Cover
Inside Cover
Title
Copyright
Foreword by Cedric Mims
Preface to the sixth edition
Acknowledgements
A contemporary approach to microbiology
Section 1: The adversaries – pathogens
Chapter 1: Pathogens as parasites
Introduction
The Varieties of Pathogens
Prokaryotes and eukaryotes
All organisms other than viruses and prions are made up of cells
Bacteria are prokaryotes; all other organisms are eukaryotes
Gram-negative bacteria have an outer lipopolysaccharide-rich layer
Microparasites and macroparasites
Microparasites replicate within the host
Organisms that are small enough can live inside cells
Living Inside or Outside Cells
Pathogens within cells are protected from many of the host’s defence mechanisms
Living outside cells provides opportunities for growth, reproduction and dissemination
Systems of Classification
Classification of bacteria and viruses
Correct identification of bacteria below the species level is often vital to differentiate pathogenic and non-pathogenic forms
Classification of viruses departs even further from the binomial system
Classification assists diagnosis and the understanding of pathogenicity
Chapter 2: The bacteria
Introduction
Structure
Bacteria are ‘prokaryotes’ and have a characteristic cellular organization
Bacteria are classified according to their cell wall as Gram-positive or Gram-negative
Many bacteria possess flagella
Pili are another form of bacterial surface projection
Nutrition
Bacteria obtain nutrients mainly by taking up small molecules across the cell wall
All pathogenic bacteria are heterotrophic
Growth and Division
A bacterial cell must duplicate its genomic DNA before it can divide
Replication must be accurate
Cell division is preceded by genome segregation and septum formation
Bacterial growth and division are important targets for antimicrobial agents
Gene Expression
Most genes are transcribed into messenger RNA (mRNA)
Transcription
Transcription is initiated at promoters
Transcription usually terminates at specific termination sites
mRNA transcripts often encode more than one protein in bacteria
Translation
Translation begins with formation of an initiation complex and terminates at a STOP codon
Transcription and translation are important targets for antimicrobial agents
Regulation of gene expression
Bacteria adapt to their environment by controlling gene expression
Expression of many virulence determinants by pathogenic bacteria is highly regulated
The most common way of altering gene expression is to change the amount of mRNA transcription
The principles of gene regulation in bacteria can be illustrated by the regulation of genes involved in sugar metabolism
Expression of bacterial virulence genes is often controlled by regulatory proteins
Many bacterial virulence genes are subject to positive regulation by ‘two-component regulators’
In some instances the pathogenic activity of bacteria specifically begins when cell numbers reach a certain threshold
Survival Under Adverse Conditions
Some bacteria form endospores
Mobile Genetic Elements
Many bacteria possess small, independently replicating (extrachromosomal) nucleic acid molecules termed plasmids and bacteriophages
Widespread use of antimicrobials has applied a strong selection pressure in favour of bacteria able to resist them
Plasmids can carry virulence genes
Plasmids are valuable tools for cloning and manipulating genes
Bacteriophages are bacterial viruses that can survive outside as well as inside the bacterial cell
Transposition
Insertion sequences are the smallest and simplest ‘jumping genes’
Transposons are larger, more complex elements, which encode multiple genes
Mobile genetic elements promote a variety of DNA rearrangements which may have important clinical consequences
Other mobile elements also behave as portable cassettes of genetic information
Mutation and Gene Transfer
Mutation
Changes in the nucleotide sequence of DNA can occur spontaneously or under the influence of external agents
Bacterial cells are not defenceless against genetic damage
Bacterial DNA repair has provided a model for understanding similar, more complex processes in humans
Gene transfer and recombination
Transformation
Some bacteria can be transformed by DNA present in their environment
Transduction
Transduction involves the transfer of genetic material by infection with a bacteriophage
Conjugation
Conjugation is a type of bacterial ‘mating’ in which DNA is transferred from one bacterium to another
The Genomics of Medically Important Bacteria
Various targeted approaches to the detection and utilization of genomic sequence information exist
Microarrays provide a more global targeted genomic analysis
DNA microarrays have been especially useful in the identification of mutations and studies on bacterial gene expression
Sequence of the entire bacterial chromosome (whole genome sequencing; WGS) represents the most global approach to genomic analysis
WGS methods continue to evolve in what has been described as generational increments
Current WGS methods have some common challenges
Major groups of bacteria
Chapter 3: The viruses
Introduction
Major Groups of Viruses
Viruses share some common structural features
The outer surface of the virus particle is the part that first makes contact with the membrane of the host cell
Infection of Host Cells
Virus particles enter the body of the host in many ways
Viruses show host specificity and usually infect only one or a restricted range of host species. The initial basis of specificity is the ability of the virus particle to attach to the host cell
Once in the host’s cytoplasm the virus is no longer infective
Replication
Viruses must first synthesize messenger RNA (mRNA)
RNA viruses produce mRNA by several different routes
Viral mRNA is then translated in the host cytoplasm to produce viral proteins
Viruses must also replicate their nucleic acid
Replication of viral DNA occurs in the host nucleus – except for poxviruses, where it takes place in the cytoplasm
The final stage of replication is assembly and release of new virus particles
Outcome of Viral Infection
Viral infections may cause cell lysis or be persistent or latent
Some viruses can ‘transform’ the host cell into a tumour or cancer cell
Tumour formation as a result of viral infection: direct and indirect mechanisms
Viral oncogenes have probably arisen from incorporation of host oncogenes into the viral genome during viral replication
Chapter 4: The fungi
Introduction
Major Groups of Disease-Causing Fungi
Importance of fungi in causing disease
Fungal pathogens can be classified on the basis of their growth forms or the type of infection they cause
Control of fungal infection
Chapter 5: The protozoa
Introduction
Protozoa can infect all the major tissues and organs of the body
Protozoa have evolved many sophisticated strategies to avoid host responses
Protozoa use a variety of routes to infect humans
Chapter 6: The helminths
Introduction
Transmission of helminths occurs in four distinct ways
The outer surfaces of helminths provide the primary host–parasite interface
Life Cycles
Many helminths have complex life cycles
The larvae of flukes and tapeworms must pass through one or more intermediate hosts, but those of nematodes can develop to maturity within a single host
Helminths and Disease
Adult tapeworms are acquired by eating undercooked or raw meat containing larval stages
The most important flukes are those causing schistosomiasis
Certain nematodes are highly specific to humans; others are zoonoses
Survival of helminths in their hosts
Chapter 7: The arthropods
Introduction
Many arthropods feed on human blood and tissue fluids
Arthropod infestation carries the additional hazard of disease transmission
Chapter 8: Prions
Introduction
‘Rogue Protein’ Pathogenesis
Prions are unique infectious agents
Prions are host-derived molecules
Development, Transmission and Diagnosis of Prion Diseases
Prions can cross species boundaries
Prion diseases are difficult to diagnose
Lessons from kuru
Prevention and Treatment of Prion Diseases
Prion diseases are incurable
Chapter 9: The host–parasite relationship
Introduction
The Microbiota and Microbiome
Identifying and understanding the microbiota and microbiome
The microbiome is acquired rapidly during and shortly after birth and changes continuously throughout life
The skin is an example of a complex microbiome due to multiple microenvironments
Both the nose and mouth can be heavily colonized by bacteria
Dental caries is one of the most common infectious diseases in developed countries
The pharynx and trachea carry their own microbiota
In the gut the density of microorganisms increases from the stomach to the large intestine
The urethra is lightly colonized in both sexes, but the vagina supports an extensive presence of bacteria and fungi
Advantages and disadvantages of the microbiota
Studies of the microbiome have confirmed the benefit of various species to the host
Studies of germ-free animals underscore the importance of the microbiota
Problems arise if members of the microbiota spread into previously sterile parts of the body
Symbiotic Associations
Commensalism, mutualism and parasitism are categories of symbiotic association
Commensalism
In commensalism, one species of organism lives harmlessly in or on the body of a larger species
Mutualism
Mutualistic relationships provide reciprocal benefits for the two organisms involved
Parasitism
In parasitism, the symbiotic relationship benefits only the parasite
The Characteristics of Parasitism
Many different groups of organisms are parasitic and all animals are parasitized
Parasitism has metabolic, nutritional and reproductive advantages
Viruses are completely dependent upon the host for all their metabolic needs
Parasite development can be controlled by the host
Disadvantages of parasitism
The Evolution of Parasitism
Bacterial parasites evolved through accidental contact
Many bacterial parasites have evolved to live inside host cells
The pathway of virus evolution is uncertain
Eukaryote parasites have evolved through accidental contact
Parasite adaptations to overcome host inflammatory and immune responses
Pressure of infection has been a major influence in host evolution
Changes in parasites create new problems for hosts
Host adaptations to overcome changes in parasites
Social and behavioural changes can be as important as genetic changes in altering host–parasite relations
Section 2: The adversaries – host defences
Chapter 10: The innate defences of the body
Introduction
The body has both ‘innate’ and ‘adaptive’ immune defences
Defences Against Entry Into the Body
A variety of biochemical and physical barriers operate at the body surfaces
Defences Once the Microorganism Penetrates the Body
Phagocytosis
Macrophages are widespread throughout the tissues
Polymorphs possess a variety of enzyme-containing granules
Phagocytosis and killing
How do phagocytes sense infection?
The phagocyte is activated through PAMP recognition
The internalized pathogen is the target for a fearsome array of killing mechanisms
Phagocytes are mobilized and targeted onto the microorganism by chemotaxis
Activation of the complement system
Complement synergizes with phagocytic cells to produce an acute inflammatory response
C9 molecules form the ‘membrane attack complex’, which is involved in cell lysis
Inflammasomes
Acute phase proteins
Other extracellular antimicrobial factors
Interferons are a family of broad-spectrum antiviral molecules
Natural killer cells attach to virally infected cells, allowing them to be differentiated from normal cells
Innate lymphoid cells (ILCs)
Eosinophils act against large parasites
Chapter 11: Adaptive immune responses bring specificity
Introduction
Lymphoid Tissues Primary and Secondary
The thymus is a highly specialized organ producing mature T cells
Secondary Lymphoid Organs
Subsets of T Cells
Why do we need so many types of T cell?
Antibody Structure and Function
Antibodies come in different classes and subclasses, with different structures and functions
Subsets of B cells
Recirculation of T and B Cells
Chapter 12: Cooperation leads to effective immune responses
Introduction
Cooperation Means Greater Efficiency
Opsonization by Antibody Enhances Phagocytosis and Leads to Complement Activation
Beneficial Inflammatory Reactions Can Also Be Enhanced by Antibodies
Activation of T Cells Involves Antigen-Presenting Cells and Additional Co-Stimulatory Signals
T cells need additional signals for activation
Complex intracellular signalling cascades follow the phosphorylation of ITAMs
T cells with a γδ TCR and other invariant T cells
Superantigens stimulate too many T cells
Clonal Expansion
Antibody Production Involves a Series of Steps Within the Germinal Centre
T-cell help for antibody production
Sometimes B cells can make antibodies without T-cell help
Monoclonal antibody technology exploits clonal expansion and transformation to produce large quantities of monoclonal antibodies
Cytokines Play an Important Part in These Cell–Cell Interactions
Immunological Memory Enables a Second Infection With the Same Microbe to Be Dealt With More Effectively
Armies Must Be Kept Under Control
Section 3: The conflicts
Chapter 13: Background to the infectious diseases
Introduction
Microbes rapidly evolve characteristics that enable them to overcome the host’s defences
Host–Parasite Relationships
The speed with which host adaptive responses can be mobilized is crucial
Adaptation by both host and parasite leads to a more stable balanced relationship
Causes of Infectious Diseases
More than 100 microbes commonly cause infection
Koch’s postulates to identify the microbial causes of specific diseases
Conclusions about causation are now reached using enlightened common sense
The Biological Response Gradient
It is uncommon for a pathogen to cause exactly the same disease in all infected individuals
Chapter 14: Entry, exit and transmission
Introduction
Receptor molecules
Exit from the body
Sites of Entry
Skin
Microorganisms gaining entry via the skin may cause a skin infection or infection elsewhere
Biting arthropods
The conjunctiva
Respiratory tract
Some microorganisms can overcome the respiratory tract’s cleansing mechanisms
Interfering with cleansing mechanisms
Avoiding destruction by alveolar macrophages
Gastrointestinal tract
Some microorganisms can survive the intestine’s defences of acid, mucus and enzymes
Crude mechanical devices for attachment
Mechanisms to counteract mucus, acids, enzymes and bile
Successful intestinal pathogens must counteract or resist mucus, acids, enzymes and bile.
Microbial exotoxin, endotoxin and protein absorption
Urogenital tract
Microorganisms gaining entry via the urogenital tract can spread easily from one part of the tract to another
Vaginal defences
Urethral and bladder defences
Mechanism of urinary tract invasion
Oropharynx
Microorganisms can invade the oropharynx when mucosal resistance is reduced
Oropharyngeal defences
Mechanisms of oropharyngeal invasion
Exit and Transmission
Microorganisms have a variety of mechanisms to ensure exit from the host and transmission
Number of microorganisms shed
Stability in the environment
Number of microorganisms required to infect a fresh host
Other factors affecting transmission
Types of Transmission Between Humans
Transmission from the respiratory tract
Respiratory infections spread rapidly when people are crowded together indoors
Transmission from the gastrointestinal tract
Intestinal infection spreads easily if public health and hygiene are poor
Transmission from the urogenital tract
Urogenital tract infections are often sexually transmitted
Sexually transmitted infections (STIs)
Semen as a source of infection
Perinatal transmission
Transmission from the oropharynx
Oropharyngeal infections are often spread in saliva
Transmission from the skin
Skin can spread infection by shedding or direct contact
Shedding to the environment
Transmission in milk
Transmission from blood
Blood can spread infection via arthropods or needles
Vertical and horizontal transmission
Vertical transmission takes place between parents and their offspring
Transmission From Animals
Humans and animals share a common susceptibility to certain pathogens
Invertebrate vectors
Insects, ticks and mites – the bloodsuckers – are the most important vectors spreading infection
Passive carriage
Biological transmission
Other invertebrate vectors spread infection either passively or by acting as an intermediate host
Transmission from vertebrates
Many pathogens are transmitted directly to humans from vertebrate animals
Domestic pets or pests?
Chapter 15: Immune defences in action
Introduction
Antimicrobial peptides protect the skin against invading bacteria
Complement
The alternative pathway and lectin-binding pathways of complement activation are part of the early defence system
Acute Phase Proteins and Pattern Recognition Receptors
C-reactive protein is an antibacterial agent produced by liver cells in response to cytokines
Collectins and ficolins
Macrophages can recognize bacteria as foreign using Toll-like receptors
Fever
It is probably unwise to generalize about the benefit or otherwise of fever
Natural Killer Cells
Natural killer cells are a rapid but non-specific means of controlling viral and other intracellular infections
NKT cells and γ δ T cells
Phagocytosis
Phagocytes engulf, kill and digest would-be parasites
Intracellular killing by phagocytes
Phagocytes kill organisms using either an oxidative or a non-oxidative mechanism
Oxidative killing
Oxidative killing involves the use of ROIs
Antimicrobial effects of ROIs
Cytotoxic lipids prolong the activity of ROIs
Non-oxidative killing
Non-oxidative killing involves the use of the phagocyte’s cytotoxic granules
Nitric oxide
Cytokines
Cytokines contribute to both infection control and infection pathology
Interferons
IFNα and IFNβ constitute a major part of the early response to viruses
Other cytokines
TNFα production can be good or bad
Antibody-Mediated Immunity
Speed, amount and duration
Affinity
Antibody classes and subclasses (isotypes)
Blocking and neutralizing effects of antibody
Immobilization and agglutination
Lysis
Opsonization
Antibody-dependent cellular cytotoxicity
Cell-Mediated Immunity
T-cell immunity correlates with control of bacterial growth in leprosy
Further evidence for the protective effects of IFNγ
Cytokine signatures
Th17 T cells
T-cell responses can be exploited in diagnostic tests for tuberculosis (TB)
Cytotoxic T lymphocytes kill by inducing ‘leaks’ in the target cell
Recovery From Infection
Nutrition may have more subtle effects on immunity to infection
Chapter 16: Spread and replication
Introduction
Features of Surface and Systemic Infections
A variety of factors determine whether an infection is a surface or a systemic infection
In systemic infections, there is a stepwise invasion of different tissues of the body
Rapid replication is essential for surface infections
Mechanisms of Spread Through the Body
Spread to lymph and blood
Invading pathogens encounter a variety of defences on entering the body
Spread from blood
The fate of microorganisms in the blood depends upon whether they are free or associated with circulating cells
Each circulating microorganism invades characteristic target organs and tissues
Spread via nerves
Certain viruses spread via peripheral nerves from peripheral parts of the body to the central nervous system and vice versa
Spread via cerebrospinal fluid
Once microorganisms have crossed the blood–cerebrospinal barrier, they spread rapidly in the cerebrospinal fluid spaces
Spread via other routes
Rapid spread from one visceral organ to another can take place via the pleural or peritoneal cavity
Genetic Determinants of Spread and Replication
The pathogenicity of a microorganism is determined by the interplay of a variety of factors
Genetic determinants in the host
The ability of a microorganism to infect and cause disease in a given host is influenced by the genetic constitution of the host
Susceptibility often operates at the level of the immune response
Genetic determinants in the pathogen
Virulence is often coded for by more than one microbial gene
Other Factors Affecting Spread and Replication
The brain can influence immune responses
Chapter 17: Parasite survival strategies and persistent infections
Introduction
Strategies to evade innate non-adaptive defences such as the phagocyte
Many pathogens target the TLR signalling pathway
Strategies to evade adaptive defences
Strategies to evade adaptive defences are more sophisticated than those for evading innate defences
Parasite Survival Strategies
Viruses are particularly good at hindering immune defences
Some pathogens are able to persist in the host for even longer
Strategies for evading host defences include causing a rapid ‘hit-and-run’ infection
Concealment of Antigens
Remaining inside cells without their antigens being displayed on the surface prevents recognition
Colonizing privileged sites keeps the pathogen out of reach of circulating lymphocytes
Cell-to-cell spread is another effective way of avoiding exposure to harmful extracellular molecules
Mimicry sounds like a useful strategy, but does not prevent the host from making an antimicrobial response
Pathogens can conceal themselves by taking up host molecules to cover their surface
Immune modulation
Infection during early embryonic life
Production of large quantities of microbial antigen or antigen–antibody complexes
Upsetting the balance between Th1 and Th2 responses
Regulatory T cells
Antigenic Variation
The best-known example of mutation is the influenza virus
The classic example of antigenic variation using gene recombination involves influenza A virus
Gene switching was first demonstrated in African trypanosomes
Gene conversion can result in the relapsing infections
Stage-specific antigens provide another useful strategy to evade immunity
Immunosuppression
Many virus infections cause a general temporary immunosuppression
Different pathogens have different immunosuppressive effects
Certain pathogen toxins are immunomodulators
Successful pathogens often interfere with signalling between immune cells, with cytotoxic T-cell recognition or with host apoptotic responses
Some pathogens interfere with the local expression of the immune response in tissues
Persistent Infections
Persistent infections represent a failure of host defences
Latent infections can become patent
Reactivation of latent infections
Reactivation is clinically important in immunosuppressed individuals
It is useful to distinguish two stages in viral reactivation
Pathogens are clever and often use a number of these evasion strategies
Chapter 18: Pathological consequences of infection
Introduction
Symptoms of infections are produced by the microorganisms or by the host’s immune responses
Pathological changes are often secondary to the activation of immunological mechanisms that are normally thought of as protective
Pathology Caused Directly by Microorganisms
Direct effects may result from cell rupture, organ blockage or pressure effects
Mode of action of toxins and consequences
Exotoxins are a common cause of serious tissue damage, especially in bacterial infection
Bacteria may produce enzymes to promote their survival or spread
Toxins may damage or destroy cells and are then known as haemolysins
Toxins may enter cells and actively alter some of the metabolic machinery
Diphtheria toxin blocks protein synthesis
Cholera toxin results in massive loss of water from intestinal epithelial cells
Tetanus and botulinum toxins are among the most potent affecting nerve impulses
Inactivation of toxins without altering antigenicity results in successful vaccines
Toxins as magic bullets
Diarrhoea
Diarrhoea is an almost invariable result of intestinal infections
Pathological Activation of Natural Immune Mechanisms
Overactivity can damage host tissues
Endotoxins are typically lipopolysaccharides
Endotoxin shock is usually associated with systemic spread of organisms
The cytokine most closely linked to disease is TNF
Complement is involved in several tissue-damaging reactions
Disseminated intravascular coagulation is a rare but serious feature of bacterial septicaemia
Pathological Consequences of the Immune Response
Overreaction of the immune system is known as ‘hypersensitivity’
Each of the four main types of hypersensitivity can be of microbial or non-microbial origin
Type I hypersensitivity
Allergic reactions are a feature of worm infections
Type II hypersensitivity
Type II reactions are mediated by antibodies to the infectious organism or autoantibodies
In blood-stage malaria, malarial antigens attach themselves to host cells
Antimyocardial antibody of group A β-haemolytic streptococcal infection is the classic autoantibody triggered by infection
Type III hypersensitivity
Immune complexes cause disease when they become lodged in tissues or blood vessels
Occupational diseases associated with inhalation of fungi are the classic examples of immune complex deposition in the tissues
Another well-known example of immune complex disease was serum sickness
Type IV hypersensitivity
Cell-mediated immune responses invariably cause some tissue destruction, which may be permanent
From the medical viewpoint, granuloma formation is the most important type IV hypersensitivity response
The clinical features of schistosomiasis are produced by cell-mediated immunity
Antibodies can also cause enhancement of pathology, as in dengue infection
Skin Rashes
A variety of skin rashes have an immunological origin
The SARS coronavirus caused lung immunopathology and T-cell loss
The hygiene hypothesis – are we too clean?
Viruses and Cancer
Human T-cell lymphotropic virus type 1 (HTLV-1) is associated with adult T-cell leukaemia / lymphoma
Epstein–Barr virus (EBV) is associated with nasopharyngeal carcinoma and lymphoma including post-transplant lymphoproliferative disease
Epstein–Barr virus is associated with Burkitt’s lymphoma
Epstein–Barr virus is also associated with Hodgkin’s lymphoma and lymphomas in immunosuppressed individuals
Certain human papillomavirus infections are associated with cervical cancer
Human papillomavirus infection is also associated with squamous cell carcinoma of the skin
Hepatitis B and hepatitis C viruses are major causes of hepatocellular carcinoma
Several DNA viruses can transform cells in which they are unable to replicate
Kaposi’s sarcoma is caused by HHV-8
Bacteria associated with cancer
Section 4: Clinical manifestation and diagnosis of infections by body system
Chapter 19: Upper respiratory tract infections
Introduction
The upper and lower respiratory tracts form a continuum for infectious agents
Generalizations can be made about upper and lower respiratory tract infections:
Rhinitis
Molecular diagnostic tests have demonstrated a much wider range of viruses that cause colds compared with older techniques
Viral co-infections are being detected using more sensitive tests
Treatment of the common cold is symptomatic
Pharyngitis and Tonsillitis
About 70% of acute sore throats are caused by viruses
Cytomegalovirus infection
Cytomegalovirus can be transmitted by saliva, urine, blood, semen and cervical secretions
Cytomegalovirus infection is often asymptomatic, but can reactivate and cause disease when cell-mediated immunity (CMI) defences are impaired
Cytomegalovirus infection can cause fetal malformations and pneumonia in immunodeficient patients
Antiviral treatment options in CMV infection
Prevention of CMV infection
Epstein–Barr virus infection
Epstein–Barr virus is transmitted in saliva
The clinical features of EBV infection are immunologically mediated
Epstein–Barr virus remains latent in a small proportion of B lymphocytes
Laboratory tests for diagnosing infectious mononucleosis should include viral capsid antigen IgM detection
Treatment of EBV infection is limited
Cancers associated with EBV
Epstein–Barr virus is closely associated with Burkitt’s lymphoma in African children
Epstein–Barr virus is closely associated with other B-cell lymphomas in immunodeficient patients
Epstein–Barr virus infection is also closely associated with nasopharyngeal carcinoma
Bacterial infections
Complications of Strep. pyogenes infection
Complications of Strep. pyogenes throat infection include quinsy, scarlet fever and rarely, rheumatic fever, rheumatic heart disease and glomerulonephritis
Diagnosis
A laboratory diagnosis is not generally necessary for pharyngitis and tonsillitis
Parotitis
Mumps virus is spread by air-borne droplets and infects the salivary glands
Treatment and prevention
Otitis and Sinusitis
Otitis and sinusitis can be caused by many viruses and a range of secondary bacterial invaders
Acute otitis media
Common causes of acute otitis media are viruses, Strep. pneumoniae and H. influenzae
Otitis externa
Causes of otitis externa are Staph. aureus, Candida albicans and Gram-negative opportunists
Acute sinusitis
Acute Epiglottitis
Acute epiglottitis is generally due to H. influenzae capsular type B infection
Acute epiglottitis is an emergency and necessitates intubation and treatment with antibiotics
Oral Cavity Infections
Saliva flushes the mouth and contains a variety of antibacterial substances
Oral candidiasis
Changes in the oral flora produced by broad-spectrum antibiotics and impaired immunity predispose to thrush
Caries
In the USA and Western Europe, 80–90% of people are colonized by Streptococcus mutans, which causes dental caries
Periodontal disease
Actinomyces viscosus, Actinobacillus and Bacteroides spp. are commonly involved in periodontal disease
Chapter 20: Lower respiratory tract infections
Introduction
Laryngitis and Tracheitis
Parainfluenza viruses are common causes of laryngitis
Diphtheria
Diphtheria is caused by toxin-producing strains of Corynebacterium diphtheriae and can cause life-threatening respiratory obstruction
Diphtheria toxin can cause fatal heart failure and a polyneuritis
Diphtheria is managed by immediate treatment with antitoxin and antibiotic
Contacts may need chemoprophylaxis or immunization
Diphtheria is prevented by immunization
Whooping Cough
Whooping cough is caused by the bacterium Bordetella pertussis
B. pertussis infection is associated with the production of a variety of toxic factors
Whooping cough is managed with supportive care and erythromycin
Whooping cough can be prevented by active immunization
Acute Bronchitis
Acute bronchitis is an inflammatory condition of the tracheobronchial tree, usually due to infection
Acute Exacerbations of Chronic Bronchitis
Infection is only one component of chronic bronchitis
Bronchiolitis
Around 75% of bronchiolitis presentations are caused by RSV infection
Respiratory Syncytial Virus (RSV) Infection
RSV is the most important cause of bronchiolitis and pneumonia in infants
RSV infection can be particularly severe in young infants
The manifestations of RSV infection appear to have an immunopathological basis
RSV RNA is detectable in throat swab specimens and ribavirin is indicated for severe disease
Hantavirus Pulmonary Syndrome (HPS)
Pneumonia
Microorganisms reach the lungs by inhalation, aspiration or via the blood
The respiratory tract has a limited number of ways in which it can respond to infection
A wide range of microorganisms can cause pneumonia
Bacterial Pneumonia
Streptococcus pneumoniae is the classic bacterial cause of acute community-acquired pneumonia
A variety of bacteria causes primary atypical pneumonia
Patients with pneumonia usually present feeling unwell and with a fever
Patients with pneumonia usually have shadows in one or more areas of the lung
Pneumonia is the most common cause of death from infection in the elderly
Sputum samples are best collected in the morning and before breakfast
The usual laboratory procedures on sputum specimens from patients with pneumonia are Gram stain and culture
Microbiological diagnosis of atypical pneumonia is usually confirmed by serology
Pneumonia is treated with appropriate antimicrobial therapy
Prevention of pneumonia involves measures to minimize exposure and pneumococcal immunization post-splenectomy and for those with sickle cell disease
Viral Pneumonia
Viruses can invade the lung from the bloodstream as well as directly from the respiratory tract
Parainfluenza Virus Infection
There are four types of parainfluenza viruses with differing clinical effects
Adenovirus Infection
Adenoviruses cause about 5% of acute respiratory tract illness overall
Human Metapneumovirus Infection
Human Bocavirus Infection
Influenza Virus Infection
Influenza viruses are classic respiratory viruses and cause endemic, epidemic and pandemic influenza
There are four types of influenza virus: A, B, C and D
The influenza virus envelope has haemagglutinin and neuraminidase spikes
Influenza viruses undergo genetic change as they spread through the host species
Transmission of influenza is by droplet inhalation
Influenzal damage to the respiratory epithelium predisposes to secondary bacterial infection
Rarely, influenza causes CNS complications
During influenza epidemics a diagnosis can generally be made clinically
Vaccines can be used to prevent influenza
Antiviral drugs can be used to treat and prevent influenza
Severe Acute Respiratory Syndrome and Middle East Respiratory Syndrome Coronavirus Infections
Reservoirs of infection
Pathogenesis may be viral as well as immune mediated
Measles Virus Infection
Secondary bacterial pneumonia is a frequent complication of measles in developing countries
Antibiotics are needed for secondary bacterial complications of measles, but the disease can be prevented by immunization
Cytomegalovirus Infection
Cytomegalovirus (CMV) infection can cause an interstitial pneumonitis in immunocompromised patients
Tuberculosis
Tuberculosis is one of the most serious infectious diseases of the resource-poor world
The pathogenesis of TB depends upon the history of previous exposure to the organism
The CMI response helps to curb further spread of M. tuberculosis
TB illustrates the dual role of the immune response in infectious disease
Primary TB is often asymptomatic
Complications of M. tuberculosis infection arise from local spread or dissemination
The Ziehl–Neelsen stain of sputum can provide a diagnosis of TB within 1 h, whereas culture can take 6 weeks
Specific antituberculosis drugs and prolonged therapy are needed to treat TB
Tuberculosis is prevented by improved social conditions, immunization and chemoprophylaxis
Cystic Fibrosis
Individuals with cystic fibrosis are predisposed to develop lower respiratory tract infections
P. aeruginosa colonizes the lungs of almost all 15- to 20-year-olds with cystic fibrosis
Lung Abscess
Lung abscesses usually contain a mixture of bacteria including anaerobes
Treatment of lung abscess should include an antianaerobic drug and last 2–4 months
Pleural effusion and empyema
Up to 50% of patients with pneumonia have a pleural effusion
Fungal Infections
Aspergillus
Aspergillus can cause allergic bronchopulmonary aspergillosis, aspergilloma or disseminated aspergillosis
Pneumocystis jirovecii (formerly P. carinii)
Pneumocystis pneumonia is an important opportunistic infection in AIDS
Protozoal Infections
A variety of protozoa localizes to the lung or involve the lung at some stage in their development
Chapter 21: Urinary tract infections
Introduction
Acquisition and Aetiology
Bacterial infection is usually acquired by the ascending route from the urethra to the bladder
The Gram-negative rod Escherichia coli is the commonest cause of ascending UTI
Viral causes of UTI appear to be rare, although there are associations with haemorrhagic cystitis and other renal syndromes
Very few parasites cause UTIs
Pathogenesis
A variety of mechanical factors predispose to UTI
Pregnancy, prostatic hypertrophy, renal calculi, tumours and strictures are the main causes of obstruction to complete bladder emptying
Catheterization is a major predisposing factor for UTI
A variety of virulence factors are present in the causative organisms
The healthy urinary tract is resistant to bacterial colonization
Clinical Features and Complications
Acute lower UTIs cause dysuria, urgency and frequency
Acute bacterial prostatitis causes systemic symptoms (fever) and local symptoms (perineal and low back pain, dysuria and frequency)
Upper UTIs
Pyelonephritis causes a fever and lower urinary tract symptoms
Laboratory Diagnosis
Infection can be distinguished from contamination by quantitative culture methods
The usual urine specimen for microbiological examination is an MSU sample
For patients with a catheter, a catheter specimen of urine is used for microbiological examination
Special urine samples are required to detect M. tuberculosis and Schistosoma haematobium
Laboratory investigations
Microscopic examination of urine allows a rapid preliminary report
A laboratory diagnosis of significant bacteriuria requires quantification of the bacteria
Interpretation of the significance of bacterial culture results depends upon a variety of factors
Treatment
Depending on clinical evaluation of the patient and local antimicrobial resistance trends, uncomplicated UTI is typically treated with an oral antibacterial for 3 days
Initial treatment of complicated UTI (pyelonephritis) usually involves a systemic antibacterial agent
Prevention
Many of the features of the pathogenesis of UTI and host predispositions are not clearly understood
Chapter 22: Sexually transmitted infections
Introduction
STIs are difficult to control
Stis and Sexual Behaviour
The spread of STIs is inextricably linked with sexual behaviour
Various host factors influence the risk of acquiring an STI
Syphilis
Syphilis is caused by the spirochete Treponema pallidum
Classically, T. pallidum infection is divided into three stages
An infected woman can transmit T. pallidum to her baby in utero
Laboratory diagnosis of syphilis
Microscopy
Serology
Non-specific tests (non-treponemal tests) for syphilis are the VDRL and RPR tests
Commonly used specific tests for syphilis include the treponemal antibody test, FTA-ABS test and the MHA-TP
Confirmation of a diagnosis of syphilis depends upon several serological tests
Treatment
Penicillin is the drug of choice for treating people with syphilis and their contacts
Gonorrhoea
Gonorrhoea is caused by the Gram-negative coccus Neisseria gonorrhoeae (the ‘gonococcus’)
The gonococcus has special mechanisms to attach itself to mucosal cells
Host damage in gonorrhoea results from gonococcal-induced inflammatory responses
Gonorrhoea is initially asymptomatic in many women, but can later cause infertility
A diagnosis of gonorrhoea is made from microscopy and culture of appropriate specimens
Antibacterials used to treat gonorrhoea are cefixime or ceftriaxone
Chlamydial Infection
C. trachomatis serotypes D–K cause sexually transmitted genital infections
Chlamydiae enter the host through minute abrasions in the mucosal surface
The clinical effects of C. trachomatis infection appear to result from cell destruction and the host’s inflammatory response
C. trachomatis can be detected directly on microscopy using the direct fluorescent antibody test
A variety of nucleic-acid-based tests are commercially available for chlamydial detection
Chlamydial infection is treated or prevented with doxycycline or azithromycin
Other Causes of Inguinal Lymphadenopathy
Lymphogranuloma venereum
Lymphogranuloma venereum is caused by C. trachomatis serotypes L1, L2 and L3
Lymphogranuloma venereum is a systemic infection involving lymphoid tissue and is treated with doxycycline or erythromycin
Chancroid (soft chancre)
Chancroid is caused by Haemophilus ducreyi and is characterized by painful genital ulcers
Chancroid is diagnosed by microscopy and culture and treated with azithromycin, ceftriaxone, erythromycin or ciprofloxacin
Donovanosis
Donovanosis is caused by Klebsiella granulomatis and is characterized by genital nodules and ulcers
Donovanosis is diagnosed by microscopy and treated with doxycycline
Mycoplasmas and Non-Gonococcal Urethritis
Mycoplasma hominis, M. genitalium and Ureaplasma urealyticum may be causes of genital tract infection
Other Causes of Vaginitis and Urethritis
Candida infection
Candida albicans causes a range of genital tract diseases, which are treated with oral or topical antifungals
Trichomonas infection
Trichomonas vaginalis is a protozoan parasite and causes vaginitis with copious discharge
Bacterial vaginosis
Bacterial vaginosis is associated with Gardnerella vaginalis plus anaerobic infection and a fishy-smelling vaginal discharge
Genital Herpes
Herpes simplex virus (HSV)-2 is the most common cause of genital herpes, but HSV-1 is being detected more frequently
Genital herpes is characterized by ulcerating vesicles that can take up to 2 weeks to heal
Genital herpes is generally diagnosed from the clinical appearance and aciclovir can be used for treatment and prophylaxis
Human Papillomavirus Infection
Many papillomavirus types are transmitted sexually and cause genital warts
Human Immunodeficiency Virus
Acquired immune deficiency syndrome (AIDS) was first recognized in 1981 in the USA
Human immunodeficiency virus that causes AIDS, was isolated from blood lymphocytes in 1983
Human immunodeficiency virus infection started in Africa between 1910 and 1930
Human immunodeficiency virus mainly infects cells bearing the CD4 glycoprotein on the cell surface and also requires chemokine co-receptors, CCR5 and CXCR4
At first the immune system fights back against HIV infection, but then begins to fail
Routes of transmission
Heterosexual transmission has not so far been as important in resource-rich as in resource-poor countries
Clinical features
Primary HIV infection may be accompanied by a mild mononucleosis-type illness
Progression to AIDS
Treatment
Antiretroviral therapy results in a dramatic improvement in disease prognosis
Antiretroviral drug resistance and improved treatment options
Treatment of AIDS involves prophylaxis and treatment of opportunist infections as well as using antiretrovirals
Laboratory tests
Laboratory tests for HIV infection involve both serological and molecular analysis
Measures to control spread
There are a number of preventative measures to reduce the spread of HIV
Vaccination
There are a number of challenges in developing a successful vaccine against HIV infection
Opportunist Stis
Opportunist STIs include salmonellae, shigellae, hepatitis A, Giardia intestinalis and Entamoeba histolytica infections
Hepatitis B virus is often transmitted sexually
Arthropod Infestations
Infection with the pubic or crab louse causes itching and is treated with permethrin shampoo
Genital scabies is also treated with permethrin cream
Chapter 23: Gastrointestinal tract infections
Introduction
Food-associated infection versus food poisoning
Diarrhoeal Diseases Caused by Bacterial or Viral Infection
Diarrhoea is the most common outcome of gastrointestinal tract infection
In the resource-poor world, diarrhoeal disease is a major cause of mortality in children
Bacterial causes of diarrhoea
Escherichia coli
There are six distinct pathotypes of E. coli with different pathogenetic mechanisms.
Enteropathogenic E. coli (EPEC) pathogens do not make any toxins.
Enterotoxigenic E. coli (ETEC) pathogens possess colonization factors (fimbrial adhesins).
Enterohaemorrhagic E. coli (EHEC) isolates produce a verotoxin.
Enteroinvasive E. coli (EIEC) pathogens attach specifically to the mucosa of the large intestine.
Enteroaggregative E. coli (EAEC) pathogens derive their name from their characteristic attachment pattern to tissue culture cells.
Diffusely adherent E. coli (DAEC) pathogens produce an alpha haemolysin and cytotoxic necrotizing factor 1.
EPEC and ETEC are the most important contributors to global incidence of diarrhoea, whereas EHEC is more important in resource-rich countries.
Specific tests are needed to identify strains of pathogenic E. coli.
Antibiotic therapy is not indicated for E. coli diarrhoea.
Salmonella
Salmonellae are the most common cause of food-associated diarrhoea in many resource-rich countries.
Salmonellae are almost always acquired orally in food or drink that is contaminated with human faeces.
Salmonella diarrhoea can be diagnosed by culture on selective media.
Fluid and electrolyte replacement may be needed for Salmonella diarrhoea.
Salmonellae may be excreted in the faeces for several weeks after a salmonella infection.
Campylobacter
Campylobacter infections are among the most common causes of diarrhoea.
Campylobacter diarrhoea is clinically similar to that caused by other bacteria such as Salmonella and Shigella.
Cultures for Campylobacter should be set up routinely in every investigation of a diarrhoeal illness.
Azithromycin is used for severe Campylobacter diarrhoea.
Cholera
Cholera flourishes in communities with inadequate clean drinking water and sewage disposal.
V. cholerae is classified into more than 200 serogroups based on the somatic (O) antigens of the lipopolysaccharide.
The symptoms of cholera are caused by an enterotoxin.
Culture is necessary to diagnose sporadic or imported cases of cholera and carriers.
Prompt rehydration with fluids and electrolytes is central to the treatment of cholera.
Cholera vaccines are not recommended for most travellers.
Shigellosis
Symptoms of Shigella infection range from mild to severe gastroenteritis, depending upon the infecting species.
Shigella diarrhoea is usually watery at first, but later contains mucus and blood.
Culture and serological typing are helpful in distinguishing Shigella from E. coli.
Antibiotics should be given only for severe Shigella diarrhoea.
Other bacterial causes of diarrhoeal disease
V. parahaemolyticus and Yersinia enterocolitica are food-borne Gram-negative causes of diarrhoea.
Clostridium perfringens and Bacillus cereus are spore-forming Gram-positive rods that cause diarrhoea.
Food Poisoning – Bacterial Toxin-Associated Diarrhoea
Staphylococcus aureus
Enterotoxigenic strains of Staph. aureus are associated with food-borne illness
Botulism
Exotoxins produced by C. botulinum cause botulism, which has a mortality rate of about 10%
Infant botulism is the most common form of botulism
Considering botulism in the differential diagnosis is key and then confirming by laboratory diagnosis
Polyvalent antitoxin is recommended as an adjunct to intensive supportive therapy for botulism
Antibiotic-associated diarrhoea – Clostridium difficile
Treatment with broad-spectrum antibiotics can be complicated by antibiotic-associated C. difficile diarrhoea
Viral Causes of Diarrhoea
Huge reductions have been seen in diarrhoeal deaths, especially in under-5-year-olds
Noroviruses
The most common cause of diarrhoea worldwide, causing nearly 20% of all diarrhoea episodes
Rotaviruses
Replicating rotavirus causes diarrhoea by damaging transport mechanisms in the gut
Rotavirus infection is confirmed by viral RNA or antigen detection
Fluid and salt replacement can be life saving in rotavirus diarrhoea
Other viruses causing diarrhoea in humans include sapoviruses, astroviruses, adenoviruses and coronaviruses
Helicobacter Pylori and Gastric Ulcer Disease
Helicobacter pylori is associated with most duodenal and gastric ulcers
Parasites and the Gastrointestinal Tract
Transmission of intestinal parasites is maintained by the release of life cycle stages in faeces
Protozoan infections
Entamoeba histolytica
E. histolytica infection is particularly common in subtropical and tropical countries.
E. histolytica infection may cause mild diarrhoea or severe dysentery.
E. histolytica infection can be diagnosed in asymptomatic patients from the presence of characteristic four-nucleate cysts in the stool.
Acute E. histolytica infection can be treated with metronidazole or tinidazole.
Giardia intestinalis
Like Entamoeba, Giardia has only two life cycle stages.
Mild Giardia infections are asymptomatic; more severe infections cause diarrhoea.
Diagnosis of Giardia infection is based on identifying cysts or trophozoites in the stool.
Giardia infection can be treated with a variety of drugs.
Cryptosporidium hominis and Cryptosporidium parvum
The protozoan genus Cryptosporidium is widely distributed in many animals.
Cryptosporidial diarrhoea ranges from moderate to severe.
Routine faecal wet preparation examinations are inadequate for diagnosing cryptosporidial diarrhoea.
Antiparasitic treatment for cryptosporidial diarrhoea is suboptimal.
Cyclospora, Cystoisospora and the microsporidia
‘Minor’ intestinal protozoa
Worm infections
The most important intestinal worms clinically are the nematodes known as the soil-transmitted helminths
Life cycle and transmission
Female Ascaris and Trichuris lay thick-shelled eggs in the intestine, which are expelled with faeces and hatch after being swallowed by another host.
Adult female hookworm lay thin-shelled eggs that hatch in the faeces shortly after leaving the host.
The adult female Strongyloides lays eggs that hatch in the intestine.
Clinical features
Large numbers of adult Ascaris worms can cause intestinal obstruction.
Moderate to severe Trichuris infection can cause chronic diarrhoea.
Hookworm disease can result in iron-deficiency anaemia.
Strongyloidiasis can be fatal in immunosuppressed people.
Laboratory diagnosis
The eggs of Ascaris, Trichuris and hookworm are characteristic.
Pinworm infection is diagnosed by finding eggs on perianal skin.
Treatment and prevention
Other intestinal worms
Many other worm species can infect the intestine, but most are uncommon in resource-rich countries.
Systemic Infection Initiated in the Gastrointestinal Tract
Enteric fevers: typhoid and paratyphoid
S. typhi and paratyphi types S. paratyphi A, S. schottmuelleri (previously named S. paratyphi B) and S. hirschfeldii (previously named S. paratyphi C) cause enteric fevers
The salmonellae multiply within and are transported around the body in macrophages
Rose spots on the upper abdomen are characteristic, but absent in up to half of patients with enteric fever
Before antibiotics, 12–16% of patients with enteric fever died, usually of complications
One to three percent of patients with enteric fever become chronic carriers
Diagnosis of enteric fever depends upon isolating S. typhi or paratyphi types using selective media
Antibiotic treatment should be started as soon as enteric fever is diagnosed
Prevention of enteric fever involves public health measures, treating carriers and vaccination
Listeriosis
Listeria infection is associated with pregnancy and reduced immunity
Viral hepatitis
An alphabetical litany of viruses directly target the liver, from hepatitis A to E
Hepatitis A
HAV is transmitted by the faecal–oral route
Clinically, hepatitis A is milder in young children than in older children and adults
Hepatitis E
Hepatitis E virus (HEV) spreads by the faecal–oral route
Hepatitis B
HB surface antigen can be found in blood and other body fluids
HBV is not directly cytopathic for liver cells, and the pathology is largely immune mediated
Certain groups of people are more likely to become carriers of hepatitis B
Complications of hepatitis B are cirrhosis and hepatocellular carcinoma
Serological tests are used in the diagnosis of HBV infection
The range of antiviral therapy has widened
Hepatitis B infection can be prevented by immunization
Hepatitis C
Hepatitis C virus was the most common cause of transfusion-associated non-A-non-B viral hepatitis
HCV transmission routes share similarities with hepatitis B
About 75–85% of HCV-infected individuals develop chronic HCV
Direct-acting antivirals (DAA) have revolutionized HCV treatment in a short time period
Hepatitis D
Hepatitis D virus can multiply only in a cell infected with HBV
Spread of HDV is similar to that of HBV and HBC
Viral hepatitis, the rest of the alphabet
Parasitic infections affecting the liver
Inflammatory responses to the eggs of Schistosoma mansoni result in severe liver damage
Liver abscesses
Despite the name, an amoebic liver abscess does not consist of pus
Biliary tract infections
Infection is a common complication of biliary tract disease
Peritonitis and intra-abdominal sepsis
Peritonitis is generally classified as primary (without apparent source of infection) or secondary (e.g. due to perforated appendicitis, ulcer, colon)
Chapter 24: Obstetric and perinatal infections
Introduction
Infections Occurring in Pregnancy
Immune and hormonal changes during pregnancy worsen or reactivate certain infections
The fetus has poor immune defences
Congenital Infections
Intrauterine infection may result in death of the fetus or congenital malformations
Congenital rubella
The fetus is particularly susceptible to rubella infection when maternal infection occurs during the first 3 months of pregnancy
Congenital rubella can affect the eye, heart, brain and ear
Fetal rubella IgM is found in cord and infant blood
Congenital rubella can be prevented by vaccination
Congenital CMV infection
Mothers with a poor T-cell proliferative response to CMV antigens are more likely to infect their fetus
Zika virus
Congenital syphilis
Congenital toxoplasmosis
Acute asymptomatic infection by Toxoplasma gondii during pregnancy can cause fetal malformation
Congenital Chagas disease
Congenital human immunodeficiency virus (HIV) infection
In resource-poor countries, approximately one-quarter of infants born to mothers with HIV are infected: about one-third of these in utero and the rest perinatally
Congenital and neonatal listeriosis
Maternal exposure to animals or foods infected with Listeria can lead to fetal death or malformations
Infections Occurring Around the Time of Birth
Effects on the fetus and neonate
The routes of infection in the fetus and neonate are shown in Fig. 24.5
Neonatal septicaemia often progresses to meningitis
Fetal infection with HSV must be considered in a baby who is acutely ill within a few days or weeks of birth
Effects on the mother
Puerperal sepsis is prevented by aseptic techniques
Other neonatal infections
Chapter 25: Central nervous system infections
Introduction
Invasion of the Central Nervous System
Natural barriers act to prevent blood-borne invasion
Invasion of the CNS via peripheral nerves is a feature of herpes simplex, varicella-zoster and rabies virus infections
The Body’s Response to Invasion
CSF cell counts increase in response to infection
The pathological consequences of CNS infection depend upon the microorganism
CNS invasion only rarely assists in the transmission of infection
Meningitis
Bacterial meningitis
Acute bacterial meningitis is a life-threatening infection, needing urgent specific treatment
Meningococcal meningitis
Neisseria meningitidis is carried by about 20% of the population, but higher rates are seen in epidemics.
Clinical features of meningococcal meningitis include a haemorrhagic skin rash.
A diagnosis of acute meningitis is usually suspected on clinical examination.
Haemophilus meningitis
Type b H. influenzae causes meningitis in infants and young children.
Acute H. influenzae meningitis is commonly complicated by severe neurological sequelae.
H. influenzae type b (Hib) vaccine is effective for children from 2 months of age.
Pneumococcal meningitis
Streptococcus pneumoniae is a common cause of bacterial meningitis, particularly in children and the elderly.
Listeria monocytogenes meningitis
Listeria monocytogenes causes meningitis in immunocompromised adults.
Neonatal meningitis
Although mortality rates due to neonatal meningitis in resource-rich countries are declining, the problem is still serious.
Tuberculous meningitis
Tuberculous meningitis usually presents with a gradual onset over a few weeks.
Fungal meningitis
Cryptococcus neoformans meningitis is seen in patients with depressed cell-mediated immunity
Coccidioides immitis infection is common in particular geographical locations
Protozoal meningitis
Viral meningitis
Viral meningitis is the most common type of meningitis
Encephalitis
Encephalitis is usually caused by viruses, but there are many cases where the infectious aetiology is not identified
HSV encephalitis (HSE) is the most common form of severe sporadic acute focal encephalitis and early aciclovir treatment is critical
Other herpesviruses less commonly cause encephalitis
Enteroviral infections
Enterovirus 71-associated hand, foot and mouth epidemic resulted in a high rate of neurological complications
Poliovirus used to be a common cause of encephalitis
Paramyxoviral infections
Mumps virus is a common cause of mild encephalitis
Nipah virus encephalitis, a zoonotic paramyxovirus infection
Rabies encephalitis
More than 55 000 people die of rabies worldwide each year
Clinical features of rabies include muscle spasms, convulsions and hydrophobia
Rabies can be diagnosed by detecting viral antigen or RNA
After exposure to a possibly infected animal, immediate preventive action should be taken
Togavirus meningitis and encephalitis
Numerous arthropod-borne togaviruses can cause meningitis or encephalitis
Flavivirus infections
Japanese encephalitis virus infection is an important cause of encephalitis in South East Asia and mostly affects children
West Nile virus infection swept rapidly through the USA after the initial reports
HIV meningitis and encephalitis
HIV can cause subacute encephalitis, often with dementia
Viral myelopathy
Guillain–Barré syndrome – an inflammatory demyelinating condition of the peripheral nervous system
Post-infectious encephalitis
Encephalitis following viral infection or vaccination possibly has an autoimmune basis
Neurological Diseases of Possible Viral Aetiology
Spongiform Encephalopathies Caused by Scrapie-Type Agents
Scrapie-type agents are closely associated with host-coded prion protein
CNS Disease Caused by Parasites
The CNS is an important target in toxoplasmosis
Cerebral malaria is a major killer
Toxocara infection can result in granuloma formation in the brain and retina
Cystic hydatid disease is characterized by cyst formation, potentially in any organ but most commonly in the liver
Cysticercosis is characterized by cyst formation in the brain and eye
Sleeping sickness is a trypanosomal infection that is being better controlled
Diagnosis is made by microscopy carried out by skilled, experienced staff and treatment is complex
Brain Abscesses
Brain abscesses are usually associated with predisposing factors
Tetanus and Botulism
Tetanus
Cl. tetani toxin is carried to the CNS in peripheral nerve axons
Clinical features of tetanus include muscle rigidity and spasms
Human antitetanus immunoglobulin should be given as soon as tetanus is suspected clinically
Botulism
Cl. botulinum toxin blocks acetylcholine release from peripheral nerves
Clinical features of botulism include weakness and paralysis
Botulism is treated with antibodies and respiratory support
Chapter 26: Infections of the eye
Introduction
Conjunctivitis
Chlamydial infections
Different serotypes of Chlamydia trachomatis cause inclusion conjunctivitis and trachoma
Two million people worldwide are visually impaired because of trachoma
Chlamydial infections are treated with antibiotic and prevented by face washing
Other conjunctival infections
In resource-rich countries, conjunctivitis is caused by a variety of bacteria
Direct infection of the eye may be associated with wearing contact lenses
Conjunctival infection may be transmitted by the blood or nervous system
Infection of the Deeper Layers of the Eye
Entry into the deeper layers occurs by many routes
Toxoplasmosis
Toxoplasma gondii infection can cause retinochoroiditis leading to blindness
Parasitic worm infections
Toxocara canis larvae cause an intense inflammatory response and can lead to retinal detachment
Onchocerca volvulus infection causes ‘river blindness’ and is transmitted by Simulium flies
Chapter 27: Infections of the skin, soft tissue, muscle and associated systems
Introduction
Infections of the skin
Microbial disease of the skin may result from any of three lines of attack
Bacterial Infections of Skin, Soft Tissue and Muscle
These can be classified on an anatomic basis
Staphylococcal skin infections
Staphylococcus aureus is the most common cause of skin infections and provokes an intense inflammatory response
Staph. aureus infections are often diagnosed clinically and treatment includes drainage and antibiotics
Staphylococcal scalded skin syndrome is caused by toxin-producing Staph. aureus
Toxic shock syndrome is caused by toxic shock syndrome toxin-producing Staph. aureus
Streptococcal skin infections
Streptococcal skin infections are caused by Strep. pyogenes (group A streptococci)
Clinical features of streptococcal skin infections are typically acute
M protein is a major virulence factor in Strep. pyogenes with over 100 types, some of which (e.g. M49) are specifically associated with diseases such as acute glomerulonephritis
Streptococcal skin infections are usually diagnosed clinically and treated with penicillin
Cellulitis and gangrene
Cellulitis is an acute spreading infection of the skin that involves subcutaneous tissues
Anaerobic cellulitis may develop in areas of traumatized or devitalized tissue
Synergistic bacterial gangrene is a relentlessly destructive infection
Necrotizing fasciitis, myonecrosis and gangrene
Necrotizing fasciitis is a frequently fatal mixed infection caused by anaerobes and facultative anaerobes
Traumatic or surgical wounds can become infected with Clostridium species
Amputation may be necessary to prevent further spread of clostridial infection
Propionibacterium acnes and acne
P. acnes go hand in hand with the hormonal changes of puberty which result in acne
Treatment of acne includes long-term administration of oral antibiotics
Mycobacterial Diseases of the Skin
Leprosy
Leprosy is decreasing in incidence but still remains a concern
Leprosy is caused by Mycobacterium leprae
The clinical features of leprosy depend upon the cell-mediated immune response to M. leprae
M. leprae are seen as acid-fast rods in nasal scrapings and lesion biopsies
Treatment
Leprosy is treated with dapsone given as part of a multidrug regimen to avoid resistance
Other mycobacterial skin infections
Mycobacterium marinum, M. ulcerans and M. tuberculosis also cause skin lesions
Fungal Infections of the Skin
Superficial and cutaneous mycoses
Pityriasis versicolor
M. furfur is the cause of pityriasis or tinea versicolor
Diagnosis of pityriasis versicolor can be confirmed by direct microscopy of scrapings
Cutaneous dermatophytes
Dermatophyte infections are acquired from many sources and are spread by arthrospores
Dermatophytes invade skin, hair and nails
Most dermatophyte species fluoresce under ultraviolet light
Dermatophyte infections are treated topically if possible
Candida and the skin
Candida requires moisture for growth
Subcutaneous mycoses
Subcutaneous fungal infections can be caused by a number of different species
Sporotrichosis is a nodular condition caused by Sporothrix schenckii
Mycetoma
Systemic fungal infections with skin manifestations include blastomycosis, coccidioidomycosis and cryptococcosis
Parasitic Infections of the Skin
Leishmaniasis may be cutaneous or mucosal (formerly termed mucocutaneous)
Schistosome infection can cause a dermatitis
Cutaneous larval migrans is characterized by itchy inflammatory hookworm larvae trails
Onchocerciasis is characterized by hypersensitivity responses to larval antigens
Arthropod infections
Some flies, mainly in the tropics and subtropics, have larvae that develop within the skin
Certain ticks, lice and mites live on blood or tissue fluids from humans
Mucocutaneous Manifestations of Viral Infections
Papillomavirus infection
Over 120 different types of papillomavirus can infect humans and are species specific
Papillomavirus infects cells in the basal layers of skin or mucosa and are tissue tropic
Papillomavirus infections are associated with cancer of the cervix, vulva, penis, rectum, head, and neck
Diagnosis of papillomavirus infection is clinical and there are many treatments
Molluscum contagiosum is an umbilicated lesion caused by a poxvirus
Orf is a papulovesicular lesion caused by a poxvirus
Herpes simplex virus infection
Herpes simplex virus infections are ubiquitous
Clinical features of HSV infection include painful vesicles and a latency state
HSV reactivation is provoked by a variety of factors
HSV DNA can be detected in vesicle fluid and infection is treated with aciclovir
Varicella-zoster virus infection
Varicella-zoster virus (VZV) infections are highly infectious and cause chickenpox (varicella) and zoster (shingles)
Varicella is characterized by crops of vesicles that develop into pustules and then scab over
Varicella is usually more severe and more likely to cause complications in adults
Zoster results from reactivation of latent VZV
Postherpetic neuralgia is a common complication of zoster
Laboratory diagnosis of VZV
Treatment of varicella and zoster infection
Rashes caused by enteroviruses
Coxsackieviruses and echoviruses cause a variety of exanthems (skin rashes)
Rashes caused by human parvovirus B19
Parvovirus B19 causes slapped cheek syndrome
Symptomless parvovirus B19 infection is common and spreads by respiratory droplets
Rashes caused by human herpesviruses-6 and -7
Human herpesvirus-6 (HHV-6) is present in the saliva of over 85% of adults and causes roseola infantum
Human herpesvirus-7 (HHV-7) is acquired slightly later in early childhood
Human herpesvirus-8 (HHV-8) is associated with all forms of Kaposi’s sarcoma skin lesions
Smallpox Virus Infection
Global smallpox eradication was officially certified in December 1979
Global eradication of smallpox was possible for a variety of reasons
Measles Virus Infection
Aetiology and transmission
Measles outbreaks occur every few years in unvaccinated populations
Clinical features of measles include respiratory symptoms, Koplik’s spots and a rash
Measles rash results from a cell-mediated immune response
Complications of measles are particularly likely among children in resource-poor countries
Diagnosis, treatment and prevention
Measles is usually diagnosed clinically; ribavirin can be used as antiviral treatment if clinically indicated and there is a safe and effective vaccine
Rubella Virus Infection
Rubella virus infection causes a multisystem infection, but its main impact is on the fetus
Rubella is diagnosed in the laboratory; there is no treatment, but there is a vaccine
Other Maculopapular Rashes Associated With Travel-Related Infections
Other Infections Producing Skin Lesions
Other bacterial, fungal and rickettsial infections produce a variety of rashes or other skin lesions
Kawasaki Syndrome
Kawasaki syndrome is an acute vasculitis and is probably caused by superantigen toxins
Viral Infections of Muscle
Viral myositis, myocarditis and pericarditis
Some viruses, particularly coxsackievirus B, cause myocarditis and myalgia
Postviral fatigue syndrome
It has been difficult to establish postviral fatigue syndrome as a clinical entity
Parasitic Infections of Muscle
Trypanosoma cruzi infection
Trypanosoma cruzi is a protozoan and causes Chagas disease
Chagas disease is complicated by cardiac conduction disorders, ventricular aneurysm formation or heart failure many years later
Taenia solium infection
The larval stages of Taenia solium invade body tissues
Trichinella infection
The larvae of Trichinella invade striated muscle
Sarcocystis
Sarcocystis is a rare muscle parasite
Joint and Bone Infections
Reactive arthritis, arthralgia and septic arthritis
Arthralgia and arthritis occur in a variety of infections and are often immunologically mediated
Circulating bacteria sometimes localize in joints, especially following trauma
Osteomyelitis
Bone can become infected by adjacent infection or haematogenously
Osteomyelitis is treated with antibiotics and sometimes surgery
Infections of the Haemopoietic System
Many infectious agents cause changes in circulating blood cells
Human T-lymphotropic virus type 1 infection
HTLV-1 is mainly transmitted by maternal milk
HTLV-1 infects T cells and up to 5% of those infected develop T-cell leukaemia
HTLV-2 infection
Chapter 28: Vector-borne infections
Introduction
Transmission of disease by vectors
In sparsely populated areas, transmission by insects is an effective means of spread
Arbovirus Infections
Arboviruses are arthropod-borne viruses
Only a small number of arboviruses are important causes of human disease
Yellow fever
Yellow fever virus is transmitted by mosquitoes and is restricted to Africa, Central and South America and the Caribbean
Clinical features of yellow fever may be mild, but in 10–20% of cases classic yellow fever with liver damage occurs, which can prove fatal
Clinical diagnosis is unreliable; there is no specific treatment, but there is a vaccine
Dengue fever
Dengue virus is transmitted by mosquitoes and occurs in SE Asia, the Pacific area, India, South and Central America
Dengue fever may be complicated by dengue haemorrhagic fever / dengue shock syndrome
Chikungunya virus infection (CHIKV)
Zika virus
Arbovirus encephalitis
The encephalitic arboviruses only occasionally cause encephalitis
Arboviruses and haemorrhagic fevers
Arboviruses are major causes of fever in endemic areas of the world
Infections Caused by Rickettsiae
The rickettsiae are small bacteria and infections tend to be persistent or become latent
Typical clinical symptoms of rickettsial infection are fever, headache and rash
Laboratory diagnosis is based on serological tests
All rickettsiae are susceptible to tetracyclines
Rocky Mountain spotted fever
Rocky Mountain spotted fever is transmitted by dog ticks and has a mortality of 10% or more
Mediterranean spotted fever
Mediterranean spotted fever is transmitted by dog ticks
African tick-bite fever
Rickettsialpox
Rickettsialpox is a mild infection
Epidemic typhus
Epidemic typhus is transmitted by the human body louse
Untreated epidemic typhus has a mortality as high as 60%
Endemic (murine) typhus
Scrub typhus
Borrelia Infections
Relapsing fever
The epidemic form of relapsing fever is caused by Borrelia recurrentis, which is transmitted by human body lice
The endemic form of relapsing fever in humans is transmitted by tick bites
Relapsing fever is characterized by repeated febrile episodes due to antigenic variation in the spirochetes
Relapsing fever is diagnosed in the laboratory and treated with tetracycline
Lyme disease
Lyme disease is caused by Borrelia spp. and is transmitted by Ixodes ticks
Erythema migrans is a characteristic feature of Lyme disease
Lyme disease commonly causes additional disease 1 week to 2 years after the initial illness
Lyme disease is diagnosed serologically and treated with antibiotics
Protozoal Infections
Malaria
Malaria is initiated by the bite of an infected female anopheline mosquito
The life cycle of the malaria parasite comprises three stages
Clinical features of malaria include a fluctuating fever and drenching sweats
Malaria has an immunosuppressive effect and interacts with HIV infection
Immunity to malaria develops gradually and seems to need repeated boosting
Malaria is diagnosed by finding parasitized red cells in thin and thick blood films
Trypanosomiasis
Three species of the protozoan Trypanosoma cause human disease
Human African trypanosomiasis
Human African trypanosomiasis is transmitted by the tsetse fly and restricted to equatorial Africa
Clinical features of HAT include lymphadenopathy and sleeping sickness
T. brucei evades host defences by varying the antigens in its glycoprotein coat
Pentamidine prophylaxis is no longer deployed
Chagas disease
T. cruzi is transmitted by the reduviid (‘kissing’) bug
Chagas disease has serious long-term effects, which include fatal heart disease
Chronic Chagas disease is usually diagnosed serologically
Leishmaniasis
Leishmania parasites are transmitted by sandflies and cause New World and Old World leishmaniasis
Leishmania is an intracellular parasite and inhabits macrophages
Untreated visceral leishmaniasis (‘kala-azar’) is fatal in 80–90% of cases
Cutaneous leishmaniasis is characterized by plaques, nodules or ulcers
Immunodeficient patients may suffer more severe leishmaniasis
Leishmaniasis is diagnosed by demonstrating the organism microscopically and is treated with antimonials
Helminth Infections
Schistosomiasis
Schistosomiasis is transmitted through a snail vector
Clinical features of schistosomiasis result from allergic responses to the different life cycle stages
Schistosomiasis is diagnosed by microscopy and treated with praziquantel
Filariasis
Filarial nematodes depend upon blood-feeding arthropod vectors for transmission
Lymphatic filariasis caused by Brugia and Wuchereria is transmitted by mosquitoes
Few drugs are really satisfactory for treating filariasis
Chapter 29: Multisystem zoonoses
Introduction
Arenavirus Infections
Arenaviruses are transmitted to humans in rodent excreta
Arenavirus infection is diagnosed by viral genome detection, serology or virus isolation
Lassa fever virus is an arenavirus that occurs naturally in bush rats in parts of West Africa
Lymphocytic choriomeningitis virus occurs worldwide
Haemorrhagic Fever With Renal Syndrome (HFRS)
The Hantaan and Seoul viruses infect rodents and cause HFRS in Asia
Ebola and Marburg Haemorrhagic Fevers
Fruit bats are the reservoir for Ebola and Marburg viruses
Ebola virus disease (EVD) – gradual evolution of outbreaks to an unprecedented epidemic in West Africa from 2013 to 2016
Interventions that reduced the transmission rate
Rapid development of diagnostic tests, antiviral agents and vaccines
Infection control strategies to manage travellers from EBOV-affected countries
Crimean–Congo Haemorrhagic Fever, a Tick-Borne Virus
Q Fever
Coxiella burnetii is the rickettsial cause of Q fever
C. burnetii is transmitted to humans by inhalation
Q fever is diagnosed serologically and treated with antibiotics
Anthrax
Anthrax is caused by Bacillus anthracis and is primarily a disease of herbivores
Anthrax is characterized by a black eschar, and the disease can be fatal if untreated
Cutaneous anthrax is diagnosed by culture and treated with ciprofloxacin
Anthrax, as a natural infection, is now mainly confined to resource-poor countries. Vaccines are available. Bioterrorism is an important threat.
Plague
The plague is caused by Yersinia pestis, which infects rodents and is spread from them by fleas to humans
Clinical features of plague include buboes, pneumonia and a high death rate
Plague is diagnosed microscopically and treated with antibiotics
Yersinia Enterocolitica Infection
Tularaemia
Tularaemia is caused by Francisella tularensis and is spread by arthropods from infected animals
Clinical features of tularaemia include painful swollen lymph nodes
Tularaemia is diagnosed clinically and serologically. Streptomycin is the drug of choice, although other antimicrobials have been used (doxycycline and gentamicin).
Pasteurella Multocida Infection
Pasteurella multocida is part of the normal flora of cats and dogs and is transmitted to humans by an animal bite or scratch
P. multocida infection causes cellulitis, is diagnosed by microscopy and treated with amoxicillin / clavulanate
Leptospirosis
Leptospirosis is caused by the spirochete Leptospira interrogans, which infects mammals such as rats
Clinical features of leptospirosis include kidney and liver failure
Leptospirosis is diagnosed mainly by serological tests and treated with antibiotics
Rat-Bite Fever
Rat-bite fever is caused by bacteria transmitted to humans by a rodent bite
Clinical features of rat-bite fever can include endocarditis and pneumonia
Rat-bite fever is diagnosed by microscopy or culture and is treated with antibiotics
Brucellosis
Brucellosis occurs worldwide and is caused by Brucella species
Clinical features of brucellosis are immune mediated and include an undulant fever and chronicity
Brucellosis is diagnosed by culture and by serological tests and treated with antibiotics
Helminth Infections
Few helminth infections are true multisystem diseases
Echinococcus
Echinococcus granulosus (cystic echinococcosis; cystic hydatid disease)
Echinococcus multilocularis (alveolar echinococcosis; alveolar hydatid disease)
Trichinella
Trichinella spiralis is transmitted in undercooked pork and causes the disease trichinosis
The clinical features of trichinosis are mainly immunopathological in origin
Trichinosis is diagnosed by microscopy and serologically and treated with anthelmintics and anti-inflammatories
Strongyloides
Strongyloides infections are generally passed between humans, but can develop in animal hosts including dogs
Strongyloides infections are usually asymptomatic, but can cause disseminated disease in patients with immunodeficiency states or malnutrition
Chapter 30: Fever of unknown origin
Definitions of Fever of Unknown Origin
Causes of FUO
Infection is the most common cause of FUO
Infective causes of classical FUO
Investigation of Classic FUO
Steps in the investigative procedure
Stage 1 comprises careful history taking, physical examination and screening tests
Stage 2 involves reviewing the history, repeating the physical examination, specific diagnostic tests and non-invasive investigations
Stage 3 comprises invasive tests
Stage 4 involves therapeutic trials
Treatment of FUO
FUO in Specific Patient Groups
The main difference between FUO in these groups and classic FUO is the time course
Infective Endocarditis
Almost any organism can cause endocarditis, but native valves are usually infected by oral streptococci and staphylococci
A patient with infective endocarditis almost always has a fever and a heart murmur
Blood culture is the most important test for diagnosing infective endocarditis
The mortality of infective endocarditis is approximately 20–50% despite treatment with antibiotics
The antibiotic treatment regimen for infective endocarditis depends upon the susceptibility of the infecting organism
People with heart defects need prophylactic antibiotics during invasive procedures
Most people with an FUO have a treatable disease presenting in an unusual manner
Chapter 31: Infections in the compromised host
Introduction
The Compromised Host
The host can be compromised in many different ways
Primary defects of innate immunity include congenital defects in phagocytic cells or complement synthesis
Secondary defects of innate defences include disruption of the body’s mechanical barriers
Primary adaptive immunodeficiency results from defects in the primary differentiation environment or in cell differentiation
Causes of secondary adaptive immunodeficiency include malnutrition, infections, neoplasia, splenectomy and certain medical treatments
Pathogens that infect the compromised host
Infections of the Host With Deficient Innate Immunity Due to Physical Factors
Burn wound infections
Burns damage the body’s mechanical barriers, neutrophil function and immune responses
The major pathogens in burns are aerobic and facultatively anaerobic bacteria and fungi
P. aeruginosa is a devastating Gram-negative pathogen of burned patients
Staph. aureus is the foremost pathogen of burn wounds
The high transmissibility of Strep. pyogenes makes it the scourge of burns wards
Traumatic injury and surgical wound infections
Staph. aureus is the most important cause of surgical wound infection
Catheter-associated infection of the urinary tract is common
Staphylococci are the most common cause of intravenous and peritoneal dialysis catheter infections
Infections of plastic devices in situ
Staph. epidermidis is the most common cause of prosthetic valve and joint infections
Infections due to compromised clearance mechanisms
Infections Associated With Secondary Adaptive Immunodeficiency
Haematological malignancy and bone marrow transplant infections
A lack of circulating neutrophils following bone marrow failure predisposes to infection
Solid organ transplant infections
Most infections occur within 3–4 months of transplantation
HIV infection leading to AIDS
The clinical definition of AIDS includes the presence of one or more opportunistic infections
Other Important Opportunist Pathogens
Fungi
Candida is the most common fungal pathogen in compromised patients
Cryptococcus neoformans infection is most common in people with impaired cell-mediated immunity
Disseminated Histoplasma capsulatum infection may occur years after exposure in immunocompromised patients
Invasive aspergillosis has a very high mortality rate in the compromised patient
Pneumocystis jirovecii (formerly P. carinii) causes symptomatic disease only in people with deficient cellular immunity
Bacteria
Nocardia asteroides is an uncommon opportunist pathogen with a worldwide distribution
Mycobacterium avium-intracellulare disease is often a terminal event in AIDS
Protozoa and helminths
Cryptosporidium and Cystoisospora belli infections cause severe diarrhoea in AIDS
Immunosuppression may lead to reactivation of dormant Strongyloides stercoralis
Viruses
Certain virus infections are both more common and more severe in compromised patients, and regular surveillance is critical
EBV infection can lead to tumour development
Respiratory virus infections
Adenovirus infection has a high mortality rate
Hepatitis B and C infection in transplant recipients
Polyomaviruses can cause haemorrhagic cystitis and progressive multifocal leukoencephalopathy
Section 5: Diagnosis and control
Chapter 32: Diagnosis of infection and assessment of host defence mechanisms
Introduction
Aims of the Clinical Microbiology Laboratory
Identification is achieved by detecting the microorganism or its products or the patient’s immune response
Specimen Processing
Specimen handling and interpretation of results is based upon a knowledge of normal microbiota and contaminants
Routine culture takes at least 18 h to produce a result
Cultivation (Culture) of Microorganisms
Bacteria and fungi can be cultured on solid nutrient or liquid media
Different species of bacteria and fungi have different growth requirements
Growth of viruses, Chlamydia and Rickettsia requires cell or tissue cultures
Identification of Microorganisms Grown in Culture
Bacteria are identified by simple characteristics and biochemical properties
Antibiotic susceptibility can be accurately determined only after the bacteria have been isolated in a pure culture
Fungi are identified by their colonial characteristics and cell morphology
Protozoa and helminths are identified by direct examination although newer molecular methods are also available
Viruses are usually identified using serological and nucleic-acid-based tests
Mass spectrometry heralds a novel diagnostic era
Non-Cultural Techniques for the Laboratory Diagnosis of Infection
Non-cultural techniques do not require microorganism multiplication before detection
Microscopy
Microscopy is an important first step in the examination of specimens
Light microscopy
Bright field microscopy is used to examine specimens and cultures as wet or stained preparations
The most important differential staining technique in bacteriology is the Gram stain
Acid-fast stains are used to detect mycobacteria
Other staining techniques can be used to demonstrate particular features of cells
Dark field (dark ground) microscopy is useful for observing motility and thin cells such as spirochetes
Phase contrast microscopy increases the contrast of an image
Fluorescence microscopy is used for substances that are either naturally fluorescent or have been stained with fluorescent dyes
Electron microscopy
Although not routinely used in the clinical laboratory, electron microscopy provides the ultimate in microbe visualization and can aid in microbe identification
Detection of microbial antigens in specimens
Specific antibody coated onto latex particles will react with the organism or its product, resulting in visible clumping
Immunoassay can be used to measure antigen concentration
Monoclonal antibodies can distinguish between species and between strains of the same species on the basis of antigenic differences
Detection of microbes by probing for their genes
Organisms can be identified using nucleic acids probes that match specific gene sequences
PCR can be used to amplify a specific DNA sequence to produce millions of copies within a few hours
For diagnostic purposes, traditional PCR has been largely replaced by real-time PCR
More than one pathogen can be detected in a single reaction – multiplexing
Advances in molecular diagnoses for infectious diseases: sequencing-based techniques
Dideoxy chain terminator sequencing
Second-generation ‘sequencing by synthesis’
Single-molecule sequencing – the third generation
Amplification-based techniques and point of care (POC) tests
Personalized molecular medicine and infectious disease
Antibody Detection Methods for the Diagnosis of Infection
Diagnoses based on detecting antibodies in patients’ sera are retrospective
Common serological tests used in the laboratory to diagnose infection
Solid-phase immunoassays can be used to estimate antibody in a given sample
Assessment of Host Defence Systems
Blood samples may be checked for complement components
Phagocytic activity is a key element of proper immune function
Lymphocytes
Individual cells secreting antibodies or cytokines can be counted by the ELISPOT technique or by flow cytometry
The ability of cytotoxic T cells to attack targets can also be assayed by flow cytometry
Putting It All Together: Detection, Diagnosis and Epidemiology
Chapter 33: Epidemiology and control of infectious diseases
Introduction
Outcome Measurements
Types of Epidemiological Studies
Cross-sectional studies
Case–control studies
Cohort studies
Intervention studies
Transmission of Infectious Disease
Infectiousness (Box 33.3)
Time periods of infections
Time periods of infectious disease
Basic and net reproduction number
Vaccine Efficacy
Chapter 34: Attacking the enemy
Introduction
Selective Toxicity
Discovery and Design of Antimicrobial Agents
Classification of Antibacterial Agents
Some antibacterial agents are bactericidal, others are bacteriostatic
There are five main target sites for antibacterial action
Antibacterial agents have diverse chemical structures
Resistance to Antibacterial Agents
The genetics of resistance
Chromosomal mutation may result in resistance to a class of antimicrobial agents (cross-resistance)
Genes on transmissible plasmids may result in resistance to different classes of antimicrobial agents (multiple resistance)
Resistance may be acquired from transposons and other mobile elements
‘Cassettes’ of resistance genes may be organized into genetic elements called integrons
Staphylococcal genes for methicillin resistance are organized into a unique cassette structure
Mechanisms of resistance
The target site may be altered
Access to the target site may be altered (altered uptake or increased exit)
Enzymes that modify or destroy the antibacterial agent may be produced (drug inactivation)
Classes of Antibacterial Agents
Inhibitors of Cell Wall Synthesis
Beta-lactams
Beta-lactams contain a beta-lactam ring and inhibit cell wall synthesis by binding to penicillin-binding proteins (PBPs)
Most beta-lactams have to be administered parenterally
Different beta-lactams have different clinical uses, but are not active against species that lack a cell wall
Resistance to beta-lactams may involve one or more of the three possible mechanisms
Resistance by alteration in target site.
Resistance by alteration in access to the target site.
Resistance by production of beta-lactamases.
Extended-spectrum beta-lactamases are especially problematic.
Side effects
Toxic effects of beta-lactam drugs include mild rashes and immediate hypersensitivity reactions.
Glycopeptides
Glycopeptides are large molecules and act at an earlier stage than beta-lactams
Vancomycin and teicoplanin must be given by injection for systemic infections
Both vancomycin and teicoplanin are active only against Gram-positive organisms
Resistance
Some organisms are intrinsically resistant to glycopeptides.
Organisms may acquire resistance to glycopeptides.
VanA is the best understood mechanism of acquired glycopeptide resistance.
Glycopeptide resistance in the staphylococci occurs by mutation or by acquisition from the enterococci.
Side effects
The glycopeptides are potentially ototoxic and nephrotoxic.
Inhibitors of Protein Synthesis
Aminoglycosides
The aminoglycosides are a family of related molecules with bactericidal activity
Aminoglycosides must be given intravenously or intramuscularly for systemic treatment
Gentamicin and the newer aminoglycosides are used to treat serious Gram-negative infections
Production of aminoglycoside-modifying enzymes is the principal cause of resistance to aminoglycosides
The aminoglycosides are potentially nephrotoxic and ototoxic
Tetracyclines
Tetracyclines are bacteriostatic compounds that differ mainly in their pharmacological properties rather than in their antibacterial spectra
Tetracyclines are active against a wide variety of bacteria, but their use is restricted due to widespread resistance
Tetracyclines should be avoided in pregnancy and in children under 8 years of age
Chloramphenicol
Chloramphenicol contains a nitrobenzene nucleus and prevents peptide bond synthesis, with a bacteriostatic result
Resistance and toxicity have limited the use of chloramphenicol
The most important toxic effects of chloramphenicol are in the bone marrow
Macrolides, lincosamides and streptogramins
Macrolides
Erythromycin is a widely used macrolide preventing the release of transfer RNA after peptide bond formation.
Macrolides are an alternative to penicillin for streptococcal infections, but resistant strains of streptococci are common.
Newer macrolide-related (macrocycle) drugs show promise for targeted therapy
Ketolides are semisynthetic derivatives of erythromycin with improved activity against respiratory pathogens
Lincosamides
Clindamycin inhibits peptide bond formation.
Clindamycin has a spectrum of activity similar to that of erythromycin.
Pseudomembranous colitis caused by C. difficile was first noted following clindamycin treatment.
Streptogramins
Oxazolidinones
Fusidic acid
Fusidic acid is a steroid-like compound that inhibits protein synthesis
Fusidic acid is a treatment for staphylococcal infections, but should be used with other antistaphylococcal drugs to prevent emergence of resistance
Fusidic acid has few side effects
Inhibitors of Nucleic Acid Synthesis
Quinolones
Quinolones are synthetic agents that interfere with replication of the bacterial chromosome
Resistance to quinolones is usually chromosomally mediated
Quinolones are used as alternatives to beta-lactam antibiotics for treating a variety of infections
Fluoroquinolones are not recommended for children or pregnant or lactating women because of possible toxic effects on cartilage development
Rifamycins
Rifampicin is clinically the most important rifamycin and blocks the synthesis of mRNA
The primary use for rifampicin is in the treatment of mycobacterial infections, but resistance is a concern
Rashes and jaundice are side effects of rifampicin treatment
Antimetabolites Affecting Nucleic Acid Synthesis
Sulphonamides
Sulphonamides are structural analogues of and act in competition with para-aminobenzoic acid
Sulphonamides are useful in the treatment of urinary tract infection, but resistance is widespread
Rarely, sulphonamides cause Stevens–Johnson syndrome
Trimethoprim (and co-trimoxazole)
Trimethoprim is a structural analogue of the aminohydroxypyrimidine moiety of folic acid and prevents the synthesis of THFA
Trimethoprim is often given with sulphamethoxazole as co-trimoxazole for urinary tract infections
Resistance to trimethoprim is provided by plasmid-encoded dihydrofolate reductases
Trimethoprim and co-trimoxazole
Other Agents That Affect DNA
Nitroimidazoles
While nitroimidazoles are generally known for their antiparasitic activity, metronidazole also exhibits antibacterial properties
Metronidazole was originally introduced for the treatment of the flagellate parasite Trichomonas vaginalis
Rarely, metronidazole causes CNS side effects
Inhibitors of Cytoplasmic Membrane Function
Lipopeptides
Lipopeptides are a newer class of membrane-active antibiotics
Polymyxins
Polymyxins act on the membranes of Gram-negative bacteria
There is renewed interest in polymyxins as a last-effort option for treating multiresistant Gram-negative infections
Urinary Tract Antiseptics
Nitrofurantoin and methenamine inhibit urinary pathogens
Antituberculosis Agents
M. tuberculosis and other mycobacterial infections need prolonged treatment
The drugs for first-line therapy of tuberculosis are isoniazid, ethambutol, rifampicin, and pyrazinamide
Isoniazid
Isoniazid inhibits mycobacteria and is given with pyridoxine to prevent neurological side effects
Ethambutol
Ethambutol inhibits mycobacteria, but can cause optic neuritis
Pyrazinamide
Mycobacterial resistance
Drug resistance and immunocompromised patients complicate tuberculosis therapy
Treatment of leprosy
The development of resistance during dapsone monotherapy for leprosy has led to its use in combination with rifampicin
Antibacterial Agents in Practice
Susceptibility tests
Diffusion tests involve seeding the organism on an agar plate and applying filter paper disks containing antibiotics
A dilution test provides a quantitative estimate of susceptibility to an antibiotic
Killing curves provide a dynamic estimate of bacterial susceptibility
Combining antibacterial agents can lead to synergism or antagonism
Antibiotic Assays
Antiviral Therapy
Antiviral drugs do not kill viruses but stop viral replication
Prodrugs that target the viral DNA polymerase
Aciclovir (acycloguanosine)
Aciclovir inhibits HSV and varicella-zoster virus (VZV) DNA polymerase.
Ganciclovir (dihydroxypropoxy-methylguanine, DHPG)
Valganciclovir
Cidofovir
Pyrophosphate analogue that blocks the pyrophosphate-binding site on the viral DNA polymerase
Foscarnet
Antiretroviral drugs
Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs): zidovudine (azidothymidine, AZT), didanosine (ddI), lamivudine (3TC), stavudine (d4T), abacavir, emtricitabine and tenofovir
Zidovudine (azidothymidine, AZT).
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Nevirapine, efavirenz, delavirdine, etravirine and rilpivirine.
Protease inhibitors (PIs)
Nelfinavir, saquinavir, indinavir, ritonavir, lopinavir plus ritonavir (Kaletra), atazanavir, amprenavir, darunavir, fosamprenavir and tipranavir.
Fusion inhibitors
Integrase inhibitors (INSTIs)
Dolutegravir, raltegravir, elvitegravir.
Chemokine receptor antagonists
Maraviroc.
Treatment combinations
Inosine monophosphate dehydrogenase inhibitor
Ribavirin
Antivirals targeting influenza viruses
Amantadine and rimantadine
Neuraminidase inhibitors
Oseltamivir, zanamavir and peramivir.
Hepatitis B treatment
Hepatitis C treatment
Interferons – immunomodulatory agents restart
Other targets
Clinical management of antiviral therapy
Viral load and antiviral resistance tests as well as therapeutic drug monitoring assist in clinical management
Antifungal Agents
Antifungals can be classified on the basis of target site and chemical structure
Azole compounds inhibit cell membrane synthesis
Echinocandins interfere with cell wall synthesis
Polyenes inhibit cell membrane function
Flucytosine and griseofulvin inhibit nucleic acid synthesis
Other topical antifungal agents include Whitfield’s ointment, tolnaftate, ciclopirox, haloprogin and naftifine
No single antifungal agent is ideal
Fungi develop resistance to antifungal agents
There is an urgent need for safer more efficacious antifungal agents
Antiparasitic Agents
Parasites pose particular problems
Drug resistance is an increasing problem
Control by Chemotherapy Versus Vaccination
The concept of selectivity, or specificity, is central to both chemotherapy and vaccination
The specificity of an antimicrobial drug resides in its ability to damage the microbe and not the host
Control Versus Eradication
Control and eradication are different objectives, although eradication is always an ideal endpoint
Realism is required when considering the long-term aims of antimicrobial control strategies
Use and Misuse of Antimicrobial Agents
Antimicrobial agents should only be used appropriately for prophylaxis or treatment
Antimicrobial use results in the selection of resistant strains
Chapter 35: Protecting the host
Introduction
Vaccination – a Four Hundred Year History
Aims of Vaccination
The aims of vaccination can vary from preventing symptoms to eradication of disease
The importance of herd immunity
Vaccines Can Be of Different Types
Adjuvants
Vaccine safety
Vaccines in current use
Diphtheria, tetanus and pertussis
Measles, mumps and rubella vaccines
Mumps vaccine
Rubella vaccine
Polio vaccine
Pneumococcal vaccines
Meningococcal vaccines
Haemophilus influenzae type b (Hib)
Influenza
Antibodies provide useful correlates of protection for most of these vaccines
BCG and new vaccines for tuberculosis (TB)
Vaccines against hepatitis
Human papillomavirus (HPV)
Rotavirus vaccine
Typhoid
Varicella
Vaccines that are required for entry into particular countries, or for particular regions
Vaccines for subgroups at high risk
Complexity of vaccine schedules
Changes in demography means new vaccine strategies are needed
New vaccines in development
HIV vaccines
Malaria
Vaccines for neglected tropical diseases are also needed
How quickly can a new vaccine be produced?
New delivery systems and technologies for future vaccines
New routes of vaccination
Chapter 36: Active, passive and adoptive immunotherapy
Introduction
Immunotherapy strategies are divided into four approaches
Adoptive Immunotherapy
Passive Immunotherapy
Certain diseases are treated by a passive transfer of immunity, which can be life saving
The use of antiserum raised in animals can cause serum sickness
Antibody in pooled serum can provide protection against infection
An effective therapy is provided by one or more monoclonal antibodies specific for a known target antigen
Engineering antibodies
Monoclonal antibodies can be generated by phage display techniques
Single-domain variable region fragments have several advantages
Monoclonal antibodies were then made more efficacious and are increasingly used in the clinical setting
Non-Specific Cellular Immunostimulation
Cytokines and other molecular mediators stimulate the immune system
There is an interesting ‘grey area’ where immunostimulation and nutrition overlap
Correction of Host Immunodeficiency
Antibody defects are the easiest to treat
Probiotics
Chapter 37: Infection control
Introduction
Many healthcare-associated infections are preventable
Common Hospital Infections
Hospital infections are frequently associated with indwelling devices
Important Causes of Hospital Infection
Staphylococci and Escherichia coli have traditionally been the most important Gram-positive and Gram-negative causes of infection, respectively, however the list is expanding
Some infections historically associated with hospitals are now increasingly seen outside of the healthcare setting
Viral infections probably account for more hospital infections than previously realized
Sources and Routes of Spread of Hospital Infection
Sources of hospital infection are people and contaminated objects
Hospital infections are spread in the air and by contact and common vehicle
Host Factors and Hospital Infection
Underlying disease, certain treatments and invasive procedures reduce host defences
A variety of factors predispose to wound infection
Consequences of Hospital Infection
Hospital infections affect both the patient and the community
Prevention of Hospital Infection
There are three main strategies for preventing hospital infection
Exclusion of sources of infection
Exclusion of inanimate sources of infection is achievable, but it can be difficult to avoid contamination by humans
Breaking the chain of infection
Control of airborne transmission of infection
Ventilation systems and air flow can play an important role in the dissemination of organisms by the airborne route.
Airborne transmission of infection can be reduced significantly by isolating patients.
Facilitation of aseptic behaviour
Bacteriologically effective hand washing is one of the most important ways of controlling hospital infection.
Enhancing the host’s ability to resist infection
Host resistance can be enhanced by boosting immunity and reducing risk factors
Boosting specific immunity
Passive immunization provides short-term protection.
Appropriate use of prophylactic antibiotics
There are well-documented uses for prophylaxis, but antibiotics tend to be misused.
Gut decontamination regimens and selective bowel contamination aim to reduce the reservoir of potential pathogens in the gut.
Care of invasive devices
Care of invasive devices is essential to reduce the risk of endogenous infection.
The majority of hospital-associated bacteraemias and candidaemias are infusion related.
Reducing the risks of postoperative infection
Prevention of postoperative infection involves minimizing the risks.
Investigating Healthcare- Associated Infection
Surveillance
Surveillance allows early recognition of any change in the number or type of hospital infections
Investigation of outbreaks
There must be a description of an outbreak in epidemiological terms
The causative organism needs to be isolated and / or detected in all patients in the outbreak
Stages in tracking infection
Epidemiological typing techniques
A variety of phenotypic and genotypic characters are used to ‘fingerprint’ bacteria for epidemiological purposes
Antibiotic susceptibility patterns
Specialized typing techniques
Serotyping distinguishes between strains, using specific antisera
Bacteriophage (phage) typing has been used to type Staph. aureus, Staph. epidermidis and Salmonella typhi
Molecular typing
Molecular typing techniques involve characterizing an organism’s DNA
Plasmid profiles are an example of ‘first-generation’ molecular epidemiology
Restriction enzymes and probes represent ‘second-generation’ molecular epidemiology
PFGE and PCR are ‘third-generation’ approaches to molecular epidemiology
‘Fourth-generation’ molecular epidemiology is based on DNA sequence analysis
Molecular techniques for epidemiological fingerprinting have many advantages
Investigation of viral infections
Corrective / preventive measures
Once tracking is complete, corrective and preventive measures can be introduced
Sterilization and Disinfection
Definitions
Sterilization is the process of killing or removing all viable organisms
Disinfection is a process of removing or killing most, but not all, viable organisms
Antiseptics are used to reduce the number of viable organisms on the skin
Pasteurization can be used to eliminate pathogens in heat-sensitive products
Deciding whether sterilization or disinfection should be used
It is easier to sterilize a clean object than a physically dirty one
The rate of killing of microorganisms depends upon the concentration of the killing agent and time of exposure
Techniques for sterilization
Heat
Dry heat sterilizes by oxidation of the cell components.
The most effective agent for sterilization is saturated steam (moist heat) under pressure.
Immersion in boiling water for a few minutes can be used as a rapid emergency measure to disinfect instruments.
Pasteurization uses heat at 62.8–65.6°C for 30 min.
Irradiation
Gamma irradiation energy is used to sterilize large batches of small-volume items.
Filtration
Filters are used to produce particle- and pyrogen-free fluid.
Chemical agents
The gases ethylene oxide and formaldehyde kill by damaging proteins and nucleic acids.
The liquid glutaraldehyde is used to disinfect heat-sensitive articles.
Many different antimicrobial chemicals are available, but few are sterilant.
Controlling sterilization and disinfection
In general, it is preferable to control the process rather than the product
Disinfectants can be monitored by microbiological ‘in-use’ tests
Bibliography – list of useful websites
Useful Websites
Pathogen parade
Viruses
Bacteria
Gram-positive Cocci
Beta-haemolytic Streptococci
Alpha-haemolytic Streptococci
Gram-positive Rods
Gram-negative Rods
Gram-negative Cocci
Other Bacteria
Fungi
Superficial Mycoses
Deep Mycoses
Protozoa
Helminths
Tapeworms
Flukes
Nematodes
Vaccine parade
