The Infectious Diseases Consult Handbook : Common Questions and Answers [1 ed.] 9783031394737, 9783031394744

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The Infectious Diseases Consult Handbook Common Questions and Answers Alexander M. Tatara

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The Infectious Diseases Consult Handbook

Alexander M. Tatara

The Infectious Diseases Consult Handbook Common Questions and Answers

Alexander M. Tatara Infectious Diseases Massachusetts General Hospital Boston, MA, USA

ISBN 978-3-031-39473-7     ISBN 978-3-031-39474-4  (eBook) https://doi.org/10.1007/978-3-031-39474-4 © 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

This work is dedicated to Evelyn Renée Tatara.

Preface

It is a joy and a privilege to practice on an infectious diseases service. As a consultant, you serve as an ally and confidant to both patients and physicians. By specializing in diseases caused by microorganisms, your services will be requested from physicians across all disciplines in the hospital, including medicine, surgery, neurology, gynecology/obstetrics, and critical care. You will work closely with other diagnosticians, such as pathologists and radiologists, to interpret clinical data in the context of the specific patient at hand. You will collaborate with other healthcare professionals, such as pharmacists and social workers, to ensure safe and logistically feasible therapeutic plans. Most of all, you will spend your days at the bedside of your patients, learning from them as you work to provide the highest level of care in their time of need. A day on service is never dull. You will meet a young man with a new diagnosis of human immunodeficiency virus infection and ensure that he understands which antiretrovirals, prophylactic antibiotics, and vaccines he requires to stay in good health. You will help diagnose an elderly woman who is recovering from spinal surgery with a surgical site infection. You will design an empiric antibiotic plan for a man in septic shock who received a heart transplant 2 months ago. At first, the variety of the different consultations will seem overwhelming. Beyond the unique circumstances of each patient, you will also learn the behaviors and patterns of different pathogens. However, with practice, passion, and perseverance, you will gain the tools needed to skillfully and efficiently serve as an infectious diseases (ID) consultant. Slowly

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but surely, you will notice a rhythm and cadence to your work and the emergence of a pattern of common consultant questions. At the end of each day as a fellow in ID at the Massachusetts General Hospital and Brigham and Women’s Hospital, I would write down interesting consult questions I had received with notes and references as I learned about each patient’s condition. By the end of the year, I had catalogued a compendium of common questions asked on our service. When I became a senior fellow, I shared some of these topics with younger fellows as well as residents and medical students who found them helpful on their ID rotation. This handbook is the result of curating and editing those notes from my cases and contains over 140 questions. In addition to the most common questions, I have also included a few unusual consultations I encountered along the way for your enjoyment (with patient information changed so as to be unidentifiable)—these unique situations are part of the je ne sais quoi of ID! In which other specialty can you explain to a primary team how their patient is infected with an organism that can change liquid to gold (Delftia acidovorans) or spend an afternoon researching the risks of exotic pet ownership to an immunocompromised patient? This handbook is written at a level that will be useful for medical students, residents, and fellows, as well as potentially other healthcare professionals that are interested in common day-to-day questions asked of the ID service. There is an introductory chapter which reviews fundamental tools essential for the ID consultant. The following chapters are divided by the type of organism, covering common consult questions specific to gram-positive, gram-negative, fungal, and viral pathogens. Staphylococci are given their own chapter due to their prevalence and virulence. The last section is divided into chapters by anatomic site, such as pulmonary, abdominal, and musculoskeletal infection. Given the breadth of the field, this book could not be inclusive of all topics pertinent to adult ID. Examples of areas not covered include global health, tick-­

Preface

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borne diseases, and transplant ID. As my training was in the USA, I often cite US guidelines and discuss medications that have been approved in the USA although the principles reviewed should apply to practice broadly. Depending on the location of your practice and the resources of your hospital, the types of patients and questions you may encounter surrounding these topics may vary greatly compared to my own experiences. This book is my perspective on answers to common ID questions and I provide data, guidelines, and references to support those answers. However, another joy of practicing ID is that each patient and each pathogen are unique, and there is seldom a one-size-fits-all approach. This book is not intended to be medical advice for any specific patient. It also does not represent the views or opinions of any of my employers. Furthermore, there are some controversial areas within the field that I highlight in the text where even seasoned experts do not agree on a single approach. As you learn and grow from the patients you serve, you will develop your own style and approach to the common consult questions in our field. The best part about working in ID is that the field is constantly evolving, much like its microorganisms. Each year, new diagnostics, therapeutics, and guidelines are created, thanks to the diligent efforts of physicians, scientists, and other passionate professionals working towards improving the lives of our patients. However, this also means that some of the recommendations in this text will become outdated. I recommend cross-referencing sections with other resources in areas that are rapidly changing for best practice. If you are reading this book in preparation for your first time on an ID service, I am thrilled for you and your journey. It is an exhilarating and life-changing experience. The goal of this guide is to serve you and your patients. I also hope that it inspires you to collect your own thoughts and reflections during your time on the ID service. Enjoy learning and growing as you practice the science and art of infectious disease!

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In preparing this text, I would like to acknowledge all the patients, attendings, co-fellows, nurses, and pharmacists who taught me so much about infectious diseases, medicine, and life over my training. Boston, MA, USA 17 May 2023

Alexander M. Tatara

Contents

1 Introduction��������������������������������������������������������������������    1 2 S  taphylococcal Infection�����������������������������������������������    9 References�����������������������������������������������������������������������   30 3 Other Gram-Positive Infections�����������������������������������   41 References�����������������������������������������������������������������������   59 4 Gram-Negative Infection����������������������������������������������   69 References�����������������������������������������������������������������������   90 5 Fungal Infection�������������������������������������������������������������  103 References�����������������������������������������������������������������������  120 6 Mycobacterial Infection������������������������������������������������  131 References�����������������������������������������������������������������������  147 7 HIV Infection�����������������������������������������������������������������  155 References�����������������������������������������������������������������������  172 8 Viral Infection����������������������������������������������������������������  181 References����������������������������������������������������������������������� 200 9 Cardiovascular Infection�����������������������������������������������  213 References�����������������������������������������������������������������������  226 10 Pulmonary Infection������������������������������������������������������  233 References�����������������������������������������������������������������������  246 11 Abdominal Infection�����������������������������������������������������  253 References�����������������������������������������������������������������������  270 12 Head and Neck Infection����������������������������������������������  279 References�����������������������������������������������������������������������  295 13 Musculoskeletal Infection���������������������������������������������  303 References�����������������������������������������������������������������������  319 14 Skin and Soft Tissue Infection��������������������������������������  327 References�����������������������������������������������������������������������  340

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15 Genitourinary Infection������������������������������������������������  347 References�����������������������������������������������������������������������  360 Index���������������������������������������������������������������������������������������  367

Chapter 1 Introduction

Abstract  Welcome to The Infectious Diseases Consult Handbook – Common Questions and Answers! In this book, we will tackle some of the most frequently asked questions of the infectious disease (ID) consultant on the adult inpatient service. Before we begin with nuanced questions regarding specific organisms and infections, let us discuss some basic mechanics of being a consultant. In this chapter, we will discuss some of the typical day-to-day operations involved in being an ID consultant, review important resources, and touch upon future directions in the field that may change practice over our careers. Q. What happens over the day on an infectious disease service? A. While there will be differences based on practice location, patient population, and style, days on service are filled with excitement and interesting problems. Infections can affect every organ system. On service, you will be consulted on questions across anatomic and clinical specialties (Fig. 1.1). While each individual day on the ID consult service presents unique challenges and learning opportunities, there is generally a rhythm or established routine. The focus of the morning is often on following the progress of patients seen previously. Did the patient have a new © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. M. Tatara, The Infectious Diseases Consult Handbook, https://doi.org/10.1007/978-3-031-39474-4_1

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Chapter 1.  Introduction

Figure 1.1 Examples of types of infections treated by infectious disease consultants

fever overnight? Has the primary team made any medication changes? Did the cultures collected over the weekend mature? Patients will be interviewed and examined each morning by the ID consultant so their progress can be assessed. Overall, is the patient better or worse on their current course of therapy? In addition to following previously seen patients, new consultations are the other major task. These are the questions from primary teams regarding diagnosis and/or management of patients your service has not yet seen. Each hospital has its own system in place, but many practices divide overnight consults between teams for the morning and then distribute new consults throughout the day. You will often juggle following up on the needs of your prior patients while receiving fresh questions with new patients to meet. I found that being methodical in approaching old and new consults and making a conscious effort to understand how to prioritize different questions was instrumental to a smooth day. It is important to remember that the first interview is not the sole opportunity to capture information or nail the diagnosis. We follow patients because infectious processes are dynamic—new symptoms, responses to

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empiric therapies, and/or evolution of exam can all provide important clues to underlying pathophysiology. The inpatient consult service is not the only way ID can be practiced. There are an increasing number of subspecialty areas of focus, and different systems may have specialized inpatient and outpatient services. Some of these areas may require additional training, such as microbiology and transplant ID.  There are also a wide variety of potential career paths outside of traditional clinical ID (Table  1.1). If you are fascinated by microorganisms but have not fallen in love with the rhythm of the general consult service, you have plenty of options left to consider! Q. What makes for a helpful consult? A. Communication is key to collaboration with the primary services. An expression is that the good consult must be the three A’s: available, affable, and able. This seems like common sense but on a hectic day with dozens of pages and many complex patients, feeling available, affable, and/or able can be difficult! There are a few important lines of communication with primary teams. The most formal is the note. These are typically written in the Electronic Table 1.1  Noncomprehensive examples of subspecialty focus areas within academic infectious diseases and alternative careers for those practicing outside of academic medicine Subspecialty areas Alternative career paths Transplant Public health/policy Microbiology

Epidemiology

HIV/AIDS

Basic science research

Antibiotic stewardship

Industry

Infection control/hospital epidemiology

Private practice

Musculoskeletal Global medicine Sexual health

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Chapter 1.  Introduction

Medical Record (EMR) of the hospital. These notes are a way to capture your impression of the patient on that day and to crystallize your thinking of their disease process. While there are many different approaches to the note (some of which are guided by medical billing), general components include the subjective portion of patient evaluation, the objective portion such as physical examination and laboratory values, an assessment of where the patient and team stands currently, and a plan with recommendations for moving forward. From an ID perspective, there are key data points to synthesize and document each day. These include the fever curve, white blood cell count, pertinent culture data, current and recent antibiotic courses, creatinine clearance (especially as pertinent to antibiotic dosing), new imaging studies, inflammatory markers if relevant, and key findings on the interview and exam. Some EMRs have templates where some of these data points are automatically populated. While a stylistic choice, I preferred a manual approach as it guaranteed that I was reviewing each data point myself and minimized chances of missing important changes. Ultimately, the assessment and plan are the most important parts of the note and should be updated daily to reflect the most current thought process behind each patient’s illness. When making recommendations for specific antibiotics in the plan, be sure to provide accurate dosing, adjusting for renal function and instructions for measuring levels if necessary. Some institutions have pharmacists that can help manage this. Being explicit about contingencies can also let the primary team understand that you are being thoughtful about their patient and cognizant of the different possible trajectories. In each note, I made my contact information transparent so that people reading the EMR would easily be able to reach me (or my covering physician) to follow up or in the event of an emergency.

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The EMR is not the only way to communicate with the primary team. Sharing recommendations in realtime, whether by in person, phone, or a hospital texting system, gives the opportunity for conversation. While there may be a temptation to not give recommendations verbally and rely solely on the EMR for times’ sake, I found that it is much more enjoyable and better for patient care to meet with teams and learn their perspective on each case. Because any points of confusion for either party can be addressed immediately, I have also found that this type of communication saves time in the long run and helps build invaluable relationships. Q.  What resources are available for learners on the service? A. Collaborative services, colleagues, antibiograms, guidelines, and other texts (digital and otherwise) are helpful. ID is a complex field, and no person can master every facet on their own. We are fortunate to have assistance from many collaborators and other resources. There are several places in the hospital that my teams during fellowship were prone to visiting, including radiology, the microbiology laboratory, and the echocardiography reading room. Imaging is often vital for diagnosis as well as monitoring therapeutic effects. Interventional radiologists can also obtain samples for culture and source control with minimally invasive procedures. With advances in imaging techniques and our understanding of infection metabolism, radiology will likely only increase in importance for infectious diseases. Likewise, echocardiography is essential when making the diagnosis of endocarditis, and discussing cases in person with reading cardiologists can be very educational. All culture specimens in the hospital are sent to the microbiology laboratory where diligent technicians process them and patiently nurse them to maturity. Technicians use microscopic morphology, specialized

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stains and growth conditions, biochemical assays, and mass spectroscopy-­based instruments to give us vital information on species’ identities and antibiotic susceptibilities. A seasoned veteran in the microbiology laboratory can be an outstanding teacher and ally in challenging diagnoses. Often adjacent to the microbiology laboratory is Pathology, where tissues go to be fixed and stained for review. Pathologists are detectives, much like ID physicians, and can help rule in and rule out different processes when tissues are available. Hospital pharmacists are instrumental in guiding dosing, monitoring for therapeutic drug concentrations, understanding potential drug–drug interactions, and avoiding adverse effects. Depending on where you practice, you may have access to specialized pharmacists with additional ID training. Hospitals in major academic centers will often have an antibiogram or collection of antibiotic susceptibility rates of common microorganisms. As rates of resistance vary locally, having your local antibiogram on hand can be indispensable when deciding empiric regimens prior to susceptibility data. One of our most valuable resources is the collective wisdom of our division. Formally or informally, members of your ID division will become topic experts in specific areas and serve as gurus when complicated cases arise. There are likely faculty who have decades of experience in niches like managing drug-resistant tuberculosis, multifaceted hardware infections, or parasitic brain abscesses. A cup of coffee with one of these masters may be worth dozens of hours poring over the literature. It is important to build relationships with your colleagues and understand where to go for help. ID has become increasingly complex—even the most seasoned in your division likely have their own panel of personal topic experts when confronted with a tough case. In addition to local resources, different national and international societies and institutions publish guidelines and consensus statements on ID topics. These

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include the Infectious Diseases Society of America (IDSA), U.S. Centers for Disease Control and Prevention, and the World Health Organization. Depending on the specific infection in question, specialty societies may also offer guidance; for example, the American Heart Association and IDSA have worked together to publish guidelines on cardiovascular implantable electronic device infection. There are also pocket guides, such as The Sanford Guide to Antimicrobial Therapy, which can be used as references for specific microbes, types of infections, or antibiotics. There are an increasing number of online references that can be frequently updated to offer up-to-date guidance. Social media, while sometimes being a source of scientific misinformation, is another resource as members of the field will often discuss new publications and data in real time. As each patient and each microbe is unique, no single reference or guideline will offer infallible answers to any specific case, including this book. But as you gain experience, learn from your mentors, and leverage these resources, you will synthesize practical information and become a stronger ID consultant. Q. How frequently does the field change? A. All the time! For example, we have been re-examining how to best give antibiotics. Infectious disease is a dynamic field. Even in my relatively short experience as a fellow, there have already been changes in practice patterns. Many of these will be discussed in further detail throughout the chapters of this book. One consistent theme is “shorter is better” regarding antibiotic courses. The traditional recommended durations of antibiotic therapy for conditions such as pneumonia, urinary tract infection, and osteomyelitis were often not evidence-based and have been moored in dogma. There are increasing data that shorter antibiotic durations are associated with less adverse events, less development of drug resistance, and

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similar efficacy to prolonged courses in many types of infections. The route of antibiotic administration is another area within ID where the current generation of physicians is actively changing practice. Traditionally, intravenous antibiotics were favored, especially for severe infections. However, as newer oral agents with better bioavailability became available over the last few decades, the dogma of favoring intravenous therapy over oral therapy was not rigorously re-evaluated. In patients that have functional gastrointestinal absorption and can achieve reasonable drug levels, there should be no magic that favors whether serum levels arrived from an oral or intravenous dose. While guidelines have been slow to adapt, each year brings more randomized trials that demonstrate that orally bioavailable drugs are as efficacious as intravenous routes with better safety and less morbidity associated with the need for vascular catheters. There are also new long-acting injectable antibiotics and antivirals with prolonged therapeutic effects that may further spare our patients from the inconvenience of frequent intravenous drug dosing. Lastly, the sequencing revolution has transformed our understanding of the micro- and mycobiome. Cell for cell, we are vastly outnumbered by the microorganisms that colonize our skin, gastrointestinal tract, and other mucosal surfaces. Correlations between microbial populations and human health are being rapidly discovered and only recently have mechanisms become more elucidated. There are now clinical trials for microbial therapeutics to treat infections (such as fecal microbiota transplants) and other disease states. In addition, the science surrounding viruses that selectively target bacteria (bacteriophages) has become increasingly developed. Each year, we see more case reports of patients with otherwise intractable infections cured with the aid of bacteriophage therapy. While the ID consultant currently recommends antibiotics or antivirals to treat infection, we likely will be prescribing microbes and viruses in the future!

Chapter 2 Staphylococcal Infection

Abstract  “We’ve got a really sick patient who just started growing four out of four bottles with gram-positive cocci in clusters—can you help?” You will hear a variation of this line over and over again throughout ID fellowship. Staphylococcus aureus, especially the infamous methicillinresistant S. aureus (MRSA), remains a common and often challenging clinical scenario where ID consultants are called for their expertise. Methicillin-susceptible S. aureus (MSSA) is no slouch either. In general, S. aureus has continued to evolve and pick up new tricks, such as increasing exotoxins and resistance mechanisms. Changes in clinical populations, such as increasing rates of injection drug use, have increased the prevalence of staphylococcal disease. Given its disproportionally large role in the life of a firstyear ID fellow, the staphylococci have earned an entire chapter in this text. We will primarily discuss bacteremia as other specific sites of focus such as staphylococcal endocarditis and osteomyelitis will be reviewed in their respective anatomic chapters. If time on the ID service teaches one lesson, it is to never underestimate the resourcefulness of S. aureus!

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. M. Tatara, The Infectious Diseases Consult Handbook, https://doi.org/10.1007/978-3-031-39474-4_2

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Chapter 2.  Staphylococcal Infection

Q. Do we really need a formal consult for Staphylococcus aureus bacteremia? A. Yes! Data indicate that ID consults for staphylococcal bacteremia save lives. As you walk through the halls during your morning rounds, you are stopped by an internist. “Hey, we have a patient now growing staphylococci in their blood cultures. I have them on vancomycin—isn’t that enough? Do we really need a formal consult?” One of the best parts of ID fellowship is getting to know your colleagues and earning their trust. They will come to depend on you to help determine when a patient formally needs to be seen by your service versus receiving informal (“curbside”) advice regarding a scenario without you having seen the patient. S. aureus bacteremia is both common and devastating, with mortality reported as high as 23% in the hospital setting [1]. It is a scenario for which the data support formal ID consultation. There have been numerous studies that have retrospectively compared outcomes of patients with S. aureus bacteremia who did and did not receive formal ID consultation. In one meta-analysis, 18 of these studies accounting for 5300 patients were analyzed to determine if patients with a formal ID consult had better 30-day mortality, 90-day mortality, and risk of relapse outcomes [2]. The trials were all published from 2009 to 2015 to help mitigate changes in practice over time. Overall 30-day mortality was ~20%; patients who received a formal ID consultation had a mortality of 12.4% compared to 26% of patients without consultation (RR 0.53; CI 0.43–0.65). 90-day mortality had a similar improvement. Recurrence was also statistically less likely in patients with ID consultation (3.8% vs 4.3%; RR 0.62; CI 0.39–0.99). ID consultation also significantly increased rates of appropriate antibiotic agents and appropriate duration of therapy. Are curbside recommendations conveyed over the phone without seeing the patient sufficient? In one retrospective study of 342 episodes of S. aureus bacteremia

Chapter 2.  Staphylococcal Infection

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at a single institution, patients were stratified based on formal ID consult versus curbside (telephone) and clinical outcomes were compared. Patients formally seen at beside by ID services had significantly less mortality than those with curbside consult at 7, 28, and 90 days [3]. Given the above data, some hospitals have instituted an automatic ID consult when S. aureus is first detected in blood cultures by the microbiology laboratory. In one study, a single center retrospectively analyzed patient outcomes before and after this change was made in hospital workflow [4]. The primary outcomes measured were changes in quality-of-care indicators (appropriate antibiotic initiation within 24 h, echocardiogram, source control within 72 h, and appropriate duration of antibiotic therapy) before and after automatic consultation was instituted. Automatic ID consultation increased consults in S. aureus bacteremia from 70% to 100% of cases and significantly decreased the time from positive culture to consultation (~15  h to 4  h). Adherence to quality-of-care indications significantly increased (45%–87% of cases), and transfer to ICU-level care decreased (38%–16%). While there were trends in decreased mortality and 30-day admission rates, these were not statistically significant. In conclusion, the data support that patients with S. aureus bacteremia should be seen formally by ID services to reduce mortality and likely morbidity. Curbside consultation does not appear to be sufficient. ID physicians should rest assured—S. aureus bacteremia guarantees job security! Q. My patient with staphylococcal bacteremia continues to have positive blood cultures. What should we do? Should we add more antibiotics? A. Do a comprehensive search for other sites of infection, and in many cases, additional antibiotics are not indicated. In both real estate and staphylococcal infection, we place importance on the mantra, “Location, location,

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location!” In patients with persistently positive blood cultures who are on appropriate antibiotic therapy, it is critical to reassess the patient for sources of infection that have not been controlled. Expert opinion is that S. aureus bacteremia beyond 7 days should prompt reassessment [5] although many would agree that any persistent bacteremia can be concerning. Common sites of staphylococcal infection include spinal osteomyelitis, septic arthritis, endocarditis, septic thrombophlebitis, empyema and/or pulmonary emboli, intracranial sites, and seeding of implanted devices. Any organ system is fair game! A thorough physical exam is the first place to start to determine if there are any suspicious niduses of infection. We will discuss the role of echocardiography in staphylococcal bacteremia later in this chapter. Other imaging modalities and diagnostic procedures may be guided by pre-test probability based on exam and history. There is an increasing body of literature that suggests positron emission tomography/ computed tomography (PET/CT) may play a role in hunting for sources of infection [6] as well as ruling out metastatic disease to avoid prolonged duration of antibiotics [7]. If the burden of bacteria remains high or sequestered in a relatively avascular anatomic location (such as dead bone), the source of infection may not be eradicated by antibiotics alone, leading to the persistence of blood cultures. While cause and effect may be difficult to tease apart, retrospective data correlate greater than 72 h of staphylococcal bacteremia with an increased risk of metastatic disease [8]. However, even in cases where source control has been achieved to the extent at which it is possible, it may still take days for blood cultures to finally become negative. Even including uncomplicated cases of staphylococcal bacteremia, 28% of patients will have bacteremia for 3  days or longer [9]. In more extreme examples such as MRSA endocarditis, the median time to clearance has been reported to be as long as 8–9 days [10]. Time to clearance correlates with

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important clinical outcomes. In one retrospective study of 1600 patients with staphylococcal bacteremia from 17 centers in Europe, a duration of staphylococcal bacteremia of greater than 48  h after initiation of antibiotic therapy was significantly associated with greater 30-day and 90-day mortality [11]. It is no wonder that primary teams (and consulting services) can become concerned when a patient continues to have bacteremia while on appropriate therapy and with appropriate source control. There is a temptation to add more antibiotics to the mix and ID services are frequently asked by inpatient teams if adding more antibiotics will improve patient outcomes. Which data support this approach? There have been in vitro and animal studies that suggest that a combination of a beta-lactam in addition to vancomycin or daptomycin can have additional benefits in the treatment of S. aureus bacteremia, including MRSA [12]. CAMERA1 was a small RCT designed to explore this question in humans. Sixty patients with MRSA bacteremia, all receiving vancomycin, were randomized to receive either no additional therapy (control) or the addition of the beta-lactam flucloxacillin [13]. Patients receiving dual therapy had one less day of active bacteremia (2 days instead of 3 days) although this difference was not statistically significant (p = 0.06). There were no differences in other endpoints—mortality, metastatic infection, or renal/hepatic toxicities. CAMERA2 randomized 352 patients with MRSA bacteremia to a control arm (daptomycin or vancomycin) and an intervention arm (daptomycin/vancomycin + an IV beta-lactam) with primary endpoints being 90-day mortality, persistent bacteremia at day 5, relapse, and treatment failure [14]. The study was ended early prior to reaching goal enrollment as combination therapy was significantly associated with greater rates of acute kidney injury without significantly improving primary endpoint outcomes. MRSA-active cephalosporins such as ceftaroline were not included. Overall,

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Chapter 2.  Staphylococcal Infection

CAMERA2 suggested that for MRSA bacteremia, there is not a benefit to using multiple agents (glyco- or lipopeptide plus beta-lactam) and in fact there may be additional toxicity. In another RCT called BACSARM, 155 patients with MRSA bacteremia were recruited from 18 hospitals in Spain and randomized to receive daptomycin or daptomycin and fosfomycin [15]. The primary endpoint was treatment success at 6  weeks (end of therapy), which was defined as resolution of clinical symptoms and negative blood cultures. Treatment failure was defined as lack of clinical improvement at day 3 or later in therapy, persistent bacteremia at day 7 or later, discontinuation of therapy due to adverse events, recurrence of MRSA bacteremia prior to 6  weeks, and/or death by any cause before completing therapy. Combination therapy had 12% higher rate of treatment success than daptomycin monotherapy, but this was not statistically significant for the primary outcome or for sub-group analysis of endocarditis. Patients treated with combination therapy had significantly greater adverse events leading to treatment discontinuation, with the most common events being cardiac failure and electrolyte disorders (particularly hypokalemia). Well, what about for MSSA infection? The DASH trial was an RCT in which patients with MSSA bacteremia treated with beta-lactams (cefazolin or cloxacillin) were randomized to a placebo or daptomycin dual therapy experimental arm [16]. The primary endpoint was at the duration of bacteremia. There were no differences between the two groups. In summary, these three recent RCTs (CAMERA2, BACSARM, and DASH) have suggested that there is no benefit to adding multiple antibiotics (specifically, anti-­staphylococcal beta-lactams plus glycopeptides or lipopeptides) for the treatment of S. aureus bacteremia. In fact, CAMERA2 had to be ended early because there was actually harm with the use of multiple agents. However, these studies were performed without the

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newer anti-MRSA beta-lactams, such as ceftaroline. Some expert opinions and a small trial have suggested that a combination of daptomycin and ceftaroline may be beneficial in challenging cases of MRSA bacteremia [17]. A retrospective study comparing ceftaroline and daptomycin combination therapy to monotherapy was negative [18]. Future work may shed more clarity if and when combination therapy should be applied. Q. Which antibiotic should we choose for this patient’s MSSA bacteremia? A.  Likely an anti-staphylococcal penicillin or cefazolin depending on the infection site and patient co-morbidities. With the dreaded MRSA, beta-lactams are off the table as therapeutic options. However, for MSSA bacteremia, beta-lactams are the agent of choice. Compared to vancomycin, beta-lactam therapy has decreased mortality for MSSA bacteremia [19, 20]. Beta-lactams also decreased MSSA bacteremia recurrence compared to treatment with vancomycin in a multi-institutional prospective observational study [21]. This difference is speculated to be due to more rapid bactericidal activity of the anti-staphylococcal beta-lactams compared to vancomycin. For example, in one in  vitro experiment, nafcillin was bactericidal after 4  h, whereas vancomycin displayed bactericidal activity after 32 h [22]. There is also in vitro evidence that beta-lactams may have additional mechanisms that improve the efficacy of host immunity against MSSA compared to vancomycin [23]. The most common anti-staphylococcal beta-lactams include oxacillin, nafcillin, and cefazolin—how does one go about picking which to use for which patient? Cefazolin is a cephalosporin, whereas oxacillin and nafcillin are penicillins. Cefazolin has the advantage of requiring less frequent dosing  – every 8  h rather than every 4  h for oxacillin and nafcillin. Administering an intravenous (IV) antibiotic six times daily can be logisti-

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cally challenging! Cefazolin may also be less expensive in many centers; in one study, cefazolin treatment cost ~$8/day whereas nafcillin treatment cost ~$168/day [24]. Traditionally, cefazolin has been thought to have poor central nervous system (CNS) penetration compared to penicillins. However, clinical studies have shown that cefazolin can achieve higher cerebrospinal fluid concentrations than penicillins [25, 26]. If cefazolin is easier to administer and not necessarily limited by CNS bioavailability, why do some recommend anti-­ staphylococcal beta-lactams as first-line therapy for MSSA bacteremia? When there is a high burden of S. aureus (estimated to be greater than 107 colony forming units), there has been a reported inoculum-dependent effect on minimum inhibitory concentration (MIC) for beta-lactams during in  vitro testing [27]. For cefazolin, this may be due to a specific beta-lactamase called BlaZ type A [28]. This phenomenon of hypothetical increased MIC with high burden is called the cefazolin inoculum effect. In one study performed in Argentina, S. aureus isolates were collected at three hospitals from patients with MSSA bacteremia [29]. Isolates were grown and tested for MIC at 105 and 107 colony-forming units per mL.  Cefazolin inoculum effect was defined as an increase of cefazolin MIC to >16  μg/mL at the higher concentration. In sum, 54.5% of isolates demonstrated inoculum effect. Isolates with inoculum effect were more likely to have come from catheter-associated bacteremia. Patients with isolates that demonstrated cefazolin inoculum effect had significantly greater 30-day mortality. There were no significant associations with endocarditis, age, and community versus hospital acquisition. There was no specific beta-lactamase or gene associated with the cefazolin inoculum effect in this cohort. On the other hand, in a meta-analysis that aggregated 14 non-­randomized studies (13 out of 14 were retrospective) comparing cefazolin to anti-­

Chapter 2.  Staphylococcal Infection

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staphylococcal penicillin therapy for S. aureus bacteremia, cefazolin treatment was not associated with increased 90-day mortality (primary endpoint) and had less nephrotoxicity than the penicillins [30]. However, there was an inherent high risk of bias given that the large majority of studies were retrospective. Given uncertainty regarding the clinical implications of the cefazolin inoculum effect, anti-­staphylococcal penicillins are often recommended in patients with a high burden of disease, such as complicated bacteremia (versus uncomplicated bacteremia). One practice style is to initiate therapy with an anti-­staphylococcal penicillin when the bacterial burden is highest and then transition to cefazolin when approaching discharge for ease of dosing after bacterial burden has theoretically been substantially decreased. The two most common anti-staphylococcal penicillins in the USA are nafcillin and oxacillin. How might a consultant choose between the two? Compared to oxacillin, nafcillin is significantly more associated with acute ­kidney injury and renal failure [31, 32]. Nafcillin is also more nephrotoxic than cefazolin [24]. Oxacillin, on the other hand, has been demonstrated retrospectively to have greater hepatotoxicity when used in children [33]. In a study in which data were mined from the FDA Adverse Events Reports System, hepatotoxicity rates were similar between nafcillin and oxacillin (2% and 4% of patients had increased liver enzymes, respectively, which was not statistically significant) [31]. Therefore, in a patient with baseline renal dysfunction, it may make more sense to use oxacillin. Likewise, in a younger patient and/or patient with baseline hepatic dysfunction, there may be an argument to prefer nafcillin over oxacillin. Overall, this is an area that would benefit from an RCT comparing anti-staphylococcal penicillins to cefazolin. Lastly, there has been some study of ceftriaxone for the treatment of MSSA bacteremia. Ceftriaxone is a

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Chapter 2.  Staphylococcal Infection

third-­generation cephalosporin with the great advantage of once-daily dosing. It does have an indication for MSSA bacteremia by the US Food and Drug Administration, so it has been used as monotherapy. In one retrospective study, 243 patients at a single center in St. Louis with MSSA bacteremia were divided by antibiotic chosen for treatment—ceftriaxone versus oxacillin or cefazolin [34]. The primary outcomes were 90-day mortality, readmission due to MSSA, and microbiological failure. By nature of retrospective design, the baseline characteristics of the two groups were different. The ceftriaxone group had significantly less patients with time spent in the intensive care unit, less patients with infective endocarditis, and patients that had a shorter duration of bacteremia. Based on these baseline characteristics, one could argue that patients in the ceftriaxone group were less sick. There were no significant differences in primary outcomes although the study was not powered to prove non-inferiority. In sub-group analysis, while not statistically significant, patients on ­ceftriaxone had worse outcomes when being treated for endocarditis. In a meta-analysis comparing ceftriaxone to other cephalosporins for the treatment of MSSA infection (including but not specific for bacteremia), which contained two RCTs and four other studies for a total of 643 patients, there were no significant differences between cephalosporins for the duration of bacteremia or recurrence of bacteremia [35]. The authors reported that these studies are small and low quality in level of evidence. In addition, they are not exclusive to bacteremia and included patients with less severe infections such as MSSA cellulitis. Until more data become available, I am less likely to recommend ceftriaxone for MSSA bacteremia. In summary (Table 2.1), oxacillin and nafcillin are firstline agents for MSSA bacteremia when there is likely a high bacterial burden, such as suspected endocarditis or osteomyelitis. Choosing between the two may depend on

Chapter 2.  Staphylococcal Infection

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Table 2.1 Summary of antibiotics to consider for methicillin-­ susceptible Staphylococcus aureus bacteremia Antibiotic Oxacillin

Class Penicillin

Dosing Every 4 h

Advantages Rapid activity against MSSA

Disadvantages Hepatotoxicity

Nafcillin

Penicillin

Every 4 h

Rapid activity against MSSA

Nephrotoxicity

Cefazolin

First-­ generation cephalosporin

Every 8 h

Well-­ tolerated, widely available, and typically less expensive

Concern for cefazolin inoculum effect

Ceftriaxone

Third-­ generation cephalosporin

Once daily

Daily dosing

May be inferior to anti-­ staphylococcal beta-lactams

Vancomycin

Glycopeptide

Dependent on host factors

Easier dosing in patients on hemodialysis

Worse outcomes when compared to beta-lactams

host baseline factors (liver and kidney function). Cefazolin may work as well as the anti-staphylococcal penicillins although there is some concern for the cefazolin inoculum effect in infections with high bacterial burden. There have been efforts to determine if ceftriaxone is comparable to the other beta-lactams, given the ease of dosing, but high-quality evidence is not available. Vancomycin is inferior to beta-lactams for the treatment of MSSA. Q.  When do we consider MRSA to be resistant to vancomycin? A. Typically at MIC of 16 or greater, although we begin to be concerned at an MIC of 2. MRSA limits our ability to treat staphylococci with beta-­lactams, leading to the usage of vancomycin and daptomycin. Vancomycin-resistant Staphylococcus

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aureus (VRSA) occurs with the acquisition of the vanA gene and is defined as MIC greater or equal to 16 [36]. Fortunately, VRSA is currently rare in the USA [37]. While VRSA is unlikely to soon be a frequent consult ­question, there has been “MIC creep” or a slow increase in vancomycin MICs among S. aureus isolates appreciated both in the USA and worldwide. For example, in a global registry between 2004 and 2009, S. aureus isolates with vancomycin MIC of 2 or greater increased from 4% to 8% [38]. S. aureus with MIC between 4 and 8 are called vancomycin-­intermediate S. aureus (VISA). Unlike VRSA, VISA isolates are not produced by a single mutation but are likely the result of a heterogenous mixture of genetic changes [36]. In addition, there is another classification called heterogenous VISA or hVISA defined as MIC greater or equal to 2. Of note, there is an alternative definition of hVISA obtained by comparing a vancomycin population analysis profile to a reference standard [39]. It is suspected that VISA arises from hVISA after selection pressure by the use of glycopeptides [40]. The prevalence of hVISA, VISA, and VRSA among MRSA isolates has been increasing globally. The implications of rising rates of vancomycin resistance in S. aureus are troubling and clinical failure occurs more often in patients that have isolates with an MIC of 2 or greater [41]. However, there have not yet been widespread reports of increasing mortality from these isolates. In a prospective observational study at a single center in South Korea, 32% of patients with MRSA bacteremia had hVISA or VISA isolates [42]. Fortunately, there were no differences in mortality between patients with MRSA and VISA in this study. These results were similar to a retrospective study at a single center in St. Louis where ~24% of patients with MRSA infection had VISA isolates and there were no differences in mortality [43].

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Current Infectious Diseases Society of America (IDSA) guidelines for MRSA with MIC greater than 2 recommend an alternative to vancomycin [5]. When vancomycin treatment failure is present, high-dose daptomycin in combination with another antibiotic such as linezolid or trimethoprim-sulfamethoxazole is recommended. Many VRSA and VISA isolates are susceptible to other antibiotics, such as ceftaroline or linezolid [44]. Of note, different MIC testing methods may overcall resistance, such as the Etest [45], and some may underestimate resistance, such as Vitek systems [46]. Therefore, when being consulted on a patient with borderline or conflicting MIC values, it may be helpful to inquire about which system was used for measurement. Q. How long do we need to treat this case of staphylococcal bacteremia? A. It depends on several factors, but treatment is typically 2–6 weeks. The duration of treatment for staphylococcal bacteremia depends on whether infections are uncomplicated or complicated as well as the species. First, let us define uncomplicated and complicated. Per MRSA guidelines by the IDSA [5], uncomplicated bacteremia is defined as a patient with positive blood cultures that meets the following criteria: (1) exclusion of endocarditis; (2) no implanted prostheses; (3) follow-up blood cultures performed on specimens obtained 2–4 days after the initial set that do not grow MRSA; (4) defervescence within 72 h of initiating effective therapy; and (5) no evidence of metastatic sites of infection. Otherwise, the infection is considered complicated. For uncomplicated MRSA bacteremia, these guidelines recommend at least 14 days of treatment based on a meta-analysis from catheter-­ associated infections [47]. This recommendation has been extrapolated to cases of MSSA.  In one prospective observational study of both MSSA and MRSA bacteremia published after the

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Chapter 2.  Staphylococcal Infection

IDSA guidelines, 111/483 (23%) of patients from a single hospital in Korea met uncomplicated criteria [48]. Patients who received less than 14 days of therapy had significantly greater relapse of their bacteremia. Furthermore, 47% of the cases were MRSA, although the authors did not comment on if resistance significantly affected rates of relapse. For complicated cases, current recommendations call for 4–6 weeks of treatment [5]. For a complicated infection with no evidence of metastatic infection, it may be reasonable to opt for 4  weeks of treatment. However, many patients with complicated S. aureus bacteremia may have another reservoir of infection where a 6-week course would be more prudent (i.e., to treat presumed endocarditis or osteomyelitis). How about the coagulase-negative staphylococci (CoNS) that occasionally cause bacteremia? Staphylococcus epidermidis bacteremia, for example, is associated with device-related infection [49]. Guidelines specific to CoNS bacteremia from catheter-related infection recommend 5–7 days of treatment if the catheter is removed and 10–14 days of treatment if the catheter is retained with the use of antibiotic locks [50]. Staphylococcus lugdunensis, while a CoNS species, produces many virulence factors and has mortality rates similar to S. aureus [51, 52]. Therefore, it is recommended to treat S. lugdunensis bacteremia more similarly to S. aureus in terms of duration than the other CoNS [50]. How do these recommendations stack up to actual clinical reality? In one multicenter RCT in the USA, 509 patients with staphylococcal bacteremia were randomized to receive “usual care” versus an algorithm that had defined duration end points to determine if an algorithmic approach to duration of therapy would improve outcomes [53]. The duration of treatment for the algorithm groups was 14  days for uncomplicated S. aureus bacteremia and 28–42  days for complicated S. aureus

Chapter 2.  Staphylococcal Infection

23

bacteremia per current guidelines. In addition to using complicated and uncomplicated criteria to classify infections, the authors also had a third category for CoNS called “simple.” Simple CoNS bacteremia occurred when there was only a single positive blood culture with negative follow-up cultures, no signs or symptoms of local infection at a catheter site, no symptoms or signs of metastatic infection, and no indwelling intravascular prosthetic devices. The algorithmic durations of treatment of CoNS bacteremia were 0–3  days for simple, 5  days for uncomplicated, and 7–28 days for complicated. Patients were excluded from the study if they had or were suspected of having complicated bacteremia. However, they were included in the final analysis if complicated bacteremia was discovered after enrollment and randomization. Out of the 509 patients recruited, 51% had simple CoNS bacteremia, 18% had uncomplicated CoNS bacteremia, 7% had complicated CoNS bacteremia, 16% had uncomplicated S. aureus bacteremia, and 7% had complicated S. aureus bacteremia. The primary outcomes were cure at day 28 and serious adverse event rate. Overall, the algorithm group was non-inferior to the usual treatment group for both outcomes yet reduced duration of antibiotics by 29%. These results suggest that following the guideline-based duration of therapy in staphylococcal bacteremia can reduce unnecessary prolongation of antibiotic therapy while maintaining good outcomes. Q. Does my patient really need intravenous therapy for the entire treatment course for staphylococcal bacteremia? A. Current guidelines recommend intravenous treatment, although there are increasing data supporting a transition to oral therapy. Intravenous (IV) therapy is challenging for both patients and clinicians. Catheters require additional maintenance and increase the risk of new infection. They can be uncomfortable and inconvenient compared

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Chapter 2.  Staphylococcal Infection

to oral (PO) therapy. However, IV therapy has been the gold standard for staphylococcal bacteremia, and IV vancomycin and daptomycin remain the first-line recommendation in guidelines for MRSA bacteremia [5]. Two RCTs comparing an oral fluoroquinolone plus rifampin to IV therapy both showed similar effectiveness for S. aureus bacteremia [54, 55]. In a pooled analysis of patients from RCTs, patients treated with linezolid (IV with conversion to PO after 7  days) had similar rates of clinical cure and survival to those treated with IV vancomycin [56]. In an RCT of patients with severe MRSA infection in which 36% had bacteremia [57], patients were treated with either IV vancomycin or trimethoprim-­sulfamethoxazole, which could be transitioned from IV to PO at the discretion of the treating physician. Trimethoprim-­ sulfamethoxazole was found to be ­non-­inferior, although mortality was twice as high in the trimethoprim-sulfamethoxazole group in patients with bacteremia (34% versus 18%, not statistically significant). In a similar study (though not restricted to only staphylococcal infection), the Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis (POET) trial was an RCT in which patients with endocarditis and bacteremia were randomized to receive IV therapy or to start with IV therapy and then transition to PO therapy after 10 or so days of IV therapy [58]. For MSSA, oral options were amoxicillin/rifampin, amoxicillin/fusidic acid, linezolid/rifampin, and linezolid/ fusidic acid. The IV to PO arm was found to be noninferior to the IV arm based on composite score (including mortality) for the primary outcome. However, the study is limited in the interpretation of staphylococcal bacteremia as only 22% of patients enrolled had S. aureus infection and none had MRSA. In summary, current society guidelines recommend IV therapy for MRSA bacteremia, and in practice this has also been adapted for MSSA bacteremia. However, with large trials such as POET, there is increasing evi-

Chapter 2.  Staphylococcal Infection

25

dence that oral agents with good bioavailability are likely non-inferior to IV therapy. Q. Does my patient with S. aureus bacteremia need an echocardiogram? Which kind? A. Given rates of endocarditis, they will likely benefit from at least transthoracic echocardiography and will probably require subsequent transesophageal echocardiogram unless specific criteria are met. Staphylococcal bacteremia is associated with endocarditis, a potentially life-threatening condition. In one observational prospective study, 103 consecutive patients with S. aureus bacteremia were evaluated by transthoracic echocardiography (TTE), transesophageal echocardiography (TEE), and Duke Criteria for definitive diagnosis of endocarditis [59]. Out of these patients, 25% were determined to have definitive endocarditis. Only 7% had clinical evidence of endocarditis. TTE found vegetations/evidence of endocarditis in only 7% and was indeterminant for another 18%. TEE found vegetations/evidence of endocarditis in 25% of patients (or 18% of patients that were “missed” by TTE). The sensitivity and specificity of TTE were 32 and 100%, respectively. The combination of TTE followed by TEE resulted in a sensitivity of 100% and a specificity of 99% (one false positive). Given the relatively high prevalence of endocarditis among patients with S. aureus bacteremia, current IDSA guidelines [5] recommend an echocardiogram for all adults and state that TEE is preferred over TTE.  Compared to TTE, TEEs are more invasive, require anesthesia and coordination of hospital resources, and can rarely result in complications such as vocal cord paralysis and esophageal perforation [60]. Therefore, in practice, ID consultants will sometimes recommend a TTE first to avoid TEE if a vegetation is large enough or in an accessible location to be viewed by TTE with a negative exam being followed by TEE due to the sensitivity and specificity of each technique.

26

Chapter 2.  Staphylococcal Infection

Are there any patients whose pre-test probability of having endocarditis in the setting of S. aureus bacteremia is so low that TEE is not warranted? One proposed set of criteria for patients that may not require TEE are as follows: (1) negative TTE; (2) nosocomial acquisition of bacteremia; (3) sterile follow-up cultures; (4) absence of intracardiac device; (5) absence of hemodialysis dependence; and (6) no clinical signs of endocarditis or other metastatic infection [61]. To fit these criteria, one envisions a patient who cleared their blood cultures rapidly with no clinical evidence of other sites of infection—conditions even more stringent than uncomplicated bacteremia. There has also been the development of new scoring systems to assist in determining the urgency of proceeding to an echocardiogram, such as the VIRSTA score [62]. In VIRSTA, different weighted points are scored based on the clinical scenario, such as C-reactive protein (CRP) >190 mg/L (1 point), positive cultures after 48 hours (2 points), and meningitis (5 points). Any score of 3 points or greater merits TEE. In a follow-up prospective study of 477 patients with S. aureus bacteremia, VIRSTA outperformed two other scoring systems in the diagnosis of endocarditis and had a negative predictive value of 99.3% [63]. Lastly, there are some patients that may receive a duration of anti-staphylococcal therapy, which would be adequate to treat endocarditis such that confirming diagnosis with imaging may not be critical. For example, a patient who has staphylococcal osteomyelitis and bacteremia may warrant 6  weeks of antibiotics regardless of additional diagnosis of endocarditis—if they do not have clinical evidence concerning for endocarditis, echocardiography may not change their clinical management. Of note, there has been increasing awareness in the literature regarding the false-positive rates of echocardiography for the diagnosis of endocarditis [64]. This has led to additional radiographic techniques, such as PET/CT for prosthetic valve endocarditis [65].

Chapter 2.  Staphylococcal Infection

27

Q. My patient is having a recurrence of their staphylococcal bacteremia! What happened? A. New or relapse of prior infection can occur depending on host and pathogen factors. In one prospective study, patients with recurrence of S. aureus bacteremia were evaluated to determine which factors led to recurrence, including relapse (same strain as prior infection) and re-infection (strain different than prior infection) [66], and ~9% of patients had recurrence. By genotype, the rates of relapse versus re-­ infection were 44% and 56%, respectively. Recurrence was significantly associated with age (younger), race (black), patients with dependence on hemodialysis, presence of a foreign body, MRSA infection, and persistence of bacteremia during initial infection. ­ Patients that were less likely to have recurrence were more likely to be within 30 days of a surgical procedure and more likely to be under treatment for a neoplasm. The authors speculated that the host cytokine response is also associated with the likelihood of recurrence, and several biomarkers may have potential in the future as predictors for recurrence of infection. Q. This patient was admitted for a seemingly unrelated complaint and has now been found to have staphylococcal infection—is there a correlation? A. Staphylococci are highly inflammatory, and symptoms of infection can manifest in unusual ways—always wise to be vigilant! Staphylococcal infection is a significant physiologic stressor. Secreted toxins, such as Panton-Valentine leucocidin and enterotoxin B [67, 68], cell envelope lipoproteins [69], and other factors cause significant host inflammation. This dysregulation of inflammation can be damaging to the host. For example, in a murine model of cutaneous staphylococcal infection, it was found that athymic mice had smaller rather than larger lesions suggesting that the host inflammatory response rather than bacterial burden was dictating lesion size associated with the infection [70].

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Chapter 2.  Staphylococcal Infection

How does this affect our patients? While CRP is not a specific biomarker for infection, it does reflect host inflammation and higher elevation of CRP during staphylococcal infection has been found to significantly correlate with greater mortality [71]. Such a high systemic inflammatory response may have other negative effects on the host. For example, at a single institution, patients with documented staphylococcal bacteremia were retrospectively studied for rates of myocardial infarction (MI) [72]. Compared to historical controls, patients with staphylococcal bacteremia were 35 times more likely to have MI. This is not necessarily a Staphylococcus-­specific phenomenon as increasing rates of MIs have also been observed in other serious infections [73, 74]. Inflammation from infection can manifest in less dramatic ways than MI. In one retrospective study at a single center in Boston, 161 patients who were admitted with falls were found subsequently to have a systemic infection [75]. Mechanical falls were the most common type reported (66% of cases). Bacteremia was observed in 40% of these cases, and the most common cause of bacteremia was S. aureus, found in 13% of all patients in this study. While this retrospective study is correlative rather than causative, it brings home the point that infections may present themselves in ways we do not always expect! Q.  This patient has a negative MRSA swab—can we change their antibiotic regimen? A. It depends on the clinical scenario. In patients with concern for septic shock or other life-­ threatening infections, we often empirically include treatment for MRSA while awaiting culture data. It has been well-established that MRSA swab has a fairly high predictive value for MRSA pneumonia as reviewed in a meta-analysis [76]. This is somewhat intuitive, given the relationship between the oropharynx and lungs. However, we are often asked about the negative predictive value (NPV) of the MRSA swab for MRSA at other sites—can vancomycin be transitioned to a beta-lactam

Chapter 2.  Staphylococcal Infection

29

in the setting of bacteremia or a wound if the patient has a negative MRSA swab? A large cohort of over 550,000 patients treated within the US VA medical system from 2007 to 2018 was retrospectively studied to determine the NPV of the MRSA swab for multiple other sites [77]. This study was done essentially without clinical data— the presence of positive MRSA on nares swab was correlated with presence of MRSA in other cultures (blood, intra-abdominal, respiratory, wound, and urine). NPV for these sites was 96.5%, 98.6%, 96.1%, 93.1%, and 99.2%, respectively. Overall, the NPV of MRSA nares for ruling out MRSA in other cultures was 96.5%. It appears the MRSA swab is least predictive of surgical sites and most predictive of pneumonia and UTI. If one feels they can generalize from the patient population in this study, it is likely reasonable to discontinue MRSAspecific antibiotic treatment in a patient with pulmonary or urinary source and negative MRSA swab. However, one must also consider when the swab was performed and the likelihood that the patient obtained a hospitalacquired MRSA infection after that time. Q. Anaerobic staphylococci—are you pulling my leg? A. There is a species of staphylococci that is anaerobic! Staphylococcus saccharolyticus is a rare pathogen only recently implicated in human infection. It is the only anaerobic staphylococcal species (so far!) and is genetically most closely related to Staphylococcus capitis [78]. In a recent review of the literature, 8 cases were collected [79]. All cases were resistant to metronidazole and two were resistant to beta-lactams. All tested clinical isolates were susceptible to fluoroquinolones, clindamycin, and vancomycin. In a study of S. saccharolyticus recovered from oral specimens, all five out of five isolates were susceptible to doxycycline [80]. The organism has also been implicated in prosthetic joint infection; in one case series, 3 cases of total shoulder arthroplasty and 5 of total hip arthroplasty infected with S. saccharolyticus complicated by bacteremia were presented [78].

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Chapter 2.  Staphylococcal Infection

References 1. Mylotte JM, Tayara A.  Staphylococcus aureus bacteremia: predictors of 30-day mortality in a large cohort. Clin Infect Dis. 2000;31:1170. https://doi.org/10.1086/317421. 2. Vogel M, Schmitz RPH, Hagel S, Pletz MW, Gagelmann N, Scherag A, Schlattmann P, Brunkhorst FM.  Infectious disease consultation for Staphylococcus aureus bacteremia  - a systematic review and meta-analysis. J Infect. 2016;72:19. https://doi. org/10.1016/j.jinf.2015.09.037. 3. Forsblom E, Ruotsalainen E, Ollgren J, Järvinen A.  Telephone consultation cannot replace bedside infectious disease consultation in the management of staphylococcus aureus bacteremia. Clin Infect Dis. 2013;56:527. https://doi.org/10.1093/cid/cis889. 4. Djelic L, Andany N, Craig J, Daneman N, Simor A, Leis JA.  Automatic notification and infectious diseases consultation for patients with Staphylococcus aureus bacteremia. Diagn Microbiol Infect Dis. 2018;91:282. https://doi.org/10.1016/j. diagmicrobio.2018.03.001. 5. Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, Kaplan SL, Karchmer AW, Levine DP, Murray BE, Rybak MJ, Talan DA, Chambers HF.  Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:285. https://doi.org/10.1093/ cid/ciq146. 6. Berrevoets MAH, Kouijzer IJE, Aarntzen EHJG, Janssen MJR, De Geus-Oei LF, Wertheim HFL, Kullberg BJ, Oever JT, Oyen WJG, Bleeker-Rovers CP. 18F-FDG PET/CT optimizes treatment in staphylococcus aureus bacteremia and is associated with reduced mortality. J Nucl Med. 2017;58:1504. https://doi. org/10.2967/jnumed.117.191981. 7. Berrevoets MAH, Kouijzer IJE, Slieker K, Aarntzen EHJG, Kullberg BJ, Oever JT, Bleeker-Rovers CP. 18F-FDG PET/ CT-guided treatment duration in patients with high-risk staphylococcus aureus bacteremia: a proof of principle. J Nucl Med. 2019;60:998. https://doi.org/10.2967/jnumed.118.221929. 8. Khatib R, Johnson LB, Fakih MG, Riederer K, Khosrovaneh A, Tabriz MS, Sharma M, Saeed S.  Persistence in staphylococcus aureus bacteremia: incidence, characteristics of

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14. Tong SYC, Lye DC, Yahav D, Sud A, Robinson JO, Nelson J, Archuleta S, Roberts MA, Cass A, Paterson DL, Foo H, Paul M, Guy SD, Tramontana AR, Walls GB, McBride S, Bak N, Ghosh N, Rogers BA, Ralph AP, Davies J, Ferguson PE, Dotel R, McKew GL, Gray TJ, Holmes NE, Smith S, Warner MS, Kalimuddin S, Young BE, Runnegar N, Andresen DN, Anagnostou NA, Johnson SA, Chatfield MD, Cheng AC, Fowler VG, Howden BP, Meagher N, Price DJ, Van Hal SJ, O’Sullivan MVN, Davis JS.  Effect of vancomycin or daptomycin with vs without an antistaphylococcal β-lactam on mortality, bacteremia, relapse, or treatment failure in patients with MRSA bacteremia: a randomized clinical trial. JAMA. 2020;323:527. https://doi.org/10.1001/ jama.2020.0103. 15. Pujol M, Miró JM, Shaw E, Aguado JM, San-Juan R, Puig-­ Asensio M, Pigrau C, Calbo E, Montejo M, Rodriguez-Álvarez R, Garcia-Pais MJ, Pintado V, Escudero-Sánchez R, Lopez-­ Contreras J, Morata L, Montero M, Andrés M, Pasquau J, Arenas MDM, Padilla B, Murillas J, Jover-Sáenz A, López-Cortes LE, García-Pardo G, Gasch O, Videla S, Hereu P, Tebé C, Pallarès N, Sanllorente M, Domínguez MÁ, Càmara J, Ferrer A, Padullés A, Cuervo G, Carratalà J. Daptomycin plus fosfomycin versus daptomycin alone for methicillin-resistant Staphylococcus aureus bacteremia and endocarditis: a randomized clinical trial. Clin Infect Dis. 2021;72:1517. https://doi.org/10.1093/cid/ciaa1081. 16. Cheng MP, Lawandi A, Butler-Laporte G, De l’Étoile-Morel S, Paquette K, Lee TC. Adjunctive daptomycin in the treatment of methicillin-susceptible Staphylococcus aureus bacteremia: a randomized, controlled trial. Clin Infect Dis. 2021;72:e196. https:// doi.org/10.1093/cid/ciaa1000. 17. Geriak M, Haddad F, Rizvi K, Rose W, Kullar R, LaPlante K, Yu M, Vasina L, Ouellette K, Zervos M, Nizet V, Sakoulas G.  Clinical data on Daptomycin plus Ceftaroline versus standard of care monotherapy in the treatment of methicillin-­ resistant Staphylococcus aureus bacteremia. Antimicrob Agents Chemother. 2019;63 https://doi.org/10.1128/AAC.02483-­18. 18. Nichols CN, Wardlow LC, Coe KE, Sobhanie MME.  Clinical outcomes with definitive treatment of methicillin-resistant Staphylococcus aureus bacteremia with retained daptomycin and Ceftaroline combination therapy vs de-escalation to monotherapy with vancomycin, daptomycin, or ceftaroline. Open Forum Infect Dis. 2021;8 https://doi.org/10.1093/ofid/ofab327.

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52. Zinkernagel AS, Zinkernagel MS, Elzi MV, Genoni M, Gubler J, Zbinden R, Mueller NJ. Significance of staphylococcus lugdunensis bacteremia: report of 28 cases and review of the literature. Infection. 2008;36:314. https://doi.org/10.1007/s15010-­0 08-­7287-­9. 53. Holland TL, Raad I, Boucher HW, Anderson DJ, Cosgrove SE, Suzanne Aycock P, Baddley JW, Chaftari AM, Chow SC, Chu VH, Carugati M, Cook P, Ralph Corey G, Crowley AL, Daly J, Gu J, Hachem R, Horton J, Jenkins TC, Levine D, Miro JM, Pericas JM, Riska P, Rubin Z, Rupp ME, Schrank J, Sims M, Wray D, Zervos M, Fowler VG.  Effect of algorithm-based therapy vs usual care on clinical success and serious adverse events in patients with staphylococcal bacteremia a ­randomized clinical trial. JAMA. 2018;320:1249. https://doi.org/10.1001/ jama.2018.13155. 54. Heldman AW, Hartert TV, Ray SC, Daoud EG, Kowalski TE, Pompili VJ, Sisson SD, Tidmore WC, Vom Eigen KA, Goodman SN, Lietman PS, Petty BG, Flexner C.  Oral antibiotic treatment of right-sided staphylococcal endocarditis in injection drug users: prospective randomized comparison with parenteral therapy. Am J Med. 1996;101:68. https://doi.org/10.1016/ S0002-­9343(96)00070-­8. 55. Schrenzel J, Harbarth S, Schockmel G, Genné D, Bregenzer T, Flueckiger U, Petignat C, Jacobs F, Francioli P, Zimmerli W, Lew DP. A randomized clinical trial to compare fleroxacin-rifampicin with flucloxacillin or vancomycin for the treatment of staphylococcal infection. Clin Infect Dis. 2004;39:1285. https://doi. org/10.1086/424506. 56. Shorr AF, Kunkel MJ, Kollef M. Linezolid versus vancomycin for Staphylococcus aureus bacteraemia: pooled analysis of randomized studies. J Antimicrob Chemother. 2005;56:923. https://doi. org/10.1093/jac/dki355. 57. Paul M, Bishara J, Yahav D, Goldberg E, Neuberger A, Ghanem-Zoubi N, Dickstein Y, Nseir W, Dan M, Leibovici L. Trimethoprim-sulfamethoxazole versus vancomycin for severe infections caused by meticillin resistant Staphylococcus aureus: randomised controlled trial. BMJ. 2015;350:h2219. https://doi. org/10.1136/bmj.h2219. 58. Iversen K, Ihlemann N, Gill SU, Madsen T, Elming H, Jensen KT, Bruun NE, Høfsten DE, Fursted K, Christensen JJ, Schultz M, Klein CF, Fosbøll EL, Rosenvinge F, Schønheyder HC, Køber L, Torp-Pedersen C, Helweg-Larsen J, Tønder N, Moser C, Bundgaard H. Partial oral versus intravenous antibiotic treat-

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ment of endocarditis. N Engl J Med. 2019;380:415. https://doi. org/10.1056/nejmoa1808312. 59. Fowler VG, Li J, Corey GR, Boley J, Marr KA, Gopal AK, Kong LK, Gottlieb G, Donovan CL, Sexton DJ, Ryan T.  Role of echocardiography in evaluation of patients with Staphylococcus aureus bacteremia: experience in 103 patients. J Am Coll Cardiol. 1997;30:1072. https://doi.org/10.1016/ S0735-­1097(97)00250-­7. 60. Côté G, Denault A.  Transesophageal echocardiography-related complications. Can J Anesth. 2008;55:622. https://doi.org/10.1007/ BF03021437. 61. Holland TL, Arnold C, Fowler VG. Clinical management of staphylococcus aureus bacteremia: a review. JAMA. 2014;312:1330. https://doi.org/10.1001/jama.2014.9743. 62. Tubiana S, Duval X, Alla F, Selton-Suty C, Tattevin P, Delahaye F, Piroth L, Chirouze C, Lavigne JP, Erpelding ML, Hoen B, Vandenesch F, Iung B, Le Moing V.  The VIRSTA score, a prediction score to estimate risk of infective endocarditis and determine priority for echocardiography in patients with Staphylococcus aureus bacteremia. J Infect. 2016;72:544. https:// doi.org/10.1016/j.jinf.2016.02.003. 63. van der Vaart TW, Prins JM, Soetekouw R, van Twillert G, Veenstra J, Herpers BL, Rozemeijer W, Jansen RR, Bonten MJM, van der Meer JTM. Prediction rules for ruling out endocarditis in patients with Staphylococcus aureus bacteremia. Clin Infect Dis. 2021;74:1442. https://doi.org/10.1093/cid/ciab632. 64. George MP, Esquer Garrigos Z, Vijayvargiya P, Anavekar NS, Luis SA, Wilson WR, Baddour LM, Sohail MR. Discriminative ability and reliability of transesophageal echocardiography in characterizing cases of cardiac device lead vegetations versus noninfectious Echodensities. Clin Infect Dis. 2021;72:1938. https://doi.org/10.1093/cid/ciaa472. 65. Bayer AS, Chambers HF. Prosthetic valve endocarditis diagnosis and management—new paradigm shift narratives. Clin Infect Dis. 2021;72:1687. https://doi.org/10.1093/cid/ciab036. 66. Choi SH, Dagher M, Ruffin F, Park LP, Sharma-Kuinkel BK, Souli M, Morse AM, Eichenberger EM, Hale L, Kohler C, Warren B, Hansen B, Medie FM, Mcintyre LM, Fowler VG. Risk factors for recurrent Staphylococcus aureus bacteremia. Clin Infect Dis. 2021;72:1891. https://doi.org/10.1093/cid/ciaa801. 67. Diep BA, Chan L, Tattevin P, Kajikawa O, Martin TR, Basuino L, Mai TT, Marbach H, Braughton KR, Whitney AR, Gardner DJ,

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Chapter 3 Other Gram-Positive Infections

Abstract  After removing the staphylococci, which grampositive infections are left? Streptococci, enterococci, and the occasional gram-positive rod will also keep the ID consultant busy. While a key feature in the workup of any infectious patient, the source is particularly important in gram-positive infection as illustrated by some of these pathogens associated with oral, gastrointestinal, and hepatobiliary flora. Antibiotic susceptibility patterns remain as important as ever, and it is very satisfying that some of these organisms can still be treated by classics like penicillin, such as Streptococcus pyogenes and Actinomycoses species. In this chapter, we will discuss gram-positive morphology, the nomenclature surrounding streptococci, the management of streptococcal and enterococcal infections, and the different diseases caused by gram-positive rods.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. M. Tatara, The Infectious Diseases Consult Handbook, https://doi.org/10.1007/978-3-031-39474-4_3

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Chapter 3.  Other Gram-Positive Infections

Q. Why do you always ask for a gram stain when we order cultures? A. Organism morphology can give important clues prior to the maturation of cultures. If gram stain demonstrates gram-positive organisms, pay close attention to the reported morphology. A trip to the microbiology laboratory can help both you and your patients regarding gram-positive cocci (GPCs), as shown in Fig.  3.1. GPCs in clusters are typically staphylococci until proven otherwise. Enterococci are often described as GPCs in short chains and pairs, whereas streptococci tend to be in longer chains. GPCs in pairs are classically Streptococcus pneumoniae and GPCs in tetrads are typically micrococci, species associated with catheter infections [1]. While the gram stain can be an invaluable tool, looks can be deceiving—preparation technique, inadequate specimen, or partially treated organisms can result in artifacts. One multicenter study demonstrated that 5% of gram stains are discrepant from final culture results, most often for organisms that do not reveal themselves on

Figure 3.1  Common gram-positive cocci morphological patterns

Chapter 3.  Other Gram-Positive Infections

43

the stain but grow in culture [2]. The reverse is also true— sometimes the gram stain will present the only clue to the patient’s infectious organism as cultures will not grow. If the gram stain returns showing gram-positive organisms, there are several antibiotics that are generally effective such as daptomycin and linezolid. While many cephalosporins can be effective against non-betalactamase-­ producing gram-positive bacteria, ceftazidime generally has poor activity against gram-positive organisms and may not be a good empiric choice [3]. Q. Streptococcus A through G—how am I supposed to interpret these different species? A. The streptococcal nomenclature is confusing. Let us work through it together. The bizarre, cumbersome, and seemingly-contradictory nomenclature associated with streptococci is so infamous that Dr. Daniel Musher published a poem [4] on the subject in a parody of the T.S.  Eliot poem, “The Naming of Cats.” Confusion can easily occur as species can be divided by hemolytic pattern (ability to break down red blood cells with hemolysins), Lancefield grouping based on carbohydrate antigens, and species name. For example, the species Streptococcus pyogenes is beta-hemolytic and by Lancefield grouping in Group A. Therefore, it will sometimes be referred to as S. pyogenes and other times as Group A Streptococcus or GAS. No wonder it is difficult to keep the nomenclature straight! Rather than memorize different (and sometimes conflicting) systems, it may be more useful to organize clinically relevant streptococci by their behavior. We will group and discuss them as pneumococcus, exotoxin-dominant streptococci (Groups A, C, and G), perinatal streptococci (Group B), gastrointestinal streptococci (Group D), and viridans streptococci. Streptococcus pneumoniae is an alpha-hemolytic diplococcus that causes community-acquired pneumonia and upper respiratory infections. To add to confusing nomenclature, this organism is also sometimes referred

44

Chapter 3.  Other Gram-Positive Infections

to as pneumococcus. Depending on geographic area, rates of antibiotic resistance of S. pneumoniae are increasing although greater than 94% isolates collected from a worldwide consortium from 2015 to 2016 remained susceptible to amoxicillin, penicillin, and ceftriaxone [5, 6]. Pneumococcal meningitis carries mortality as high as 30% and most frequently occurs in adults with preceding pneumonia, otitis, sinusitis, cerebrospinal fluid leak, or a history of immunosuppression [7]. Empiric treatment of pneumococcal meningitis includes steroid therapy in addition to vancomycin and ceftriaxone [8]. Since adopting steroid therapy, mortality from pneumococcal pneumonia has fallen from 30% to 20% [9]. While this book focuses on inpatient ID consults, it is important to understand the timing and indications for S. pneumoniae vaccination, which is most often performed in the outpatient setting. While all streptococci produce exotoxins, those from Groups A, C, and G secrete a similar cluster of particularly virulent toxic factors such as streptolysin and streptokinase [10, 11]. Streptococcus pyogenes is a beta-­ hemolytic species also known as Group A Streptococcus (GAS). It colonizes the oropharynx and skin and is responsible for a variety of diseases, ranging from pharyngitis, impetigo, and cellulitis to life-threatening illnesses such as necrotizing fasciitis and streptococcal toxic shock syndrome [12]. GAS is not only dangerous due to its virulence but also associated with autoimmune diseases including rheumatic fever and poststreptococcal glomerulonephritis. Fortunately, the majority of isolates remain quite susceptible to penicillin although there have been sporadic outbreaks of beta-­ lactam-­resistant strains [13]. Group C and Group G streptococci (GCS and GGS, respectively) can colonize similar areas as GAS such as the oropharynx and skin [14]. They can be carried by cows, horses, and canines and cause zoonotic disease [15]. GCS and GGS are associated with pharyngitis and skin infections and also tend to be sensitive to penicillin therapy [14].

Chapter 3.  Other Gram-Positive Infections

45

Streptococcus agalactiae or Group B streptococcus (GBS) is a colonizer of male and female genitourinary and gastrointestinal tracts [16]. Patients with pregnancy and colonization are more prone to premature delivery [17]. Even more concerning, neonates who have perinatal infection with GBS can develop invasive diseases, such as pneumonia and meningitis. In the 1970s, GBS was the leading cause of neonatal sepsis and meningitis [18]. However, with the implementation of screening and treatment during pregnancy, rates of perinatal transmission have decreased [19]. While not a common pathogen outside of perinatal settings, GBS can cause disease in other hosts, such as endocarditis [20]. Calling Group D streptococcus (GDS) gastrointestinal streptococci is a bit misleading, given that many streptococci are part of gastrointestinal flora. However, it highlights a historical aspect of streptococci classification—enterococci, named after the intestinal system, were once thought to be streptococci and were placed in the GDS family [21]. Unlike enterococci, GDS are typically susceptible to cephalosporins [22]. Group D streptococci are associated with endocarditis. One species in particular, Streptococcus gallolyticus subspecies gallolyticus (formerly S. bovis biotype I), is associated with colorectal cancer, and 60% of patients with S. bovis species infection have been found to have adenomas/carcinomas [23]. In a case-control study, the odds ratios of having significant advanced adenoma or invasive carcinoma with S. gallolyticus subsp. gallolyticus infection were 3.5 and 2.9, respectively [24]. The mechanism behind this relationship is under active investigation but may be due to changes in the tumor microenvironment that allow the bacterium to proliferate [25]. In patients with invasive S. gallolyticus disease, colonoscopy should be considered. The viridans streptococci are native to the oral microbiome and can also be found among gastrointestinal and genitourinary flora [26]. Viridans species have been called a “grab bag” and include Streptococcus anginosus, Streptococcus mitis, Streptococcus mutans, Streptococcus

46

Chapter 3.  Other Gram-Positive Infections

salivarius, and Streptococcus sanguinis [27]. Adding to the chaos of streptococcal identification, depending on whether isolates are alpha- or beta-­hemolytic, S. anginosus and S. mitis may be classified as Group F streptococcus and some may consider S. bovis as viridans rather than Group D streptococcus. As a class, the viridans streptococci are associated with endocarditis, particularly from oral translocation [28]. While many of the viridans cause transient bacteremia or endocarditis, particularly in diseased valves, the S. anginosus group (including S. anginosus, Streptococcus constellatus, and Streptococcus intermedius) is particularly virulent and prone to develop abscesses [27]. In one retrospective review of 463 patients with S. anginosus group infection, S. anginosus was the most common of the three species (55%) and the most common infectious site for S. anginosus was abdominal although chest and skin/soft tissue infections were relatively common [29]. In a patient with S. anginosus group bacteremia, it is important to be vigilant for abscess formation in the abdomen, lungs, extremities, and even intracranial space. In summary, there is pneumococcus (pneumonia and meningitis), exotoxin-secreting streptococci (associated with pharyngitis, skin/soft tissue infection, and autoimmune disease in the case of GAS), perinatal streptococci (associated with neonatal pneumonia and meningitis), gastrointestinal streptococci (associated with endocarditis and some species linked to colorectal cancer), and the viridans streptococci (oral flora and endocarditis). Many streptococci remain susceptible to beta-lactams, although your individual hospital antibiogram should be consulted for geographic variance. Q. My patient has streptococcal bacteremia—what are the odds they also have endocarditis? A. This will depend on the specific streptococcal species and host factors. Streptococci are a relatively common cause of infectious endocarditis. In one retrospective study analyzing trends in infectious endocarditis across the USA from

Chapter 3.  Other Gram-Positive Infections

47

1998 to 2009, streptococci were responsible for 24.7% of cases [30]. However, not all streptococcal species carry the same risk. In a retrospective study of over 6500 cases of streptococcal bacteremia in Denmark, the rates of associated endocarditis per species were determined [31]. Overall, endocarditis was found in 7.1% of cases. S. pneumoniae and S. pyogenes bacteremia were least likely to be associated with endocarditis (3)-beta-D-glucan concentrations in hemodialysis patients. Nephron. 2001;89:15–9. https:// doi.org/10.1159/000046037. 10. Prattes J, Hoenigl M, Rabensteiner J, Raggam RB, Prueller F, Zollner-Schwetz I, Valentin T, Hönigl K, Fruhwald S, Krause R.  Serum 1,3-beta-d-glucan for antifungal treatment stratifi-

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cation at the intensive care unit and the influence of surgery. Mycoses. 2014;57:679–86. https://doi.org/10.1111/myc.12221. 11. Mennink-Kersten MASH, Ruegebrink D, Verweij PE.  Pseudomonas aeruginosa as a cause of 1,3-beta-D-glucan assay reactivity. Clin Infect Dis. 2008;46:1930–1. https://doi. org/10.1086/588563. 12. Barton C, Vigor K, Scott R, Jones P, Lentfer H, Bax HJ, Josephs DH, Karagiannis SN, Spicer JF.  Beta-glucan contamination of pharmaceutical products: how much should we accept? Cancer Immunol Immunother. 2016;65:1289–301. https://doi. org/10.1007/s00262-­0 16-­1875-­9. 13. Ito S, Ashizawa M, Sasaki R, Ikeda T, Toda Y, Mashima K, Umino K, Minakata D, Nakano H, Yamasaki R, Kawasaki Y, Sugimoto M, Yamamoto C, Fujiwara S-I, Hatano K, Sato K, Oh I, Ohmine K, Muroi K, Suzuki J, Hatakeyama S, Morisawa Y, Yamada T, Kanda Y.  False-positive elevation of 1,3-beta-­ D-glucan caused by continuous administration of penicillin G.  J Infect Chemother. 2018;24:812–4. https://doi.org/10.1016/j. jiac.2018.06.008. 14. Agnelli C, Bouza E, del Carmen Martínez-Jiménez M, Navarro R, Valerio M, Machado M, Guinea J, Sánchez-Carrillo C, Alonso R, Muñoz P, for the Collaborative Group on Mycosis (COMIC) Study Group. Clinical relevance and prognostic value of persistently negative (1,3)-β-D-glucan in adults with Candidemia: a 5-year experience in a tertiary hospital. Clin Infect Dis. 2020;70:1925–32. https://doi.org/10.1093/cid/ciz555. 15. Gudlaugsson O, Gillespie S, Lee K, Vande Berg J, Hu J, Messer S, Herwaldt L, Pfaller M, Diekema D. Attributable mortality of nosocomial candidemia, revisited. Clin Infect Dis. 2003;37:1172– 7. https://doi.org/10.1086/378745. 16. Lee RA, Zurko JC, Camins BC, Griffin RL, Rodriguez JM, McCarty TP, Magadia J, Pappas PG. Impact of infectious disease consultation on clinical management and mortality in patients with Candidemia. Clin Infect Dis. 2019;68:1585–7. https://doi. org/10.1093/cid/ciy849. 17. Mohr A, Simon M, Joha T, Hanses F, Salzberger B, Hitzenbichler F. Epidemiology of candidemia and impact of infectious disease consultation on survival and care. Infection. 2020;48:275–84. https://doi.org/10.1007/s15010-­020-­0 1393-­9. 18. Nunes CZ, Marra AR, Edmond MB, da Silva VE, Pereira CAP.  Time to blood culture positivity as a predictor of clinical outcome in patients with Candida albicans blood-

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26. Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, Reboli AC, Schuster MG, Vazquez JA, Walsh TJ, Zaoutis TE, Sobel JD. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62:e1–50. https://doi.org/10.1093/cid/civ933. 27. Jung P, Mischo CE, Gunaratnam G, Spengler C, Becker SL, Hube B, Jacobs K, Bischoff M.  Candida albicans adhesion to central venous catheters: impact of blood plasma-driven germ tube formation and pathogen-derived adhesins. Virulence. 2020;11:1453–65. https://doi.org/10.1080/21505594.2020.1836902. 28. Janum S, Afshari A.  Central venous catheter (CVC) removal for patients of all ages with candidaemia. Cochrane Database Syst Rev. 2016;7:CD011195. https://doi.org/10.1002/14651858. CD011195.pub2. 29. Martin-Loeches I, Antonelli M, Cuenca-Estrella M, Dimopoulos G, Einav S, De Waele JJ, Garnacho-Montero J, Kanj SS, Machado FR, Montravers P, Sakr Y, Sanguinetti M, Timsit J-F, Bassetti M.  ESICM/ESCMID task force on practical management of invasive candidiasis in critically ill patients. Intensive Care Med. 2019;45:789–805. https://doi.org/10.1007/s00134-­0 19-­05599-­w. 30. Fernández-Cruz A, Cruz Menárguez M, Muñoz P, Pedromingo M, Peláez T, Solís J, Rodríguez-Créixems M, Bouza E, GAME Study Group (Grupo de Apoyo al Manejo de la Endocarditis). The search for endocarditis in patients with candidemia: a systematic recommendation for echocardiography? A prospective cohort. Eur J Clin Microbiol Infect Dis. 2015;34:1543–9. https:// doi.org/10.1007/s10096-­0 15-­2384-­z. 31. Foong KS, Sung A, Burnham JP, Kronen R, Lian Q, Salazar Zetina A, Hsueh K, Lin C, Powderly WG, Spec A.  Risk factors predicting Candida infective endocarditis in patients with ­candidemia. Med Mycol. 2020;58:593–9. https://doi.org/10.1093/ mmy/myz104. 32. Breazzano MP, Bond JB, Bearelly S, Kim DH, Donahue SP, Lum F, Olsen TW.  American Academy of Ophthalmology recommendations on screening for endogenous candida endophthalmitis. Ophthalmology. 2022;129:73–6. https://doi.org/10.1016/j. ophtha.2021.07.015. 33. Seidelman J, Fleece M, Bloom A, Lydon E, Yang W, Arnold C, Weber DJ, Okeke NL.  Endogenous Candida endophthalmitis: who is really at risk? J Infect. 2021;82:276–81. https://doi. org/10.1016/j.jinf.2020.12.032.

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BH, Ullmann AJ, Vehreschild JJ, MJGT V, Walsh TJ, White PL, Wiederhold NP, Zaoutis T, Chakrabarti A, Mucormycosis ECMM MSG Global Guideline Writing Group. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Lancet Infect Dis. 2019;19:e405–21. https://doi.org/10.1016/S1473-­3099(19)30312-­3. 65. Palejwala SK, Zangeneh TT, Goldstein SA, Lemole GM.  An aggressive multidisciplinary approach reduces mortality in rhinocerebral mucormycosis. Surg Neurol Int. 2016;7:61. https://doi. org/10.4103/2152-­7806.182964. 66. Gupta MK, Kumar N, Dhameja N, Sharma A, Tilak R. Laboratory diagnosis of mucormycosis: present perspective. J Family Med Prim Care. 2022;11:1664–71. https://doi.org/10.4103/jfmpc. jfmpc_1479_21. 67. Chamilos G, Lewis RE, Kontoyiannis DP.  Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis. Clin Infect Dis. 2008;47:503–9. https://doi. org/10.1086/590004. 68. Smith C, Lee SC. Current treatments against mucormycosis and future directions. PLoS Pathog. 2022;18:e1010858. https://doi. org/10.1371/journal.ppat.1010858. 69. Wheat LJ.  Approach to the diagnosis of the endemic mycoses. Clin Chest Med. 2009;30:379–89, viii. https://doi.org/10.1016/j. ccm.2009.02.011. 70. Basso RP, Poester VR, Benelli JL, Stevens DA, Xavier MO.  Disseminated histoplasmosis in persons with HIV/AIDS, southern Brazil, 2010–2019. Emerg Infect Dis. 2022;28:721–4. https://doi.org/10.3201/eid2803.212150. 71. de Perio MA, Benedict K, Williams SL, Niemeier-Walsh C, Green BJ, Coffey C, Di Giuseppe M, Toda M, Park J-H, Bailey RL, Nett RJ.  Occupational histoplasmosis: epidemiology and prevention measures. J Fungi (Basel). 2021;7:510. https://doi. org/10.3390/jof7070510. 72. Joseph Wheat L.  Current diagnosis of histoplasmosis. Trends Microbiol. 2003;11:488–94. https://doi.org/10.1016/j. tim.2003.08.007. 73. Azar MM, Hage CA.  Laboratory diagnostics for histoplasmosis. J Clin Microbiol. 2017;55:1612–20. https://doi.org/10.1128/ JCM.02430-­16.

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74. Galgiani JN, Ampel NM, Blair JE, Catanzaro A, Johnson RH, Stevens DA, Williams PL, Infectious Diseases Society of America. Coccidioidomycosis. Clin Infect Dis. 2005;41:1217–23. https://doi.org/10.1086/496991. 75. Williams SL, Chiller T.  Update on the epidemiology, diagnosis, and treatment of Coccidioidomycosis. J Fungi (Basel). 2022;8:666. https://doi.org/10.3390/jof8070666. 76. Galgiani JN, Ampel NM, Blair JE, Catanzaro A, Geertsma F, Hoover SE, Johnson RH, Kusne S, Lisse J, MacDonald JD, Meyerson SL, Raksin PB, Siever J, Stevens DA, Sunenshine R, Theodore N. 2016 Infectious Diseases Society of America (IDSA) clinical practice guideline for the treatment of coccidioidomycosis. Clin Infect Dis. 2016;63:e112–46. https://doi. org/10.1093/cid/ciw360. 77. Saccente M, Woods GL.  Clinical and laboratory update on Blastomycosis. Clin Microbiol Rev. 2010;23:367–81. https://doi. org/10.1128/CMR.00056-­09. 78. McBride JA, Gauthier GM, Klein BS.  Clinical manifestations and treatment of blastomycosis. Clin Chest Med. 2017;38:435–49. https://doi.org/10.1016/j.ccm.2017.04.006. 79. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America— PubMed. https://pubmed-­ncbi-­nlm-­nih-­gov.treadwell.idm.oclc. org/18462107/. Accessed 27 Feb 2023.

Chapter 6 Mycobacterial Infection

Abstract  Each Monday morning, the fellows and attendings in our division gather over coffee and pastries to discuss the most complicated cases seen over the past week and offer guidance based on the collected experience of the division. Despite not living in an endemic area, talk of mycobacteria (and Mycobacterium tuberculosis in particular) often dominates the conference. Why do these organisms generate so much interest? Mycobacterial infections carry diagnostic and therapeutic challenges. Given the infectiousness of tuberculosis, cases are also infection control challenges. Epidemiology can assist in diagnosis and affect resistance patterns. Treatment itself carries significant toxicities, so decision-making for empiric management is difficult. Mycobacteria are mysterious and complex, especially compared to other bacteria which can typically be treated with source control and antibiotic monotherapy within a few weeks. To understand mycobacteria is to understand the complexities of the ID service! This chapter will provide an overview of diagnostic and treatment frameworks for tubercular diseases in the format of frequent consult questions, but given the complexity of mycobacterial disease, consultation with local mycobacterial experts is recommended for challenging cases.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. M. Tatara, The Infectious Diseases Consult Handbook, https://doi.org/10.1007/978-3-031-39474-4_6

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Q. How contagious is pulmonary tuberculosis? A. It is hard to predict, but healthcare workers are certainly at risk. When exposed to patients with active tuberculosis (TB), there is a chance of contracting TB or latent tuberculosis infection (LTBI). LTBI may progress to active TB with increased risk for the immunocompromised [1]. Personal protective equipment (PPE) such as N95 respirators can help lower the risk of spread [2]. However, it is not always obvious that a patient has active TB and N95 respirators are not routinely worn. In a study in Japan, 11 patients over 5 years were found to have active TB after admission [3]. A total of 512 close or high-risk contacts from the hospitalization were identified and screened. Subsequently, 34/512 (6.6%) were interferon-­gamma release assay (IGRA) positive; four of those contacts (0.7%) had imaging evidence of active disease and the remaining 30 were treated for LTBI. What is the risk specifically to the ID fellow? In one study, 8/104 (7.7%) of US fellows in infectious diseases and pulmonary medicine converted their tuberculin skin test while training [4]. Specifically, 7/62 (11%) of pulmonary fellows had conversion, whereas only 1/42 (2.4%) of ID fellows had conversion, perhaps due to a higher risk of aerosolizing procedures. In another study, the ­conversion rates of TB sanatorium workers versus people who lived at home with TB patients were compared, and rates were 14% and 10%, respectively [5, 6]. In one chilling case, 29 healthcare workers were exposed to a single patient with active TB for 2 h in the emergency room and 10 h in the intensive care unit prior to recognition [7]. Out of 17 exposed healthcare workers that were previously tuberculin skin test negative, 10 (59%) had conversion to positive skin test and 3 (18%) developed active TB. What about conversion rates in the community? One fascinating study from the 1960s involved a school bus driver with undiagnosed active TB [8]. Contact tracing was done on the school children of their route, and

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cases were divided by the daily time they spent on the bus: if on the bus less than 10 min, 22% converted; if on the bus 10–39 min, 30% converted; and those that rode the bus for greater than 40 min had a 57% conversion rate. In another somewhat bizarre study, patients with known TB had their number of coughs per night counted [9]. If patients had less than 12 coughs per night, their family members converted 27% of the time. Patients who coughed more than 48× per night had family members that converted 44% of the time. A more recent prospective study was undertaken to better understand the duration of exposure and development of LTBI [10]. Patients diagnosed with active TB were recruited, and their close contacts at nine health departments in the USA and Canada were interviewed and screened. Out of 3040 contacts, 1390 were diagnosed with LTBI. In a multivariate analysis, risks for contacts being diagnosed with LTBI included age greater than 5 years, non-US/Canadian born, active TB patient being smear-positive, and shared bedroom with the active TB patient. For every 250 exposure hours to the patient (~10 days), the risk of LTBI increased by 8.2%. Exposure hours are important in seroconversion and should be minimized among close contacts during treatment. Of note, non-household contacts with ANY exposure correlated to having a greater than 33% chance of LTBI. In sum, exposed healthcare workers are certainly at risk for developing active TB and/or LTBI. The degree of risk likely depends on the exposure time, the type of exposure, and host factors. Q. I was exposed to a patient with active tuberculosis – when should I get tested? A. Current guidelines recommend upon exposure and again in 8–10 weeks. When exposed without PPE to a patient with active TB, close contacts, including healthcare workers, should be screened. In one study from a platoon of 32 soldiers that were exposed to an index patient, four developed active

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TB [11]. The remaining 27 troops had IGRAs performed at 0, 2, 4, 8, 14, 18, and 30 weeks or until a positive test. Subsequently, 17 soldiers had positive results with the first IGRA. Of the remaining 10 soldiers, three converted at 2  weeks, three converted at 4  weeks, and three at 14 weeks. Only one subject did not convert over the 30-week study period. In addition, 90% of cases were discovered in the first 8 weeks. The US Centers for Disease Control and Prevention recommends TB screening at the time of exposure and 8–10  weeks later [12]. Your local occupational health office likely has policies that can provide more specific guidance. Q. This person has a positive tuberculosis test. Do they have tuberculosis infection? A.  There are different categories of tests and disease states. People are often tested for TB during immigrations, for occupational health screening, and prior to the initiation of certain medications such as TNF-alpha inhibitors or other forms of immunosuppression. There are broadly two types of Mycobacterium tuberculosis disease: active TB and latent TB infection. In the USA, the most common screening for any sort of TB disease are the tuberculin skin test (TST) and serum-based interferon-­gamma release assays (IGRAs). Both of these tests measure host immunity against mycobacterial antigens rather than directly measuring organism. IGRA has several advantages over TST, including no need to return to the clinic for measuring the size of subsequent skin lesions and no false positives in people with prior Bacille CalmetteGuérin vaccine although this effect diminishes with time from vaccination [13]. Both types of tests can have false positives for patients with a history of non-tubercular mycobacteria (NTM) infection, likely due to immune cross-reactivity from mycobacterial antigens. Given that both of these tests rely on the host immune system, both are susceptible to false negatives in immunocompro-

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mised patients, particularly those with advanced age and with decreased lymphocyte counts [14]. If a patient is thought to have a true positive result from a screening test, the next consideration is LTBI versus active TB.  Symptoms of active tuberculosis (which are often nonspecific) should be ruled out, including unexplained weight loss, night sweats, fevers, cough, hemoptysis, and back pain. Chest radiography is key in the diagnosis of pulmonary TB. Prior exposure/ infection can result in calcified granulomas and hilar lymph nodes. The most common radiographic evidence of active tuberculosis is heterogenous consolidations involving the apical and posterior upper lungs with cavitation appreciated in 20–45% of cases [15]. Computed tomography (CT) imaging is more sensitive than traditional radiography, and there are some data to support positron emission tomography/CT for diagnosis and also to monitor response to treatment [15]. Ultimately, radiographic findings can be highly suspicious for active TB but are nonspecific as there are other infections that can cause consolidations with cavitation. Therefore, if a patient has imaging and/or symptoms concerning for active tuberculosis, they will undergo further diagnostics. Otherwise, if they have positive TST or IGRA in the absence of concerning imaging or symptoms for active tuberculosis, then they likely have LTBI and should proceed with LTBI management. When I see patients for consideration of LTBI, I spend significant time explaining the differences between LTBI and active TB.  TB diagnosis carries a significant stigma, and it is important to support patients and dispel misinformation when possible [16]. There are different online calculators available online that help assess risk, true positive predictive value of testing, rate of conversion from LTBI to active TB depending on host factors, and potential toxicity of LTBI treatment [17]. I will go through these calculators with patients in real time and explain how the different factors contrib-

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ute to their risk of illness. We then talk about different treatment options for their LTBI. The backbone of LTBI treatment is isoniazid (INH) and rifamycins. In the USA, LTBI strains are generally susceptible to INH and rifampin, which is not always the case globally [18]. The three preferred regimens in the USA are 3 months of once-weekly INH plus rifapentine, 4 months of daily rifampin, or 3 months of daily rifampin plus INH [19]. As rifamycins may be contraindicated in some patients due to drug–drug interactions, an alternative regimen is 6 months of daily INH with some preferring 9  months for LTBI treatment in patients with human immunodeficiency virus (HIV) [19]. Given the inconvenience and duration of many LTBI regimens, completion rates have high variance and were found to be 39–96% among the general population in one metaanalysis, which is one of the reasons that shorter, rifamycin-based regimens are preferred [19, 20]. INH can cause liver toxicity with a higher risk in older patients. This toxicity can occur without symptoms, so routine laboratory monitoring while on therapy is advised [21]. In addition, INH inhibits the metabolism of vitamin B6 (pyridoxine), which can lead to deficiency and subsequent polyneuropathy, especially in patients with other risks for polyneuropathy, such as HIV.  Supplemental pyridoxine can prevent INH-induced polyneuropathy, although it does contribute to the pill burden [22]. Depending on where you practice, there may be additional paperwork for your local Department of Public Health to complete to indicate initiation and completion of LTBI treatment. These medications may also be covered by your local government free of cost to the patient. Once LTBI treatment is complete, it is important to clearly document completion and provide the patient with this documentation so they can avoid unnecessary LTBI treatments in the future. As diagnostics rely on immune memory, there is no test of cure and patients who previously had positive TST or IGRA will likely continue to have positive tests following LTBI treatment.

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Q. In a patient with equivocal imaging for active pulmonary tuberculosis, which diagnostics are warranted? A. Sputum culture with smear and nucleic acid amplification testing. The most common reference standard for diagnosis of active tuberculosis is sputum culture, which is typically performed in those with positive radiologic tests and/or concerning symptoms. However, given the slow growth of mycobacteria, culture can take weeks to become positive – continuing respiratory airborne precautions costs valuable resources and is isolating for patients [23]. Are there more rapid methods for ruling out active disease? At the same time as cultures are taken, AFB smear microscopy can be performed on sputum. The sensitivity of a single smear is only 53.8%; however, this increases with serial studies for a sensitivity of ~70% with three smears [24]. In addition, patients who are smear negative but culture positive likely have less burden of mycobacteria and are at decreased risk for transmission (estimated to be responsible for 8–20% of TB transmissions [25]). Another more rapid active TB diagnostic is the nucleic acid amplification test (NAAT). The sensitivity of NAATs is variable, and it is recommended that the test be performed in conjunction with smear and culture [24, 26]. An additional benefit of NAAT is the ability to screen for genetic mutations associated with resistance, especially to rifampin [26]. Current guidelines recommend NAAT be performed on the first sputum sample obtained [24]. But what if my patient cannot provide sputum? Some patients are unable to generate sufficient sputum samples even after induction. Unfortunately, IGRA and TST have poor sensitivity/specificity for active pulmonary TB, especially in older adults [27]. If TB is suspected and cannot be exonerated by serial sputum testing, bronchoscopy is recommended [24]. Culture and smear can be performed on bronchoalveolar lavage (BAL), and tissue can be collected for NAAT-based diagnostics. We often ask our colleagues in pulmonology to also collect a post-bronchoscopy sputum sample,

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which increases the diagnostic yield of testing when combined with BAL [28, 29]. Active work is being done to develop other rapid diagnostics. In a prospective cohort study called the STAMP trial, patients in Malawi and South Africa with HIV were randomized to have TB testing using traditional sputum testing or sputum testing plus urine testing [30]. The primary outcome was all-cause mortality at 2 months. Patients were excluded if they had previously been treated for TB or LTBI. A total of 322 patients had laboratory-confirmed TB and were included in the analysis. Admission median CD4 was 75 cells/mm3. Furthermore, 66.1% of urine samples were positive by TB-­ LAM (a biomarker-based test) and 40.5% were positive by Xpert (NAAT-based test); in sum, 78% were positive by any urinary measure. Many of these patients, despite antiviral therapy, had poor virologic control, so it is presumed that urinary TB was consistent with TB dissemination. Mortality in the study was over 30%. Positive urinary tests were associated with a severely ill clinical phenotype. This may be a helpful biomarker in patients with significant immunosuppression and concern for disseminated TB given the time it takes to obtain satisfactory sputum samples versus urine samples. However, it likely is not a suitable test for many cases of pulmonary tuberculosis in the USA. In sum, current practice for ruling out active pulmonary tuberculosis is obtaining three sputum samples in which NAAT is performed at least once. Individual hospitals may have different policies, but many will allow for removal of isolation if smear/NAAT is negative, given that culture will take weeks to grow if positive. While the most common form of active disease, pulmonary tuberculosis is only one possible anatomic site for TB infection. Other extra-pulmonary TB sites include lymph nodes, bone and joints, central nervous system tuberculomas, the abdomen, genitourinary tract, pericardium, and disseminated/miliary TB [31]. For patients with risk factors and otherwise unexplained

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symptoms that could be associated with TB, it will remain a common item to consider on the differential. Q. We have a patient with active tuberculosis. How is this treated? A. Active tuberculosis is treated with directly observed therapy using multiple agents for at least 6 months. Treatment of active TB is a critical issue both for individual patients and for public health. Unlike other infectious diseases, we use directly observed therapy (DOT) for active tuberculosis treatment. In DOT, patients are monitored while taking their medications by healthcare professionals. Currently, video-based DOT is becoming more widely used and is associated with similar (or even better) medication adherence than in-person DOT [32]. The patient’s local health department will often oversee DOT in collaboration with the medical team. For treatment, “RIPE” (rifampin, INH, pyrazinamide, and ethambutol) have been clinical mainstays. Typical first-­line therapy for TB is 2  months of treatment with all four medications (“intensive phase”) followed by 4 months of treatment with INH and rifampin (“continuation phase”) [33]. Similar to LTBI treatment, pyridoxine should be given to prevent INH-associated neuropathy. If the isolate is susceptible to both INH and rifampin, ethambutol can be discontinued during the intensive phase. Current guidelines recommend monthly sputum studies (or at least one after the intensive phase of therapy) to determine when the patient converts to culture negative [33]. Patients who continue to be smear-positive at 2  months and/or have cavitation on imaging are more likely to have a relapse of disease following treatment [34]. For these patients, it is recommended to extend the continuation phase of their treatment for an additional 3  months for 9  months of total treatment [33]. Hepatotoxicity is one of the most common reasons that TB treatment regimens are discontinued [35]. In addition to monitoring liver function

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and chemistries, ethambutol can cause optic neuritis and patients should receive baseline visual acuity and color discrimination tests as well as ophthalmologic monitoring while taking ethambutol [33]. The treatment of drug-resistant tuberculosis is more complicated. In regions where fluoroquinolone susceptibility is typical, World Health Organization guidelines recommend a six-month oral regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin [36]. An international RCT (TB-PRACTECAL) in patients with drugresistant TB compared this four-drug 24-week regimen to 9–20-month-long standard of care regimens and found a significant reduction in adverse event rates and noninferiority for a primary outcome, which was a composite of death, treatment failure, treatment ­ discontinuation, loss to follow-up, or recurrence of tuberculosis [37]. When fluoroquinolone resistance is a concern, there is a nine-month regimen, which consists of bedaquiline for 6  months started with 4  months of intensive-phase ethambutol, high-dose INH, ethionamide, pyrazinamide, clofazimine, and levofloxacin/moxifloxacin followed by 5  months of continuation-phase ethambutol, pyrazinamide, clofazimine, and levofloxacin/moxifloxacin. The intensive phase can be extended to two more months if the patient remains smear positive. As one can imagine, these regimens can be difficult to tolerate (seven drugs in the intensive phase!) and require careful monitoring. While current guidelines recommend at least 6  months of treatment for active tuberculosis, newer RCTs have been promising for regimens of shorter duration in part due to the availability of new antimicrobials, including linezolid and bedaquiline. In the international TRUNCATE-­ TB RCT, 660 adults with rifampin-­ susceptible pulmonary TB were randomized to five different regimens: (1) standard 24-week RIPE; or 8 weeks of INH, pyrazinamide, and ethambutol combined with either (2) rifampin and clofazimine; (3) rifampin and linezolid; (4) rifapentine and linezolid; or (5) bedaquiline and linezolid [38]. Ethambutol was replaced with levofloxacin in the group with rifapentine. Serial sputum

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and radiographs were obtained at follow-up visits. If patients had evidence of persistent disease at 8  weeks (positive sputum or symptoms), their treatment regimen was extended up to 12  weeks. At 12  weeks, those with persistent clinical disease were switched to a standard treatment course for 24  weeks of treatment. Initially, patients with 3+ sputum smear, cavity greater than 4 cm on chest radiograph, and/or people living with HIV were not eligible, but these exclusion criteria were later removed during the study. The primary outcome was a composite of active disease, need for ongoing ­treatment, and death 96 weeks after enrollment. The standard treatment, rifampin–linezolid, and bedaquline–linezolid groups had full enrollment at the completion of the study, and the bedaquline–linezolid group was noninferior in primary outcome to standard treatment. As treatment could be extended for those who had evidence of clinical persistence, the mean treatment times were 180 days in the standard treatment group, 106 days in the rifampin–linezolid group, and 85  days in the bedaquiline–linezolid group. Eight-six percent of patients in the bedaquiline–linezolid group were able to complete their course at 8  weeks without the need for prolongation. There were no differences in adverse event rates between the three treatment groups. While further studies need to be performed to understand if this shorter bedaquiline–linezolid regimen is generalizable to more complicated populations (no people living with HIV were recruited even after enrollment was opened up further), these results suggest that shorter regimens may be both efficacious and safe for susceptible TB. Q. Does our management of active tuberculosis change for people living with HIV? A. People living with HIV are at risk for worse outcomes. TB management in people living with HIV (PLWH) can be more challenging as they are more likely to have extrapulmonary disease and infection progresses more rapidly [39]. Worldwide, TB is the most common cause of hospitalization and is responsible for ~25% of in-­ hospital

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deaths among PLWH [40]. For patients on antiretroviral treatment (ART) with drug-susceptible TB, the standard regimen of INH, rifampin, ethambutol, and pyrazinamide for 2 months followed by INH and rifampin for 4 months is thought to be sufficient with daily-dosing regimens preferred over intermittent regimens [39]. Some experts recommend extending treatment to 9  months (three additional months of INH and rifampin) for those not taking ART [33]. PLWH have poorer outcomes with resistant TB compared to those living without HIV, even with the use of ART [41]. The World Health Organization recommends a six-month regimen (bedaquiline, pretomanid, linezolid, and moxifloxacin) when possible for the treatment of MDR-TB in PLWH. Current guidelines do not recommend longer therapy for MDR-TB in PLWH, although drug toxicity may occur more often due to interactions between ART regimens and the multiple drugs in TB treatment regimens [36]. Peripheral neuropathy and persistent vomiting were more commonly observed in PLWH being treated for active TB although there were no differences in discontinuation of TB treatment between arms in one retrospective study of patients in England [35]. In people with a new diagnosis, the World Health Organization recommends initiation of ART within the first 8 weeks of initiation of TB treatment and some recommend even sooner [42]. Q.  How should we manage a patient with tubercular meningitis? A. Dexamethasone therapy should be added to treatment. In a landmark RCT, 545 patients in Vietnam with TB meningitis were randomized to determine if dexamethasone reduced the risk of death or severe disability at 9 months (primary endpoint) versus placebo [43]. Patients were subdivided into three groups based on level of disease with Grade I being mild with Glasgow Coma Scale (GCS) of 15, Grade II having GCS 11–14, and the most severe cases (GCS less than 11) as Grade III.  Patients with Grade I received 2 weeks of intravenous (IV) dexa-

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methasone (0.3 mg/kg QD for week 1, 0.2 mg/kg QD for week 2) followed by 4 weeks of oral (0.1 mg/kg/day for week 3 followed by 3 mg per day decreasing by 1 mg each week). Grades II and III received 4 weeks of IV dosing. In an analysis of the primary outcome (survival and disability), patients in Group I had significantly decreased rates of death or severe disability when treated with dexamethasone compared to ­ placebo (21.1 vs 34.9%; p = 0.04). There were no significant differences in Grades II or III (bleak outcomes all around) and no significant differences when all three groups were combined (primary outcome). This study highlights in general the poor outcomes of TB meningitis as well as possible therapeutic advantages in co-­treatment with steroids. Since that trial, meta-analysis of data from patients with TB meningitis further supported that corticosteroids in addition to standard-of-­care antibiotics reduce mortality and current guidelines recommend adjunctive corticosteroid treatment [44]. Q.  This patient undergoing treatment for disseminated tuberculosis has evidence of worsening liver injury— what is our differential? A. Hepatotoxicity could be due to infection or adverse drug effects. Active tuberculosis causes relatively high morbidity and mortality. Unfortunately, treatment is not benign, which can complicate decisions surrounding empiric therapy. For example, our service had an elderly patient with hepatic steatosis taking TNF-alpha inhibitors due to rheumatoid arthritis with concern for disseminated tuberculosis. They later developed rising alkaline phosphatase while on RIPE.  There are four main mechanisms for TB-related hepatotoxicity: (1) disseminated TB with diffuse hepatic involvement (the most likely scenario for the patient I described); (2) granulomatous hepatitis; (3) liver tuberculoma (TB abscess); or (4) drug-induced liver injury from medications used to treat TB. Direct liver involvement is not uncommon—in 280 patients in India with tuberculosis, 15.7% were found to have hepatobiliary involvement

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[45]. In patients with no prior liver disease, RIPE in the setting of hepatobiliary involvement is generally tolerated well. In patients with pre-existing liver disease, pyrazinamide should be avoided if possible. Liver toxicity is one of the reasons it is not used routinely for LTBI treatment [46]. One pyrazinamide-sparing regimen for those with advanced liver disease is an intensive phase with INH, rifampin, and ethambutol for 2 months followed by a continuation phase of INH and rifampin for 7 months [33, 47]. However, the other drugs in RIPE can also be culpable. INH and rifampin are more hepatotoxic when used in combination [47]. Ethambutol, aminoglycosides, and fluroquinolones are generally tolerated well. For patients with unstable cirrhosis, some experts recommend using a three-drug regimen, including a fluoroquinolone and ethambutol for at least 18–24 months [33, 47]. While our patient initially had imaging and laboratory data most suggestive of liver insult from disseminated tuberculosis, they later developed hyperbilirubinemia. Could this be due to RIPE toxicity? Transient asymptomatic elevations in aminotransferase levels are the most common adverse drug effect and occur in as many as 20% of patients taking INH [48]. However, biliary toxicity has also been rarely described. In one retrospective nationwide database cohort of the hospital system in Taiwan, acute biliary events occurred in 0.12% of patients on therapy [49]. INH and rifampin are thought to inhibit bile salt export and may cause more rapid cholesterol stone formation. In general, confirming etiology as well as determining the best management for worsening liver injury in patients undergoing treatment for active tuberculosis can be very challenging. Co-management with colleagues in Hepatology can be very helpful, especially in patients with prior liver disease.

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Q. Our patient is growing a non-tubercular mycobacterium in their sputum. Should we treat them? What does treatment entail? A. Treatment depends on confirmation of disease as well as weighing the risks/benefits of drug toxicity versus symptoms and the likelihood of cure. We co-exist with all sorts of environmental microorganisms, including non-tubercular mycobacteria (NTM) species that inhabit soil and water. NTM can be classified by growth rate on solid media as “slow” (Mycobacterium avium complex and Mycobacterium kansasii), “intermediate” (Mycobacterium marinum), and “rapid growers” (Mycobacterium abscessus and Mycobacterium chelonae) [50]. Pulmonary infection is the most frequent type of NTM disease and occurs particularly in people with pre-existing structural lung disease. Because these organisms can be environmental contaminants and/or colonizers without contributing to major pathology, diagnostic criteria have been established [51]. Patients must have pulmonary or systemic symptoms consistent with NTM infection. They must have either nodular or cavitary opacities on chest radiographs or CT with bronchiectasis and multiple nodules. Lastly, they must have two positive sputum cultures, one positive culture from bronchoscopy, or one positive lung biopsy with consistent histological features and positive sputum culture. The species can also be a clue—M. kansasii and M. abscessus are examples of particularly virulent species [51, 52]. Even if a patient meets diagnostic criteria for pulmonary NTM infection, there are considerations to make rather than reflexively start treatment. For example, current guidelines recommend initial therapy with at least 3–4 susceptible agents and recommend initial intravenous therapy for M. abscessus pulmonary infection [51]. Depending on susceptibilities, a typical regimen may entail 8–12  weeks of initiation therapy with amikacin, azithromycin, and imipenem or tigecycline followed by maintenance therapy with clofazimine, bedaquilin, and/

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or azithromycin for 12  months after first negative sputum culture. Patients treated surgically (in addition to antibiotics) may have longer remissions, although surgery carries its own additional risks [53]. Despite these intense treatment regimens, cure rates for M. abscessus infection are relatively low and have been reported between 34% and 70% [24, 54]. Patients who are not cured may need repeat treatments with monitoring to ensure resistance has not developed. Given the potential antibiotic toxicities without a guarantee of cure, a patient with minimal symptoms may opt for the strategy of “watchful waiting” with serial imaging and clinical exams rather than move forward with treatment. This needs to be undertaken seriously as mycobacteria such as M. abscessus can cause progressive lung disease if left unchecked. The above approach using M. abscessus as an example can be taken for other pulmonary NTM and guidelines are available for recommendations on antibiotic choices and duration of therapy [24]. These cases can be very challenging and should be discussed with local mycobacterial experts, especially when treatment decisions are not obvious. Q. Our patient is growing a non-tubercular mycobacterium from a non-pulmonary source. Can these cause infections outside of the lungs? A.  Of course! Cutaneous (and deeper) infections can occur particularly in immunocompromised hosts although there are some species and situations where infection can occur in the immunocompetent. In addition to pulmonary disease, NTMs can cause infection of soft and hard tissues as opportunistic pathogens. For example, I treated several patients during fellowship with musculoskeletal M. chelonae infection. In one retrospective study, 100 cases of M. chelonae affecting skin, soft tissue, and bones were characterized [55]. Sources included dissemination of cutaneous infection (53%), trauma (15%), catheter-associated (12%), surgical site

References

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(8%), post-injection (6%), and with no clear source (5%). Only 6% of patients with cutaneous disease had positive blood cultures. Possibly due to the predilection of some NTM species to grow better at temperatures lower than 37 °C, many of the cutaneous lesions were at distal sites. A majority of patients in the study received corticosteroids prior to infection, which is likely a major risk factor for disseminated cutaneous M. chelonae. While most NTM are opportunistic pathogens that infect only the immunocompromised or those with structural disease, M. marinum and Mycobacterium ulcerans are two species that are known to cause cutaneous infections even in immunocompetent hosts [52]. M. marinum in particular can be associated with fish tank maintenance and is sometimes called “fish tank granuloma” [56]. Another relatively common non-pulmonary cause of NTM infection in immunocompetent hosts that I saw during fellowship was the unfortunate consequence of medical tourism. Cosmetic surgery in some countries is associated with rapidly growing NTM infection, and many of these cases require surgery for source control in addition to long courses with multiple antibiotics for therapy [57].

References 1. Shea KM, Kammerer JS, Winston CA, Navin TR, Horsburgh CR. Estimated rate of reactivation of latent tuberculosis infection in the United States, overall and by population subgroup. Am J Epidemiol. 2014;179:216–25. https://doi.org/10.1093/aje/ kwt246. 2. Welbel SF, French AL, Bush P, DeGuzman D, Weinstein RA. Protecting health care workers from tuberculosis: a 10-year experience. Am J Infect Control. 2009;37:668–73. https://doi. org/10.1016/j.ajic.2009.01.004. 3. Hirama T, Hagiwara K, Kanazawa M.  Tuberculosis screening programme using the QuantiFERON-TB Gold test and chest computed tomography for healthcare workers acciden-

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tally exposed to patients with tuberculosis. J Hosp Infect. 2011;77:257–62. https://doi.org/10.1016/j.jhin.2010.11.012. 4. Malasky C, Jordan T, Potulski F, Reichman LB.  Occupational tuberculous infections among pulmonary physicians in training. Am Rev Respir Dis. 1990;142:505–7. https://doi.org/10.1164/ ajrccm/142.3.505. 5. Ramakrishnan CV, Andrews RH, Devadatta S, Fox W, Radhakrishna S, Somasundaram PR, Velu S. Influence of segregation to tuberculous patients for one year on the attack rate of tuberculosis in a 2-year period in close family contacts in South India. Bull World Health Organ. 1961;24:129–48. 6. Kamat SR, Dawson JJ, Devadatta S, Fox W, Janardhanam B, Radhakrishna S, Ramakrishnan CV, Somasundaram PR, Stott H, Velu S. A controlled study of the influence of segregation of tuberculous patients for one year on the attack rate of tuberculosis in a 5-year period in close family contacts in South India. Bull World Health Organ. 1966;34:517–32. 7. Griffith DE, Hardeman JL, Zhang Y, Wallace RJ, Mazurek GH. Tuberculosis outbreak among healthcare workers in a community hospital. Am J Respir Crit Care Med. 1995;152:808–11. https://doi.org/10.1164/ajrccm.152.2.7633747. 8. Rogers EF. Epidemiology of an outbreak of tuberculosis among school children. Public Health Rep (1896). 1962;77:401–9. 9. Loudon RG, Spohn SK.  Cough frequency and infectivity in patients with pulmonary tuberculosis. Am Rev Respir Dis. 1969;99:109–11. https://doi.org/10.1164/arrd.1969.99.1.109. 10. Reichler MR, Khan A, Yuan Y, Chen B, McAuley J, Mangura B, Sterling TR, Tuberculosis Epidemiologic Studies Consortium Task Order 2 Team (2020) Duration of exposure among close contacts of patients with infectious tuberculosis and risk of latent tuberculosis infection. Clin Infect Dis 71:1627–1634. doi: https:// doi.org/10.1093/cid/ciz1044. 11. Lee SW, Oh DK, Lee SH, Kang HY, Lee C-T, Yim J-J.  Time interval to conversion of interferon-gamma release assay after exposure to tuberculosis. Eur Respir J. 2011;37:1447–52. https:// doi.org/10.1183/09031936.00089510. 12. Sosa LE.  Tuberculosis screening, testing, and treatment of U.S. Health Care Personnel: recommendations from the National Tuberculosis Controllers Association and CDC, 2019. MMWR Morb Mortal Wkly Rep. 2019;68 https://doi.org/10.15585/mmwr. mm6819a3. 13. Farhat M, Greenaway C, Pai M, Menzies D.  False-positive tuberculin skin tests: what is the absolute effect of BCG

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24. Lewinsohn DM, Leonard MK, LoBue PA, Cohn DL, Daley CL, Desmond E, Keane J, Lewinsohn DA, Loeffler AM, Mazurek GH, O’Brien RJ, Pai M, Richeldi L, Salfinger M, Shinnick TM, Sterling TR, Warshauer DM, Woods GL.  Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: diagnosis of tuberculosis in adults and children. Clin Infect Dis. 2017;64:111–5. https://doi.org/10.1093/cid/ciw778. 25. Asadi L, Croxen M, Heffernan C, Dhillon M, Paulsen C, Egedahl ML, Tyrrell G, Doroshenko A, Long R.  How much do smear-­ negative patients really contribute to tuberculosis transmissions? Re-examining an old question with new tools. EClinicalMedicine. 2022;43:101250. https://doi.org/10.1016/j.eclinm.2021.101250. 26. MacLean E, Kohli M, Weber SF, Suresh A, Schumacher SG, Denkinger CM, Pai M.  Advances in molecular diagnosis of tuberculosis. J Clin Microbiol. 2020;58:e01582–19. https://doi. org/10.1128/JCM.01582-­19. 27. de Visser V, Sotgiu G, Lange C, Aabye MG, Bakker M, Bartalesi F, Brat K, Chee CBE, Dheda K, Dominguez J, Eyuboglu F, Ghanem M, Goletti D, Dilektasli AG, Guglielmetti L, Koh W-J, Latorre I, Losi M, Polanova M, Ravn P, Ringshausen FC, Rumetshofer R, de Souza-Galvão ML, Thijsen S, Bothamley G, Bossink A, TBNET.  False-negative interferon-γ release assay results in active tuberculosis: a TBNET study. Eur Respir J. 2015;45:279–83. https://doi.org/10.1183/09031936.00120214. 28. George PM, Mehta M, Dhariwal J, Singanayagam A, Raphael CE, Salmasi M, Connell DW, Molyneaux P, Wickremasinghe M, Jepson A, Kon OM.  Post-bronchoscopy sputum: improving the diagnostic yield in smear negative pulmonary TB.  Respir Med. 2011;105:1726–31. https://doi.org/10.1016/j.rmed.2011.07.014. 29. Malekmohammad M, Marjani M, Tabarsi P, Baghaei P, Sadr Z, Naghan PA, Mansouri D, Masjedi MR, Velayati AA. Diagnostic yield of post-bronchoscopy sputum smear in pulmonary tuberculosis. Scand J Infect Dis. 2012;44:369–73. https://doi.org/10.310 9/00365548.2011.643820. 30. Gupta-Wright A, Fielding K, Wilson D, van Oosterhout JJ, Grint D, Mwandumba HC, Alufandika-Moyo M, Peters JA, Chiume L, Lawn SD, Corbett EL. Tuberculosis in hospitalized patients with human immunodeficiency virus: clinical characteristics, mortality, and implications from the rapid urine-based screening for tuberculosis to reduce AIDS related mortality in hospitalized

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Wiltshire C, Avihingsanon A, Sarin R, Papineni P, Nunn AJ, Crook AM.  Treatment strategy for rifampin-susceptible tuberculosis. N Engl J Med. 2023;388:873–87. https://doi.org/10.1056/ NEJMoa2212537. 39. Meintjes G, Brust JCM, Nuttall J, Maartens G. Management of active tuberculosis in adults with HIV. Lancet HIV. 2019;6:e463– 74. https://doi.org/10.1016/S2352-­3018(19)30154-­7. 40. Ford N, Matteelli A, Shubber Z, Hermans S, Meintjes G, Grinsztejn B, Waldrop G, Kranzer K, Doherty M, Getahun H.  TB as a cause of hospitalization and in-hospital mortality among people living with HIV worldwide: a systematic review and meta-analysis. J Int AIDS Soc. 2016;19:20714. https://doi. org/10.7448/IAS.19.1.20714. 41. Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB Treatment–2017, Ahmad N, Ahuja SD, Akkerman OW, Alffenaar J-WC, Anderson LF, Baghaei P, Bang D, Barry PM, Bastos ML, Behera D, Benedetti A, Bisson GP, Boeree MJ, Bonnet M, Brode SK, JCM B, Cai Y, Caumes E, Cegielski JP, Centis R, Chan P-C, Chan ED, Chang K-C, Charles M, Cirule A, Dalcolmo MP, D’Ambrosio L, de Vries G, Dheda K, Esmail A, Flood J, Fox GJ, Fréchet-Jachym M, Fregona G, Gayoso R, Gegia M, Gler MT, Gu S, Guglielmetti L, Holtz TH, Hughes J, Isaakidis P, Jarlsberg L, Kempker RR, Keshavjee S, Khan FA, Kipiani M, Koenig SP, Koh W-J, Kritski A, Kuksa L, Kvasnovsky CL, Kwak N, Lan Z, Lange C, Laniado-Laborín R, Lee M, Leimane V, Leung C-C, Leung EC-C, Li PZ, Lowenthal P, Maciel EL, Marks SM, Mase S, Mbuagbaw L, Migliori GB, Milanov V, Miller AC, Mitnick CD, Modongo C, Mohr E, Monedero I, Nahid P, Ndjeka N, O’Donnell MR, Padayatchi N, Palmero D, Pape JW, Podewils LJ, Reynolds I, Riekstina V, Robert J, Rodriguez M, Seaworth B, Seung KJ, Schnippel K, Shim TS, Singla R, Smith SE, Sotgiu G, Sukhbaatar G, Tabarsi P, Tiberi S, Trajman A, Trieu L, Udwadia ZF, van der Werf TS, Veziris N, Viiklepp P, Vilbrun SC, Walsh K, Westenhouse J, Yew W-W, Yim J-J, Zetola NM, Zignol M, Menzies D. Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis. Lancet. 2018;392:821–34. https://doi.org/10.1016/S0140-­6736(18)31644-­1. 42. Gandhi RT, Bedimo R, Hoy JF, Landovitz RJ, Smith DM, Eaton EF, Lehmann C, Springer SA, Sax PE, Thompson MA, Benson CA, Buchbinder SP, Del Rio C, Eron JJ, Günthard HF, Molina J-M, Jacobsen DM, Saag MS. Antiretroviral drugs for treatment

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disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline. Eur Respir J. 2020;56:2000535. https://doi. org/10.1183/13993003.00535-­2020. 52. Johansen MD, Herrmann J-L, Kremer L.  Non-tuberculous mycobacteria and the rise of Mycobacterium abscessus. Nat Rev Microbiol. 2020;18:392–407. https://doi.org/10.1038/ s41579-­020-­0331-­1. 53. Jarand J, Levin A, Zhang L, Huitt G, Mitchell JD, Daley CL.  Clinical and microbiologic outcomes in patients receiving treatment for Mycobacterium abscessus pulmonary disease. Clin Infect Dis. 2011;52:565–71. https://doi.org/10.1093/cid/ciq237. 54. Weng Y-W, Huang C-K, Sy C-L, Wu K-S, Tsai H-C, Lee SS-J.  Treatment for Mycobacterium abscessus complex-lung disease. J Formos Med Assoc. 2020;119(Suppl 1):S58–66. https:// doi.org/10.1016/j.jfma.2020.05.028. 55. Wallace RJ, Brown BA, Onyi GO.  Skin, soft tissue, and bone infections due to Mycobacterium chelonae chelonae: importance of prior corticosteroid therapy, frequency of disseminated infections, and resistance to oral antimicrobials other than clarithromycin. J Infect Dis. 1992;166:405–12. https://doi.org/10.1093/ infdis/166.2.405. 56. Wu T-S, Chiu C-H, Yang C-H, Leu H-S, Huang C-T, Chen Y-C, Wu T-L, Chang P-Y, Su L-H, Kuo A-J, Chia J-H, Lu C-C, Lai H-C.  Fish tank granuloma caused by Mycobacterium marinum. PLoS One. 2012;7:e41296. https://doi.org/10.1371/journal. pone.0041296. 57. Schnabel D, Esposito DH, Gaines J, Ridpath A, Barry MA, Feldman KA, Mullins J, Burns R, Ahmad N, Nyangoma EN, Nguyen DB, Perz JF, Moulton-Meissner HA, Jensen BJ, Lin Y, Posivak-Khouly L, Jani N, Morgan OW, Brunette GW, Pritchard PS, Greenbaum AH, Rhee SM, Blythe D, Sotir M.  Multistate US outbreak of rapidly growing mycobacterial infections associated with medical tourism to The Dominican Republic, 2013– 20141. Emerg Infect Dis. 2016;22:1340–7. https://doi.org/10.3201/ eid2208.151938.

Chapter 7 HIV Infection

Abstract  Human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) changed the way society views infection and disease transmission. AIDS is defined as when a person living with HIV has a CD4 count less than 200 cells/mm3, or CD4 cells as less than 14% of their total lymphocyte population, or if they contract an opportunistic infection categorized as an AIDS-defining illness. While previously an illness that resulted in untimely death, advances in antiretroviral therapy (ART) have led to successful HIV management and a gracefully aging population. Developments such as injectable therapy and new regimens for pre-­exposure prophylaxis continue to change the field. HIV care has become increasingly complex and many fellowships offer specialized tracks or even additional subspecialty training in HIV medicine. With the success of ART, most HIV care takes place in the outpatient setting in today’s practice. However, there are still important consult questions on inpatient services, especially during new diagnosis. In this chapter, we will discuss HIV diagnostics, management of acute HIV in the hospitalized setting, newer ART options, interpretation of CD4 cell counts, and management of a few representative coinfections.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. M. Tatara, The Infectious Diseases Consult Handbook, https://doi.org/10.1007/978-3-031-39474-4_7

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Q. This patient with new leukemia has a reactive HIV test! Do they have HIV? A. The positive predictive value of HIV screening is low in low prevalence areas. Confirmatory testing should be performed before making any diagnosis. A new chronic illness can be a traumatic event for any patient and HIV continues to carry a significant stigma despite improvements in management. Therefore, it is important to understand current diagnostic algorithms and areas where screening tests should be interpreted with caution. The current US Centers for Disease Control and Prevention guidelines for HIV screening recommend using an HIV 1/2 antigen/antibody combination immunoassay as the first stage of screening [1]. The current “fourth generation” of these tests measures levels of the HIV antigen p24 and antibodies to HIV-1 and HIV-2. In cases of acute infection, p24 may be present prior to the development of host antibodies [2]. If both arms of the immunoassay are negative, the screen is considered negative. As in all diagnostics, false positives can occur. In one retrospective study of 468 cases of false-positive HIV infection at a center in China using one testing platform over a single year, the most common clinical diagnoses in those with false positives included cancer (19.4%) and infection (11.1%) [3]. It is speculated that at least some of these false-positive results are due to the cross-reactivity of antibody-­ inducing disease processes. In areas with low prevalence of HIV, the positive predictive value of fourth-­generation antigen-antibody testing is low. In one study in Korea, the positive predictive value was only 31.2% [4], and another study in Japan showed a positive predictive value of only 3.7% when screening pregnant women [5]. Given the possibility of false-positive testing and the potential psychological trauma of receiving false-­ positive results [6], the results of screens are often not shared with patients until confirmatory testing can be performed.

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If the immunoassay is positive, the next stage of testing is the differentiation assay. The antibody differentiation immunoassay differentiates HIV-1 antibodies from HIV-2 antibodies. If a patient has a positive fourth-­ generation immunoassay and negative HIV antibody differentiation assay, then HIV-1 nucleic acid testing (sometimes called “HIV viral load”) should be performed as a tiebreaker. In cases where acute HIV infection is in the differential, it is recommended to obtain the HIV viral load upfront (in addition to antigen/antibody immunoassay) as the intent is not for screening but for diagnosis and antigen/antibody immunoassays may give false-negative results in the early infection window [7]. Q. When should we start antiretrovirals in this patient with a new diagnosis of HIV? A. In most cases, antiretrovirals should be started as soon as possible. In the 2022 recommendations from the International Antiviral Society (USA Panel), ART was recommended to be initiated as soon as possible in patients with new diagnosis of HIV. This is ideally within 7 days but can be as soon as on the day of diagnosis if the patient is ready and there is no suspicion at that time for concurrent opportunistic infection [8]. Particularly in patients with opportunistic infection and severely low CD4 counts, there is a concern for immune reconstitution inflammatory syndrome (IRIS). As immune function returns due to ART, these patients can have a paradoxical deterioration as their body now recognizes infectious processes and immune-mediated inflammation rapidly increases [9]. The majority of IRIS is self-limited, and it is still recommended to start ART within 2 weeks of HIV diagnosis with careful observation with few exceptions. Cryptococcal meningitis is associated with IRIS that has significant mortality (10– 30%) and guidelines recommend waiting 2–4  weeks after the initiation of antifungal treatment before start-

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ing ART and only if the patient is in a setting where they can be monitored closely [8, 10]. Tuberculosis is another disease which can cause a more severe IRIS.  Recent guidelines recommend starting ART within 2 weeks of starting tuberculosis treatment and to use high-dose steroids in those with tubercular meningitis [11]. Recommended first-line regimens include those with integrase inhibitors, such as bictegravir/emtricitabine/ tenofovir or dolutegravir and lamivudine/tenofovir [8]. Genotypic testing, or resistance testing based on the patient’s viral genome, is currently recommended for all new diagnoses although is not needed prior to starting a regimen unless the patient contracted HIV while on preexposure prophylaxis or if their partner is known to have failed suppression on an integrase inhibitor [8]. However, there is some disagreement in the field. In the era of effective integrase-based regimens, there is thought that baseline transmitted resistance is unlikely and not cost-effective to screen, although providers may be in a difficult position if a patient later needs to change regimens due to adverse events while suppressed [12]. Q. Which other infections should we consider in patients with new diagnosis? A. Screen for other sexually transmitted infections, hepatitis, and opportunistic infections. In addition to HIV, coinfection with other sexually transmitted infections, such as syphilis, gonorrhea, and chlamydia, should be ruled out following HIV diagnosis [13]. When performing screening for chlamydia and gonorrhea, it is important to consider multiple anatomic sites. In one study of 586 asymptomatic people living with HIV at a clinic in San Francisco screened for chlamydia and gonorrhea, there were 60 cases in which only 7 (12%) were urethral and the other 53 (88%) were either pharyngeal or rectal [14]. While a sensitive topic, patients should be carefully counseled about safe

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sexual practices given increased risk with HIV coinfection. Counseling can help process diagnosis and to work through perceived stigma during this challenging period [15]. Sharing techniques for decreasing risk of sexually transmitted infection as well as discussing “U=U” (patients with viral suppression cannot sexually transmit virus) is also important during new diagnosis counseling [16]. Patients should be tested for hepatitis B and C viruses [17]. Hepatitis B virus (HBV) is screened by surface antibody, surface antigen, and core antibody to better understand if someone has had vaccination, prior infection, or current infection. If a patient does have HBV coinfection with HIV, it is recommended that their HIV regimen include at least two antiviral agents that also have activity against HBV such as tenofovir, emtricitabine, and/or lamivudine. Hepatitis C virus (HCV) is screened by antibody testing or nucleic acid testing in patients where there is a high clinical suspicion for acute infection. Opportunistic infections (OIs) are infections seen in immunocompromised patients, such as those with AIDS. Some OIs are AIDS-defining infections given as they typically occur only in severely immunocompromised individuals. Organisms include mycobacteria (Mycobacterium tuberculosis and Mycobacterium avium complex), fungi (Candida, Pneumocystis, Cryptococcus, Histoplasma, and Coccidioides), viruses (cytomegalovirus especially), and parasites (Toxoplasma, Cryptosporidium, and Isospora). While the rates of OIs have decreased in recent years, a retrospective analysis of over 63,000 people living with HIV in North America showed that 9% developed at least one OI with Pneumocystis pneumonia being the most common [18]. Patients with HIV are at higher risk of tuberculosis infection even in low prevalence areas [19]. Current recommendations are screening of all patients with HIV for tuberculosis regardless of exposure history.

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Unfortunately, as both tuberculin skin testing and interferon gamma release assays rely on host immune function, both tests are prone to false negatives especially in patients with low CD4 cell count, and it is recommended to repeat tuberculosis screening again after recovery of CD4 greater than 200 cells/mm3 [20]. People living with HIV who are diagnosed with latent tuberculosis infection can receive similar treatment regimens to those without HIV, including 3 months of weekly rifapentine and isoniazid [21]. Toxoplasma gondii serology should be performed when patients are diagnosed with HIV [22]. If patients do not have IgG to T. gondii, they should be counseled to prevent acquisition by avoiding raw and undercooked meats and shellfish. For patients that live in endemic areas, it is also reasonable to obtain serology for Coccidioides as newly positive serology without evidence of active disease may be an indication for antifungal therapy while CD4 count recovers [23]. Globally, cryptococcal disease is estimated to account for 19% of AIDS-related mortality and 4.4% of adults living with HIV and CD4 count less than 200 cells/mm3 are infected [24]. Screening for cryptococcus antigen in the serum is recommended for patients diagnosed with CD4 count less than 100  cells/mm3. A positive test should be followed by lumbar puncture with cerebral spinal fluid testing [22]. Cytomegalovirus infection, including retinitis, was very common in the pre-ART era, and patients were previously recommended to have retinal examination every 3  months with CD4 less than 50  cells/mm3 [22]. However, retinitis rates have substantially decreased with effective ART and there is no longer a blanket recommendation for retinal exam on diagnosis. In one retrospective study at a single center in Japan, patients with HIV underwent routine ophthalmologic exam at their first visit [25]. Out of 1515 patients, 2% were diagnosed with cytomegalovirus retinitis, 8% were diag-

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nosed with HIV retinopathy, and 4 patients (0.3%) were diagnosed with syphilis uveitis. All patients with cytomegalovirus retinitis had CD4 counts less than 200 cells/mm3. Based on data such as these, some clinicians recommend baseline retinal exam for patients with HIV and CD4 less than 100  cells/mm3, although this is not a formal guideline recommendation [22]. For patients who do not know their vaccination status, measles serology (and/or mumps and rubella) can be measured. In one study of patients living with HIV in Nebraska, seroprevalence of measles antibody was only found in 70.3%, and self-reported vaccine status was not associated with immunity suggesting that increased screening may be needed [26]. Likewise, patients with negative varicella serology may benefit from primary varicella vaccination (if CD4 counts are greater than 200 cells/mm3) or for zoster vaccination if positive serology and older than 60 years [27]. In summary, people with new diagnosis of HIV should undergo screening for other sexually transmitted infections, hepatitis viruses, tuberculosis, and toxoplasmosis exposure via serology (Table 7.1). Depending on their travel history and CD4 count, they may also benefit from screening for coccidiomycosis and cryptococcal disease. While not a formal guideline recommendation, retinal exam in asymptomatic patients is considered by some experts when patients have low CD4 counts. Those whose immunity to measles is unknown should receive serology testing with plan for vaccination when CD4 count has recovered above 200  cells/mm3. These are screening recommendations for asymptomatic individuals—for patients with new diagnosis of HIV that have symptoms, additional diagnostics are warranted, which may include imaging, cultures, and other laboratory tests directed toward the patient’s symptoms.

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Table 7.1 Diseases to screen in patients with a new diagnosis of HIV Screening for patients with HIV diagnosis Notes Syphilis Treponemal and non-treponemal tests Gonorrhea and chlamydia

Based on sexual practices, consider testing multiple sites

Hepatitis B virus (HBV)

Chronic infection should be tested for HBV e antibody and antigen and HBV viral load

Hepatitis C virus (HCV)

Consider nucleic acid testing if the patient may have acute infection

Tuberculosis

Tuberculin skin test or interferon gamma release assay

Toxoplasmosis serology

Counsel those with negative IgG to avoid raw/undercooked meats and shellfish

Coccidiomycosis serology

Applicable to those in endemic areas

Cryptococcus antigen

Applicable to those with CD4 count less than 100 cells/mm3

Cytomegalovirus retinitis

Consider retinal screening if CD4 count is less than 100 cells/mm3

Measles and varicella serology

Consider if unknown vaccination status

Q. How can we prevent future opportunistic infections as the patient is undergoing immune recovery following treatment? A. Depending on CD4 count and exposure history, there may be chemoprophylactic options and vaccines to mitigate risk of some opportunistic infections. As the proverb goes, “An ounce of prevention is worth a pound of cure.” Preventing opportunistic infections in vulnerable patients is a powerful strategy. Depending on immune function, there are several targets for chemoprophylaxis and vaccination.

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Pneumocystis pneumonia is the most common OI in patients with HIV in the USA [18]. Current US guidelines recommend prophylaxis against Pneumocystis in people living with HIV who have CD4 counts less than 200 cells/mm3 or a CD4 cell percentage less than 14% [22]. However, one multicenter retrospective study in Europe suggested that prophylaxis was not required in patients with CD4 greater than 100  cells/mm3 if they achieve viral suppression [28]. First-line prophylaxis is trimethoprim-sulfamethoxazole with alternatives including dapsone and atovaquone. For patients at risk, there may be prophylactic options for other fungi as well. For those living with HIV with CD4 counts less than 150 cells/mm3 and with high exposure to histoplasmosis either by occupation or geography, itraconazole can be used as prophylaxis [22]. Similarly, if a patient lives in a coccidiomycosis-endemic area and has positive serology, they may benefit from daily fluconazole until recovery of CD4 count greater than 250 cells/ mm3 [23]. Talaromycosis is caused by the dimorphic Talaromyces marneffei found in southeast Asia with increased incidence during rainy months [29]. For people living with HIV in endemic areas and CD4 less than 100 cells/mm3 that are unable to start effective ART, prophylaxis with itraconazole is recommended [22]. Prophylaxis for toxoplasmosis should be offered to all people living with HIV with positive IgG and CD4 count less than 100 cells/mm3 [22]. Fortunately, many of the first-line options for prophylaxis against Pneumocystis (trimethoprim-sulfamethoxazole, atovaquone, dapsone if pyrimethamine and leucovorin are added) are also effective as toxoplasmosis prophylaxis. Primary prophylaxis for Mycobacterium avium complex is no longer recommended for adults who immediately initiate ART regardless of CD4 count. In patients who are not receiving ART or are not on a suppressive regimen, prophylaxis (typically with a macrolide) is recommended for those with CD4 less than 50 cells/mm3 [22].

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Vaccination is another potent strategy to prevent infection. Several live vaccines are contraindicated in the immunocompromised due to risk of causing infection. For those with CD4 counts less than 200 cells/mm3, the following live vaccines should be avoided: MMR (measles, mumps, and rubella), varicella, live attenuated typhoid, and yellow fever [27]. The live attenuated influenza vaccine is contraindicated for people living with HIV.  In addition to the standard vaccination schedule recommended for adults in the USA, people living with HIV are also recommended to be vaccinated against hepatitis A virus, HBV, meningococcus, and pneumococcus [27]. Patients who have untreated HIV infection or CD4 count less than 200 cells/mm3 may require additional doses of COVID-19 vaccination [8]. Q. This admitted patient is only on two antiviral agents—is their regimen incomplete? A. Perhaps not! There is increasing evidence for safety with two-agent regimens. Historically, the three-drug HIV ART regimens were first developed in 1996 [30]. Most included a protease inhibitor or non-nucleoside reverse transcriptase inhibitor with a backbone of two nucleoside reverse transcriptase inhibitors. This was standard of care for a decade or so. In 2007, integrase inhibitors were approved by the US Food and Drug Administration, and threedrug combinations in a single pill including integrase inhibitors gained popularity [31]. For approximately 25 years, three-drug regimens have been the standard of care with the idea that combination therapy creates a synergistically elevated barrier to resistance. However, more drugs (especially over the course of a lifetime) can potentially lead to more side effects, such as weight gain and metabolic disease [32]. In this age with highly effective agents available, are two drugs sufficient? In 2018, there were two RCTs published called SWORD 1 and SWORD 2 [33]. Patients with HIV who were well-­controlled on a three- or four-drug regimen

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(viral load less than 50 copies/mL) with no major mutations of significance were randomized to be transitioned to a two-drug regimen (dolutegravir and rilpivirine). The primary endpoint was viral load suppression (less than 50 copies/mL) at 48 weeks. There were no significant differences between the two groups, suggesting that a two-drug regimen can maintain viral suppression in patients with well-controlled disease. Of note, patients on the two-drug regimen had more adverse events resulting in withdrawal (3%) than patients on their prior regimen (1%)—the most common adverse event that was associated more strongly with dolutegravir/rilpivirine was headache. If dolutegravir, an integrase inhibitor with a relatively high barrier to resistance, and rilpivirine, a non-nucleoside reverse transcriptase inhibitor, are effective in combination as a two-drug regimen, does this effect hold with other classes of ART? In 2020, a phase 3 trial was published comparing dolutegravir and lamivudine (a nucleoside reverse transcriptase inhibitor) to three- or four-drug regimens (including tenofovir alafenamide) called the TANGO study [34]. It was an open-label RCT in which patients that were well-controlled at baseline (viral load less than 50 copies/mL) were switched to once-daily dolutegravir and lamivudine (n = 370) versus their prior ­tenofovir-­containing regimen (n = 370). It was designed for non-­inferiority with the primary endpoint being viral suppression at 48 weeks. Enrolled patients, in addition to already having virologic control for greater than 6  months, had to not have any evidence of integrase- or nucleoside reverse transcriptase-associated mutations, HBV infection, or severe hepatic disease. In addition, patients that had virologic failure in the past requiring regimen change were also ineligible. By 48  weeks, one patient in the two-drug arm had virologic failure and two patients in the standard treatment arm had failure, showing non-inferiority of the two-drug regimen. A similar RCT called SALSA was performed in 2023 using dolutegravir and

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lamivudine as the two-drug regimen but removing the limitation that patients had to have had tenofovir alafenamide as part of their original regimen [35]. One patient in the two-drug regimen and three patients in the standard regimen had virologic failure at endpoint, once again demonstrating non-­inferiority of two-drug regimens for suppression in patients that were wellcontrolled on a three- or four-­ drug regimen previously. Can ART-naïve patients be initiated on a two-drug regimen rather than transitioned from a three-drug regimen after achieving viral suppression? The GEMINI RCTs compared dolutegravir and lamivudine to threedrug regimens in treatment-naïve patients with no significant baseline mutations, viral load of less than 500,000 copies/mL, and negative hepatitis B surface antigen [36]. The primary endpoint was viral suppression (less than 50 copies/mL) at 48  weeks. This was achieved in 91% of patients on the two-drug regimen and 93% of patients on the three-drug regimen (adjusted treatment difference − 1.7%, CI -4.4-1.1) demonstrating non-inferiority. No patients developed resistance including those with failure in the two-drug arm. In summary, the standards for ART therapy continue to evolve. With new drugs that have a high barrier to ­resistance such as integrase inhibitors, there are increasing high-quality data supporting the efficacy of twodrug regimens for patients without significant resistance, with no prior history of virologic failure, and who were previously well-controlled. Based on the GEMINI trials, there is also evidence that two-drug regimens can be the first-treatment regimen for patients if they have no baseline mutations and no active HBV infection. However, given that starting ART as soon as possible improves patient outcomes and that assays that measure resistance such as genotype often take some time to be performed, many patients will likely continue to be started on a three-drug regimen until virologic suppression is achieved.

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Q. Are there any options for this patient who struggles to take daily pills? A. Injectable antiretroviral therapy is an exciting new option for people living with HIV. Some patients find taking pills each day to be burdensome. Some may have cognitive disabilities which make managing their medication difficult. Others may have socioeconomic challenges, such as unstable housing, where storing medications safely is near impossible. Injectable options for ART are becoming increasingly available as another option for people living with HIV to receive their therapy. In an international multicenter RCT called ATLAS, 616 patients were transitioned to an oral regimen of daily cabotegravir and rilpivirine for 4 weeks and then randomized to either continue that regimen orally (n = 308) or to receive monthly intramuscular injections of cabotegravir and rilpivirine (n = 308) [37]. To be eligible, patients had to have been on ART for at least 6 months prior to enrollment with no changes in medication or virologic failure. Patients were also excluded if they had active HBV infection or mutations conferring resistance to integrase inhibitors or non-nucleoside reverse transcriptase inhibitors. The primary endpoint of the study was a viral load of 50 copies per mL or greater at week 48. Secondary outcomes included virologic failure, development of resistance (either genotypic or phenotypic), CD4 counts, adverse events, plasma concentration of drug, and patient satisfaction via survey. By the primary endpoint, injection therapy was non-inferior to oral therapy with 1.6% and 1% of patients having more than 50 viral copies per mL at 48  weeks (adjusted difference of 0.6%; CI, 1.2–2.5). None of the patients with virologic failure in the injection group had missed any of their injections, and failure was attributed to new mutations conferring resistance to rilpivirine. Eighty-­three percent of patients in the injection group had injection site reactions; how-

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ever, 99% of these injection site reactions were mild or moderate severity, and 88% of them resolved within 1 week. In terms of patient-­reported outcomes, patients in the injection group had greater satisfaction from baseline than the oral group. A follow-up study, ATLAS-2M, used similar eligibility criteria and study design with the same primary endpoint as ATLAS [38]. Patients were treated with injectable therapy every 4 weeks (n = 522) versus injection every 8  weeks (n  =  523). Injection every 8  weeks was found to be non-inferior to every 4 weeks with viral load greater than 50 copiers per mL in 2% and 1% of patients, respectively (adjusted difference of 0.8%, CI 0.6–2.2). When virologic failure occurred in the eight-­ week arm, it most often occurred earlier (within the first 24 weeks). Eight-week injection therapy had previously been shown to be non-inferior in the smaller LATTE-2 trial to 4-week injection therapy and oral therapy as well [39]. These RCTs were designed to treat patients that were already well-controlled on an ART regimen. What about more “real-world” type scenarios where patients may not be so well-controlled? In a case series at a single center in San Francisco, 51 patients were enrolled for injection therapy without any oral lead-in time [40]. Patients were initially treated with injections every 4  weeks and then transitioned to every 8 weeks if they had sustained viral suppression for 6  months, based on the results of the early failures in ATLAS-2M [38]. Patients were given a 1-month supply of oral cabotegravir and rilpivirine to have on hand and instructed to start it if they missed injections by more than 7 days. Fifteen of the patients in this case series had a viral load higher than 30 copies per mL at the time of first injection with median CD4 count of 99  cells/mm3. Twelve of these patients achieved and maintained viral suppression including a patient who had a baseline resistance mutation to rilpivirine (N155H). Of the three patients who did not achieve suppression, all

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did have a greater than two-log reduction in viral load. While more data will be needed to understand if injectable therapy can be started in patients with viremia including treatment-­naïve patients, this real-world case series conducted by a clinic with many dedicated staff and resources shows the promise of injectable therapy in treating patients that otherwise have difficulty maintaining suppression with traditional oral ART. In addition to treatment of HIV, injectable cabotegravir was also found to be superior to oral daily tenofovir-emtricitabine for HIV pre-­exposure prophylaxis in a large trial of cisgender men and transgender women [41]. Injectable ART is an exciting new development to give patients more options for life-saving medication. Q. This patient who recently lapsed in their antiretroviral therapy would benefit from elective surgery. How can we best mitigate surgical site infection risk? A. CD4 cell count may correlate with postsurgical infection risk. From a mechanistic point of view, CD4 cells are involved in wound healing and coordinating the immune response to infection [42]. In general, people living with HIV have a higher risk for surgical site infection [43]. For example, patients with HIV are more likely to require revision arthroplasty [44]. Do CD4 cell counts correlate with surgical site infection rates? This was retrospectively examined at a single center in Atlanta for patients requiring emergency orthopedic trauma surgery [45]. People living with HIV had an infection rate of 23% versus historic controls of patients without HIV with rates of 3.9%. In a linear regression model of factors associated with subsequent surgical site infection, CD4 less than 300  cells/mm3 was statistically significantly associated with higher infection risk. Only three of 64 patients with HIV had postoperative infection with CD4 greater than 300  cells/mm3, which is closer to baseline infection rates of patients without

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HIV. In another retrospective study of patients undergoing orthopedic surgery at a single site in China, low CD4 counts were also found to be an independent risk factor for surgical site infection in patients with HIV [46]. The authors calculated a CD4 count of 430  cells/ mm3 being a “break point” for infection risk. Note that CD4 does not always correlate with adherence to ART.  Regardless of HIV status, critical illness can cause a reversible CD4 lymphopenia [47, 48]. Some viral infections, especially SARS-CoV-2, cause lymphopenia. For example, in a retrospective review of 72 patients living with HIV from five hospitals in New York City, baseline CD4 levels were compared to CD4 levels during acute COVID-19 pneumonia [49]. In these patients, the average CD4 prior to COVID-19 pneumonia was 554 (33% of T cells) and decreased to 220 (23% of T cells) during COVID-19 pneumonia. In a multivariate model, CD4 count (baseline and change during COVID-­19) did not significantly predict mortality. Overall, these retrospective studies are difficult to interpret as many people living with HIV with low CD4 counts may have other physiologic and socioeconomic insults, and it is not clear that CD4 counts alone are causative versus correlative for subsequent surgical site infection. However, if surgery can be safely and ­reasonably delayed, restarting ART for viral suppression and CD4 rebound may decrease the risk of surgical site infection as well as give time to improve other factors which are associated with better outcomes such as nutrition. Q. We have a patient with AIDS and cryptosporidiosis. How should we treat them? A. Provide supportive care and antiretroviral therapy. Cryptosporidium is a protozoan that causes diarrheal disease and can be diagnosed by observation of oocysts in fecal samples or by nucleic acid testing [50]. The biggest burden of cryptosporidiosis falls in areas of the world where ART is not readily available. As a largely self-­

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resolving illness in the USA, it is often not formally diagnosed in immunocompetent patients. However, even patients well-controlled on ART can have significant disease when infected. Transmission is through the oral-fecal route by contaminated water or food. In the USA, it is generally associated with waterborne outbreaks including an infamous episode affecting 403,000 people in Wisconsin [51]. Seropositivity in the USA is estimated to be as high as 89% [52]. Statistically significant host risk factors for infection in people living with HIV include CD4 less than 200 cells/mm3, younger age, male sex, white race, anal sex, and having more than one sexual partner. Presentation is typically with a painless watery diarrhea. While symptoms typically last for 1–2 weeks in immunocompetent patients, patients with AIDS can have courses lasting weeks to months with significant weight loss, dehydration, wasting, and even fatal outcomes. While nitazoxanide may be an effective therapy in non-­immunocompromised patients, a meta-analysis of seven clinical trials using nitazoxanide in immunocompromised patients failed to show efficacy in cryptosporidiosis [53]. In an RCT called CRYPTOFAZ, patients with HIV and cryptosporidiosis were treated with clofazimine or placebo with a primary endpoint of reduction in pathogen shedding [54]. The study did not show differences between arms in primary outcome or for reduction of duration of diarrhea. Current recommendations are initiation of ART, fluid and electrolyte repletion, and consideration of antimotility agents. Interestingly, there are some in vitro and animal data that protease inhibitors may have anti-­ cryptosporidium activity [55]. Q. We have a very sick patient with low CD4 count and pleural effusions. These effusions are negative on culture – what else should be on our differential? A. Kaposi sarcoma can have pleural involvement. Kaposi sarcoma (KS) is a cutaneous and mucosal cancer caused by herpesvirus-8 primarily in immunocom-

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promised individuals. It is an AIDS-defining illness and its violaceous plaques were a stigmatizing sign of HIV infection during the US HIV epidemic in the preART era [56]. While it classically presents on the skin or mucosal-lined organs, pleuropulmonary KS is not uncommon. In one early series of patients with AIDS and KS, 20% had pleural involvement and 13% had pleural effusions [57]. When tapped, these effusions were often serosanguineous. Patients with pleuropulmonary KS had significantly decreased survival (all 21 passed away in this series) compared to patients with AIDS and no pleuropulmonary KS, although this study was in a time prior to effective ART.  Pleuropulmonary KS can present with violaceous plaques appreciated on bronchoscopy [58]. Pleuropulmonary KS has been associated with bony involvement [59]. In one case, bony lesions improved with ART alone [60]. In general, for KS, the treatment of choice in patients with AIDS is ART.  In patients with severe KS and/or progression on ART, liposomal doxorubicin can be added [56].

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29. Le T, Wolbers M, Chi NH, Quang VM, Chinh NT, Huong Lan NP, Lam PS, Kozal MJ, Shikuma CM, Day JN, Farrar J.  Epidemiology, seasonality, and predictors of outcome of AIDS-associated Penicillium marneffei infection in Ho Chi Minh City, Viet Nam. Clin Infect Dis. 2011;52:945–52. https://doi. org/10.1093/cid/cir028. 30. Collier AC, Coombs RW, Schoenfeld DA, Bassett RL, Timpone J, Baruch A, Jones M, Facey K, Whitacre C, McAuliffe VJ, Friedman HM, Merigan TC, Reichman RC, Hooper C, Corey L.  Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. AIDS Clinical Trials Group. N Engl J Med. 1996;334:1011–7. https://doi.org/10.1056/ NEJM199604183341602. 31. Antiretroviral drug discovery and development | NIH: National Institute of Allergy and Infectious Diseases. https://www.niaid. nih.gov/diseases-­conditions/antiretroviral-­drug-­development. Accessed 18 Apr 2023. 32. Sax PE, Erlandson KM, Lake JE, Mccomsey GA, Orkin C, Esser S, Brown TT, Rockstroh JK, Wei X, Carter CC, Zhong L, Brainard DM, Melbourne K, Das M, Stellbrink H-J, Post FA, Waters L, Koethe JR. Weight gain following initiation of antiretroviral therapy: risk factors in randomized comparative clinical trials. Clin Infect Dis. 2020;71:1379–89. https://doi.org/10.1093/ cid/ciz999. 33. Llibre JM, Hung C-C, Brinson C, Castelli F, Girard P-M, Kahl LP, Blair EA, Angelis K, Wynne B, Vandermeulen K, Underwood M, Smith K, Gartland M, Aboud M.  Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-­ inferiority SWORD-1 and SWORD-2 studies. Lancet. 2018;391:839–49. https://doi.org/10.1016/ S0140-­6736(17)33095-­7. 34. van Wyk J, Ajana F, Bisshop F, De Wit S, Osiyemi O, Portilla Sogorb J, Routy J-P, Wyen C, Ait-Khaled M, Nascimento MC, Pappa KA, Wang R, Wright J, Tenorio AR, Wynne B, Aboud M, Gartland MJ, Smith KY. Efficacy and safety of switching to dolutegravir/lamivudine fixed-dose 2-drug regimen vs continuing a tenofovir alafenamide-based 3- or 4-drug regimen for maintenance of virologic suppression in adults living with human immunodeficiency virus type 1: phase 3, randomized, noninferiority TANGO study. Clin Infect Dis. 2020;71:1920–9. https://doi. org/10.1093/cid/ciz1243.

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35. Llibre JM, Brites C, Cheng C-Y, Osiyemi O, Galera C, Hocqueloux L, Maggiolo F, Degen O, Taylor S, Blair E, Man C, Wynne B, Oyee J, Underwood M, Curtis L, Bontempo G, van Wyk J.  Efficacy and safety of switching to the 2-drug regimen dolutegravir/lamivudine versus continuing a 3- or 4-drug regimen for maintaining virologic suppression in adults living with human immunodeficiency virus 1 (HIV-1): week 48 results from the phase 3, noninferiority SALSA randomized trial. Clin Infect Dis. 2023;76:720–9. https://doi.org/10.1093/cid/ciac130. 36. Cahn P, Madero JS, Arribas JR, Antinori A, Ortiz R, Clarke AE, Hung C-C, Rockstroh JK, Girard P-M, Sievers J, Man C, Currie A, Underwood M, Tenorio AR, Pappa K, Wynne B, Fettiplace A, Gartland M, Aboud M, Smith K, GEMINI Study Team. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-­ inferiority, phase 3 trials. Lancet. 2019;393:143–55. https://doi. org/10.1016/S0140-­6736(18)32462-­0. 37. Swindells S, Andrade-Villanueva J-F, Richmond GJ, Rizzardini G, Baumgarten A, Masiá M, Latiff G, Pokrovsky V, Bredeek F, Smith G, Cahn P, Kim Y-S, Ford SL, Talarico CL, Patel P, Chounta V, Crauwels H, Parys W, Vanveggel S, Mrus J, Huang J, Harrington CM, Hudson KJ, Margolis DA, Smith KY, Williams PE, Spreen WR. Long-acting Cabotegravir and Rilpivirine for maintenance of HIV-1 suppression. N Engl J Med. 2020;382:1112–23. https:// doi.org/10.1056/NEJMoa1904398. 38. Overton ET, Richmond G, Rizzardini G, Jaeger H, Orrell C, Nagimova F, Bredeek F, García Deltoro M, Swindells S, Andrade-­ Villanueva JF, Wong A, Khuong-Josses M-A, Van Solingen-­Ristea R, van Eygen V, Crauwels H, Ford S, Talarico C, Benn P, Wang Y, Hudson KJ, Chounta V, Cutrell A, Patel P, Shaefer M, Margolis DA, Smith KY, Vanveggel S, Spreen W.  Long-­ acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-­ inferiority study. Lancet. 2021;396:1994–2005. https://doi. org/10.1016/S0140-­6736(20)32666-­0. 39. Margolis DA, Gonzalez-Garcia J, Stellbrink H-J, Eron JJ, Yazdanpanah Y, Podzamczer D, Lutz T, Angel JB, Richmond GJ, Clotet B, Gutierrez F, Sloan L, Clair MS, Murray M, Ford SL, Mrus J, Patel P, Crauwels H, Griffith SK, Sutton KC, Dorey

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D, Smith KY, Williams PE, Spreen WR.  Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial. Lancet. 2017;390:1499–510. https://doi. org/10.1016/S0140-­6736(17)31917-­7. 40. Christopoulos KA, Grochowski J, Mayorga-Munoz F, Hickey MD, Imbert E, Szumowski JD, Dilworth S, Oskarsson J, Shiels M, Havlir D, Gandhi M. First demonstration project of long-acting injectable antiretroviral therapy for persons with and without detectable human immunodeficiency virus (HIV) viremia in an urban HIV clinic. Clin Infect Dis. 2023;76:e645–51. https://doi. org/10.1093/cid/ciac631. 41. Landovitz RJ, Donnell D, Clement ME, Hanscom B, Cottle L, Coelho L, Cabello R, Chariyalertsak S, Dunne EF, Frank I, Gallardo-Cartagena JA, Gaur AH, Gonzales P, Tran HV, Hinojosa JC, Kallas EG, Kelley CF, Losso MH, Madruga JV, Middelkoop K, Phanuphak N, Santos B, Sued O, Huamaní JV, Overton ET, Swaminathan S, del Rio C, Gulick RM, Richardson P, Sullivan P, Piwowar-Manning E, Marzinke M, Hendrix C, Li M, Wang Z, Marrazzo J, Daar E, Asmelash A, Brown TT, Anderson P, Eshleman SH, Bryan M, Blanchette C, Lucas J, Psaros C, Safren S, Sugarman J, Scott H, Eron JJ, Fields SD, Sista ND, Gomez-Feliciano K, Jennings A, Kofron RM, Holtz TH, Shin K, Rooney JF, Smith KY, Spreen W, Margolis D, Rinehart A, Adeyeye A, Cohen MS, McCauley M, Grinsztejn B. Cabotegravir for HIV prevention in cisgender men and transgender women. N Engl J Med. 2021;385:595–608. https://doi. org/10.1056/NEJMoa2101016. 42. Tatara AM, Kontoyiannis DP, Mikos AG.  Drug delivery and tissue engineering to promote wound healing in the immunocompromised host: current challenges and future directions. Adv Drug Deliv Rev. 2018;129:319. https://doi.org/10.1016/j. addr.2017.12.001. 43. Zhang L, Liu B-C, Zhang X-Y, Li L, Xia X-J, Guo R-Z.  Prevention and treatment of surgical site infection in HIV-infected patients. BMC Infect Dis. 2012;12:115. https://doi. org/10.1186/1471-­2334-­12-­115. 44. Pruzansky JS, Bronson MJ, Grelsamer RP, Strauss E, Moucha CS. Prevalence of modifiable surgical site infection risk factors in hip and knee joint arthroplasty patients at an urban academic hospital. J Arthroplast. 2014;29:272–6. https://doi.org/10.1016/j. arth.2013.06.019.

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45. Guild GN, Moore TJ, Barnes W, Hermann C.  CD4 count is associated with postoperative infection in patients with orthopaedic trauma who are HIV positive. Clin Orthop Relat Res. 2012;470:1507–12. https://doi.org/10.1007/s11999-­0 11-­2223-­1. 46. Ma R, He J, Xu B, Zhao C, Zhang Y, Li X, Sun S, Zhang Q.  Nomogram prediction of surgical site infection of HIV-­ infected patients following orthopedic surgery: a retrospective study. BMC Infect Dis. 2020;20:896. https://doi.org/10.1186/ s12879-­020-­05613-­3. 47. Hohlstein P, Gussen H, Bartneck M, Warzecha KT, Roderburg C, Buendgens L, Trautwein C, Koch A, Tacke F.  Prognostic relevance of altered lymphocyte subpopulations in critical illness and sepsis. J Clin Med. 2019;8:353. https://doi.org/10.3390/ jcm8030353. 48. Aldrich J, Gross R, Adler M, King K, MacGregor RR, Gluckman SJ.  The effect of acute severe illness on CD4+ lymphocyte counts in nonimmunocompromised patients. Arch Intern Med. 2000;160:715–6. https://doi.org/10.1001/archinte.160.5.715. 49. Ho H, Peluso MJ, Margus C, Matias Lopes JP, He C, Gaisa MM, Osorio G, Aberg JA, Mullen MP. Clinical outcomes and immunologic characteristics of coronavirus disease 2019  in people with human immunodeficiency virus. J Infect Dis. 2020;223:403– 8. https://doi.org/10.1093/infdis/jiaa380. 50. Thompson RCA, Koh WH, Clode PL.  Cryptosporidium—what is it? Food Waterborne Parasitol. 2016;4:54–61. https://doi. org/10.1016/j.fawpar.2016.08.004. 51. Hoxie NJ, Davis JP, Vergeront JM, Nashold RD, Blair KA. Cryptosporidiosis-associated mortality following a massive waterborne outbreak in Milwaukee, Wisconsin. Am J Public Health. 1997;87:2032–5. https://doi.org/10.2105/ajph.87.12.2032. 52. O’connor RM, Shaffie R, Kang G, Ward HD. Cryptosporidiosis in patients with HIV/AIDS.  AIDS. 2011;25:549–60. https://doi. org/10.1097/QAD.0b013e3283437e88. 53. Abubakar I, Aliyu SH, Arumugam C, Hunter PR, Usman NK.  Prevention and treatment of cryptosporidiosis in immunocompromised patients. Cochrane Database Syst Rev. 2007:CD004932. https://doi.org/10.1002/14651858.CD004932. pub2. 54. Iroh Tam P, Arnold SLM, Barrett LK, Chen CR, Conrad TM, Douglas E, Gordon MA, Hebert D, Henrion M, Hermann D, Hollingsworth B, Houpt E, Jere KC, Lindblad R, Love MS, Makhaza L, McNamara CW, Nedi W, Nyirenda J, Operario DJ,

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Phulusa J, Quinnan GV, Sawyer LA, Thole H, Toto N, Winter A, Van Voorhis WC.  Clofazimine for treatment of cryptosporidiosis in human immunodeficiency virus infected adults: an experimental medicine, randomized, double-blind, placebo-­ controlled phase 2a trial. Clin Infect Dis. 2021;73:183–91. https:// doi.org/10.1093/cid/ciaa421. 55. Hommer V, Eichholz J, Petry F.  Effect of antiretroviral protease inhibitors alone, and in combination with paromomycin, on the excystation, invasion and in  vitro development of Cryptosporidium parvum. J Antimicrob Chemother. 2003;52:359–64. https://doi.org/10.1093/jac/dkg357. 56. Cesarman E, Damania B, Krown SE, Martin J, Bower M, Whitby D.  Kaposi sarcoma. Nat Rev Dis Primers. 2019;5:9. https://doi. org/10.1038/s41572-­0 19-­0 060-­9. 57. O’Brien RF, Cohn DL.  Serosanguineous pleural effusions in AIDS-associated Kaposi’s sarcoma. Chest. 1989;96:460–6. https://doi.org/10.1378/chest.96.3.460. 58. Zibrak JD, Silvestri RC, Costello P, Marlink R, Jensen WA, Robins A, Rose RM.  Bronchoscopic and radiologic features of Kaposi’s sarcoma involving the respiratory system. Chest. 1986;90:476–9. https://doi.org/10.1378/chest.90.4.476. 59. Krishna G, Chitkara RK.  Osseous Kaposi sarcoma. JAMA. 2003;289:1106. https://doi.org/10.1001/jama.289.9.1106. 60. Dirweesh A, Khan MY, Hamiz SF, Karabulut N.  Pulmonary Kaposi sarcoma with osseous metastases in an human immunodeficiency virus (HIV) patient: a remarkable response to highly active antiretroviral therapy. Am J Case Rep. 2017;18:181–5. https://doi.org/10.12659/AJCR.902355.

Chapter 8 Viral Infection

Abstract  Viruses are agents that contain machinery allowing them to replicate within host cells, often to the detriment of those infected. The impact of viral infections can range from relatively benign, such as the common cold, to devastating and lethal, such as hantavirus. Unlike bacterial and fungal microorganisms, there are less available therapeutics for viral infection. Diagnostics continue to improve although are often based on nucleic acid testing so may not be agnostic if infection is caused by a virus for which common assays do not contain primers. In this century, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the disease it causes, coronavirus disease 2019 (COVID-19), have caused a massive pandemic with high rates of global morbidity and mortality. During my time in fellowship, writing my notes about diagnostics and treatments for SARS-CoV-2 felt like describing shipbuilding while aboard the Titanic. As a field, clinical virology has made large strides in response to the pandemic, although there is still much work to be done. In this chapter, we will discuss common hepatitis viruses; examine some concepts involving herpesviruses, cytomegalovirus, and adenovirus; and review the management of COVID-19.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. M. Tatara, The Infectious Diseases Consult Handbook, https://doi.org/10.1007/978-3-031-39474-4_8

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Q. Does this patient with a positive surface antigen have hepatitis B virus infection? A.  Let us discuss interpretation of hepatitis B virus testing. Current guidelines recommend that all US adults 18  years or older should undergo hepatitis B virus (HBV) screening at least once in their lifetime, screening during pregnancy, and additional periodic testing for individuals who are at high risk [1]. Screening is done with the “triple panel” of serology: HBV surface antigen (HBsAg), HBV surface antibody (HBsAb), and HBV core antibody (HBcAb). There are five broad patterns (Table  8.1): (1) uninfected and unexposed, (2) vaccinated, (3) acute infection, (4) chronic infection, and (5) resolved infection [2]. Surface antigen is a marker that is actively produced by the virus, so any patient with positive HBsAg has infection (acute or chronic). Most HBV vaccines use recombinant versions of HBsAg to generate antibodies against surface antigen and facilitate immunity [3]. Patients who have been vaccinated will have positive surface antibodies without other positive markers. HBcAb is an antibody directed against the nucleocapsid core of the virus and will be positive in patients that have been infected but is not positive by vaccine alone. In patients with acute infection, HBcAb may be an IgM antibody, whereas patients with chronic Table 8.1  Different patterns of hepatitis B virus testing Surface Surface Core antigen antibody antigen Uninfected − − − Vaccinated

−

+

−

Acute infection

+

−

+IgM/IgG

Chronic infection

+

−

+IgG

Resolved infection

−

+/−

+

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infection will have HBcAb IgG.  Another definition of chronic HBV infection is the presence of HBsAg for more than 6  months [4]. Patients that are able to clear their infection will no longer have circulating surface antigen and may or may not have HBsAb present but will remain HBcAb positive. These cases may require HBV viral load to distinguish chronic infection from cleared infection as the presence of HBV DNA indicates active infection. There are exceptions to every rule. One example is serology testing in patients who have received intravenous immunoglobulin (IVIG) therapy. In a retrospective analysis of 870 patients with malignancy who received IVIG and HBV prescreening prior to IVIG therapy, 15% of these patients became HBcAb positive but none became HBsAg or HBV viral load positive, suggesting that this may have been from passive transfer of core antibodies rather than an actual infection [5]. Q. Should this patient with chronic hepatitis B virus infection be treated? A. Depending on liver and HBV markers, some patients can undergo monitoring without active treatment, although this is an active area of research. If left untreated, HBV can cause a cycle of hepatic inflammation that eventually results in liver cancer. What determines whether a patient with chronic HBV merits treatment? Patients without elevated liver enzymes, with no evidence of liver fibrosis, and with persistently low or undetectable levels of HBV DNA may undergo monitoring rather than treatment. Current guidelines recommend distinguishing patients with chronic infection by measuring pre-core e antigen (HBeAg) [4]. In patients that are HBeAg positive with elevated alanine transaminase (ALT), it is recommended to start treatment if HBV viral load is greater than 20,000 copies/mm3. If HBV viral load is lower but ALT is elevated, it is recommended to monitor viral

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load every 1–3  months. Likewise, if the patient has chronic HBV infection and HBeAg positivity with normal ALT, it is recommended to monitor ALT and HBV viral load every 3–6  months and HBeAg every 6–12  months. In patients with chronic HBV and negative HBeAg testing, treatment is recommended at lower levels of HBV viral load (greater than 2000 copies/mm3) if patients have elevated ALT [4]. Regardless of viral load and HBeAg, patients with chronic HBV that have evidence of liver fibrosis with invasive or noninvasive diagnostics should be treated. Should we be using ALT to distinguish those who may benefit from treatment? In a multicenter RCT called TORCH-B, patients with chronic HBV with viral loads greater than 2000  copies/mm3 and no treatment with minimally increased ALT were randomized to receive placebo or tenofovir [6]. There were  ~  80 patients per group. The primary outcomes were changes in fibrosis and necroinflammation severity assessed via biopsy. There was significantly less progression in terms of fibrosis in the group receiving tenofovir although no significant differences in necroinflammation. Patients treated with tenofovir were also more likely to have normalization of ALT and remission of HBV viral load. While not a primary outcome, there were significantly greater acute hepatitis flairs in patients in the placebo group (2 versus 13 patients) which required those patients to receive entecavir. These data suggest that treatment may benefit patients with chronic HBV even prior to elevations in markers such as ALT, although larger trials may provide more conclusive evidence. Q. Who should receive treatment for hepatitis C virus? A. Everyone who is positive should be treated and treatment should not be delayed. In the USA, hepatitis C virus (HCV) is transmitted primarily through injection drug use and contaminated needles. With the opioid epidemic, the incidence of HCV has increased nearly fourfold over the past

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decade [7, 8]. Guidelines recommend that all US adults ages 18–79 years old be screened for HCV at least once and for people who inject drugs to undergo annual screening [8, 9]. If a patient has a positive screen (anti-­ HCV antibody), they should undergo HCV viral load measurement. There are some patients that will naturally clear infection (negative HCV viral load), and they should be counseled that they are not protected from reinfection. For those that have active infection, guidelines recommend assessing severity of liver disease preferably through a noninvasive diagnostic test, such as liver serum enzymes, serum fibrosis markers, imaging, or elastography [10]. Patients should also undergo screening for HBV and HIV. It is recommended that all adults with acute or chronic HCV undergo treatment, unless they have a short life expectancy that cannot be reversed with HCV treatment. Patients should undergo treatment upon diagnosis without waiting to see if they have spontaneous resolution of their viremia [10]. For patients without any complicating factors (cirrhosis, prior HCV treatment, end-stage renal disease, coinfection with HIV or HBV, suspected hepatocellular carcinoma, or prior liver transplantation), treatment can begin with either 8 weeks of glecaprevir/pibrentasvir or 12 weeks of sofosbuvir/velpatasvir. Viral load and liver enzymes should be measured after 12  weeks to confirm virologic cure and transaminase normalization [10]. For patients with compensated cirrhosis, HCV genotype is recommended as those with HCV genotype 3 and cirrhosis should not be treated with sofosbuvir/velpatasvir. Patients should be counseled after virologic cure that they are still vulnerable to reinfection upon reexposure. Much of HCV treatment is initiated in the outpatient setting. However, patients may be more likely to be engaged and complete treatment if it is started in the inpatient setting with the proper counseling, and integrated community centers may be another method to achieve sustained virologic response [11, 12].

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Q.  How should we manage this patient with painful shingles? A. Oral antivirals may help if given early in the disease process. Herpes zoster is an infection caused by the reactivation of varicella-zoster virus (VZV), which lies dormant in nerve roots following primary VZV infection (“chicken pox”). Reactivation occurs along sensory ganglia and is associated with painful lesions in individual dermatomes. There is typically a prodromal period of several days where patients have pain prior to the appearance of vesicular lesions [13]. Vesicles will form ulcers that crust in 1–2 weeks and resolve in 3–4 weeks. The continued appearance of new lesions for over 1  week is not typical and is concerning for immunodeficiency [13]. The clinical exam is often sufficient for diagnosis although nucleic acid testing from swabs of lesions can be performed if diagnosis is not clear from dermatomal distribution. For stable patients with mild disease, firstline therapy is 7–10 days of oral antivirals. Valacyclovir and famciclovir require less frequent dosing and are often preferred over acyclovir. If patients present greater than 72 h after lesion onset and do not have new lesions occurring, they may not benefit from additional antivirals as the disease course is often self-limiting. Droplet precautions should be observed until patients have crusted lesions. Disseminated zoster is defined as more than 20 vesicles outside of the primary dermatome and immediately adjacent dermatomes [14]. Disseminated disease occurs most often in the immunocompromised and can be life-­threatening when visceral organs are involved. VZV can also cause aseptic meningitis even without rash [13]. For immunocompromised patients and those with severe disease, intravenous acyclovir is recommended with transition to oral therapy once disease is controlled [13]. Fortunately, acyclovir resistance is rare. Rates of resistance are estimated to be 0.1–0.7% in the immunocompetent and 3.5–14% in some immunocom-

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promised populations that likely have prior antiviral exposure [15]. Some resistance can be overcome by increased acyclovir dosing, although other cases may require changing agents to foscarnet or cidofovir [15]. There are other complicated manifestations of herpes zoster. Herpes zoster ophthalmicus occurs with reactivation along the ophthalmic nerve of the trigeminal ganglia and causes periorbital rash [16]. Lesions on the tip or side of the nose are known as Hutchinson’s sign. If there is any suspicion for ophthalmic involvement, consultation with an ophthalmologist is recommended. Oral treatment of herpes zoster ophthalmicus is sufficient if there is no evidence of dissemination [17]. Postherpetic neuralgia is the most common complication of herpes zoster and can result in chronic neuropathic pain. A single-arm non-randomized study in Houston suggested that gabapentin was effective in reducing postherpetic pain when given in the acute phase compared to historical controls [18]. However, in a multicenter RCT in Spain, patients presenting within 72 h of rash were all treated with 7 days of valacyclovir and randomized to receive gabapentin (n = 33) or placebo (n = 42) for 5 weeks with 18.2% of patients in the gabapentin group and 9.5% of patients in the control group reporting pain at the primary endpoint, suggesting that gabapentin was not effective [19]. The best treatment is prevention. Vaccination of the immunocompromised and those over 50  years old is important for preventing herpes zoster. There is also VZV immunoglobulin for postexposure prophylaxis, although it is not available everywhere and oral acyclovir has also been used [20]. Q. Do we need to be concerned about cytomegalovirus in an immunocompetent patient? A. These infections are unusual, and viremia alone may not predict disease. Most patients who suffer from disease caused by cytomegalovirus (CMV) are immunocompromised. CMV

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can cause primary infection in the immunocompetent that typically presents as a self-limiting mononucleosis-­ like viral syndrome [21]. However, severe disease can rarely occur. The most common site of severe CMV disease in the immunocompetent in one review of cases was the gastrointestinal tract with symptoms including fever, abdominal pain, nausea/vomiting, diarrhea, hematochezia, and melena [21]. A meta-analysis of CMV colitis in the immunocompetent suggested that spontaneous resolution occurred in 32% of patients and more often in those that were younger than 55 years old [22]. Histopathologic evidence of direct CMV-induced tissue damage rather than only PCR-based diagnostics can help differentiate CMV viremia from infection in colitis. Patients can also rarely suffer from primary central nervous system disease, including CMV encephalitis [21, 23, 24]. In addition to focal infections such as colitis and encephalitis, CMV reactivation can occur in the immunocompetent during times of critical illness. In one prospective observational study of 120 CMV seropositive critically ill patients in two Seattle hospitals, 33% had positive CMV viral load at any point during their illness, and 20% had viral load greater than 1000 copies/mm3 [25]. The only risk factor clearly associated with reactivation in this study was level of critical illness as defined by a clinical scoring system. The primary endpoint was a composite of continued hospitalization or death at 30 days. The presence of any amount of CMV, as well as patients with more than 1000  copies/mm3, correlated with both greater mortality and greater increased hospital length of stay. This finding of CMV reactivation in immunocompetent but critically ill patients has been replicated by others [26, 27]. However, CMV replication does not necessarily correlate with CMV disease. It may essentially function as a biomarker indicating poor immune function in the setting of critical illness. In one prospective observational (but not randomized) study, immunocompetent critically ill

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patients who received antiviral treatment with positive CMV viral load did not have improved mortality compared to those who were not treated with antivirals [27]. As it is not always obvious if disease is being caused by active viral replication or if replication is only a bystander effect of immune dysfunction in a critically ill host, the decision to treat CMV in an immunocompetent individual is not simple. In patients with no other clear source for their symptoms and with positive CMV viral load, treatment with close monitoring of both symptoms and CMV markers may be warranted [28]. Effective antivirals include ganciclovir, valganciclovir, and foscarnet, although these have not been formally studied in the immunocompetent [29]. Q. We have a sick patient with a focal consolidation on lung imaging but with negative bacterial cultures—are there any viral pneumonias to consider? A. Adenovirus pneumonia is rare but very devastating. While a common cause of upper respiratory infection, adenovirus rarely causes pneumonia. In one systemic review of the literature, 15 cases of adenovirus pneumonia were identified in immunocompetent patients with a mortality of at least 53% [30]. Asymptomatic presence of adenovirus is fairly common in both healthy patients and those post-lung transplant. In one study, 18/80 (22.5%) of patients at two Canadian centers had positive serum PCR in the first 12  months following lung transplantation, but only 4/18 of these patients had any symptoms at the time, which were most often influenza-­ like [31]. In one case series of 308 patients who underwent lung transplantation in Pittsburgh, 4 (1.3%) suffered from adenovirus pneumonia, and all patients died with the infection with autopsy-proven disease [32]. In one large prospective case series of patients suffering from viral pneumonias after lung transplantation, only two had adenovirus and one of those patients died [33]. On imaging, adenovirus pneumonia can appear as nonspecific focal consolidations [34]. Diagnosis can be

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made by sequencing from deep samples (such as those from bronchoscopy) or direct staining from tissue biopsies [32, 33]. In immunocompetent patients with severe disease, cidofovir may be the treatment of choice. In one series of 7 patients, all survived and had symptomatic improvement in a median 12 days [35]. However, another retrospective study of patients with severe adenovirus pneumonia compared 13 patients treated with cidofovir and 9 patients without and did not show significant differences in outcome [36]. Further work to better understand cidofovir efficacy in both immunocompetent and immunocompromised hosts with severe adenoviral disease will hopefully shed clarity. More commonly than adenovirus, influenza can cause devastating and lethal pneumonias, although patients are more likely to be screened for influenza when presenting with respiratory symptoms than adenovirus at this time. Q. How do we interpret COVID-19 diagnostics including cycle threshold? A. Nucleic acid-based testing is most accurate and may be semiquantitative, although clinical decision-making surrounding cycle threshold values has not been validated. Severe acute respiratory syndrome coronavirus 2 (SARS-­CoV-­2) is the virus that caused a massive pandemic starting in 2019 with a viral syndrome named COVID-­ 19. The virus spreads through the air and enters mucosal surfaces, such as the nares, oropharynx, and eyes. It binds to human angiotensin-converting enzyme 2 receptor to gain entry into cells and further replicates, most often causing severe disease in the lower respiratory tract [37]. The large variance of disease and nonspecific symptoms caused by COVID-19 makes clinical diagnosis challenging. In one meta-analysis of 90 COVID-19 studies reviewing 96 different symptoms, only cough had a sensitivity above 50% (with specificity of 45.4%) [38]. Fever had a sensitivity of 37.6% with a specificity of 75.2%. Anosmia, or loss of

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sense of smell, was fairly specific with a sensitivity of 26.4% and a specificity of 94.2%. Shortness of breath, another signature of COVID-19, had a sensitivity of only 23.3% and a specificity of 75.7%. If clinical symptoms are not very sensitive for COVID-19 diagnosis, which laboratories may be helpful? During the early days of the COVID-19 pandemic in Boston, our nucleic acid-based testing would initially take many hours. However, some traditional laboratory values did have diagnostic and prognostic correlations with COVID-19. Elevations in inflammatory markers, such as C-reactive protein, erythrocyte sedimentation rate, lactate dehydrogenase, ferritin, and d-dimer, are commonly seen and may correlate with disease severity [39]. Interleukin 6 (IL-6) is another nonspecific marker of inflammation that is elevated in severe disease and serves as a target for immunomodulation to improve outcomes in some cases [40, 41]. During that first wave of patients, we also frequently saw lymphopenia. In a retrospective study at four hospitals in Florida, lymphopenia (less than 1 × 109 lymphocytes per liter) in 4485 inpatients admitted with COVID-19 from March 2020 to January 2021 correlated with significantly greater intensive care unit admission, mechanical ventilation, renal failure requiring hemodialysis, and inhospital mortality [42]. Radiographic markers have also been studied for COVID-19 diagnosis, and chest computed tomography had a sensitivity of 67–100% and a low specificity of 25–80% [43]. Ultimately, traditional laboratory values and imaging are non-specific, although may be informative in understanding host inflammation, offer prognostic data, and help stratify patients for different treatment modalities (such as IL-6 blockade). Nucleic acid amplification tests (NAATs) are much more specific for SARS-CoV-2. For sputum samples, NAAT sensitivity is 65.2–69.6% with a specificity of 90.5–100% [44]. In addition, NAAT can be used as a surrogate for viral load by measuring cycle

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threshold. In simplistic terms, the cycle threshold is the number of amplification cycles required to generate sufficient viral RNA to be detected. Therefore, the higher the cycle threshold, the less initial viral RNA was present in the sample. This could correlate with degree of viral burden. For example, 754 samples from 425 symptomatic patients from the UK during a 3-month period showed that cycle threshold values were typically at their lowest during symptom onset (suggesting this is the time of highest viral burden) and then steadily decreased over a 2-week period [45]. Similar results were found in a prospective study where asymptomatic patients had the highest cycle threshold [46]. Studies surrounding cycle threshold as a marker of disease severity have been mixed, which may reflect that host inflammation plays major role in pathology in addition to viral replication [47]. Cycle threshold may also be used in individual patients over time to track response to different therapies with the important caveat that it has not been appropriately validated for this use [48]. In general, cycle threshold values may not be reliable due to heterogeneity in patient samples, differences across NAAT platforms, and their nature as semiquantitative tests. The Infectious Diseases Society of America and Association for Molecular Pathology issued a joint statement advising caution when interpreting cycle threshold for clinical decision-making [49]. Lastly, rapid antigen tests using lateral flow assays became widely available for home testing during the COVID-19 pandemic. These tests work by using immunochromatography with colorimetric labels to cause binding in the presence of SARS-CoV-2 antigen [50]. The sensitivity and specificity of rapid antigen tests depends on whether or not patients are symptomatic— one study found a sensitivity of 63.5% and specificity of 100% but a sensitivity of only 35% in asymptomatic patients [51]. Despite less accuracy than NAAT, these rapid antigen tests play an important role in breaking

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community transmission, given that people can easily perform them at home and then quarantine if positive. Q. Which immunomodulators are effective for the treatment of COVID-19? A. Corticosteroids have benefit in patients with moderate-­ to-­severe COVID-19. The severity of COVID-19 is often due to an overexuberant inflammatory host immune response rather than direct viral damage [52]. Therefore, strategies to modulate the immune response to prevent hyperinflammation have been an active area of research. In the RECOVERY trial, patients hospitalized with COVID-­ 19 were randomized to receive 6  mg daily of oral or intravenous dexamethasone for up to 10 days (n = 2104) or to receive usual standard of care (n = 4321) [53]. The primary endpoint was all-cause mortality at 28  days. There was a slight benefit in the dexamethasone group (22.9% versus 25.7% mortality; risk ratio 0.83; 95% CI, 0.75–0.93). In subgroup analysis, the benefit was much larger in patients that were intubated (29.3% versus 41.4%; risk ratio 0.64; 95% CI, 0.51–0.81) and still present (albeit modest) in patients requiring oxygen without mechanical ventilation at enrollment. In patients that required no respiratory support, there was no significant difference in mortality, although there was a non-significant trend toward harm (17.8% versus 14.0%; risk rate 1.19; 95% CI, 0.92–1.55). Corticosteroids have become the standard of care to reduce severe outcomes such as ventilation and death for patients with COVID-­ 19 and hypoxemia. However, inappropriate corticosteroid use in patients without hypoxemia has been associated with secondary infections, such as mucormycosis [54]. IL-6 is an inflammatory cytokine that is associated with COVID-19 disease severity. Tocilizumab is a monoclonal antibody inhibitor of IL-6. Initial RCTs studying the effect of tocilizumab on patient outcome had heterogenous results. In the CORIMUNO-TOCI-1

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trial, patients at nine centers in France requiring supplemental oxygen (at least 3 L/minute) but not mechanical ventilation were randomized to receive tocilizumab (n = 60) or standard care alone (n = 67) with a primary outcome of survival without the need for mechanical ventilation by days 4 and 14 [55]. The study did not meet its day 4 primary endpoint, but at day 14, there was less need for mechanical ventilation in patients that received tocilizumab (24% vs 36%, HR 0.58; 90% CI, 0.33–1.00). However, as a secondary outcome, there was no difference in 28-day mortality between the two groups. In a follow-up study that looked at outcomes greater than 90  days, there was a significant relationship between those who benefited from tocilizumab and those that had the highest levels of inflammatory biomarkers [40]. Tocilizumab therapy in COVID-19 patients requiring at least 3  L/min of oxygen receiving dexamethasone did not find reduce rates of death or progression to mechanical ventilation by day 14 [56]. Some advocate for tocilizumab for patients with increasing oxygen requirement early in disease course if they have C-reactive protein or other inflammatory markers higher than certain thresholds, such as 75  mg/dL.  Another ­immunomodulatory approach that has been studied is the use of Janus kinase inhibitors, especially baricitinib. Meta-analysis of studies in patients with moderate to severe COVID-19 suggested a slight decrease in allcause mortality at day 28 [57]. In a retrospective study of patients with severe COVID-19 at hospitals in Georgia who received either tocilizumab (n  =  291) or baricitinib (n  =  291) in addition to standard of care (which could include dexamethasone and/or remdesivir), the two immunomodulators were equivalent in terms of the primary outcome of mortality at 28  days, and tocilizumab was associated with higher rates of secondary infection [58]. These results were supported by an open-label RCT at a single center in Greece, where baricitinib was non-inferior to tocilizumab for

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preventing death and/or progression to mechanical ventilation by day 28 in severe COVID-19 [59]. Ultimately, we are still in a relatively early phase of understanding which patients benefit the most from which type of immunomodulation during which phase of their infection. However, these results are promising and strategies where specific cytokines are targeted during infection will continue to mature. While not an immunomodulator per se, convalescent plasma is an immune-derived therapy. Specifically, it is pooled plasma from people who have recovered from COVID-19 infection that presumably contains anti-­ SARS-­ CoV-2 antibodies. In an early meta-analysis, which included four RCTs and 1060 patients, convalescent plasma did not improve mortality, length of hospital stay, or ventilation use [60], and no benefit was found in a later meta-analysis of eight RCTs [61]. However, a meta-analysis that specifically studied the effects of convalescent plasma in hospitalized immunocompromised patients did show mortality benefit in those who cannot mount a traditional immune response to vaccination and/or COVID-19 infection [62]. Experts advocate for its use in immunocompromised patients early in disease course for maximal benefit in combination with other therapies such as antivirals [63]. Q.  Which antivirals are effective for the treatment of COVID-19? A. Remdesivir has the most data available but is limited to intravenous delivery. Antivirals are therapeutics which directly target viral mechanisms of disease. Effective SARS-CoV-2 antivirals were unavailable at the beginning of the COVID-19 pandemic. These early days were dark times. I was deployed in the emergency department during the first major wave to hit Boston and remember the distinct feelings of helplessness, given our lack of effective treatments for the masses of patients arriving in respiratory distress. Suddenly, there was a manuscript that claimed

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hydroxychloroquine, an anti-malarial drug also used to treat autoimmune disease, was effective as an antiviral against SARS-CoV-2. This was followed by massive off-­ label use in a desperate attempt to treat patients as well as a flurry of studies to prove if it indeed had benefit [64]. Later, it was demonstrated in a number of RCTs that it was not effective [65, 66]. Similarly, the antiparasitic ivermectin was claimed to have antiviral benefits against COVID-19, but multiple RCTs have not demonstrated efficacy [67, 68]. An entire industry of pseudoscience surrounding different off-label treatments and preventions for COVID-19 has been fueled by poor-­ quality studies and has caused harm to patients, degraded trust in the US health system, and diverted resources from trials for other therapeutics that may have efficacy. If hydroxychloroquine and ivermectin are examples of drugs that were not effective as antivirals, which medications do have evidence of efficacy? Remdesivir is an antiviral which inhibits SARSCoV-2 RNA polymerase to limit replication. In an international RCT, patients with severe disease (on ventilation, requiring supplemental oxygen, or with oxygen saturation of less than 94% on ambient air or tachypnea greater than 24 breathes per minute) were randomized to receive remdesivir (n = 541) or placebo (n = 521) with a primary outcome of time to recovery defined as discharge from the hospital or hospitalization for infection-­control purposes alone [69]. Patients who received remdesivir had a median recovery time of 10 days versus 15 days in the placebo group (p