MEDICAL MICROBIOLOGY NOTE TO INSTRUCTORS: Contact your Elsevier Sales Representative for teaching resources, including slides and image banks, for Medical Microbiology, 8e, or request these supporting materials at: http://evolve.elsevier.com/Murray/microbiology/ 8TH EDITION MEDICAL MICROBIOLOGY PATRICK R. MURRAY, PhD Senior Worldwide Director, Scientific Affairs BD Diagnostics Systems Sparks, Maryland; Adjunct Professor, Department of Pathology University of Maryland School of Medicine Baltimore, Maryland KEN S. ROSENTHAL, PhD Professor of Biomedical Sciences Director of Microbiology and Immunology Roseman University of Health Sciences College of Medicine Las Vegas, Nevada; Emeritus Professor Northeastern Ohio Medical University Rootstown, Ohio MICHAEL A. PFALLER, MD Chief Medical Officer T2 Biosystems Lexington, Massachusetts; Professor Emeritus University of Iowa College of Medicine and College of Public Health Iowa City, Iowa 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 MEDICAL MICROBIOLOGY, EIGHTH EDITION ISBN: 978-0-323-29956-5 Copyright © 2016, Elsevier Inc. All rights reserved. Previous editions copyrighted 2013, 2009, 2005, 2002, 1998, 1994, 1990. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data Murray, Patrick R., author. Medical microbiology / Patrick R. Murray, Ken S. Rosenthal, Michael A. Pfaller ; consultant, JMI Laboratories.—8th edition. p. ; cm. Includes bibliographical references and index. ISBN 978-0-323-29956-5 (pbk. : alk. paper) I. Rosenthal, Ken S., author. II. Pfaller, Michael A., author. III. Title. [DNLM: 1. Microbiology. 2. Microbiological Techniques. 3. Parasitology. QW 4] QR46 616.9′041—dc23 2015030867 Senior Content Strategist: James Merritt Content Development Manager: Kathryn DeFrancesco Publishing Services Manager: Catherine Jackson Project Manager: Rhoda Howell Design Direction: Brian Salisbury Printed in Canada Last digit is the print number: 9 8 7 6 5 4 3 2 1 • To all who use this textbook, that they may benefit from its use as much as we did in its preparation PREFACE Our knowledge about microbiology and immunology is inclusion in this textbook. Each chapter has been carefully constantly growing, and by building a good foundation updated and expanded to include new, medically relevant of understanding in the beginning, it will be much easier to discoveries. In each of these chapters, we have attempted to understand the advances of the future. present the material that we believe will help the student gain Medical microbiology can be a bewildering field for the an interest in as well as a clear understanding of the signifi- novice. We are faced with many questions when learning cance of the individual microbes and their diseases. microbiology: How do I learn all the names? Which infec- With each edition of Medical Microbiology we refine and tious agents cause which diseases? Why? When? Who is at update our presentation. There are many changes to the risk? Is there a treatment? However, all these concerns can eighth edition, both in the print and e-versions of the book. be reduced to one essential question: What information do The book starts with a general introduction to microbiology I need to know that will help me understand how to diag- and new chapters on the human microbiome and epidemiol- nose and treat an infected patient? ogy of infectious diseases. The human microbiome (that is, Certainly, there are a number of theories about what a the normal population of organisms that populate our student needs to know and how to teach it, which supposedly bodies) can now be considered as another organ system with validates the plethora of microbiology textbooks that have 10 times as many cells as human cells. This microbiota edu- flooded the bookstores in recent years. Although we do not cates the immune response, helps digest our food, and pro- claim to have the one right approach to teaching medical tects us against more harmful microbes. Additional chapters microbiology (there is truly no one perfect approach to in the introductory section introduce the techniques used by medical education), we have founded the revisions of this microbiologists and immunologists and are followed by textbook on our experience gained through years of teaching chapters on the functional immune system. The immune medical students, residents, and infectious disease fellows, as cells and tissues are introduced, followed by an enhanced well as on the work devoted to the seven previous editions. chapter on innate immunity and updated chapters on anti- We have tried to present the basic concepts of medical gen-specific immunity, antimicrobial immunity, and vac- microbiology clearly and succinctly in a manner that cines. The sections on bacteria, viruses, fungi, and parasites addresses different types of learners. The text is written in a have also been reorganized. Each section is introduced by straightforward manner with, it is hoped, uncomplicated the relevant basic science chapters and then the specific explanations of difficult concepts. In this edition, we chal- microbial disease summary chapter before proceeding into lenged ourselves to improve the learning experience even descriptions of the individual microbes, “the bug parade.” more. We are using the new technology on StudentConsult. Each chapter on the specific microbes begins with a summary com (e-version) to enhance access to the material. New to (including trigger words), which is keyed to the appropriate this edition, chapter summaries and learning aids are placed part of the chapter in the e-version. As in previous editions, at the beginning of each of the microbe chapters, and on the there are many summary boxes, tables, clinical photographs, e-version these are keyed to the appropriate sections in the and original clinical cases. Clinical Cases are included chapter. In addition, many of the figures are enhanced to because we believe students will find them particularly inter- assist learning. Details are summarized in tabular format esting and instructive, and they are a very efficient way to rather than in lengthy text, and there are colorful illustra- present this complex subject. Each chapter in the “bug tions for the visual learner. Clinical Cases provide the rele- parade” is introduced by relevant questions to excite students vance that puts reality into the basic science. Important and orient them as they explore the chapter. Finally, students points are emphasized in boxes to aid students, especially in are provided with access to the new Student Consult website, their review, and the study questions, including Clinical which provides links to additional reference materials, clini- Cases, address relevant aspects of each chapter. Each section cal photographs, animations (including new animations), (bacteria, viruses, fungi, parasites) begins with a chapter that and answers to the introductory and summary questions of summarizes microbial diseases, and this also provides review each chapter. Many of the figures are presented in step-by- material. step manner to facilitate learning. A very important feature Our understanding of microbiology and immunology is on the website is access to more than 200 practice exam rapidly expanding, with new and exciting discoveries in all questions that will help students assess their mastery of the areas. We used our experience as authors and teachers to subject matter and prepare for their course and licensure choose the most important information and explanations for exams. In essence, this edition provides an understandable vii viii    PREFACE text, details, questions, examples, and a review book all in immune response to the infection? What are the specific one. conditions or mechanisms for replicating the microbe? What are all the disease characteristics and consequences? What is the epidemiology of infection? How can you prevent its • To Our Future Colleagues: disease? What is its treatment? Answering the DIVIRDEPT The Students questions will require that you jump around in the chapter to find the information, but this will help you learn the mate- On first impression, success in medical microbiology would rial. For each of the microbes, learn three to five words or appear to depend on memorization. Microbiology may seem phrases that are associated with the microbe—words that to consist of only innumerable facts, but there is also a logic will stimulate your memory (trigger words, provided in the to microbiology and immunology. Like a medical detective, new chapter summary) and organize the diverse facts into a the first step is to know your villain. Microbes establish a logical picture. Develop alternative associations. For niche in our bodies; some are beneficial and help us to digest example, this textbook presents organisms in the systematic our food and educate our immune system, while others may taxonomic structure (frequently called a “bug parade,” but cause disease. Their ability to cause disease, and the disease which the authors think is the easiest way to introduce the that may result, depend on how the microbe interacts with organisms). Take a given virulence property (e.g., toxin pro- the host and the innate and immune protective responses duction) or type of disease (e.g., meningitis) and list the that ensue. organisms that share this property. Pretend that an imagi- There are many ways to approach learning microbiology nary patient is infected with a specific agent and create the and immunology, but ultimately the more you interact with case history. Explain the diagnosis to your imaginary patient the material using multiple senses, the better you will build and also to your future professional colleagues. In other memory and learn. A fun and effective approach to learning words, do not simply attempt to memorize page after page is to think like a physician and treat each microbe and its of facts; rather, use techniques that stimulate your mind and diseases as if it were an infection in your patient. Create a challenge your understanding of the facts presented through- patient for each microbial infection, and compare and out the text and it will be more fun. Use the summary contrast the different patients. Perform role-playing and chapter at the beginning of each organism section to review ask the seven basic questions as you approach this material: and help refine your “differential diagnosis” and classify Who? Where? When? Why? Which? What? and How? For organisms into logical “boxes.” Get familiar with the text- example: Who is at risk for disease? Where does this organ- book and its bonus materials and you will not only learn the ism cause infections (both body site and geographic area)? material but also have a review book to work from in the When is isolation of this organism important? Why is this future. organism able to cause disease? Which species and genera No textbook of this magnitude would be successful are medically important? What diagnostic tests should be without the contributions of numerous individuals. We are performed? How is this infection managed? Each organism grateful for the valuable professional help and support pro- that is encountered can be systematically examined. Use the vided by the staff at Elsevier, particularly Jim Merritt, Katie following acronym to create a clinical case and learn the DeFrancesco, and Rhoda Howell. We also want to thank the essential information for each microbe: DIVIRDEPT. How many students and professional colleagues who have offered does the microbial disease present in the patient and the their advice and constructive criticism throughout the devel- differential diagnosis? How would you confirm the diagnosis opment of this eighth edition of Medical Microbiology. and identify the microbial cause of disease? What are the virulence properties of the organism that cause the disease? Patrick R. Murray, PhD; Ken S. Rosenthal, PhD; What are the helpful and harmful aspects of the innate and and Michael A. Pfaller, MD SECTION 1 INTRODUCTION CHAPTER 1 INTRODUCTION TO MEDICAL MICROBIOLOGY Imagine the excitement felt by the Dutch biologist Anton today rivals the limits of the imagination. We now know that van Leeuwenhoek in 1674 as he peered through his care- there are thousands of different types of microbes that live fully ground microscopic lenses at a drop of water and dis- in, on, and around us—and hundreds that cause serious covered a world of millions of tiny “animalcules.” Almost 100 human diseases. To understand this information and orga- years later, the Danish biologist Otto Müller extended van nize it in a useful manner, it is important to understand some Leeuwenhoek’s studies and organized bacteria into genera of the basic aspects of medical microbiology. To start, the and species according to the classification methods of microbes can be subdivided into the following four general Carolus Linnaeus. This was the beginning of the taxonomic groups: viruses, bacteria, fungi, and parasites, each having its classification of microbes. In 1840, the German pathologist own level of complexity. Friedrich Henle proposed criteria for proving that microor- ganisms were responsible for causing human disease (the “germ theory” of disease). Robert Koch and Louis Pasteur • Viruses confirmed this theory in the 1870s and 1880s with a series of elegant experiments proving that microorganisms were Viruses are the smallest infectious particles, ranging in diam- responsible for causing anthrax, rabies, plague, cholera, and eter from 18 to 600 nanometers (most viruses are < 200 nm tuberculosis. Other brilliant scientists went on to prove that and cannot be seen with a light microscope). Viruses typically a diverse collection of microbes was responsible for causing contain either deoxyribonucleic acid (DNA) or ribonucleic human disease. The era of chemotherapy began in 1910, acid (RNA) but not both; however, some viral-like particles when the German chemist Paul Ehrlich discovered the first do not contain any detectable nucleic acids (e.g., prions), antibacterial agent, a compound effective against the spiro- whereas the recently discovered Mimivirus contains both chete that causes syphilis. This was followed by Alexander RNA and DNA. The viral nucleic acids required for replica- Fleming’s discovery of penicillin in 1928, Gerhard Domagk’s tion are enclosed in a protein shell with or without a lipid discovery of sulfanilamide in 1935, and Selman Waksman’s membrane coat. Viruses are true parasites, requiring host discovery of streptomycin in 1943. In 1946, the American cells for replication. The cells they infect and the host response microbiologist John Enders was the first to cultivate viruses to the infection dictate the nature of the clinical manifesta- in cell cultures, leading the way to the large-scale production tion. More than 2000 species of viruses have been described, of virus cultures for vaccine development. Thousands of sci- with approximately 650 infecting humans and animals. Infec- entists have followed these pioneers, each building on the tion can lead either to rapid replication and destruction of the foundation established by his or her predecessors, and each cell or to a long-term chronic relationship with possible inte- adding an observation that expanded our understanding of gration of the viral genetic information into the host genome. microbes and their role in disease. The factors that determine which of these takes place are only Our knowledge of microbiology is now undergoing a partially understood. For example, infection with the human remarkable transformation founded in the rapid technologic immunodeficiency virus, the etiologic agent of the acquired advances in genome analysis. The Human Genome Project immunodeficiency syndrome (AIDS), can result in the latent was a multinational program that concluded in 2005 with infection of CD4 lymphocytes or the active replication and the comprehensive sequencing of the human genome. The destruction of these immunologically important cells. Like- techniques developed for this program have rapidly moved wise, infection can spread to other susceptible cells, such as into the research and clinical laboratories, leading to micro- the microglial cells of the brain, resulting in the neurologic bial sequencing and revealing previously unappreciated manifestations of AIDS. The virus determines the disease and insights about pathogenic properties of organisms, taxo- can range from the common cold to gastroenteritis to fatal nomic relationships, and functional attributes of the endog- catastrophes such as rabies, Ebola, smallpox, or AIDS. enous microbial population. Clearly, we are at the early stages of novel approaches to diagnostics and therapeutics based on the monitoring and manipulations of this popula- • Bacteria tion (the microbiome). The world that van Leeuwenhoek discovered was complex, Bacteria are relatively simple in structure. They are prokary- consisting of protozoa and bacteria of all shapes and sizes. otic organisms—simple unicellular organisms with However, the complexity of medical microbiology we know no nuclear membrane, mitochondria, Golgi bodies, or 2 CHAPTER 1  IntroductIon to MedIcal MIcrobIology    3 endoplasmic reticulum—that reproduce by asexual division. Our innate and immune responses evolved to protect us The bacterial cell wall is complex, consisting of one of two from infection. At the same time, the microbes that live in basic forms: a gram-positive cell wall with a thick peptido- our bodies as normal flora or disease-causing organisms glycan layer, and a gram-negative cell wall with a thin pep- must be able to withstand or evade these host protections tidoglycan layer and an overlying outer membrane. Some sufficiently long to be able to establish their niche within our bacteria lack this cell wall structure and compensate by sur- bodies or spread to new hosts. The peripheral damage that viving only inside host cells or in a hypertonic environment. occurs during the war between the host protections and The size (1 to 20 µm or larger), shape (spheres, rods, spirals), microbial invaders contributes to or may be the cause of the and spacial arrangement (single cells, chains, clusters) of the symptoms of the disease. Ultimately, the innate and immune cells are used for the preliminary classification of bacteria, responses are the best prevention and cure for microbial and the phenotypic and genotypic properties of the bacteria disease. form the basis for the definitive classification. The human body is inhabited by thousands of different bacterial species— some living transiently, others in a permanent parasitic rela- • Microbial Disease tionship. Likewise, the environment that surrounds us, including the air we breathe, water we drink, and food we One of the most important reasons for studying microbes is eat, is populated with bacteria, many of which are relatively to understand the diseases they cause and the ways to control avirulent and some of which are capable of producing life- them. Unfortunately, the relationship between many organ- threatening disease. Disease can result from the toxic effects isms and their diseases is not simple. Specifically, most of bacterial products (e.g., toxins) or when bacteria invade organisms do not cause a single well-defined disease, normally sterile body tissues and fluids. although there are certainly ones that do (e.g., Clostridium tetani [tetanus], Ebola virus [Ebola], Plasmodium species [malaria]). Instead, it is more common for a particular • Fungi organism to produce many manifestations of disease (e.g., Staphylococcus aureus—endocarditis, pneumonia, wound In contrast to bacteria, the cellular structure of fungi is more infections, food poisoning) or for many organisms to produce complex. These are eukaryotic organisms that contain a the same disease (e.g., meningitis caused by viruses, bacteria, well-defined nucleus, mitochondria, Golgi bodies, and endo- fungi, and parasites). In addition, relatively few organisms plasmic reticulum. Fungi can exist either in a unicellular can be classified as always pathogenic, although some do form (yeast) that can replicate asexually or in a filamentous belong in this category (e.g., rabies virus, Bacillus anthracis, form (mold) that can replicate asexually and sexually. Most Sporothrix schenckii, Plasmodium species). Instead, most fungi exist as either yeasts or molds; however, some fungi organisms are able to establish disease only under well- can assume either morphology. These are known as dimor- defined circumstances (e.g., introduction of an organism phic fungi and include such organisms as Histoplasma, Blas- with a potential for causing disease into a normally sterile tomyces, and Coccidioides. site such as the brain, lungs, and peritoneal cavity). Some diseases arise when a person is exposed to organisms from external sources. These are known as exogenous infections, • Parasites and examples include diseases caused by influenza virus, C. tetani, Neisseria gonorrhoeae, Coccidioides immitis, and Ent- Parasites are the most complex microbes. Although all para- amoeba histolytica. Most human diseases, however, are pro- sites are classified as eukaryotic, some are unicellular and duced by organisms in the person’s own microbial flora that others are multicellular. They range in size from tiny proto- spread to normally sterile body sites where disease can ensue zoa as small as 4 to 5 µm in diameter (the size of some (endogenous infections). bacteria) to tapeworms that can measure up to 10 meters in The interaction between an organism and the human host length and arthropods (bugs). Indeed, considering the size is complex. The interaction can result in transient coloniza- of some of these parasites, it is hard to imagine how these tion, a long-term symbiotic relationship, or disease. The organisms came to be classified as microbes. Their life cycles virulence of the organism, the site of exposure, and the host’s are equally complex, with some parasites establishing a per- ability to respond to the organism determine the outcome of manent relationship with humans and others going through this interaction. Thus the manifestations of disease can range a series of developmental stages in a progression of animal from mild symptoms to organ failure and death. The role of hosts. One of the difficulties confronting students is not only microbial virulence and the host’s immunologic response is an understanding of the spectrum of diseases caused by discussed in depth in subsequent chapters. parasites but also an appreciation of the epidemiology of The human body is remarkably adapted to controlling these infections, which is vital for developing a differential exposure to pathogenic microbes. Physical barriers prevent diagnosis and an approach to the control and prevention of invasion by the microbe; innate responses recognize molecu- parasitic infections. lar patterns on the microbial components and activate local defenses and specific adapted immune responses that target the microbe for elimination. Unfortunately, the immune • Immunology response is often too late or too slow. To improve the human body’s ability to prevent infection, the immune system can It is difficult to discuss human microbiology without also be augmented either through the passive transfer of antibod- discussing the innate and immune responses to the microbes. ies present in immune globulin preparations or through