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(BQ) Part 1 book Sherris medical microbiology presentation of content: Immune response to infection, emergence and global spread of infection, pathogenesis of viral infection, hepatitis viruses, viruses of diarrhea, papilloma and polyoma viruses, streptococci and enterococci,... and other contents.
Sixth Edition SHERRIS MEDICAL MICROBIOLOGY EDITORS KENNETH J RYAN, MD C GEORGE RAY, MD New York Chicago San Francisco Athens London Madrid Mexico City Milan New Delhi Singapore Sydney Toronto Copyright © 2014 by McGraw-Hill Education All rights reserved Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher ISBN: 978-0-07-181826-1 MHID: 0-07-181826-X The material in this eBook also appears in the print version of this title: ISBN: 978-0-07-181821-6, MHID: 0-07-181821-9 eBook conversion by codeMantra Version 1.0 All trademarks are trademarks of their respective owners Rather than put a trademark symbol after every occurrence of a trademarked name, we use names in an editorial fashion only, and to the benefit of the trademark owner, with no intention of infringement of the trademark Where 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be uninterrupted or error free Neither McGraw-Hill Education nor its licensors shall be liable to you or anyone else for any inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom McGraw-Hill Education has no responsibility for the content of any information accessed through the work Under no circumstances shall McGraw-Hill Education and/or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even if any of them has been advised of the possibility of such damages This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise EDITORS Kenneth J Ryan, MD Professor of Immunobiology Emeritus Professor of Pathology and Microbiology University of Arizona College of Medicine Tucson, Arizona C George Ray, MD Clinical Professor of Pathology and Medicine University of Arizona College of Medicine Tucson, Arizona AUTHORS Nafees Ahmad, PHD Professor of Immunobiology Director, Immunity and Infection University of Arizona College of Medicine Tucson, Arizona W Lawrence Drew, MD, PHD Emeritus Professor of Laboratory Medicine and Medicine School of Medicine University of California, San Francisco Mount Zion Medical Center San Francisco, California Michael Lagunoff, PHD Professor of Microbiology University of Washington School of Medicine Seattle, Washington Paul Pottinger, MD Associate Professor of Medicine Division of Allergy and Infectious Diseases Director, Infectious Disease and Tropical Medicine Clinic University of Washington School of Medicine Seattle, Washington L Barth Reller, MD Professor of Pathology and Medicine Duke University School of Medicine Durham, North Carolina Charles R Sterling, PHD Professor and Interim Director School of Animal and Comparative Biomedical Sciences University of Arizona Tucson, Arizona 148 PART II PATHOGENIC VIRUSES H5N1 influenza virus Epithelial cells Macrophage Virus replication and release Viral peptide Immunoreceptor Activated macrophage T cell Figure 7-5 Cytokine storm In highly virulent viruses such as bird flu virus (h5N1) or swine flu virus of 2009 (h1N1) and others, infected patients develop acute respiratory distress syndrome (arDS) caused by a cytokine storm of a healthy, competent, and robust immune system after viral infections, interferon-γ and other proinflammatory cytokines (mainly tNF-α, IL-1, and IL-6) are secreted that stimulate multiple organ systems Cytokine storm is caused by rapidly proliferating and highly activated t cells or natural killer cells, which are activated by infected macrophages Moreover, other immune components such as antigen–antibody complex, complement, CtLs and proinflammatory cytokines cause cell damage Some autoimmune diseases are initiated by viral infections because of molecular mimicry Activated T cell Uncontrolled exuberant immune response Chemoattractants proinflammatory cytokines Proinflammatory cytokines Chemoattractants proinflammatory cytokines Acute respiratory distress syndrome Necrosis Tissue destruction Influx of leukocytes Dilatation of blood vessels called molecular mimicry Both viral epitope-specific antibody and T lymphocytes may react with cognate epitopes on the host proteins, which may elicit an autoimmune response Viral proteins, such as the polymerase of hepatitis B, contain sequences similar to the encephalitogenic epitope of myelin basic protein (MBP), which is a major component of myelin sheath in the CNS Immune responses against an epitope of hepatitis B polymerase induce an immune response against MBP, initiating an autoimmune disease process Coxsackie virus infection has also been linked to autoimmune responses associated with type diabetes as a result of molecular mimicry between a viral protein and a protein found in islet cells called glutamic acid decarboxylase (GAD) ViruS-iNDuCeD iMMuNOSuPPreSSiON Viral infections can cause suppression of the immune response Viruses infecting either CD4+ helper T cells or antigen presenting cells cause immunosuppression Viral gene products can cause immunosuppression by stimulating proinflammatory cytokines Ryan_CH07_p131-150.indd 148 Viral infections, in several instances, can suppress the immune response Immunosuppression can be achieved either by direct viral replication or by viral antigens Some viruses specifically infect and kill immune cells In some instances, immunosuppression is often associated with antenatal or perinatal infections Historically, immunosuppression was first described approximately a century ago when patients lost their tuberculin sensitivity during, and weeks after, measles infection In the last decade, immunosuppression has been the topic of discussion, concern, and treatment in the HIV/AIDS epidemic because HIV specifically infects and destroys the major type of immune cells, CD4+ T lymphocytes Table 7-7 shows the mechanisms of selected human viruses causing immune suppression Several mechanisms have been proposed for virus-induced immune suppression: (1) viral replication in a major immune cells (CD4+ helper T lymphocytes) or antigen-presenting cells (dendritic cells or macrophages) leading to apoptosis; (2) viral antigens stimulating proinflammatory cytokines causing cell death; (3) tolerance generated by clonal deletion of T lymphocytes by viral antigens, generally associated with perinatal infections; and 24/01/14 11:03 AM v 14 PART I InfectIon outbreaks or recognizing new epidemiologic patterns have usually pointed the way to the isolation of new agents Epidemic spread and disease are facilitated by malnutrition, poor socioeconomic conditions, natural disasters, and hygienic inadequacy Epidemics, caused by the introduction of new organisms of unusual virulence, often result in high morbidity and mortality rates We are currently witnessing a new and extended AIDS pandemic, but the prospect of recurrence of old pandemic infections (influenza, cholera) remains Modern times and technology have introduced new wrinkles to epidemiologic spread Intercontinental air travel has allowed diseases to leap continents even when they have very short incubation periods The efficiency of the food industry has sometimes backfired when the distributed products are contaminated with infectious agents The outbreaks of hamburger-associated E coli O157:H7 bloody diarrhea and hemolytic uremic syndrome are an example The nature of massive meat-packing facilities allowed organisms from infected cattle on isolated farms to be mixed with other meat and distributed rapidly and widely By the time outbreaks were recognized, cases of disease were widespread, and tons of meat had to be recalled In simpler times, local outbreaks from the same source might have been detected and contained more quickly Of course, the most ominous and uncertain epidemiologic threat of these times is not amplification of natural transmission but the specter of unnatural, deliberate spread Anthrax is a disease uncommonly transmitted by direct contact with animals or animal products Under natural conditions, it produces a nasty, but not life-threatening, ulcer The inhalation of human-produced aerosols of anthrax spores could produce a lethal pneumonia on a massive scale Smallpox is the only disease officially eradicated from the world It took place sufficiently long ago that most of the population has never been exposed or immunized and is, thus, vulnerable to its reintroduction We not know whether infectious bioterrorism will work on the scale contemplated by its perpetrators; however, in the case of anthrax, we know that sophisticated systems have been designed to attempt it We hope never to learn whether bioterrorism will work on a large scale Each agent has its own mode of spread Poor socioeconomic conditions foster infection Modern society may facilitate spread Anthrax and smallpox are new bioterrorism threats PATHOGENESIS Pathogenicity is multifactorial Pathogens have molecules that bind to host cells Invasion requires adaptation to new environments Inflammation alone can result in injury When a potential pathogen reaches its host, features of the organism determine whether or not disease ensues The primary reason pathogens are so few in relation to the microbial world is that being a successful at producing disease is a very complicated process Multiple features, called virulence factors, are required to persist, cause disease, and escape to repeat the cycle The variations are many, but the mechanisms used by many pathogens have now been dissected at the molecular level The first step for any pathogen is to attach and persist at whatever site it gains access This usually involves specialized surface molecules or structures that correspond to receptors on human cells Because human cells were not designed to receive the microorganisms, the pathogens are often exploiting some molecule important for some other essential function of the cell For some toxin-producing pathogens, this attachment alone may be enough to produce disease For most pathogens, it just allows them to persist long enough to proceed to the next stage—invasion into or beyond the surface mucosal cells For viruses, invasion of cells is essential, because they cannot replicate on their own Invading pathogens must also be able to adapt to a new milieu For example, the nutrients and ionic environment of the cell surface differs from that inside the cell or in the submucosa Some of the steps in pathogenesis at the cellular level are illustrated in Figure 1–6 Persistence and even invasion not necessarily translate immediately to disease The invading organisms must disrupt function in some way For some, the inflammatory response they stimulate is enough For example, a lung alveolus filled with neutrophils responding to the presence of Streptococcus pneumoniae loses its ability to exchange oxygen The longer a pathogen can survive in the face of the host response, the greater the compromise in host function Most pathogens more than this Destruction of host cells through the production of digestive enzymes, toxins, or intracellular multiplication is among the more common mechanisms Other pathogens operate by altering the function of a cell without injury Diphtheria is caused by a bacterial toxin that blocks protein Chapter Emergence and Global Spread of Infection E pidemiology, the study of the distribution of determinants of disease and injury in human populations, is a discipline that includes both infectious and noninfectious diseases Most epidemiologic studies of infectious diseases have concentrated on the factors that influence acquisition and spread, because this knowledge is essential for developing methods of prevention and control Historically, epidemiologic studies and the application of the knowledge gained from them have been central to the control of the great epidemic diseases, such as cholera, plague, smallpox, yellow fever, and typhus An understanding of the principles of epidemiology and the spread of disease is essential to all medical personnel, whether their work is with the individual patient or with the community Most infections must be evaluated in their epidemiologic setting For example, what infections, especially viral, are currently prevalent in the community? Has the patient recently traveled to an area of special disease prevalence? Is there a possibility of nosocomial infection from recent hospitalization? What is the risk to the patient’s family, schoolmates, and work or social contacts? The recent recognition of emerging infectious diseases has heightened appreciation of the importance of epidemiologic information A few examples of these newly identified infections are cryptosporidiosis, hantavirus pulmonary syndrome, and severe acute respiratory syndrome (SARS) coronavirus disease In addition, some well-known pathogens have assumed new epidemiologic importance by virtue of acquired antimicrobial resistance (eg, penicillin-resistant pneumococci, vancomycin-resistant enterococci, carbapenemresistant enterobacteraciae, and multiresistant Mycobacterium tuberculosis) Over the past two decades, powerful new molecular methods have been developed that have greatly enhanced the ability to even more clearly understand the origins, evolution and spread of a wide variety of infectious agents This discipline is called molecular epidemiology The fundamental methodologies are described in Chapter 4, and their specific applications are discussed in many other chapters throughout this book Factors that increase the emergence or reemergence of various pathogens include: 23/01/14 4:04 PM Ryan_CH01_p001-018.indd 14 Influenza, ParaInfluenza, resPIratory syncytIal VIrus ubiquitous and have been found in humans, simians, rodents, cattle, and a variety of other hosts They have been studied in great detail as experimental models, revealing much basic knowledge about viral genetics and pathogenesis at the molecular level Three serotypes are known to infect humans; however, their role and importance in human disease remain uncertain Reoviruses causing arboviral diseases are discussed in Chapter 16 CHAPTER 183 85 Ryan_CH05_p085-094.indd 85 this 9-month-old boy was born prematurely, requiring treatment in a neonatal intensive care unit for the first month of life after discharge, he remained well until days ago, when symptoms of a common cold progressed to cough, rapid and labored respiration, lethargy, and refusal to eat On examination, his temperature was 38.5°C, respiratory rate 60/min, and pulse 140/min auscultation of the chest revealed coarse crackles and occasional wheezes abnormal laboratory findings included hypoxemia and hypercarbia a chest radiograph showed hyperinflation, interstitial perihilar infiltrates, and right upper lobe atalectasis QUESTIONS Which of these viruses is the least likely cause of this baby’s illness? Influenza A Parainfluenza Influenza C Respiratory syncytial virus Adenovirus MM The mechanism of “antigenic drift” in influenza viruses includes all but one of the following: A Can involve either H or N antigens B Mutations caused by viral RNA polymerase C Can predominate under selective host population immune pressures D Reassortment between human and animal or avian reservoirs E Can involve genes encoding structural or nonstructural proteins MM A B C D E Which of the following agents can be used to prevent RSV pneumonia? Amantadine Vaccine to F protein Oseltamivir Zanamivir Monoclonal antibody ANSWERS 1(C), 2(D), 3(E) Ryan_CH09_p161-184.indd 183 • Population movements and the intrusion of humans and domestic animals into new habitats, particularly tropical forests • Deforestation, with the development of new farmlands and exposure of farmers and domestic animals to new arthropods and primary pathogens • Irrigation, especially primitive irrigation systems, which fail to control arthropods and enteric organisms • Uncontrolled urbanization, with vector populations breeding in stagnant water • Increased long-distance air travel, with contact or transport of arthropod vectors and primary pathogens • Social unrest, civil wars, and major natural disasters, leading to famine and disruption of sanitation systems, immunization programs, etc Association with human disease is uncertain AN I NFA NT WIT H RES PIRATORY DIST RES S MM A B C D E 24/01/14 11:06 AM 24/01/14 10:59 AM This page intentionally left blank Contents Preface ix PA RT I Infection 1 C George Ray, L Barth Reller, and Kenneth J.Ryan Chapter Infection—Basic Concepts Chapter 10 Viruses of Mumps, Measles, Rubella, and Other Childhood Exanthems 185 Chapter 11 Poxviruses 201 Chapter 12 Enteroviruses 211 Chapter 13 Hepatitis Viruses 223 Chapter 14 Herpesviruses 245 Chapter Immune Response to Infection 19 Chapter 15 Viruses of Diarrhea 271 Chapter Sterilization, Disinfection, and Infection Control 43 Chapter 16 Arthropod-Borne and Other Zoonotic Viruses 281 Chapter 17 Rabies 301 Chapter 18 Retroviruses: Human T-Lymphotropic Virus, Human Immunodeficiency Virus, and Acquired Immunodeficiency Syndrome 309 Chapter Principles of Laboratory Diagnosis of Infectious Diseases 55 Chapter Emergence and Global Spread of Infection 85 PA RT II Pathogenic Viruses Chapter 19 Papilloma and Polyoma Viruses 333 95 Nafees Ahmad, W Lawrence Drew, and Michael Lagunoff Chapter Viruses—Basic Concepts 97 Chapter Pathogenesis of V iral Infection 131 Chapter Antiviral Agents and Resistance Chapter Influenza, Parainfluenza, Respiratory Syncytial Virus, Adenovirus, and Other Respiratory Viruses 151 161 Chapter 20 Persistent Viral Infections of the Central Nervous System 343 PART I I I Pathogenic Bacteria 351 Paul Pottinger, L Barth Reller, and Kenneth J Ryan Chapter 21 Bacteria—Basic Concepts 353 Chapter 22 Pathogenesis of Bacterial Infections 391 Chapter 23 Antibacterial Agents and Resistance 407 viii contents Chapter 24 Staphylococci 433 Chapter 25 Streptococci and Enterococci 447 Chapter 26 Corynebacterium, Listeria, and Bacillus 473 Chapter 27 Mycobacteria 489 Chapter 28 Actinomyces and Nocardia 507 Chapter 29 Clostridium, Peptostreptococcus, Bacteroides, and Other Anaerobes 515 Chapter 30 Neisseria 535 Chapter 31 Haemophilus and Bordetella 551 Chapter 32 Vibrio, Campylobacter, and Helicobacter 565 Chapter 33 Enterobacteriaceae 579 Chapter 34 Legionella and Coxiella 609 Chapter 35 Pseudomonas and Other Opportunistic Gram-negative Bacilli 617 Chapter 36 Plague and Other Bacterial Zoonotic Diseases 627 Chapter 37 Spirochetes Chapter 45 Dermatophytes, Sporothrix, and Other Superficial and Subcutaneous Fungi 719 Chapter 46 Candida, Aspergillus, Pneumocystis, and Other Opportunistic Fungi 729 Chapter 47 Cryptococcus, Histoplasma, Coccidioides, and Other Systemic Fungal Pathogens 745 PART V Pathogenic Parasites 761 Paul Pottinger and Charles R Sterling Chapter 48 Parasites—Basic Concepts 763 Chapter 49 Pathogenesis and Diagnosis of Parasitic Infection 773 Chapter 50 Antiparasitic Agents and Resistance 779 Chapter 51 Apicomplexa and Microsporidia 787 Chapter 52 Sarcomastigophora— The Amebas 813 641 Chapter 53 Sarcomastigophora— The Flagellates 823 Chapter 38 Mycoplasma 661 Chapter 54 Intestinal Nematodes 845 Chapter 39 Chlamydia 667 Chapter 55 Tissue Nematodes 863 Chapter 40 Rickettsia, Ehrlichia, Anaplasma, and Bartonella 677 Chapter 56 Cestodes 881 Chapter 57 Trematodes 895 Chapter 41 Dental and Periodontal Infections 687 PA RT IV Pathogenic Fungi 911 Practice Questions In USMLE Format 931 695 697 Glossary 943 Index 961 Kenneth J Ryan Chapter 42 Fungi—Basic Concepts Infectious Diseases: Syndromes and Etiologies Chapter 43 Pathogenesis and Diagnosis of Fungal Infection 705 Chapter 44 Antifungal Agents and Resistance 713 Preface W ith this 6th edition, Sherris Medical Microbiology enters its fourth decade We are pleased to welcome new authors, Michael Lagunoff (virology) and Paul Pottinger (antibiotics, parasitology) from the University of Washington; L Barth Reller (laboratory diagnosis, bacteriology) from Duke University; and Charles R Sterling (parasitology) from the University of Arizona Jim Plorde, an author since the first edition, is enjoying a well-deserved rest John Sherris, the founding editor, continues to act as an inspiration to all of us BOOK STRUCTURE The goal of Sherris Medical Microbiology remains unchanged from that of the first edition (1984) This book is intended to be the primary text for students of medicine and medical science who are encountering microbiology and infectious diseases for the first time Part I opens with a chapter that explains the nature of infection and the infectious agents at the level of a general reader The following four chapters give more detail on the immunologic, diagnostic, and epidemiologic nature of infection with minimal detail about the agents themselves Parts II-V form the core of the text with chapters on the major viral, bacterial, fungal, and parasitic diseases, and each begins with its own chapters on basic biology, pathogenesis, and antimicrobial agents CHAPTER STRUCTURE In the specific organism/disease chapters, the same presentation sequence is maintained throughout the book First, features of the Organism (structure, metabolism, genetics, etc) are described; then aspects of the Disease (epidemiology, pathogenesis, immunity) the organism causes are explained; the sequence concludes with the Clinical Aspects (manifestations, diagnosis, treatment, prevention) of the disease The opening of each section is marked with an icon and a snapshot of the disease(s) called the Clinical Capsule, which is placed at the juncture of the Organism and Disease sections A clinical Case Study followed by questions in USMLE format concludes each of these chapters In Sherris Medical Microbiology, the emphasis is on the text narrative, which is designed to be read comprehensively, not as a reference work Considerable effort has been made to supplement this text with other learning aids such as the above-mentioned cases and questions as well as tables, photographs, and illustrations The Glossary gives brief definitions of medical and microbiologic terms which appear throughout the book STUDY AIDS The marginal notes, a popular feature since the first edition, are nuggets of information designed as an aid for the student during review If a marginal note is unfamiliar, the relevant 680 PART III Infect vascular endothelium with resultant vasculitis and thrombosis Increased vascular permeability leads to hypotension Pathogenic Bacteria of endothelial proliferation and perivascular infiltration leading to thrombosis and leakage of red blood cells into the surrounding tissues account for the rash and petechial lesions Vascular lesions occur throughout the body and produce the systemic manifestations of the disease They are obviously most apparent in skin but most serious in the adrenal glands Orientia tsutsugamushi infects mononuclear cells but still produces fever and rash RICKETTSIAL DISEASE: CLINICAL ASPECTS SPOTTED FEVER GROUP Many tick-borne rickettsioses occur throughout the world The most important rickettsial disease in North America is Rocky Mountain spotted fever (RMSF), which is caused by Rickettsia rickettsii A number of other spotted fever rickettsioses are found in other parts of the world (Table 40–1); the name often reveals the locale (eg, Mediterranean spotted fever, Marseilles fever) They are caused by Rickettsia species, serologically related to, but distinct from, R rickettsii (eg, R conorii, R africae, etc) Another less severe spotted fever, rickettsialpox, also occurs in North America MM Rocky Mountain Spotted Fever Rocky Mountain spotted fever is an acute febrile illness that occurs in association with residential and recreational exposure to wooded areas where infected ticks exist The disease has a significant mortality rate (25%) if untreated Epidemiology Ticks naturally infected Transovarial spread perpetuates tick infection Most cases in children Rickettsia rickettsii is primarily a parasite of ticks In the western United States, the wood tick (Dermacentor andersoni) is the primary vector In the East, the dog tick (Dermacentor variabilis) is the natural carrier and vector of the disease; and in the Southwest and Midwest, the vector is the Lone Star tick (Amblyomma americanum) Recently, another dog tick, Rhipicephalus sanguineus, has been implicated in cases occurring in rural eastern Arizona Rickettsia rickettsii does not kill its arthropod host, so the parasite is passed through unending generations of ticks by transovarial spread Adult females require a blood meal to lay eggs and thus may transmit the disease Infected adult ticks have been shown to survive as long as years without feeding Rickettsia rickettsii is found in North, Central, and South America The United States has over 500 cases per year, and the highest attack rate is in the mid-Atlantic states with North Carolina being the epicenter (Figure 40–2) More than two-thirds of cases are in children younger than 15 years The illness is generally seen between April and September because of increased exposure to ticks A history of tick bite can be elicited in approximately 70% of cases Manifestations Incubation period to 14 days after tick bite Rash spreads from extremities to trunk and often involves palms and soles The incubation period between the tick bite and the onset of illness is usually to7 days, but it may be from days to weeks Fever, headache, rash, toxicity, mental confusion, and myalgia are the major clinical features The rash is the most characteristic feature of the illness, but may not occur in up to one-third of cases Rash usually develops on the second or third day of illness as small erythematous macules that rapidly become petechial (Figure 40–3) The lesions appear initially on the wrists and ankles and then spread up the extremities to the trunk in a few hours A diagnostic feature of RMSF is the frequent appearance of the rash on the palms and soles, a finding not usually seen in maculopapular eruptions associated with other infections, including typhus Muscle tenderness, especially in the gastrocnemius, is characteristic and maybe extreme If untreated, or occasionally in patients despite therapy, complications such as disseminated intravascular coagulation, thrombocytopenia, encephalitis, vascular collapse, and renal and heart failure may ensue Diagnosis Culture of rickettsiae is both difficult and hazardous Their isolation in fertile eggs or cell cultures is generally attempted only in reference centers with special facilities and personnel experienced in handling the organisms For this reason, serologic tests are the primary means of specific diagnosis A number of test systems using specific rickettsial antigens RICKETTSIA, EHRLICHIA, ANAPLASMA, AND BARTONELLA CHAPTER 40 681 Rocky Mountain Spotted fever Number of reported cases, by county — United States, 2006 1-14 >15 have been developed, of which the indirect fluorescent antibody (IFA) method is generally the most sensitive and specific This test is usually available only in reference laboratories For rapid diagnosis, examination of biopsies such as skin lesions by immunofluorescence or immunoenzyme methods to detect antigens can be used It is often difficult to establish the diagnosis of RMSF early in the course of illness However, antibodies may appear by the sixth or seventh day of illness, and a fourfold rise in antibody titer between acute serum and convalescent serum establishes the diagnosis A skin lesion biopsy may be stained with specific immunofluorescent antibody to provide rapid confirmation of the diagnosis Most often specific therapy must be started solely on the basis of clinical signs, symptoms, and epidemiologic considerations and can be life-saving FIGURE 40–3. Distribution of Rocky Mountain spotted fever Number and distribution of cases in the United States in 2006 (Reprinted with permission from Centers for Disease Control and Prevention Summary of Notifiable Diseases, MMWR 2008;55(53):63.) In-vitro cultivation is hazardous IFA method usually employed for serologic diagnosis Rising antibody titers or DFA of skin biopsy confirm diagnosis Prompt initiation of therapy based on clinical and epidemiologic features Treatment Appropriate antibiotic therapy is highly effective if given during the first week of illness If delayed into the second week or when pathologic processes such as disseminated intravascular coagulation are present, therapy may be futile The antibiotic of choice is doxycycline Sulfonamides may worsen the disease process and are thus contraindicated Before specific therapy became available, the mortality rate associated with RMSF was approximately 25% Treatment has reduced this figure to between 5% and 7% Death results primarily in patients in whom diagnosis and therapy are delayed into the second week of illness Early empirical treatment crucial Doxycycline is the treatment of choice Prevention The major means of preventing RMSF is avoidance or reduction of tick contact Frequent deticking in tick-infested areas is important, because ticks generally must feed for hours or longer before they can transmit the disease Tick surveys in the Carolinas have shown infection in about 5% of samples Killed vaccines prepared from infected ticks or rickettsiae grown in embryonated eggs and cell cultures have been developed None is licensed for clinical use at present MM Rickettsialpox Rickettsialpox was first recognized in 1946 in New York City, where an average of cases per year continue to occur It has been reported in other US cities and in eastern Europe, Korea, and South Africa It is a benign rickettsial illness caused by Rickettsia akari and transmitted by a rodent mite Distinguishing features of the disease include an eschar at the Frequent deticking, avoidance, and protective clothing is important in prevention 682 PART III Benign disease transmitted by rodent mites Local eschar followed by fever and vesicular rash Doxycycline therapy Pathogenic Bacteria site of the bite and a vesicular rash The house mouse and other semidomestic rodents are the primary reservoirs Humans acquire infection when the mite seeks an alternative host Rickettsialpox is a biphasic illness The first phase is the local lesion at the bite, which starts as a papulovesicle and develops into a black eschar in to days Fever and constitutional symptoms appear as the organism disseminates The second phase of the disease is a diffuse rash distributed randomly in the body, which, like the local lesion, becomes vesicular and develops into eschars However, the rash does not occur in palms or soles Rickettsialpox is self-limiting after week, and no deaths have been reported Doxycycline therapy shortens the course to to days TYPHUS GROUP MM Epidemic Louse-Borne Typhus Fever Severe louse-borne disease due to R prowazekii Endemic foci in the homeless population Infection involves feeding and defecation by louse Fever, headache, and rash with high mortality rate Louse control is primary prevention Primary louse-borne typhus fever is caused by Rickettsia prowazekii, which is transmitted to humans by the body louse Historically, it has appeared during times of misery (war, famine) that create conditions favorable to human body lice (crowding, infrequent bathing) This is the only rickettsial disease that can occur as an epidemic Foci of typhus persist in parts of Africa, Latin America, and Asia After the Civil War in Burundi in 1993, upwards of 100 000 cases of epidemic typhus occurred in refugees with case-fatality rates exceeding 5% In disrupted countries, the homeless population is a focus Epidemic typhus has not been seen in the United States for more than half a century Rickettsia prowazekii has been recovered from flying squirrels and their ectoparasites in the southeastern United States, and a few human cases of sylvatic typhus have occurred in these areas The chain of epidemic typhus infection starts with R prowazekii circulating in a patient’s blood during an acute febrile infection The human body louse becomes infected during one of its frequent blood meals, and after to 10 days of incubation, large numbers of rickettsiae appear in its feces Since the louse defecates while it feeds, the organisms can be rubbed into the louse bite wounds when the host scratches the site Dried louse feces are also infectious through the mucous membranes of the eye or respiratory tract The louse dies of its infection in to weeks, and the rickettsiae are not transmitted transovarially Fever, headache, and rash begin to weeks after the bite A maculopapular rash occurs in 20% to 80% of patients and appears first on the trunk and then spreads centrifugally to the extremities, a pattern opposite to that of RMSF Headache, malaise, and myalgia are prominent components of the illness Complications include myocarditis and central nervous system dysfunction In untreated disease, the fatality rate increases with age from 10% to as high as 60% The diagnostic test of choice is serology, but therapy must be initiated immediately on clinical suspicion Treatment with doxycycline is effective Louse control is the best means of prevention and is particularly important in controlling epidemics No effective vaccine is available Endemic (Murine) Typhus Transmitted by rat fleas Resembles typhus but less severe R typhi shares antigens with R prowazekii Endemic or murine typhus is caused by Rickettsia typhi and transmitted to humans by the rat flea (Xenopsylla cheopis) Human illness is incidental to the natural transmission of the disease among urban rodents, which serve as the reservoir The disease occurs worldwide but only 50 to 100 cases of murine typhus are reported in the United States each year These typically occur along the Gulf Coast of Texas and in Southern California The pathogenesis is similar to that of louse-borne typhus, but the history includes exposure to rats, rat fleas, or both The flea defecates when it takes a blood meal, and the infected feces gain access through the bite wound After an incubation period of to weeks, illness begins with headache, myalgia, and fever The rash is maculopapular, not petechial; it starts on the trunk and then spreads to the extremities in a manner similar to typhus Because of antigens shared by R typhi and R prowazekii, serologic tests may not separate the two diseases In the untreated patient, fever may last 12 to 14 days With doxycycline therapy, the course is reduced to to days Mortality and complications are rare, even if the disease is untreated Scrub Typhus Scrub typhus is found predominantly in South Asia, China, and Indonesia (the scrub typhus triangle) The causative organism is Orientia tsutsugamushi, a rickettsial organism RICKETTSIA, EHRLICHIA, ANAPLASMA, AND BARTONELLA Mites that infest rodents are the reservoir and vectors and transmit the rickettsiae to their own progeny via infected ova Humans pick up the mites as they pass by low trees or brush The mite larvae (chiggers) deposit rickettsiae as they feed The typical initial lesion, a necrotic eschar at the site of the bite on the extremities, develops in only 50% to 80% of cases Fever increases slowly over the first week, sometimes reaching 40.5°C Headache, rash, and generalized lymphadenopathy follow later The maculopapular rash, which appears after about days, is more evanescent than that seen with louse-borne or murine typhus Hepatosplenomegaly and conjunctivitis may also appear Specific diagnosis requires demonstration of a serologic response with the IFA test or polymerase chain reaction (PCR) on blood or biopsy The prognosis is good with doxycycline therapy, but the mortality rate of untreated patients is as high as 30% CHAPTER 40 683 Scrub typhus transmitted by rodent mite larvae (chiggers) Local eschar followed by fever, headache, rash, and lymphadenopathy Serologic diagnosis by IFA EHRLICHIA and ANAPLASMA Ehrlichia and Anaplasma include several species of tick-borne Gram-negative bacteria that cause animal and human disease The principal diseases are human monocytic ehrlichiosis (HME), which is due to Ehrlichia chaffeensis, and human granulocytic anaplasmosis (HGA), which is due to Anaplasma phagocytophilum The structure of these species does not include lipopolysaccharide or peptidoglycan, but they can independently carry out basic metabolic tasks such as the Krebs cycle and generation of ATP All are obligate intracellular pathogens that infect WBCs The preferred bone marrow derived lineage of WBC varies with the animal species infected In humans, Echaffeensis primarily infects mononuclear cells and A phagocytophilum polymorphonuclear cells (PMNs) They enter their preferred cell type by receptor-induced endocytosis and multiply in the endocytotic vacuole The replicative cycle includes replicative forms and denser infectious forms in inclusions (morulae) similar to those seen in Chlamydia Replication and survival is enhanced by blocking lysosomal fusion with their vacuole and resistance to killing by reactive oxygen species No toxins or other virulence factors have been described Injury in human disease is primarily related to inflammatory host responses and can be especially severe in HIV-positive patients Ehrlichia chaffeensis infections tend to occur in the southeastern and lower midwestern United States, whereas HGA tends to cluster in the northern states with a distribution similar to Lyme disease (Chapter 37) It has also been reported from other areas of the world, including Asia and Europe Human granulocytic anaplasmosis is the predominant form of ehrlichiosis and is second only to Lyme disease as a tick-borne infection in the United States Human monocytic ehrlichiosis is transmitted by deer ticks, and the white-tailed deer is the animal reservoir HGA is transmitted by Ixodes ticks, as is Lyme disease, and the animal reservoir is small mammals (eg, mice, rats, voles) The findings are clinically similar to RMSF, but rashes are less commonly seen Other ehrlichieae are shown in Table 40–1 On occasion, the diagnosis of ehrlichiosis may be suggested by observation of characteristic ehrlichial intracytoplasmic inclusions (morulae) in granulocytes (HGA) or mononuclear cells (HME) (Figure 40–4) The diagnosis is usually made serologically by a fourfold No LPS or peptidoglycan Obligate intracellular parasites of mononuclear cells or PMNs Endocytotic vacuole resists lysosomal fusion Tick-borne and WBC-associated FIGURE 40–4. Rocky Mountain spotted fever The rash begins on the arms and legs and spreads centrally (Reproduced with permission from Nester EW: Microbiology: A Human Perspective, 6th edition 2009.) 684 PART III Intracytoplasmic inclusions (morulae) in monocytes or granulocytes Treatment is doxycycline Pathogenic Bacteria or greater rise in IFA antibody or a titer greater than or equal to 1:64 to the specific antigen These tests require the assistance of specialized laboratories Another diagnostic test for detection of ehrlichia DNA is PCR Laboratory clues to human ehrlichiosis include a falling leukocyte count, thrombocytopenia, anemia, and impaired liver and renal function Doxycycline is the drug of choice for ehrlichiosis The risk of infection can be reduced by avoiding wooded areas and tick bites BARTONELLA Persist in vascular endothelial cells and RBCs Tumor-like vascular lesions filled with bacteria B quintana causes trench fever FIGURE 40–5. Ehrlichia inclusions Mononuclear cell in the cerebrospinal fluid containing Ehrlichia intracytoplasmic inclusions or morulae (arrow) (Reprinted with permission from Dunn BE, Monson TP, Dumler JS, et al Identification of Ehrlichia chaffeensis morulae in cerebrospinal fluid mononuclear cells J Clin Microbiol 1992;30:2207-2210.) Bartonella species cause a variety of diseases, the best known of which are trench fever (B quintana) and cat-scratch disease (B henselae) They are coccobacillary Gram-negative bacilli genomically most closely related to the genus Brucella (Chapter 36) Contrary to other bacteria discussed in this chapter Bartonella species can be cultured on artificial media Pathogenically they employ a unique strategy which involves persistence in an intraerythrocytic niche in both the bloodsucking arthropods that transmit them and the animals they infect The mammalian reservoirs vary with each species Upon infection Bartonella species are unable to enter erythrocytes directly but must first mature in a primary niche thought to be vascular endothelial cells Following release from the primary niche, they attach to RBCs, form pits, invade, and multiply inside Pathologically, tumor-like angiogenic lesions filled with immature capillaries, swollen endothelium, and bacteria may be produced This cycle of multiplication within two vascular cell types also shields Bartonella from both innate and adaptive immune responses Bartonella quintana causes trench fever, which has a worldwide distribution The name derives from its prominence in the trenches of World War I This disease has a reservoir in humans, and its vector is the body louse Most cases are mild or subclinical When symptomatic, the patient has sudden onset of chills, headache, relapsing fever, and a maculopapular rash on the trunk and abdomen Illness can last for to days, can recur in repeated 4- to 5-day bouts, or can persist uninterruptedly for up to weeks The disease is suggested by a history of louse contact More recently, B quintana bacteremia and endocarditis have been described in homeless alcoholic men in both France and the United States The diagnosis can be made by culturing the organism on special agar medium or by demonstrating seroconversion Bartonella bacilliformis, the first discovered Bartonella, is the cause of Oroya fever, an acute hemolytic anemia and, in its chronic phase, verruga peruana which features nodular, highly vascular skin lesions The link between the two was not known until a Peruvian medical student inoculated himself with blood from a verruga peruana lesion and tragically died from Oroya fever Infections with this agent are seen only in South America at intermediate altitudes, in keeping with the distribution of its sandfly vector Another species, B henselae, has been associated with a number of diseases, the most common of which is cat-scratch disease Cat-scratch disease is a febrile lymphadenitis with systemic symptomatology that sometimes persists for weeks to months Approximately 25 000 cases occur in the United States each year The disease is thought to be transmitted RICKETTSIA, EHRLICHIA, ANAPLASMA, AND BARTONELLA by cat scratches or bites and perhaps by the bites of cat fleas Manifestations may include skin rashes, conjunctivitis, encephalitis, and prolonged fever Occasionally, retinitis, endocarditis, and granulomatous or suppurative hepatosplenic and osseous lesions have also been seen Bartonella henselae has been isolated directly from the blood of cats, although the latter not appear ill It can also be isolated from human blood, lymph nodes, and other materials using special media Organisms can sometimes be directly demonstrated in infected tissues by using the Warthin-Starry silver impregnation stain A serologic response to B henselae antigens is the primary method of diagnosis Azithromycin or erythromycin may reduce the duration of lymph node enlargement and symptoms Bacillary angiomatosis, a proliferative disease of small blood vessels of the skin and viscera, seen in patients with AIDS and other immunocompromised hosts, has been associated with Bartonella by molecular methods Polymerase chain reaction was used to amplify ribosomal RNA gene fragments directly from tissue samples Subsequently, both B henselae and B quintana have been cultured from AIDS patients with bacillary angiomatosis Other conditions seen primarily in patients with AIDS, such as hepatitis and bacteremia with fever, have also been associated with B henselae Bartonella infections in AIDS and other immunosuppressed patients, as well as the bacteremia observed in alcoholic and homeless men, generally respond to prolonged courses of erythromycin or doxycycline Bartonella endocarditis usually requires valve replacement as well FEVER A ND R A SH F OL L OW I NG TI CK B I T E A 6-year-old girl from Nor th Carolina was in her usual state of good health until 10 days before admission, when she had a tick removed from her scalp She developed a sore throat, malaise, and a low-grade fever days after tick removal She was seen by her pediatrician when she began developing a pink, macular rash, which started on her palms and lower extremities and spread to cover her entire body The pediatrician’s diagnosis was viral exanthem One day before admission, she developed purpura, emesis, diarrhea, myalgias, and increased fever On the day of admission, she was taken to her local hospital emergency room because of mental status changes Her physical examination was significant for diffuse purpura; periorbital, hand and foot edema, cool extremities with weak pulses, and hepatosplenomegaly Her laboratory studies revealed: Na+ level of 125 mmol/L, platelet count 26 000/mm3 WBC count 14 900/ mm3, hemoglobin level of 8.8 g/L, and greatly increased coagulation times Ampicillin therapy was begun, and she was intubated but died soon after transfer to another institution QUESTIONS MM What feature in this patient’s history is most helpful? A Sore throat B Rash C Tick bite D Diarrhea E Leukocytosis MM To confirm a diagnosis of Rocky Mountain spotted fever, what would be the most useful laboratory test? A Culture B Gram stain C Serology D Darkfield examination CHAPTER 40 685 Cat-scratch disease is common in children Persistent lymphadenitis is the usual finding AIDS and other immunocompromised states are associated with more severe, protracted infections 686 PART III Pathogenic Bacteria MM The primary cause of the fatal outcome in this patient is the tropism of Rickettsia for: A Skin B WBCs C Enterocytes D Muscle E Blood vessels ANSWERS 1(C), 2(C), 3(E) Chapter 41 Dental and Periodontal Infections D ental caries, periodontitis, and the tooth loss and other sequelae that follow are secondary to the microbial build up on teeth called plaque The prevention and/or halting of the progression of these diseases relies on the elimination of dental plaque from the tooth surfaces In addition to causing caries and chronic periodontitis, the bacteria of dental plaque play a role in more aggressive forms of periodontitis and necrotizing periodontal diseases DENTAL PLAQUE Dental plaque is an adherent dental deposit that forms on the tooth surface composed almost entirely of bacteria derived from the resident flora of the mouth From a microbial pathogenesis standpoint, dental plaque is the most prevalent and densest of human biofilms (Figure 41–1) The biofilm first forms in relation to the dental pellicle, which is a physiologic thin organic film covering the mineralized tooth surface composed of proteins and glycoproteins derived from saliva and other oral secretions As the plaque biofilm evolves, it does so in relation to the pellicle, not the mineralized tooth itself The formation of plaque takes place in stages and layers at two levels The first is the anatomic location of the plaque in relation to the gingival line The earliest plaque is supragingival, which may then extend to subgingival plaque The second level is the layering within the plaque, the bacterial species involved, and the bacteria/pellicle and bacteria/bacteria binding mechanisms required The initial supragingival plaque primarily involves Gram-positive bacteria using specific ionic and hydrophobic interactions as well as lectin-like (carbohydrate binding) surface structures to adhere to the pellicle and to each other The prototype early colonizer is Streptococcus sanguis, but other streptococci (S mutans, S mitis, S salivarius, S oralis, S gordonii), lactobacilli, and Actinomyces species are usually present If the early colonizers are undisturbed, the late colonizers appear in the biofilm in as little as to days These are primarily Gram-negative anaerobes including anaerobic spirochetes These include Fusobacterium, Porphyromonas, Prevotella, Veillonella, Treponema denticola, and more Actinomyces species These bacteria use similar mechanisms to bind to the early colonizers and to each other This sets up a highly complex biofilm in which coaggregation involves structures that the bacteria brought with them (lectins), quorum sensing, and new metabolic activity An example of the latter is the formation of extracellular glucan polymers, which act like a cement binding the plaque biofilm together The biofilm also fastens nutrient and growth regulatory relationships between its members and provides a shield from the outside In all, there are thought to be 300 to 400 bacterial species present in mature dental plaque The structure of the involved bacteria is shown in Figure 41–1 and its gross and microscopic appearance in Figure 41–2 Dental plaque would coat the tooth surfaces uniformly but for its physical removal during chewing and other oral activities Characteristically, plaque remains in the non– self-cleansing areas of the teeth such as pits and fissures, along the margins of the gingiva, and between the teeth For this reason, the plaque-related diseases—caries, gingivitis, and Dental plaque is a bacterial biofilm Plaque forms in stages Attachment of bacteria to dental pellicle begins colonization Early and late colonizers differ Adhesion mechanisms create biofilm 687 688 PART III Pathogenic Bacteria Statherin Actinobacillus actinomycetemcomitans pp on em as Veillonella atypica Porphyromonas gingivalis Bacterial cell fragment ep Streptococcus oralis Salivary agglutinin Tr Streptococcus gordonii Propionibacterium acnes Tooth surface Acquired enamel pellicle Alpha-amylase Fusobacterium nucleatum Sialylated mucins Streptococcus oralis Streptococcus mitis Streptococcus sanguis s lu e hi za op en m flu a e in H ara p Bacterial cell fragment na es Streptococcus gordonii Proline-rich protein Ac tin om yc es Bacterial cell fragment lu nd i i Proline-rich protein Early colonizers Late colonizers FIGURE 41–1. Dental plaque biofilm The stages of formation of the bacterial biofilm called dental plaque are shown Early colonizers bind to the enamel pellicle and late colonizers bind to the other bacteria (Reproduced with permission from Willey JM: Prescott, Harley, & Klein’s Microbiology, 7th edition McGraw-Hill, 2008.) Plaque accumulates in non– self-cleansing areas Subgingival plaque differs in bacterial composition periodontitis—occur most frequently and most severely at these locations Subgingival plaque extends below the gum line to the sulcus around the tooth and periodontal pockets, which are pathologic extensions of the sulcus This plaque has a thin adherent layer attached to the tooth surface and a nonadherent bacterial zone between that and the epithelial cells lining the sulcus Supragingival plaque lacks such a distinct nonadherent zone The bacterial composition of subgingival plaque is shifted toward the Gram-negative anaerobic bacteria and spirochetes In addition to the late colonizers cited above, it may also include members of the Campylobacter, Capnocytophagia, and Eikenella genera Because the causative organisms of both dental caries and chronic periodontitis are believed to be in the dental plaque, a prime method for maintaining oral health is regular home care practices for plaque removal Dental plaque cannot be effectively removed from the teeth solely by chemical or enzymatic means, and the use of antibiotics for prophylactic DENTAL AND PERIODONTAL INFECTIONS A CHAPTER 41 689 B FIGURE 41–2. Dental plaque A Disclosing tablets containing vegetable dye stain heavy plaque accumulation at the junction of the tooth and gingival (Reproduced with permission from Willey JM: Prescott, Harley, & Klein’s Microbiology, 7th edition McGraw-Hill, 2008.) B Scanning electron micrograph of supragingival plaque inhibition of plaque formation cannot be clinically justified, although patients undergoing long-term antibiotic treatment for other medical reasons demonstrate a lower incidence of caries and periodontal disease Antiseptic substances that bind to tooth surfaces and inhibit plaque formation, such as the bis-biguanides, chlorhexidine, and alexidine, have been shown to be effective in reducing plaque, caries, and gingival inflammation A commercial preparation containing 0.12% chlorhexidine can be used in controlling dental plaque and associated disease Toothpaste and mouth rinse additives such as phenolic compounds, essential oils, triclosan, fluorides, herbal extracts, and quaternary ammonium compounds have been shown to have some plaque-reducing ability as well The use of these substances must be accompanied by proper tooth brushing, flossing, and periodic professional cleaning to ensure effective disease prevention Removal of plaque prime element of oral hygiene Chemicals may be used along with brushing and flossing DENTAL CARIES Dental caries are the result of progressive destruction of the mineralized tissues of the tooth They are primarily caused by the acid products of glycolytic metabolic activity when the plaque bacteria are fed the right substrate The basic characteristic of the carious lesion is that it progresses inward from the tooth surface, either the enamel-coated crown, or the cementum of the exposed root surface, involving the dentin and finally the pulp of the tooth (Figures 41–3 and 41–4) From there, infection can extend into the periodontal tissues at the root apex or apices The microbial basis of dental caries has been long established based on work first with Lactobacillus acidophilus and then Streptococcus mutans Although S mutans is now regarded as the dominant organism for the initiation of caries, multiple members of the plaque biofilm participate in the evolution of the lesions These include other streptococci (S salivarius, S sanguis, S sobrinus), lactobacilli (L acidophilus, L casei), and actinomycetes (A viscosus and A naeslundii) The acid products produced by the interaction of S mutans with multiple species in the biofilm are the underlying cause of dental caries Dietary monosaccharides and disaccharides such as glucose, fructose, sucrose, lactose, and maltose provide an appropriate substrate for bacterial glycolysis and acid production to Caries produced by plaque bacteria Members of biofilm produce acid S mutans is most cariogenic 690 PART III Pathogenic Bacteria Acquired pellicle Enamel Fusobacterium Pellicle formation Streptococci Spirochetes Lactobacili Actinomyces Acid Acid formation and caries development Initial colonization by bacteria and plaque formation FIGURE 41–3. Cariogenesis A microscopic view of pellicle and plaque formation, acidification, and destruction of tooth enamel (Reproduced with permission from Willey JM: Prescott, Harley, & Klein’s Microbiology, 7th edition McGraw-Hill, 2008.) FIGURE 41–4. Hemisected human tooth showing an advanced carious lesion on the right side of the crown and a much smaller lesion on the left side Note the progression of the lesion through the enamel and dentin, pointing toward the pulp chamber in the center of the tooth DENTAL AND PERIODONTAL INFECTIONS cause tooth demineralization A possible edge for S mutans is its ability to metabolize sucrose more efficiently than other oral bacteria It also has regulatory systems which stimulate the conversion of dietary carbohydrates to acid and intracellular storage polymers Ingested carbohydrates permeating the dental plaque are absorbed by the bacteria, and are metabolized so rapidly that organic acid products accumulate and cause the pH of the plaque to drop to levels sufficient to react with the hydroxyapatite of the enamel, demineralizing it to soluble calcium and phosphate ions Production of acid and the decreased pH are maintained until the substrate supply is exhausted Upon exhaustion of the immediate source S mutans is able to survive long periods of sugar starvation Obviously, foods with high sugar content, particularly sucrose, which adhere to the teeth and have long oral clearance times are more cariogenic than less retentive foodstuffs such as sugar-containing liquids Once the substrate is exhausted, the plaque pH returns slowly to its more neutral pH resting level and some recovery can take place This sets up a demineralization–remineralization cycle, which depends on carbohydrate refueling from the diet With repeated snacking between meals, the plaque pH may never return to normal and demineralization dominates An additional factor with sucrose is that it is also used in the synthesis of extracellular polyglycans such as dextrans and levans by transferase enzymes on the bacterial cell surfaces This polyglycan production by S mutans contributes to aggregation and accumulation of the organism on the tooth surface Extracellular polyglycan may also increase cariogenicity by serving as an extracellular storage form of substrate Certain microorganisms synthesize extracellular polyglycan when sucrose is available but then break it down into monosaccharide units to be used for glycolysis when dietary carbohydrate is exhausted Some oral bacteria also use dietary monosaccharides and disaccharides internally to form glycogen, which is stored intracellularly and used for glycolysis after the dietary substrate has been exhausted; thus, the period of acidogenesis is again prolonged and the cariogenicity of the microorganism increased These microorganisms can prolong acidogenesis beyond the oral clearance time of the substrate The most common complications of dental caries are extension of the infection into the pulp chamber of the tooth (pulpitis), necrosis of the pulp, and extension of the infection through the root canals into the periapical area of the periodontal ligament Periapical involvement may take the form of an acute inflammation (periapical abscess), a chronic nonsuppurating inflammation (periapical granuloma), or a chronic suppurating lesion that may drain into the mouth or onto the face via a sinus tract A cyst may form within the chronic nonsuppurating lesion as a result of inflammatory stimulation of the epithelial rests normally found in the periodontal ligament If the infectious agent is sufficiently virulent or host resistance is low, the infection may spread into the alveolar bone (osteomyelitis) or the fascial planes of the head and neck (cellulitis) Alternatively, it may ascend along the venous channels to cause septic thrombophlebitis Because most carious lesions represent a mixed infection by the time cavities have developed, it is not surprising that most oral infections resulting from the extension of carious lesions are mixed and frequently include anaerobic organisms Dental caries is the single greatest cause of tooth loss in the child and young adult Its onset can occur very soon after the eruption of the teeth The first carious lesions usually develop in pits or fissures on the chewing surfaces of the deciduous molars and result from the metabolic activity of the dental plaque that forms in these sites Later in childhood, the incidence of carious lesions on smooth surfaces increases; these lesions are usually found between the teeth The factors involved in the formation of a carious lesion are (1) a susceptible host or tooth, (2) the proper microflora on the tooth, and (3) a substrate from which the plaque bacteria can produce the organic acids that result in tooth demineralization The newly erupted tooth is most susceptible to the carious process It gains protection against this disease during the first year or so by a process of posteruptive maturation believed to be attributable to improvement in the quality of surface mineral on the tooth Saliva provides protection against caries, and patients with dry mouth (xerostomia) suffer from high caries attack rates unless suitable measures are taken In addition to the mechanical flushing and diluting action of saliva and its buffering capacity, the salivary glands also secrete several antibacterial products Thus, saliva is known to contain lysozyme, a thiocyanate-dependent sialoperoxidase, and immunoglobulins, principally those of the secretory IgA class The individual importance of these antibacterial factors is unknown, but they clearly play some role in determining the ecology of the oral microflora CHAPTER 41 691 Demineralization is by acid production from dietary carbohydrate Acid production facilitated by sticky carbohydrates Demineralization–remineralization related to snacking Extracellular polyglycans from sucrose important in adherence and carbohydrate storage Acidogenesis prolonged by intracellular glycogen stores Extension to pulp and periapical locations complicate infections Severe complications spread to bone or local fascia Greatest cause of tooth loss in children and young adults Require microflora and suitable substrates for organic acid production Saliva protects by mechanical flushing and multiple chemical actions 692 PART III Fluoride produces more acidresistant mineral phase of tooth Pathogenic Bacteria Proper levels of fluoride, either systemically or topically administered, result in dramatic decreases in the incidence of caries (50% to 60% reduction by water fluoridation, 35% to 40% reduction by topical application) In the case of systemic fluoridation, the protective effect is thought to result from the incorporation of fluoride ions in place of hydroxyl ions of the hydroxyapatite during tooth formation, producing a more perfect and acid-resistant mineral phase of tooth structure Topical application of fluoride is believed to achieve the same result on the surface of the tooth by initial dissolution of some of the hydroxyapatite, followed by recrystallization of apatite, which incorporates fluoride ions into its lattice structure Another important mode of action, namely, the inhibition of demineralization, and the promotion of remineralization of incipient carious lesions by fluoride ions in the oral fluid, has more recently been proposed as an important anticaries mechanism of fluoride, perhaps more important than the other proposed mechanisms In any event, fluoridation represents the most effective means known for rendering the tooth more resistant to the carious process CHRONIC PERIODONTITIS Causes destruction of supporting tissues Subgingival plaque causes collagen loss Polymicrobial anaerobic infection from subgingival plaque Synergistic interaction facilitate growth Virulence factors cause disease Chronic periodontitis causes tooth loss Plaque-induced periodontal disease encompasses two separate disease entities: gingivitis and chronic periodontitis These diseases are believed to be related, in that gingivitis, although a reversible condition, is thought to be an early stage leading ultimately to chronic periodontitis in the susceptible subject The term gingivitis is used when the inflammatory condition is limited to the marginal gingiva and bone resorption around the necks of teeth has not yet begun Gingivitis develops within weeks in individuals who fail to practice effective tooth cleansing Chronic periodontitis is used to connote the stage of chronic periodontal disease in which there is progressive loss of tooth support owing to resorption of the alveolar bone and periodontal ligament Periodontitis can also lead to periodontal abscess when the chronic inflammatory state around the necks of the teeth becomes acute at a specific location Both gingivitis and chronic periodontitis are caused by bacteria in the dental plaque that lie in close proximity to the necks of the teeth and marginal gingival tissues Thus, subgingival plaque found within the gingival crevice or the sulcus around the necks of the teeth is thought to house the etiologic agent(s) The characteristic histopathologic picture of gingivitis is of a marked inflammatory infiltrate of polymorphonuclear leukocytes, lymphocytes, and plasma cells in the connective tissue that lies immediately adjacent to the epithelium lining the gingival crevice and attached to the tooth Collagen is lost from the inflamed connective tissue There does not seem to be any direct invasion of the gingival tissues by large numbers of intact bacteria, at least in the early stages of the disease All forms of periodontitis are polymicrobial infections primarily involving anaerobic bacteria in much the same way described for other anaerobes in Chapter 29 The agents involved are derived from the predominantly Gram-negative anaerobic flora of the subgingival plaque (see previous text) led by Porphyromonas gingivalis and Treponema denticola Just as bacteria–bacteria interactions determine the plaque, cross-feeding and growth stimulation have been observed between these two organisms when grown together This kind of synergism between P gingivalis, T denticola, and other plaque members is felt to foster progression of gingivitis to chronic periodontitis Some of these organisms have also been shown to produce virulence factors similar to those associated with other invasive bacterial pathogens Treponema denticola is able to bind serum factors that interfere with complement deposition, and P gingivalis is a potent producer of extracellular proteases The former facilitates survival in tissues and the latter injury to those tissues Chronic periodontitis is responsible for most tooth loss in people older than 35 to 40 years The disease progresses slowly and results in the progressive destruction of the supporting tissues of the tooth (periodontal ligament and alveolar bone) from the margins of the gingiva toward the apices of the roots of the teeth Progression may occur as a series of acute episodes separated by quiescent periods of indeterminate duration More aggressive forms of periodontitis result in more rapid loss of tooth support Aggressive types of disease called localized aggressive periodontitis occur in adolescents, and generalized aggressive periodontitis occurs in young adults There is some evidence that the causative agents may differ in this form of periodontitis A small capnophilic (carbon dioxide-requiring) DENTAL AND PERIODONTAL INFECTIONS A CHAPTER 41 693 B FIGURE 41–5. Periodontitis A Normal gingival B Periodontal disease, with plaque, inflammatory changes, bleeding, and shortening of the gingival between the teeth (Reproduced with permission from Nester EW: Microbiology: A Human Perspective, 6th edition 2009.) Gram-negative rod (Actinobacillus actinomycetemcomitans) has been indicted based on studies of the flora of disease sites A virulence factor found in those strains of A actinomycetemcomitans that are associated with this disease is the production of a leukotoxin by the bacteria As the disease progresses, a point may be reached at which the alveolar bone around the necks of the teeth is resorbed; the condition is then no longer termed gingivitis, but periodontitis With resorption of the bone, the attachment of the periodontal ligament is lost and the gingival sulcus deepens into a periodontal pocket Periodontitis is not considered to be a reversible disease in that the lost alveolar bone and periodontal ligament not regenerate with cessation of the inflammation, even though further progression may be halted If unchecked, bone resorption progresses to loosening of the tooth, which may ultimately be exfoliated Figure 41–5 shows a case of advanced chronic periodontitis Occasionally, the neck of a periodontal pocket becomes constricted, the bacteria proliferate causing an acute inflammatory response in the occluded pocket, and a periodontal abscess results This acute exacerbation requires drainage in the same way as abscesses elsewhere for the patient to obtain symptomatic relief Acute juvenile periodontitis associated with Actinobacillus With continued progress, periodontitis and bone resorption develop Periodontal abscess may result NECROTIZING PERIODONTAL DISEASES Necrotizing ulcerative gingivitis (also called acute necrotizing ulcerative gingivitis, Vincent infection, or trench mouth) and necrotizing ulcerative periodontitis represent a spectrum of acute inflammatory disease starting with destruction limited to the soft tissues (gingivitis) and extending to destruction of the alveolar bone and periodontal ligament (periodontitis) This disease spectrum is distinctly different from gingivitis–chronic periodontitis It has an acute onset, frequently associated with periods of stress and poor oral hygiene Rapid ulceration of the interdental areas of the gingiva results in destruction of the interdental papillae The inflammatory condition initially confined to the gingival tissues can quickly extend into pathologic bone resorption Unlike gingivitis and chronic periodontitis, acute necrotizing periodontal disease is painful As the oral epithelium is destroyed, the causative bacteria come into direct contact with the underlying tissues and may invade them Spirochetes and fusiform bacteria have been implicated; thus, the term fusospirochetal disease has been used to describe this infection, which can also be manifested as ulceration in other areas of the pharynx or oral cavity Prevotella intermedia has also been found in high numbers in the lesions Morphologic studies have shown that the spirochetes actually appear to invade the tissues The disease may be treated with systemic antibiotics and topical antimicrobials for immediate relief of symptoms, but resolution depends on thorough professional cleaning of the teeth and institution of good home care Acute onset with painful ulcerative lesions Fusospirochetal etiology together with other anaerobes This page intentionally left blank ... 978-0-07 -18 1826 -1 MHID: 0-07 -18 1826-X The material in this eBook also appears in the print version of this title: ISBN: 978-0-07 -18 18 21- 6, MHID: 0-07 -18 18 21- 9 eBook conversion by codeMantra Version 1. 0... Concepts Chapter 10 Viruses of Mumps, Measles, Rubella, and Other Childhood Exanthems 18 5 Chapter 11 Poxviruses 2 01 Chapter 12 Enteroviruses 211 Chapter 13 Hepatitis Viruses 223 Chapter 14 Herpesviruses... influenzae conjugate vaccine (19 90) 200 19 00 19 20 19 40 19 60 19 80 2000 Year the experimental method The methods they developed lead to the first golden age of microbiology (18 75 -19 10), when many bacterial