinolones. (b) At 6-month follow-up, the patient regained best corrected visual acuity of 2/200 with persistent corneal haze

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Figure 1.3  Acute-onset endophthalmitis. A 66-year-old male patient with acute-onset post-operative endophthalmitis following cataract surgery. (a) The patient presented with conjunctival congestion, fibrinous reaction in the anterior chamber, hypopyon, polypropylene suture at 12 o’clock to close a sector iridectomy, restricted view to the posterior segment, and hand motions (HM) visual acuity. The patient underwent vitreous tap and intraocular antibiotics and was culture positive for coagulase-negative Staphylococcus. (b) At 1-year follow-up, the patient regained best corrected visual acuity of 20/30. The polypropylene suture was not removed at the time of treatment

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Chapter 1.  Endophthalmitis: Classification and Most…

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Figure 1.4  Acute-onset endophthalmitis. A 70-year-old male patient with acute-onset post-operative endophthalmitis following cataract surgery. (a) The patient presented with conjunctival congestion, mild corneal edema, hypopyon, and hand motions (HM) visual acuity. Patient underwent vitreous tap and intraocular antibiotics and was culture positive for coagulase-negative Staphylococcus. (b) At 1-year follow-­up, the patient regained best corrected visual acuity of 20/25

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Figure 1.5 Acute-onset endophthalmitis. A 76-year-old female patient with acute-onset endophthalmitis following cataract surgery with intracameral moxifloxacin. (a) The patient presented with conjunctival congestion, fibrinous reaction in the anterior chamber, hazy view to the posterior segment, and hand motions (HM) visual acuity. Patient underwent vitreous tap and intraocular antibiotics (vancomycin and ceftazidime) and was culture negative. (b) At 3-week follow-up, the patient regained best corrected visual acuity of 20/25 with resolution of inflammation

Chapter 1.  Endophthalmitis: Classification and Most…

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Figure 1.6  Acute-onset endophthalmitis. A 78-year-old male patient with acute-onset post-operative endophthalmitis following cataract surgery. (a) The patient presented with conjunctival congestion, mild corneal edema, hypopyon, fibrinous membrane in the anterior chamber, and hand motions (HM) visual acuity. Patient underwent vitreous tap and intraocular antibiotics and was culture positive for methicillin-sensitive Staphylococcus aureus (MSSA) susceptible to fourth-generation fluoroquinolones. (b) At 6-month follow-up, the patient regained best corrected visual acuity of 20/50. The visual acuity reduction was associated with cystoid macular edema

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Figure 1.7  Acute-onset endophthalmitis. A 74-year-old male patient with acute-onset post-operative endophthalmitis following cataract surgery. (a) The patient presented with conjunctival congestion, fibrinous membrane in the anterior chamber over the intraocular lens, hazy view of the posterior segment, and hand motions (HM) visual acuity. The patient underwent vitreous TAP (culture negative) and intraocular antibiotics. (b) At 2-week follow-up, the patient regained best corrected visual acuity of 20/25 with resolving inflammation and infection

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Chapter 1.  Endophthalmitis: Classification and Most…

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Figure 1.8  Acute-onset endophthalmitis. A 78-year-old male patient with acute-onset post-operative endophthalmitis 1  day following cataract surgery. (a) The patient presented with conjunctival congestion, mild corneal edema, hypopyon, fibrinous membrane in the anterior chamber, hazy view of the posterior segment, and light perception (LP) visual acuity. The patient underwent pars plana vitrectomy and intraocular antibiotics. The vitreous culture was positive for Serratia marcescens. (b) At 1-year follow-up, the patient regained best corrected visual acuity of 20/50

Chapter 1.  Endophthalmitis: Classification and Most…

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Figure 1.9  Acute-onset endophthalmitis. A 65-year-old male patient with acute-onset post-operative endophthalmitis following cataract surgery. (a) The patient presented with conjunctival congestion, mild corneal edema, hypopyon, polypropylene suture in the iris superiorly, fibrinous membrane in the anterior chamber, hazy view of the posterior segment, and light perception (LP) visual acuity. The patient underwent vitreous tap and intraocular antibiotics. The vitreous culture was positive for Streptococcus viridans. (b) At 1-year follow-­up, the patient regained best corrected visual acuity of 20/25

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Chapter 1.  Endophthalmitis: Classification and Most…

Figure 1.10 Acute-onset endophthalmitis. A 76-year-old female patient with acute-onset endophthalmitis following cataract surgery with intracameral moxifloxacin. Presenting features 4  days after cataract surgery include fibrin in anterior chamber, hazy view of the vitreous cavity, and cystic retinal thickness on OCT

Chapter 1.  Endophthalmitis: Classification and Most…

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Figure 1.11 Bleb-associated endophthalmitis. A 66-year-old male patient with bleb-associated endophthalmitis following trabeculectomy. (a) The patient presented with conjunctival congestion, purulent blebitis, mild corneal edema, hypopyon, fibrinous membrane in the anterior chamber and pupillary area, hazy view to the posterior segment, and hand motions (HM) visual acuity. The patient underwent pars plana vitrectomy and intraocular antibiotics. The vitreous culture was positive for coagulase-negative Staphylococcus. (b) At 6-month follow-up, the patient regained best corrected visual acuity of 20/30 with resolution of endophthalmitis

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Chapter 1.  Endophthalmitis: Classification and Most…

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Figure 1.12 Bleb-associated endophthalmitis. A 66-year-old male patient with bleb-associated endophthalmitis following trabeculectomy. (a) The patient presented with conjunctival congestion, bleb infection, mild corneal edema, hazy view to the posterior segment, and light perception (LP) visual acuity. The patient underwent pars plana vitrectomy and intraocular antibiotics. The vitreous culture was positive for Moraxella species. (b) At 6-month follow-up, the patient regained best corrected visual acuity of 20/100 with resolution of endophthalmitis

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Figure 1.13  Bleb-associated endophthalmitis. A 72-year-old female patient with bleb-associated endophthalmitis following trabeculectomy. (a) At presentation, the patient had conjunctival congestion, bleb infection, corneal edema, hazy view to the posterior segment, and hand motions (HM) visual acuity. The patient underwent pars plana vitrectomy and intraocular antibiotics. The vitreous culture was positive for Streptococcus species. (b) At 1-year follow-up, the patient had resolution of endophthalmitis, but the visual acuity deteriorated to no light perception (NLP)

Chapter 1.  Endophthalmitis: Classification and Most…

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Figure 1.14  Bleb-associated endophthalmitis. A 72-year-old female patient with bleb-associated endophthalmitis following trabeculectomy. (a) At presentation patient had conjunctival congestion, bleb infection, corneal edema, hypopyon, fibrinous membrane in the anterior chamber and pupillary area, hazy view to the posterior segment, and light perception (LP) visual acuity. The patient underwent vitreous tap and intraocular antibiotics. The vitreous culture was positive for Enterococcus faecalis. (b) At 2-month follow-up, the inflammation and infection started resolving, but the visual acuity deteriorated to no light perception (NLP)

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Figure 1.15  Bleb-associated endophthalmitis. A 66-year-old female patient with bleb-associated endophthalmitis following trabeculectomy. (a) At presentation, the patient had conjunctival congestion, bleb infection, corneal edema, hypopyon, hazy view to the posterior segment, and 2/200 visual acuity. The patient underwent vitreous tap and intraocular antibiotics. The vitreous culture was negative for any organism. (b) At 6-month follow-up, the patient had complete resolution of endophthalmitis and best corrected visual acuity improved to 20/400

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Chapter 1.  Endophthalmitis: Classification and Most…

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Figure 1.16  Chronic/delayed-onset post-operative endophthalmitis. A 69-year-old male patient with delayed-onset post-operative endophthalmitis following cataract surgery. (a) The patient presented with gradual painless decrease in vision, conjunctival congestion, hypopyon, inflammatory cells in the anterior chamber, and 20/200 visual acuity. Patient underwent pars plana vitrectomy and intraocular antibiotics injection. The vitreous culture was positive for Cutibacterium acnes. A repeat pars plana vitrectomy, removal of the intraocular lens, and intraocular antibiotics injection were performed. (b) At 6-month follow-up, the patient regained best corrected visual acuity of 20/25 with resolution of inflammation

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Figure 1.17 Chronic/delayed-onset post-operative endophthalmitis. A 77-year-old female patient with delayed-onset post-operative endophthalmitis following cataract surgery. (a) The patient presented with gradual painless decrease in vision, conjunctival congestion, hypopyon, fibrinous membrane in the anterior chamber, and hand motions (HM) visual acuity. The patient underwent pars plana vitrectomy and intraocular antibiotics injection. The vitreous culture was positive for Xanthomonas species. (b) At 1-year follow-up, the patient regained best corrected visual acuity of 20/50 with resolution of inflammation

Chapter 1.  Endophthalmitis: Classification and Most…

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Figure 1.18  Endogenous endophthalmitis. (a) A 60-year-old female patient with uncontrolled diabetes mellitus presented with sudden blurring of vision, vitreous floaters, and hand motions (HM) visual acuity. The fundus examination showed hyperemic disc and presence of subretinal exudates at the posterior pole. The patient underwent vitreous tap and intraocular antibiotics. The vitreous culture was positive for Staphylococcus aureus. (b) At 1-month follow-up, the inflammation and infection started resolving with best corrected visual acuity improving to 20/40

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Figure 1.19  Endophthalmitis after intravitreal injection. A 56-yearold male patient presented 1 day after intravitreal anti-VEGF injection for age-related macular degeneration (AMD) with sudden painful decrease in vision. (a) The patient presented with conjunctival congestion, conjunctival chemosis, hypopyon, fibrinous membrane in the anterior chamber, hazy view of the posterior segment, and hand motions (HM) visual acuity. The patient underwent vitreous tap and intraocular injection (vancomycin, ceftazidime, and dexamethasone). The vitreous culture was positive for coagulase-negative Staphylococcus. (b) At 1-year follow-up, the inflammation and infection resolved with best corrected visual acuity improved to 20/50

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Chapter 1.  Endophthalmitis: Classification and Most…

Figure 1.20  Endophthalmitis after intravitreal injection. A 60-yearold male patient with neovascular age-related macular degeneration (AMD) presented 1 day after intravitreal aflibercept injection with sudden painful decrease in vision. The patient presented with conjunctival congestion, corneal edema, hypopyon, fibrinous reaction in the anterior chamber, hazy view of the posterior segment, and light perception (LP) visual acuity. The patient underwent pars plana vitrectomy and intraocular injection (vancomycin and ceftazidime). The vitreous culture was culture negative

Chapter 1.  Endophthalmitis: Classification and Most…

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Figure 1.21 A 60-year-old male patient with age-related macular degeneration (AMD) received compounded intravitreal bevacizumab. Two days after injection, the patient presented with pain, redness, and counting fingers (CF) visual acuity. (a) Slit-lamp examination showed the presence of fibrin in anterior chamber. (b) Posterior segment was hazy with no clarity of fundus details. The patient underwent a vitreous tap and intraocular injection of antibiotics. (c) At 6  months follow-up, the inflammation and infection resolved and best corrected visual acuity improved to 20/25. The patient was one of the 12 patients among an outbreak of Streptococcus endophthalmitis after compounded intravitreal bevacizumab

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Chapter 1.  Endophthalmitis: Classification and Most…

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Figure 1.22  Endophthalmitis after intravitreal injection. A 60-yearold male patient with central retinal vein occlusion/neovascular glaucoma (CRVO/NVG) presented 2 days after intravitreal aflibercept injection with sudden painful decrease in visual acuity. (a) The patient presented with conjunctival congestion, corneal edema, exudates filling the anterior chamber, no view of the posterior segment, and light perception (LP) visual acuity. The patient underwent vitreous tap and intraocular injection. (b) At 3-week follow-up, the inflammation and infection persisted, and visual acuity deteriorated to no light perception (NLP). The patient underwent evisceration, and the specimen culture was positive for Streptococcus species

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Figure 1.23 A 72-year-old male patient with bleb-associated endophthalmitis following trabeculectomy. (a) The patient presented with conjunctival congestion, bleb infection, mild corneal edema, hypopyon, cataract, hazy view to the posterior segment and counting fingers (CF) visual acuity. Patient underwent vitreous tap and intraocular antibiotics. The vitreous culture was positive for Moraxella species. (b) At 6-month follow-up, the patient regained best corrected visual acuity of 20/25 after subsequent cataract surgery

Chapter 1.  Endophthalmitis: Classification and Most…

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Figure 1.24  Endophthalmitis after intravitreal injection. A 60-yearold male patient with neovascular age-related macular degeneration (AMD) presented 2  days after intravitreal ranibizumab injection with sudden painful decrease in vision. (a) Slit-lamp examination showed conjunctival congestion, corneal edema, hypopyon, infectious exudates in the anterior chamber, no view of the posterior segment, and light perception (LP) visual acuity. The patient underwent vitreous tap and intraocular antibiotic injection. The vitreous culture was positive for Streptococcus mitis/oralis. (b, c) Inflammation and infection remained uncontrolled. (d) Two weeks after pars plana vitrectomy, lensectomy, and silicone oil injection, inflammation and infection reduced. However, 6 months later, the patient underwent enucleation for the painful blind eye

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Chapter 1.  Endophthalmitis: Classification and Most…

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Figure 1.25  Endophthalmitis after intravitreal injection. A 60-yearold male patient with neovascular age-related macular degeneration (AMD) presented 1  day after intravitreal ranibizumab injection with sudden painful decrease in vision. (a) Slit-lamp examination showed conjunctival congestion, corneal edema, hypopyon, fibrinous membrane in the anterior chamber, no view of the posterior segment, and hand motions (HM) visual acuity. The patient underwent vitreous tap and intraocular antibiotic injection. The vitreous culture was positive for Streptococcus sanguis. (b–d) Inflammation and infection persisted and visual acuity became no light perception (NLP)

Chapter 1.  Endophthalmitis: Classification and Most…

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References: Endophthalmitis (General Reviews) • American Academy of Ophthalmology Cataract/Anterior Segment Summary Benchmark–2021 for Preferred practice pattern guidelines. https://www.aao.org/summary-­ benchmark-­detail/cataract-­anterior-­segment-­summary-­ benchmark-­2020. Accessed 3 April 2022 • Cataract in the Adult Eye PPP - 2021. American Academy of Ophthalmology (AAO) Preferred PRactice Pattern (PPP) Cataract/Anterior Segment Panel, Hoskin Center for Quality Eye Care. Accessed April 4 2022 • Packer M, Chang DF, Dewey SH, Little BC, Mamalis N, Oetting TA, et al. Prevention, diagnosis, and management of acute postoperative bacterial endophthalmitis. J Cataract Refract Surg 2011;37(9):1699–714 • Schwartz SG, Flynn Jr. HW, Scott IU.  Endophthalmitis: classification and current management. Expert Rev Ophthalmol 2007;2(3):385–96 • Vaziri K, Schwartz SG, Kishor K, Flynn HW, Jr. Endophthalmitis: state of the art. Clin Ophthalmol 2015;9:95–108 • Wykoff CC, Parrott MB, Flynn HW, Shi W, Miller D, Alfonso EC. Nosocomial acute-onset postoperative endophthalmitis at a university teaching hospital (2002–2009). Am J Ophthalmol 2010;150(3):392–8.e2 • Kernt M, Kampik A. Endophthalmitis: pathogenesis, clinical presentation, management, and perspectives. Clin Ophthalmol 2010 Mar 24;4:121–35 • Scott IU, Flynn HW Jr, Feuer W, Pflugfelder SC, Alfonso EC, Forster RK, Miller D.  Endophthalmitis associated with microbial keratitis. Ophthalmology 1996 Nov;103(11):1864–70 • Reyes-Capo DP, Yannuzzi NA, Smiddy WE, Flynn HW Jr; Endophthalmitis/Anti-VEGF Study Group*. Trends in Endophthalmitis associated with intravitreal injection of anti-VEGF Agentsat a tertiary referral center. Ophthalmic Surg lasers imaging Retina 2021 Jun;52(6):319–326

Chapter 2 Differential Diagnosis of Endophthalmitis

Endophthalmitis is a clinical diagnosis, confirmed with subsequent laboratory testing. Endophthalmitis must be distinguished from noninfectious inflammation as well as noninflammatory cellular infiltration, including hemorrhage and tumor cells. Endophthalmitis with negative intraocular cultures is relatively common, reported in the range of about 20% following intraocular surgery and up to 50% following intravitreal injection. It is important to consider the various conditions which may mimic as infectious endophthalmitis. The following are some conditions that should be differentiated from infectious endophthalmitis: (a) Toxic anterior segment syndrome (TASS) (b) Retained lens material (c) Flare-up of pre-existing uveitis (d) Chronic vitreous hemorrhage (e) Retinoblastoma (in children) (f) Retained triamcinolone acetonide (g) Viral retinitis (h) Pseudoendophthalmitis from intravitreal injections

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 H. W. Flynn Jr. et al., Endophthalmitis in Clinical Practice, In Clinical Practice, https://doi.org/10.1007/978-3-031-35184-6_2

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Chapter 2.  Differential Diagnosis of Endophthalmitis

Toxic Anterior Segment Syndrome (Fig. 2.1) Toxic anterior segment syndrome (TASS) is an acute post-­ operative sterile inflammation of the anterior segment which occurs due to toxic effects on corneal endothelium (Fig. 2.1). The following are characteristic features of TASS: • Usually identified on the first day following cataract surgery—Symptoms of TASS characteristically appear 12–48 h after the surgery. • Prominent corneal edema is observed from limbus to limbus—Corneal edema with limbus to limbus involvement is noted in most cases. • Prominent anterior chamber cells (usually without hypopyon)—The inflammation usually does not involve the vitreous. Inflammation in the anterior segment is may be severe with fibrinous reaction. The most common symptom of TASS is blurred vision. Patients may present with blurred vision and mild pain on the same day of the surgery or within 24 h after the surgery. In addition, the iris may be irregular with unreactive pupils. Damage to the trabecular meshwork may result in secondary

Figure 2.1  Toxic anterior segment syndrome (TASS) with limbus to limbus corneal edema

Toxic Anterior Segment Syndrome

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glaucoma. Differentiating features between TASS and endophthalmitis are shown in Table 2.1. TASS can be treated with frequent administration of topical steroids. Toxic substances which have been shown in studies to cause damage to corneal endothelial cells are Table 2.1 Differences between toxic anterior segment syndrome (TASS) and endophthalmitis Differences between TASS and endophthalmitis TASS Endophthalmitis Cause Noninfectious Bacterial, fungal, or reaction to toxic viral infection agent present in: • Irrigating solutions • Antibiotic injection • Endotoxin • Residue Onset

12–24 h

4–7 days

Signs/symptoms (distinguishing features as reported in literature)

Blurry vision Pain: None or mild to moderate Corneal edema: Diffuse, limbus to limbus Pupil: Dilated, irregular, nonreactive, increased IOP Anterior chamber: Mild to severe reaction with cells, flare, hypopyon, fibrin Signs and symptoms are limited to anterior chamber Gram stain and culture negative

Decreased VA Pain (25% have no pain), lid swelling with edema Conjunctival injection, hyperemia Anterior chamber: Marked inflammatory response with hypopyon Inflammation in entire ocular cavity—Vitreous involvement present

(continued)

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Chapter 2.  Differential Diagnosis of Endophthalmitis

Table 2.1  (continued)

Differences between TASS and endophthalmitis TASS Endophthalmitis Treatment

Rule out infection Daily observation Intensive corticosteroids Monitor IOP closely for signs of damage to trabecular meshwork and side effects of steroids

Culture anterior chamber and vitreous fluid Intravitreal and topical antibiotics Vitrectomy in selected cases

pre-operative disinfectant, intraocular irrigating solution, highly concentrated intraocular medicine, preservatives, remnants of cleaning solutions for surgical devices, hydrogen peroxide, or the insertion of air into the anterior segment. References: Toxic Anterior Segment Syndrome (TASS) • Chang DF, Mamalis N, Cionni RJ, et al. Guidelines for the cleaning and sterilization of intraocular surgical instruments. Journal of Cataract & Refractive Surgery. 2018;44(6):765–773. • Sengillo JD, Chen Y, Perez Garcia D, Schwartz SG, Grzybowski A, Flynn HW, Jr. Postoperative Endophthalmitis and Toxic Anterior Segment Syndrome Prophylaxis: 2020 Update. Annals of translational medicine. 2020;8(22):1548. • Hernandez-Bogantes E, Navas A, Naranjo A, et al. Toxic anterior segment syndrome: A review. Survey of ophthalmology. 2019;64(4):463–476. • American Society of Cataract, Refractive Surgery,American Society of Ophthalmic Registered N. Recommended practices for cleaning and sterilizing intraocular surgical instruments. Insight. 2018. https://www.aao.org/clinical-­statement/ guidelines-­cleaning-­sterilization-­intraocular. • Gottsch JD, Schein OD.  Taking TASS to task. Ophthalmology. 2012;119(7):1295–6.

Retained Lens Fragments

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• Mamalis N.  Toxic anterior segment syndrome update. J Cataract Refract Surg. 2010;36(7):1067–8

Retained Lens Fragments (Figs. 2.2 and 2.3) Patients with retained lens fragments after cataract surgery may develop marked intraocular inflammation with hypopyon in the absence of infection (Figs. 2.2 and 2.3). However,

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Figure 2.2  Retained lens fragments. A 79-year-old man with acute-­ onset post-operative endophthalmitis. (a) Slit-lamp examination revealed conjunctival congestion, corneal edema, and an anterior chamber inflammation with a small hypopyon. (b) Ultrasound B-scan showed moderate density echogenic vitreous opacities filling the globe suggestive of membranes with vitreous debris. The patient underwent tap and intravitreal injections (vancomycin, ceftazidime, dexamethasone) followed by gradual resolution of inflammation. Microbiology culture report was negative. (c) Slit-lamp photograph on day 2 after intravitreal antibiotics shows contracting fibrin in the anterior chamber. (d) Two weeks follow-up exam showed quiet conjunctiva, clear cornea with a resolution of anterior chamber inflammation. At 1-year follow-up, the visual acuity was 20/30

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Chapter 2.  Differential Diagnosis of Endophthalmitis

Figure 2.3  Retained lens fragments

concomitant endophthalmitis also may be present and it is important to make the correct diagnosis. It is possible that the eyes with retained lens fragments may be at increased risk for endophthalmitis. In patients with retained lens fragments and intraocular inflammation, neither the presence of pain nor the duration since the surgery may be used to distinguish between infectious and noninfectious etiologies. Diagnostic ultrasound is a useful tool in evaluating eyes with dense vitritis after cataract extraction when retained lens material is suspected. Lens material typically appears as reflective, mobile material in the vitreous cavity. Lens material may be involved with extensive epiretinal inflammatory membranes, however, and may not be mobile at the time of examination. References: Retained Lens Material • Salabati M, Mahmoudzadeh R, Wakabayashi T, Hinkle JW, Ho AC.  Indications for surgical management of retained lens fragments. Current opinion in ophthalmology. 2022;33(1):15–20.

Flare-Up of Pre-existing Uveitis

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• Patel NA, Gangasani N, Yannuzzi NA, Melo G, Flynn HW, Smiddy WE.  Indications and Outcomes for the Removal of Intraocular Lens Implants in a Retinal Surgery Practice. Ophthalmic surgery, lasers & imaging retina. 2019;50(8):504–508. • Kim JE, Flynn HW, Rubsamen PE, Murray TG, Davis JL, Smiddy WE.  Endophthalmitis in patients with retained lens fragments after phacoemulsification. Ophthalmology. 1996;103(4):575–8.

Flare-Up of Pre-existing Uveitis Patients with pre-existing uveitis may have an exacerbation of their uveitis after cataract surgery which may mimic endophthalmitis (Fig.  2.4). Diagnosis, control of inflammation, pre-operative management, particularities of the surgical techniques, and post-operative complications in patients with a history of uveitis are essential to best visual results. Inflammation should be controlled in patients with pre-­ existing uveitis before proceeding with elective intraocular surgery. Frequent administration of topical anti-inflammatory drugs as well as systemic administration of corticosteroids or corticosteroid-sparing agents may be utilized in such cases once endophthalmitis is ruled out. References: Flare-Up of Pre-existing Uveitis • Kumar V, Surve A, Azad S, et  al. Juvenile idiopathic arthritis-­ related uveitis mimicking endophthalmitis. ­Journal of AAPOS: the official publication of the American Association for Pediatric Ophthalmology and Strabismus. 2019;23(4):238–241. • Toh ZH, Agrawal R. Diagnostic dilemma: Unilateral panuveitis mimicking endophthalmitis in very severe HLA B27-associated uveitis. American journal of ophthalmology case reports. 2020;17:100589. • Berrocal A, Davis J. Uveitis following intraocular surgery. Ophthalmol Clin N Am. 2002;15(3):357–64.

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Chapter 2.  Differential Diagnosis of Endophthalmitis

Figure 2.4 Flare-up of pre-existing uveitis. A 70-year-old female patient with urinary tract infection and initial early diagnosis of endogenous endophthalmitis presented with painless decrease in vision and vitreous floaters. The fundus examination showed presence of pigmented scars (from toxoplasmosis) at the posterior pole with an active patch of retinitis and creamy-white opacities in the vitreous

• Kluger N.  Tatoo-associated uveitis with or without systemic sarcoidosis: a comparative review of the literature. Journal of European Academy of Dermatology & Venereology. 2018;32(11): 1852–61.

Vitreous Hemorrhage Chronic long-standing vitreous hemorrhage may present with mild to moderate inflammation of anterior segment and restricted view of the posterior segment (Figs. 2.5, 2.6, 2.7, and

Vitreous Hemorrhage

29

Figure 2.5  Acute Posterior Multifocal Placoid Pigment Epitheliopathy (APMPPE): A 30-year-old man presented with decreased vision (20/40) and floaters in the right eye for 2 weeks. On ocular examination, anterior segment was unremarkable and fundus picture showed presence of yellowish-white exudates adjacent to fovea. After excluding the infectious causes, the patient was started on oral corticosteroids in tapering doses. The visual acuity improved to 20/20 with few RPE changes adjacent to fovea at 2 months

2.8). Chronic long-standing vitreous hemorrhage may have an appearance similar to endophthalmitis when the hemorrhage becomes white-gray color after degenerative changes in the hemoglobin content. These clinical features can mimic as endophthalmitis, but the relatively quiet eye can help in excluding endophthalmitis. Perivasculitis and intraretinal hemorrhage may be early signs of endophthalmitis.

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Chapter 2.  Differential Diagnosis of Endophthalmitis

Figure 2.6 Vitreous hemorrhage. A 72-year-old man with left eye vitreous hemorrhage. Hazy view of the posterior segment may mimic endophthalmitis

a

b

Figure 2.7  (a) Slit-lamp photograph of hypopyon from old vitreous hemorrhage on the initial examination and (b) hypopyon from a combination of old and new vitreous hemorrhage 1 week later

Vitreous Hemorrhage

31

Figure 2.8  Slit-lamp photograph of hypopyon and clump of white debris in the anterior chamber on the initial examination

References: Vitreous Hemorrhage • Schwartz SG, Mieler WF, Holz ER, et  al. Intravitreal hemoglobin spherulosis: a rare complication of subretinal hemorrhage. Arch Ophthalmol 2002;120(1):85–7. • Godley BF, Folk JC. Retinal hemorrhages as an early sign of acute bacterial endophthalmitis. Am J Ophthalmol. 1993;116(2):247–9. • Jeng BH, Kaiser PK, Lowder CY.  Retinal vasculitis and posterior pole “hypopyons” as early signs of acute bacterial endophthalmitis. Am J Ophthalmol. 2001;131(6):800–2. • Nguyen JK, Fung AE, Flynn HW, Jr., Scott IU. Hypopyon and pseudoendophthalmitis associated with chronic vitreous hemorrhage. Ophthalmic Surg Lasers Imaging. 2006;37(4):317–9.

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Chapter 2.  Differential Diagnosis of Endophthalmitis

Retinoblastoma In children, retinoblastoma may mimic endophthalmitis (Fig.  2.9). It is important to differentiate between endophthalmitis (pseudo-retinoblastoma) and retinoblastoma as the management is entirely different for the two entities. Shields et  al. (2013) reported a retrospective series of 604 patients who presented as pseudo-retinoblastomas, and only 2% (10) were due to endogenous endophthalmitis. In a series reported in 1991 by Shield et  al., among 500 patients ­presenting with pseudo-retinoblastoma, endophthalmitis was reported in only two cases (0.4%).

Figure 2.9  Retinoblastoma with white calcific deposits on the retina

Uveal Melanoma

33

Endophthalmitis usually has prominent inflammation involving the anterior segment, hypopyon, or synechiae formation. Ultrasonography and CT scan are useful investigations that may show the presence of diffuse faint vitreous echoes in the case of endophthalmitis while mass lesion or dystrophic calcification in case of retinoblastoma. References: Retinoblastoma • Raina UK, Tuli D, Arora R, Mehta DK, Taneja M. Tubercular endophthalmitis simulating retinoblastoma. Am J Ophthalmol. 2000;130(6):843–5. • Shields CL, Schoenberg E, Kocher K, Shukla SY, Kaliki S, Shields JA.  Lesions simulating retinoblastoma (pseudoretinoblastoma) in 604 cases: results based on age at presentation. Ophthalmology. 2013;120(2):311–6. • Shields CL, Shields JA, Shah P.  Retinoblastoma in older children. Ophthalmology. 1991;98(3):395–9. • Shields JA, Shields CL, Eagle RC, Jr., Barrett J, De Potter P.  Endogenous endophthalmitis simulating retinoblastoma. The 1993 David and Mary Seslen Endowment Lecture. Retina. 1995;15(3):213–9.

Uveal Melanoma Uveal melanoma can mimic uveitis in adults (Fig.  2.9). The disease is vision threatening as well as potentially fatal. Feng et al. (2014) reported the incidence of uveal melanoma about 1200–1500 new cases per year in the United States. Male sex, age older than 65 years, and delay in presentation are well-known risk factors. Uveal melanoma cases may present asymptomatically. Rarely, anterior segment inflammation may be the initial presenting feature of uveal melanoma. A mixture of tumor cells, pigment cells, and inflammatory cells are present in the anterior chamber while in immune-mediated anterior uveitis T-cells are present in the anterior chamber.

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Chapter 2.  Differential Diagnosis of Endophthalmitis

References: Uveal Melanoma • Macedo SS, Teixeira M, Correia A, Novais A, Cabral C. Ocular Melanoma Presenting as Masquerade Syndrome. European journal of case reports in internal medicine. 2019;6(7):001118. • Feng L, Zhu J, Gao T, Li B, Yang Y. Uveal melanoma in the peripheral choroid masquerading as chronic uveitis. Optom Vis Sci. 2014;91(9):e222–5. • Maat W, Ly LV, Jordanova ES, de Wolff-Rouendaal D, Schalij-Delfos NE, Jager MJ. Monosomy of chromosome 3 and an inflammatory phenotype occur together in uveal melanoma. Invest Ophthalmol Vis Sci. 2008;49(2):505–10. • Tsai T, O’Brien JM. Masquerade syndromes: malignancies mimicking inflammation in the eye. Int Ophthalmol Clin. 2002;42(1):115–31.

Intravitreal Triamcinolone Acetonide Retained triamcinolone may present with deposits in the anterior chamber also known as pseudoendophthalmitis. These sterile post-injection responses are due to the migration of medication to the anterior chamber (Figs.  2.10 and 2.11). Rarely true endophthalmitis can occur after triamcinolone intravitreal injection. References: Retained Triamcinolone Acetonide Particles • Mason RH, Ballios BG, Yan P. Noninfectious endophthalmitis following intravitreal triamcinolone acetonide: ­clinical case and literature review. Canadian journal of ophthalmology Journal canadien d’ophtalmologie. 2020;55(6):471–479. • Șuță MC, Karancsi OL, Mușat O, et al. Triamcinolone acetonide induces sterile endophthalmitis in patients with intermediate uveitis: A case report series. Experimental and therapeutic medicine. 2020;20(3):2524–2528. • Magalhaes E, Nehemy P, Santos DV, Fujji G, Nehemy MB.  Clinical characteristics and incidence of infectious and non-infectious endophthalmitis after intravitreous

Intravitreal Triamcinolone Acetonide

a

c

35

b

d

Figure 2.10 Patients showing pseudoendophthalmitis after IVTA injection(a–d)

a

b

Figure 2.11 (a) Retained triamcinolone acetonide particles mimicking hypopyon and pseudoendophthalmitis. (b) The pseudoendophthalmitis resolved on follow-up

injection of triamcinolone acetonide. Arq Bras Oftalmol. 2006;69(6):791–4. • Nelson ML, Tennant MT, Sivalingam A, Regillo CD, Belmont JB, Martidis A. Infectious and presumed noninfectious endophthalmitis after intravitreal triamcinolone acetonide injection. Retina. 2003;23(5):686–91.

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Chapter 2.  Differential Diagnosis of Endophthalmitis

• Roth DB, Flynn HW, Jr. Distinguishing between infectious and noninfectious endophthalmitis after intravitreal triamcinolone injection. Am J Ophthalmol. 2008;146(3):346–7. • Schwartz SG, Flynn HW Jr, Smiddy WE. Infectious endophthalmitis vs noninfectious “pseudohypopyon” after intravitreal triamcinolone acetonide. J Vitreoretin Dis 2023;7(2):178-181.

Viral Retinitis Viral retinitis including acute retinal necrosis, infectious retinitis caused by cytomegalovirus, herpes simplex, and herpes zoster may have clinical presentation overlapping with endophthalmitis (Fig. 2.12). The patient may present with yellow-­ white retinitis lesions and/or perivasculitis, with or without retinal hemorrhage. Evaluation of the systemic status of such patients is important. References: Viral Retinitis • Seki K, Harimoto K, Takeuchi M.  Cytomegalovirus Retinitis with Hypopyon Similar to Bacterial Endophthalmitis in a Patient with non-Hodgkin’s Lymphoma. Ocular immunology and inflammation. 2021:1–2. • Blumenkranz M, Clarkson J, Culbertson WW, Flynn HW, Lewis ML, Young GA. Vitrectomy for retinal detachment associated with acute retinal necrosis. Am J Ophthalmol. 1988;106(4):426–9. • Blumenkranz M, Clarkson J, Culbertson WW, Flynn HW, Lewis ML, Young GM.  Visual results and complications after retinal reattachment in the acute retinal necrosis ­syndrome. The influence of operative technique. Retina. 1989;9(3):170–4. • Blumenkranz MS, Culbertson WW, Clarkson JG, Dix R. Treatment of the acute retinal necrosis syndrome with intravenous acyclovir. Ophthalmology. 1986;93(3):296–300.

Viral Retinitis

37

Figure 2.12  A 68-year-old man presented with a 1-week history of blurred vision in his right eye. The patient had a positive history of chicken pox in childhood. His best corrected visual acuity was 20/80 in the right eye and slit-lamp examination showed fine keratic precipitates and 2+ cells in the anterior chamber. Fundus picture showed hazy view with a white retinitis patch suggestive of acute retinal necrosis

• Clarkson JG, Blumenkranz MS, Culbertson WW, Flynn HW, Jr., Lewis ML.  Retinal detachment following the acute retinal necrosis syndrome. Ophthalmology. 1984;91(12):1665–8. • Culbertson WW, Clarkson JG, Blumenkranz M, Lewis ML.  Acute retinal necrosis. Am J Ophthalmol. 1983;96(5):683–5. • Culbertson WW, Blumenkranz MS, Haines H, Gass DM, Mitchell KB, Norton EW.  The acute retinal necrosis syn-

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Chapter 2.  Differential Diagnosis of Endophthalmitis

drome. Part 2: histopathology and etiology. Ophthalmology. 1982;89(12):1317–25. • Fisher JP, Lewis ML, Blumenkranz M, Culbertson WW, Flynn HW, Jr., Clarkson JG, et al. The acute retinal necrosis syndrome. Part 1: clinical manifestations. Ophthalmology. 1982;89(12):1309–16. • Pakravan P, Patel V, Lai J, et al. Intraocular inflammation incidence following intravitreal brolucizumab injection for exudative age-related macular degeneration. Reina 2023 June 13 (online ahead of print).

 oninfectious Inflammation from Intravitreal N Injections A cluster of injection-related sterile intraocular inflammation was reported within the first 3  months after approval of aflibercept (Eylea; Regeneron, Inc., Tarrytown, NY) by the US Food and Drug Administration on November 18, 2011. Figure  2.13 shows a case of pseudoendophthalmitis from intravitreal aflibercept injection. In 2015, Kim et  al. reported sterile inflammation after intravitreal injection of aflibercept in a Korean population. In this retrospective, single-center study, four cases of post-­ injection sterile inflammation were identified from 723 aflibercept injections in 233 patients. Patients presented 1–13  days after intravitreal aflibercept injection (mean, 5  days). Sterile inflammation after intravitreal aflibercept injection in this case series typically presented without pain, and the visual outcomes were generally favorable. However, 60% (9/15) patients with sterile inflammation after intravitreal aflibercept injection presented with pain among the cases (from February 2012 until the end of March 2012) reported by the Therapeutic Surveillance Subcommittee of the American Society of Retina Specialists. Visual acuity ­generally recovered to baseline levels with nearly identical mean visual acuities at baseline in these cases.

Noninfectious Inflammation from Intravitreal Injections

a

b

c

d

39

Figure 2.13 Post-aflibercept inflammation. A 57-year-old female patient with neovascular age-related macular degeneration (wet-­ AMD) presented 14 days after intravitreal aflibercept injection with blurred vision (20/400). (a) and (b) Slit-lamp examination showed quiet conjunctiva, well-dilated pupil, vitritis, and hazy view of the posterior segment. (c) and (d) At day 38 follow-up, the inflammation and infection resolved with best corrected visual acuity improved to 20/30

40

Chapter 2.  Differential Diagnosis of Endophthalmitis

References: Pseudoendophthalmitis Anti-VEGFs

from

Intravitreal

• Schwartz SG, Flynn HW Jr., Emerson GG, et  al. Distinguishing between infectious endophthalmitis and non-­ infectious inflammation following intravitreal antiVEGF injection. J Vitreoretinal Diseases 2019;3:42–44. • Glading JA, Lake SR, Craig JE, Supramaniam D. Delayed onset panuveitis following intravitreal aflibercept injection. BMJ Case Rep. 20 14;20 14(jun11 1):bcr2013202515-bcr. • Grewal DS, Schwartz T, Fekrat S.  Sequential sterile intraocular inflammation associated with consecutive intravitreal injections of aflibercept and ranibizumab. Ophthalmic Surg Lasers Imaging Retina. 2017;48(5):428–31. • Hahn P, Chung MM, Flynn HW, Jr., Huang SS, Kim JE, Mahmoud TH, et al. Postmarketing analysis of aflibercept-­ related sterile intraocular inflammation. JAMA Ophthalmol. 2015;133(4):421–6. • Hahn P, Kim JE, Stinnett S, Chung MM, Dugel PU, Flynn HW, Jr., et  al. Aflibercept-related sterile inflammation. Ophthalmology. 2013;120(5):1100–101 e1–5. • Kim JY, You YS, Kwon OW, Kim SH. Sterile inflammation after intravitreal injection of aflibercept in a Korean population. Korean J Ophthalmol. 2015;29(5):325–30.

Brolucizumab-Related Intraocular Inflammation Intravitreal Brolucizumab was approved for the treatment of neovascular age-related macular degeneration in October 2019. Phase 3 reports stated that brolucizumab had higher rates of ocular inflammation including anterior uveitis, vitritis, and vasculitis. An extended 96-week safety outcomes report from HAWK and HARRIER reported a 4.4% rate of intraocular inflammation associated with brolucizumab (compared to 0.8% in aflibercept), with six patients developing an associated occlusive retinal vasculitis. Cytopathologic analysis of the

Brolucizumab-Related Intraocular Inflammation

41

Figure 2.14  Intraocular inflammation and occlusive retinal vasculitis in a patient after treatment with intravitreal brolucizumab. Reprinted with permission from Thomas Albini, MD

vitreous sample ruled out a toxic reaction and favored an immune response, specifically a delayed-type hypersensitivity reaction. Due to safety concerns, the FDA added a warning label in June 2020. In June of 2022, the FDA approved brolucizumab for treatment of diabetic macular edema. All antiVEGF agents may cause noninfectious ­endophthalmitis and inflammation although brolucizumab appears to have the highest risk. It remains unclear why anti-VEGF drugs can induce intraocular inflammation. One of the possible suggested explanations of its mechanism is that the intraocular tissues produce antibodies to anti-VEGF (Fig. 2.14). References: Intraocular Inflammation Brolucizumab Intravitreal Injection

Secondary

to

• Dugel PU, Singh RP, Koh A, et al. HAWK and HARRIER: ninety-six-week outcomes from the phase 3 trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology. 2021;128(1):89–99.

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Chapter 2.  Differential Diagnosis of Endophthalmitis

• Iyer PG, Peden MC, Suñer IJ, Patel N, Dubovy SR, Albini TA. Brolucizumab-related retinal vasculitis with exacerbation following ranibizumab retreatment: A clinicopathologic case study. American journal of ophthalmology case reports. 2020;20:100989. • Baumal CR, Spaide RF, Vajzovic L, et al. Retinal vasculitis and intraocular inflammation after intravitreal injection of brolucizumab. Ophthalmology. 2020;127(10):1345–1359. • Jain A, Chea S, Matsumiya W, et al. Severe vision loss secondary to retinal arteriolar occlusions after multiple intravitreal brolucizumab administrations. American journal of ophthalmology case reports. 2020;18:100687. • Haug SJ, Hien DL, Uludag G, et al. Retinal arterial occlusive vasculitis following intravitreal brolucizumab administration. American journal of ophthalmology case reports. 2020;18:100680 • Schwartz SG, Flynn HW Jr., Emerson GG, et  al. Distinguishing between infectious endophthalmitis and noninfectious inflammation following intravitreal antiVEGF injection. Journal of VitreoRetinal Diseases 2019;3:42–44. • Iyer PG, Albini TA.  Review of intraocular inflammation after antivascular endothelial growth factor agents. 2022;62(3):35–47.

 rug-Associated Uveitis (a Rare Cause D of Pseudoendophthalmitis) Intraocular inflammatory reactions in the form of uveitis can be induced by the application of various ophthalmic local drugs as well as systemic drugs. Topical drugs used to control intraocular pressure, which could induce mild uveitis include alpha-2 adrenergetic agonists and prostaglandin analogues. Intracameral injection of vancomycin that is used to prevent

Drug-Associated Uveitis (a Rare Cause…

43

endophthalmitis after cataract surgery can be associated with hemorrhagic occlusive retinal vasculitis (HORV). Among systemic medications that can cause uveitis are cidofovir (nucleotide analog to inhibit viral DNA polymerase), fluoroquinolones, rifabutin (used to treat Mycobacterium avium complex (MAC) in patients with immunosuppression), bisphosphonates (used in osteoporosis treatment), TNF-𝛼 inhibitors (anti-inflammatory agents to treat rheumatologic diseases), drugs used for the treatment of metastatic ­melanoma (protein kinase inhibitors and immune checkpoint inhibitors), sulfonamides, sulfonylureas, and diuretics. Additionally, uveitis can be associated with various vaccines such as BacilleCalmette-Guerin (BCG), vaccines against hepatitis B, influenza, human papillomavirus, varicella, and SARS-CoV-2 viruses. Uveitis can also be associated with the intake of podophyllum, capsaicin, betaxolol, oral contraceptives, diethylcarbamazine, corticosteroids, quinidine, topiramate, and tuberculin skin tests. Uveitis caused by these drugs usually resolves spontaneously after cessation of the pharmacologic agent and administration of local steroids. Tattoo ink can also be associated with uveitis. • Iqbal KM, Hay MW, Emami-Naeini P. Medication-induced Uveitis: An Update. J Ophthalmic Vis Res. 2021 Jan 20;16(1):84–92. doi: 10.18502/jovr.v16i1.8254. PMID: 33520131; PMCID: PMC7841282. • Moorthy R, Valluri S, Jampol L. Drug-induced uveitis. Surv Ophthalmol 1998;42:557–570. • Cordero-Coma M, Salazar-Méndez R, Garzo-García I, Yilmaz T.  Drug-induced uveitis. Expert Opin Drug Saf 2015;14:111–126. • Schwartz SG, Relhan N, O’Brien TP, Flynn Jr. HW. A new complication associated with the use of prophylactic intracameral antibiotics: hemorrhagic occlusive retinal vasculitis. Ophthalmology 2017;124:578–579.

Chapter 3 Diagnosis of Endophthalmitis: Clinical Presentation, Pathology, Microbiology, and Echography The diagnosis of endophthalmitis usually can be made based on clinical examination findings. The patient may present with gradual or sudden onset of symptoms including lid swelling, pain, redness, discharge, and a decrease in vision.

Clinical Presentations The diagnosis of endophthalmitis usually can be made based on clinical examination findings. The patient may present with gradual or sudden onset of symptoms including lid swelling, pain, redness, discharge, and decrease in vision. Slit-lamp examination may show lid swelling, conjunctival congestion, chemosis, glaucoma implant exposure, corneal edema, epithelial defect, corneal infiltrate, hypopyon, and infiltrates/fibrin membrane in the anterior chamber, plaque inside the capsular bag, loss of fundus red reflex, or infiltrates in the vitreous cavity (Figs. 3.1, 3.2, and 3.3).

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 H. W. Flynn Jr. et al., Endophthalmitis in Clinical Practice, In Clinical Practice, https://doi.org/10.1007/978-3-031-35184-6_3

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46

a

c

Chapter 3.  Diagnosis of Endophthalmitis…

b

d

Figure 3.1  Acute-onset endophthalmitis. Signs of acute-onset post-­ operative endophthalmitis following cataract surgery. (a) Conjunctival congestion, mild corneal edema, hypopyon, and hand motions (HM) vision on the day of presentation. (b) Fibrinous membrane in the anterior chamber and pupillary area. (c) Vitritis and hazy view of the posterior segment. (d) Ultrasound demonstrates the presence of echogenic shadows in the vitreous cavity

Microbiology

47

Figure 3.2 Acute-onset endophthalmitis. A 73-year-old female patient with acute-onset post-operative endophthalmitis following cataract surgery presented with conjunctival congestion, mild corneal edema, hypopyon, fibrinous membrane in the pupillary area, and hazy view of the posterior segment

Figure 3.3  Acute-onset endophthalmitis. A 69-year-old male patient with acute-onset post-operative endophthalmitis following cataract surgery presented with conjunctival congestion, mild corneal edema, hypopyon, fibrinous reaction in the anterior chamber, and hazy view of the posterior segment

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Chapter 3.  Diagnosis of Endophthalmitis…

Microbiology Microorganisms able to access the intraocular space, especially the vitreous, find favorable conditions for growth. Endophthalmitis is characterized by the proliferation of polymorphonuclear leukocytes. Bacterial infections typically produce one or few large abscesses, while fungal infections may produce multiple smaller abscesses. Relatively less virulent organisms may proliferate inside the capsular bag and lead to chronic (delayed-onset) post-operative endophthalmitis.

How to Perform TAP and Inject Treatment of endophthalmitis includes obtaining a vitreous sample for cultures and injection of intravitreal antimicrobials. By obtaining vitreous sample and using it to identify the causative microorganisms, further management of the patient can be planned after the initial empiric treatment. Traditional approach for vitreous aspiration (TAP) as per Endophthalmitis Vitrectomy Study (EVS): The Endophthalmitis Vitrectomy Study (EVS) provided guidelines for the vitreous tap as well as pars plana vitrectomy (PPV). As per the EVS, 0.2–0.5 mL of vitreous sample was collected by way of the pars plana either by needle aspiration or by vitreous biopsy through a single sclerotomy using a vitrectomy cutter. After the TAP, injections of intravitreal antibiotics were given in separate syringes. If an adequate sample could not be safely obtained, a vitreous biopsy using a vitrectomy instrument was performed. The EVS reported that in a subgroup of patients presenting visual acuity of hand motions or better, there was no difference in the visual outcome (immediate PPV or TAP). However, in the subgroup of patients presenting visual acuity of light perception only, visual outcomes were better with immediate PPV compared to TAP. In the EVS, “immediate” PPV was defined as within 6 h. Current day TAP and injection options (Fig. 3.4): The procedure can be performed in the outpatient clinic under local

Microbiology

a

b

c

d

e

f

49

Figure 3.4 Vitreous TAP. (a) Standard preoperative preparation with povidone–iodine. (b) Local anesthesia (retrobulbar or peribulbar block) with lidocaine solution. (c) Speculum placement. (d) Use a 23-gauge butterfly needle on 10  cc syringe for tap. (e) Insert a 23-gauge butterfly needle into a 10-cc syringe through pars plana. (f) Tap 0.2–0.5  ml of vitreous by slow suction followed by antibiotic injection through pars plana

anesthesia (retro−/peribulbar block) or topical anesthesia. The lids and conjunctiva are prepared with 5% povidone– iodine followed by placement of the speculum. A needle mounted on a syringe is inserted through pars plana, and approximately 0.2–0.5  mL of vitreous is aspirated once the needle tip is at the center of the globe. The authors recommend a 23-gauge needle mounted on a 5 cc or 10 cc syringe. Once the vitreous sample is removed, antimicrobials are injected into the vitreous cavity. The vitreous sample obtained is sent for the microbiology evaluation including smear and culture. In case of growth on the culture media, antimicrobial susceptibility tests are further performed. A 25G or 27G needle can also be used for vitreous aspiration but additional

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Chapter 3.  Diagnosis of Endophthalmitis…

force may be required to aspirate vitreous through a narrower needle. Other modifications: A modification of the vitreous TAP procedure has been recently published. In this modified technique under subconjunctival anesthesia, a valved 25-gauge trocar cannula is inserted through pars plana, and subsequent aspiration of exudates/vitreous and antimicrobial injections are performed through the single port. In a prospective, randomized, single-center trial, Vahedi et al. compared comfort and procedural facility using a 25-gauge trocar cannula as a port to aspirate vitreous and inject intravitreal antibiotics to treat acute-onset endophthalmitis. Since there were no significant differences in patient comfort, physician ease-of-use scores, vitreous sample volume, successful vitreous taps, and microbiological yield between the two groups, the study concluded that 25-gauge trocar technique is a viable option (Fig.  3.5). Comparison of traditional versus 25-gauge trocar cannula-based vitreous TAP is shown in Table 3.1.

a

d

b

c

e

Figure 3.5  Pars Plana Tap and Inject assisted with a 25-gauge trochar technique. (a) After sterile preparation, subconjunctival lidocaine is injected locally (b) 25-gauge trochar is inserted. (c) Using the 25-gauge trochar, we can obtain a vitreous aspirate using a 20-cc syringe. (d) Using the 25-gauge trochar, we can then inject intravitreal antimicrobial agents. (e) Trochar is removed using forceps

Microbiology

51

Table 3.1 A comparison of the traditional versus 25-gauge trocar cannula-based vitreous TAP Standard 23-gauge 25-Gauge trocar needle-based cannula-based TAP and inject Low

TAP and inject Higher

Anesthesia utilized

Retro−/peribulbar

Subconjunctival

Number of needle entries

Multiple

One

Instrument cost

Intravitreal Antimicrobial Injection In the management of endophthalmitis, vitreous tap prior to antibiotic injection is a common standard practice. In most of the cases, empiric antibiotics with a wide spectrum of activity are used and subsequently tailored per the microbiology report. The selection of antimicrobial agents is important, and the decision should be based on the type of endophthalmitis and suspected microbiological profile. Using a 30-G needle mounted on a 1-cc syringe, antimicrobials are injected intravitreally: • For presumed bacterial cases: Intravitreal vancomycin and ceftazidime via separate syringes. Intravitreal dexamethasone can be considered. Intravitreal ceftriaxone may be substituted for ceftazidime depending on availability. • For presumed fungal cases: Intravitreal amphotericin B or voriconazole without intravitreal steroids. References: How to Perform TAP and Inject • Results of the Endophthalmitis Vitrectomy Study. A randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Endophthalmitis Vitrectomy Study Group. Arch Ophthalmol. 1995;113(12):1479–96. • Chan A, Leng T, Moshfeghi DM. Cannula-based 25-gauge vitreous tap and injection: a new surgical technique. Retina. 2012;32(5):1021–2.

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• Han DP, Wisniewski SR, Kelsey SF, Doft BH, Barza M, Pavan PR. Microbiologic yields and complication rates of vitreous needle aspiration versus mechanized vitreous biopsy in the Endophthalmitis Vitrectomy Study. Retina. 1999;19(2):98–102. • Hohn F, Kretz FT, Sheth S, Natarajan S, Singh P, Koch FH, et  al. Portable single port 23-gauge vitrectomy in postoperative endophthalmitis. Clin Ophthalmol. 2015;9:1457–61. • Park I, Lee SJ. Factors affecting precipitation of vancomycin and ceftazidime on intravitreal injection. J Ocul Pharmacol Ther. 2013;29(1):23–6. • Relhan N, Pathengay A, Schwartz SG, Flynn HW, Jr. Emerging worldwide antimicrobial resistance, antibiotic stewardship and alternative Intravitreal agents for the treatment of endophthalmitis. Retina. 2017;37(5):811–8. • Vaziri K, Schwartz SG, Kishor K, Flynn HW, Jr. Endophthalmitis: state of the art. Clin Ophthalmol. 2015;9:95–108. • Vahedi S, Adam MK, Dollin M, Maguire JI. 25-gauge Trocar cannula for acute endophthalmitis-related in-office vitreous tap and injection: Patient comfort and physician ease of use. Retina. 2017;37(4):657–61.

 esults of Anterior Chamber TAP Versus Vitreous R TAP Microbiologic diagnosis of endophthalmitis is made based on the identification of organisms from samples obtained from either anterior chamber fluid or vitreous. Culture positivity rates are reported to be lower with aqueous humor (approximately 22–30% of cases) compared to vitreous (approximately 40–69% of cases). Therefore, anterior chamber paracentesis should not substitute a vitreous tap or biopsy for establishing the diagnosis of bacterial endophthalmitis. Some series have questioned the importance of obtaining cultures. In most patients, a change in management following the initial treatment (either TAP or pars plana vitrectomy) is

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influenced by the clinical course, rather than the microbiologic results. Nevertheless, obtaining cultures is preferable whenever possible. References: Results of Anterior Chamber TAP Versus Vitreous TAP • Results of the Endophthalmitis Vitrectomy Study. A randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Endophthalmitis Vitrectomy Study Group. Arch Ophthalmol. 1995;113(12):1479–96. • Microbiologic factors and visual outcome in the endophthalmitis vitrectomy study. Am J Ophthalmol. 1996;122(6):830–46. • Auclin F, Pollet E, Roman S, Boureau-Andrieux C, Leroux-­ Les-­Jardins S, Ullern M.  Fifty-two cases of postoperative endophthalmitis treated with one protocol: anatomical and functional results. J Fr Ophtalmol. 2001;24(7):687–91. • Donahue SP, Kowalski RP, Jewart BH, Friberg TR. Vitreous cultures in suspected endophthalmitis. Biopsy or vitrectomy? Ophthalmology. 1993;100(4):452–5. • Han DP, Wisniewski SR, Kelsey SF, Doft BH, Barza M, Pavan PR. Microbiologic yields and complication rates of vitreous needle aspiration versus mechanized vitreous biopsy in the Endophthalmitis Vitrectomy Study. Retina. 1999;19(2):98–102. • Kunimoto DY, Das T, Sharma S, Jalali S, Majji AB, Gopinathan U, et al. Microbiologic spectrum and susceptibility of isolates: part II.  Posttraumatic endophthalmitis. Endophthalmitis Research Group. Am J Ophthalmol. 1999;128(2):242–4. • Sharma S, Jalali S, Adiraju MV, Gopinathan U, Das T. Sensitivity and predictability of vitreous cytology, biopsy, and membrane filter culture in endophthalmitis. Retina. 1996;16(6):525–9. • Barza M, Pavan PR, Doft BH, Wisniewski SR, Wilson LA, Han DP, et  al. Evaluation of microbiological diagnostic techniques in postoperative endophthalmitis in the

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•

• •

•

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Endophthalmitis Vitrectomy study. Arch Ophthalmol. 1997;115(9):1142–1150. Sjoholm-Gomez de Liano C, Soberon-Ventura VF, Salcedo-­ Villanueva G, Santos-Palacios A, Guerrero-­ Naranjo JL, Fromow-Guerra J, et al. Sensitivity, specificity and predictive values of anterior chamber tap in cases of bacterial endophthalmitis. Eye Vis (Lond). 2017 Jul 11;4:18. PMID: 28706959. Patel SN, Storey PP, Levin H, et al. Endophthalmitis after cataract surgery: changes in management based on microbiologic cultures. Ophthalmol Retina 2021;5:16–22. AlBloushi AF, Ajamil-Rodanes S, Testi I, Wagland C, Grant-McKenzie N, Pavesio C. Diagnostic value of culture results from aqueous tap versus vitreous tap in cases of bacterial endophthalmitis. Br J Ophthalmol. 2022 Jun;106(6):815–819. Colucciello M. CONTROVERSIES IN CARE: The Value of Vitreous and Aqueous Sampling for Culture in ­Endophthalmitis: Should there be a change in culture? Retinal Physician, Volume: 18, Issue: Jan/Feb 2021, page(s): 42–46.

Culture Media To detect and identify causative organisms, aqueous and vitreous sample obtained from the biopsy is analyzed as follows: • Staining of the smear. • Inoculation of culture media. Various stains and culture media used for microbiological diagnosis are discussed and shown in Table 3.2 and Fig. 3.6. The culture growth guides the management of endophthalmitis in cases of unusual and resistant causative organisms. In peripheral settings and satellite offices, it is not always possible to have consistent access to microbiology laboratories where the vitreous specimens can be handled

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Table 3.2 Stains and culture media used for microbiological diagnosis Stains/ Smears Gram-positive organisms versus Gram-­negative Gram stain organisms Acid-fast For Mycobacteria stains Calcofluor white

Fluorescent stain (fungi, microsporidia, and Acanthamoeba)

Chocolate agar

• Used as an enriched medium for the recovery of fastidious organisms (i.e., Neisseria gonorrhoeae and Haemophilus influenzae) • Also, is used as a general-purpose medium for the recovery of bacteria, yeasts, and molds from aqueous and vitreous fluids

5% sheep blood agar

• A general-purpose medium for recovery of the most common bacterial and fungal endophthalmitis isolates

Thioglycollate broth

• An all-purpose, enriched medium for the recovery of low numbers of aerobic or anaerobic (including Cutibacterium acnes) organisms from ocular fluids and tissues

Anaerobic blood agar

• An all-purpose medium for the recovery of both anaerobic and facultative anaerobic organisms • Should be included for all chronic endophthalmitis or where Cutibacterium acnes is suspected

Sabouraud agar

• A selective medium used to promote the growth of fungi (yeasts and molds)

Blood culture bottles

• Contain specially prepared for the recovery of both aerobic and anaerobic bacteria and fungi • Undiluted fluids, inoculated in pediatric bottles; diluted samples, inoculated in adult bottles

Lowenstein-­ Jensen medium

• A selective medium for the recovery of acid-­ fast organisms (Mycobacteria, Nocardia) from aqueous and vitreous fluids

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Figure 3.6 Culture media to identify causative organisms from aqueous and vitreous samples

effectively and efficiently. In such situations, it is not advisable to delay the antibiotic injections. The surgeon may use pediatric blood and chocolate agar bottles to inoculate whatever smallest amount of vitreous sample is obtained. Also, important is to be aware of the case scenario where the surgeon may encounter a dry vitreous tap and is then bound to proceed without obtaining the vitreous tap. In some patients, prompt injection of two antibiotics with coverage of both Gram-positive and Gram-negative organisms is a reasonable strategy. References • Flynn HW Jr. MD, and Garg S, MD. CONTROVERSIES IN CARE: The Value of Vitreous and Aqueous Sampling for Culture in Endophthalmitis Should there be a change in culture? (compiled by By Michael Colucciello, MD) available at https://www.retinalphysician.com/issues/2021/

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jan-­feb-­2021/controversies-­in-­care-­the-­value-­of-­vitreous-­ and-­aq#.YtlhHWpnBX8.gmail • Patel SN, Storey PP, Levin H, et al. Endophthalmitis after cataract surgery: changes in management based on microbiologic cultures. Ophthalmol Retina. 2020;S2468-S6530(20)30256–6. doi:https://doi. org/10.1016/j.oret.2020.06.028 • Patel SN, Storey PP, Pancholy M, et al. Changes in management based on vitreous culture in endophthalmitis after intravitreal anti-vascular endothelial growth factor injection. Am J Ophthalmol. 2019;207:224–231. ­doi:https://doi. org/10.1016/j.ajo.2019.06.008

Other Testing Polymerase Chain Reaction (PCR)—PCR is an easy, cheap, simple to understand, highly sensitive, and reliable technique to repeatedly replicate a focused segment of DNA to produce millions to billions of copies of a specific product for sequencing, cloning, and analysis. One major limitation of PCR is that precise sequence is required in order to generate the primers to allow selective amplification. Also, the possibility of error by DNA polymerases and nonspecific binding of primers may result in incorrect interpretation. Peptide Nucleic Acid - Fluorescence in situ hydridization (PNA–FISH)—Molecular techniques are increasingly used to identify pathogens. Fluorescence in situ hybridization (FISH) is a technique whereby DNA probes labeled with fluorophores are attached to a target DNA for identification. The FISH technique has been used for over 20 years for the detection of trisomy in genetics. A new molecular application of fluorescence hybridization can be used to rapidly identify microorganisms (Staphylococcus, Pseudomonas, Candida species) in blood cultures from patients in the intensive care unit with septicemia. FISH has been shown to improve patient outcomes in terms of survival, hospital stay, and total cost.

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In ophthalmology, endophthalmitis remains an important cause of ocular morbidity. Changes in the prevalence of causative organisms and their antimicrobial susceptibilities over time have been reported. Current methodology of plating and subsequent reading of growth is labor and time intensive. Consequently, there exists a growing need for more rapid and accurate detection of pathogens. If PNA–FISH is proven useful for quick diagnosis of endophthalmitis, it can further be utilized for diagnosis of various other ocular infections. References: PCR and PNA–FISH • Patel N, Miller D, Relhan N, Alfonso EC and Flynn HW Jr. Novel Use of Fluorescence In Situ Hybridization for the Rapid Identification of Microorganisms in Endophthalmitis and Keratitis. Ophthalmic Surg Lasers Imaging Retina. 2019 May 1;50(5):S9-S12. PMID: 31100176. • Lee CS, Hong B, Kasi SK, et al. Prognostic utility of whole-­ genome sequencing and polymerase chain reaction tests of ocular fluids in postprocedural endophthalmitis. American journal of ophthalmology. 2020;217:325–334. • Jones DB.  Emerging vancomycin resistance: what are we waiting for? Arch Ophthalmol. 2010;128(6):789–91. • Poppert S, Essig A, Stoehr B, Steingruber A, Wirths B, Juretschko S, et al. Rapid diagnosis of bacterial meningitis by real-time PCR and fluorescence in situ hybridization. J Clin Microbiol. 2005;43(7):3390–7. • Sachse F, Becker K, von Eiff C, Metze D, Rudack C. Staphylococcus aureus invades the epithelium in nasal polyposis and induces IL-6  in nasal epithelial cells in  vitro. Allergy. 2010;65(11):1430–7. • Schwartz SG, Flynn HW, Jr. Update on the prevention and treatment of endophthalmitis. Expert Rev. Ophthalmol. 2014;9(5):425–30. • Silva RA, Sridhar J, Miller D, Wykoff CC, Flynn HW, Jr. Exogenous fungal endophthalmitis: an analysis of isolates and susceptibilities to antifungal agents over a 20-year period (1990–2010). Am J Ophthalmol. 2015;159(2):257– 64 e1.

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Echography In order to achieve the optimal treatment outcome in cases presenting with endophthalmitis, prompt diagnosis and institution of effective therapy treatment are necessary. Echography is often utilized because the opaque media prevents detailed visualization of the posterior segment. Echographic features in combination with clinical presentation aid in the diagnosis and influence clinical decision-­ making. Echographic features including vitreous opacities, vitreous membranes, retinal detachment, subhyaloid opacities, subretinal opacities, choroidal detachment, fundus thickening, and signs of orbital inflammation (Table  3.3) were reported to be associated with endophthalmitis. In the Endophthalmitis Vitrectomy Study, echography was performed when the ocular media precluded direct visualization of the posterior pole to determine if choroidal detachment, retinal detachment, or both were present. Initial echographic findings in infectious endophthalmitis are nonspecific with respect to visual prognosis and causative microorganisms (Figs.  3.7 and 3.8). The presence of echographic findings as mentioned above correlates with worse visual prognosis, but there is no correlation with the possible causative organism.

Figure 3.7  Echographic appearance of eye in infectious versus noninfectious ocular inflammation

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Figure 3.8 Echography and anterior segment ultrasound biomicroscopy (UBM) of eye with infectious ocular inflammation. Patient with endophthalmitis with B-scan showing vitreous opacities and membranes. Corresponding UBM shows prominent cells in the anterior chamber without fibrin

References: Diagnosis of Endophthalmitis (Echography) • Byrne SF, Green RL.  Ultrasound of the eye and orbit. second ed. St Louis: Mosby Year Book; 2002. • Dacey MP, Valencia M, Lee MB, Dugel PU, Ober RR, Green RL, et al. Echographic findings in infectious endophthalmitis. Arch Ophthalmol. 1994;112(10):1325–33. • Fisher YL, Slakter JS, Friedman RA, Yannuzzi LA. Kinetic ultrasound evaluation of the posterior vitreoretinal interface. Ophthalmology. 1991;98(7):1135–8. • Kohanim S, Daniels AB, Huynh N, Eliott D, Chodosh J.  Utility of ocular ultrasonography in diagnosing infectious endophthalmitis in patients with media opacities. Semin Ophthalmol. 2012;27(5–6):242–5. • Maneschg O, Csakany B, Nemeth J. Ultrasonographic findings in endophthalmitis following cataract surgery: a review of 81 cases. Ophthalmologe. 2009;106(11):1012–5. • Rachitskaya AV, Flynn HW, Jr., Fisher YL, Ayres B.  Correlation between baseline echographic features of endophthalmitis, microbiological isolates, and visual outcomes. Clin Ophthalmol. 2013;7:779–85. • Roth DB, Modi KK, Brunswick N, Flynn HW Jr. Distinguishing infection post-intravitreal injection. http:// www.reviewofophthalmology.com/article/distinguishing-­ infection-­post-­intravitreal-­injection-­41670. Assessed 4 July 2017.

Chapter 4 Acute-Onset Endophthalmitis: Clinical Categories, Incidence Rates, Signs/Symptoms, Risk Factors, Microbiology, Treatment, and Follow-Up  cute-Onset Post-Operative Endophthalmitis A Following Cataract Surgery Acute-onset post-operative endophthalmitis occurs within 6  weeks of cataract surgery or secondary intraocular lens (IOL) implantation.

Incidence Reported rates vary between about 0.03 and 0.2%.

Signs/Symptoms The patient presents with lid swelling, pain, redness, discharge, a marked decrease in the vision, etc. A slit-lamp © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 H. W. Flynn Jr. et al., Endophthalmitis in Clinical Practice, In Clinical Practice, https://doi.org/10.1007/978-3-031-35184-6_4

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a

b

Figure 4.1  Acute-onset endophthalmitis. A 78-year-old male patient with acute-onset post-operative endophthalmitis following cataract surgery. (a) The patient presented with conjunctival congestion, mild corneal edema, hypopyon, hazy view to the posterior segment, and counting fingers (CF) visual acuity. The patient underwent vitreous TAP and intravitreal antibiotics (vancomycin and ceftazidime) and was culture positive for coagulase-negative Staphylococcus resistant to all fluoroquinolones. (b) At the 6-month follow-up, the patient regained best corrected visual acuity of 20/80 with resolution of inflammation. At the 2-year follow-up, the patient achieved visual acuity of 20/20

examination may show lid swelling, conjunctival congestion, chemosis, corneal edema, epithelial defect, hypopyon, infiltrates/fibrin membrane in the anterior chamber, loss of red reflex from the retina, and infiltrates in the vitreous cavity (Fig. 4.1).

Risk Factors • Pre-operative: –– Blepharitis. –– Use of corticosteroids. –– Prosthesis in fellow eye. –– Active systemic infection. –– Diabetes mellitus. –– Older age.

Acute-Onset Post-Operative Endophthalmitis Following…

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• Intraoperative: –– Failure to use topical povidone–iodine preparation. –– Prolonged surgery. –– Intraoperative complications, including Posterior capsular rupture (Fig. 4.2). • Post-operative: –– Wound leak (Fig. 4.3). –– Contaminated eye drops.

Microbial Isolates Following are the microorganisms most commonly associated with acute-onset post-operative endophthalmitis following cataract surgery (Endophthalmitis Vitrectomy Study data): • Coagulase-negative Staphylococci—70.0%. • Staphylococcus aureus—9.9%.

a

b

Figure 4.2  Acute-onset endophthalmitis. A 69-year-old male patient with acute-onset post-operative endophthalmitis following cataract surgery and posterior chamber intravitreal lens implantation following posterior capsular rent. (a) The patient presented with conjunctival congestion, corneal edema, hypopyon, fibrinous membrane in the anterior chamber, hazy view of the posterior segment, and hand motions (HM) vision. Patient underwent vitreous TAP and intraocular antibiotics. (b) At 1-year follow-up, the patient regained best corrected visual acuity of 20/50

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a

b

Figure 4.3 Wound leak-associated endophthalmitis. A 57-year-old male with acute-onset endophthalmitis after cataract surgery. (a) Slit-­ lamp examination revealed conjunctival congestion, corneal edema, anterior chamber inflammation, hypopyon, and a single nylon suture placed temporally with a leaking clear corneal wound. Visual acuity was hand motions (HM). The patient underwent pars plana vitrectomy and additional suture placement onto the leaking wound. (b) Two months after suture removal visual acuity improved to 20/25

• • • •

Streptococcus species—9.0%. Enterococcus species—2.2%. Gram-negative bacteria—5.9%. Other Gram-positive bacteria—3.1%.

I nitial Management of Acute-Onset Post-Operative Endophthalmitis • Vitreous TAP or pars plana vitrectomy. • Injection of intravitreal antimicrobial agents. Vitreous TAP: A small needle is inserted through pars plana into the vitreous, and a sample is withdrawn. The vitreous sample is then sent to the microbiology laboratory for culture and analysis to identify the microorganism and the antibiotic or antifungal medication that it is sensitive to. The following are important considerations while performing vitreous tap:

Acute-Onset Post-Operative Endophthalmitis Following…

65

• Location—Clinic lane/minor procedure room/operating room. • Anesthesia—Peribulbar/retrobulbar/topical may be considered. • Equipment—23 gauge, 1 inch needle (butterfly-style needle may be helpful) (Fig. 3.4). • Microbiology—Culture plates or blood culture bottles for specimens (Fig. 3.6). Pars plana vitrectomy (PPV): Pars plana vitrectomy is a surgical procedure that involves removal of infectious infiltrates and vitreous gel from the eye. A vitreous sample is sent to the microbiology laboratory for culture and analysis (Fig. 4.4). Following are important considerations while performing PPV: • Location—Operating room. • Anesthesia— General/Peribulbar/retrobulbar/sub-tenon/ topical. • Equipment—Transconjunctival small gauge, standard 3 port PPV, or 2 port approach if view is limited.

Figure 4.4  Pars plana vitrectomy (25 gauge assisted by wide field viewing)

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Chapter 4.  Acute-Onset Endophthalmitis: Clinical…

Intravitreal antimicrobials (Fig. 4.5) For presumed bacterial cases (in separate syringes): • Vancomycin 1 mg/0.1 mL (for coverage of Gram-positive organisms). • Ceftazidime 2.25  mg/0.1  mL (for coverage of Gram-­ negative organisms). –– Ceftriaxone 2 mg/0.1 mL may be substituted for ceftazidime if this is more readily available. –– Amikacin 0.4 mg/0.1 mL can be substituted for ceftazidime but has the risks of aminoglycoside macular toxicity. –– Dexamethasone 4  mg/0.1  mL may be considered for acute-onset bacterial cases but should be avoided in suspected fungal endophthalmitis and delayed-onset (chronic) endophthalmitis until the organism is identified.

Figure 4.5  Intravitreal injections in syringes. Syringes (1  cc) filled with vancomycin (1 mg/0.1 mL), ceftazidime (2.25 mg/0.1 mL), and dexamethasone (0.4 mg/0.1 mL). The reconstituted syringes have a lot number, date of expiration, and storage guidelines (2–8 °C)

Acute-Onset Post-Operative Endophthalmitis Following…

67

For presumed fungal cases: • Voriconazole 0.1 mg/0.2 mL and/or. • Amphotericin B 0.005 mg/0.1 mL

 ollow-Up Management of Acute-Onset Post-­ F Operative Endophthalmitis (Fig. 4.6) In the United States, systemic antibiotics are generally not used for these patients. In other parts of the world, systemic antibiotics are more frequently used.

a

b

c

d

Figure 4.6 Follow-up of endophthalmitis. Follow-up course of a patient with acute-onset post-operative endophthalmitis following cataract surgery. (a) Conjunctival congestion, mild corneal edema, hypopyon, and hand motions (HM) vision on the day of presentation. (b) 1 day after vitreous TAP and intraocular antibiotics hypopyon reduced, fibrinous membrane contracted in the pupillary zone, and vision improved to 3/200. (c) At the 2-day follow-up, inflammation reduced further and vision improved to 20/400. (d) At 6-week follow-up, the patient regained best corrected visual acuity of 20/20 with resolution of inflammation

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Chapter 4.  Acute-Onset Endophthalmitis: Clinical…

First Morning after Initial Treatment • Topical antimicrobials. –– Consider fortified topical antibiotics if available: Vancomycin 25 mg/mL hourly during the day Ceftazidime 50 mg/mL hourly during the day –– Alternatively, commercially available topical antibiotics are used. –– For fungal cases, topical amphotericin B has poor intraocular penetration and is not used. • Topical steroids four times daily (not for suspected/proven fungal infection). • Topical cycloplegics daily. *Topical antibiotics hourly may result in corneal epithelial toxicity as a result of preservatives in commercial p ­ reparations. Topical medications are generally not used during night hours while sleeping. Subconjunctival antibiotics at the time of initial treatment provide adequate ocular surface medication for nighttime coverage.

Two to Three Days after Initial Treatment • If clinically improving—Continue to observe and taper topical steroids over several weeks. • If clinically worsening: –– Consider repeat intraocular cultures and/or reinjection of intraocular antibiotics (and possibly intraocular steroids in acute-onset bacterial cases). –– Consider PPV if not performed initially. Decisions about reinjecting antibiotics, performing PPV, or changing antibiotics are based on clinical parameters rather than culture results. In a situation where the clinical appearance is improving but the intraocular cultures report resistance to the initially used antibiotics, it may be appropriate to continue treatment as is.

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References: Acute-Onset Post-Operative Endophthalmitis Associated with Cataract Surgery • Peck TJ, Patel SN, Ho AC. Endophthalmitis after cataract surgery: an update on recent advances. Current opinion in ophthalmology. 2021;32(1):62–68. • Patel SN, Storey PP, Levin H, et al. Endophthalmitis after Cataract Surgery: Changes in Management Based on Microbiologic Cultures. Ophthalmology Retina. 2021;5(1):16–22. • Grzybowski A, Turczynowska M, Schwartz SG, Relhan N, Flynn HW Jr. The role of systemic antimicrobials in the treatment of endophthalmitis: a review and an international perspective. Ophthalmol Ther 2020;9(3):485–498. • Shivaramaiah HS, Relhan N, Pathengay A, Mohan N, Flynn HW, Jr. Endophthalmitis caused by gram-positive bacteria resistant to vancomycin: Clinical settings, causative organisms, antimicrobial susceptibilities, and ­treatment outcomes. American journal of ophthalmology case reports. 2018;10:211–214. • Chang VS, Schwartz SG, Davis JL, Flynn HW, Jr. Endophthalmitis following cataract surgery and intracameral antibiotic: Moxifloxacin resistant Staphylococcus epidermidis. American journal of ophthalmology case reports. 2019;13:127–130. • Yannuzzi NA, Si N, Relhan N, Kuriyan AE, Albini TA, Berrocal AM, et  al. Endophthalmitis after clear corneal cataract surgery: outcomes over two decades. Am J Ophthalmol. 2017;174:155–9. • Shirodkar AR, Pathengay A, Flynn HW, Jr., Albini TA, Berrocal AM, Davis JL, et  al. Delayed— versus Acute-­ onset endophthalmitis after cataract surgery. Am J Ophthalmol. 2012;153(3):391–8 e2. • Pathengay A, Khera M, Das T, Sharma S, Miller D, Flynn HW, Jr. Acute postoperative endophthalmitis following cataract surgery: a review. Asia—Pacific Journal of Ophthalmology (Philadelphia, Pa). 2012;1(1):35–42. • Lalwani GA, Flynn HW, Jr., Scott IU, Quinn CM, Berrocal AM, Davis JL, et  al. Acute-onset endophthalmitis after

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clear corneal cataract surgery (1996–2005). Clinical features, causative organisms, and visual acuity outcomes. Ophthalmology. 2008;115(3):473–6. • Results of the Endophthalmitis Vitrectomy Study. A randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Endophthalmitis Vitrectomy Study Group. Arch Ophthalmol. 1995;113(12):1479–96. For further details of the Endophthalmitis Vitrectomy Study – See Chap. 7.

 cute-Onset Endophthalmitis Following Pars A Plana Vitrectomy Incidence Endophthalmitis following pars plana vitrectomy is an uncommon cause of endophthalmitis. The incidence ranges between 0.03 and 0.14% for 20 G PPV.

Signs/Symptoms Endophthalmitis after pars plana vitrectomy may present as acute or delayed-onset endophthalmitis. These patients usually have a hypopyon and dense vitritis. Some cases, however, may lack vitritis due to the lack of vitreous.

Risk Factors (Table 4.1)

Acute-Onset Endophthalmitis Following Pars Plana…

71

Table 4.1  Risk factors associated with endophthalmitis after pars plana vitrectomy Surgery-related risk factors Patient-related risk factors •  Inadequate wound closure • Hypotony •  Vitreous incarceration • Endotamponade agent (air, gas, or silicone oil) • Subconjunctival and intravitreal injections • Surgeon learning curve (non-beveled sclerotomies)

• Diabetes mellitus or other causes of immune compromise • Trauma or excessive eye rubbing • Noncompliance with treatment

Microbial Isolates The most common organism causing endophthalmitis after pars plana vitrectomy is coagulase-negative Staphylococci. Other causative organisms include: • • • • •

Coagulase-negative Staphylococci. Pseudomonas species. Propionibacterium species. Enterococci species. Bacillus species.

Endophthalmitis in eyes following vitrectomy with silicone oil may present a diagnostic dilemma because the clinical signs may resemble noninfectious inflammation. In advanced cases, PPV with silicone oil exchange may be considered.

 ndophthalmitis after Pars Plana Vitrectomy E for Vitreous Floaters (Fig. 4.7) Endophthalmitis following pars plana vitrectomy for symptomatic vitreous floaters is rare but can be a devastating complication. Patient with floaters are often young and phakic with good pre-operative visual acuity. Pars plana vitrec-

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Chapter 4.  Acute-Onset Endophthalmitis: Clinical…

a

b

c

d

Figure 4.7  A 24-year-old female on post-operative day 1 after pars plana vitrectomy for vitreous floaters. (a) Fundus photography demonstrates mildly hazy media with vascular sheathing and perivascular hemorrhages. (b) Spectral domain optical coherence tomography shows retinal thickening and irregular intraretinal precipitates. (c) Early-phase fluorescein angiography demonstrates blockage corresponding to areas of perivascular hemorrhage. (d) Late-phase fluorescein angiography reveals leakage from retinal vessels and from the optic disc

tomy is being performed usually with small-gauge surgical instruments. References: Endophthalmitis after PPV for Floaters • Scott IU, Flynn HW Jr., Acar N, et al.: Incidence of endophthalmitis after 20-gauge versus 23-gauge versus 25-gauge pars plana vitrectomy. Graefes Arch Clin Exp Ophthalmol 2011;249: 377–380. • Henry CR, Smiddy WE, Flynn HW Jr.: Pars plana vitrectomy for vitreous floaters: is there such a thing as minimally invasive vitreoretinal surgery? Retina 2014; 34: 1043–1045.

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• Lin Z, Zhang R, Liang QH, Lin K, Xiao YS, Moonasar N, Wu RH.  Surgical Outcomes of 27-Gauge Pars PLana Vitrectomy for Symptomatic Vitreous Floaters. J Ophthalmol. 2017;2017:5496298. • Henry CR, Schwartz SG, Flynn HW, Jr. Endophthalmitis following pars plana vitrectomy for vitreous floaters. Clin Ophthalmol. 2014;8:1649–53. • Henry CR, Smiddy WE, Flynn HW, Jr. Pars plana vitrectomy for vitreous floaters: is there such a thing as minimally invasive vitreoretinal surgery? Retina. 2014;34(6):1043–5.

I nitial Management of Acute-Onset Endophthalmitis Following Vitrectomy TAP and inject is a relatively easy and quick initial approach to manage cases of endophthalmitis occurring after pars plana vitrectomy.

 ollow-Up Management in Patients with Acute-­ F Onset Endophthalmitis Following Vitrectomy First Morning after Initial Treatment • Topical antimicrobials. –– Consider fortified topical antibiotics if available: Vancomycin 25 mg/mL hourly during the day. Ceftazidime 50 mg/mL hourly during the day. –– Alternatively, commercially available topical antibiotics are used. –– For fungal cases, topical amphotericin B has poor intraocular penetration and is not used. • Topical steroids four times daily (not for suspected/proven fungal infection). • Topical cycloplegics daily.

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* Topical antibiotics hourly may result in corneal epithelial toxicity as a result of preservatives in commercial preparations. Topical medications are generally not used during night hours while sleeping. Subconjunctival antibiotics at the time of initial treatment provide adequate ocular surface medication for nighttime coverage.

Two to Three Days after Initial Treatment • If clinically improving—Continue to observe and taper topical steroids over several weeks. • If clinically worsening: –– Consider repeat intraocular cultures and/or reinjection of intraocular antibiotics (and possibly intraocular steroids in acute-onset bacterial cases). –– Consider repeat PPV and injection of antibiotics if no improvement is observed. References: Vitrectomy

Acute-Onset

Endophthalmitis

Following

• Weiss SJ, Adam MK, Gao X, et al. Endophthalmitis After Pars Plana Vitrectomy: Efficacy of Intraoperative Subconjunctival Antibiotics. Retina (Philadelphia, Pa). 2018;38(9):1848–1855. • Dave V Pathengay A, Schwartz SG, Flynn H,. Endophthalmitis following pars plana vitrectomy: a literature review of incidence, causative organisms, and treatment outcomes. Clin Ophthalmol. 2014:2183. • Henry CR, Schwartz SG, Flynn HW Jr. Endophthalmitis following pars plana vitrectomy for vitreous floaters. Clin Ophthalmol 2014;8:1649–53. • Chiang A, Kaiser RS, Avery RL, Dugel PU, Eliott D, Shah SP, et  al. Endophthalmitis in microincision vitrectomy. Retina. 2011;31(8):1513–7. • Wykoff CC, Parrott MB, Flynn HW Jr., Shi W, Miller D, Alfonso EC. Nosocomial Acute-onset postoperative endo-

Post-Traumatic Endophthalmitis

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phthalmitis at a University Teaching Hospital (2002–2009). Am J Ophthalmol. 2010;150(3):392–8.e2.

Post-Traumatic Endophthalmitis Open globe injury endophthalmitis.

may

lead

to

post-traumatic

Incidence Reported rates of post-traumatic endophthalmitis are variable, up to 90% in one series but generally less than 10%. Intraocular foreign bodies (IOFBs) have been reported in 10–41% of open globe injuries. In open globe injuries with endophthalmitis on presentation, IOFB may be even more common, up to 53%.

Signs/Symptoms Patients present with a history of open globe injury and marked loss of vision. Slit-lamp examination may show associated hypopyon, fibrinous membranes in anterior chamber, vitreous infiltrates/opacities, or retained intraocular foreign body (Figs. 4.8 and 4.9). The microorganisms that cause post-­ traumatic endophthalmitis are often more virulent and may be polymicrobial.

Risk Factors • Intraocular foreign body (IOFB) (Fig. 4.10)—Higher risk with vegetable matter. • Delayed presentation after open globe injury. • Contaminated wound. • Traumatic lens rupture. • Cornea wound (Fig. 4.11).

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Figure 4.8 Slit-lamp examination of a patient with open globe injury and post-traumatic endophthalmitis showing conjunctival hyperemia, corneal laceration, corneal edema, hypopyon with no view of posterior segment

Figure 4.9 Slit-lamp examination of a patient with open globe injury shows subconjunctival hemorrhage and presence of fibrinous exudates localized in the lens

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Figure 4.10  Intraocular foreign body (IOFB). A 38-year-old male patient developed post-traumatic endophthalmitis. Fundus photograph shows vitreous hemorrhage, hazy view of the posterior segment, and retained intraocular foreign body (metallic) in the vitreous

Microbial Isolates Most common causative organisms include: • • • • • •

Bacillus species (Fig. 4.12). Staphylococcus species. Pseudomonas. Streptococcus species. Gram-negative organisms. Fungi.

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Figure 4.11  A 42-year-old male patient with open globe injury. Slit-­ lamp examination showed conjunctival congestion, corneal laceration with iris tissue prolapse, focal corneal edema, hyphema, and no view of posterior segment

a

b

Figure 4.12 Post-traumatic endophthalmitis. A 17-year-old male patient with open globe injury and post-traumatic endophthalmitis. (a) Fundus photograph shows localized retinal exudates in the inferior retina. The vitreous culture was positive for Bacillus cereus. (b) A 6-month follow-up shows resolved inflammation with residual retinal scarring and vision improved to 20/400

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79

I nitial Management of Post-Traumatic Endophthalmitis Post-traumatic endophthalmitis is typically caused by more virulent organisms, therefore early pars plana vitrectomy may be indicated. In addition, systemic, as well as intraocular antibiotics are generally used. • Post-traumatic endophthalmitis is an ophthalmic emergency, which requires immediate treatment including wound closure, possibly vitrectomy, and administration of intravitreal and systemic antimicrobials. • Pars plana vitrectomy and intravitreal antibiotics—In patients with post-traumatic endophthalmitis, pars plana vitrectomy with injection of intravitreal antibiotics is generally recommended. • Systemic antibiotics in endophthalmitis associated with open globe injury—In cases of endophthalmitis associated with open globe injury, outcomes data regarding the use or nonuse of systemic antibiotics are limited. Large series of patients with open globe injuries without endophthalmitis at initial presentation, early wound closure and prophylactic use of systemic levofloxacin were associated with a very low endophthalmitis risk (Colyer et al. 2007). Most treating ophthalmologists do utilize systemic antibiotics in such cases. Retained intraocular foreign bodies (IOFBs) have a high risk for endophthalmitis and toxicity. IOFBs can be classified according to their location (anterior segment, posterior segment), material characteristics (metallic, magnetic, wood), size, mechanism of injury, setting (work-related, battlefield), and duration (acute, long standing). IOFB associated with endophthalmitis should be treated promptly. In 1995, a standardized classification of ocular trauma was proposed by ocular trauma experts (Kuhn et  al.). Various definitions of the proposed ocular trauma terms are shown in Table 4.2. In this classification, ocular trauma system was proposed as follows:

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Table 4.2  Ocular trauma classification terminology Terms Definitions Eyewall Sclera and cornea Closed globe injury

The eyewall does not have a full-thickness wound

Open globe injury

The eyewall does have a full-thickness wound

Rupture

Full-thickness wound of the eyewall, caused by a blunt object; the impact results in a momentary increase of the IOP and an inside-­ out injury mechanism

Laceration

Full-thickness wound of the eyewall, usually caused by a sharp object; the wound occurs at the impact site by an outside-in mechanism

Penetrating injury

Single laceration of the eyewall, usually caused by a sharp object

Intraocular foreign body injury

Retained foreign object(s) causing entrance laceration(s)

Perforating injury

Two full-thickness lacerations (entrance + exit) of the eyewall, usually caused by a sharp object or missile

Entry site of the wound (wound’s most posterior extent) helps in determining the zone of injury. In 1997, the Ocular Trauma Classification Group (Pieramici et al.) described the zone of injury as follows: • Zone 1—cornea and limbus. • Zone 2— ≤ 5 mm posterior to the limbus. • Zone 3—greater than 5 mm posterior to the limbus.

 ollow-Up Management in Patients with Post-­ F Traumatic Endophthalmitis First Morning after Initial Treatment • Topical antimicrobials.

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–– Consider fortified topical antibiotics if available: Vancomycin 25 mg/mL hourly during the day. Ceftazidime 50 mg/mL hourly during the day. –– Alternatively, commercially available topical antibiotics are used. –– For fungal cases, topical amphotericin B has poor intraocular penetration and is not used. Consider: • Topical steroids four times daily (not for suspected/proven fungal infection). • Topical cycloplegics daily. *Topical antibiotics hourly may result in corneal epithelial toxicity as a result of preservatives in commercial preparations. Topical medications are generally not used during night hours while sleeping. Subconjunctival antibiotics at the time of initial treatment provide adequate ocular surface medication for nighttime coverage.

Two to Three Days after Initial Treatment • If clinically improving—Continue to observe and taper topical steroids over several weeks. • If clinically worsening: –– Consider repeat intraocular cultures and/or reinjection of intraocular antibiotics (and possibly intraocular steroids in acute-onset bacterial cases). –– Consider PPV if not performed initially. Change antibiotics if indicated by initial culture results. References: Endophthalmitis Associated with Open Globe Injuries • Burdová M, Donátová K, Mahelková G, Chrenková V, Dotřelová D.  Post-traumatic exogenous endophthalmitis caused by Nocardia farcinica. J Ophthalmic Inflamm Infect. 2021;11(1):16.

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• Watanachai N, Choovuthayakorn J, Chokesuwattanaskul S, et  al. Risk factors and outcomes of post-traumatic endophthalmitis: a retrospective single-center study. J ­ Ophthalmic Inflamm Infect. 2021;11(1):22. • Banker TP, McClellan AJ, Wilson DW BS, Juan FM, Kuriyan AE, Relhan N, Chen FV, Albini TA, Berrocal AM, Sridhar J, Gregori NZ, Townsend JH, Flynn HW Jr. Culture-­ Positive Endophthalmitis after Open Globe Injuries with and without Retained Intraocular Foreign Bodies. OSLI Retina 2017 Aug 1;48(8):632–7. • Jindal A, Pathengay A, Mithal K, Jalali S, Mathai A, Pappuru RR, et al. Endophthalmitis after open globe injuries: changes in microbiological spectrum and isolate susceptibility patterns over 14  years. J Ophthalmic Inflamm Infect. 2014;4(1):5. • Long C, Liu B, Xu C, Jing Y, Yuan Z, Lin X.  Causative organisms of post—traumatic endophthalmitis: a 20-year retrospective study. BMC Ophthalmol. 2014;14(1):34. • Parke DW, third, Flynn HW, Jr., Fisher YL. Management of intraocular foreign bodies: a clinical flight plan. Can J Ophthalmol. 2013;48(1):8–12. • Parke third DW, Pathengay A, Flynn HW Jr., Albini T, Schwartz SG. Risk factors for endophthalmitis and retinal detachment with retained intraocular foreign bodies. J Ophthalmol 2012;2012:758526. • Pathengay A, Miller DM, Flynn HW, Jr., Dubovy SR.  Curvularia endophthalmitis following open globe injuries. Arch Ophthalmol. 2012;130(5):652–4. • Ahmed Y, Schimel AM, Pathengay A, Colyer MH, Flynn HW, Jr. Endophthalmitis following open-globe injuries. Eye (Lond). 2012;26(2):212–7. • Lieb DF, Scott IU, Flynn HW, Jr., Miller D, Feuer WJ. Open globe injuries with positive intraocular cultures: factors influencing final visual acuity outcomes. Ophthalmology. 2003;110(8):1560–6. • Foster RE, Martinez JA, Murray TG, Rubsamen PE, Flynn HW, Jr., Forster RK.  Useful visual outcomes after treatment of Bacillus cereus endophthalmitis. Ophthalmology. 1996;103(3):390–7.

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Endophthalmitis Associated with Intravitreal Injection Endophthalmitis can occur following intravitreal anti-VEGF therapy for the treatment of age-related macular degeneration (AMD), diabetic macular edema (DME), or retinal vascular diseases. Among possible mechanisms are contamination of the vial, contamination of the needle or syringe, and inadequate preparation of the ocular surface prior to intravitreal injection.

Incidence Reported rates are 0.016–0.08% per injection for anti-­ vascular endothelial growth factor (VEGF) agents. Many patients receive a series of injections, so the per-patient rate is generally higher. Probably the rates are higher for intravitreal corticosteroids. *The per-injection rate of clinically suspected endophthalmitis incidence rate after anti-VEGF injections at the Bascom Palmer Eye Institute (BPEI) between January 1, 2018, and December 31, 2020, was 0.014% (10/71,858) and of culture positive was 0.008 (6/71,858). The incidence rates of post-­ intravitreal injection endophthalmitis among the three intravitreal anti-VEGF agents were: bevacizumab 0%, ranibizumab 0.019%, aflibercept 0.022%, and brolucizumab 0%. Treatment outcomes were variable but were generally better in culture-­ negative cases. In 2021, Reyes-Capo et  al. reported the rates of endophthalmitis per intravitreal injection of anti-vascular endothelial growth factor inhibitors at Bascom Palmer Eye Institute as well as the rates of previous studies (Table 4.3). The rates of endophthalmitis following intravitreal anti-­ vascular endothelial growth factor inhibitors remain low and similar to prior reports.

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Table 4.3 Incidence of endophthalmitis after intravitreal anti-­ VEGF injections in selected studies Rate of infection per Study Year Medication injection n (%) Reyes-capo 2021 A, B, Br, R 10/ 71,858 (0.014%) et al Yannuzzi et al.

2018

A, B, P, R

24/183,898 (0.013%)

Gregori et al

2017

A, B, P, R

20/121,285 (0.016%)

Xu et al

2018

A, B, R

40/258,357 (0.016%)

Moshfeghi et al

2011

B, R

12/60,332 (0.020%)

Fintak et al

2008

B, R

6/26,905 (0.022%)

Rayess et al

2019

A, B, R

56/168,247 (0.033%)

Klein et al

2009

B, P, R

15/30,736 (0.049%)

Shah et al

2011

B, R

23/27,736 (0.083%)

CATT

2015

B, R

11/18,509 (0.06%)

Fileta et al

2014

A, B, P, R

197/350,535 (0.056%)

Reibaldi et al

2018

A, B, P, R

244/639,391 (0.038%)

Key: A  =  aflibercept, B  =  bevacizumab, Br  =  brolucizumab, P = pegatanib, R = ranibizumab

 igns/Symptoms of Endophthalmitis after S Intravitreal Injections The patient presents with vision loss, pain, redness, and discharge generally within a few days of the intravitreal injection. Slit-lamp examination may show lid edema, discharge, conjunctival congestion, chemosis, corneal edema, hypopyon, fibrinous infiltrates in the anterior chamber, or vitreous (Fig.  4.13). However, it is important to differentiate post-­ intravitreal injection endophthalmitis from noninfectious post-injection inflammation (Table  4.4 and also see section “Pseudoendophthalmitis with intravitreal anti-VEGFs”).

Endophthalmitis Associated with Intravitreal Injection

a

b

c

d

85

Figure 4.13 Follow-up course post-TAP and injection for endophthalmitis. (a) Post-intravitreal injection endophthalmitis with conjunctival congestion, chemosis, hypopyon, fibrinous membrane in anterior chamber, and hand motions (HM) vision. (b and c) Day 1 after intravitreal injection of antibiotics showing retracting fibrinous membrane in the anterior chamber. (d) At 6-month follow-up inflammation and infection resolved. The visual acuity improved to 20/50

Risk Factors • Nonuse of povidone–iodine. • (Possible) exposure to oral flora during injection. • Topical antibiotics do not reduce rates of endophthalmitis associated with intravitreal injection.

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Table 4.4  Differentiating features between post-intravitreal injection endophthalmitis and noninfectious post-injection inflammation (pseudoendophthalmitis) More common features Infectious Noninfectious Pain Moderate to Usually mild severe pain pain Vision loss

Severe

Mild to moderate

Fibrin

Always present

Rare

Hypopyon

Very common

Rare

Vitreous opacity

Usually prominent

Usually mild

Conjunctival vascular congestion

Very common

Often absent

Microbial Isolates Common causative organisms include: • Staphylococcus species. • Streptococcus species (Fig. 4.14).

I nitial Management of Endophthalmitis Associated with Intravitreal Injection The treatment includes vitreous TAP or pars plana vitrectomy with intravitreal antimicrobials.

 ollow-Up Management in Patients F with Endophthalmitis Associated with Intravitreal Injection First Morning after Initial Treatment • Topical antimicrobials. –– Consider fortified topical antibiotics if available:

Endophthalmitis Associated with Intravitreal Injection

a

87

b

Figure 4.14  Post-intravitreal injection endophthalmitis. An 80-yearold male patient with neovascular age-related macular degeneration (AMD) presented 2  days after intravitreal ranibizumab injection with sudden painful decrease in vision. (a) The patient presented with conjunctival congestion, corneal edema, hypopyon, fibrinous reaction in the anterior chamber, hazy view of the posterior segment, and hand motions (HM) vision. The patient underwent vitreous TAP and intraocular injection. (b) At 3-month follow-up, the inflammation and infection persisted and visual acuity deteriorated to no light perception (NLP). The patient underwent evisceration and the specimen culture was positive for Streptococcus intermedius

Vancomycin 25 mg/mL hourly during the day. Ceftazidime 50 mg/mL hourly during the day. –– Alternatively, commercially available topical antibiotics are used. –– For fungal cases, topical amphotericin B has poor intraocular penetration and is not used. • Topical steroids four times daily (not for suspected/proven fungal infection). • Topical cycloplegics daily. *Topical antibiotics hourly may result in corneal epithelial toxicity as a result of preservatives in commercial preparations. Topical medications are generally not used during night hours while sleeping. Subconjunctival antibiotics at the time of initial treatment provide adequate ocular surface medication for nighttime coverage.

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Two to Three Days after Initial Treatment • If clinically improving—Continue to observe and taper topical steroids over several weeks. • If clinically worsening: –– Consider repeat intraocular cultures and/or reinjection of intraocular antibiotics (and possibly intraocular steroids in acute-onset bacterial cases). –– Consider PPV if not performed initially. • In most circumstances, decisions about reinjecting antibiotics, performing PPV, or changing antibiotics are based on clinical parameters rather than culture results. In a situation where the clinical appearance is improving but the intraocular cultures report resistance to the initially used antibiotics, it may be appropriate to continue treatment as is. References: Intravitreal Injection Guidelines and Endophthalmitis Associated with Intravitreal Injections • Aiello LP, Brucker AJ, Chang S, Cunningham ET, Jr., D’Amico DJ, Flynn HW, Jr., et al. Evolving guidelines for intravitreous injections. Retina. 2004;24(5 Suppl):S3–19. • Avery RL, Bakri SJ, Blumenkranz MS, Brucker AJ, Cunningham ET, Jr., D’Amico DJ, et al. Intravitreal injection technique and monitoring: updated guidelines of an expert panel. Retina. 2014;34(Suppl 12):S1-S18. • Patel SN, Cai LZ, Mahmoudzadeh R, et al. Endophthalmitis after intravitreal anti-vascular endothelial growth factor injections: outcomes of eyes managed without microbiologic cultures. Am J Ophthalmol 2022;235:1–6. • Reyes-Capo DP, Yannuzzi NA, Smiddy WE, Flynn HW, Jr. Trends in Endophthalmitis Associated With Intravitreal Injection of Anti-VEGF Agentsat a Tertiary Referral Center. Ophthalmic surgery, lasers & imaging retina. 2021;52(6):319–326. • Patel SN, Storey PP, Pancholy M, et al. Changes in management based on vitreous culture in endophthalmitis after

Endophthalmitis Associated with Intravitreal Injection

•

•

•

• •

•

• •

•

89

intravitreal anti-vascular endothelial growth factor injection. Am J Ophthalmol 2019;207:224–31. Yannuzzi NA, Gregori NZ, Rosenfeld PJ, Relhan N, Patel NA, Si N, Miller D, Dubovy SR, Smiddy WE, Schwartz SG, and Flynn HW Jr., Endophthalmitis Associated with Intravitreal Injections of Anti- VEGF Agents at a Tertiary Referral Center: In-House and Referred Cases. Ophthalmic Surg Lasers Retina. 2018; 49; 313–319. PMID: 29772041. Goldberg RA, Flynn HW, Jr., Isom RF, Miller D, Gonzalez S.  An outbreak of streptococcus endophthalmitis after intravitreal injection of bevacizumab. Am J Ophthalmol. 2012;153(2):204–8 e1. Goldberg RA, Flynn HW, Jr., Miller D, Gonzalez S, Isom RF. Streptococcus endophthalmitis outbreak after intravitreal injection of bevacizumab: one—year outcomes and investigative results. Ophthalmology. 2013;120(7):1448–53. Gonzalez S, Rosenfeld PJ, Stewart MW, Brown J, Murphy SP. Avastin doesn’t blind people, people blind people. Am J Ophthalmol. 2012;153(2):196–203 e1. Gregori NZ, Flynn HW, Jr., Schwartz SG, Rosenfeld PJ, Vaziri K, Moshfeghi AA, et  al. Current Infectious Endophthalmitis Rates After Intravitreal Injections of Anti—Vascular Endothelial Growth Factor Agents and Outcomes of Treatment. Ophthalmic Surg Lasers Imaging Retina. 2015;46(6):643–8. Hahn P, Chung MM, Flynn HW, Jr., Huang SS, Kim JE, Mahmoud TH, et  al. Postmarketing analysis of aflibercept—related sterile intraocular inflammation. JAMA Ophthalmol. 2015;133(4):421–6. Hahn P, Kim JE, Stinnett S, Chung MM, Dugel PU, Flynn HW, Jr., et  al. Aflibercept—related sterile inflammation. Ophthalmology. 2013;120(5):1100–101 e1–5. Matthews JL, Dubovy SR, Goldberg RA, Flynn HW, Jr. Histopathology of streptococcus mitis/oralis endophthalmitis after intravitreal injection with bevacizumab: a report of 7 patients. Ophthalmology. 2014;121(3):702–8. McCannel CA.  Meta—analysis of endophthalmitis after intravitreal injection of anti—vascular endothelial growth

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•

•

•

• •

• • • •

•

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factor agents: causative organisms and possible prevention strategies. Retina. 2011;31(4):654–61. Moshfeghi AA, Rosenfeld PJ, Flynn HW, Jr., Schwartz SG, Davis JL, Murray TG, et al. Endophthalmitis after intravitreal vascular [corrected] endothelial growth factor antagonists: a six—year experience at a university referral center. Retina. 2011;31(4):662–8. Rayess N, Rahimy E, Storey P, Shah CP, Wolfe JD, Chen E, et al. Postinjection endophthalmitis rates and characteristics following intravitreal bevacizumab, ranibizumab, and aflibercept. Am J Ophthalmol. 2016;165:88–93. Roth DB, Chieh J, Spirn MJ, Green SN, Yarian DL, Chaudhry NA. Noninfectious endophthalmitis associated with intravitreal triamcinolone injection. Arch Ophthalmol. 2003;121(9):1279–82. Roth DB, Flynn HW, Jr. Distinguishing between infectious and noninfectious endophthalmitis after intravitreal triamcinolone injection. Am J Ophthalmol. 2008;146(3):346–7. Schimel AM, Scott IU, Flynn HW, Jr. Endophthalmitis after intravitreal injections: should the use of face masks be the standard of care? Arch Ophthalmol. 2011;129(12):1607–9. Schwartz SG, Flynn HW, Jr. Endophthalmitis Associated with Intravitreal Anti—Vascular Endothelial Growth Factor Injections. Curr Ophthalmol Rep. 2014;2(1):1–5. Scott IU, Flynn HW, Jr. Reducing the risk of endophthalmitis following intravitreal injections. Retina. 2007;27(1):10–2. Shienbaum G, Flynn HW, Jr. Compounding bevacizumab for intravitreal injection: does USP always apply? Retina. 2013;33(9):1733–4. Tabandeh H, Boscia F, Sborgia A, Ciraci L, Dayani P, Mariotti C, et al. Endophthalmitis associated with intravitreal injections: office—based setting and operating room setting. Retina. 2014;34(1):18–23. Wykoff CC, Flynn HW, Jr. Endophthalmitis after intravitreal injection: prevention and management. Retina. 2011;31(4):633–5.

Additional Discussion Points

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• Wykoff CC, Flynn HW, Jr., Han DP. Allergy to povidone— iodine and cephalosporins: the clinical dilemma in ophthalmic use. Am J Ophthalmol. 2011;151(1):4–6. • Wykoff CC, Flynn HW, Jr., Rosenfeld PJ. Prophylaxis for endophthalmitis following intravitreal injection: antisepsis and antibiotics. Am J Ophthalmol. 2011;152(5):717–9 e2. • Lytvynchuk L, Sergienko A, Savytska I, Albert R, Glittenberg C, Binder S, Petrovski G.  Comparative cyto-­ histological study of needle tip aspirates and entry sites after intravitreal injection using different needle types. PLoS One. 2017 Jul 10;12(7):e0174467. • Schwartz SG, Flynn HW Jr, Smiddy WE. Infectious endophthalmitis vs noninfectious “pseudohypopyon” after intravitreal triamcinolone acetonide. J Vitreoret Dis 2023;7(2):178–81.

Additional Discussion Points Vitreous TAP Versus AC TAP/Paracentesis The rates of positive cultures from a vitreous TAP are higher than from anterior chamber (AC) paracentesis. The EVS reported positive microbiological culture results in 69% of vitreous TAP versus 27% of aqueous fluid specimens. Early identification of infection agents (real-time PCR) and its susceptibility to antibiotics can improve the efficiency of therapeutic approaches. References • Barza M, Pavan PR, Doft BH, Wisniewski SR, Wilson LA, Han DP, et  al. Evaluation of microbiological diagnostic techniques in postoperative endophthalmitis in the Endophthalmitis Vitrectomy study. Arch Ophthalmol. 1997;115(9):1142–1150. • Sjoholm-Gomez de Liano C, Soberon-Ventura VF, Salcedo-­ Villanueva G, Santos-Palacios A, Guerrero-­ Naranjo JL, Fromow-Guerra J, et al. Sensitivity, specificity

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and predictive values of anterior chamber TAP in cases of bacterial endophthalmitis. Eye Vis (Lond). 2017 Jul 11;4:18. PMID: 28706959. • Chiquet C, Bron AM, Lundström M, Maurin M.  Acute postoperative endophthalmitis: Microbiology from the laboratory to the bedside. Surv Ophthalmol. 2022 Jul 14:S0039–6257(22)00089–3. doi: https://doi.org/10.1016/j. survophthal.2022.07.001.

Controversies in Care In the management of endophthalmitis, vitreous TAP prior to antibiotic injection is a common standard practice. In most of the cases, antibiotics with a wide spectrum of activity are used and subsequently tailored per the microbiology report. The culture growth guides the management of endophthalmitis in cases of unusual and resistant causative organisms. In peripheral settings and satellite offices, it is not always possible to have consistent access to microbiology laboratories where the vitreous specimens can be handled effectively and efficiently. In such situations, it is not advisable to delay the antibiotic injections. The surgeon may use pediatric blood and chocolate agar bottles to inoculate whatever smallest amount of vitreous sample is obtained. Also, important is to be aware of the case scenario where the surgeon may encounter dry vitreous TAP and is then bound to proceed without obtaining the vitreous tap. In some patients, prompt injection of two antibiotics with coverage of both Gram-positive and Gramnegative organisms is a reasonable strategy. References • Flynn HW Jr. MD, and Garg S, MD. CONTROVERSIES IN CARE: The Value of Vitreous and Aqueous Sampling for Culture in Endophthalmitis Should there be a change in culture? (compiled by By Michael Colucciello, MD) available at https://www.retinalphysician.com/issues/2021/ jan-­feb-­2021/controversies-­in-­care-­the-­value-­of-­vitreous-­ and-­aq#.YtlhHWpnBX8.gmail

Additional Discussion Points

93

• Patel SN, Storey PP, Levin H, et al. Endophthalmitis after cataract surgery: changes in management based on microbiologic cultures. Ophthalmol Retina. 2020;S2468-S6530(20)30256–6. doi:https://doi. org/10.1016/j.oret.2020.06.028 • Patel SN, Storey PP, Pancholy M, et al. Changes in management based on vitreous culture in endophthalmitis after intravitreal anti-vascular endothelial growth factor injection. Am J Ophthalmol. 2019;207:224–231. doi:https://doi. org/10.1016/j.ajo.2019.06.008

 ystemic Immunosuppressives and the Risk S of Post-Cataract Surgery Endophthalmitis The ocular and general health of patients with cataracts remains an important factor to impact surgical outcomes directly or indirectly. In a retrospective case control study 57/22091 patients developed post-cataract surgery endophthalmitis, and patients on immunosuppressive treatment (for ocular or systemic disorders) were at higher risk of developing endophthalmitis. References • Rahmani S, Eliott D.  Postoperative Endophthalmitis: A Review of Risk Factors, Prophylaxis, Incidence, Microbiology, Treatment, and Outcomes. Semin Ophthalmol. 2018;33(1):95–101.PMID: 29172849. • Montan PG, Koranyi G, Setterquist HE, Stridh A, Philipson BT, Wiklund K.  Endophthalmitis after cataract surgery: risk factors relating to technique and events of the operation and patient history: a retrospective case-control study. Ophthalmology. 1998 Dec;105(12):2171–7. PMID: 9855143. • Kunkler AL, Sengillo JD, Al-Khersan H, et  al. Acute-­ Onset Postoperative Endophthalmitis After Cataract Surgery Performed by Resident and Attending Physicians at a University Teaching Hospital. Journal of Cataract & Refractive Surgery. 2022:10.1097.

Chapter 5 Delayed-Onset (Chronic) Endophthalmitis and Miscellaneous Categories: Incidence Rates, Signs/Symptoms, Risk Factors, Microbiology, Treatment, and Follow-Up  elayed-Onset (Chronic) Post-Operative D Endophthalmitis Following Cataract Surgery The Endophthalmitis Vitrectomy Study (EVS) defined acuteonset endophthalmitis as occurring within six weeks of cataract surgery or secondary intraocular lens implantation. The terms “delayed-onset” and “chronic” endophthalmitis are frequently used interchangeably but they refer to distinct clinical situations. Chronic endophthalmitis may occur due to the introduction of low virulence infectious organisms at the time of intraocular procedures. This slowly progressive chronic endophthalmitis may become clinically apparent months or years after the procedure. The term localized endophthalmitis has also been used. It describes the source of the inflammation -usually the capsular bag, which can produce recurrent endophthalmitis with granulomatous response even after a vitrectomy was performed. © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 H. W. Flynn Jr. et al., Endophthalmitis in Clinical Practice, In Clinical Practice, https://doi.org/10.1007/978-3-031-35184-6_5

95

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By contrast, delayed-onset post-operative endophthalmitis results from a weakness in the ocular surface allowing entry of organisms. Examples of delayed-onset endophthalmitis include infection through glaucoma filtering blebs, exposed tubes from glaucoma drainage devices, corneal sutures, or fistulas from previous trauma. However, these terms are used interchangeably in this chapter.

Incidence Incidence rates are very low. The rates vary depending upon the predisposing risk factors (e.g., thin bleb, inferior bleb, and multiple corneal sutures).

Signs/Symptoms In chronic post-operative endophthalmitis, the patient presents with persistent inflammation and a mild to moderate decrease in vision. Slit-lamp examination may show low-­ grade inflammation not responding to topical antibiotics or steroids, posterior capsular plaque, and/or cells in the vitreous (Fig. 5.1). Additionally, multiple brown or white precipitates on the anterior or/and posterior intraocular lens surface may be seen. With delayed-onset endophthalmitis, patients may present with acute-onset of symptoms with red eye and all features hallmark of acute onset endophthalmitis.

Risk Factors • Pre-operative: –– –– –– ––

Diabetes mellitus. Older age. Blepharitis. Use of corticosteroids.

Delayed-Onset (Chronic) Post-Operative…

a

c

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b

d

Figure 5.1  Delayed-onset (chronic) post-operative endophthalmitis. A 70-year-old male patient with delayed-onset post-operative endophthalmitis following cataract surgery. (a) The patient presented with low-grade inflammation in the anterior chamber, capsular plaque, and 20/100 visual acuity. (b and c) Inflammation was recurrent with persisting capsular plaque and low-grade inflammation. The patient underwent pars plana vitrectomy with removal of the intraocular lens and capsular bag, plus intravitreal antibiotics. The vitreous culture was positive for Acremonium species. (d) At 1-year follow-up, the patient regained the best corrected visual acuity of 20/40 with a resolution of inflammation

–– Prosthesis in fellow eye. –– Active systemic infection. • Intra-operative: –– Posterior capsular rupture. –– Contamination of intraocular lens and ophthalmic viscoelastic devices.

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Microbial Isolates Common causative organisms include: • Cutibacterium (previously Propionibacterium) acnes (Figs. 5.2 and 5.3). • Coagulase-negative Staphylococci. • Diphtheroid species. • Fungi (Fig. 5.4). • Rare: Actinomyces, Nocardia, Achromobacter, Cephalosporium, Acremonium, Paecilomyces, Ochrobactrum, and Aspergillus.

Figure 5.2  Delayed-onset (chronic) post-operative endophthalmitis. A 69-year-old female patient with delayed-onset postoperative endophthalmitis following cataract surgery. The patient presented with a gradual painless decrease in vision, conjunctival congestion, prominent granulomatous keratic precipitates, and 20/400 visual acuity. Patient underwent pars plana vitrectomy and intraocular antibiotics injection in the capsular bag behind the intraocular lens. The vitreous culture was positive for Cutibacterium acnes

Delayed-Onset (Chronic) Post-Operative…

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Figure 5.3  Delayed-onset (chronic) post-operative endophthalmitis. A 69-year-old female patient with delayed-onset post-operative endophthalmitis following cataract surgery. (a) The patient presented with gradual painless decrease in vision, conjunctival congestion, mild corneal edema, capsular plaque, and hand motions (HM) visual acuity. Patient underwent pars plana vitrectomy and intraocular antibiotics injection in the capsular bag behind the intraocular lens. The vitreous culture was positive for Cutibacterium acnes. (b) At 6-month follow-up, the patient regained best corrected visual acuity of 20/30 with resolution of inflammation

I nitial Management of Delayed-Onset Endophthalmitis In patients with delayed-onset postoperative endophthalmitis, the microorganisms are usually sequestered in the capsular plaque. Initial treatment of mild inflammatory reaction may include topical fortified antibiotics and steroids followed by intravitreal injection of vancomycin and aminoglycoside with dexamethasone. It has been proposed to perform an antibiotic injection through anterior chamber directly into the capsular bag, which can increase the chances of recovery and retain the capsule/IOL complex. In cases with moderate and severe

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Figure 5.4  Delayed-onset (chronic) postoperative endophthalmitis. A 72-year-old male patient with delayed-onset postoperative endophthalmitis following cataract surgery with gradual painless decrease in vision, conjunctival congestion, mild corneal edema, and creamy-­ white-­colored plaques over intraocular lens. The vitreous culture was positive for Candida parapsilosis

chronic endophthalmitis treatment may involve removal of the capsular plaque along with IOL explantation in addition to pars plana vitrectomy and injection of intravitreal antibiotics. If the situation allows it is recommended to perform en bloc capsulotomy in order to acquire the material for cultivation.

 ollow-Up Management in Patients with Delayed-­ F Onset Post-Operative Endophthalmitis First Morning after Initial Treatment • Topical antimicrobials. –– Consider fortified topical antibiotics if available. Vancomycin 25 mg/mL hourly during the day. Ceftazidime 50 mg/mL hourly during the day.

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–– Alternatively, commercially available topical antibiotics are used. –– For fungal cases, topical amphotericin B has poor intraocular penetration and is not used. • Topical steroids four times daily (not for suspected/proven fungal infection). • Topical cycloplegics daily. *Topical antibiotics hourly may result in corneal epithelial toxicity as a result of preservatives in commercial preparations. Topical medications are generally not used during night hours while sleeping. Subconjunctival antibiotics at the time of initial treatment provide adequate ocular surface medication for nighttime coverage.

Two to Three Days after Initial Treatment • If clinically improving—Continue to observe and taper topical steroids over several weeks. • If clinically worsening: –– Consider repeat intraocular cultures and/or reinjection of intraocular antibiotics (and possibly intraocular steroids in acute-onset bacterial cases). –– Consider PPV if not performed initially. Change antibiotics if indicated by initial culture results. References: Delayed-Onset Endophthalmitis

(Chronic)

Postoperative

• Fowler BJ, Miller D, Yan X, Yannuzzi NA, Flynn HW, Jr. Postoperative Endophthalmitis Caused by Cutibacterium (Formerly Propionibacterium) acnes: Case Series and Review. Case reports in ophthalmology. 2021;12(1):1–10. • Clark WL, Kaiser PK, Flynn HW, Belfort A, Miller D, Meisler DM.  Treatment strategies and visual acuity outcomes in chronic postoperative Propionibacterium acnes endophthalmitis11 The authors have no proprietary interest in any products or procedure described in this article. Ophthalmology. 1999;106(9):1665–70.

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• Fox GM, Joondeph BC, Flynn HW, Jr., Pflugfelder SC, Roussel TJ. Delayed-onset pseudophakic endophthalmitis. Am J Ophthalmol. 1991;111(2):163–73. • Javey G, Albini TA, Flynn HW, Jr. Resolution of pigmented keratic precipitates following treatment of pseudophakic endophthalmitis caused by Propionibacterium acnes. Ophthalmic Surg Lasers Imaging. 2010:1–3. • Jonas JB.  Postoperative Proprionibacterium acnes endophthalmitis. Ophthalmology. 2001;108(4):633. • Shirodkar AR, Pathengay A, Flynn HW, Jr., Albini TA, Berrocal AM, Davis JL, et al. Delayed- versus acute-onset endophthalmitis after cataract surgery. Am J Ophthalmol. 2012;153(3):391–8 e2. • Thach AB, Das A, Lopez PF. En bloc capsulectomy in the diagnosis and treatment of refractory, chronic, recurrent pseudophakic endophthalmitis. Ophthalmic Surg. 1994 Jun;25(6):361–4. PMID: 8090414. • Owens SL, Lam S, Tessler HH, Deutsch TA.  Preliminary study of a new intraocular method in the diagnosis and treatment of Propionibacterium acnes endophthalmitis following cataract extraction. Ophthalmic Surg. 1993 Apr;24(4):268–72. PMID: 8321509.

 onjunctival Filtering Bleb: Associated C Infection and Endophthalmitis Infection of the conjunctival filtering bleb or associated endophthalmitis may occur months or years following trabeculectomy surgery (Figs. 5.5 and 5.6). However, the presentation of endophthalmitis may be of abrupt and sudden onset.

Incidence of Bleb-Associated Endophthalmitis Reported 5-year cumulative incidence: 0.45–1.3%.

Conjunctival Filtering Bleb: Associated Infection…

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b

c

d

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Figure 5.5 Bleb-associated infections without endophthalmitis (Blebitis). Follow-up course of a patient (87-year-old female) with bleb-associated infection following trabeculectomy with mitomycin C. (a and b) Conjunctival congestion, mild corneal edema, and blebitis on the day of presentation. (c and d) 1 year after bleb revision and subconjunctival antibiotics, blebitis resolved. At 2-year follow­up, the visual acuity was 20/60

Signs/Symptoms The patient may present with lid swelling, pain, redness, discharge, a marked decrease in vision, etc. Slit-lamp examination may show lid swelling, conjunctival congestion, blebitis, conjunctival discharge, corneal edema, hypopyon, infiltrates/ fibrin membrane in the anterior chamber, loss of red reflex from the retina, and infiltrates in the vitreous cavity.

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a

b

Figure 5.6 Bleb-associated endophthalmitis. A 73-year-old male patient with bleb-associated endophthalmitis following trabeculectomy. (a) The patient presented with conjunctival congestion, blebitis, mild corneal edema, hypopyon, fibrinous membrane in the anterior chamber and pupillary area, hazy view to the posterior segment, and hand motions (HM) visual acuity. The patient underwent vitreous TAP and intraocular antibiotics. The vitreous culture was positive for coagulase-negative Staphylococcus. (b) At 6-month follow-­up, the patient regained best corrected visual acuity of 20/400 with resolution of endophthalmitis

Risk Factors • Intra-operative: –– Inferior trabeculectomy. –– Thin avascular bleb. • Post-operative: –– Blebitis. –– Late-onset bleb leak.

Microbial Isolates Common causative organisms include: • Streptococcus species. • Haemophilus influenzae. • Staphylococcus species.

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I nitial Management of Conjunctival Filtering Bleb-­ Associated Endophthalmitis The treatment of conjunctival filtering bleb-associated infection or endophthalmitis may include subconjunctival antibiotics in addition to the vitreous tap/pars plana vitrectomy and intravitreal antibiotics injection. An infected filtering bleb with leakage may be rinsed out with povidone-iodine and antibiotic solution, and closed (use of pericardium if needed) to decrease the risks for reinfection and intraocular hypotony.

 ollow-Up Management in Patients F with Conjunctival Filtering Bleb-Associated Infection or Endophthalmitis First Morning after Initial Treatment • Topical antimicrobials. –– Consider fortified topical antibiotics if available: Vancomycin 25 mg/mL hourly during the day. Ceftazidime 50 mg/mL hourly during the day. –– Alternatively, commercially available topical antibiotics are used. –– For fungal cases, topical amphotericin B has poor intraocular penetration and is not used. • Topical steroids four times daily (not for suspected/proven fungal infection). • Topical cycloplegics daily. *Topical antibiotics hourly may result in corneal epithelial toxicity as a result of preservatives in commercial preparations. Topical medications are generally not used during night hours while sleeping. Subconjunctival antibiotics at the time of initial treatment provide adequate ocular surface medication for nighttime coverage.

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Two to Three Days after Initial Treatment • If clinically improving (Fig. 5.7)—Continue to observe and taper topical steroids over several weeks. • If clinically worsening: –– Consider repeat intraocular cultures and/or reinjection of intraocular antibiotics (and possibly intraocular steroids in acute-onset bacterial cases). –– Consider PPV if not performed initially. Change antibiotics if indicated by initial culture results.

a

b

c

d

Figure 5.7  Bleb-associated endophthalmitis. A 72-year-old female patient with bleb-associated endophthalmitis following trabeculectomy. (a) At presentation, the patient had conjunctival congestion, blebitis, corneal edema, hypopyon, cataract, hazy view to the posterior segment, and 5/200 visual acuity. (b and c) After pars plana vitrectomy intraocular antibiotics, the visual acuity improved to 20/400 with resolving inflammation and infection. The vitreous culture was positive for Moraxella species. (d) At 1-year follow-up, the patient regained best corrected visual acuity of 20/60 after subsequent cataract surgery

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References: Endophthalmitis Associated with Conjunctival Filtering Blebs • Islam YFK, Vanner EA, Khurshid SG, Flynn Jr. HW, Greenfield DS.  Comparison of Outcomes from Delayed Onset Bleb-related Endophthalmitis Treated with Pars Plana Vitrectomy versus Vitreous Biopsy. Journal of Glaucoma.2022. 10.1097. • Vaziri K, Kishor K, Schwartz SG, Maharaj AS, Moshfeghi DM, Moshfeghi AA, et  al. Incidence of bleb—associated endophthalmitis in the United States. Clin Ophthalmol. 2015;9:317–22. • Brillat—Zaratzian E, Bron A, Aptel F, Romanet JP, Cornut PL, Vandenesch F, et  al. FRIENDS Group: clinical and microbiological characteristics of post—filtering surgery endophthalmitis. Graefes Arch Clin Exp Ophthalmol. 2014;252(1):101–7. • Jacobs DJ, Pathengay A, Flynn HW, Jr., Leng T, Miller D, Shi W. Intravitreal dexamethasone in the management of delayed—onset bleb—associated endophthalmitis. Int J Inflam. 2012;503,912. • Jacobs DJ, Leng T, Flynn HW, Jr., Shi W, Miller D, Gedde SJ.  Delayed—onset bleb—associated endophthalmitis: presentation and outcome by culture result. Clin Ophthalmol. 2011;5:739–44. • Leng T, Miller D, Flynn HW, Jr., Jacobs DJ, Gedde SJ.  Delayed—onset bleb—associated endophthalmitis (1996–2008): causative organisms and visual acuity outcomes. Retina. 2011;31(2):344–52. • Scott IU, Cruz—Villegas V, Flynn HW, Jr., Miller D.  Delayed—onset, bleb—associated endophthalmitis caused by Lecythophora mutabilis. Am J Ophthalmol. 2004;137(3):583–5. • Song A, Scott IU, Flynn HW, Jr., Budenz DL. Delayed— onset bleb—associated endophthalmitis: clinical features and visual acuity outcomes. Ophthalmology. 2002;109(5):985–91. • Kangas TA, Greenfield DS, Flynn HW, Jr., Parrish RK, second, Palmberg P.  Delayed—onset endophthalmitis associated with conjunctival filtering blebs. Ophthalmology. 1997;104(5):746–52.

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Endophthalmitis Associated with Glaucoma Drainage Devices Glaucoma drainage device-associated endophthalmitis may occur months or years following glaucoma drainage device implantation (Fig.  5.8). However, the presentation of endophthalmitis may be of abrupt and sudden onset.

a

b

Figure 5.8  Glaucoma drainage device-associated endophthalmitis. A 66-year-old female patient with a history of prior ocular surgery (retinal detachment and glaucoma drainage implantation). (a) The patient presented with lid edema, exposed glaucoma drainage device beneath upper eyelid, conjunctival congestion, severe conjunctival chemosis, corneal edema, hypopyon, fibrinous reaction in the anterior chamber, hazy view to the posterior segment, and 2/200 visual acuity. The patient underwent removal of glaucoma drainage implant, hydrogel scleral buckle, and subconjunctival and intravitreal vancomycin. In addition, the patient was given oral fluoroquinolones (levofloxacin) and topical vancomycin. The cultures were negative (both intraocular and external). (b) At 1-year follow-up, the patient had resolution of endophthalmitis and best corrected visual acuity improved to 20/400

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Incidence Reported rates are approximately 1.7%, but rates are only estimates when considering a 5-year follow-up. Incidence rates most likely increase over time.

Signs/Symptoms The patient may present with lid swelling, pain, redness, discharge, a marked decrease in the vision, etc. Slit-lamp examination may show lid swelling, conjunctival congestion, exposed tube or implant or device, conjunctival discharge, corneal edema, hypopyon, infiltrates/fibrin membrane in the anterior chamber, loss of red reflex from the retina, and infiltrates in the vitreous cavity. In rare cases, infectious ­ agents can migrate through the filtering tubes into sub-tenon space and cause periocular inflammation.

Risk Factors • Intra-operative: Inferior placement. • Post-operative: Exposure of device (Fig. 5.9).

a

b

Figure 5.9  Glaucoma drainage device-associated endophthalmitis. Patient with exposed glaucoma drainage device leading to endophthalmitis (a, b)

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Microbiology Common causative organisms include: • Coagulase-negative Staphylococci. • Streptococcus species. • Staphylococcus species.

I nitial Management of Glaucoma Drainage Device-Associated Endophthalmitis The treatment of glaucoma drainage device-associated endophthalmitis may include removal of the exposed tube/ implant/device. When the tube is not obviously exposed then it may be initially retained. Vitreous TAP/pars plana vitrectomy and intravitreal antibiotics injection are performed based on clinical features and physician preference.

 ollow-Up Management in Patients F with Endophthalmitis Associated with Glaucoma Drainage Devices First Morning after Initial Treatment • Topical antimicrobials. –– Consider fortified topical antibiotics if available: Vancomycin 25 mg/mL hourly during the day. Ceftazidime 50 mg/mL hourly during the day. –– Alternatively, commercially available topical antibiotics are used. –– For fungal cases, topical amphotericin B has poor intraocular penetration and is not used. • Topical steroids four times daily (not for suspected/proven fungal infection). • Topical cycloplegics daily.

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*Topical antibiotics hourly may result in corneal epithelial toxicity as a result of preservatives in commercial preparations. Topical medications are generally not used during night hours while sleeping. Subconjunctival antibiotics at the time of initial treatment provide adequate ocular surface medication for nighttime coverage.

Two to Three Days after Initial Treatment • If clinically improving—Continue to observe and taper topical steroids over several weeks. • If clinically worsening: –– Consider repeat intraocular cultures and/or reinjection of intraocular antibiotics (and possibly intraocular steroids in acute-onset bacterial cases). –– Consider PPV if not performed initially. Change antibiotics if indicated by initial culture results. References: Endophthalmitis Associated with Glaucoma Drainage Device • Banitt MR, Feuer WJ, Schiffman JC, Parrish RK, 2nd. Adverse vitreoretinal outcomes of glaucoma drainage devices based on verified and unverified financial claims data. Ophthalmic Surg Lasers Imaging Retina. 2015;46(4):463–70. • Cherof AM, SooHoo JR, Kahook MY, Seibold LK.  Endophthalmitis with corneal infiltrate after EX— PRESS glaucoma drainage device implantation. J Glaucoma. 2016;25(3):e277–9. • Gedde SJ, Scott IU, Tabandeh H, Luu KK, Budenz DL, Greenfield DS, et al. Late endophthalmitis associated with glaucoma drainage implants. Ophthalmology. 2001;108(7):1323–7. • Levinson JD, Giangiacomo AL, Beck AD, Pruett PB, Superak HM, Lynn MJ, et al. Glaucoma drainage devices: risk of exposure and infection. Am J Ophthalmol. 2015;160(3):516–21 e2.

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• Mandalos A, Sung V. Glaucoma drainage device surgery in children and adults: a comparative study of outcomes and complications. Graefes Arch Clin Exp Ophthalmol. 2017;255(5):1003–11. • Medina CA, Butler MR, Deobhakta AA, Banitt MR, Albini TA, Smiddy WE, et al. Endophthalmitis associated with glaucoma drainage implants. Ophthalmic Surg Lasers Imaging Retina. 2016;47(6):563–9. • Stewart MW, Bolling JP, Bendel RE. Nocardia brasiliensis endophthalmitis in a patient with an exposed Ahmed glaucoma drainage implant. Ocul Immunol Inflamm. 2013;21(1):69–70.

Delayed-Onset Endophthalmitis Associated with Keratitis Endophthalmitis associated with keratitis may occur in chronic, large, deep corneal ulcers nonresponsive to topical antimicrobial therapy.

Incidence Generally considered uncommon.

Signs/Symptoms The patient presents with a chronic, large-sized corneal ulcer involving deeper layers of the cornea. These corneal infections are nonresponsive to antimicrobial therapy. Slit-lamp examination may show corneal ulcer, hypopyon, infiltrates in anterior chamber, or vitreous. These cases are difficult to manage. Corneal perforation is an important risk factor for endophthalmitis.

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 isk Factors for Keratitis that May Lead R to Endophthalmitis • • • • •

Topical steroid use. Contact lens misuse. Systemic immunosuppression. Diabetes mellitus. Descemetocele.

Microbial Isolates Common causative organisms include: • Pseudomonas aeruginosa. • Staphylococcus species. • Fungal species (Figs. 5.10 and 5.11).

a

b

Figure 5.10  Delayed-onset Keratitis-associated endophthalmitis. A 54-year-old woman with corneal ulcer with a history of soft contact lens use. (a) Slit-lamp examination revealed conjunctival congestion, corneal edema, corneal infiltrate, and anterior chamber inflammation with hypopyon. The culture from corneal infiltrates was positive for Fusarium species. The patient underwent penetrating keratoplasty, pars plana vitrectomy, lensectomy, and intravitreal voriconazole. (b) A 3-week follow-up exam showed a clear corneal graft with resolution of the hypopyon and anterior chamber inflammation

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b

c

Figure 5.11  A 62-year-old female presents with a delayed onset of Candida parapsilosis corneal wound infection and endophthalmitis in the left eye after cataract surgery 7  months prior, now with a visual acuity of 20/50. Slit lamp photography of the left eye demonstrates stromal infiltration along the clear cornea cataract incision temporally with 1 mm hypopyon (a). Images are obtained one week after pars plana vitrectomy, removal of intraocular lens and capsular bag, cornea patch graft, and intravitreal voriconazole and amphotericin B (b). After 3  years and removal of sutures, the patient remains free of recurrence with visual acuity of 20/25 with rigid permeable contact lenses (c)

I nitial Management of Endophthalmitis Associated with Keratitis In patients with endophthalmitis associated with keratitis, the corneal scraping or biopsy may reveal the causative organism and help in guiding the management. The management may involve therapeutic keratoplasty in addition to the pars plana vitrectomy and injection of intravitreal antibiotics. It is always better to perform keratoplasty in a quiet eye with no inflammation. In cases of recalcitrant and fulminant keratitis, the infected cornea can be removed as part of treatment of endophthalmitis.

 ollow-Up Management in Patients F with Endophthalmitis Associated with Keratitis First Morning after Initial Treatment • Topical antimicrobials. –– Consider fortified topical antibiotics if available:

The Role of Corneal Collagenous Cross-Linking…

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Vancomycin 25 mg/mL hourly during the day. Ceftazidime 50 mg/mL hourly during the day. –– Alternatively, commercially available topical antibiotics are used. –– For fungal cases, topical amphotericin B has poor intraocular penetration and is not used. • Topical steroids four times daily (not for suspected/proven fungal infection). • Topical cycloplegics daily. *Topical antibiotics hourly may result in corneal epithelial toxicity as a result of preservatives in commercial preparations. Topical medications are generally not used during night hours while sleeping. Subconjunctival antibiotics at the time of initial treatment provide adequate ocular surface medication for nighttime coverage.

Two to Three Days after Initial Treatment • If clinically improving—Continue to observe and taper topical steroids over several weeks. • If clinically worsening: –– Consider repeat intraocular cultures and/or reinjection of intraocular antibiotics (and possibly intraocular steroids in acute-onset bacterial cases). –– Consider PPV if not performed initially. Change antibiotics if indicated by initial culture results.

 he Role of Corneal Collagenous Cross-­ T Linking (CXL) in the Treatment of Keratitis and Corneal Ulcers Corneal collagenous cross-linking (CXL) can improve the condition of the cornea in cases of keratitis and corneal ulcers associated with endophthalmitis. Its efficacy is based on the

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properties of ultraviolet light and photoactivated riboflavin, which have antimicrobial action. Moreover, the corneal collagen due to newly formed intra- and inter-fibrillar bounds becomes more stable against destructive properties of active proteases. Enhanced stability and clarity of the cornea may improve visualization thereby the control of the inflammation in keratitis-associated endophthalmitis. It was reported that bacterial keratitis and ulcers showed beneficial results, while in cases of fungal and parasitic keratitis the efficacy of this treatment was lower. References: Endophthalmitis Associated with Keratitis • Scott IU, Flynn HW, Jr., Feuer W, et  al. Endophthalmitis associated with microbial keratitis. Ophthalmology. 1996;103(11):1864–1870. • Christopher KL, Hood CT, Mian SI, Ayres B. Endophthalmitis in Advanced Microbial Keratitis: Risk Factors and Examination Findings. Cornea. 2020;39(9):1096–1101. • Viruni N, Zhang AY, Wang X, Handa JT, Liu TYA.  Quantitative Ocular Ultrasound Findings in Microbial Keratitis-­ A ssociated Endophthalmitis. Ophthalmology Retina. 2020;4(6):560–567. • Tran KD, Yannuzzi NA, Si N, et al. Clinical features, antimicrobial susceptibilities, and treatment outcomes of patients with culture positive endophthalmitis after penetrating keratoplasty. American journal of ophthalmology case reports. 2018;9:62–67. • Palioura S, Relhan N, Leung E, et  al. Delayed-onset Candida parapsilosis cornea tunnel infection and endophthalmitis after cataract surgery: Histopathology and clinical course. American journal of ophthalmology case reports. 2018;11:109–114. • Zapp D, Loos D, Feucht N, et  al. Microbial keratitis-­ induced endophthalmitis: incidence, symptoms, therapy, visual prognosis and outcomes. BMC ophthalmology. 2018;18(1):112.

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• Henry CR, Flynn HW, Jr., Miller D, Forster RK, Alfonso EC. Infectious keratitis progressing to endophthalmitis: a 15-year study of microbiology, associated factors, and clinical outcomes. Ophthalmology. 2012;119(12):2443–2449. • Garg P, Das S, Roy A. Collagen Cross-linking for Microbial Keratitis. Middle East Afr J Ophthalmol. 2017 Jan-Mar;24(1):18–23. • Tabibian, D., Mazzotta, C. & Hafezi, F.  PACK-CXL: Corneal cross-linking in infectious keratitis. Eye and Vis 3, 11 (2016). • Price MO, Price FW Jr. Corneal cross-linking in the treatment of corneal ulcers. Curr Opin Ophthalmol. 2016 May;27(3):250–5.

 he Role of Photodynamic Therapy T in Advanced Keratitis with Threat of Endophthalmitis Photodynamic therapy (PDT) has been shown to play a role in treating cases of keratitis. In a pilot study, Naranjo et  al. demonstrated that rose bengal PDT was used successfully as an adjunct therapy for cases of infectious, progressive and severe keratitis, avoiding therapeutic keratoplasty. Rose bengal PDT was shown to inhibit the growth of organisms causing keratitis such as Methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa. After a mean of 47 months of follow-up, no complications secondary to riboflavin PDT treatment were observed (Fig. 5.12). References care • Naranjo A, Arboleda A, Martinez JD, et  al. Rose bengal photodynamic antimicrobial therapy for patients with progressive infectious keratitis: a pilot clinical study. American journal of ophthalmology. 2019;208:387–396. • Durkee H, Arboleda A, Aguilar MC, et  al. Rose bengal photodynamic antimicrobial therapy to inhibit

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b

Figure 5.12 (a) Endophthalmitis after refractive surgery procedures presenting with hazy Descemet graft, corneal edema, and hypopyon. (b) Two-year follow-up shows resolution of infection after initial management with pars plana vitrectomy with intraocular antibiotics

Pseudomonas aeruginosa keratitis isolates. Lasers in medical science. 2020;35(4):861–866. • Halili F, Arboleda A, Durkee H, et  al. Rose bengal–and riboflavin-mediated photodynamic therapy to inhibit methicillin-resistant Staphylococcus aureus keratitis isolates. American journal of ophthalmology. 2016;166:194–202. • Martinez JD, Arboleda A, Naranjo A, et  al. Long-term outcomes of riboflavin photodynamic antimicrobial therapy as a treatment for infectious keratitis. American journal of ophthalmology case reports. 2019;15:100481.

Endophthalmitis after Pterygium Removal Pterygium surgery is generally considered a safe procedure, and thus endophthalmitis secondary to pterygium removal is rare. The pathogenesis of endophthalmitis involves deep penetration of the sclera and/or corneal tissue during surgery. The use of intra- and post-operative mitomycin C during pterygium removal can contribute to endophthalmitis.

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References care • Au Eong KG, Tseng PS, Lim AS. Scleral necrosis and infection 15 years following pterygium excision. Singapore Med J. 1995;36(2):232–4. • Kassir MS.  Corneal perforation after excision of pterygium and use of 0.02% mitomycin eyedrops. J Fr Ophtalmol. 1999 Aug-Sep;22(7):776–9. • Kolomeyer AM, Bhagat N, Chu DS.  Haemophilus influenza endophthalmitis after pterygium surgery. Eye Contact Lens. 2013;39(2):186–7. • Peponis V, Rosenberg P, Chalkiadakis SE, Insler M, Amariotakis A. Fungal scleral keratitis and endophthalmitis following pterygium excision. Eur J Ophthalmol. 2009;19(3):478–80. • **endophthalmitis after pterygium Dr. Flynn AJO.

Endophthalmitis After Strabismus Surgery Endophthalmitis after strabismus surgery is extremely rare. The most common organisms include Staphylococcus species, Alpha hemolytic Streptococcus species, and Pneumococcal organisms. The most common surgeries involving endophthalmitis were rectus muscle recession surgeries. The cause of endophthalmitis in strabismus surgery is unclear and does not seem to favor perforating or penetrating injuries during surgery given its rarity. References care • Simonsz HJ, Rutar T, Kraft S, et al. Endophthalmitis after strabismus surgery: incidence and outcome in relation to age, operated eye muscle, surgical technique, scleral perforation and immune state. Acta ophthalmologica. 2021;99(1):37–51.

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• Zloto O, Mezer E, Ospina L, Stankovic B, Wygnanski-Jaffe T. Endophthalmitis Following Strabismus Surgery: IPOSC Global Study. Current eye research. 2017;42(12):1719–1724. • Villegas VM, Schwartz SG, McKeown CA, et  al. Long-­ term chorioretinal changes following strabismus surgery-­ possible occult needle penetration. Int J Ophthalmol 2020;13:518–519.

Endophthalmitis Post-Suture Removal Endophthalmitis post-suture removal is a rare and devastating cause of acute endophthalmitis. The majority of case reports and series have been described in pediatric populations, with Streptococcus pneumoniae being the most common isolate, although Haemophilis influenzae has also been described. Visual outcomes are poor despite prompt treatment. It is recommended that in order to reduce the source of endophthalmitis, application of 5% povidone-iodine solution before and after the procedure be done in addition to the use of sterile instruments. Some authors also recommend the use of prophylactic antibiotics for 1 week (Fig. 5.13). References care • Panchal B, Tyagi M, Pathengay A, et  al. Endophthalmitis following Suture Removal  - Clinical Outcomes and Microbiological Profile. Seminars in ophthalmology. 2019;34(2):115–123. • Yoder DM, Scott IU, Flynn HW, Jr., Miller D.  Endophthalmitis caused by Haemophilus influenzae. Ophthalmology. 2004;111(11):2023–2026. • Staropoli PC, Yannuzzi NA, Jacobs D, Flynn Jr. HW. Endophthalmitis after corneal suture removal. JCRS Online Case Reports. 2022;10(2):e00073.

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Figure 5.13  64-year-old male with a history of dehisced radial keratotomy incision and closed with nylon sutures. Suture was removed three months later and presented the next day with pain and decreased vision. (a) Slit-lamp photograph showing conjunctival injection, corneal edema, 2.4 mm hypopyon with anterior chamber fibrinous reaction, and (b) corneal infiltrate in the area of several removed

 ndophthalmitis after Blepharoplasty E (Fig. 5.14) There are two reports published on acute endophthalmitis following blepharoplasty. The cause is thought to be secondary to partial or full-thickness globe penetration occurring during the bilateral lower eyelid blepharoplasty or through needle anesthesia of the eyelid. These cases highlight the importance of meticulous attention to surgical technique. The use of cornea protectors may be beneficial in preventing complications from blepharoplasty surgery.

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Figure 5.14 Appearance at presentation of a 59-year-old female after blepharoplasty procedure. External (a) and slit lamp (b) examination of the patient demonstrating conjunctival injection with necrotizing scleritis and purulent discharge inferotemporally (a) as well as posterior synechiae with dense vitritis (b). (c) B-scan ultrasound of the OD demonstrating dense mesh-like vitritis with posterior membrane formation

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References care • Venincasa MJ, Shoji MK, Al-Khersan H, Maeng MM, Johnson TE, Flynn HWJ.  Acute Onset Endophthalmitis Following Bilateral Upper and Lower Eyelid Bleph­ aroplasty. Ophthalmic Plastic & Reconstructive Surgery. 9900:https://doi.org/10.1097/IOP.0000000000002176. • Tabatabaei S, Mohammad S, Mohammad Z, Dantism S.  Endophthalmitis after lower lid blepharoplasty: a rare complication. JOJ Ophthalmology 2017;4:001–002.

Chapter 6 Endogenous Endophthalmitis: Incidence Rates, Signs/ Symptoms, Risk Factors, Microbiology, Treatment, and Follow-Up Endogenous Fungal Endophthalmitis Endogenous fungal endophthalmitis is an uncommon disease caused by hematogenous spread of fungi. Endogenous endophthalmitis may occur even without obvious systemic infection. With increasing worldwide prevalence of intravenous drug use, endogenous endophthalmitis remains an important challenge for the ophthalmologists and physicians. The opioid crisis in the United States has been associated with an increase in the number of endogenous fungal and bacterial endophthalmitis cases.

Incidence Reported rates are 0.05–0.4% among patients with fungemia.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 H. W. Flynn Jr. et al., Endophthalmitis in Clinical Practice, In Clinical Practice, https://doi.org/10.1007/978-3-031-35184-6_6

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Signs/Symptoms The patient presents with mild to moderate decrease in the vision in one or both eyes in a delayed-onset manner. The patient may have a severe systemic illness or may appear healthy. Slit-lamp examination may show a relatively quiet anterior segment. However, the patient may have creamy-­ white fungal vitreous opacities, focal white raised retinal lesions, retinal infiltrates with retinal vasculitis, or subretinal abscess (Fig. 6.1).

Risk Factors • • • • •

Intravenous drug use Diabetes mellitus Immune compromise Major surgery on gastrointestinal tract Intravenous catheter

Malignancy • Longer hospital stays/prolonged intravenous antibiotic administration.

Microbial Isolates Common causative organisms include: • Candida species (USA, Europe) (Figs. 6.2, 6.3, 6.4, and 6.5) • Aspergillus species (USA, Europe) • Cryptococcus, Fusarium species, Sporothrix, Histoplasma, Blastomyces, Scedosporium spermum

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Figure 6.1 Endogenous fungal endophthalmitis. A 30-year-old female patient with a recent history of abdominal surgery presented with sudden blurring of vision and vitreous floaters. The fundus examination showed the presence of creamy-white opacities in the vitreous with hazy view of the retina. Candida was isolated from the vitrectomy specimen

I nitial Management of Endogenous Fungal Endophthalmitis Patients with suspected endogenous fungal endophthalmitis should undergo systemic investigations (including blood culture, urine culture, and infectious disease consultation). In patients with endogenous fungal endophthalmitis, systemic antifungals are started. Intravitreal antifungal injections are employed in visually threatening situations, and pars plana vitrectomy can also be considered.

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Figure 6.2  Endogenous endophthalmitis. (a) A 60-year-old female patient with breast cancer (on chemotherapy and radiotherapy) presented with sudden blurring of vision, vitreous floaters, and 20/400 visual acuity. The fundus examination showed a white patch of retinitis and overlying vitreous inflammation at the posterior pole. The patient underwent pars plana vitrectomy and intravitreal injection of amphotericin B.  The vitreous culture was positive for Candida species. (b) At 6-month follow-up, the inflammation and infection resolved with residual scarring at the posterior pole. The best corrected visual acuity improved to 20/50

 ollow-Up Management in Patients F with Endogenous Fungal Endophthalmitis  irst Morning After Initial Treatment (Based F on Clinical Examination) • Topical antimicrobials –– Topical natamycin. –– Topical amphotericin B has poor intraocular penetration and is not used. • Topical cycloplegics daily.

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Figure 6.3 Endogenous endophthalmitis. A 60-year-old female patient presented with sudden blurring of vision, vitreous floaters, and 20/400 visual acuity. (a) The fundus examination showed vitreous haze with a white patch of retinitis in the inferior retina. The patient underwent pars plana vitrectomy and intravitreal injection of amphotericin B.  The vitreous culture was positive for Candida species. (b) At 6-month follow-up, the inflammation and infection resolved with residual scarring. The best corrected visual acuity improved to 20/25

 wo to Three Days After Initial Treatment (Based T on Clinical Examination) • If clinically improving—Continue oral antifungal agents as indicated. • If clinically worsening: –– If not already done, consider intraocular cultures and/or injection (or reinjection) of intraocular antifungals. –– Consider PPV if not performed initially. References: Endogenous Fungal Endophthalmitis • Cunningham ET, Flynn HW, Relhan N, Zierhut M.  Endogenous Endophthalmitis. Ocular immunology and inflammation. 2018;26(4):491–495. • Kuriyan A, Schwartz SG, Davis JL, Flymm HW Jr. Endogenous Endophthalmitis Chap. 90. Sadda SR,

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Figure 6.4 Endogenous endophthalmitis. A 67-year-old female patient presented with sudden blurring of vision, vitreous floaters, and hand motions (HM) visual acuity. (a) The fundus examination showed a creamy-­white patch of retinitis at the posterior pole. The patient underwent pars plana vitrectomy and intravitreal injection of amphotericin B. The vitreous culture was positive for Aspergillus species. (b) At 1-year follow-up, the inflammation and infection resolved with residual scarring at the posterior pole. The best corrected visual acuity improved to 20/400

• •

• •

Schachat AP, Wilkinson CP, et al. Ryan’s Retina 7e. Elsevier Health Sciences; 2023. Relhan N, Schwartz SG, Flynn HW Jr. Endogenous fungal endophthalmitis – An increasing problem among intravenous drug users. JAMA 2017;318(8):741–2. Tirpack AR, Duker JS, Baumal CR.  An Outbreak of Endogenous Fungal Endophthalmitis Among Intravenous Drug Abusers in New England. JAMA Ophthalmol. 2017;135(6):534–40. Modjtahedi BS, Finn AV, Papakostas TD, Durand M, Husain D, Eliott D.  Intravenous Drug Use  – Associated Endophthalmitis. Ophthalmology Retina 2017;1:192–9. Adam CR, Sigler EJ.  Multimodal imaging findings in endogenous Aspergillus endophthalmitis. Retina. 2014;34(9):1914–5.

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Figure 6.5  Endogenous endophthalmitis. A 77-year-old male patient presented with sudden blurring of vision, vitreous floaters, and hand motions (HM) vision. (a) The fundus examination showed a yellow-­ white patch of retinitis and subretinal exudates at the posterior pole. The patient underwent pars plana vitrectomy and intravitreal injection of amphotericin B.  The vitreous culture was positive for Aspergillus species. (b) At 1-year follow-up, the inflammation and infection resolved with residual scarring at the posterior pole. The best corrected visual acuity improved to 20/400

• Sridhar J, Flynn HW, Jr., Kuriyan AE, Miller D, Albini T. Endogenous fungal endophthalmitis: risk factors, clinical features, and treatment outcomes in mold and yeast infections. J Ophthalmic Inflamm Infect. 2013;3(1):60. • Lingappan A, Wykoff CC, Albini TA, Miller D, Pathengay A, Davis JL, et  al. Endogenous fungal endophthalmitis: causative organisms, management strategies, and visual acuity outcomes. Am J Ophthalmol. 2012;153(1):162–6 e1. • Aziz HA, Berrocal AM, Sisk RA, Hartley K, Diaz— Barbosa M, Johnson RA, et al. Intraocular infections in the neonatal intensive care unit. Clin Ophthalmol. 2012;6:733–7. • Schiedler V, Scott I, Flynn H, Davis J, Benz M, Miller D. Culture—proven endogenous endophthalmitis: clinical

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features and visual acuity outcomes*1. Am J Ophthalmol. 2004;137(4):725–31. Flynn HW, Jr. The clinical challenge of endogenous endophthalmitis. Retina. 2001;21(6):572–4. Brod RD, Flynn HW Jr., Miller D.  Endogenous fungal endophthalmitis. In Tasman W, Jaeger E. (eds.) Duane’s clinical ophthalmology CV Mosby, St. Louis, Chapter 11, Vol 3: 2000, 1–40 Weishaar PD, Flynn HW, Jr., Murray TG, Davis JL, Barr CC, Gross JG, et al. Endogenous Aspergillus endophthalmitis. Clinical features and treatment outcomes. Ophthalmology. 1998;105(1):57–65. Essman TF, Flynn HW, Jr., Smiddy WE, Brod RD, Murray TG, Davis JL, et al. Treatment outcomes in a 10-year study of endogenous fungal endophthalmitis. Ophthalmic Surg Lasers. 1997;28(3):185–94. Brod RD, Flynn HW, Jr., Clarkson JG, Pflugfelder SC, Culbertson WW, Miller D.  Endogenous Candida endophthalmitis. Management without intravenous amphotericin B. Ophthalmology. 1990;97(5):666–72. disc: 72–4.

Screening of Endogenous Candida Endophthalmitis in the Hospital Setting Previous practices involved an ophthalmologist to be consulted in the hospital to screen for intraocular Candida endophthalmitis in patients with Candida septicemia found on routine blood cultures. Recent studies have found a rate of less than 1% in routinely screened patients with endophthalmitis from Candida septicemia. In 2021, the American Academy of Ophthalmology reported that they did not recommend routine ophthalmologic consultation after laboratory findings of systemic Candida septicemia, and recommended consultation in patients with signs or symptoms suggestive of ocular infection or in patients who are obtunded or who cannot report their subjective visual function.

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Reference • Breazzano MP, Bond JB, third, Bearelly S, et al. American Academy of Ophthalmology Recommendations on Screening for Endogenous Candida Endophthalmitis. Ophthalmology. 2021.

Endogenous Bacterial Endophthalmitis Endogenous bacterial endophthalmitis is an uncommon disease caused by hematogenous spread of bacteria. Endogenous endophthalmitis may occur even without obvious systemic infection

Incidence Reported rates are about 0.04% among patients with bacteremia

Signs/Symptoms The patient presents with mild to moderate decrease in the vision in one or both eyes. The patient may have a severe concurrent systemic illness. Slit-lamp examination may show conjunctival congestion, corneal edema, hypopyon, fibrinous membrane in the anterior chamber, and vitreous infiltrates.

Risk Factors • Diabetes mellitus • Immune compromise • Intravenous Drug use

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Malignancy • Longer hospital stays/prolonged intravenous antibiotic administration.

Microbial Isolates Common causative organisms include: • • • • • •

Staphylococcus aureus (USA, Europe) (Fig. 6.6) Gram-negative bacteria (USA, Europe) Streptococcus species (USA, Europe) S. aureus (USA, Europe) Gram-positive bacteria (USA, Europe) Klebsiella (East Asia)

I nitial Management of Endogenous Bacterial Endophthalmitis Patient with suspected endogenous bacterial endophthalmitis should undergo systemic investigations (including blood ­culture, urine culture, and infectious disease consultation) to look for the source of infection. In patients with endogenous bacterial endophthalmitis, systemic antibiotics are started after consultation with an infectious disease or internal medicine specialist. Intravitreal antibiotic injections are usually employed and pars plana vitrectomy can be considered especially in visually-threatening situations.

 ollow-Up Management in Patients F with Endogenous Bacterial Endophthalmitis.  irst Morning After Initial Treatment (Based F on Clinical Exam). • Topical antimicrobials.

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Figure 6.6  Endogenous endophthalmitis. (a) A 60-year-old female patient with uncontrolled diabetes mellitus presented with sudden blurring of vision, vitreous floaters, and hand motions (HM) visual acuity. The fundus examination showed a hyperemic disc and the presence of subretinal exudates at the posterior pole. The patient underwent vitreous tap and intravitreal antibiotics. The vitreous culture was positive for Staphylococcus aureus. (b) At 1-month follow-up, the inflammation and infection started resolving with best corrected visual acuity improving to 20/40

–– Consider fortified topical antibiotics if anterior segment involved: –– Vancomycin 25 mg/mL hourly during the day. –– Ceftazidime 50 mg/mL hourly during the day. –– Alternatively, commercially available topical antibiotics are used. • Topical steroids four times daily (not for suspected/proven fungal infection). • Topical cycloplegics daily. *Topical antibiotics hourly may result in corneal epithelial toxicity as a result of preservatives in commercial preparations. Topical medications are generally not used during night hours while sleeping. Subconjunctival antibiotics at the time of initial treatment provide adequate ocular surface medication for nighttime coverage.

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 wo to Three Days After Initial Treatment (Based T on Clinical Exam). • If clinically improving—Continue to observe and taper topical steroids over several weeks. • If clinically worsening: –– If not already done, consider intraocular cultures and/or injection (or reinjection) of intraocular antibiotics (and possibly intraocular steroids in acute-onset bacterial cases). –– Consider PPV if not performed initially. References: Endogenous Bacterial Endophthalmitis • Greenwald MJ, Wohl LG, Sell CH.  Metastatic bacterial endophthalmitis: a contemporary reappraisal. Surv Ophthalmol. 1986;31(2):81–101. • Aziz HA, Berrocal AM, Sisk RA, Hartley K, Diaz— Barbosa M, Johnson RA, et al. Intraocular infections in the neonatal intensive care unit. Clin Ophthalmol. 2012;6:733–7. • Flynn HW, Jr. The clinical challenge of endogenous endophthalmitis. Retina. 2001;21(6):572–4. • Harris EW, D’Amico DJ, Bhisitkul R, Priebe GP, Petersen R. Bacterial subretinal abscess: a case report and review of the literature. Am J Ophthalmol. 2000;129(6):778–85. • Lakosha H, Pavlin CJ, Lipton J. Subretinal Abscess Due to Nocardia Farcinica Infection. Retina. 2000;20(3):269–47. • Okada AA, Johnson RP, Liles WC, D’Amico DJ, Baker AS.  Endogenous bacterial endophthalmitis. Report of a ten—year retrospective study. Ophthalmology. 1994;101(5):832–8. • Schiedler V, Scott I, Flynn H, Davis J, Benz M, Miller D. Culture—proven endogenous endophthalmitis: clinical features and visual acuity outcomes. American Journal of Ophthalmology. 2004;137(4):725–31. • Sridhar J, Flynn HW, Jr., Kuriyan AE, Dubovy S, Miller D.  Endophthalmitis caused by Klebsiella species. Retina. 2014;34(9):1875–81.

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• Wong JS, Chan TK, Lee HM, Chee SP. Endogenous bacterial endophthalmitis: an east Asian experience and a reappraisal of a severe ocular affliction. Ophthalmology. 2000;107(8):1483–91. • Wu Z, Huang J, Huynh S, Sadda S.  Bilateral endogenous endophthalmitis secondary to group B streptococcal sepsis. Chin Med J (Engl). 2014;127(10):1999

Chapter 7 Pars Plana Vitrectomy for the Management of Endophthalmitis: Endophthalmitis Vitrectomy Study and Beyond Pars plana vitrectomy is commonly utilized in the management of endophthalmitis. In the following chapter, the techniques and outcomes of vitrectomy for endophthalmitis are discussed.

Endophthalmitis Vitrectomy Study The Endophthalmitis Vitrectomy Study (EVS) was a randomized clinical trial (RCT) which provides guidelines for the management of post-operative endophthalmitis following cataract surgery or secondary intraocular lens (IOL) implantation (Tables 7.1 and 7.2).

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 H. W. Flynn Jr. et al., Endophthalmitis in Clinical Practice, In Clinical Practice, https://doi.org/10.1007/978-3-031-35184-6_7

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Table 7.1 The Endophthalmitis Vitrectomy Study (EVS): enrollment criteria, exclusion criteria, treatment arms, and results Endophthalmitis vitrectomy study (EVS) EVS enrollment criteria •  Acute-onset post-operative endophthalmitis • Within 6 weeks of cataract surgery or secondary intraocular lens (IOL) implantation •  Visual acuity between 20/50 and light perception (LP) EVS exclusion criteria •  Other endophthalmitis etiologies •  Presence of cloudy cornea preventing pars plana vitrectomy • Pre-existing comorbidities (advanced glaucoma, age-related macular degeneration) which could result in worse than 20/200 visual acuity outcomes Patients were randomized into four treatment arms: •  PPV without intravenous antibiotics •  PPV with intravenous ceftazidime and amikacin •  Vitreous TAP (TAP) without intravenous antibiotics •  TAP with intravenous ceftazidime and amikacin EVS results •  For patients with presenting visual acuity of:  – Hand motions (HM) or better: No significant differences in VA outcomes between PPV and TAP  – Light perception (LP): PPV was associated with significantly better visual outcomes • For patients initially presenting with VA of LP, PPV was associated with:  – Higher rates of VA of 20/40 or better (33% PPV, 11% TAP)  – Twofold increase in frequency of achieving VA of 20/100 or better (56% PPV, 30% TAP)  – Twofold decrease in frequency of sustaining Severe Vision Loss defined as VA worse than 5/200 (20% PPV, 47% TAP) • No significant differences in visual outcomes with or without intravenous ceftazidime and amikacin VA = visual acuity

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Table 7.2 The Endophthalmitis Vitrectomy Study (EVS): Patient selection, guidelines, conclusions, and comments EVS: Patient selection, guidelines, conclusions, and comments •  Patient selection  – EVS selected only patients with acute-onset post-operative endophthalmitis within 6 weeks of cataract surgery or secondary IOL implantation.  – Other forms of endophthalmitis (post-traumatic/ endogenous/bleb-associated endophthalmitis) were not eligible for EVS. •  Cataract surgery techniques at the time of the EVS  – Cataract surgery was predominantly extracapsular cataract extraction or limbal tunnel phacoemulsification.  – Topical antibiotics gentamicin or polymyxin B-trimethoprim were commonly used for cataract surgery.  – Subconjunctival antibiotics (generally gentamicin) were routinely administered during cataract surgery.  – 10 EVS patients received antibiotics in the irrigating fluid at the time of the cataract surgery and yet developed endophthalmitis. •  EVS additional guidelines for selection of initial treatment  – Based on visual acuity at presentation  – HM or better: TAP without systemic antibiotics  – LP: PPV is preferable if this is achievable  – Initial TAP, followed by close observation and PPV if necessary, may lead to favorable outcomes  – The EVS results did not state that PPV was contraindicated in eyes with VA HM or better  – Initial management with TAP is more time and cost-­ efficient •  Retinal detachment in EVS  – Occurred after treatment in 8%  – The RD rate was 7.8% in the PPV group, and 9.0% in the TAP group (no statistical significance in these rates) (continued)

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Table 7.2 (continued) •  EVS—Conclusions and comments  – Intravenous ceftazidime and amikacin were reported to be not beneficial in the EVS.  – Oral gatifloxacin and moxifloxacin may achieve vitreous penetration but their value is uncertain.  – Oral gatifloxacin is no longer available due to systemic adverse events.  – Newer systemic antibiotics may be considered in selected patients with more severe signs and symptoms. •  The role of systemic and intravitreal steroids:  – All patients in EVS were treated with prednisone 30 mg twice daily for 5–10 days.  – The value of this treatment is uncertain.  – There are significant risks, especially in diabetic patients.  – Intravitreal steroids were not studied in the EVS.

Baseline Characteristics • Median age was 75 years. –– Median time from cataract extraction until presentation with endophthalmitis was 6 days. –– Pain reported in 74%. –– 86% had visual acuity worse than 5/200. –– Hypopyon was present in 86%. –– In 80% of patients, no retinal vessels could be seen with indirect ophthalmoscopy. The theoretical advantages of pars plana vitrectomy include debriding the intravitreal infection, removing the vitreous opacities obstructing vision, larger volume of culture material than TAP, and allowing better distribution of intravitreal antibiotics. Before the EVS, there were widely divergent opinions regarding the role of vitrectomy in endophthalmitis management. In the early 1970s, the mainstay of endophthalmitis management was the use of systemic antibiotics, which would require hospitalization. In a situation in which a patient with acute-onset post-operative endo-

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phthalmitis has visual acuity of light perception but it is not feasible to perform prompt PPV, it may be acceptable to treat with TAP and inject and then follow the patient closely. Risks of PPV in eyes with endophthalmitis include iatrogenic retinal tears. In addition, the original surgical wound (for example, a clear cornea incision) may be unstable and cause leakage during surgery, so suturing the corneal wound may be necessary. The findings of EVS should be interpreted with caution, especially when applying its findings to categories of endophthalmitis other than acute-onset post-operative endophthalmitis. References: Endophthalmitis Vitrectomy Study • Results of the Endophthalmitis Vitrectomy Study. A randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Endophthalmitis Vitrectomy Study Group. Arch Ophthalmol. 1995;113(12):1479–96. • Microbiologic factors and visual outcome in the endophthalmitis vitrectomy study. Am J Ophthalmol. 1996;122(6):830–46. • Bannerman TL, Rhoden DL, McAllister SK, Miller JM, Wilson LA.  The source of coagulase-negative staphylococci in the Endophthalmitis Vitrectomy Study. A comparison of eyelid and intraocular isolates using pulsed-field gel electrophoresis. Arch Ophthalmol. 1997;115(3):357–61. • Barza M, Pavan PR, Doft BH, Wisniewski SR, Wilson LA, Han DP, et  al. Evaluation of microbiological diagnostic techniques in postoperative endophthalmitis in the Endophthalmitis Vitrectomy Study. Arch Ophthalmol. 1997;115(9):1142–50. • Davis JL. Intravenous antibiotics for endophthalmitis. Am J Ophthalmol. 1996;122(5):724–6. • Doft BH.  The endophthalmitis vitrectomy study. Arch Ophthalmol. 1991;109(4):487–9.

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• Doft BH, Kelsey SF, Wisniewski SR.  Additional procedures after the initial vitrectomy or tap-biopsy in the Endophthalmitis Vitrectomy Study. Ophthalmology. 1998;105(4):707–16. • Doft BH, Wisniewski SR, Kelsey SF, Fitzgerald SG, Endophthalmitis Vitrectomy Study G. Diabetes and postoperative endophthalmitis in the endophthalmitis vitrectomy study. Arch Ophthalmol. 2001;119(5):650–6. • Doft BM, Kelsey SF, Wisniewski SR. Retinal detachment in the endophthalmitis vitrectomy study. Arch Ophthalmol. 2000;118(12):1661–5. • Javey G, Schwartz SG, Moshfeghi AA, Asrani S, Flynn HW Jr. Methicillin-resistant Staphylococcus epidermidis isolation from the vitrectomy specimen four hours after initial treatment with vancomycin and ceftazidime. Clin Ophthalmol 2010;4:101–4. • Durand M.  Microbiologic factors and visual outcome in the Endophthalmitis Vitrectomy Study. Am J Ophthalmol. 1997;124(1):127–30. • Han DP, Wisniewski SR, Wilson LA, Barza M, Vine AK, Doft BH, et al. Spectrum and susceptibilities of microbiologic isolates in the Endophthalmitis Vitrectomy Study. Am J Ophthalmol. 1996;122(1):1–17. • Johnson MW, Doft BH, Kelsey SF, Barza M, Wilson LA, Barr CC, et  al. The Endophthalmitis Vitrectomy Study. Relationship between clinical presentation and microbiologic spectrum. Ophthalmology. 1997;104(2):261–72. • Peyman GA.  EVS, a different point of view. (Editorial) Arch de la Sociedad Espanola de Oftalmologia 1996;3: 205–7. • Sternberg P, Jr., Martin DF.  Management of endophthalmitis in the post-endophthalmitis vitrectomy study era. Arch Ophthalmol. 2001;119(5):754–5. • Wisniewski S.  Characteristics after cataract extraction or secondary lens implantation among patients screened for the Endophthalmitis Vitrectomy Study. Ophthalmology. 2000;107(7):1274–82.

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• Wisniewski SR, Hammer ME, Grizzard WS, Kelsey SF, Everett D, Packo KH, et al. An investigation of the hospital charges related to the treatment of endophthalmitis in the Endophthalmitis Vitrectomy Study. Ophthalmology. 1997;104(5):739–45.

 arly Vitrectomy for Endophthalmitis (beyond E the EVS) The multicenter, prospective randomized Endophthalmitis Vitrectomy Study (EVS) helped establish guidelines for the management of infectious endophthalmitis following cataract surgery (reported in 1994). However, recently there has been a debate whether early vitrectomy may be beneficial to patients with endophthalmitis. While the EVS used 20-gauge vitrectomy, currently available small gauge vitrectomy and wide-angle viewing systems may provide an advantage. Early vitrectomy may also be beneficial in improved pathogen identification, removal of infectious material, and reduction of inflammation. However, vitrectomy surgery can be associated with complications such as retinal detachment and cataract formation in phakic eyes. While non-controlled, retrospective studies may present benefits of early vitrectomy, a comparative trial is required to make a conclusion. Currently, there are trials that are underway. During the EVS (early 1990s), most PPVs were performed in hospital settings and therefore emergency after-hours PPVs could be performed with on-call hospital staff. Currently, in the United States and in many other nations, most PPVs are performed in ambulatory surgical centers which do not allow emergency after-hours surgical cases. At the same time, many or most hospitals which used to perform PPVs have lost their capability to do so. The net effect is that, at present, it is more difficult in many parts of the United States to obtain emergency after-hours PPV than it was previously.

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Again, the single most important factor to obtain best outcomes is prompt administration of antibiotics, regardless of whether this is done through TAP and inject or PPV. References • Flynn HW, Jr., Scott IU.  Legacy of the endophthalmitis vitrectomy study. Arch Ophthalmol. 2008;126(4):559–61. • Flynn HW Jr., Meredith TA. Interpreting the results of the EVS (Letter to Editor). Arch Ophthalmol. 1996;114: 1027–8. • Dib B, Morris RE, Oltmanns MH, Sapp MR, Glover JP, Kuhn F.  Complete and Early Vitrectomy for Endophthalmitis After Cataract Surgery: An Alternative Treatment Paradigm [Response To Letter]. Clinical Ophthalmology (Auckland, NZ). 2021;15:3705. • Dib B, Morris RE, Oltmanns MH, Sapp MR, Glover JP, Kuhn F. Complete and early vitrectomy for endophthalmitis after cataract surgery: an alternative treatment paradigm. Clinical Ophthalmology (Auckland, NZ). 2020;14:1945. • Grzybowski A, Turczynowska M, Kuhn F. The treatment of postoperative endophthalmitis: should we still follow the endophthalmitis vitrectomy study more than two decades after its publication? Acta ophthalmologica. 2018;96(5):e651-e654. • Forster RK.  The endophthalmitis vitrectomy study. Archives of ophthalmology. 1995;113(12):1555–1557.

Endophthalmitis in Phakic Eyes In phakic eyes, removal of an uninvolved crystalline lens is generally not necessary. If the crystalline lens is involved, then lensectomy may be beneficial, although placement of an

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intraocular lens during this surgery risks trapping infectious material in the capsular bag. References • Townsend J, Pathengay A, Flynn HW, Jr., Miller D.  Management of endophthalmitis while preserving the uninvolved crystalline lens. Clin Ophthalmol. 2012;6:453–7.

Endoscopic Vitrectomy for Endophthalmitis Endoscopy-assisted pars plana vitrectomy for endophthalmitis can be performed when visualization if poor due to corneal opacity, dense cataract, or vitritis. While visual acuity in the majority of these patients remains poor, endoscopy may decrease evisceration of eyes. Endoscopy can aid in performing safe and therapeutic vitrectomy in certain cases of endophthalmitis with poor view posteriorly. References • Dave VP, Pappuru RR, Tyagi M, Pathengay A, Das T. Endoscopic vitrectomy in endophthalmitis: initial experience of 33 cases at a tertiary eye care center. Clinical Ophthalmology (Auckland, NZ). 2019;13:243. • Pan Q, Liu Y, Wang R, et al. Treatment of Bacillus cereus endophthalmitis with endoscopy-assisted vitrectomy. Medicine. 2017;96(50). • Ren H, Jiang R, Xu G, et  al. Endoscopy-assisted vitrectomy for treatment of severe endophthalmitis with retinal detachment. Graefe’s Archive for Clinical and Experimental Ophthalmology. 2013;251(7):1797–1800. • De Smet MD, Carlborg EA. Managing severe endophthalmitis with the use of an endoscope. Retina (Philadelphia, Pa). 2005;25(8):976–980.

Chapter 8 Antimicrobial Treatment, Resistance, and Alternatives

Antimicrobial Routes • Intravitreal antimicrobials: For presumed bacterial cases (in separate syringes): –– Vancomycin 1  mg/0.1  mL (for coverage of Gram-­ positive organisms) –– Ceftazidime 2.25  mg/0.1  mL (for coverage of Gram-­ negative organisms) For presumed fungal cases: –– Amphotericin B 0.005 mg/0.1 mL AND/OR –– Voriconazole 0.1 mg/0.2 mL

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 H. W. Flynn Jr. et al., Endophthalmitis in Clinical Practice, In Clinical Practice, https://doi.org/10.1007/978-3-031-35184-6_8

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Chapter 8.  Antimicrobial Treatment…

–– Amikacin may be substituted for ceftazidime (EVS-­ proven efficacy) (Risks of aminoglycoside toxicity are similar to gentamicin). –– Ceftriaxone (2  mg/0.1  mL) may be substituted for ceftazidime if more readily available. –– Dexamethasone 4  mg/0.1  mL may be considered for acute-onset bacterial cases but should be avoided in suspected fungal endophthalmitis and delayed-onset (chronic) endophthalmitis until the organism is identified. Periocular/subconjunctival antimicrobials: Periocular antibiotics can be considered in all categories of endophthalmitis but may be most useful in bleb-related endophthalmitis. • Systemic antimicrobials: –– For endogenous bacterial endophthalmitis Vancomycin 1 g IV bid plus ceftazidime 1 g IV bid Systemic fluoroquinolones for susceptible organisms For endogenous bacterial endophthalmitis, systemic antimicrobials are generally chosen by internal medicine or infectious disease specialists based on the clinical history and examination. An example of a broad-spectrum combination is vancomycin plus ceftazidime. –– For endogenous fungal endophthalmitis Voriconazole 200 mg PO bid for 2–4 weeks Fluconazole 200 mg PO bid for 2–4 weeks Amphotericin B 0.25–1.0 mg/kg IV every 6 hours as tolerated

Summary of Antimicrobial Dosages…

151

For endogenous fungal endophthalmitis, systemic antimicrobials are generally chosen by internal medicine or infectious disease specialists based on the clinical history and examination. • Topical antimicrobials: Commercially available topical antibiotics may be used. In locations where there is access to fortified topical antibiotics, the following may be chosen: –– Topical Antibiotic therapy: Fortified vancomycin: 25  mg/mL (2.5%) or 50  mg/ mL (5%) Fortified ceftazidime: 50 mg/mL (5%) Fortified cefazolin: 50 mg/mL (5%) Fortified gentamicin: 14 mg/mL (1.4%) Fortified tobramycin: 14 mg/mL (1.4%) Fortified amikacin: 8 mg/mL (2.5%) Fortified linezolid: 2 mg/mL (0.2%) Fortified imipenem–cilastin: 10 mg/mL (1%) –– Topical Antifungals therapy: Fortified amphotericin B: 1.5 mg/mL (0.15%) Fortified voriconazole: 10 mg/mL (1%) Itraconazole

 ummary of Antimicrobial Dosages S (Table 8.1)

Antifungal

0.005 mg/0.1 mL

0.05 mg/0.1 mL

Voriconazole

0.4 mg/0.1 mL

Amikacin

Amphotericin B

2.25 mg/0.1 mL

Ceftazidime

–

–

25 mg/0.5 mL

100 mg/0.5 mL

10 (1%)

1.5 (0.15%)

8

50

Table 8.1  Commonly used antimicrobial agents and recommended doses Intravitreal Subconjunctival Topical (mg/mL) Antibiotics Vancomycin 1 mg/0.1 mL 25 mg/0.25 mL 25

200 mg PO

0.25–1.0 mg/kg IV q6h

–

1 g IV bid

Intravenous/oral 1 g IV bid

152 Chapter 8.  Antimicrobial Treatment…

Preparation of Antimicrobials

153

Preparation of Antimicrobials Preparation of Intravitreal Antimicrobials (Table 8.2) They are prepared in a volume of 10  mL or greater and labeled in a sealed sterile vial. The treating physician will then withdraw the appropriate dose in a tuberculin syringe for injection. Table 8.2  Preparation of intravitreal antimicrobial agents Intravitreal antimicrobials Vancomycin (1 mg/0.1 mL) • Start with vancomycin 500 mg vial (powder). • Add 10 mL of 0.9% sodium chloride for injection, USP (no preservatives), or balanced salt solution (BSS). • Inject 2 mL of the above solution into a sterile empty vial. • Add 8 mL of 0.9% sodium chloride for injection, USP (no preservatives), or BSS. • Seal this vial. Ceftazidime (2.25 mg/0.1 mL) • Start with ceftazidime 500 mg vial (powder). • Add 10 mL of 0.9% sodium chloride for injection, USP (no preservatives), or BSS. • Inject 1 mL of the above solution into a sterile empty vial. • Add 1.2 mL of 0.9% sodium chloride for injection, USP (no preservatives), or BSS. • Seal this vial. Amikacin (0.4 mg/0.1 mL) • Start with amikacin 500 mg/2 mL (solution). • Inject 0.16 mL of this solution into a sterile empty vial. • Add 9.84 mL of 0.9% sodium chloride for injection, USP (no preservatives). • Seal this vial. (continued)

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Chapter 8.  Antimicrobial Treatment…

Table 8.2 (continued) Intravitreal antimicrobials Amphotericin B (0.005 mg/0.1 mL) • Start with amphotericin B 50 mg vial. • Add 10 mL sterile water for injection, USP (no preservatives). • Inject 0.1 mL of the above solution into a sterile empty vial. • Add 9.9 mL of sterile water for injection, USP (no preservatives) to the above solution. • Seal this vial. Voriconazole (0.05 mg/0.1 mL) • Start with voriconazole 200 mg vial and reconstitute with 19 mL of sterile water for injection, USP (no preservatives). • Withdraw 1 mL of this solution and dilute with 19 mL of sterile water for injection, USP (no preservatives). • Transfer this solution into two sterile empty vials. • Seal these vials.

Preparation of Antimicrobials

155

Preparation of Subconjunctival Antibiotics (Table 8.3) Table 8.3  Preparation of subconjunctival antibiotics Volume Final dose Volume for Amount in added injection Antibiotic package (mL) (mL) Vancomycin 500 mg 5 0.25 25 mg/0.25 mL Ceftazidime

500 mg

2.5

0.5

100 mg/0.5 mL

Cefazolin

500 mg

2.5

0.5

100 mg/0.5 mL

Amikacin

100 mg/2 mL 0

0.5

25 mg/0.5 mL

Gentamycin

80 mg/2 mL

0

0.5

20 mg/0.5 mL

Tobramycin

80 mg/2 mL

0

0.5

20 mg/0.5 mL

Clindamycin 600 mg/4 mL 0

0.33

50 mg/0.33 mL

Methicillin

1 g

5

0.5

100 mg/0.5 mL

Cephalothin

1 g

5

0.5

100 mg/0.5 mL

Ampicillin

1 g

5

0.5

100 mg/0.5 mL

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 reparation of Fortified Topical Antimicrobials P (Table 8.4) Table 8.4  Preparation of fortified topical antimicrobial agents Vancomycin (25 mg/mL) • Start with vancomycin 500 mg vial (powder). • Add 20 mL of 0.9% sodium chloride for injection, USP (no preservatives), or artificial tears. • Refrigerate and shake well before instillation. Ceftazidime (50 mg/mL) • Start with ceftazidime 500 mg vial (powder). • Add 9.2 mL of artificial tears. • Take 5 mL of this solution, and dilute it with 5 mL of artificial tears. • Refrigerate and shake well before instillation. Cefazolin (50 mg/mL) • Start with ceftazidime 500 mg vial (powder). • Reconstitute with 2 mL sterile water. • Add 8 mL of artificial tears to reconstituted solution. • Refrigerate and shake well before instillation. Amikacin (8 mg/mL) • Start with amikacin 500 mg/2 mL (solution). • Add 0.48 mL of this solution to 15 mL of sterile water (preservative free). • Refrigerate and shake well before instillation. Fortified gentamicin eye drops: 14 mg/mL (1.4%) • Add 2 mL/80 mg of parenteral gentamicin to commercial gentamicin ophthalmic solution 0.3% 5 mL (15 mg/5 mL). • Shelf life: 1 week in refrigerator at 4 °C and 4 days at room temperature. Fortified tobramycin: 14 mg/mL (1.4%) • Add 2 mL/80 mg of parenteral tobramycin to commercially available tobramycin eye drops 0.3% 5 mL (15 mg/5 mL). • Shelf life: 1 week in refrigerator at 4 °C and 4 days at room temperature.

Adverse Effects of Antimicrobials

157

Table 8.4 (continued) Topical linezolid 2 mg/mL (0.2%) • Can use directly from parenteral linezolid (Lancure/Adlid/ Rapidline) available as 200 mg/100 mL (2 mg/mL) IV infusion Topical imipenem–cilastin eye drops 1% • To parenteral imipenem (500 mg)–cilastin (500 mg), add 10 mL sterile water to create a solution of strength 50 mg/mL. • Take 1 mL of this solution and add 4 mL sterile water to make topical imipenem 1%–1 mg/mL. • Storage—in amber-colored bottles. • Stability—3 days at 2–8 °C. Topical amphotericin B 0.15% • Add 10 mL distilled or sterile water to parenteral 50 mg of amphotericin B powder for injection. • Draw 3 mL of this and add to 7 mL of artificial tears eye drops. • Storage: Refrigerate at 4 °C. • Shelf life: 7 days in refrigerator at 4 °C and 4 days at room temperature. Topical voriconazole eye drops 1% • Mix 20 mL Ringer’s Lactate to 200 mg voriconazole lyophilized powder. • Stability: 30 days at 4 °C or room temperature.

Adverse Effects of Antimicrobials Adverse effects of intravitreal antimicrobials: • Intravitreal aminoglycoside—Risk of macular infarction (Fig. 8.1) • Intravitreal vancomycin—Hemorrhagic occlusive retinal vasculitis (HORV Fig. 8.2) • Intravitreal amphotericin B—Risk of retinal damage • Intravitreal fluoroquinolones—Risk of retinal/systemic toxicity

158

a

Chapter 8.  Antimicrobial Treatment…

b

Figure 8.1 Macular infarction after intravitreal amikacin. Retinal toxicity with intravitreal amikacin. (a) Fundus photo showing retinal hemorrhages at the posterior pole. (b) Fundus fluorescein angiography demonstrates lack of perfusion at the posterior pole with ischemic macula and patches of hypofluorescence in the area of retinal hemorrhages

a

b

Figure 8.2 Hemorrhagic occlusive retinal vasculitis (HORV) in both eyes developing within 1 week of cataract surgery in right eye with intracameral vancomycin. The fundus pictures show multiple retinal hemorrhages and retinal vasculitis

Adverse effects of systemic antimicrobials • Systemic fluoroquinolones—Disabling and potentially permanent serious side effects involving the tendons, muscles, joints, nerves, and central nervous system. As of

Adverse Effects of Antimicrobials

159

May 10, 2017, the US Food and Drug Administration (FDA) does not support that fluoroquinolones result in retinal detachment or aortic aneurysm/dissection. • Systemic amphotericin B—Nephrotoxicity, nausea, vomiting, rigors, fever, hypertension or hypotension, and hypoxia. • Systemic voriconazole—Generally well tolerated, reversible disturbance of vision (altered color discrimination, blurred vision, the appearance of bright spots and wavy lines, and photophobia), fever, nausea, skin rash, vomiting, and chills. References: Adverse Effects of Antimicrobials • Aydin E, Kazi AA, Peyman GA, Esfahani MR. Intravitreal toxicity of moxifloxacin. Retina. 2006;26(2):187–90. • Brown GC, Eagle RC, Shakin EP, Gruber M, Arbizio VV.  Retinal toxicity of intravitreal gentamicin. Arch Ophthalmol. 1990;108(12):1740–4. • FDA Drug Safety Communication: FDA updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side effects. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM513019.pdf. (Accessed 23 June 2017). • Galloway G, Ramsay A, Jordan K, Vivian A.  Macular infarction after intravitreal amikacin: mounting evidence against amikacin. Br J Ophthalmol. 2002;86(3):359–60. • Kazi AA, Jermak CM, Peyman GA, Aydin E, Riazi-­ Esfahani M.  Intravitreal toxicity of levofloxacin and gatifloxacin. Ophthalmic Surg Lasers Imaging. ­ 2006;37(3):224–9. • Laniado-Laborin R, Cabrales-Vargas MN.  Amphotericin B: side effects and toxicity. Revista iberoamericana de micologia. 2009;26(4):223–7. • Peyman GA, Lad EM, Moshfeghi DM. Intravitreal injection of therapeutic agents. Retina. 2009;29(7):875–912. • Souri EN, Green WR. Intravitreal amphotericin B toxicity. Am J Ophthalmol. 1974;78(1):77–81.

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Antimicrobial Resistance and Alternatives Emergence of resistance to commonly used antimicrobial agents is a great challenge in health care. The overuse of antibiotics in hospitals and outpatient clinics, widespread agricultural use of antibiotics, and intrinsic genetic factors may all contribute to increasing antimicrobial resistance. Antimicrobial Resistance Data from EVS: • 100% of Gram-positive isolates were susceptible to vancomycin. • 89.5% of Gram-negative isolates were susceptible to both amikacin and ceftazidime. Among Gram-negative isolates, 2/19 (one Pseudomonas vesicularis and one Flavobacterium, not speciated) were resistant to both amikacin and ceftazidime.

Data on Antimicrobial Resistance • In the Centers for Disease Control and Prevention (CDC) guidelines for appropriate use of vancomycin and the report by the Rockefeller University Workshop published in 1994, the prophylactic use of vancomycin was discouraged in view of the risk of increasing the prevalence of vancomycin-resistant Enterococci (VRE) and methicillin-­ resistant Staphylococcus aureus (MRSA). • In 2016, Relhan et al. reviewed 27 cases of Gram-positive endophthalmitis with reduced vancomycin susceptibility or vancomycin resistance. • Another review by Dave et al. reported 11 cases of Gram-­ negative endophthalmitis with ceftazidime resistance. • These 11 cases of endophthalmitis caused by ceftazidime-­ resistant Gram-negative organisms were reported from a single center in India. These cases were subsequently managed with intravitreal imipenem. Alternative intravitreal agents: Following antimicrobial options are available in cases of resistance (Tables 8.5, 8.6, and 8.7):

Streptogramin

Cyclic lipoglycopeptide

Glycylcycline

Quinupristin/ dalfopristin (Synercid®)

Daptomycin (Cubicin®)

Tigecycline (Tygacil®)

Inhibits bacterial protein synthesis by irreversibly binding to 30S ribosomal unit

Terminates bacterial DNA, RNA, and protein synthesis and cell death by forming transmembrane channels in cell membrane and depolarization of membrane potential

Inhibits bacterial protein synthesis by interfering with function of 23S RNA (quinupristin/dalfopristin, 3:7)

Table 8.5  Alternative intravitreal antimicrobial agents for Gram-­positive organisms Name of drugs Class of drugs Mechanism of action Linezolid Oxazolindinone Inhibits initiation of protein synthesis by (Zyvox®) binding 23S rRNA of the 50S subunit of bacterial ribosome

0.5–1 mg/0.1 mL (rabbits)

200 μg/0.1 mL (case report in humans)

0.4 mg/0.1 mL (rabbits and case reports in humans)

300 μg/0.1 mL (rabbits and case series in humans)

Intravitreal dose Antimicrobial Resistance and Alternatives 161

Fluoroquinolones

Fluoroquinolones

Levofloxacin (Levaquin®)a

Moxifloxacin (Avelox®)

Same as above

Same as above

Inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, and recombination

0.2 mg/0.1 mL (case report in humans)

0.1 mL of 0.5% ophthalmic solution (rabbits)

0.1 mg/0.1 mL

Intravitreal dose 50 μg/0.1 m (case series in humans)

a

It was determined that intravitreal dose of 625 μg/0.1 mL is not toxic to the retina (Peyman et al.)

Fluoroquinolones

Ciprofloxacin (Cipro®)

Table 8.6  Alternative intravitreal antimicrobial agents for Gram-­negative organisms Name of drugs Class of drugs Mechanism of action Imipenem Carbapenem Interrupts cell wall synthesis of various (Primaxin®) GPO and GNO and is a strong inhibitor of β-lactamases from some GNO that are resistant to most β-lactam antibiotics

162 Chapter 8.  Antimicrobial Treatment…

Echinocandin

Micafungin (Mycamine®)

It inhibits an enzyme essential for fungal cell wall synthesis

Blocks the synthesis of β(1,3)-d-glucan of the fungal cell wall, by noncompetitive inhibition of the enzyme β(1,3)-d-glucan synthase. β(1,3)-d-­Glucan is an essential component of the cell wall of numerous fungal species

0.025 mg/0.1 mL (rabbits)

50 μg/0.1 mL (rabbits and mice)

Intravitreal dose 25 μg/0.1 mL (case series in humans)

Tables adapted from Relhan N, Pathengay A, Schwartz SG, Flynn HW Jr. Emerging Worldwide Antimicrobial Resistance, the Need for Antibiotic Stewardship and Alternative Intravitreal Agents for the Treatment of Endophthalmitis. Retina. 2017 May;37(5):811–818

Echinocandin

Caspofungin (Cancidas®)

Table 8.7  Alternative intravitreal antimicrobial agents for fungal organisms (update?) Name of drugs Class of drugs Mechanism of action Miconazole Azole Effects on respiration and cell permeability. It inhibits the growth of several species of Candida

Antimicrobial Resistance and Alternatives 163

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Chapter 8.  Antimicrobial Treatment…

Pharmacokinetics and Pharmacodynamics of Antimicrobials The efficacy of antimicrobials depends on their ability to reach the target tissues, their intrinsic antimicrobial action, and the duration of drug availability. In circumstances where systemic antimicrobials are used, it may be preferable to use the same agent systemically and intravitreally, because intraocular absorption from the systemic circulation may augment the action of the intravitreal agent. The blood–retinal barrier, which ordinarily limits access to systemic medications, may be impaired in cases with inflammation such as endophthalmitis. Finally, a vitrectomized eye will typically “clear” intravitreal medications faster than an eye with intact vitreous. References: Antimicrobial Resistance and Alternative Intravitreal Agents • Dave VP, Pathengay A, Nishant K, Pappuru RR, Sharma S, Sharma P, et  al. Clinical presentations, risk factors and outcomes of ceftazidime-resistant gram-negative endophthalmitis. Clin Exp Ophthalmol. 2017;45(3):254–60. • Grzybowski A, Schwartz SG, Matsuura K, Ong Tone S, Arshinoff S, Ng JQ, et al. Endophthalmitis prophylaxis in cataract surgery: overview of current practice patterns around the world. Curr Pharm Des. 2017;23(4):565–73. • Meredith TA.  Antimicrobial pharmacokinetics in endophthalmitis treatment: studies of ceftazidime. Trans Am Ophthalmol Soc. 1993;91:653–99. • Pflugfelder SC, Hernandez E, Fliesler SJ, Alvarez J, Pflugfelder ME, Forster RK.  Intravitreal vancomycin. Retinal toxicity, clearance, and interaction with gentamicin. Arch Ophthalmol. 1987;105(6):831–7. • Radhika M, Mithal K, Bawdekar A, Dave V, Jindal A, Relhan N, et al. Pharmacokinetics of intravitreal antibiotics in endophthalmitis. J Ophthalmic Inflamm Infect. 2014;4(1):22. • Relhan N, Albini TA, Pathengay A, Kuriyan AE, Miller D, Flynn HW.  Endophthalmitis caused by Gram-positive

Pharmacokinetics and Pharmacodynamics…

•

•

•

•

•

• • • • •

165

organisms with reduced vancomycin susceptibility: literature review and options for treatment. Br J Ophthalmol. 2016;100(4):446–52. Relhan N, Pathengay A, Schwartz SG, Flynn HW, Jr. Emerging worldwide antimicrobial resistance, antibiotic stewardship and alternative intravitreal agents for the treatment of endophthalmitis. Retina. 2017;37(5):811–8. Schwartz SG, Flynn HW, Jr., Grzybowski A, Relhan N, Ferris FL, 3rd. Intracameral antibiotics and cataract surgery: endophthalmitis rates, costs, and stewardship. Ophthalmology. 2016;123(7):1411–3. Witkin AJ, Chang DF, Jumper JM, Charles S, Eliott D, Hoffman RS, et  al. Vancomycin-associated hemorrhagic occlusive retinal vasculitis: clinical characteristics of 36 eyes. Ophthalmology. 2017;124(5):583–95. Witkin AJ, Shah AR, Engstrom RE, Kron-Gray MM, Baumal CR, Johnson MW, et  al. Postoperative hemorrhagic occlusive retinal vasculitis: expanding the clinical spectrum and possible association with vancomycin. Ophthalmology. 2015;122(7):1438–51. Ferrer C, Rodríguez A, Abad JL, Fernandez J, Alió JL.  Bactericidal effect of intravitreal levofloxacin in an experimental model of endophthalmitis. Br J Ophthalmol. 2008 May;92(5):678–82. Radhika, M., Mithal, K., Bawdekar, A. et  al. Pharmacokinetics of intravitreal antibiotics in endophthalmitis. J Ophthal Inflamm Infect 4, 22 (2014). Peyman GA, Schulman JA. Intravitreal drug therapy. Jpn J Ophthalmol. 1989;33(4):392–404. PMID: 2696799. Gurler B, Ozkul Y, Bitiren M, Karadede S, Gurkan T.  A study on the toxicity of intravitreal levofloxacin in rabbits. Curr Eye Res. 2002 Apr;24(4):253–62. Peyman G, Lee P, Seal D. Pharmacology: in Lee, P.J., David V Seal MD, & Peyman, G.A. (Eds.). (2004). Endophthalmitis: Diagnosis and Treatment (first ed.). CRC Press. Jafari Ozumchelouei E, Hamidian AH, Zhang Y, Yang M.  Physicochemical properties of antibiotics: A review with an emphasis on detection in the aquatic environment. Water Environ Res. 2020 Feb;92(2):177–188.

Chapter 9 Endophthalmitis Prophylaxis

Antisepsis This is the prophylaxis of infection by inhibiting or arresting the growth and multiplication of germs (infectious agents) which is usually achieved by povidone-iodine, hydrogen peroxide, chlorhexidine, or polyhexanide application on the skin (Fig. 9.1). Povidone-iodine antisepsis is well documented to reduce the rates of endophthalmitis in patients undergoing intraocular surgery (Figure 9.1a–b). Povidone-iodine is a rapidly bactericidal, low-cost antiseptic agent with no antibiotic resistance, activity against multidrug-­resistant bacteria, fungi, viruses, including novel pathogens, such as SARS-CoV-2, lack of inducible resistance, bactericidal and used worldwide. In 2013, a prospective randomized study (Friedman et  al.) of patients undergoing intravitreal injections reported that the use of 5% povidone-iodine leads to a significant reduction in bacterial colonies, and exposure of 30 seconds appeared to be an adequate time to decrease conjunctival bacterial counts. Modjtahedi et  al. (2016) retrospectively analyzed cases of endophthalmitis occurring in patients with self-reported iodine allergy who underwent intravitreal injections without povidone-iodine antisepsis. The study concluded that avoiding povidone-iodine owing to self-reported iodine “allergy” © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 H. W. Flynn Jr. et al., Endophthalmitis in Clinical Practice, In Clinical Practice, https://doi.org/10.1007/978-3-031-35184-6_9

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168

a

Chapter 9.  Endophthalmitis Prophylaxis

b

Figure 9.1  Preoperative povidone-iodine antisepsis. (a) Skin antisepsis with povidone-iodine. (b) Conjunctival antisepsis with 5% povidone-­iodine drops

risks substantial ocular morbidity. Povidone-iodine solution tissue toxicity is concentration dependent. Interestingly, bactericidal free iodine concentration is higher, and the killing time is shorter, in dilute povidone-­iodine solution compared with concentrated (5–10%) povidone-iodine solution. The frequent application of dilute povidone-iodine solution during ocular surgery is a way to maximize bactericidal activity and minimize toxicity. Chlorhexidine gluconate is a biguanide germicide available for pre-operative antisepsis. Concentrations of 0.1–4% to be highly active against a variety of Gram-positive and Gram-negative bacterial pathogens as noted in in vitro experiments. Chlorhexidine concentration of 2.0 and 4.0% in the external irrigating fluid has been shown to slow the corneal epithelial healing rate. Prolonged corneal contact with chlorhexidine may cause irreversible corneal endothelial damage. Most patients who report they are “allergic” to povidone-­ iodine do not have a true allergy in the sense of an immune response to the substance. Most of these patients are intolerant of prolonged povidone-iodine on the ocular surface and find it objectionable due to ocular discomfort. A surgeon should be very hesitant to avoid the use of povidone-iodine

Antisepsis

169

because there is an increased risk of endophthalmitis if povidone-iodine is not used. The use of chlorhexidine for endophthalmitis prophylaxis is not generally recommended due to the risk of corneal toxicity. References: Antisepsis • Ahmed Y, Scott IU, Pathengay A, Bawdekar A, Flynn HW, Jr. Povidone-iodine for endophthalmitis prophylaxis. Am J Ophthalmol. 2014;157(3):503–4. • Apt L, Isenberg SJ, Yoshimori R, Chang A, Lam GC, Wachler B, et  al. The effect of povidone-iodine solution applied at the conclusion of ophthalmic surgery. Am J Ophthalmol. 1995;119(6):701–5. • Apt L, Isenberg SJ, Yoshimori R, Spierer A.  Outpatient topical use of povidone-iodine in preparing the eye for surgery. Ophthalmology. 1989;96(3):289–92. • Friedman DA, Mason JO, third, Emond T, McGwin G, Jr. Povidone-iodine contact time and lid speculum use during intravitreal injection. Retina. 2013;33(5):975–81. • Hamill MB, Osato MS, Wilhelmus KR.  Experimental evaluation of chlorhexidine gluconate for ocular antisepsis. Antimicrob Agents Chemother. 1984;26(6):793–6. • Mendivil Soto A, Mendivil MP. The effect of topical povidone–iodine, intraocular vancomycin, or both on aqueous humor cultures at the time of cataract surgery. Am J Ophthalmol. 2001;131(3):293–300. • Merani R, Hunyor AP. Endophthalmitis after intravitreal injections in patients with self-reported iodine allergy. Am J Ophthalmol. 2017;176:256–7. • Modjtahedi BS, van Zyl T, Pandya HK, Leonard RE, second, Eliott D. Endophthalmitis after intravitreal injections in patients with self-reported iodine allergy. Am J Ophthalmol. 2016;170:68–74. • Nakashizuka H, Shimada H, Hattori T, Noguchi T, Kokubo N, Yuzawa M.  Vitrectomy using 0.025% povidone-iodine in balanced salt solution plus for the treatment of postoperative endophthalmitis. Retina. 2015;35(6):1087–94.

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• Nentwich MM, Ta CN, Kreutzer TC, Li B, Schwarzbach F, Yactayo-Miranda YM, et  al. Incidence of postoperative endophthalmitis from 1990 to 2009 using povidone-iodine but no intracameral antibiotics at a single academic institution. J Cataract Refract Surg. 2015;41(1):58–66. • Wan KH, Radke N, Lam DS. Endophthalmitis after intravitreal injections in patients with self-reported iodine allergy. Am J Ophthalmol. 2017;176:260. • Wykoff CC, Flynn HW, Jr., Han DP. Allergy to povidone-­ iodine and cephalosporins: the clinical dilemma in ophthalmic use. Am J Ophthalmol. 2011;151(1):4–6. • Ciulla TA, Starr MB, Masket S. Bacterial endophthalmitis prophylaxis for cataract surgery: an evidence-based update. Ophthalmology. 2002;109(1):13–24. • Chang Rhee.

Topical Antibiotics Topical antibiotics are utilized for endophthalmitis prophylaxis in two settings: • Pre-operative topical antibiotics. • Post-operative topical antibiotics. Pre-operative topical antibiotics—A review by Packer et  al. (2011) discussed the roles of surgical technique and topical antibiotic prophylaxis in prevention of endophthalmitis. The optimal timing and frequency of topical antibiotic prophylaxis as per this review has been the subject of debate. According to the European Society of Cataract & Refractive Surgeons (ESCRS) guidelines and several national European recommendations (Sweden, Denmark, France), the pre-­ operative use of topical antibiotics is not justified when intracameral antibiotics are used. Generally, preoperative topical antibiotics are more commonly used for prophylaxis in the United States. Post-operative topical antibiotics—A review by Kuklo et al. (2017) reported wide variations in prophylaxis practices

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around the world. As per this review, there is no consensus on the use of prophylactic perioperative antibiotics to prevent endophthalmitis after cataract surgery. Another systematic review and meta-analysis of randomized controlled trials and observational studies performed by Huang et al. (2016) failed to show any evidence to support the use of post-operative topical antibiotics to prevent endophthalmitis after ocular surgery. However, post-operative topical antibiotics are very commonly used in the United States to prevent endophthalmitis after ocular surgery.

Topical Antibiotics: Literature Following are a few selected studies regarding the role of topical antibiotics in specific case scenarios: • Topical Antibiotic after Cataract Surgery. –– Allen HF and Mangiaracine AB (1974): In a series of 36,000 cataract operations, the low rate of infection (0.086% 31/36,000 cataract surgeries) was reported to be achieved by following three principles: (1) meticulous aseptic technique, (2) minimally traumatic surgery, and (3) pre-operative antibiotic prophylaxis using a combination of chloramphenicol-polymyxin B sulfate drops and erythromycin ointment. –– Jabbarvand et  al. (2016): This retrospective, single-­ center, cross-sectional descriptive study evaluated patients who underwent cataract surgery in an eye hospital in Iran from 2006 through 2014. The incidence of endophthalmitis was reported to be 0.023% (112/480,104 operations). This series demonstrated 40–50% reduced odds of endophthalmitis with short-term treatment with topical or systemic preoperative antibiotics or post-­ operative subconjunctival injection compared with no prophylaxis.

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• Topical Antibiotic after Intravitreal Injections. –– Kim SJ et  al. (2010): This prospective, observational study of 48 eyes (24 patients) demonstrated substantial levels of resistance to third- and fourth-generation fluoroquinolones and multidrug resistance among ­ coagulase-­negative Staphylococcus isolated from patients undergoing multiple intravitreal injections for choroidal neovascularization. –– Kim SJ et  al. (2011): In this prospective, randomized, controlled, clinical trial of 48 eyes (24 patients) undergoing unilateral intravitreal injections for choroidal neovascularization, it was concluded that repeated exposure of surface ocular flora to ophthalmic antibiotics selects for resistant strains. –– Cheung CSY et  al. (2012): Retrospective, comparative case series reported the effect of different antibiotic prophylaxis strategies on the incidence of endophthalmitis after intravitreal injections of anti-vascular endothelial growth factors and triamcinolone acetonide. In this study, the rate of endophthalmitis after intravitreal injection was greater with the use of post-operative topical antibiotics (given for 5  days after injection) compared with no antibiotics. Category •  no antibiotics

Rates of endophthalmitis, n/N (%) •  2/5266 (0.04%)

•  with antibiotics

•  7/10,629 (0.07%)

–– Yannuzzi et al. (OSLI-Retina 2017): This is a retrospective case series (2006 and 2016) of 38 patients with endophthalmitis associated with intravitreal injection of anti-VEGF agents [27 (71%) referred and 11 (29%) in-­ house patients]. At the Bascom Palmer Eye Institute, topical antibiotics were not used before, during, or after intravitreal injections after 2008. The rates of post-­ injection endophthalmitis during the time period when no topical antibiotics were used (2015–2016) were approximately 1 in 20,000 compared to the time period

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when topical antibiotics were utilized (2006–2007) which were approximately 1  in 4000 injections performed. This implies that topical antibiotics are not essential to prevent post-intravitreal injection endophthalmitis. –– Reyes Capo (OSLI-Retina 2021): This retrospective case series (2018–2020) showed a very low rate of endophthalmitis in spite of using no topical therapy before or after intravitreal injections. References: Pre-Operative Topical Antibiotics • Allen HF. Aseptic technique in ophthalmology. Trans Am Ophthalmol Soc. 1959;57:377–472. • Allen HF.  Recent advances in aseptic surgical technique. Trans Am Acad Ophthalmol Otolaryngol. 1960;64:493–9. • Allen HF, Mangiaracine AB.  Bacterial endophthalmitis after cataract extraction. II. Incidence in 36,000 consecutive operations with special reference to preoperative topical antibiotics. Arch Ophthalmol. 1974;91(1):3–7. • Cheung CS, Wong AW, Lui A, Kertes PJ, Devenyi RG, Lam WC.  Incidence of endophthalmitis and use of antibiotic prophylaxis after intravitreal injections. Ophthalmology. 2012;119(8):1609–14. • Huang J, Wang X, Chen X, Song Q, Liu W, Lu L. Perioperative antibiotics to prevent acute endophthalmitis after ophthalmic surgery: a systematic review and meta-analysis. PLoS One. 2016;11(11):e0166141. • Jabbarvand M, Hashemian H, Khodaparast M, Jouhari M, Tabatabaei A, Rezaei S.  Endophthalmitis occurring after cataract surgery: outcomes of more than 480,000 cataract surgeries, epidemiologic features, and risk factors. Ophthalmology. 2016;123(2):295–301. • Kim SJ, Toma HS. Ophthalmic antibiotics and antimicrobial resistance a randomized, controlled study of patients undergoing intravitreal injections. Ophthalmology. 2011;118(7):1358–63. • Kim SJ, Toma HS, Midha NK, Cherney EF, Recchia FM, Doherty TJ. Antibiotic resistance of conjunctiva and naso-

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pharynx evaluation study: a prospective study of patients undergoing intravitreal injections. Ophthalmology. 2010;117(12):2372–8. • Yannuzzi NA, Gregori NZ, Rosenfeld PJ, Relhan N, Patel NA, Si N, Miller D, Dubovy SR, Smiddy WE, Schwartz SG, Flynn HW Jr. Endophthalmitis associated with intravitreal injections of anti-vascular endothelial growth factor agents at a tertiary referral center (in-house and referred cases). (OSLI-Retina 2017). • Kuklo P, Grzybowski A, Schwartz SG, Flynn HW, Pathengay A. Hot topics in perioperative antibiotics for cataract surgery. Curr Pharm Des. 2017;23(4):551–557. • Packer M, Chang DF, Dewey SH, Little BC, Mamalis N, Oetting TA, et al. Prevention, diagnosis, and management of acute postoperative bacterial endophthalmitis. J Cataract Refract Surg. 2011;37(9):1699–714.

Systemic Antibiotics Pre- or post-operative systemic antibiotics may be utilized in some cases to reduce rates of post-operative endophthalmitis. • Sharma et al. (2015) showed that oral antibiotics achieve low intraocular concentrations as compared to topical antibiotics in patients undergoing cataract surgery. The role of oral antibiotics in preventing post-operative endophthalmitis after cataract surgery remains unknown. • However, in patients presenting with open globe injury, systemic antibiotics (pre-operative/intra-operative/post-­ operative) are utilized. Prophylactic systemic antibiotics are considered as follows in cases of open globe injury: –– Vancomycin 1 g IV bid plus ceftazidime 1 g IV bid prior to surgery. –– Levofloxacin 500–750 mg PO prior to surgery.

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References: Povidone-Iodine • Ahmed Y, Scott IU, Pathengay A, Bawdekar A, Flynn HW, Jr. Povidone-iodine for endophthalmitis prophylaxis. Am J Ophthalmol. 2014;157(3):503–4. • Apt L, Isenberg SJ, Yoshimori R, Chang A, Lam GC, Wachler B, et  al. The effect of povidone-iodine solution applied at the conclusion of ophthalmic surgery. American Journal of Ophthalmology. 1995;119(6):701–5. • Apt L, Isenberg SJ, Yoshimori R, Spierer A.  Outpatient topical use of povidone-iodine in preparing the eye for surgery. Ophthalmology. 1989;96(3):289–92. • Friedman DA, Mason JO, third, Emond T, McGwin G, Jr. Povidone-iodine contact time and lid speculum use during intravitreal injection. Retina. 2013;33(5):975–81. • Mendivil Soto A, Mendivil MP. The effect of topical povidone–iodine, intraocular vancomycin, or both on aqueous humor cultures at the time of cataract surgery. Am J Ophthalmol. 2001;131(3):293–300. • Merani R, Hunyor AP. Endophthalmitis after intravitreal injections in patients with self-reported iodine allergy. Am J Ophthalmol. 2017;176:256–7. • Modjtahedi BS, van Zyl T, Pandya HK, Leonard RE, second, Eliott D. Endophthalmitis after intravitreal injections in patients with self-reported iodine allergy. Am J Ophthalmol. 2016;170:68–74. • Nakashizuka H, Shimada H, Hattori T, Noguchi T, Kokubo N, Yuzawa M.  Vitrectomy using 0.025% povidone-iodine in balanced salt solution plus for the treatment of postoperative endophthalmitis. Retina. 2015;35(6):1087–94. • Nentwich MM, Ta CN, Kreutzer TC, Li B, Schwarzbach F, Yactayo-Miranda YM, et  al. Incidence of postoperative endophthalmitis from 1990 to 2009 using povidoneiodine but no intracameral antibiotics at a single academic institution. J Cataract Refract Surg. 2015;41(1):58–66.

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• Sharma T, Kamath MM, Kamath MG, Nayak RR, Bairy KL, Musmade PB. Aqueous penetration of orally and topically administered moxifloxacin. Br J Ophthalmol. 2015;99(9):1182–5. • Wan KH, Radke N, Lam DS. Endophthalmitis after intravitreal injections in patients with self-reported iodine allergy. Am J Ophthalmol. 2017;176:260. • Wykoff CC, Flynn HW, Jr., Han DP. Allergy to povidone-­ iodine and cephalosporins: the clinical dilemma in ophthalmic use. Am J Ophthalmol. 2011;151(1):4–6.

 ndophthalmitis Prophylaxis for Specific Case E Scenarios • Endophthalmitis prophylaxis for cataract surgery. • Endophthalmitis prophylaxis for intravitreal injections. • Endophthalmitis prophylaxis for open globe injuries.

Endophthalmitis Prophylaxis for Cataract Surgery • Pre-operative povidone-iodine antisepsis is well documented to reduce endophthalmitis rates (Fig. 9.1). –– 5% povidone-iodine to ocular surface in holding room prior to surgery –– 10% povidone-iodine to lids and lashes immediately before surgery –– Drape to cover eyelashes and lid margins. • Pre- and post-operative topical antibiotics are widely used but there is relatively little evidence to support their efficacy in actually reducing endophthalmitis rates. • Intracameral antibiotics. –– The European Society of Cataract & Refractive Surgeons (ESCRS) randomized patients to topical levofloxacin, intracameral cefuroxime, both, or neither. They reported an approximate fivefold reduction in

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endophthalmitis rates associated with intracameral cefuroxime. Criticisms of the ESCRS study: Relatively high rates of endophthalmitis in eyes not treated with intracameral cefuroxime (about 0.2%). Multiple surgical techniques were allowed. Use of topical levofloxacin, rather than fourth-­ generation fluoroquinolones. –– Many retrospective series have documented a decreased rate of endophthalmitis associated with intracameral antibiotics. These studies generally compare patients from an earlier time frame (operated without intracameral antibiotics) to patients from a later time frame (operated with intracameral antibiotics). Criticisms of these cohort studies: Endophthalmitis rates may decrease over time for many reasons other than the use of intracameral antibiotics. Multiple surgeons. Different patients. Different techniques. Different equipment. Unknown factors. Current status of intracameral antibiotics—The use of intracameral antibiotics during cataract surgery varies widely around the world. For example, they are used routinely in Europe, but much less frequently in the US and other locations. Three antibiotics for intracameral use during cataract surgery have been primarily reported. These are vancomycin, cefuroxime, and moxifloxacin. All three antibiotics have limitations and risks that must be considered. • Vancomycin, a glycopeptide antibiotic, is usually effective against most Gram-positive organisms (Streptococcus, Staphylococcus, and Bacillus species). Vancomycin is associated with hemorrhagic occlusive retinal vasculitis (HORV), a poorly understood and potentially devastating complication.

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• Cefuroxime is a second-generation cephalosporin antibiotic and has broad-spectrum activity against the beta-­ lactamase-­positive pathogens. It is effective against various organisms, such as Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Escherichia coli, Neisseria gonorrhea, and many others. Intracameral cefuroxime has been studied in a RCT, but a prepackaged formulation indicated for intracameral use (Aprokam, Thea Pharmaceuticals, Clermont-Ferrand, France) is unavailable in many nations, including the United States, India, and Japan. This has been associated with risks of dilution error and infection during reconstitution. • Moxifloxacin is a fourth-generation synthetic fluoroquinolone antibacterial agent and is used as an off-label intracameral antibiotic. This is increasingly used as the drug is readily available. It is active against a broad spectrum of bacteria including Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella spp., Moraxella catarrhalis, Enterobacter spp., Mycobacterium spp., and Bacillus anthracis. The paper by Stringham et  al. (JAMA 2017) highlights the increasing trend of fluoroquinolone nonsusceptibilities among coagulase-negative Staphylococcus isolates causing endophthalmitis reviewed over the past 22 years at the Bascom Palmer Eye Institute, Miami. This study reported that among coagulase-negative Staphylococcus isolates, non-susceptibility to fluoroquinolones increased over time. The risks of compounding errors, contamination, storage, and transport of the drug are important concerns. Cakir et al. (2009) reported a case series of Fusarium endophthalmitis in eight patients in whom compounded intracameral cefuroxime was used. There is a potential risk for toxic anterior segment syndrome (TASS) and corneal endothelial toxicity with all intracameral agents. Aside from toxicity, there are concerns about fluoroquinolone’s antimicrobial efficacy. Coagulase-negative Staphylococcus (CoNS ) is the most common cause of post-­

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cataract surgery endophthalmitis. In the United States, fluoroquinolone (including moxifloxacin) resistance rates among CoNS endophthalmitis isolates have been reported as high as 40–60%. All intracameral antibiotics are associated with increased costs (moxifloxacin costs average retail price ranges from $175 to $22 per vial in the United States) as well as increased risks of emergence of drug resistance. The risk of post-cataract surgery endophthalmitis in the United States without the use of intracameral antibiotics is about 0.02– 0.1%. Even using a 0.1% incidence rate for calculations, it would require intracameral injection in 999 cases in order to prevent one case of endophthalmitis. These 999 patients would be exposed to increased costs in addition to risks of dilution errors, TASS, and corneal endothelial toxicity.

Corneal Wound Closure Modern cataract surgery is generally sutureless. Post-­ operative reopening of self-sealed incisions could create a risk for influx of potentially contaminated tear fluid. Ernest et al. reported that proper construction of squared clear corneal incision may reduce the risk of endophthalmitis due to improved adhesion of the corneal stroma. Wallin et  al. reported 40 times increased endophthalmitis risk in patients with wound leaks on the first post-operative day. References: European Society of Cataract and Refractive Surgeons (ESCRS) Multicenter Study • Barry P.  Adoption of intracameral antibiotic prophylaxis of endophthalmitis following cataract surgery: update on the ESCRS Endophthalmitis Study. J Cataract Refract Surg. 2014;40(1):138–42. • Barry P, Seal DV, Gettinby G, Lees F, Peterson M, Revie CW. ESCRS study of prophylaxis of postoperative endophthalmitis after cataract surgery. J Cataract Refract Surg. 2006;32(3):407–10.

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• Behndig A, Cochener B, Guell JL, Kodjikian L, Mencucci R, Nuijts RM, et al. Endophthalmitis prophylaxis in cataract surgery: overview of current practice patterns in 9 European countries. J Cataract Refract Surg. 2013;39(9):1421–31. • Beselga D, Campos A, Castro M, Fernandes C, Carvalheira F, Campos S, et  al. Postcataract surgery endophthalmitis after introduction of the ESCRS protocol: a 5-year study. Eur J Ophthalmol. 2014;24(4):516–9. • Endophthalmitis Study Group ESoC, Refractive S. Prophylaxis of postoperative endophthalmitis following cataract surgery: results of the ESCRS multicenter study and identification of risk factors. J Cataract Refract Surg. 2007;33(6):978–88. • Garcia-Saenz MC, Arias-Puente A, Rodriguez-Caravaca G, Banuelos JB. Effectiveness of intracameral cefuroxime in preventing endophthalmitis after cataract surgery Ten-­ year comparative study. J Cataract Refract Surg. 2010;36(2):203–7. • Seal DV, Barry P, Gettinby G, Lees F, Peterson M, Revie CW, et  al. ESCRS study of prophylaxis of postoperative endophthalmitis after cataract surgery: case for a European multicenter study. J Cataract Refract Surg. 2006;32(3):396–406. References: Endophthalmitis Prophylaxis for Cataract Surgery References: General • Ahmed Y, Scott IU, Pathengay A, Bawdekar A, Flynn HW, Jr. Povidone-iodine for endophthalmitis prophylaxis. Am J Ophthalmol. 2014;157(3):503–4. • Chang DF, Braga-Mele R, Henderson BA, Mamalis N, Vasavada A, Committee ACC.  Antibiotic prophylaxis of postoperative endophthalmitis after cataract surgery: results of the 2014 ASCRS member survey. J Cataract Refract Surg. 2015;41(6):1300–5.

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• Ciulla TA, Starr MB, Masket S. Bacterial endophthalmitis prophylaxis for cataract surgery: an evidence-based update. Ophthalmology. 2002;109(1):13–24. • Miller D, Flynn PM, Scott IU, Alfonso EC, Flynn HW, Jr. In vitro fluoroquinolone resistance in staphylococcal endophthalmitis isolates. Arch Ophthalmol. 2006;124(4):479–83. • Scott IU, Flynn HW Jr., Endophthalmitis: prevention and Management. In: Han Eds: Cataract surgery and retinal diseases: optimizing visual outcome. BMC, Philadelphia. ISBN: 978–0–615-84,030-7, 2013. • Wallin T, Parker J, Jin Y, Kefalopoulos G, Olson RJ. Cohort study of 27 cases of endophthalmitis at a single institution. J Cataract Refract Surg. 2005 Apr;31(4):735–41. • Grzybowski A., Koerner J.C., George M.J.  Postoperative endophthalmitis after cataract surgery: A worldwide review of etiology, incidence and the most studied prophylaxis measures. Expert Review of Ophthalmology 2019 doi: https://doi.org/10.1080/17469899.2019.1674140 • Sengillo J.D., Chen Y., Garcia Perez D., Schwartz S.G., Grzybowski A., Flynn Jr. H.W.  Postoperative Endophthalmitis and Toxic Anterior Segment Syndrome Prophylaxis: 2020 Update. Annals of Translational Medicine 2020, doi: https://doi.org/10.21037/ atm-­2019-­rcs-­02 References: Cataract Surgery (Pre-Operative/Post-Operative Prophylaxis) • Chen RW, Rachitskaya A, Scott IU, Flynn HW, Jr. Is the use of topical antibiotics for intravitreal injections the standard of care or are we better off without antibiotics? JAMA Ophthalmol. 2013;131(7):840–2. • Yannuzzi NA, Si N, Relhan N, Kuriyan AE, Albini TA, Berrocal AM, et  al. Endophthalmitis after clear corneal cataract surgery: outcomes over two decades. Am J Ophthalmol. 2017;174:155–9.

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• Grzybowski A., Shimada H, Nakashizuka H, Koerner J.  Low-concentration povidone-iodine for the prevention of intraocular infections in ophthalmic surgery Current Opinion in Ophthalmology 2021 Nov 1. doi: https://doi. org/10.1097/ICU.0000000000000817 References: Cataract Surgery (Intra-Operative Prophylaxis) • Alfonso EC, Flynn HW, Jr. Controversies in endophthalmitis prevention. The risk for emerging resistance to vancomycin. Arch Ophthalmol. 1995;113(11):1369–70. • Axer-Siegel R, Stiebel-Kalish H, Rosenblatt I, Strassmann E, Yassur Y, Weinberger D. Cystoid macular edema after cataract surgery with intraocular vancomycin. Ophthalmology. 1999;106(9):1660–4. • Gills JP.  Filters and antibiotics in irrigating solution for cataract surgery. J Cataract Refract Surg. 1991;17(3):385. • Gills JP, Rowsey JJ. Bacterial endophthalmitis prophylaxis: Author reply. Ophthalmology. 2003;110(8):1668. • Gritz DC, Cevallos AV, Smolin G, Whitcher JP, Jr. Antibiotic supplementation of intraocular irrigating solutions. An in  vitro model of antibacterial action. Ophthalmology. 1996;103(8):1204–8; discussion 8–9. • Mendivil Soto A, Mendivil MP. The effect of topical povidone–iodine, intraocular vancomycin, or both on aqueous humor cultures at the time of cataract surgery. Am J Ophthalmol. 2001;131(3):293–300. • Montan PG, Wejde G, Koranyi G, Rylander M. Prophylactic intracameral cefuroxime. J Cataract Refract Surg. 2002;28(6):977–81. • Packer M, Chang DF, Dewey SH, Little BC, Mamalis N, Oetting TA, et al. Prevention, diagnosis, and management of acute postoperative bacterial endophthalmitis. J Cataract Refract Surg. 2011;37(9):1699–714. • Rahman N, Murphy CC. Impact of intracameral cefuroxime on the incidence of postoperative endophthalmitis following cataract surgery in Ireland. Ir J Med Sci. 2015;184(2):395–8.

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• Schimel AM, Alfonso EC, Flynn HW, Jr. Endophthalmitis prophylaxis for cataract surgery: are intracameral antibiotics necessary? JAMA Ophthalmol. 2014;132(11):1269–70. • Schwartz SG, Flynn HW, Jr., Grzybowski A, Relhan N, Ferris FL, 3rd. Intracameral antibiotics and cataract surgery: endophthalmitis rates, costs, and stewardship. Ophthalmology. 2016;123(7):1411–3. • Townsend-Pico WA, Meyers SM, Langston RH, Costin JA.  Coagulase-negative Staphylococcus endophthalmitis after cataract surgery with intraocular vancomycin. Am J Ophthalmol. 1996;121(3):318–9. • Witkin AJ, Shah AR, Engstrom RE, Kron-Gray MM, Baumal CR, Johnson MW, et  al. Postoperative hemorrhagic occlusive retinal vasculitis: expanding the clinical spectrum and possible association with vancomycin. Ophthalmology. 2015;122(7):1438–51. • Fine IH, Hoffman RS,Packer M.Profile of clear corneal cataract incisions demonstrated by ocular coherence tomography.J Cataract Refract Surg.2007;33(1):94–97. • Results suggest that by suturing the corneal incisions, by initiating antibiotic eye drops within the first 24 h of surgery and by instilling povidone-iodine drops after closure, the incidence of endophthalmitis after cataract surgery could possibly be reduced. • Zafar S, Dun C, Srikumaran D, Wang P, Schein OD, Makary M, Woreta F.  Endophthalmitis Rates among Medicare Beneficiaries Undergoing Cataract Surgery between 2011 and 2019. Ophthalmology. 2022 Mar;129(3):250–257. References: Cataract Surgery Prophylaxis (Intracameral Antibiotics) • Cakir M, Imamoglu S, Cekic O, Bozkurt E, Alagoz N, Oksuz L, et al. An outbreak of early-onset endophthalmitis caused by Fusarium species following cataract surgery. Curr Eye Res. 2009;34(11):988–95. • Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013: centers for

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•

•

•

• •

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disease control and prevention, US Department of Health and Human Services, 2013. CDC issues recommendations for preventing spread of vancomycin resistance. Am J Health Syst Pharm 1995;52(12):1272–4. Cook RJ, Sackett DL. The number needed to treat: a clinically useful measure of treatment effect. BMJ. 1995;310(6977):452–4. Delyfer MN, Rougier MB, Leoni S, Zhang Q, Dalbon F, Colin J, et al. Ocular toxicity after intracameral injection of very high doses of cefuroxime during cataract surgery. J Cataract Refract Surg. 2011;37(2):271–8. Grzybowski A, Schwartz SG, Matsuura K, Ong Tone S, Arshinoff S, Ng JQ, et al. Endophthalmitis prophylaxis in cataract surgery: overview of current practice patterns around the world. Curr Pharm Des. 2017;23(4):565–73. Haripriya A, Chang DF, Namburar S, Smita A, Ravindran RD. Efficacy of intracameral moxifloxacin endophthalmitis prophylaxis at Aravind eye hospital. Ophthalmology. 2016;123(2):302–8. Herrinton LJ, Shorstein NH, Paschal JF, Liu L, Contreras R, Winthrop KL, et al. Comparative effectiveness of antibiotic prophylaxis in cataract surgery. Ophthalmology. 2016;123(2):287–94. Jabbarvand M, Hashemian H, Khodaparast M, Jouhari M, Tabatabaei A, Rezaei S.  Endophthalmitis occurring after cataract surgery: outcomes of more than 480,000 cataract surgeries, epidemiologic features, and risk factors. Ophthalmology. 2016;123(2):295–301. Liesegang TJ.  Intracameral antibiotics: questions for the United States based on prospective studies. J Cataract Refract Surg. 2008;34(3):505–9. Schimel AM, Miller D, Flynn HW, Jr. Endophthalmitis isolates and antibiotic susceptibilities: a 10-year review of culture-proven cases. Am J Ophthalmol. 2013;156(1):50–2 e1.

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• Schwartz SG, Flynn HW, Jr., Grzybowski A, Relhan N, Ferris FL, 3rd. Intracameral antibiotics and cataract surgery: endophthalmitis rates, costs, and stewardship. Ophthalmology. 2016;123(7):1411–3. • Sharma S, Sahu SK, Dhillon V, Das S, Rath S. Reevaluating intracameral cefuroxime as a prophylaxis against endophthalmitis after cataract surgery in India. J Cataract Refract Surg. 2015;41(2):393–9. • Witkin AJ, Chang DF, Jumper JM, Charles S, Eliott D, Hoffman RS, et  al. Vancomycin-associated hemorrhagic occlusive retinal vasculitis: clinical characteristics of 36 eyes. Ophthalmology. 2017;124(5):583–95.

 ndophthalmitis Prophylaxis for Intravitreal E Injections The community standard for endophthalmitis prophylaxis during intravitreal injections continues to evolve, but there appears to be a shift toward focusing on antisepsis and away from the use of peri-intravitreal injection antibiotics. Table 9.1 provides the updated guidelines of an expert panel. References: Intravitreal Injections (Endophthalmitis Prophylaxis) • Aiello LP, Brucker AJ, Chang S, Cunningham ET, Jr., D’Amico DJ, Flynn HW, Jr., et al. Evolving guidelines for intravitreous injections. Retina. 2004;24(5 Suppl):S3–19. • Avery RL, Bakri SJ, Blumenkranz MS, Brucker AJ, Cunningham ET, Jr., D’Amico DJ, et al. Intravitreal injection technique and monitoring: updated guidelines of an expert panel. Retina. 2014;34 Suppl 12:S1-S18. • Wykoff CC, Flynn HW, Jr. Endophthalmitis after intravitreal injection: prevention and management. Retina. 2011;31(4):633–5.

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Table 9.1 Guidelines of an expert panel on intravitreal injection technique and monitoring Injection 2014 technique 2004 Pupillary dilation Necessary No consensus Sterile drape

No

No

Gloves (universal precautions)

Yes

Yes, but many do not use gloves

Speculum use

Recommended

No consensus

Povidone-iodine: Prep

Yes, lids, lashes, and ocular surface

Yes, last drop applied to ocular surface (+/− lids)

Povidone-iodine: Allergy

Rare (consider skin test)

Rare (use focal application)

Pre-, peri-, or post-injection antibiotics

Considered but no consensus

No, 100% agreement

Needle size

27 g or smaller

30 g or smaller

Masks or minimize speaking

Not addressed

Yes

Monitor IOP

Yes

Yes

AC paracentesis

Generally, avoid

Generally, avoid

Post-inject call to patient

Call within 1 week

Tailored to individual patient

• Wykoff CC, Flynn HW, Jr., Rosenfeld PJ. Prophylaxis for endophthalmitis following intravitreal injection: antisepsis and antibiotics. Am J Ophthalmol. 2011;152(5):717–9 e2. • Lytvynchuk LM, Petrovski G, Dam A, Hiemstra J, Wimmer T, Savytska I, Binder S, Stieger K.  Novel Needle for Intravitreal Drug Delivery: Comparative Study of Needle Tip Aspirates, Injection Stream and Penetration Forces. Clin Ophthalmol. 2021 Feb 19;15:723–734. doi: https://doi. org/10.2147/OPTH.S297139.

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 ndophthalmitis Prophylaxis for Open Globe E Injuries • Prophylactic Intravitreal Antibiotics. –– Zone 1 open globe injury—May be considered depending upon the nature of injury. –– Zone 2 or 3 open globe injury—Intravitreal antibiotics are more often considered. • Prophylactic Systemic Antibiotics Guidelines: –– Vancomycin 1 g IV bid plus ceftazidime 1 g IV bid prior to surgery or. –– Levofloxacin 500–750 mg PO prior to surgery. References: Endophthalmitis Associated with Open Globe Injuries • Andreoli MT, Andreoli CM. Surgical rehabilitation of the open globe injury patient. Am J Ophthalmol. 2012;153(5):856–60. • Cebulla CM, Flynn HW, Jr. Endophthalmitis after open globe injuries. Am J Ophthalmol. 2009;147(4):567–8. • Parke DW, third, Flynn HW, Jr., Fisher YL. Management of intraocular foreign bodies: a clinical flight plan. Can J Ophthalmol. 2013;48(1):8–12. • Parke DW, third, Pathengay A, Flynn HW, Jr., Albini T, Schwartz SG. Risk factors for endophthalmitis and retinal detachment with retained intraocular foreign bodies. J Ophthalmol. 2012;2012:758,526. • Reynolds DS, Flynn HW, Jr. Endophthalmitis after penetrating ocular trauma. Curr Opin Ophthalmol. 1997;8(3):32–8.

Chapter 10 Retinal Detachment (RD) and Endophthalmitis

In patients with endophthalmitis, the occurrence of rhegmatogenous retinal detachment (RD) is generally associated with poor visual outcomes. Management of such patients can pose a surgical challenge. While managing the endophthalmitis, RD can be identified at the time of presentation, during vitrectomy, or in the post-operative time period. Indirect ophthalmoscopy, echography, or direct visualization under an operating microscope may confirm the diagnosis. • • • •

Frequency Visual outcomes Presentation Risk factors associated with poor visual outcomes

 requency: Retinal Detachment F in Endophthalmitis • In the Endophthalmitis Vitrectomy Study (EVS), patients with RD at initial diagnosis of endophthalmitis were excluded. However, 8.3% patients overall developed RD during follow-up.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 H. W. Flynn Jr. et al., Endophthalmitis in Clinical Practice, In Clinical Practice, https://doi.org/10.1007/978-3-031-35184-6_10

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• The rates of RD among group of patients undergoing vitrectomy, needle vitreous aspiration, and mechanical vitreous biopsy were 7.8, 11, and 8%, respectively (not statistically significant).

 isual Outcomes: Retinal Detachment V in Endophthalmitis • In the EVS patients with available data, final visual acuity 20/40 or better was reported in 27% patients with RD compared to 55% patients without RD. • The overall visual outcomes in this subgroup of the EVS were reported to be poor with more than half, 53.3%, of patients with RD achieving visual acuity worse than 5/200 despite a high anatomic success rate of 78%.

 resentation: Retinal Detachment P in Endophthalmitis • Patients with endophthalmitis and concurrent RD • Patients with endophthalmitis and delayed-onset RD In the setting of endophthalmitis, RD developing after vitrectomy surgery has been reported to range from 4.6 to 16% (compared to 5% in vitrectomy performed for non-­ endophthalmitis cases).

 isk Factors Associated with Poor Visual R Outcomes in Eyes with RD and Endophthalmitis RD associated with endophthalmitis is associated with generally poor anatomic and visual outcomes. The following are the risk factors associated with poor visual outcomes:

Hyperoleon

191

• Infection with more virulent organisms • Open globe injuries • Retained intraocular foreign body

 ole of Silicone Oil in Endophthalmitis R Patients (Fig. 10.1) Silicone oil may be utilized in cases with endophthalmitis. Silicone oil is reported to have antimicrobial properties as well as stabilize the eye and may even help in maintaining the integrity of the eyeball (prevent the need for evisceration/ enucleation). Silicone oil tamponade changes the pharmacokinetics of intravitreal antibiotics and makes the time of drug activity and calculation of the dosing unpredictable. Generally, it is recommended to inject 50% of antibiotic solution used for non-vitrectomized eyes due to antibiotics’ retinal toxicity.

Hyperoleon Retinal detachment surgery following infusion of silicone oil may result in many complications. One such complication is that emulsification of silicone oil may fill the superior portion of the anterior chamber, and manifest as an inverted hypopyon, also known as hyperoleon. Hyperoleon can masquerade hypopyon from endophthalmitis.

Antimicrobial Properties of Silicone Oil • Ozdamar et  al. (In 1999)—This experimental study showed antimicrobial activity of silicone oil against endophthalmitis-­causing agents in vitro. In this study, the antimicrobial activity of silicone oil (1300 centistokes) was demonstrated against Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Candida albicans, and Aspergillus spp. However, in one

192

Chapter 10.  Retinal Detachment (RD)…

Figure 10.1  59-year-old female with a superior hyperoleon of the right eye. The external photography demonstrates a large, superior silicone oil emulsification with clear cornea. Slit-lamp photograph shows silicone oil in the anterior chamber (left)

report by Arici et  al. (2016), anaerobic bacteria such as Cutibacterium acnes were reported to be resistant to silicone oil.

 iterature: Silicone Oil in Endophthalmitis L and Rhegmatogenous Retinal Detachment • Nagpal et  al. (2012)—This is a prospective, randomized, interventional, comparative study comprising 129 eyes with endophthalmitis (postsurgical and traumatic) that underwent PPV.  Anatomic and visual outcomes among the following groups were compared: • Group 1 (pars plana vitrectomy alone n = 65 eyes) • Group 2 (pars plana vitrectomy with silicone oil injection, n = 64 eyes) In this study, group undergoing pars plana vitrectomy (PPV) with silicone oil injection resulted in significantly better anatomic outcomes and significantly less need for additional surgery as compared with PPV alone.

Hyperoleon

a

193

b

Figure 10.2  (a) Post-intravitreal injection endophthalmitis following penetrating keratoplasty. (b) Eye underwent pars plana vitrectomy fluid-air exchange, injection of intravitreal voriconazole and amphotericin-­B and silicone oil injection which lead to resolution of infection and inflammation

• Dave et  al. (2017)—Anatomic and functional treatment outcomes of 93 patients with endophthalmitis and concurrent or delayed-onset retinal detachment are reported (Figs. 10.2 and 10.3). RD was diagnosed at presentation in 20/93 (21.5%) patients (concurrent group—group 1) and during follow-up in the remaining 73/93 (78.5%) patients (delayed-onset group—group 2). In group 1, the initial treatment consisted of vitrectomy, intravitreal antibiotics, and silicone oil injection in 19/20 patients. In group 2, patients did not receive silicone oil during initial treatment but underwent silicone oil injection during subsequent surgery for repair of retinal detachment. • Group 1 (concurrent group)—Rates of complete retinal reattachment and visual acuity ≥20/400 were 73.7 and 30.0%, respectively. • Group 2 (delayed-onset group)—Rates of complete retinal reattachment and visual acuity ≥20/400 were 98.5 and 39.7%, respectively. The median visual acuity at the last follow-up in 44 eyes undergoing silicone oil removal was 20/100 (logMAR 0.7) while in the remaining 49 eyes which did not undergo silicone oil removal was 20/2000 (logMAR 2.0). Although 53/93

194

Chapter 10.   Retinal Detachment (RD) …

a

b

c

d

e

f

Figure 10.3 Post-intravitreal injection endophthalmitis—80-yearold male patient with neovascular age-related macular degeneration (AMD) presented 2  days after intravitreal ranibizumab injection with sudden painful decrease in vision (Steers et al., 2002). (a) Slit-­ lamp examination showed conjunctival congestion, corneal edema, hypopyon, fibrinous reaction in the anterior chamber, hazy view of the posterior segment, and light perception (LP) visual acuity. The patient underwent vitreous TAP and intraocular antibiotic injection. The vitreous culture was positive for Streptococcus mitis/Streptococcus oralis. (b, c) Inflammation reduced but vitreous exudates persisted. (d–f) Six days after pars plana vitrectomy, lensectomy, and silicone oil injection showing resolving inflammation, retinal thinning on OCT, pale optic disc, and attached retina in silicone oil-filled eye

(57%) eyes in this series had a final vision as only light perception or no light perception, none of the eyes needed to be eviscerated or enucleated. In these endophthalmitis patients with concurrent or delayed-onset retinal detachment, the use of silicone oil can be a useful adjunct. References: Retinal Detachment (RD) in Endophthalmitis • Affeldt JC, Flynn HW, Jr., Forster RK, Mandelbaum S, Clarkson JG, Jarus GD.  Microbial endophthalmitis

Hyperoleon

•

• •

• • •

• •

• •

195

resulting from ocular trauma. Ophthalmology. 1987;94(4):407–13. Arici C, Aras C, Tokman HB, Torun MM.  An in  vitro experimental study on the antimicrobial activity of silicone oil against anaerobic bacteria. Ocul Immunol Inflamm. 2016;24(2):173–7. Brinton GS, Topping TM, Hyndiuk RA, Aaberg TM, Reeser FH, Abrams GW.  Posttraumatic endophthalmitis. Arch Ophthalmol. 1984;102(4):547–50. Dave VP, Pathengay A, Relhan N, et  al. Endophthalmitis and concurrent or delayed-onset rhegmatogenous retinal detachment managed with pars plana vitrectomy, intravitreal antibiotics, and silicone oil. OSLI Retina 2017 Jul 1;48(7):546–551. PMID:28728182. Doft BM, Kelsey SF, Wisniewski SR. Retinal detachment in the endophthalmitis vitrectomy study. Arch Ophthalmol. 2000;118(12):1661–5. Foster RE, Rubsamen PE, Joondeph BC, Flynn HW, Jr., Smiddy WS.  Concurrent endophthalmitis and retinal detachment. Ophthalmology. 1994;101(3):490–8. Nagpal M, Jain P, Nagpal K. Pars plana vitrectomy with or without silicone oil endotamponade in surgical management of endophthalmitis. Asia Pac J Ophthalmol (Phila). 2012;1(4):216–21. Nelsen PT, Marcus DA, Bovino JA.  Retinal detachment following endophthalmitis. Ophthalmology. 1985;92(8):1112–7. Ozdamar A, Aras C, Ozturk R, Akin E, Karacorlu M, Ercikan C.  In vitro antimicrobial activity of silicone oil against endophthalmitis-causing agents. Retina. 1999;19(2):122–6. Vahey JB, Flynn HW, Jr. Results in the management of Bacillus endophthalmitis. Ophthalmic Surg. 1991;22(11):681–6. Parke DW 3rd, Pathengay A, Flynn HW Jr., Albini T, Schwartz SG. Risk factors for endophthalmitis and retinal detachment with retained intraocular foreign bodies. J Ophthalmol 2012;2012:758526

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• Imamura T, Kakinoki M, Hira D, Kitagawa T, Ueshima S, Kakumoto M, Terada T, Kawamoto I, Murase M, Ohji M.  Pharmacokinetics of Intravitreal Vancomycin and Ceftazidime in Silicone Oil-Filled Macaque Eyes. Transl Vis Sci Technol. 2021 Mar 1;10(3):1. • Leung, E.H., Stout, J.T. Antibiotics and antifungals in silicone oil. Int J Retin Vitr 5, 50 (2019).

Chapter 11 Antibiotic Stewardship

In order to address emerging antimicrobial resistance (Fig. 11.1), the US Centers for Disease Control and Prevention (CDC) recommends antibiotic stewardship programs to opti-

a

b

Figure 11.1 Antimicrobial resistance determination. (a) E-test showing Leuconostoc species with minimum inhibitory concentration (MIC) levels of 4  μg/mL (black Arrow) to vancomycin E-test strip, indicating intermediate resistance to vancomycin. (b) Lower part of the culture plate shows clear zone around vancomycin disc (30  μg). Growth of Leuconostoc species over brain–heart infusion (BHI) agar containing vancomycin (6  μg/mL) indicating reduced vancomycin susceptibility © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 H. W. Flynn Jr. et al., Endophthalmitis in Clinical Practice, In Clinical Practice, https://doi.org/10.1007/978-3-031-35184-6_11

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mize antibiotic selection and reduce the inappropriate use of broad-spectrum antibiotics especially for prophylaxis. The new medication management standards (MM.09.01.01) for hospitals, critical access hospitals, and nursing care centers became effective January 1, 2017, and are available online at h tt p s : / / w w w. j o i n t c o m m i s s i o n . o rg / a s s e t s / 1 / 6 / N e w _ Antimicrobial_Stewardship_Standard.pdf. This new antimicrobial stewardship standard includes elements of leadership commitment (accountability documents, budget plans, performance improvement plans, strategic plans, use of electronic health records), education of staff and patients, multidisciplinary teams, analysis of individual medical center data, and application of these results toward improvement in treatment outcomes. In ophthalmology, antimicrobial use is mostly prophylactic, with little peer-reviewed evidence to support its use. There is no conclusive peer-reviewed evidence that pre- and post-­ operative topical antibiotics are beneficial for patients undergoing cataract surgery, yet these agents are very widely used around the world. With regard to elective intraocular procedures, antisepsis, rather than antibiotics, may be more ­important. In cataract surgery, there is no worldwide consensus regarding antibiotic prophylaxis in general and intracameral antibiotics in particular. Intracameral antibiotics are used more commonly in Europe than in the United States although the gap appears to be narrowing over time. For example, in the 2021 survey of members of the American Society of Cataract and Refractive Surgery (ASCRS), 66% reported the use of intracameral antibiotics, an increase from 50% in 2014. Prophylactic antibiotics are associated with increased costs, risks to the individual patient (dilution errors, contamination during compounding, toxic anterior segment syndrome (TASS), corneal endothelial toxicity, hemorrhagic occlusive retinal vasculitis (HORV), toxic effects on the retina, and others), and risks to society as a whole by contributing to emerging antimicrobial resistance. Of particular concern is vancomycin, which was reported used by 6% of US members of ASCRS in 2021 (a decrease from 52% in 2014). Vancomycin

Chapter 11.  Antibiotic Stewardship

199

is ­associated with a severe complication, HORV. In addition, vancomycin is a key component in the treatment of endophthalmitis, and its use in prophylaxis risks diminishing its effectiveness in treatment of established infections. For this reason, the US Centers for Disease Control and Prevention has recommended against the use of vancomycin in surgical prophylaxis. Antibiotic stewardship programs are hospital-based programs which can optimize the treatment of infections, reduce adverse events associated with antibiotic use, and help to mitigate these concerns. References: Antibiotic Stewardship • CDC guidelines  - Centers for Disease Control and Prevention. Core elements of hospital antibiotic stewardship programs. https://www.cdc.gov/getsmart/healthcare/ pdfs/core-­elements.pdf. Accessed 21 Jun 2017. • Relhan N, Albini TA, Pathengay A, Kuriyan AE, Miller D, Flynn HW.  Endophthalmitis caused by Gram-positive organisms with reduced vancomycin susceptibility: literature review and options for treatment. Br J Ophthalmol. 2016;100(4):446–52. • Relhan N, Pathengay A, Schwartz SG, Flynn HW, Jr. Emerging worldwide antimicrobial resistance, antibiotic stewardship and alternative intravitreal agents for the treatment of endophthalmitis. Retina. 2017;37(5):811–8. • Schwartz SG, Flynn HW, Jr., Grzybowski A, Relhan N, Ferris FL, 3rd. Intracameral antibiotics and cataract surgery: endophthalmitis rates, costs, and stewardship. Ophthalmology. 2016;123(7):1411–3. • Sengillo JD, Chen Y, Perez Garcia D, et al. Postoperative endophthalmitis and toxic anterior segment syndrome prophylaxis: 2020 update. Ann Transl Med 2020;8(22):1548. • Grzybowski A, Schwartz SG, Matsuura K, et  al. Endophthalmitis prophylaxis in cataract surgery: overview of current practice patterns around the world. Curr Pharm Des 2017;23(4):565–573

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• Chang DF, Rhee DJ. Antibiotic prophylaxis of postoperative endophthalmitis after cataract surgery: results of the 2021 ASCRS member survey. J Cataract Refract Surg 2022;48(1):3–7. • Schwartz SG, Relhan N, O’Brien TP, Flynn HW Jr. “A new complication associated with the use of prophylactic intracameral antibiotics: hemorrhagic occlusive retinal vasculitis. Ophthalmology 2017;124(5):578–9. • CDC issues recommendations for preventing spread of vancomycin resistance. Am J Health Syst Pharm 1995;52(12):1272–4.

Chapter 12 Outcomes (Anatomic and Functional) and Treatment-Related Complications Treatment outcomes are highly variable and are related to the infecting organism as well as the time to diagnosis and treatment. Prompt treatment is more important than any other consideration, including the decision between TAP and PPV. Treatment outcomes may be substantially worse in certain categories of endophthalmitis, such as post-traumatic and post-PPV, due to preexisting or concomitant posterior segment disease.

 reatment Outcomes of Acute-Onset Post-­ T Operative Endophthalmitis Following Cataract Surgery Treatment outcomes are discussed as reported by the following studies: (a) The EVS (b) Lalwani et al. (Ophthalmology, 1998) (c) Yannuzzi et al. (AJO 2017) (d) Kunkler et al. (JCRS 2022)

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Outcomes as Reported by the EVS The multicenter, randomized clinical trial enrolled 420 patients with clinical evidence of endophthalmitis within 6 weeks of cataract surgery or secondary intraocular lens (IOL) implantation. The EVS determined the roles of immediate pars plana vitrectomy and systemic antibiotic treatment in the management of acute-onset post-operative endophthalmitis. The reported outcomes were as follows: • 53% of patients had final visual acuity of 20/40 or better • 15% of patients had final visual acuity of 20/200 or worse • Coagulase-negative Staphylococci associated with best outcomes

Lalwani et al. 2008 Retrospective case series of 73 eyes of 73 patients with endophthalmitis treated at a single medical center between January 1, 1996, and December 31, 2005, for clinically diagnosed, culture-positive endophthalmitis occurring within 6 weeks of clear corneal cataract surgery. The reported outcomes were as follows: • Hypopyon was present in 60 of 73 (82.2%) eyes. The initial treatment included intravitreal vancomycin, ceftazidime, and dexamethasone. A vitreous tap and intravitreal injection were performed in 54 of 73 (74.0%) eyes and pars plana vitrectomy in 19 of 73 (26.0%) eyes. • Coagulase-negative Staphylococcus was isolated in 50 of 73 (68.4%) eyes. Other isolates included Staphylococcus aureus in 5/73 (6.8%) and Streptococcus species in 6 of 73 (8.2%). • A visual acuity of 20/40 or better was achieved in 36 of 73 patients (49.3%) at final follow-up. • The features and outcomes of endophthalmitis associated with clear corneal cataract surgery were similar to those

Treatment Outcomes of Acute-Onset Post-Operative…

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reported in the EVS, which are associated with scleral incisions, but the time to diagnosis was later with clear corneal incisions.

Yannuzzi et al. 2016 Retrospective case series of 63 eyes of 63 patients (clinical and microbiology records) with culture-positive endophthalmitis occurring within 6 weeks of clear corneal cataract surgery who presented to a tertiary referral center between 2006 and 2015 were analyzed. The reported outcomes were as follows: • Coagulase-negative Staphylococcus was isolated in 39 of 63 (62%) eyes, Staphylococcus aureus in 7 of 63 (11%) eyes, and Streptococcus species in 7 of 63 (11%) eyes. • A VA of 20/40 or better was achieved in 24 of 63 (38%) eyes. • A number of isolates were resistant to cephalosporins and fluoroquinolones. Comparison of Yannuzzi et  al. (2016) vs. Lalwani et  al. (2008). Both studies were reported from the same medical center. • The number of patients presenting with 5/200 or better was similar in both studies, but mean time to presentation was reported to be shorter in Yannuzzi et al. (8 vs. 13 days). • The overall distribution of organisms was similar between the two studies with coagulase-negative Staphylococcus comprising most cases. • While 19 (26%) of 73 eyes were treated with PPV as the initial treatment in Lalwani et al., only 6 (10%) of 73 eyes were treated with PPV as the initial treatment in Yannuzzi et al. (p = 0.013). • Final visual outcomes were slightly more favorable in Lalwani et al. with a larger proportion of patients achieving 20/40 and 20/100 or better, although these differences

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were not statistically significant (p = 0.189 and p = 0.058, respectively). There was, however, a statistically significant difference in the percentage of eyes ending with 5/200 or better (63 of 73 eyes, 86%, in Lalwani et al. vs. 45 of 63 eyes, 71%, in Yannuzzi et al. (p = 0.032). • Of the eyes with coagulase-negative Staphylococcus, 31 (62%) of 52 eyes achieved 20/40 or better in Lalwani et al. in comparison to 20 (51%) of 39  in Yannuzzi et  al. p = 0.310. • Both patients treated with tap and inject as the initial treatment and those treated with PPV and inject as the upfront treatment in Yannuzzi et  al. study fared slightly worse than Lalwani et  al. with fewer achieving 20/40 or 20/100 or better. A number of retrospective case series have been published on visual outcomes of endophthalmitis following cataract surgery. The Yannuzzi (2016) series reported final visual ­acuity outcomes of 20/40 or better in 38% of eyes, compared to the Lalwani (2008) series at 49.3%. The EVS (1995) achieved this outcome in 53% of eyes, but the EVS excluded patients with advanced diseases such as AMD, DME, and glaucoma. References: Treatment Outcomes Acute-Onset Endophthalmitis • Results of the Endophthalmitis Vitrectomy Study. A randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Endophthalmitis Vitrectomy Study Group. Arch Ophthalmol. 1995;113(12):1479–96. • Lalwani GA, Flynn HW, Jr., Scott IU, Quinn CM, Berrocal AM, Davis JL, et  al. Acute-onset endophthalmitis after clear corneal cataract surgery (1996–2005). Clinical features, causative organisms, and visual acuity outcomes. Ophthalmology. 2008;115(3):473–6. • Sridhar J, Yonekawa Y, Kuriyan AE, Joseph A, Thomas BJ, Liang MC, et  al. Microbiologic spectrum and visual out-

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comes of acute-onset endophthalmitis undergoing therapeutic pars plana vitrectomy. Retina. 2017;37(7):1246–51. • Thomas BJ, Mehta N, Yonekawa Y, Sridhar J, Kuriyan AE, Relhan N, et al. Pars plana vitrectomy for late vitreoretinal sequelae of infectious endophthalmitis: surgical management and outcomes. Retina. 2017;37(4):651–6. • Yannuzzi NA, Si N, Relhan N, Kuriyan AE, Albini TA, Berrocal AM, et  al. Endophthalmitis after clear corneal cataract surgery: outcomes over two decades. Am J Ophthalmol. 2017;174:155–9.

 reatment Outcomes of Delayed-Onset Post-­ T Operative Endophthalmitis Following Cataract Surgery The EVS only recruited patients with acute-onset post-­ operative endophthalmitis following cataract surgery or secondary intraocular lens (IOL) implantation. The EVS did not recruit patients with other categories of endophthalmitis. Visual outcomes are discussed as reported by the following two studies: (a) Clark et al. (1999) (b) Shirodkar et al. (2012)

Clark et al. Clark et  al. (1999) reported the treatment strategies and visual acuity outcomes of chronic postoperative endophthalmitis caused by Propionibacterium acnes (now known as Cutibacterium acnes). In this retrospective noncomparative case series of 36 patients treated at two institutions from 1974 to 1996, the mean follow-up after the last treatment was 2.9 years. Patients underwent three different initial treatment strategies: 1. Intraocular antibiotic injection alone (IOAB; n = 12)

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2. Pars plana vitrectomy and IOAB injection (PPV; n = 10) 3. PPV with subtotal capsulectomy and IOAB injection (PPV-PC; n = 14) • The number of patients with recurrent or persistent inflammation after one of the three initial treatment strategies was as follows: (1) IOAB alone, 12 (100%); (2) PPV, 5 (50%); and (3) PPV-PC, 2 (14%). • None of the patients that underwent subsequent PPV, total capsular bag removal, IOAB injection, and either intraocular lens (IOL) exchange or removal had persistent or recurrent intraocular inflammation. • Overall, final visual acuity was 20/40 or better in 18 patients (50%), and a total of 28 patients (78%) retained 20/400 or better vision. –– In this series of chronic C. acnes endophthalmitis, initial treatment with IOAB injection alone or vitrectomy without capsulectomy was associated with high rates of recurrent or persistent intraocular inflammation. –– Pars plana vitrectomy, partial capsulectomy, and IOAB injection without IOL exchange were usually successful on long-term follow-up. –– In patients with recurrent intraocular inflammation, pars plana vitrectomy, total capsular bag removal, IOAB injection, and IOL exchange or removal were a uniformly successful strategies. The study recommended that in contrast to other types of post-operative endophthalmitis, IOL exchange can be considered in these patients after total capsular bag removal.

Shirodkar et al. (2012) Shirodkar et  al. (2012) reported a large retrospective consecutive case series of 118 patients with delayed- and acute-­ onset endophthalmitis (culture-proven) after cataract surgery, who were treated at a tertiary referral center between January 2000 and December 2009. The study results were as follows (Table 12.1):

Treatment Outcomes of Delayed-Onset Post-Operative…

207

Table 12.1  Results of retrospective case series by Shirodkar et  al. 2012 Acute-onset Delayed-onset endophthalmitis (≤6 endophthalmitis (>6 weeks after surgery) weeks after surgery) Number of cases 92 26 Presenting visual acuity 5/200 or worse

89%

31%

Hypopyon

80%

46%

Most frequent isolate

Coagulase-negative staphylococcus (57/92)

Cutibacterium acnes (11/26)

Visual outcome of 20/100 or better in patients with most frequent isolate

56%

91%

Intraocular lens removed or exchange

–

19 of 26 cases (73%) Of these 19 cases, 13 achieved a visual outcome of 20/100 or better

Visual Outcome • Patients with delayed-onset endophthalmitis generally presented with better initial visual acuities, had a lower frequency of hypopyon, and had better visual outcomes compared to acute-onset patients. Microbiology • In the delayed-onset endophthalmitis group—Cutibacterium acnes was the most common organism cultured and was associated with the best visual acuity outcomes. • In the acute-onset endophthalmitis group, Coagulase-­ negative Staphylococcus was the most common organism cultured and was associated with the best visual acuity outcomes.

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References: Treatment Outcomes Delayed-Onset Endophthalmitis • Clark WL, Kaiser PK, Flynn HW, Belfort A, Miller D, Meisler DM.  Treatment strategies and visual acuity outcomes in chronic postoperative Propionibacterium acnes endophthalmitis. Ophthalmology. 1999;106(9):1665–70. • Shirodkar AR, Pathengay A, Flynn HW, Jr., Albini TA, Berrocal AM, Davis JL, et al. Delayed- versus acute-onset endophthalmitis after cataract surgery. Am J Ophthalmol. 2012;153(3):391–8 e2. • Fowler BJ, Miller D, Yan X, Yannuzzi NA, Flynn Jr. HW.  Postoperative endophthalmitis caused by Cutibacterium (formerly Propionibacterium) acnes: case series and review. Case Reports in Ophthalmology. 2021;12(1), 1–10.

 reatment Outcomes of Endophthalmitis after T Pars Plana Vitrectomy Visual outcomes after treatment of post-PPV endophthalmitis are generally worse than after cataract surgery. Underlying retinal pathology could be the reason for poor visual potential. A review by Dave et al. of various series on endophthalmitis post-vitrectomy is shown in Table 12.2. References: Treatment Outcomes of Endophthalmitis after Pars Plana Vitrectomy • Dave VP, Pathengay A, Schwartz SG, Flynn HW, Jr. Endophthalmitis following pars plana vitrectomy: a literature review of incidence, causative organisms, and treatment outcomes. Clin Ophthalmol. 2014;8:2183–8.

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Table 12.2  Review of literature on various series on endophthalmitis post pars plana vitrectomy Diagnosis at Visual outcome Paper time of PPV Year Cases at last visit Cohen ERM, MH, 1995 18/12,216 3 EV, 6 NLP, et al. PDR 1 HM, 1 LP, 2 20/400, 1 20/50, 1 20/30, 1 20/25 and 2 20/20 Aaberg et al.

–

1998

3/6557

All eyes NLP

Eifrig et al.

PDR, macular pucker, recurrent RD

2004

6/15,326

3 NLP, 1 LP, 1 2/200, and 1 20/200

Joondeph et al.

VH, MH, ERM, RD

2005

5/10,397

2 NLP, 1 HM, 1 20/200 and 1 20/50

Shaikh et al.

ERM

2007

2/129

One 20/400, one 20/40

Scott et al.

ERM, PDR, CRVO, disc pit

2008

13/7682

1 LP, 1 HM, 1 20/400, 1 5/200, 2 20/150, 1 20/100, 2 20/20, 2 20/40, 2 20/30

Shimada et al.

ERM

2008

2/6935

Both cases NLP

Chen et al.

VH, TRD with VH

2009

2/3477

One 20/200, one 20/125

Mollan et al.

MH, PDR

2009

2/5278

One 1/60, one 6/12

Scott et al.

RD, MH, ERM

2011

3/8554

One HM, one 20/100, one 20/40 (continued)

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Table 12.2 (continued) Diagnosis at Paper time of PPV Mutoh et al.

CME, ERM

Year 2012

Cases 4/502

Visual outcome at last visit One 20/30, one 20/100, one 20/20, one 20/25

Abbreviations: PPV pars plana vitrectomy, NLP no light perception, LP light perception, HM hand motion vision, ERM epiretinal membrane, RD retinal detachment, VH vitreous hemorrhage, CRVO central retinal vein occlusion, PDR proliferative diabetic retinopathy, CME cystoid macular edema, MH macular hole, TRD traction retinal detachment, EV eviscerated

 reatment Outcomes of Endophthalmitis T Following Glaucoma Surgery • Conjunctival filtering bleb-associated infection and endophthalmitis • Endophthalmitis associated with glaucoma drainage devices

 onjunctival Filtering Bleb-Associated Infection C and Endophthalmitis Leng et al. (2011) Leng et  al. (2011) reported the clinical features, organisms, and outcomes of 71 eyes from 68 patients with delayed-onset bleb-associated endophthalmitis. In this retrospective consecutive case series, patients who have treated for delayed-­ onset bleb-associated endophthalmitis between January 1, 1996, and July 1, 2008, at a single institution were included. Infections within 1 month of glaucoma filtering surgery, inadvertent filtering blebs after cataract surgery, and patients with glaucoma drainage devices were excluded. The study results were as follows:

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• An adjunctive antifibrotic agent was used in 48 eyes (68%). • The mean time between surgery and endophthalmitis was 4.8 years (range, 0.1–16; standard deviation, 3.6). • The average follow-up time after initial treatment was 37 months (range 1–144; standard deviation, 41). • At presentation, 17 eyes (24%) had a bleb leak. • Fifty-seven eyes (83%) were culture positive. • The most common causative organisms were Streptococcus species in 20 eyes (30%), Gram-negative organisms in 19 eyes (28%), and coagulase-negative Staphylococcus in 12 eyes (18%). • All Gram-positive isolates were sensitive to vancomycin. • Nine eyes (13%) eventually underwent evisceration or enucleation secondary to pain and/or poor vision. • The main outcome measure was best-corrected visual acuity at the last follow-up examination. • Final visual acuities in the initial tap/inject group (n = 45) versus the initial vitrectomy group (n = 24) were as follows: 20/40 or better (29% vs. 4.2%), 20/50–20/400 (36% vs. 29%), and worse than 5/200 (36% vs. 62%). • Streptococcus species and Gram-negative organisms were the most common causative isolates identified in this case series of delayed-onset bleb-associated endophthalmitis. • Despite treatment of the infection, visual outcomes were generally poor. References: Treatment Outcomes of Endophthalmitis Following Glaucoma Surgery • Leng T, Miller D, Flynn HW, Jr., Jacobs DJ, Gedde SJ. Delayed-onset bleb-associated endophthalmitis (1996– 2008): causative organisms and visual acuity outcomes. Retina. 2011;31(2):344–52. • Song A, Scott IU, Flynn HW, Jr., Budenz DL.  Delayed-­ onset bleb-associated endophthalmitis: clinical features and visual acuity outcomes. Ophthalmology. 2002;109(5):985–91.

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Endophthalmitis Associated with Glaucoma Drainage Devices Medina et al. (2016) Medina et al. (2016) reported the clinical features, organisms, and treatment outcomes in patients with endophthalmitis associated with glaucoma drainage implants. In this retrospective noncomparative case series of 13 patients, exposure occurred in eight eyes, including exposure of the tube in four eyes, exposure of the patch graft in three eyes, and exposure of the plate in one eye. In the remaining five eyes, either recent implant placement or conjunctival revision occurred. • Intravitreal antibiotics were administered in all eyes, with the exception of one eye (primary evisceration). • Removal of the implant was performed in six eyes and evisceration or enucleation was performed in three eyes. • Median preinfection visual acuity was 20/80 (range, 20/30 to hand motion). • Visual acuity at last follow-up was no light perception (five eyes), light perception (two eyes), hand motion (one eye), and better than or equal to 20/200 (five eyes). –– Clinical features associated with endophthalmitis include implant exposure and a history of recent surgery. –– The most common organism was Staphylococcus epidermidis (five eyes). –– In some patients, successful treatment could be achieved even without removal of implant. –– Visual outcomes were generally poor. References: Treatment Outcomes of Endophthalmitis Associated with Glaucoma Drainage Devices • Medina CA, Butler MR, Deobhakta AA, Banitt MR, Albini TA, Smiddy WE, et al. Endophthalmitis associated with glaucoma drainage implants. Ophthalmic Surg Lasers Imaging Retina. 2016;47(6):563–9.

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• Tai AX, Song JC. Surgical outcomes of Baerveldt implants in pediatric glaucoma patients. J AAPOS. 2014;18(6):550–3.

 reatment Outcomes of Post-Traumatic T Endophthalmitis Outcomes of post-traumatic endophthalmitis are highly variable depending upon the causative organism, associated globe injuries, presence of intraocular foreign bodies, delayed presentation after injury, and type of injury (gunshot wound/ infected wound/clean wound). Retained intraocular foreign bodies (IOFBs) are associated with endophthalmitis in approximately 7–13% of cases: (a) Colyer et al. (Ophthalmology 2007) (b) Mieler et al. (Ophthalmology 1990) (c) Banker et al. (OSLI Retina, 2017)

Colyer et al. (Ophthalmology 2007) The study by Colyer et al. reported the long-term follow-up results of intraocular foreign body (IOFB) removal from February 2003 through November 2005. This study also looked at the prognostic factors for visual outcomes in this patient population. In this retrospective, noncomparative, interventional case series, 79 eyes of 70 patients sustained IOFB injuries and subsequently were treated with a minimum of 6 months of follow-up were analyzed. • Final visual acuity, rate of proliferative vitreoretinopathy, and rate of endophthalmitis were the primary outcome measures. • Average patient age was 27 years, with an average of 331 days of post-operative follow-up. • Average IOFB size was 3.7 mm (range, 0.1–20 mm).

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• Median time to IOFB removal was 21 days (mean, 38 days; range, 2–661 days). • Mean pre-operative visual acuity was 20/400 (1.36 logarithm of mean angle of resolution [logMAR] units) and mean final visual acuity was 20/120 (0.75 logMAR). • There were no cases of endophthalmitis (0/79 eyes; 95% confidence interval, 0%–3.1%), siderosis bulbi, or sympathetic ophthalmia. • Timing of vitrectomy did not correlate with visual outcome. • The most common systemic antibiotic administered was levofloxacin, whereas the most common topical antibiotic administered was moxifloxacin. • Delayed IOFB removal with a combination of systemic and topical antibiotic coverage can result in good visual outcome without an apparent increased risk of endophthalmitis or other deleterious side effects.

Mieler et al. (Ophthalmology 1990) Mieler et  al. reviewed retained IOFBs presented between July 1986 and June 1989. A total of 27 cases were evaluated and surgically treated. All eyes presenting within 24 hours of injury underwent immediate surgery (average, 4.5 hours after presentation). • None of the 27 cases presented with or developed clinical signs of endophthalmitis, yet bacterial cultures of the removed intraocular material were positive in seven cases (foreign body in five cases, the aqueous fluid and the vitreous fluid in one case each). • Of the seven eyes with positive intraocular cultures, all had pars plana vitrectomy removal of the IOFB, and three of these eyes received intravitreal antibiotics at the time of surgery over concern of a high risk of infection. Two of these eyes eventually grew out of the Bacillus sp. Even after the positive cultures, no signs of clinical infection developed in any of the eyes.

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• All eyes received subconjunctival antibiotics and postoperative topical and systemic antibiotics. • All seven eyes retained excellent visual acuity of 20/70 or better at an average of 10 months follow-up. • Follow-up ranged from 1 to 31 months.

Banker et al. (OSLI Retina, 2017) Banker et  al. reported the visual and anatomical outcomes and microbiologic spectrum of culture-positive endophthalmitis in open globe injuries with or without intraocular foreign bodies (IOFBs). In this retrospective, interventional case series 718 patients with open globe injury treated at a University Referral Center between 2004 and 2015 were included. • Culture-positive cases of endophthalmitis after open globe repair occurred in 2.1% (n = 15/718) of eyes; two eyes had evidence of endophthalmitis on presentation. • The most common organism was Staphylococcus sp. (5/17). • An IOFB was present in 6.8% (n = 49/718) of eyes. • All eyes received prophylactic intravitreal antimicrobials. • In eyes with IOFB, the rate of culture-positive endophthalmitis after initial globe repair in eyes with IOFB was 8.1% (n = 4/49) vs. 1.6% (n = 11/669) in eyes without IOFB (p < 0.01). • Culture-positive endophthalmitis was identified after open globe injuries more often in eyes with a concurrent IOFB. References: Treatment Outcomes of Endophthalmitis Associated with Open Globe Injuries • Banker TP, McClellan AJ, Wilson DW BS, Juan FM, Kuriyan AE, Relhan N, Chen FV, Albini TA, Berrocal AM, Sridhar J, Gregori NZ, Townsend JH, Flynn HW Jr. Culture-­positive endophthalmitis after open globe injuries with and without retained intraocular foreign bodies. OSLI Retina 2017 Aug 1;48(8):632–7.

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• Colyer MH, Weber ED, Weichel ED, Dick JS, Bower KS, Ward TP, Haller JA.  Delayed intraocular foreign body removal without endophthalmitis during Operations Iraqi Freedom and Enduring Freedom. Ophthalmology. 2007;114(8):1439–47. • Mieler WF, Ellis MK, Williams DF, Han DP.  Retained Intraocular Fore ign Bodies and Endonhthalmltls. Ophthalmology. 1990;97(11):1532–8.

 reatment Outcomes of Endogenous T Endophthalmitis Outcomes of endogenous endophthalmitis as reported by the following studies are discussed: (a) Schiedler et al. (2004) (b) Lingappan et al. (2012) (c) Sridhar et al. (2016)

Schiedler et al. (2004) Schiedler et al. reported the clinical features and visual acuity outcomes associated with endogenous endophthalmitis. In this retrospective, observational case series of 21 eyes of 21 patients treated at the Bascom Palmer Eye Institute for culture-­ proven endogenous endophthalmitis between 1996 and 2002 were reviewed. • Compared with published series of postoperative or post-­ traumatic endophthalmitis, patients with endogenous endophthalmitis were more likely to have fungal isolates with a predominance of Candida albicans. • Endogenous endophthalmitis was generally associated with high mortality and poor visual acuity outcomes, particularly when caused by more virulent species such as Aspergillus.

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Lingappan et al. (2012) Lingappan et  al. reported the causative organisms, management strategies, and visual outcomes in endogenous fungal endophthalmitis. In this observational case series of 65 eyes of 51 patients with culture-positive endogenous fungal endophthalmitis between January 1, 1990, and July 1, 2009, were analyzed (mean follow-up of 18 months). • Yeasts were the most common causative organism in 38 (75%) patients compared with molds in 13 (25%) patients. • Visual acuity of 20/200 or better was present in 28 (56%) eyes with yeasts and in 5 (33%) eyes with molds at the last follow-up. –– Endogenous fungal endophthalmitis was generally associated with poor visual acuity outcomes, especially when caused by molds. –– Retinal detachment was reported in 26% (17/65) of eyes during follow-up.

Sridhar et al. (2013) Sridhar et al. reported risk factors, clinical features, and treatment outcomes in patients with endogenous fungal endophthalmitis with yeast and mold infections. In this retrospective consecutive case series, 67 eyes of 53 patients were identified, 51 eyes of 39 patients had positive cultures for yeast, and 16 eyes of 14 patients had positive cultures for molds. Patients with molds as a causative organism (compared to those patients with yeast as a causative organism): • Had significantly shorter duration of symptoms prior to diagnosis (molds 3.8 days, yeast 21.0 days, p = 0.002). • Were more likely to be receiving iatrogenic immunosuppression (molds 57.1%, yeast 7.7%, p = 0.001). • Have a history of whole-organ transplantation (molds 35.7%, yeast 2.6%, p = 0.001).

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• Were more likely to have hypopyon at the time of diagnosis (molds 37.5%, yeast 6.0%, p = 0.001). • Had significantly worse visual acuity at the time of diagnosis (logMAR visual acuity molds 1.80, yeast 1.15, p = 0.008) and at final visit (logMAR visual acuity molds 1.97, yeast 1.05, p = 0.005). • There was no significant difference in the rate of retinal detachment between the two groups (mold 12.5%, yeast 30.6%, p = 0.201). • Patients with cultures positive for mold were significantly more likely to undergo enucleation (molds 25.0%, yeast 0%, p < 0.001). –– Outcomes—While endogenous fungal endophthalmitis is generally associated with poor visual acuity outcomes, infection with mold species was associated with worse visual acuity on presentation and on final follow-up than infection with yeast species. Enucleation rates were much higher in mold cases. References: Treatment Outcomes of Endogenous Endophthalmitis • Lingappan A, Wykoff CC, Albini TA, Miller D, Pathengay A, Davis JL, et  al. Endogenous fungal endophthalmitis: causative organisms, management strategies, and visual acuity outcomes. Am J Ophthalmol. 2012;153(1):162–6 e1. • Schiedler V, Scott I, Flynn H, Davis J, Benz M, Miller D.  Culture-proven endogenous endophthalmitis: clinical features and visual acuity outcomes*1. Am J Ophthalmol. 2004;137(4):725–31. • Sridhar J, Flynn HW, Jr., Kuriyan AE, Miller D, Albini T. Endogenous fungal endophthalmitis: risk factors, clinical features, and treatment outcomes in mold and yeast infections. J Ophthalmic Inflamm Infect. 2013;3(1):60.

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 reatment Outcomes of Endophthalmitis T Associated with Intravitreal Injection Outcomes of endophthalmitis associated with intravitreal injections as reported by the following studies are discussed: (a) Goldberg et al. (Ophthalmology 2013) (b) Gregori et al. (Retina 2015) (c) Yannuzzi et al. (OSLI-Retina, 2017)

Goldberg et al. (Ophthalmology 2013) Goldberg et  al. reported the 1-year clinical outcomes of an outbreak of Streptococcus endophthalmitis after intravitreal injection of bevacizumab, in this retrospective consecutive case series of 12 eyes of 12 patients who developed endophthalmitis after receiving intravitreal bevacizumab prepared by a single compounding pharmacy: • All patients received initial vitreous tap and injection, and eight patients (67%) subsequently underwent pars plana vitrectomy (PPV). • After 12-month follow-up, outcomes have been poor. Seven patients (58%) required evisceration or enucleation, and only one patient regained preinjection visual acuity. • Molecular testing using real-time polymerase chain reaction, partial sequencing of the groEL gene, and multilocus sequencing of seven housekeeping genes confirmed the presence of a common strain of Streptococcus mitis/Streptococcus oralis in vitreous specimens and seven unused syringes prepared by the compounding pharmacy at the same time.

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• An FDA investigation of the compounding pharmacy noted deviations from standard sterile technique, inconsistent documentation, and inadequate testing of equipment required for safe preparation of medications. –– In this outbreak of endophthalmitis, outcomes have been generally poor, and PPV did not improve visual results at 1-year follow-up.

Gregori et al. (Retina 2015) Gregori et  al. reported the outcomes of infectious endophthalmitis after intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents from January 1, 2005, through December 31, 2014. • In this study, the population-based rate of endophthalmitis after anti-VEGF injections from 2011 to 2013 was 391/740,757 (0.053%). • The Bascom Palmer Eye Institute’s rate was 20/121,285 (0.016%) during the study period: eight after bevacizumab (0.012%), six after ranibizumab (0.018%), and six after aflibercept (0.031%) injection. • Nine cases (45%) were culture positive: Streptococcus species (5), coagulase-negative Staphylococcus (3), and non-­ anthracis Bacillus (1). • Final visual acuity varied from 20/25 to no light perception. • Treatment outcomes were variable but generally fared better in the culture-negative cases.

Yannuzzi et al. (OSLI-Retina 2018) Yannuzzi et al. reported the treatment outcomes in patients with endophthalmitis (between 2006 and 2016) associated with intravitreal injection of anti-VEGF agents, in this retrospective case series of 38 eyes of 38 patients including 27 (71%) referred and 11 (29%) in-house patients:

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• The per-injection rate of all clinically suspected endophthalmitis was 0.014% (23/159,066). • The most common isolates were coagulase-negative Staphylococcus and Streptococcus. • A VA of 5/200 or better was achieved in 21/38 (55%) eyes overall and 2/14 (14%) eyes infected with Streptococcus. • The rate of in-house post-intravitreal injection endophthalmitis was low. –– Outcomes were generally poor and the worst in Streptococcus cases. References: Treatment Outcomes of Endophthalmitis Associated with Intravitreal Injections • Goldberg RA, Flynn HW, Jr., Miller D, Gonzalez S, Isom RF.  Streptococcus endophthalmitis outbreak after ­intravitreal injection of bevacizumab: one-year outcomes and investigative results. Ophthalmology. 2013;120(7):1448–53. • Gregori NZ, Flynn HW, Jr., Schwartz SG, Rosenfeld PJ, Vaziri K, Moshfeghi AA, et  al. Current infectious endophthalmitis rates after intravitreal injections of anti-­ vascular endothelial growth factor agents and outcomes of treatment. Ophthalmic Surg Lasers Imaging Retina. 2015;46(6):643–8. • Yannuzzi NA, Gregori NZ, Rosenfeld PJ, Relhan N, Patel NA, Si N, Miller D, Dubovy SR, Smiddy WE, Schwartz SG, Flynn HW Jr. Endophthalmitis associated with intravitreal injections of anti-vascular endothelial growth factor agents at a tertiary referral center (in-house and referred cases). Ophthalmic Surg Lasers Imaging Retina. 2018;49(5):313–19.

Complications Associated with Endophthalmitis Prophylaxis/Treatment • Complications associated with prophylaxis: –– Hemorrhagic occlusive retinal vasculitis (Fig.  12.1)— Poorly understood entity. May occur following intra-

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Figure 12.1  Hemorrhagic Occlusive Retinal Vasculitis (HORV)

cameral or intravitreal injection of vancomycin. Appears to represent a delayed-onset hypersensitivity to vancomycin. May respond to intravitreal corticosteroids. –– Toxic anterior segment syndrome (TASS). • Complications associated with treatment: –– Mechanical complications related to the ophthalmic intervention (TAP or PPV). –– Damage to crystalline lens (in phakic eyes). –– Peripheral retinal tears or retinal detachment. –– Wound leak. –– Elevated intraocular pressure. –– Toxicity of antimicrobials.

Complications Associated with Endophthalmitis…

a

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b

Figure 12.2  Macular infarction after intravitreal amikacin. Retinal toxicity with intravitreal amikacin. (a) Fundus photo showing multiple retinal hemorrhages, white appearance of macula, and multiple cotton wool spots surrounding disc. (b) Fundus fluorescein angiography demonstrates lack of perfusion at the posterior pole with ischemic macula and patches of hypofluorescence in the area of retinal hemorrhages and cotton wool spots

Macular infarction (Fig. 12.2): Associated with aminoglycosides with no known treatment (gentamicin appears to be more toxic than amikacin). Optic atrophy. References: Endophthalmitis Treatment-Related Complications • Results of the Endophthalmitis Vitrectomy Study. A randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Endophthalmitis Vitrectomy Study Group. Arch Ophthalmol. 1995;113(12):1479–96. • Doft BH, Kelsey SF, Wisniewski SR.  Additional procedures after the initial vitrectomy or tap-biopsy in the Endophthalmitis Vitrectomy Study. Ophthalmology. 1998;105(4):707–16. • Doft BM, Kelsey SF, Wisniewski SR. Retinal detachment in the endophthalmitis vitrectomy study. Arch Ophthalmol. 2000;118(12):1661–5.

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• Lalwani GA, Flynn HW, Jr., Scott IU, Quinn CM, Berrocal AM, Davis JL, et  al. Acute-onset endophthalmitis after clear corneal cataract surgery (1996–2005). Clinical features, causative organisms, and visual acuity outcomes. Ophthalmology. 2008;115(3):473–6. • Sridhar J, Yonekawa Y, Kuriyan AE, Joseph A, Thomas BJ, Liang MC, et  al. Microbiologic spectrum and visual outcomes of acute-onset endophthalmitis undergoing therapeutic pars plana vitrectomy. Retina. 2017;37(7):1246–51. • Thomas BJ, Mehta N, Yonekawa Y, Sridhar J, Kuriyan AE, Relhan N, et al. Pars plana vitrectomy for late vitreoretinal sequelae of infectious endophthalmitis: Surgical Management and Outcomes. Retina. 2017;37(4):651–6. • Yannuzzi NA, Si N, Relhan N, Kuriyan AE, Albini TA, Berrocal AM, et  al. Endophthalmitis after clear corneal cataract surgery: outcomes over two decades. Am J Ophthalmol. 2017;174:155–9. • Witkin AJ, Chang DF, Jumper JM, Charles S, Eliott D, Hoffman RS, Mamalis N, Miller KM, Wykoff CC.  Vancomycin-­ Associated Hemorrhagic Occlusive Retinal Vasculitis: Clinical Characteristics of 36 Eyes. Ophthalmology. 2017;124(5):583–95. • Witkin AJ, Shah AR, Engstrom RE, Kron-Gray MM, Baumal CR, Johnson MW, Witkin DI, Leung J, Albini TA, Moshfeghi AA, Batlle IR, Sobrin L, Eliott D. Postoperative Hemorrhagic Occlusive Retinal Vasculitis: Expanding the Clinical Spectrum and Possible Association with Vancomycin. Ophthalmology. 2015;122(7):1438–51. • Schwartz SG, Relhan N, O’Brien TP, Flynn HW Jr. A new complication associated with the use of prophylactic intracameral antibiotics: hemorrhagic occlusive retinal vasculitis. Ophthalmology. 2017; 124(5):578–79.