Professional Documents
Culture Documents
Microbiology
made memorable
17. Encephalitis and other nervous system 46. Genetically modified micro-organisms
infections 42 (GMOS) in the environment and
biotechnology 115
18. Eye infections 44
47. Immunisation to infectious disease 116
19. Viral skin rashes 46
vii
M E D I C A L
MICROBIOLOGY
I ntroduction to micro-organisms
Micro-organisms are mostly harmless, and because some of them are capable
non-pathogenic, and indeed may be beneficial. of causing disease.
It is estimated that a human body has about • Eukarya, with their larger, more diverse
10" cells, but only 10% of these are human in and complicated cells (Fig. 1.2), include
origin; the rest is almost entirely microbial flora. fungi (yeasts and moulds) and parasites
Medical microbiology is the study of microscopic (single-celled protozoa and helminths).
organisms and their effect on man. It encompasses • Viruses, viroids and prions are not truly
their biology, diagnosis, treatment and prevention. 'living' agents, but are transmissible and
able to replicate.
There is a vast array of agents that are capable of
causing human disease ( Table 1.1). A 'family tree' If we are to reduce morbidity and mortality
of all living organisms is shown opposite (Fig. 1.1). from infection, a number of issues must be
This tree, with its three main branches, is very considered. The environment must be managed
different from that suggested twenty years ago through public health measures to reduce the
and has come about because of advances in chances of contact with virulent micro-organisms.
molecular biology. The eukaryotic domain is a In hospitals, this process is called 'infection control'
single group containing an almost unbelievable and it includes steps to ensure that patients with
amount of diversity, from single-celled amoebae hazardous agents do not disseminate them to
through worms, fungi and plants right up to others. Innate and specific immunity are clearly
complex animals such as humans. important in determining the outcome of contact
with pathogenic organisms; we must understand
The prokaryotes are divided up into two
how immunity works, what happens when it is
fundamentally separate domains: the Archaea
disturbed through modern medical treatments
and Bacteria. But just because many bacteria look
and how it might be increased by methods such
the same under the microscope, it doesn't follow
as immunisation. Disease must be diagnosed
that they will behave similarly - indeed there
quickly and accurately, either clinically or
is as much difference between the genes of the
through laboratory methods, before it has spread
bacteria Treponema pallidum and Staphylococcus
to others or the individual is too ill to be saved.
aureus as there is between those of human beings
We must develop and apply high-quality,
and sweet corn!
evidence-based treatments which include the
• The Archaea are a group of prokaryotes that prompt and appropriate use of drugs; the ideal
live in extreme conditions such as thermal antibiotic will kill the infecting micro-organism
pools. Whilst they may be very important to but not the commensal bacterial flora or the
the health of natural environments, they are patient, and yet will not lead to antibiotic
not known to cause human infection. resistance amongst virulent bacteria over time.
• The Bacteria, however, are very significant Infections are extremely common, and it is vital
when it comes to human health, both because that all medical doctors thoroughly understand
some of them must live on us or in us if we basic microbiology if they are to prevent,
are to remain healthy (our commensal flora) diagnose and treat infections effectively.
2
Basic features of infectious agents
Prokaryotes Eukaryotes
M E D I C A L
MICROBIOLOGY
Termed after the Latin for 'poison', viruses are Classification of viruses
the smallest and simplest of the agents of
infection in man, with the possible exception of Viruses are currently classified into different
prions (Fig. 2.1). They are both the commonest taxonomic groups on the basis of:
organisms found in the environment and the most • the nature of the host (animal, plant,
frequent cause of human infection. The following bacterial, insect or fungal)
properties distinguish them from living • whether they possess an envelope
(prokaryotic and eukaryotic) cells: • the type of nucleic acid they possess
• They are acellular and have a simple • the morphology of their capsid
organisation. • the diameter of the virion or nucleocapsid
• They possess either DNA or RNA in the • their immunological properties
same structure. • the intracellular location of viral replication
• They cannot replicate independently of • their clinical features, i.e. disease(s) caused
host cells. and method of transmission.
They can exist extracellularly as virions with The first three of these are the most commonly
few, if any, enzymes and intracellularly when used. In addition, there is a commonly used term
they 'hijack' the host biochemical machinery to 'arbovirus' which encompasses a range of virus
produce copies of virion components. families which are all arthropod-borne. The term
'phage' is used to denote viruses which parasitise
Virus structure and morphology bacteria, i.e. bacteriophage.
Virions are 15-400 nm in diameter and exhibit The range of viruses that infect humans is shown
one of five basic morphologies (Fig. 2.2). They in Table 2.1.
basically consist of a shell, called a capsid which
may be icosahedral or helical in shape. Capsids Viral replication
may be surrounded by an outer membrane,
All viruses make copies of themselves in the
called the envelope. There is a fifth structure
intracellular phase. The major difference between
type, termed complex, with a capsid structure
viruses is their strategy for genome replication.
which is neither helical nor icosahedral; complex
All viruses have to generate messenger RNA to
viruses may also possess an envelope. The capsid
produce protein and nucleic acid copies. The
is an arrangement of protein subunits, termed
protomers or capsomeres. Enclosed within the route by which they do this forms the Baltimore
system of classification (Fig. 2.3).
capsid is the genetic material, which is either
RNA or DNA, and may be single stranded or The end-result of viral infection may be lysis
double stranded. If single-stranded RNA, this of the cell, lysogeny where the host cell is not
may be capable of acting as messenger RNA, destroyed but continues to support viral
so-called positive-sense, or will have to be made replication, or latency where there is little,
into a complementary copy to do so, termed or no, viral replication. In the latter states the
negative-sense. Some genomes are also viral genome may be integrated into that of
segmented, such as rotaviruses. the host.
FIG 2.2 Basic virus morphologies (In addition there is a complex morphology that
does not follow a regular structure)
• (in addition there is a complex morphology that does not follow a regular structure)
M E D I C A L
MICR0131OLOGY
Bacteria are divided into two main groups flagellae which, when rotated, lead to the
by chemical staining and light microscopy: movement of the bacterial cell.
Gram-positive and Gram-negative. The Gram • Fimbriae (also called pili) are hair-like
stain, established in the 19th century, involves structures typically 6 nm thick, I tm long.
fixing of the bacterium with heat or alcohol and There may be up to 1000 per cell, and they are
staining with crystal violet, and then iodine. composed of proteins (adhesins) that enable
If the bacterium is Gram-positive, this blue the specific attachment of the bacterium to
stain is then resistant to decolorisation with its target.
alcohol or acetone. Gram-negative bacteria are • Sex pili are straighter, thicker and longer than
decolorised and then counter-stained with a red fimbriae. A pilus can extend from one cell to
dye, safranin or carbol-fuchsin. The differential another 'receptive' bacterium and allows the
staining is based on a major difference in the transfer of plasmid DNA.
cell wall (Fig. 3.1). Both have a lipid bilayer
Most bacteria that commonly affect human health
cytoplasmic membrane with various inserted
are described in Table 3.1, although there are a
proteins, the most important of which are
few that do not take up the Gram stain:
membrane-spanning permeases that control
active transport of nutrients and waste products • Mycobacterium species, have a thick waxy
into and out of the cell. A complex web of coat which can be detected by the
cross-linked peptidoglycan outside the Ziehl-Neelsen stain
cytoplasmic membrane provides the cell with • Chlamydia, Rickettsia and Mycoplasma species,
mechanical strength. It is particularly abundant which do not have conventional cell walls;
in Gram-positives, when it also contains strands specialised techniques are used for their
of teichoic and lipoteichoic acid. Gram-negatives visualisation and culture
have an additional outer membrane enclosing a • the spirochaetes (Borrelia, Leptospira and
thin layer of peptidoglycan and enzymes within Treponema).
the periplasm, an environment controlled by
the movement of substrates through membrane Bacteria may be small, but what they do, they do
porins. Some bacterial species may have a well. Most that cause disease grow at human
loosely-adherent polysaccharide capsule exterior body temperature (37°C). The majority grow in
to the cell wall and possibly additional structures air (aerobes) but can grow without it (facultative
which project from the cell surface: anaerobes); a few can only grow in the absence
of oxygen (true anaerobes). Bacteria multiply
• Flagellae are whip-like cords, typically 0.02 pm by binary fission, each cell dividing into two
thick, 10 ttm in length. A cell may have 1-20 'daughter' cells, and, with division times as short
as 20 minutes, their growth can be explosive
(Table 3.2). Although mutations can occur in
chromosomal DNA, their rapid adaptability is
due to the ability to exchange DNA:
Gram stain reactions of common bacteria
Gram-positive Gram-negative • Some bacteria take up DNA from solution
outside the cell and incorporate it into their
Cocci (=round)
chromosomes (transformation).
Staphylococcus (clusters) Neisseria (pairs)
Streptococcus (chains/pairs) Moraxella • Many cells contain small circular pieces of
Enterococcus(chains) DNA, called plasmids, in addition to their
chromosome. Plasmids may contain genes
Bacilli ( =rod-like)
Listeria
for virulence factors and antibiotic resistance,
Enterobacteriaceae
Bacillus • Escherichia and they can move from one bacterial cell to
Corynebacterium • Klebsiella another (conjugation).
• Salmonella
• Bacterial cells can be infected by specialised
• Shigella
• Proteus viruses, called bacteriophages or phages,
which move between cells, sometimes
Pseudomonas
carrying genes for virulence factors
Haemophilus
(transduction).
Bordetella
Legionella
The great majority of bacteria do not cause
Campylobacter
disease and live quite happily, and often to our
Helicobacter
benefit, on us or in us as commensals (Fig. 3.2).
Vibrio
However, under some conditions, these, or more
Clostridium (anaerobic) Bacteroides (anerobic) virulent micro-organisms, cause infections which
may be life-threatening.
FIG 3.1 The bacterial cell wall
0 1
1 8
2 64
3 512
4 4096
5 32 768
6 262 144
7 2 097 152
8 16 777 216
9 134 217 728
10 1 073 741 824
11 8 589 934 592
12 68 719 476 736
M E D I C A L
MICROBIOLOGY
Fungi are eukaryotic organisms that comprise characteristic red inflammation with central
yeasts, moulds (filamentous fungi) and higher clearing that forms at the site of infection.
fungi (mushrooms and toadstools). They are Dermatophyte infection affects various sites:
widely distributed in the environment and can e.g. scalp (tinea capitis), foot (tinea pedis:
survive in extreme conditions where nutrients are 'athletes foot') and groin (tinea cruris).
limited. Most fungi are saprophytes (living off Although becoming less common, tinea pedis
dead organic matter) in soil and water and are is still the most common fungal infection in the
vital to the carbon cycle. Certain fungi are also United Kingdom.
of great commercial value in the production of
Yeast infections are most commonly caused by
bread, alcohol and antibiotics.
Candida albicans and are confined to the vagina,
Yeasts are the simplest of the fungi. They are mouth and soft skin (candidiasis or 'thrush').
unicellular, spherical in shape and reproduce by A commensal of the vagina and gastrointestinal
budding (Fig. 4.1). In some yeasts, including the tract, the organism can flourish if ill health,
medically important genus Candida, the buds impaired immunity or antibiotic treatment alter
elongate to form filaments (pseudohyphae). the normal bacterial flora.
Moulds are composed of numerous microscopic Subcutaneous mycoses These are infections
branching, filamentous hyphae, known caused by a number of different fungi that arise
collectively as mycelia, that are involved in gaining from injury to the skin. They usually involve
nutrients and reproduction. The reproductive the dermis, subcutaneous tissues and muscle.
mycelia produce spores, termed conidia, either The fungi commonly live saprophytically on
by asexual or sexual reproduction from opposite thorn bushes, roses and tree bark, from which
mating strains. Spores are disseminated in the wounds can occur. Certain occupational groups
atmosphere, enabling fungi to colonise new (e.g. florists and agricultural workers) are more
environments. at risk from infection. Such mycoses are difficult
to treat and may require surgical intervention.
Certain pathogenic fungi are dimorphic, being a
yeast form when invading tissues but a mould Systemic (deep) mycoses These are
when living in the environment. The exception life-threatening invasive infections caused by
is Candida, which forms pseudohyphae when in a variety of fungi.
the body.
The primary pathogenic fungi infect previously
healthy persons and are caused by dimorphic
Diseases caused by fungi fungi normally found in soil. Infection usually
arises from inhaling spores, and the lungs are the
The study of fungi is called mycology, and the
main site of infection. However, dissemination
diseases they cause, mycoses. Mycoses are
to other organs and the central nervous system
classified depending on the degree of tissue
can occur. The incidence is largely confined to
involvement and mode of entry into the host
endemic areas in North and South America.
(Table 4.1):
The opportunistic fungi infect persons who,
• superficial - localised to the epidermis,
usually, have some serious immune or metabolic
hair and nails but can extend deeper into
defect, are on broad-spectrum antibiotics or
keratinised tissue
immunosuppressive drugs, or have undergone
• subcutaneous - confined to the dermis,
major surgery.
subcutaneous tissue or adjacent structures
• systemic - deep infections of the internal
organs caused by: Other fungi-related diseases
- primary pathogenic fungi that infect Certain fungi may indirectly cause human
previously healthy persons infections. Constant exposure to fungal spores in
- opportunistic fungi of marginal the atmosphere can induce respiratory allergies,
pathogenicity that infect the particularly among certain occupational groups
i mmunocompromised host. (e.g. Farmer's lung). Some mushrooms and
Superficial mycoses These are the most toadstools cause poisoning if ingested. Certain
common mycoses of humans and are acquired moulds produce toxic secondary metabolites
from the environment, infected humans or ( mycotoxins) that can contaminate food.
natural animal hosts.
Diagnosis and treatment
Pityriasis versicolor is an infection of the
superficial skin and hair which is prevalent in the The diagnosis and treatment of common mycoses
tropics. Fungi that invade deeper into keratinised and related diseases is by microscopy and culture
cells are termed dermatophytes. These diseases of lesions or serology. Antifungal agents are
are often called tinea or ringworm because of the discussed elsewhere.
8
Common human mycoses
Superficial: epidermis, hair Candida albicans Dimorphic Oral thrush; vaginitis; cutaneous candidiasis World-wide
and nails but can extend
Malassezia furfur Dimorphic Pityriasis versicolor: brown discoloration of World-wide,
deeper into keratinised tissue
the skin especially tropics
Subcutaneous: arise from Sporothrix schenckii Dimorphic Sporotrichosis: ulcerative skin lesion World-wide; common
i njury to skin and contamination progressing along the lymphatics in soil and vegetable
with organic matter
matter
Systemic - primary Histoplasma capsulatum Dimorphic Histoplasmosis: lung lesions (similar to North and
pathogenic fungi: i nternal those seen in tuberculosis) spreading into South America
infections in previously reticuloendothelial system and other organs
healthy persons
Blastomyces dermatitrdis Dimorphic Blastomycosis: primarily in lung but can spread Eastern parts of USA,
to skin, bone, viscera and meninges Canada, Africa
Penicillium
Mycotoxins
e.g. Claviceps purpurea Ergotism ('madness'): from bread made with rye World-wide
infected with fungal mycotoxin but now rare
Poisoning
e.g. Amanita phalloides Nausea, vomiting, bronchospasm, bradycardia, World-wide
(' Death cap' mushroom) hallucination, collapse
Pneumocystis carinii is an intracellular organism, with a life cycle of trophozoite and cyst. Formerly considered to be a protozoan, DNA and RNA sequence
analysis have established that it is related to the yeasts.
FIG 4.1 (a) Mould, with branching hyphae, forming the mycelium, and fluffy colony;
(b) Yeast with budding cells, and smooth-surfaced colony
9
M E D I C A L
MICROBIOLOGY
Protozoa, from the Greek meaning 'first animal', form a resistant cyst stage able to survive in the
refers to simple, eukaryotic organisms composed environment. Those that infect the gut are true
of a microscopic single cell. Reproduction is parasites being unable to reproduce except in a
through simple asexual cell division, or binary living host. Others occur naturally in soil and
fission, in which two daughter cells are formed water and are not true parasites. They are termed
or, if many daughter cells are formed, multiple 'free-living' and infect humans as opportunistic
fission. Certain protozoa have complex life cycles pathogens.
involving both asexual (schizogony) and sexual
Flagellates These organisms have a trophozoite
reproduction. Some protozoa form resistant cysts
form but also possess flagella for locomotion
that can survive in the environment.
and food gathering. All pathogenic species are
There are over 65 000 known species of protozoa, true parasites, being unable to reproduce outside
of which approximately 10 000 are parasites, the host.
deriving nourishment and environmental
protection from inhabiting a living animal Ciliates These possess rows of hair-like cilia
host. However, the majority of parasites are around the outside of the body for motility
non-pathogenic, living as harmless commensals and also to direct food into a primitive mouth
within the host. Some animals can harbour termed a cytostome. All ciliates possess two
parasites and serve as reservoirs for human nuclei: a large polyploid micronucleus and a
disease. Infections that are naturally transmitted small micronucleus active only during sexual
between animals and humans are termed reproduction. Some species form cysts.
zoonoses. These may be acquired either by direct Apicomplexa This is a unique group lacking
contact with an animals or indirectly through any visible means of locomotion. They are all
the ingestion of contaminated water and food. parasitic and most are intracellular, having a
Some zoonoses are spread by the bite of an insect,
life cycle involving both sexual and asexual
termed a vector in which part of the organism's reproduction. The common feature of all
life cycle is completed. members is the presence of an apical complex
Only a small number of protozoa cause human (visible only be electron microscopy) at the
disease but those that do affect millions of people anterior pole in one or more stages of the life
world-wide, causing considerable suffering, cycle. The exact components of the apical
mortality and economic hardship. Protozoal complex vary among members. Its function is
diseases are largely confined to countries thought to enable cell penetration.
with poor economic and social structure.
Diagnosis and treatment The relatively large
However, trichomoniasis, crytosporidiosis,
size of the protozoa enables most human
and toxoplasmosis are common in developed
pathogens to be easily identified by microscopic
countries. Protozoa of medical importance are
examination of clinical material. Those of the
summarised in Table 5.1.
gut are observed in freshly taken faecal samples.
The pathogenic protozoa are part of the Blood and tissue protozoa are visualised after
subkingdom Protozoa. Those of medical importance staining. Detection of elevated antibodies to the
are placed in the phyla Sarcomastigophora, infecting organism may be diagnostic in some
Apicomplexa and Ciliophora. Within these phyla instances (e.g. toxoplasmosis). Culture methods
the protozoa are divided into four major classes are not routinely used, as they are technically
based on their locomotive form: the amoebae demanding and time consuming: an exception
(Sarcodina), the flagellates (Mastigophora), the is the diagnosis of trichomoniasis.
sporozoa, and the ciliates (Kinetofragminophorea).
Antiprotozoal therapy is generally unsatisfactory.
Examples of common pathogenic protozoa are
Treatment is hampered by lack of effective
shown in Fig. 5.1.
agents for many diseases, their potential toxicity
Amoebae These are the simplest of the protozoa to humans and inability to destroy all forms of
and are characterised by a feeding and dividing the organism. The emergence of drug resistance
trophozoite stage that moves by temporary has also limited the therapeutic potential of
extensions of the cell called pseudopodia many agents.
('false feet'). In some species the trophozoite can
10
Common protozoa) infections of humans
Organism Disease and site of infection Mode of transmission Geographic distribution
Amoebae
Entamoeba histolytica Amoebiasis: gut and occasionally liver Faecal-oral ingestion of cysts World-wide
Flagellates
Trichomonas vagina/is Trichomoniasis: vagina and urethra Sexually transmitted (usually World-wide
asymptomatic in males)
Trypanosome gambiense African trypanosomiasis ('sleeping sickness'): Bite of tsetse fly (Glossing): West Africa: T gambiense
and T rhodesiense general febrile illness, drowsiness, coma, death a zoonosis from domestic and East Africa T rhodesiense
wild animals
Trypanosome cruzii American trypanosomiasis ('Chagas' disease'): Triatomid bug faeces which Mexico, Central and
swelling at bite site (chagoma), fever, enters bite wound: a zoonosis South America
lymphadenopathy, hepatosplenomegaly, from domestic and wild animals
heart disease, death
Leishmania tropics and L. major Cutaneous leishmaniasis: skin sores Bite of sandfly ( Phlebotomus) Mediterranean, Middle East,
North Africa, India, USSR
L. mexicana and L. bra ziliensis Mucocutaneous leishmaniasis: nose, Bite of sandfly ( Phlebotomus) Mexico, Central and
mouth and palate destruction South America
Leishmania donovani Visceral leishmaniasis (' kola-azar'): l iver, Bite of sandfly ( Phlebotomus) As for other Leishmania
spleen, bone marrow and other organs species
Ciliates
Balantidium coli Balantidiosis: gut necrosis, ulceration, Faecal-oral ingestion of cyts; Russia, northern Europe,
bloody diarrhoea; may be asymptomatic pigs common reservoir North and South America
and Asia
Apicomplexa
Plasmodium falciparum, P vlvax, Malaria: liver and erythrocyte infection Female Anopheles mosquito Africa, Asia and
P ovate and P ma/arise Latin America
Cryptosporidium parvum Cryptosporidiosis: gut; mild diarrhoea but Faecal-oral ingestion of oocysts World-wide
severe and chronic in immunocompromised
t=j
11
M E 0 1 C A L
MICROBIOLOGY
Helminths (from the Greek helminthos, meaning Filaria The filaria are microscopic nematodes,
worm) refers to all parasitic worms of humans. transmitted by biting insect vectors in which
They are complex, multicellular organisms, part of the organism's life cycle is completed.
ranging in size from the microscopic filarial On infecting humans the larvae mate and the
parasites to the giant tapeworms, several metres females produce microfilariae which develop
in length. Sexual reproduction occurs in all in the blood, lymphatic system, skin and eye.
cases, usually by mating between male and This can result in gross swelling of infected
female larvae. However, some helminths are tissues, most notably in the groin and legs.
hermaphroditic, possessing both male and
Cestodes (tapeworms) The tapeworms are flat,
female reproductive organs, and can reproduce
ribbon-like worms that can grow up to 10 metres
by self-fertilisation, termed parthenogenesis.
in length. They produce eggs which are excreted
Human helminth diseases occur world-wide into the environment and can infect a variety of
but are most prevalent in countries with poor hosts in which the life cycle continues. Humans
socio-economic development. They seldom cause become infected from consuming contaminated
acute disease but produce chronic infections that meat. They are characterised by:
can have a severely debilitating effect on the host
• absent mouth, digestive tract and vascular
(see Appendix 5, p. 129).
system
Parasitic helminths comprise the nematodes • a scolex (head) that attaches to the intestinal
(roundworms, filaria), cestodes (tapeworms) wall by suckers
and trematodes (flukes) (Figs 6.1 and 6.2). • a tegument (body) of the scolex through
which nutrients are absorbed
Nematodes These are typically worm-like in
• proglottids (segments) forming the tegument,
appearance and have the following characteristics:
each containing male and female reproductive
• They possess a mouth, digestive tract, anus organs producing infective eggs
and sexual organs. • eggs that hatch in the gut, releasing motile
• They occur as male or female forms. larvae that migrate through the gut wall and
• They reproduce by mating or through blood vessels to encyst in muscle forming
parthenogenesis of hermaphroditic forms. cysticerci (fluid-filled cysts each containing
a scolex).
The intestinal pathogenic nematodes may be
divided into those that develop in the soil (larvae Trematodes (flukes) The trematodes are flat,
being the infectious stage) and those that do not leaf-like organisms. They have complicated life
(eggs are the infectious stage): cycles, alternating between a sexual reproductive
cycle in the final host (man) and an asexual
• Development in soil - larvae being infective.
multiplicative cycle in a snail host. They cause
The larvae are shed in the faeces and mature
infection of the liver, bladder and rectum. Their
in the soil. They infect humans by burrowing
major features are:
into the skin (usually through the soles of the
feet) and enter the blood stream to be carried • They possess a mouth and digestive tract but
to the heart and lungs. They then force their no anus.
way into the alveolus and trachea, and, on • They are hermaphroditic, except for the
reaching the epiglottis, are swallowed. The life schistosomes which have a boat-shaped male
cycle then continues in the small intestine. and a cylindrical female form.
• Survival in soil - eggs being infective. The eggs • Part of their life cycle is completed in an
are the infectious form in which the larvae aquatic snail host.
develop. When ingested the larvae hatch in
Diagnosis and treatment Intestinal helminths
the small intestine, penetrate the mucosa and
are identified by microscopic examination of
are carried through the blood stream to the
faeces. Filaria are detected in blood and tissue
heart and lungs. The rest of the life cycle is
samples after staining. As with the protozoa,
as described above.
helminth infections are difficult to treat, because
In other nematodes the eggs hatch in the intestine of the lack of effective agents. Those that are
where the worms develop and produce eggs that available are toxic and unable to destroy all the
are shed in the faeces. The larvae can sometimes biological forms (see Chapter 44).
migrate through the body to infect other organs.
12
FIG 6.1 Classification of human helminths
FIG 6.2 Principal features of (a) nematodes (b) cestodes (c) tematodes
13
M E D I C A L
MICROBIOLOGY
These infectious agents are simpler than viruses. offers a plausible explanation for the strain
Viroids cause, predominantly, plant diseases such variation that is known to occur in scrapie.
as potato spindle-tuber disease. They consist of
circular, single-stranded RNA, usually 250 to Transmissible degenerative encephalopathies
370 nucleotides long. In plants they are found Scrapie is a transmissible degenerative
mainly in the nucleolus, but little else is known encephalopathy (TDE) of sheep, and many other
of the pathogenic mechanisms that they employ. ungulates suffer this disorder (Table 7.1). It is
Human disease due to viroids is not yet now recognised that TDEs also occur in man
recognised. (Table 7.2). The features of a TDE are:
Prions are putative infectious agents so-called • the presence of aggregates of prion proteins
because they are proteinaceous infectious into amyloid fibrils
particles (the originator changed it from prom). • the presence of 'holes' in the neuronal matrix
Although there is not universal agreement that ('spongiform' degeneration) caused by
they exist in vivo, the evidence for them is now amyloid (Fig. 7.1)
considerable. The best studied is the prion that • a long incubation period (several months to
causes a degenerative disorder of the central many years)
nervous system of sheep, scrapie. This agent • that they are rapidly progressive
appears to be a 33-35 kDa hydrophobic protein • clinical presentation with cognitive
which has been termed PrP (for prion protein). impairment, ataxia, myoclonus and
The gene that encodes for this protein exists in extrapyramidal signs.
normal sheep, but the product in diseased
The tentative diagnosis of human TDE is made
animals has a mutant peptide sequence and
from the clinical features, which occur usually in
an abnormal isoform with (3-pleated sheets
patients between 40 and 70 years of age; 'variant'
replacing a-helical domains; the normal cellular
Creutzfeld-Jakob (vCJD) disease, however,
protein is termed PrPc, the abnormal PrPsc.
involves younger patients. Confirmation of
The abnormal protein further differs from the
the diagnosis currently depends on the
normal cellular protein by being insoluble in
neuropathological features found at post-mortem,
detergents, highly resistant to proteases and
although newer methods based on detection of
having a tendency to aggregate. Prion proteins
the abnormal PrP by labelled-specific antibody are
have been shown to be infectious and to have
becoming more widely available and constitute
a high but not absolute degree of species
the definitive test. Currently there is no treatment,
specificity.
so prevention forms the bedrock of control. Brain
An alternative hypothesis for the infectious agent and spinal cord appear to be the predominant
of scrapie has been the virino. This putative agent reservoir of infection, and transmission has
has a tiny, as yet undetectable, scrapie-specific been shown to occur with infected corneal
nucleic acid coated in PrP There is currently no and dura mater grafts, growth hormone and
evidence for the existence of this agent, but it gonadotrophin injections and the use of
contaminated neurosurgical instruments. Kuru is
thought to have arisen because of cannibalism of
human brains. There is also a genetic component
to disease susceptibility, with 10% of CJD cases
being familial and a higher prevalence of
Transmissible degenerative encephalopathies of animals
sporadic CJD in, for example, Israeli Jews of
Disease Host Libyan origin. The human prion protein gene is
located on chromosome 20, and homozygosity
Scrapie Sheep, goats
Bovine spongiform encephalopathy (BSE) Cattle at codon 129 (methionine or valine) confers
Feline spongiform encephalopathy (FSE) Cats susceptibility to CJD, although this mutation
Transmissible mink encephalopathy (TME) Mink is not directly linked to disease causation.
Chronic wasting disease (CWD) Mule deer, elk
Exotic ungulate encephalopathy (EUE) Nyala, greater kudu Such markers may be useful in the future for
diagnostic and screening purposes.
14
Human prion diseases
Disease Notes
Creutzfeld-Jakob disease (CJD) Can be iatrogenic, sporadic or familial. latrogenic cases have
mean incubation periods from 18 months for intracerebral
inoculation by contaminated neurosurgical instruments to
13 years from the use of contaminated gonadotrophin given
parenterally
Fatal familial insomnia (FFI) Familial. Rare. Originally described in Italian families with
selective neuropathology in the thalamus
15
Epidemiology is 'the study of the occurrence, levels throughout the year, although others may
distribution and control of disease in populations. vary - for example the rise in respiratory tract
The risk of infection is not just dependent upon infections during the winter. The periodicity of
an individual's susceptibility but on the level of some infections is measured over a much longer
disease within the population, the degree of scale, for example the roughly 4-yearly cycle in
population mixing and herd immunity, as well mycoplasma pneumonias.
as specific features such as the communicable
Infections that have a stable incidence within
period, route and ease (infectiousness) of
the population are described as endemic (or
transmission.
hyperendemic if the incidence is extremely high).
Cases are frequently unconnected and are
Route of transmission therefore referred to as sporadic. A number of
terms are used to describe situations in which the
For an infectious agent to persist within a
number of infections is greater than that which might
population there must be a cycle of transmission
be anticipated from previous experience:
from a contaminated source, through a portal
of entry, into a susceptible host and on again • A cluster of cases in a single household or
(Fig. 8.1): over a small area is described as an outbreak.
It may relate to exposure to a local source,
• Direct transmission, the most common and
and suitable detective work and control
important route, involves all forms of physical
procedures may prevent further transmission.
contact between humans, including sexual
• An increase in cases over a larger region,
transmission, faecal-oral spread, and direct
perhaps an entire country, is described as an
respiratory spread via large droplets.
epidemic. This is less likely to be due to a
• Vector-borne transmission is mediated by
single source, and more extensive measures
arthropods or insects; it is mechanical if the
will be required to control the spread.
vector is simply a source of contamination,
• If the increase occurs over a larger area still,
but biological if it is necessary for the
for example several countries, it is described
multiplication or maturation of the
as a pandemic.
infectious agent.
• Vehicle-borne transmission describes the The burden of infectious diseases varies
spread from all contaminated inanimate enormously throughout the world ( Table 8.1),
objects. Vehicles include clothing, food, water, dependent upon factors such as environmental
surgical instruments and also biological conditions, wealth and nutritional status, local
substances such as blood and tissues. human behaviour and the efficiency of health
• Airborne transmission is mediated by care. Health service managers clearly need this
aerosols suspended in the air for long periods. information to plan for the future; however,
• A zoonosis is any infection spread from a it is vital that every clinician be aware
vertebrate animal to a human. of regional patterns of disease for the effective
diagnosis, treatment and control of infection
within their own practice of medicine (Table 8.2).
Disease in the population
For serious communicable diseases in the UK,
Prevalence is 'the number of cases of infection surveillance is achieved through a legal
per unit of population at a single point in time'. requirement for medical practitioners to inform
Incidence refers to 'the number of new cases of the local 'consultant in communicable disease
infection per unit of population over a specified control' (or the 'consultant in public health
period of time'. For acute infections, lasting only medicine' in Scotland) of all cases of notifiable
a few days or possibly weeks, the incidence may disease (see Appendix 3). For less serious
be very high but the prevalence relatively low. infections, individual general practices or
However, for chronic infections, lasting months hospital units may volunteer to report their cases
or years, the prevalence may be relatively high of infection through government or professional
even though the incidence is low. Infections like association programmes.
urinary tract infections occur at roughly steady
Tuberculosis World-wide, esp. 1/3 of the world population infected 3 million deaths/year
developing countries ( 50 million multi-drug resistant cases?)
Malaria Tropical and subtropical regions 300-500 million clinical cases/year 1.5-2.5 million deaths/year
Schistosomiasis Africa, Latin America & S.E. Asia 200 million infected 20 000 deaths/year
I nfectious diarrhoea World-wide, esp. 1500 million cases/year 4 million deaths of children < 5 years
developing countries
Gonorrhoea World-wide, esp. 62 million new cases/year I nfertility; T risk HIV infection; up to 30
developing countries neonates - ophthalmia neonatorum
Leishmaniasis Mostly tropical and 12 million infected 500 000 cases visceral leishmaniasis
subtropical areas
Dengue haemorrhagic fever C. America & S.E. Asia 500 000 hospital cases/year 1000 deaths/year
Neonatal tetanus Developing countries, esp. Asia 400 000 cases/year Case fatality rate up to 80
Vaccination 791
Neoplasms 492
Skin/ subcutaneous tissue infections 471
19
M E D I C A L
MICROBIOLOGY
20
Non-specific
I nfectious agent Mechanism
Giardia lamblia Mechanical 'gripping disc'
Staphylococcus epidermidis Polysaccharide slime
Pseudomonas aeruginosa Alginate production
Specific (adhesins)
I nfectious agent Adhesin Receptor
Entamoeba histolytica Galactose-binding lectin Galactose
Escherichia coli (fi mbrial) P fimbriae Uroepithelial cells;
P blood group antigen
Yersinia enterocolitica (non-fimbrial) Ail protein Epithelial integrin
Human immunodeficiency virus (HIV) gp 120 CD4 antigen
Cholera toxin Vibrio cholerae GM1 ganglioside Activation of adenylate cyclase; secretory diarrhoea
Diphtheria toxin Corynebacterium diphtheriae EGF-like growth factor precursor I nhibition of protein synthesis; cell death
Oedema factor Corynebacterium anthracis Unknown glycoprotein I Target cell cAMP; haemolysis
Shiga toxin Shigella dysenteriae Globotriaosylcer-amide 1 Protein synthesis; cell death
Tetanus toxin Clostridium tetani Ganglioside I Neurotransmitter release; spastic paralysis
TSST-1 Staphylococcus aureus T-cell receptor ' Superantigen', uncoordinated immunological stimulation
21
M E D I C A L
MICROBIOLOGY
Symptoms of infection arise from direct damage destroyed. Parenchymal cells are, however, more
to tissues, 'poisoning of cells', immune-mediated commonly damaged by extracellular products
damage (immunopathology), or a combination of such as toxins, enzymes and pH change.
these. Subclinical infection may occur, however, Helicobacter pylori, for example, produces urease
without any such damage. Disease severity which causes H' ion changes and mucinase
depends on both host factors and virulence which degrades the protective mucous layer of
determinants of the micro-organism (Tables 10.1 the stomach cavity; both of these mechanisms
and 10.2); even in an outbreak arising from a are thought to contribute to the cell damage that
single pathogen, there is often a spectrum of results in gastritis and peptic ulceration.
clinical presentation.
Cell toxicity
Damage to tissues
Viruses can be broadly considered as cell poisons.
Most viruses cause damage to the cells they Bacteria exert most of their direct cell and tissue
infect. Viruses abort host replicative mechanisms damage through the production of toxins. The
and may cause death of the cell that way or, end result tends to be loss of function which
when mature, lyse the cell when they erupt. might be manifest as oedema and necrosis of
If a large fraction of the cells is infected then there tissue, but may not have macroscopic effects.
is extensive tissue damage. Programmed cell Some fungi can also produce toxins, a
death, or apoptosis is also now recognised as a well-characterised example being aflatoxin
common mechanism that many viruses, such as produced by Aspergillus flavus which
HIV and influenza A, use to cause cell damage. contaminates monkey nuts.
Macroscopically, extensive tissue necrosis is,
however, rare, and patchy necrosis with oedema
due to membrane damage is all that is seen. I nflammation and immunopathology
Viral infection is also characterised by changes
Acute inflammation with an influx of neutrophils
in the cytoskeleton and organelles. There may
and other inflammatory cells can produce
be shrinkage of the nucleus, pyknosis, and
obvious changes in the tissue (Fig. 10.1). If this
aggregations of newly formed virus seen as
is extensive then long-term fibrotic changes
inclusion bodies. Some viruses, such as
may result. Immunopathology can result from
paramyxoviruses, also cause cell-to-cell fusion
different types of immune reaction to infection
to yield multinucleate cells.
(Table 10.3). The cell-mediated immune
Viruses such as hepatitis B virus, herpesviruses response to Mycobacterium tuberculosis results
(particularly EBV) and papillomaviruses are in characteristic pathology with granulomata
known to be oncogenic. The precise mechanisms exhibiting central caseous ('cheesy') necrosis
of cancer causation are not fully elucidated but (Fig. 10.2).
genes that provide oncogenic potential are
The production of autoantibodies (to DNA,
identified: for example the product of the X-gene
erythrocytes, etc.) is not uncommon, but overt
of hepatitis B virus has been shown to inhibit
autoimmune disease occurs as a result of few
DNA repair mechanisms and therefore allow the
infections ( Table 10.4). Simplistically, these arise
accumulation of mutations.
because of molecular mimicry between host
Bacteria may exist intracellularly within components and foreign antigens, with an
phagocytic cells. These cells may then be immune response initially directed against an
antigen on the microbe then recognising a similar
structure of a host component as foreign.
22
Immunopathological reactions
Type I mmunopathology Examples
I Antigen binds to IgE - mast cell degranulation - release Helminth infections,
of cytokines - anaphylaxis, allergic type response RS virus wheezing
II Antigen binds to antibody on cell surface - activation of (?) Fulminant viral hepatitis
complementADCC -> cytotoxicity
III Antigen binds to free antibody - immune complexes Arthritis in hepatitis B
-> vasculitis/inflammation
IV Antigen reacts with sensitised T cells - delayed cytotoxicity Tuberculosis, leprosy
- inflammation/tissue damage
23
M E D I C A L
MICROBIOLOGY
24
Source and effects of some selected cytokines
Cytokine Source Target Action
I nterleukin-6 (IL-6) Macrophages & CD4' T cells B lymphocytes Differentiation & antibody secretion
Hepatocytes Synthesis of acute-phase proteins
Granulocyte/macrophage-colony T cells, macrophages, Granulocytes & monocytes I ncreased growth and differentiation
stimulating factor (GM-CSF) endothelial cells, macrophages of precursors
Interleukin-10 (IL-10) Lymphocytes & macrophages T cells & macrophages I nhibits cytokine production
Antigen presenting cells Decreases HLA class II expression
FIG 11.1 Non-specific defence mechanisms FIG 11.2 Phagocytosis and intracellular killing
25
M E D I C A L
MICROBIOLOGY
26
I mmunoglobulins and their functions
FIG 12.3 Basic structure of an antibody molecule FIG 12.4 Antibody production during infection
27
Timely and accurate diagnosis of infectious In more severe disease the clinical findings direct
disease requires clinical acumen and liaison the choice of primary investigations. Of particular
between clinician and microbiologist. As in all value is the total and differential white cell
clinical diagnoses, the starting point must be a count. Basic biochemical investigations such as
clear history and full examination. Particular urea, creatinine, electrolytes and liver function
points to establish in the history are: tests give an indication of the severity of disease
and renal or hepatic impairment. Conventional
• ti ming and nature of fevers (constant, nightly,
i maging techniques such as X-rays are now
rigors, sweats)
frequently supplemented by scans using
• contact with other cases of infection
ultrasound, tomography and magnetic resonance
• predisposing factors (diabetes,
and direct visualisation using endoscopic devices.
i mmunosuppression, chronic obstructive
airways disease, etc.) Appropriate cultures must always be collected
• history of recent or recurrent infection before antimicrobial therapy is started. An
( urinary tract, skin, etc.) important exception to this rule is suspected
• travel history and relevant meningococcal infection where GPs are advised
i mmunisations/prophylaxis to give parenteral penicillin immediately. First
• animal contacts consideration should be given to blood cultures.
• recent or current antimicrobial therapy Although the positivity rate is low (typically
• drug allergies. around 10% in the UK), positive cultures are
extremely helpful in both diagnosis and
Some patients have symptoms that clearly treatment. As with all specimens from normally
indicate the focus of infection; others have fever sterile sites, care must be taken to avoid
without localising features. Systemic infections contamination. Clinical features will guide the
may present with potentially misleading collection of other appropriate specimens from
symptoms (e.g. cough in typhoid and diarrhoea specific sites. The general principles of specimen
in Legionnaires' disease). The examination collection are given in Table 13.1.
should include:
Organism detection in specimens may involve a
• the temperature (noting the site where this variety of methods (Table 13.2). Many of these
was taken) techniques are rapid and provide presumptive
• a search for local or generalised diagnoses within minutes of specimen receipt.
lymphadenopathy Culture is still the commonest detection
• the skin (signs of breaks in the skin - trauma, technique - it is cheap and provides isolates
ulcers, wounds, i.v. line sites and description for susceptibility tests but is slow and labour
of rashes) intensive.
• careful examination of each organ system,
Sophisticated molecular techniques are
particularly the respiratory and
gastrointestinal tracts. increasingly available and invaluable for
organisms that are difficult, slow or impossible
A review of the clinical features may establish a to culture. It is also possible to detect the
diagnosis without specific investigations. This is molecular basis of resistance (e.g. rifampicin
typically the case in general practice in mild resistance in M. tuberculosis), and this may have
upper respiratory tract infections where the more widespread application in the future.
majority of cases are viral in origin and treatment
Infectious agents may also be detected by
is largely symptomatic and unlikely to be
serological techniques - the antibody response
influenced by cultures or serology. In other cases
(Table 13.3). Antibody production may not be
(e.g. otitis media without perforation) suitable
detectable at the time of presentation, and
specimens may not be readily accessible and
specimens are classically collected as paired
treatment is usually empirical. Many general
acute and convalescent sera. A four-fold rise in
practitioners (GPs) treat uncomplicated urinary
titre confirms a significant response in acute
tract infections without sending urine for culture.
infections. A single raised titre is suggestive of
However, the choice of empirical antimicrobial
infection but may be diagnostic in chronic
treatment must be based on up-to-date
infections (e.g. HBV, HIV). Assays that detect
susceptibility data from local isolates. Similarly,
specific IgM are also available for many infections.
even in conditions that are usually self-limiting
(e.g. influenza and infectious diarrhoea), Skin tests have a limited role in diagnosis but the
epidemiological data from specimens is essential Mantoux (tuberculin) test is still widely used to
for effective communicable disease control (e.g. demonstrate cell-mediated hypersensitivity to
vaccine development and food safety measures). M. tuberculosis.
Collection of specimens
Aspect Measures to be taken
Detection of organisms
Time scale Method Examples
One or more days Solid & liquid culture Most bacteria, yeasts,
Tissue culture Some viruses (e.g. Herpes simplex)
Toxin detection Cl. difficile cytotoxin in cell culture
Serological techniques
Method Examples
31
Upper respiratory tract infections
The upper respiratory tract (Fig. 14.1) is the initial widespread pandemic, as even partial prior
site of infection or a site of colonisation for most i mmunity to a completely new strain is absent.
infections of the respiratory tract. It is also the site
for a number of resident organisms, the prevalence Sore throat / pharyngitis and tonsillitis Over
of which will vary in individuals (Table 14.1). two-thirds of sore throats are viral in aetiology
Some of these resident flora have the propensity to and may be a continuum of infection of the nasal
be pathogenic. Infections of the upper respiratory mucosa (common cold). Streptococcus pyogenes
tract (URTIs) are the commonest acute illness. is the commonest bacterial cause and can be
associated with severe complications (Table 14.2).
Common colds / rhinitis Children suffer
2-6 colds per year in industrialised countries, Diphtheria is caused by Corynebacterium
with this frequency halving in adulthood. This diphtheriae. There is much local inflammation of
high incidence of colds is attributable to the high the nasopharynx, with a characteristic 'bull neck'
number of viruses and serotypes involved. Both appearance from enlarged lymph nodes.
aerosol and fomite transmission contribute to Toxigenic strains of C. diphtheriae produce a
spread of infection. polypeptide that causes local destruction of
epithelial cells and spreads systemically to cause
The principal findings of rhinorrhoea and myocarditis and polyneuritis.
sneezing are found in almost all cases. In
addition there may be sore throat, headaches The aetiological diagnosis is made by culture
and constitutional upset with fever. Earache is of a throat swab or by serological assays. With
frequent in childhood. The diagnosis of the diphtheria, toxin production should also be
syndrome is clinical; laboratory identification is sought. Most viral sore throats are self-limiting
not required because of the current absence of and are managed symptomatically. S. pyogenes
appropriate antiviral therapy. Anti-rhinoviral infections should be treated (most frequently
therapy is, however, a possibility as drugs are with a penicillin) to prevent complications.
developed that block the interaction between the Diphtheria toxin can be neutralised with
major host cell receptor (ICAM-1) and the virus antitoxin. Contacts of diphtheria should be
anti-receptor in a canyon that occurs on the screened and given booster vaccination and/or
surface of the viral capsid. Symptomatic therapy chemoprophylaxis as appropriate.
with analgesics and decongestants is commonly Sinusitis / acute otitis media These conditions
employed. Vaccine development is hindered by are most frequently a complication of common
the diverse aetiology. colds but may also be due to secondary bacterial
I nfluenza Unlike common colds, which are invaders (Fig. 14.1). Localised pain is the most
non-life-threatening illnesses, much mortality frequent symptom, but children with otitis media
is attributable to influenza, particularly in may present with unexplained fever or vomiting.
the elderly and those with underlying If chronic infection results, surgery may be
cardiopulmonary disease. Clinically, there are necessary in addition to antibiotics.
three features that distinguish influenza infection Epiglottitis This is most commonly a disease of
from common colds: an acute onset, presence
of a fever in almost all cases (occurs in the young children as a result of spread of bacteria
from the nasopharynx. Haemophilus influenzae
minority of common colds) and more marked type b is the classic cause, but other bacteria
constitutional upset with myalgia. Amantadine may now be more frequent. Bacteraemia is
and rimantadine are used in the treatment and frequent, and epiglottitis may present as an
prophylaxis of influenza A infections. A vaccine acute medical emergency with respiratory
is recommended for patients with underlying obstruction. Antibiotics may need to be given
chronic cardiopulmonary disease, chronic renal intravenously.
failure, or diabetes mellitus, and in the
i mmunosuppressed. This vaccine is changed Tracheitis / laryngotracheitis This causes
annually because the virus undergoes genetic hoarseness and retrosternal discomfort on both
change either through minor sequence changes inspiration and expiration. Parainfluenza (and
(resulting in 'antigenic drift') or through other) viruses cause swelling of the mucous
recombination (resulting in 'antigenic shift') membrane that results in inspiratory stridor,
which produce changes in one or both surface termed 'croup'. Diagnosis of the specific
proteins, the haemagglutin (H) or neuraminidase aetiology is made by identification from a throat
(N). Antigenic shift increases the likelihood of a swab or serologically.
35
M E D I C A L
MICROBIOLOGY
The lower respiratory tract is defined as below changes are greater than might be suspected
and including the larynx. Due to the mucociliary given the few signs on chest examination. The
escalator, the complex and abundant bacterial severity of pneumonia and likely outcome can be
flora of the upper tract is much reduced in the judged by simple measures such as respiratory
larynx and trachea, and the bronchi are sterile in rate, blood pressure, blood urea, O Z saturation
health. Respiratory tract infections are the most and pulse rate. Mycoplasina and Chlamydia
frequent cause of GP consultation. The great (causes of atypical pneumonia) can infect the
majority of infections are, however, self-limiting, previously healthy, as can S. pneumoniae, which
and a provisional diagnosis should be based is the only cause of a pneumonia with a truly
upon the signs and symptoms (Fig. 15.1), with lobar distribution. The remaining causes of
laboratory investigation confined to those that bronchopneumonia are more likely to infect
may be serious (Table 15.1). Different organisms those in poor health and to be responsible for
characteristically affect different parts of the acute exacerbation of Chronic Obstructive
respiratory tract, although, once infection has Pulmonary Disease (COPD), although most
been initiated, the inflammation can become exacerbations are due to viral causes.
widespread. L. pneumophila is spread by aerosol, such as
those created by poorly-maintained showers
Airway infection Although infection in the
and air-conditioners, and typically affects the
larynx and/or trachea and/or the bronchi may
borderline immunocompromised - for example,
occur at any age, it is extremely common in the
heavy-drinking, heavy-smoking elderly persons
young (croup) and in elderly smokers.
returning from a holiday in the sun!
• The diagnosis of Bordetella pertussis infection The choice of antibiotic for a community-acquired
should be made clinically on the basis of the
pneumonia is described in Fig. 15.2; a hospital-
characteristic severe paroxysmal spasmodic
acquired pneumonia is more likely to be caused
' whooping' cough, as laboratory confirmation
by antibiotic-resistant organisms, and a second
is slow and unreliable. Erythromycin may or third generation cephalosporin may be the
reduce spread, but it is rarely possible to give
treatment of choice.
the antibiotic sufficiently early for this to be
worthwhile; vaccination is more helpful. Tuberculosis This was a decreasing problem
• Influenza may be complicated by until recently when the numbers started to rise
super-infection with bacteria, especially again, particularly amongst the poor, immigrant
pneumococcal and staphylococcal pneumonia. groups and HIV-positive patients. However, it
Influenza vaccine should be given to all should never be forgotten as a cause of serious
' at risk' persons in the autumn, and the drug disease. The chest is usually the main site of
amantidine may be useful if given early in infection, classically causing cough, haemoptysis,
infection. pleuritic pain, weight loss and night sweats,
• RSV causes a severe bronchiolitis in those but it may disseminate to any site in the body.
aged less than 2 (and the elderly), which may Antibiotic resistance may arise during treatment,
either be fatal or produce sufficient lung which usually involves prolonged therapy with
damage to bring about asthma later in life. pyrazinamide, isoniazid, ethambutol and
It is easily transmitted within hospitals but rifampicin.
may respond to the drug ribavirin. Cystic fibrosis In cystic fibrosis, the combination
of thickened secretions and repeated viral,
Parenchymal infection (pneumonia) Pneumonia
S. aureus and H. influenzae infections in early life
is infection involving the lung interstitium
lead to severe bronchiectasis; chronic infection
manifest as fever, increased respiratory difficulty
with Pseudornonas aeruginosa, and sometimes
and cough productive of purulent sputum. It is
Burkholderia cepacia, results in fatal destruction
most commonly caused by a bacterium in adults,
of the lung in spite of frequent courses of potent
detectable by culture of sputum (not saliva).
i.v. and nebulised antibiotics. However, the life
In contrast to bronchopneumonia, in atypical expectancy has increased dramatically with
pneumonia there is less production of sputum, i mproved management and may do so further
but the systemic symptoms and chest X-ray with gene therapy.
36
Diagnosis of lower respiratory tract infection
Bronchiolitis Nasopharyngeal aspirate Antigen detection & viral culture Respiratory syncitial virus (RSV)
The segment sizes of the pie chart are proportional to the frequency with which that organism is responsible for infection.
The area of shading within a segment indicates the usefulness of the antibiotic against that organism.
37
M E D I C A L
MICROBIOLOGY
Meningitis
Infection of the meninges follows invasion but B and C are commonest in western Europe.
of pathogens across the blood-brain or Acute meningococcal disease may present as a
blood-cerebrospinal fluid barrier. In rare septicaemic illness without meningitis. Such
instances organisms may gain direct access infections are often characterised by a petechial
following surgery, trauma or (in amoebic rash, and patients may develop endotoxic shock.
infections) directly through the cribriform Research into the mediators of meningococcal
plate. The characteristic clinical features of toxaemia has lead to searches for novel
meningitis are: therapeutic interventions in addition to antibiotic
therapy Meningitis caused by Streptococcus
• headache
pneumoniae occurs at all ages but particularly
• irritability or drowsiness, sometimes with
in children under 2 years, the elderly and those
alteration of consciousness
with immune defects (e.g. sickle-cell disease
• fever
and post-splenectomy).
• neck stiffness
• photophobia Meningitis in adolescents and young adults is
• Positive Kernig's sign (pain in the lumbar most commonly caused by meningococci. In later
region on straight-leg raising). life, pneumococci are more likely pathogens.
Most infections are acute and the commonest Listeria monocytogenes is a relatively rare cause
pathogens are viruses, especially in children and but should be considered particularly in pregnant
young adults. Patients with viral meningitis often and immunocompromised patients.
present with a history of an influenza-like illness Tuberculous meningitis Tubercle bacilli may
with headache, sore throat and muscle pains. The spread from distant sites via the lymphatic
features of meningitis then follow but tend to be system and the bloodstream, particularly in acute
milder than in bacterial infections and less rapid miliary tuberculosis. The onset of disease is often
in onset. The viral causes of meningitis are shown gradual with days or weeks of general malaise
in Table 16.1. Most cases of viral meningitis before the onset of meningeal features. Diagnosis
resolve completely without specific treatment. may be difficult in the early stages, but localising
Mumps virus is second to enteroviruses as a cause neurological signs such as cranial nerve palsies
of meningitis. The most prominent manifestation are helpful.
is, however, parotitis. Epididymo-orchitis may,
Diagnosis Blood cultures should always be
uncommonly, result in sterility; thyroiditis and
taken, preferably before antibiotics are started.
pancreatitis, meningo-encephalitis, myocarditis
Although there are contra-indications (especially
and arthritis are rare complications.
raised intracranial pressure) to lumbar puncture,
In contrast, bacterial meningitis may be examination of cerebrospinal fluid is advisable
life-threatening and have serious sequelae for whenever possible. CSF findings are shown in
those who survive ( Table 16.2). Whilst it may be Table 16.3. Additional investigations in suspected
i mpossible to predict the causative agent from the meningococcal disease should include the
clinical features, some pathogens are commoner following, particularly if the patient has already
at certain ages. received antibiotics:
• throat swab
Bacterial meningitis • acute serum for meningococcal antibodies
Neonatal meningitis may be classified as early- and antigen detection
( within 7 days of birth) or late-onset disease • blood for meningococcal polymerase chain
(occurring between 1 week and 3 months). Early reaction (PCR)
infections are acquired from the mother, whereas • scrapings of petechiae for Gram stain and
late infections may result from cross-infection culture.
after birth. The commonest causes of early-onset
Treatment and prophylaxis of bacterial
disease are Group B (3-haemolytic streptococci
meningitis Treatment must be prompt, and
and coliforms such as Escherichia coli. Listeria
immediate parenteral penicillin (before hospital
monocytogenes is less common but, like Group B
admission) is recommended in suspected
3-haemolytic streptococci, may also cause
meningococcal disease. Appropriate antimicrobials
late-onset disease.
are shown in Table 16.2. Chemoprophylaxis of
The majority of cases of bacterial meningitis close contacts is recommended in meningococcal
occur in childhood. The introduction of Hib (and Hib) disease to reduce the risk of secondary
vaccine against type b strains of Haemophilus cases. In addition, contacts of cases of serotypes
influenzae has significantly reduced the incidence A and C meningococcal disease may be vaccinated
of invasive infections caused by this organism. - a reliable type B vaccine is still awaited.
The commonest cause is now Neisseria Patients over 2 years of age at increased risk of
meningitidis. The three common serotypes A, B pneumococcal disease should be immunised
and C vary in prevalence around the world, with a polyvalent vaccine.
38
aThe ratio of CSF/blood glucose is more important that the absolute level - normal CSF glucose is
approximately 60% of blood glucose
39
M E D I C A L
MICROBIOLOGY
42
Causes of encephalitis
Cause Features
Herpes simplex virus (HSV) Bitemporal localisation detectable on CT, MRI & EEG.
HSV-2 common in neonates, HSV-1 in adults
Rabies virus (Rhabdovirus) Transmitted by bites from dogs, foxes, bats & other
mammals. Incubation period of weeks to months.
Fatal if not treated
43
M E D I C A L
MICROBIOLOGY
Eye infections
The exposed nature of the eye, with its warm Gonococcal neonatal conjunctivitis (ophthalmic
moist environment, makes it vulnerable to a neonatorum) and chlamydial inclusion
variety of microbial infections that can result in conjunctivitis are serious conditions acquired
permanent loss of visual acuity or blindness from the female genital tract during birth.
(Table 18.1). Infection can progress to keratitis, perforation and
blindness. Trachoma is a more severe chlamydial
A cross-section of the eye with its major
infection that occurs in tropical countries and
structures is shown in Fig. 18.1. Sites prone to
infection are the: affects all age groups. Over 600 million people are
infected world-wide, resulting in 10-20 million
• conjunctiva, producing conjunctivitis cases of blindness.
• cornea, producing keratitis
Cornea Viruses, bacteria, fungi, and protozoa
• anterior chamber, producing intraocular
can all cause keratitis. Bacteria are the most
endophthalmitis
frequent cause in the northern hemisphere and
• retina and the choroid, producing
fungi in the southern. Infection usually arises
retinochoroiditis.
from direct injury to the cornea or following eye
Natural defence mechanisms protect the eye surgery. The condition can also be associated
from infection. The blinking action of the eyelids with contact lens wear. Symptoms present as a
wipes micro-organisms from the eye surface and painful corneal stromal infiltrate or central
prevents attachment. The tearfilm that constantly abscess with overlying epithelial defect. The
bathes the external surface of the eye has resulting ulcer can lead to corneal perforation
antimicrobial components. These include: and blindness. Keratitis is a serious infection,
requiring prompt diagnosis, intensive
• lysozyme, active against Gram-positive
antimicrobial therapy and may necessitate
bacteria
corneal grafting.
• secretory IgA, which coats microbes and
hampers attachment I ntraocular Endophthalmitis occurs when
• lactoferrin, which complexes iron and organisms invade and multiply inside the eye
deprives bacteria of an important growth chamber. The condition usually arises from
factor. accidental injury or following eye surgery
(e.g. cataract removal). Bacterial flora from the
Eyelid Infection of the eyelash glands and hair
eyelid and conjunctiva) sac are the common
follicles (styes) or lid margins (blepharitis) are
cause. It is therefore usual to use prophylactic
common. The condition is characterised by
topical antibiotics or antiseptics preoperatively.
excessive secretion of the sebaceous glands,
Rarely, endophthalmitis can arise endogenously
causing a 'gritty' sensation and stickiness of the
in association with septicaemia. It is is a
eye on waking. Bacteria are the common cause.
potentially blinding infection that can necessitate
Conjunctiva The conjunctiva is particularly surgical removal of the eye. Prompt diagnosis
prone to infection, and conjunctivitis is a and intensive intravitreal and systemic antibiotic
relatively common condition caused by bacteria, therapy are vital in the successful treatment of
chlamydia and viruses. Symptoms are intense the condition.
hyperaemia of the conjunctiva) vessels ('pink eye'),
Orbital cellulitis This is an infection of the
excessive discharge and a 'gritty' sensation in the
extraocular orbital tissues, resulting in painful
eye. The discharge is usually watery in viral
swelling around the eye. Bacteria are the main
conjunctivitis or thick and purulent in bacterial
cause, and infection usually arises from a
conjunctivitis, resulting in 'sticky eye'.
haematogenous spread to the eye.
44
Common microbial eye pathogens
Site Organism Disease Comment Diagnosis Treatment
Eye margin Bacteria
Staphylococcus aureus Styes (eye lid follicles); A common condition Clinical appearance; Not usually necessary;
blepharitis (lid margin) swab culture topical chloramphenicol
if recurrent infection
Orbit Bacteria
Haemophilus influenzae Cellulitis of Common in children under Blood culture Systemic antibiotics
serotype b periorbital tissues 5 years prior to introduction
of Hib vaccine
j3-haemolytic Affects all age groups Ditto Ditto
streptococci
Conjunctiva Bacteria
Haemophilus influenzae Conjunctivitis Swab culture Topical chloramphenicol
Streptococcus Ditto Topical antibiotics
pneumoniae (e.g. chloramphenicol)
Neisseria gonorrhoeae Ophthalmic Acquired during birth Ditto Parenteral antibiotics;
neonatorum from an infected mother topical chloramphenicol
(newborn)
Chlamydia
Chlamydia trachomatis Trachoma; Common in tropics; person Swab culture; Topical tetracycline and
serotypes A-C conjunctivitis and to person transmission from immunodiagnosis oral erythromycin
keratitis contaminated flies, fingers,
towels, etc.
Chlamydia trachomatis I nclusion Acquired from birth canal of Ditto Ditto
serotypes D-K conjunctivitis infected mother
Viruses
Adenovirus Can spread from ophthalmic Swab culture in None
(serotypes 3,7,8,18) i nstruments and shared eye mammalian cell lines
protectors (`shipyard eye')
Enterovirus (serotype 70) Ditto None
Coxsackie A (serotype 24) Ditto None
Measles virus Ditto None
Cornea Bacteria
Pseudomonas Keratitis Trauma, eye surgery or use of Corneal scraping Topical and systemic
aeruginosa contaminated contact lens solutions culture antibiotics
Virus
Herpes simplex virus Conjunctivitis Viral dormancy in ophthalmic Corneal scraping Topical acyclovir
and keratitis division of the trigeminal culture in
ganglia can lead to reactivation mammalian cell lines
and dendritic corneal ulcer
Fungi
Aspergillus, Candida Keratitis and Uncommon ocular pathogens Corneal scraping Topical and systemic
albicans, Fusarium endophthalmitis microscopy and antifungal agents: e.g.
and others culture ketoconazole, miconazole,
amphotericin B
Protozoa
Acanthamoeba Keratitis Soil and water amoeba; most Corneal scraping Topical polyhexamethylene
common in contact lens wearers microscopy and biguanide and/or
culture propamidine isethionate
Microsporidia Keratitis and Recently recognised intracellular Corneal scraping Albendazole
conjunctivitis eye pathogens; mostly found in microscopy
i mmunosuppressed persons
Intraocular Bacteria
Staphylococci and Endophthalmitis From flora of eyelid and Aqueous humour I ntravitreal and systemic
streptococci conjunctiva) sac fluid microscopy antibiotics depending on
and culture organism sensitivity
Pseudomonas Can contaminate antiseptic Ditto
aeruginosa solutions used in surgery
Virus
Rubella Lens cataract Acquired in utero Serology None
(clouding) and
retinochoroiditis
Retina and Virus
choroid Cytomegalovirus Retinochoroiditis Can be acquired in utero; Serology Systemic/intravitreal
reactivation in AIDS produces ganciclovir or cidofovir
serious disease
Protozoa and helminths
Toxoplasma gondii Toxoplasmosis; Usually acquired in utero; Serology Pyrimethamine with
retinochoroiditis i mmunosuppression may lead sulphonamides
to reactivation
Toxocara cants and call Toxocariasis; I nfection from contaminated dog Serology Diethylcarbamazine,
retinochoroiditis and cat faeces can result in thiabendazole and
ocular larval migrans (OLM) mebendazole
Onchocerca vo lvul us Onchocerciasis Transmitted by Simulium biting flies Serology Ivermectin
('river blindness');
may also involve
keratitis
45
MEDICAL
MICROBIOLOGY
Viruses cause rashes with four basic components Recurrence of chickenpox is rare. HSV similarly
(Fig. 19.1): exhibits latency in ganglia, with recurrence in the
• macular/maculopapular skin of the supplied nerve. HSV-2 has a higher
• vesicular/pustular recurrence rate than HSV-1.
• papular/nodular Diagnosis of these infections is clinical, although
• haemorrhagic/petechial. VZV and HSV infection can be confirmed
serologically. Smallpox resembled chickenpox
Enteroviruses cause rashes of any type, including
but has now been eradicated. Aciclovir and
vesicular rashes with a zosteriform distribution.
derivatives are used in potentially complicated
Macular/maculopapular rashes (Table 19.1) herpesvirus (VZV and HSV) infections, including
Most commonly diseases of childhood, these are ophthalmic infection.
not true infections of the skin but exanthems, the
The vesicles in these infections contain virus, and
primary infection occurring elsewhere with the transmissibility is high to susceptible individuals
rash as a secondary, probably immune-mediated
such as the immunocompromised and newborn.
phenomenon; virus cannot be easily, if at all, Hand-foot and mouth disease is not severe, but
isolated from the rash. An enanthem, a rash on a
mucous membrane, may also be detectable early herpesvirus infections may become disseminated,
in the illness; in measles these are called Koplik's with organ damage and possible fatality.
Infection control measures should be considered
spots, manifest as white flecks on the buccal
and exposed susceptible individuals managed
mucoua. Transmission is by the respiratory route,
with antivirals and/or, in the case of VZV
with upper respiratory tract symptoms being
infection, zoster immune-globulin.
common, if transient.
Measles, a paramyxovirus, can cause a severe Papular/nodular rashes (Table 19.3) The
infection with constitutional symptoms and causes of these rashes are common, infectious
marked upper respiratory tract symptoms. It may and, usually, non-life-threatening. The exception
be complicated by secondary bacterial pneumonia, is specific types of HPV (mainly types 16 and 18)
typically due to Staphylococcus aureus. It may which are associated with cervical cancer.
also be complicated by neurological disease: acute Diagnosis is clinical, and treatment is by physical
' methods such as freezing, chemicals or surgery
post-infectious' measles encephalitis, which is
i mmune-mediated; subacute encephalitis (if warts are large). Interferon has also been used
occurring in immunocompromised patients; with success by injection into warts.
rarely, subacute sclerosing panencephalitis (SSPE) Haemorrhagic/petechial rashes (Table 19.4)
occurring 5-10 years after primary infection. Some viruses uncommonly cause
In children, particularly those with protein thrombocytopaenia which may manifest as
malnutrition, measles remains a common cause
of death in the developing world. petechiae or, less frequently, haemorrhage: EBV,
Rubella virus, CMV, parvovirus B19, HIV, VZV
Rubella may be complicated by encephalitis, and measles. Other clinical manifestations are
haematological deficiencies and an arthritis that usually present.
affects small and medium-sized joints. The most Some tropical viral haemorrhagic fever viruses
serious manifestation is, however, congenital
(Table 19.4) produce widespread haemorrhage
rubella syndrome (neural, cardiac, bone & other into the skin and organs by disseminated
abnormalities). intravascular coagulation (DIC) which, in turn,
Confirmation of a clinical diagnosis is not usually results in thromboses, infarcts and increased
required but can be made by culture of the virus vascular permeability. Diagnosis is by serology.
from respiratory tract or urine (measles and Lassa fever is treatable with ribavirin.
rubella), or serologically (rubella, B19, HHV 6).
Management of cases is symptomatic unless Mucocutaneous lymph node syndrome
complicated. MMR vaccination should be (Kawasaki disease) This is an acute febrile
instituted in early childhood. illness of children which is caused by widespread
vasculitis. Its aetiology is thought to be microbial.
Vesicular/pustular rashes (Table 19.2) The manifestations are conjunctivitis,
Chickenpox is also an infection spread by the desquamative erythema affecting the mouth,
respiratory route with an exanthem and tongue, hands and feet, and lymphadenopathy.
enanthem. Initial acquisition of virus results in There is a high 'complication rate with
dormancy in the dorsal ganglia. Subsequent arthralgia, obstructive jaundice and life-
reduced cell-mediated immunity (as occurs in threatening myocarditis. Clinical diagnosis,
the elderly, with cancer patients or those on accompanied by electrocardiography, should be
i mmunosuppressive therapy) allows the virus to prompt so that treatment can be instituted with
track down the sensory nerve to cause a rash in immunoglobulin and anti-platelet therapy.
the supplied dermatome: herpes zoster.
46
Macular/maculopapular viral rashes Vesicular/vesicopustular viral skin rashes
Disease Cause Characteristic clinical features Disease Cause Characteristic clinical features
Measles Morbilli Fever prior to rash, conjunctivitis, upper Chickenpox Varicella-zoster Rash appears on trunk in crops,
( measles) respiratory tract symptoms, pronounced virus (VZV) then spreads centrifugally.
virus coalescent rash Macules turn into papules which
become vesicles then pustules,
Rubella Rubella Occipital and other lymphadenopathy; fever
(German virus with several stages seen at any
of short duration if present. Rash appears
one time on the body. There may
measles) on face then spreads to trunk with
be intense pruritus. May be
desquamation as it fades
complicated by pneumonia,
Erythema Parvovirus Evanescent rash on face ('slapped cheeks'). Reye's syndrome, encephalitis
i nfectiosum B19 In adults may be complicated by arthropathy. and secondary bacterial infection
Mid-trimester infection may result in
Herpes zoster Varicella-zoster Unilateral chickenpox-like rash
hydropic fetus/loss. May precipitate aplastic
virus (VZV) affecting a dermatome. May
crises in haemolytic anaemia
result in neuralgia, particularly in
Roseola Human 3-5 days of fever which subsides prior to elderly. Ophthalmic zoster may
i nfantum herpesvirus 6 rash which appears on trunk then spreads cause corneal scarring. Lack of
centrifugally cell-mediated immunity may
result in disseminated zoster
with generalised rash
47
M E D I C A L
MICROBIOLOGY
Cutaneous infections
bacterial and fungal
The skin provides an important physical barrier children. When the dermis is infected, a red
to infection. In addition, the normal commensal demarcated rash appears called erysipelas.
flora helps to prevent the multiplication and Infection spreading beneath the dermis to involve
invasion of pathogens. Infections of the skin and the subcutaneous fat is cellulitis. This severe
deeper tissues often follow trauma or surgery condition may occur at any site but commonly
but may arise without obvious precipitating involves the legs and presents with a demarcated
factors. As with other infections, patients with red lesion often with blisters. The patient is
i mpairment of their immune system or diabetes usually systemically unwell and febrile. 'Scalded
are at greater risk. skin syndrome' is an acute infection of babies
and young children. Staphylococcal toxin causes
Some infections involve only the superficial
splitting within the epidermis, leading to large
structures of the skin, whilst others affect the
areas of skin loss.
deeper soft tissues below the dermis (Fig. 20.1).
The infection may be localised or spreading Death of tissue leads to gangrene. Synergistic
depending on the tissue plane involved and gangrene generally affects the groin and genitals
the virulence of the pathogen. Some of the and is confined to the skin. Widespread necrosis
commoner skin pathogens are shown in Table 20.1. of deeper tissues is seen in necrotizing fasciitis
In addition many systemic infections may have caused by 'flesh-eating bugs'. Both conditions
skin features (Table 20.2). require extensive debridement to avoid a fatal
Superficial, localised infections Folliculitis is outcome. Some organisms release gas into the
infection of the hair follicles. Furuncles (boils) tissue (gas gangrene) which may be detected
consist of walled-off collections of organisms and clinically as crepitus or seen in soft tissue X-rays.
associated inflammatory cells in follicles and This typically follows trauma, ischaemia or
sebaceous glands that eventually 'point' and may contaminated surgery such as lower-limb
discharge pus. A carbuncle is a cluster of infected amputation.
follicles commonly seen on the neck. Recurrent
Mycobacterial infections of the skin Primary
boils may be associated with carriage of S. aureus
infection of the skin with M. tuberculosis (lupus
in the nose and other sites, requiring treatment
vulgaris) is rare, but subcutaneous infection,
with antiseptics or topical antimicrobials. particularly of cervical lymph nodes, is well
Paronychia is infection of the tissues around
recognised. Atypical mycobacteria cause skin
the nails. infections, notably M. marinum which is
Candida infection of the skin is often associated associated with 'fish-tank' or 'swimming pool'
with moist sites where skin folds rub together granuloma. Tuberculoid leprosy causes red
(intertrigo), e.g. the nappy area in children. anaesthetic lesions on the face, body and limbs.
Ringworm (tinea) is a localised infection of the Lepromatous leprosy is associated with
epithelium caused by dermatophyte fungi. These destruction of the nose and maxilla.
arise from human, animal or soil sources and
I nvestigations and treatment Whilst pus or
infect skin and hair to produce circular scaly
swabs may be adequate for superficial infections,
lesions (Fig. 20.2).
tissue should be sent wherever possible. In
Wound infections and abscesses Traumatic systemic disease, blood cultures are essential.
and surgical wounds may develop localised or Adequate treatment requires drainage of pus and
spreading infections. Necrotic tissue or foreign debridement of devitalised tissue in addition to
materials (including sutures) act as a focus for appropriate antimicrobials (Table 20.1).
infection. Localised walled-off infection leads to
Animal bites, human bites and 'clenched fist
the formation of an abscess.
injuries' must be carefully explored, and
Animal bites Bites and scratches from dogs, prophylaxis started, without delay.
cats, other pets and wild animals may lead to
Dermatophyte culture may take several weeks,
local or systemic bacterial infections, including
and the diagnosis is often confirmed initially by
cat-scratch disease caused by Bartonella henselae.
the demonstration of fungal hyphae in skin
Spreading infections Impetigo is infection scrapes or nail clippings. Many superficial fungal
li mited to the epidermis, presenting as yellow infections respond to topical agents, but infections
crusting lesions, most often on the face in young of hair and nails require oral antifungals.
48
Common bacterial and fungal pathogens
FIG 20.1 Skin structures and infections FIG 20.2 Dermatophyte infections: trichophyton,
microsporum arid epidermophyton
49
M E D I C A L
MICROBIOLOGY
Gastrointestinal infections
Gastrointestinal tract infections are among the have a short incubation period and often produce
most commonly reported disease throughout the both diarrhoea and vomiting which resolves
world, causing considerable morbidity and within a day or two.
mortality. Although most prevalent in countries
Food-poisoning Food is a common means by
where sanitation and drinking water quality are
which pathogens can infect the gastrointestinal
poor, intestinal infections are common in the
tract, usually as a result of contamination by an
United Kingdom, and surveys indicate that the
infected person during preparation. Alternatively,
incidence is rising.
the organisms may be part of an animal's
All parts of the gastrointestinal tract are susceptible normal flora and contaminate the food during
to infection by a variety of micro-organisms slaughtering and processing. However, in true
(Table 21.1), and, with the exception of certain food-poisoning, bacteria actively multiply in the
nematodes that penetrate the skin, infection food. This does not necessarily result in spoiling
arises from ingestion: of the food, which appears fit for consumption
and hence increases the challenge dose and
• directly from an infected human or animal
likelihood of infection.
by hand to mouth (faecal-oral)
• indirectly from contaminated food or water Symptoms typically include both diarrhoea
• by consumption of food in which microbes and vomiting and result either directly from
have multiplied (food-poisoning). the presence of live bacteria or from toxins
produced in the food during growth (Table 21.2).
Although the gastrointestinal tract is vulnerable
The time between food consumption and onset
to infection, it is also well defended. The acidity
of symptoms can indicate the likely cause in
of the stomach fluids (pH 2.0) is a barrier to most
food-poisoning (Table 21.1).
microbes and stops entry of pathogens into the
intestinal tract. The small and large intestine are Antibiotic-associated diarrhoea Certain
rich in commensal bacterial flora that prevent antibiotics with broad-spectrum activity can
pathogen colonisation (the colon may contain seriously disturb the normal flora of the gut.
10' 2 bacteria/g of faeces). Secretory IgA and Clostridium difficile, part of the gut flora in low
lymphoid tissue (Peyer's patches) in the small numbers, can flourish under such circumstances.
intestine also provide immune protection. This may result in a severe infection termed
pseudomembranous colitis due to toxin
Gastroenteritis Infection of the gastrointestinal
production by the bacterium. Hospitalised elderly
tract results in gastroenteritis and refers to a
patients are particularly prone to infection.
collection of symptoms that include nausea,
vomiting, diarrhoea and abdominal discomfort. Peptic ulceration The bacterium Helicobacter
Symptoms vary with the type of organism and pylori has recently been implicated as a cause of
health of the person. The young, old or chronic gastritis and peptic ulcer disease. The
i mmunosuppressed are particularly susceptible pathogenesis of helicobacter-associated peptic
to severe illness, which may be life-threatening. ulcers is still being investigated, although a direct
link between the bacterium and gastric disease is
Infections are usually confined to the intestinal
now accepted.
mucosa, but some organisms invade through the
gut wall and disseminate into the blood stream, Diagnosis and treatment Intestinal infections
causing fever (e.g. typhoid). Diarrhoea is a are diagnosed by the detection of organisms
natural response by the body to expel the in faecal specimens: electron microscopy,
pathogen and is usually due to infection within immunoassay or gene detection for viruses;
the small intestine. It does, however, also aid the culture and biochemical identification of bacteria;
spread of the organism and infection of others. microscopy and immunoassays for protozoa
Dysentery is an inflammatory disorder of the and helminths.
gastrointestinal tract associated with blood and
Antibiotic treatment is not usually indicated in
pus in the faeces, fever and pain, usually
viral and bacterial gastrointestinal infections
resulting from infection of the large intestine.
except in severe cases, as this only prolongs
Enterocolitis is inflammation of both the small
symptoms and encourages drug resistance.
and large intestine.
Exceptions are in pseudomembranous colitis,
Bacterial infections are generally slow in onset, helicobacter-associated peptic ulcers and typhoid
producing diarrhoea without vomiting that may fever. Antiprotozoal and antihelminthic agents
last for a week or more. In contrast, viral infections are usually necessary in parasite infections.
50
Common causes of gastroenteritis
Pathogen I ncubation time Duration Diarrhoea Vomiting Pain Fever
Bacteria
Bacillus cereus toxin 1 -6 h 2-24 h + +++
Campylobacter 2-11 days 3 days-3 weeks +++ ++ ++
Clostridium botulinum toxin (botulism) 22->48 h weeks-months (+)
Clostridium difficile (pseudomembranous colitis) 3-4 days several weeks ++ + +1-
C/oaf ridium perfringens toxin 18-36 h 24 h - 3 days + ++ +
Verotoxigenic E. toll (VTEC) 1 -5 days 3-5 days ++ + ++ +
Enterotoxigenic E. toll (ETEC) 1-5 days 3-5 days +++ ( +) ++ +
Helicobacfer pylori (gastritis and peptic ulcers) Unknown Several weeks (with treatment) +
or chronic carriage
Salmonella (salmonellosis) 18-36 h 48 h - 7 days ++ + +
Salmonella typhi and paratyphi 7-21 days 4-6 weeks or chronic carriage ( +) ++
(typhoid and paratyphoid fever)
Shigella (bacillary dysentery) 1-4 days 2-3 days +++ + +
Staphylococcus aureus toxin 0.5-6 h 2-12 h (+) +++
Vibrio cholerae (cholera) 2-3 days 1-7 days ++++ +
Vibrio parahaemolyticus 8 h - 2 days 3 days ++ + + +
Yersinia enterocolitica 4-7 days 1-2 weeks ++ ++ +
Viruses
Adenovirus (types 40,41) 2-4 days 1-2 days ++ +
Astrovirus 1 -2 days 1 -2 days ++ +
Calicivirus 16-24 h 1-2 days + ++ +
Norwalk virus 1-3 days 1-2 days + ++
Rotavirus 1-3 days 2-5 days ++ ++
Protozoa
Cryptospondium parvum (cryptosporidiosis) 3-6 days immunocompetent: 7-21 days ++ ( +)
immunocompromised: chronic +++ (+)
En/amoeba histolytica (amoebiasis) days-weeks 7-14 days or chronic carriage ++ ++ +
Giardia lamblia ( giardiasis) 5-21 days 7-10 days or chronic carriage + +
Helminths
Ascaris lumbricoides, Enferobius vermicularis, These helminths infect the gut as part of their life cycles. However, they do not usually cause symptoms of
Trichuris tnchuria, hookworms, Strongyloides gastroenteritis. Further details are given elsewhere (see Chapter 6)
stercoralis, Trichinella spiralis, Toxocara
VTEC toxin acts on gut mucosa, causing a bloody diarrhoea ( haemorrhagic colitis) or systemically, resulting in haemolysis and renal failure ( haemolytic
uraemic syndrome)
51
M E D I C A L
MICROBIOLOGY
I nfection of the liver and pancreas occurs via the About 10% of cases of hepatitis do not have an
blood stream, rarely from the gastrointestinal identifiable cause, and new viruses such as
tract, even when the route of acquisition is hepatitis G and TT virus have been discovered
faecal-oral. Biliary tract infection and peritonitis by modern molecular methods in some cases.
are, conversely, due to locally spread infection. Their aetiological role has, however, yet to be
defined.
Hepatitis The classic clinical triad of jaundice,
dark urine and pale stools accompanying fever is Liver abscess These may be primary infections
often missing, particularly in children, who are or secondary to haematogenous spread from
more often asymptomatic. The vast majority of another site. Usually bacterial, with mixed
cases are of viral aetiology, with hepatitis A, B anaerobic and aerobic flora (including
and C being the commonest (Table 22.1). Enterobacteriaceae and Streptococcus milleri
Diagnosis of viral (and leptospiral) infection is group), they consist of pus that has been walled
serological, by either detection of antigen or off by a fibrinous layer; this can be detected by
specific antibody. i maging. Single lesions are often asymptomatic
unless very large. Broad-spectrum antibiotics are
The detection of hepatitis B surface antigen
used to treat the condition, but surgical drainage
( HBsAg) confirms the diagnosis of hepatitis B
may also be required.
virus, and the presence of hepatitis B 'e' antigen
( HBeAg) indicates a high infectious risk. Other Biliary tract infection This occurs secondary to
markers are determined in specific cases (Fig. 22.1). obstruction - either gallstones or malignancy.
Jaundice in carriers, in whom HBsAg persists for Ascending cholangitis, liver abscess and
6 months or more, is most likely to have another septicaemia may be sequelae. Diagnosis is
cause, which should be sought. Hepatitis A virus clinical, with imaging used as a confirmatory test.
( HAV) infection is diagnosed by anti-HAV 1gM. Treatment consists of removal of the obstruction
Serological assays for the diagnosis of hepatitis C and broad-spectrum antibiotics.
do not offer early diagnosis, as they are based on
the detection of specific IgG, which may take Peritonitis Contamination of the sterile
several weeks; diagnosis is thus retrospective but peritoneal cavity occurs through breach of the
can be made early by gene amplification methods bowel or urogenital wall. This may be iatrogenic,
such as PCR. such as occurs in surgery, or through diseases
such as inflammatory bowel disease, appendicitis
Management of acute viral hepatitis is supportive,
and malignancy. Occasionally tuberculosis or
with bed rest at the peak of liver inflammation.
actinomycosis of the genital tract may have been
Chronic hepatitis therapy is evolving, with drugs
the initial site of infection. Genital chlamydia
such as interferon, immunomodulators and
and gonococcal infections can also ascend to
ribavirin being used with moderate success in
cause perihepatitis (so-called FitzHugh-Curtis
delaying progression of liver disease, although
syndrome). Clinical diagnosis is confirmed
viral eradication is not achieved. Prevention of
operatively, or through laparoscopy, with pus
infection involves public health measures and
and/or adhesions visible between the peritoneal
vaccination for hepatitis A and hepatitis B.
layers. Treatment with broad-spectrum antibiotics
Travellers from the UK to higher-prevalence
may be required, as infections arising from the
areas (outside northern and western Europe
gut are polymicrobial.
and North America) should consider vaccination
for hepatitis A. Although universal vaccination Panereatitis This can be caused by a number of
for hepatitis B is being introduced in several viruses (Table 22.2). Mumps is the commonest.
countries, in the UK it is targeted at higher-risk Diabetes mellitus is associated with preceding
groups, such as medical, nursing and laboratory enterovirus infection. Bacteria can cause
staff, 'gay' men, and residents of mental pancreatitis, with mixed flora, if there is
institutions. In the event of contacts with both obstruction at the ampulla of Vater, usually due
hepatitis A and hepatitis B, passive immunisation to malignancy.
is available for susceptible individuals.
52
Infective causes of hepatitis I nfective causes of acute pancreatitis
Cause Route of Characteristic features Mumps
transmission Enteroviruses
Cytomegalovirus
Hepatitis A Faecal-oral I ncubation period of 2-4 weeks. <11% of cases Epstein-Barr virus
are fulminant Mixed bacterial flora
Hepatitis B Blood-borne I ncubation period of 1-3 months. Immune complex
form and may cause arthralgia, urticarial rash and
glomerulonephritis. 10% become chronic carriers,
with subsequent chronic hepatitis, cirrhosis and
hepatocellular carcinoma. High prevalence of
infection, carriage and hepatoma in S.E. Asia
53
M E D I C A L
MICROBIOLOGY
54
FIG 23.1 Aortic vegetation seen on echocardiography
Myocarditis Pericarditis
Viruses
Enteroviruses, especially coxsackie Enteroviruses, especially coxsackie
Echovirus I nfluenza A & B
I nfluenza A & B
Rubella
Epstein-Barr virus
Cytomegalovirus
Bacteria
Coxiella burnetii Mycoplasma pneumoniae
Leptospira spp. Strep. pneumoniae
Mycoplasma pneumoniae Strep. pyogenes
N. meningitidis Staph. aureus
Mycobacterium tuberculosis
Coxiella burnetii
55
M E D I C A L
MICROBIOLOGY
Urinary tract infections are more common at patients should be collected by needle aspiration
certain ages in males and females (Fig. 24.1). Whilst from the catheter tubing. In children specimens
many infections are mild, renal infections may may be collected in adhesive bags, but, to avoid
lead to long-term renal damage, and the urinary contamination, suprapubic aspiration may be
tract is a common source of life-threatening required. Where there may be a delay in
Gram-negative bacteraemia. Several clinical examination, specimens should be refrigerated or
syndromes are recognised (Table 24.1), the collected in containers with boric acid to prevent
commonest being lower urinary tract infection bacterial multiplication in transit. Microscopy
of the bladder (cystitis). Upper urinary tract for white and red blood cells may be helpful in
i nfection (pyelonephritis) may result from the interpretation of culture results, but their
haematogenous or ascending routes of infection. presence does not necessarily indicate urinary
tract infection. Squamous epithelial cells usually
indicate contamination of the specimen.
Pathogenesis
Quantitative culture is followed by susceptibility
The pathogenesis of urinary tract infections is testing of significant isolates. Some clinicians and
summarised in (Table 24.2). The additional laboratories use screening methods to exclude
risk factors (including instrumentation and urinary infection. Dipstick tests are available
catheterisation) in hospitalised patients lead to a for the detection of blood, leucocyte esterase
difference in the organisms isolated (Fig. 24.2). (indicating white blood cells) and nitrite
(indicating the presence of nitrate-reducing
The normal urinary tract is sterile, but urine may
bacteria).
be contaminated with organisms from the distal
urethra during voiding. Kass defined the term The interpretation of culture results depends on
significant bacteriuria as >10' colony-forming clinical details (symptoms, previous antibiotics),
units (cfu) of a single organism per millilitre quality of specimen, delay in culture and species
of urine. This figure was derived from studies isolated. Repeat specimens may be required with
in women and was found to distinguish low bacterial counts, evidence of contamination
pyelonephritis from contamination. However, or so-called 'sterile pyuria' - white blood cells
despite regular usage since, this figure is not i n the urine without bacterial growth. This may
validated for other urinary infections or those in be caused by:
men or children. In patients with symptomatic
• prior antibiotics
infections, counts may be as low as 10 2 cfu/ml.
• urethritis (chlamydia or gonococci)
About 50% of women who present with the • vaginal infection or inflammation
clinical features of cystitis do not have positive • fastidious organisms (controversial significance)
urine cultures, a condition known as abacterial • non-infective inflammation (e.g. tumours,
cystitis or 'urethral syndrome'. The aetiology of chemicals)
this condition is controversial, but explanations • urinary tuberculosis.
include:
Where tuberculosis is considered, three early
• i nfection with low counts of bacteria morning urine specimens should be collected for
• infection with fastidious organisms not culture when the urine is most concentrated.
detected on routine culture
• sexually transmitted infections, e.g. chlamydia
• non-infective inflammation, e.g. chemical.
Treatment
Uncomplicated cystitis should be treated with
Asymptomatic bacteriuria occurs in about 5%
a short (typically 3 day) course of an oral
of women and is important in pregnancy, where,
antibacterial agent such as trimethoprim or
untreated, 20-30% of cases will develop acute
nitrofurantoin. Post-treatment follow-up cultures
pyelonephritis. Bacteriuria in pregnancy is also
are particularly important in children and
associated with premature birth, low birth weight
pregnant women. For patients with complicated
and increased perinatal mortality. It is therefore
infections, antibiotics such as cephalosporins or
i mportant that all women have their urine
gentamicin are often indicated depending on
cultured early in pregnancy.
antibiotic susceptibility (Fig. 24.3). In catheterised
patients, antimicrobial treatment is usually only
Microbiological investigations recommended in patients with systemic features.
and interpretation The catheter should be removed whenever
possible. Pyelonephritis requires treatment,
Urine specimens need to be collected with care
initially systemic, for a total of 10-14 days.
to minimise contamination with periurethral
organisms. The first portion of voided urine In selected cases a prophylactic dose of an
is discarded and a midstream urine ( MSU) antibacterial agent given at night may reduce
specimen collected. Specimens from catheterised the incidence of recurrent cystitis.
56
FIG 24.1 Prevalence of urinary tract infections by age
Asymptomatic
covert bacteriuria Detected only by culture.
Important in children and pregnancy
Bacterial factors
Faecal flora Potential urinary pathogens colonise
periurethral area
Adhesion Fimbriae and adhesins allow attachment to
urethra) and bladder epithelium
K antigens Allow some E. toll to resist host defences by
producing polysaccharide capsule
Haemolysins Damage membranes and cause renal damage
Urease Produced by some bacteria, e.g. Proteus
57
M E D I C A L
MICROBIOLOGY
58
Detection and treatment of genital tract infection
Herpes simplex virus Clinical, viral culture, electron microscopy Aciclovir or related drug
Human papilloma virusa Clinical only Chemical or surgical removal
N. gonorrhoeae Culture, microscopy, DNA amplification Ciprofloxacin, 3rd generation cephalosporin, azithromycin
C. trachomatis Antigen detection, DNA amplification, (tissue culture) Tetracycline, azithromycin
Mycoplasma genital/urn Culture Tetracycline
T pallidum Antibody detection Penicillin
Anaerobic vaginosis Culture, microscopy Metronidazole, (co-amoxyclav)
( Gardnerella vaginalis anaerobes)
Haemophilus ducreyi Microscopy & culture Erythromycin
Calymmatobacterium granuloma fix Culture Tetracycline
59
M E D I C A L
MICROBIOLOGY
Both the pregnant woman and the newborn and attendant staff in nurseries and neonatal
infant are to some extent immunocompromised. intensive care units (Fig. 26.1). Staphylococcal
Most infections in pregnancy are not more infections are usually minor but may present as
common (an exception is urinary tract infection) the 'scalded skin' syndrome. Gastroenteritis
but are more likely to be severe or reactivate (bacterial or viral) can be life-threatening in
(Table 26.1). Primary infection in the mother low-birth-weight babies.
induces IgM antibodies, but these do not pass the
placenta to the fetus. Infection may result in fetal
death and spontaneous abortion or congenital
Diagnosis and management
infection and associated malformations. The
of neonatal infections
baby may also acquire infection around the TORCH is an acronym for a screen for infections
ti me of birth (perinatal infection) or after birth that are associated with neonatal disease. It stands
(postnatal infection). Infections diagnosed in for Toxoplasama, Rubella, Cytomegalovirus and
the first 3 months after birth are termed neonatal Herpes simplex. It is a useful aide memoire but is
infections. by no means all-inclusive. Diagnosis of these
infections is mainly serological, although the
herpesviruses can be grown from infected sites.
Prenatal / congenital infections
If confirmed then treatment (not available for
Most congenital infections (Table 26.2) follow rubella) should be given if symptomatic or,
primary maternal infection, but reactivation of in the case of toxoplasma infections, even if
CMV in pregnancy can lead to infection of the asymptomatic to prevent long-term sequelae.
fetus. Many of the organisms responsible for
Chlamydial infections are detected by
congenital infections may also cause spontaneous
i mmunofluorescence or ELISA and treated with
abortion. Typically, most foetal infections are
topical antibiotics.
associated with mild or subclinical infections in
the mother. With suspected covert bacterial infection, blood
cultures and CSF must be cultured promptly
Diagnosis depends on clinical suspicion, contact
together with swabs of superficial sites (e.g.
history enhanced by serology of maternal blood.
umbilicus, ear and rectum). Urgent antibacterial
Confirmation may be made, via cordocentesis,
treatment should then be started.
by serology or PCR of fetal blood. First-trimester
primary rubella infection caries such a high risk Risk factors for group B streptococcal disease
to the fetus of subsequent congenital rubella can be identified and pregnant women screened
syndrome, that termination is usually advised for carriage of the organism in the vagina and
if spontaneous abortion does not occur. Rubella rectum. Antibiotic prophylaxis is given to
infection after the fourth month does not pose at-risk mothers during labour and to the baby
a significant risk. after birth. Some viruses, e.g. HIV, may be
transmitted by breast-feeding, which should
be avoided.
Perinatal infections
Scrupulous attention to aseptic techniques and
Most of the perinatal pathogens (Table 26.3)
other infection control procedures is essential in
arise from the birth canal or blood. Some bacteria
the care of neonates.
silently colonise the maternal genital and
gastrointestinal tracts until ascending infection
produces severe and disseminated disease in the Puerperal infections
baby. Such infections are more common when (postnatal infections in the mother)
there has been premature rupture of membranes.
Puerperal sepsis, caused by group A streptococci,
Early-onset infection in the neonate (within the
is now uncommon since the introduction of
first week of life) usually presents as a severe
hand washing by attendants and associated
septicaemia, whereas, late-onset disease often
procedures.
presents as meningitis.
Other organisms associated with puerperal
Other organisms are genital pathogens that may
infections include anaerobes and coliforms that
be acquired during delivery and generally cause
may be introduced during instrumentation,
localised rather then systemic infections. Eye
especially septic abortions. The risk of infection
infection in the newborn is known as ophthalmic
is also increased if products of conception are
neonatorum.
retained in the uterus. Blood cultures and
carefully taken high vaginal swabs should be
Postnatal infections sent and empirical antibiotic treatment started.
Infection acquired after birth may be associated Staph. aureus may cause breast abscesses in the
with cross-infection from babies, their mothers mother a week or so after birth.
62
Effects of pregnancy on i nfection Perinatal infections
Urinary tract infections Cytomegalovirus (CMV) Group B haemolytic streptococci Meningitis, septicaemia Ascending or
during delivery
Candida vulvovaginitis Herpes simplex virus
Esch. coli
I nfluenza Epstein-Barr virus
Listeria monocytogenes
Chicken pox (pneumonia) Polyomavirus (BK, JC)
Viral hepatitis N. gonorrhoeae Conjunctivitis During delivery
Poliomyelitis Chlamydia trachomatis Conjunctivitis, pneumonia
Papillomavirus Laryngeal warts
Malaria
Lists riosis Herpes simplex virus Skin lesions, Maternal blood
Coccidioidomycosis disseminated infection at delivery
Hepatitis B virus Generalised infection
HIV
Congenital infections
Rubella Microcephaly, cataracts, deafness, Rubella IgM in cord blood Vaccination in childhood
heart defects, hepatosplenomegaly Virus isolation (throat, urine) Screening in pregnancy
Cytomegalovirus Deafness, mental retardation CMV IgM in cord blood No current vaccine
Virus isolation (throat, urine)
Varicella-zoster Skin, CNS and musculoskeletal abnormalities Isolation of virus from vesicles, Anti-varicella-zoster immunoglobulin
VZV IgM or rise in IgG (for infections late in pregnancy)
Herpes simplex Limb deformities, disseminated infection Virus isolation Caesarian section
Prophylactic acyclovir
HIV Failure to thrive, oral thrush, lymphadenopathy, HIV PCR as maternal antibody Screening in pregnancy
hepatomegaly, childhood AIDS persists for up to 18 months Prophylactic antiretroviral therapy
Treponema pallidum Lesions in skin, bones, teeth and cartilage T pallidum I gM in fetus Screening in pregnancy
Hepatosplenomegaly, lymphadenopathy Treatment of mother (early pregnancy)
Toxoplasma gondii Microcephaly, eye lesions, Toxoplasma IgM in cord blood Selected screening in pregnancy
Hepatosplenomegaly, jaundice Avoidance of primary infection
Treatment of infection in pregnancy
63
M E D I C A L
MICROBIOLOGY
Infections of bone and joint may arise from a Reactive arthritis (Table 27.2) The sterile
number of sources (Fig. 27.1). Predisposing arthritis caused by an immune response to an
factors include: infection is termed post-infectious or reactive
• arthritis. In many cases this follows infection
age - infections are commoner in neonates
and the elderly with enteric pathogens and is associated with the
• HLA B27. In viral infections, e.g. rubella, multiple
pre-existing local pathology, e.g. trauma,
joints are often involved, especially the hands,
tumours, sickle cell disease
• wrists, knees, ankles and elbows, and the
distant sites of infection, e.g. skin, chest, urine
• prosthetic material arthropathy 'flits' from one joint to another.
• disorders of immunity, e.g. steroid or cytotoxic I nvestigation and management X-rays show
therapy. distension of the joint capsule and soft-tissue
The following clinical features may be present: swelling - destructive changes are only seen
in cases which present late. These findings are
• fever (often with systemic illness)
not diagnostic of infection, and inflammatory
• pain
conditions (e.g. rheumatoid arthritis and gout)
• swelling
need to be considered. Blood cultures should be
• erythema
taken and joint fluid aspirated. In bacterial
• raised white cell count
infections about 50% of aspirates show bacteria in
• acute phase response (T plasma viscosity and
the Gram stain and 90% are positive on culture.
C-reactive protein).
Patients thought to have arthritis associated with
gonococci or following gastrointestinal infections
I nfections of bone - osteomyelitis should have appropriate additional specimens
taken. When tuberculosis is suspected synovial
Infections may be classified as acute or chronic.
biopsies should be taken. Serology is used to
The most frequent sites of infection are the lower
determine viral infection.
li mbs and the humerus.
Acute bacterial arthritis requires 2-3 weeks
In acute osteomyelitis, X-rays may not show an
antibiotic treatment, initially by the i.v. route.
abnormality at presentation, but computerised
Open surgical drainage may also be necessary.
tomography (CT) or white-cell scans can be
helpful. Prosthetic joint infections have an incidence
of < 1 % following hip or knee replacement but
Systemic features are less common in chronic
are very difficult to diagnose and treat. Most
osteomyelitis, though local signs such as sinus
infections are probably acquired at operation and
formation may be present. Periosteal reaction,
often present months later. Coagulase-negative
cysts or sequestra (dead bone within a cavity)
staphylococci are common pathogens and form
may be seen on X-ray (Fig. 27.2). Blood cultures
a polysaccharide matrix, which binds the
should always be taken and may be positive in
organisms to the prosthesis. Microbiological
about 50% of cases. Surgical material should
diagnosis requires careful culture of multiple
be obtained for urgent microscopy and culture,
operative specimens to distinguish pathogens
particularly in chronic infections to guide
from contaminant skin flora. Treatment usually
long-term therapy.
requires complete removal of the joint and
Treatment may require both surgical drainage associated cement.
(which is usually essential in chronic cases)
and antibiotic therapy. The choice of antibiotics
I nfections of muscle
should ideally be governed by culture results
(see Table 27.1), but empirical therapy should Acute bacterial cellulitis caused by Group A
include an anti-staphylococcal agent. Acute (3-haemolytic streptococci may involve underlying
infections generally require 3-6 weeks therapy, fascia and muscles. Gangrene may follow trauma
but in chronic cases treatment should continue or infection with mixed organisms, including
for several months with close monitoring of streptococci, anaerobes and coliforms. Both
response. The parenteral route should be used potentially fatal infections require prompt
for at least the first week and preferably longer. antibiotic therapy and full surgical debridement.
Viral myositis produces self-limiting muscle
pain and may be caused by coxsackieviruses,
Infections of joints - arthritis
mumps or influenza. Parasitic infections
Septic arthritis (Table 27.1) Most bacterial include Trypanosome cruzii (Chagas' disease)
joint infections follow haematogenous spread which may destroy cardiac muscle, Taenia solium
and lead to septic arthritis with joint effusions, which produces calcified muscle cysts, and
most commonly in the knee or hip. Chronic Trichinella spiralis which causes fever and
infections may develop, particularly with muscle pains.
mycobacteria or fungi.
64
Osteomyelitis
Septic Empirical
Pathogen Acute Chronic arthritis Treatments
Streptococci / / / Penicillin
Enterobacteriaceae / R
Pseudomonas spp. / R
Anaerobes / R Metronidazole
H. influenzae R R Ceftriaxone
N. gonorrhoeae R Penicillin
FIG 27.1 Sources of infection of FIG 27.2 X-ray showing chronic ostemyelitis of the tibia
I
bone, joint and muscle
Strep. pyogenes
Salmonella
Shigella
Campylobacter
Yersinia
Borrelia burgdorferi (Lyme disease)
Chlamydia trachomatis
Mycoplasma pneumoniae
Rubella
B19
Hepatitis B virus
Ross River virus
Alphaviruses
Other viruses rarely
65
M E D I C A L
MICROBIOLOGY
Septicaemia
Septicaemia is a clinical term describing signs of a careful review of the clinical findings (including
infection associated with micro-organisms in the other cultures) may allow a clearer assessment of
blood stream. The term bacteraemia simply significance. Such interpretations require close
refers to the presence of bacteria in the blood, liaison between the microbiologist and clinician.
sometimes transiently, with or without symptoms.
Positive cultures from blood (and other sites)
Septicaemia carries a high mortality and must be
also guide antimicrobial therapy. General
recognised, investigated and treated promptly.
suggestions for empiric therapy are given in
The risk factors associated with septicaemia Table 28.2. When susceptibilities are available,
are shown in Table 28.1. The incidence of many antimicrobial therapy is always reviewed and
community-acquired infections has changed little modified as required.
in recent years. In hospital-acquired infections
Blood cultures may be negative in septicaemic
the increasing use of invasive procedures,
patients because:
immunosuppressive therapy and broad-spectrum
antimicrobials has lead to an increase in the • the patient has received antimicrobial therapy
proportion of Gram-positive isolates, especially • the bacteraemia is intermittent
coagulase-negative staphylococci and enterococci. • the patient has circulating bacterial toxins
Fig. 28.1 shows the organisms isolated in a large rather than viable organisms
teaching hospital laboratory. • the media used are not optimal for fastidious
organisms
The clinical features often include:
Some organisms (e.g. pneumococci and
• fever, sometimes with rigors
meningococci) may be detected in blood (and
• tachycardia
other body fluids) by non-cultural techniques
• hypotension
such as antigen detection or PCR. Techniques for
• confusion or agitation
detection of circulating toxins are not currently
• evidence of a focus of infection.
available for routine use.
In severe cases the patient may present with
Gram-negative septicaemia is most commonly
circulatory collapse (shock) and the temperature
associated with coliforms but may be caused
may be paradoxically low. Acute infections are
by meningococci. Endotoxin released from
traditionally associated with Gram-negative
Gram-negative bacteria leads to tissue damage
bacteria but cannot be distinguished clinically
mediated by cytokines such as interleukins and
from Gram-positive septicaemia. A careful
tumour necrosis factor. Current research into
history and examination may reveal the source
these mechanisms may identify agents that could
of infection and help predict the likely organism
be used to inhibit tissue damage. Severe disease
(Table 28.2). Even in an emergency situation it is
may also accompany Gram-positive septicaemia,
vital to collect at least one set of blood cultures
particularly Staphylococcus aureus and (3-haemolytic
(and preferably any other cultures) before
streptococci, especially Group A (Streptococcus
antimicrobial treatment is started (see Table 28.3).
pyogenes).
Blood cultures are generally incubated for
The management of septicaemia requires
5-7 days but often become positive within the more than appropriate antimicrobial therapy.
first 48 h. The first report is the Gram stain The patient's general condition requires
of the cultures that may allow a provisional close monitoring with particular regard to
early identification - possible coliforms,
cardiovascular, respiratory and renal function.
staphylococci, streptococci, etc. This information
Many patients will require fluid replacement, and
may help to identify the source of infection in
the more severe cases may well require supportive
the absence of clinical clues. The isolation of management in an intensive care unit. The typical
Gram-negative bacteria from blood suggests a complications of severe septicaemia include:
urinary (or gastrointestinal) source; staphylococci
might suggest a wound infection, abscess or
• acute renal failure
osteomyelitis. The specific identification may
• respiratory failure - acute respiratory distress
give further help with the diagnosis: e.g. the syndrome (ARDS)
Streptococcus milleri group is associated with • haematological failure - disseminated
intravascular coagulation (DIC).
abscess formation or infective endocarditis.
Prevention of some cases of septicaemia is
Careful interpretation of the significance of
possible, particularly in the hospital setting.
positive blood cultures is important. Skin
Successful interventions include:
organisms such as coagulase-negative
staphylococci and diphtheroid bacilli often • appropriate use of antimicrobial prophylaxis
represent contamination but may be significant • strict attention to aseptic technique and care of
in line infections and prosthetic valve end ocarditis. indwelling devices
Further blood cultures taken from peripheral • prompt diagnosis and treatment of infective
veins or through intravascular lines together with sources.
66
Organisms in blood cultures - clinical associations and treatment Principles of blood culture techniques
Organism Associated with Empirical antimicrobialsa • Disinfect hands using alcohol hand rub
• Identify suitable venepuncture site and/or
Gram-negative intravascular line
Coliforms (E. coli, Urinary tract infections Gentamicin
Klebsiella app., etc) Gastrointestinal tract • Disinfect patient's skin (e.g. using 70
Neutropenic sepsis Gentamicin + piperacillin alcohol) and allow to dry
• Prepare blood culture bottles (disinfecting
Pseudomonas aeruginosa Urinary tract Gentamicin
Respiratory tract (ventilated patients) tops of bottles if required)
• Collect blood sample (typically 20 ml from
Salmonella app. Enteric fever Ciprofloxacin
adults, 1-5 ml from children) without
I nvasive infections at extremes of age
touching venepuncture site; use a different
Neisseria meningitides Septicaemia Benzylpenicillin venepuncture for each blood culture set
Meningitis • I noculate blood culture bottles (typically
Haemophilus influenzae Meningitis Ceftriaxone aerobic and anaerobic set) - if other
Skin, bone and joint infections blood tests are required, always inoculate
blood culture bottles before filling other
Gram-positive specimen bottles, to avoid contamination
Staphylococcus aureus Wounds and other broken skin sites Flucloxacillin • Complete request form with full clinical
I ntravascular line sites (vancomycin for MRSA) details including site of sample (vein or
Septic arthritis or osteomyelitis intravascular line)
I nfective endocarditis
• Transport cultures rapidly to laboratory or
Coagulase-negative staph. Colonised intravascular lines Vancomycin place in incubator
I nfective endocarditis
Specific details vary-check local hospital
Streptococcus pneumoniae Pneumonia Benzylpenicillin (ceftriaxone
information
Meningitis for resistant strains)
Streptococcus pyogenes Cellulitis Benzylpenicillin
Group B streptococci Obstetric and neonatal infections
Enterococcus app. Colonised intravascular lines Ampicillin
I nfective endocarditis
Listens monocytogenes Meningoencephalitis Ampicillin
Anaerobes
Bacteroides app. Gastrointestinal tract Metronidazole
Clostridium app. Female genital tract
Gangrene
Fungi
Candida app. Colonisation of intravascular line Amphotericin
I mmunocompromised host
a
Examples only are given; specific choices depend on patient factors and local susceptibilities and
prescribing policies - some patients may require alternatives or combination treatment
67
M E D I C A L
MICROBIOLOGY
Acquired immunodeficiency
syndrome (AIDS)
AIDS is the commonest cause of death in young AIDS AIDS is symptomatic HIV infection. It is
adults in many parts of the world. The major a clinical diagnosis made with the presence of a
burden of infection is in Africa, S.E. Asia and number of 'AIDS-defining illnesses', usually with
India, and S. America where heterosexual detectable anti-HIV antibody. These illnesses are,
transmission predominates and the number of with few exceptions, 'opportunistic' infections
cases in men and women are approximately equal. and tumours. There are several international
In Europe and North America, homosexual definitions of AIDS, but the most common
transmission has been responsible for the examples of infections and tumours found are
majority of cases. Apart from transmission by given in Table 29.1.
sex, transfer has also occurred by blood and
Diagnosis of HIV infection The presence of
blood products, including injectable drug use,
antibodies to structural proteins, particularly
and vertically from mother to child.
gpl20, is detected by ELISA or Western blot
The viruses There are two viruses - Human analysis to confirm infection with HIV. There is,
Immunodeficiency Virus (HIV) type 1 and however, a window period (up to 3 months is
HIV-2 - which are accepted causes of AIDS. generally accepted as the time period for
Structurally, these viruses are identical (Fig. 29.1). reliability of a negative response) where the
They are retroviruses, so-called because they antibody response is not detectable by current
encode an enzyme, reverse transcriptase (RT), serological assays. In neonates, the presence of
that makes a DNA copy of genomic RNA when it maternal antibody makes serological diagnosis
infects cells; this is 'backwards' (Greek retro) to difficult for up to 18 months. If infection is
the classic RNA from DNA. The replication cycle considered to be likely then PCR detection of
of HIV -1 is shown in Fig. 29.2. viral genome is the test of choice. Quantitative
PCR to determine viral load is also the
The viruses undergo rapid evolution, with
preferred method of monitoring progression
quasispecies being produced as the RT enzyme
and treatment of disease (CD4 count is a
makes mistakes in copying the original genome.
common alternative).
These are grouped as strains or Glades, with
HIV-1 B being the virus that was first recognised Management of HIV disease In the early stages
in the USA. there is treatment of HIV itself, but with the
onset of immunosuppression, there is also the
HIV disease and pathogenesis HIV infects
management and prophylaxis of opportunistic
T lymphocytes and macrophages. These cells
infections and tumours.
express receptors for the virus, CD4 (and others
such as CCRS). Early infection takes place HIV is best treated with a combination of
predominantly in the lymph nodes, although antiretroviral drugs (Fig. 29.2). Treatment is
CD4-positive cells in tissues such as the brain and probably best instituted early in infection
gut are also infected. This initial infection elicits a when the balance between the host immune
vigorous immune response which is detectable as system and virus is still in favour of the former.
anti-HIV antibody after 4-8 weeks. In many cases All the currently available drugs have serious
this primary illness (or 'seroconversion illness') side-effects, and treatment needs to be adjusted
is manifest as a glandular fever-like illness to minimise these.
2-12 weeks after initial infection. Uncommonly,
Drug therapy is complicated when opportunistic
infection is aborted at this stage, but in the
infections arise, as there is a high risk of adverse
majority there follows a long incubation period
drug interactions. Management is best undertaken
with continued viral replication (over 10 billion
in specialist centres, as this area of antimicrobial
new viruses per day) accompanied by a large
drug development is the most active and new
turnover of immune cells. This period lasts months
drugs are emerging rapidly and being used
and years, with increasing lymph node activity
before licensing,
which can be eventually detected clinically as a
persistent generalised lymphadenopathy (PGL). A vaccine for HIV would be ideal but is beset by
As the destruction of immune cells becomes the rapid evolution of the virus.
greater than new production, AIDS develops.
70
Tumours
• Kaposi's sarcoma (skin, disseminated)
• Burkitt's and other lymphomas
• I nvasive cervical cancer
• Oral hairy leukoplakia
FIG 29.2 Replication cycle of human retroviruses with targets for antiretroviral therapy
71
M E D I C A L
MICROBIOLOGY
I nfectious mononucleosis
and other systemic infections
There are infections that most commonly manifest diagnosis. Serious illness, and those occurring in
as fever and/or a non-localised infection. Many pregnancy, require treatment, with drugs such as
infections can present in this way but have a pyrimethamine, spiramycin and atovaquone,
predilection for a particular organ system and often in combination.
are described elsewhere.
o fever and other rickettsial infections
I nfectious mononucleosis This is also called Coxiella burnetii infection is a zoonosis from
glandular fever because of the presence of sheep which presents as a non-specific fever but
generalised lymphadenopathy. It is most may progress to an atypical pneumonia and/or
commonly caused by primary infection with endocarditis. Diagnosis is based on the detection
Epstein-Barr virus (EBV), a herpesvirus of complement-fixing antibody to phase 1
(Fig. 30.1 and Table 30.1). Sore throat, tonsillar antigen (acute Q fever) or to phase 1 and phase 2
enlargement and palatal petechiae also occur; antigens (chronic Q fever). Treatment is with a
with the potential complications of splenomegaly, prolonged course of tetracycline or erythromycin.
hepatitis and autoimmune haemolytic anaemia.
Other rickettsial infections have arthropod
Large numbers of atypical monocytes in a
blood film, the presence of cold agglutinins vectors (ticks, mites and fleas) and cause flu-like
and a heterophil antibody response to horse illnesses with or without a petechial rash: typhus,
or sheep erythrocytes, which causes a positive Rocky Mountain spotted fever, Mediterranean
Paul-Bunnell or Monospot test, is also typical. spotted fever, rickettsial pox and trench fever
Confirmation of EBV infection is made by being the best recognised. Serological tests are
specific serology. Treatment is supportive. used to confirm the diagnosis, and treatment is
usually with tetracyclines.
EBV is an aetiological agent in a number of other
diseases (Table 30.2). Mycobacterial infections Tuberculosis is most
commonly caused by M. tuberculosis, and less
Other common infectious causes of generalised
often by the related M. bovis, M. microti and
lymphadenopathy, with or without fever, are
M. a fricanum. Clinically, there is primary disease
cytomegalovirus and Toxoplasma gondii. The
which most commonly occurs in the lung with
former is generally acquired during childhood
a Ghon focus of tubercle bacilli and hilar
via saliva, although other body fluids may also
lymphadenopathy, the so-called primary
contain virus. Infection is more typically silent
complex. Post-primary tuberculosis is manifest
but, as with other herpesvirus infections,
as tuberculomata, granulomatous lesions with
reactivation occurs. It is a common cause of fever
Gaseous 'cheesy' necrosis, in the lung and
in post-transplant patients, and of retinitis and
elsewhere. Diagnosis is based on microscopy of
pneumonia in AIDS. Primary infection during
infected material with Ziehl-Neelsen staining,
pregnancy or at term is particularly problematic,
and culture which may take several weeks.
as congenital infection may result. 5% of these
Treatment is with a combination of drugs to
will be symptomatic at birth, with jaundice, eye,
reduce drug resistance and enhance therapy.
brain and other abnormalities. These have a poor
The tuberculin test, intradermal inoculation of
prognosis. The others are asymptomatic at birth,
purified (tuberculosis) protein derivative (PPD),
but a minority of these patients will have hearing is also a useful diagnostic and screening test,
i mpairment and other defects later in childhood.
although it does not distinguish between
Diagnosis depends on detecting the virus in
active and old infection and previous BCG
urine, blood or saliva and/or serologically.
vaccination.
Complications require treatment.
Other mycobacteria also cause disease (Table 30.3).
Toxoplasmosis is a zoonosis, with cats as the
predominant source of infection for humans. Plague This is a disease still present in many
The commonest presentation is of a transient parts of the world. Caused by Yersinia pestis, it
febrile illness, often with lymphadenopathy; presents as a bite from an infected rodent with
but intrauterine infection may cause stillbirth or local tender lymphadenopathy ('buboes') and
congenital abnormalities, and infection in the fever. Multisystem involvement can occur with
i mmunocompromised may result in cerebral high mortality. Organisms can be identified from
infection with characteristic multiple calcified lymph nodes or sputum (in pneumonic plague)
lesions seen on X-ray. The dye test which utilises and should be treated with streptomycin and/or
patient serum to kill viable toxoplasma in vitro tetracycline.
is being replaced by specific ELISA assays for
72
Human herpesviruses
Human herpesvirus 1 Herpes simplex Oral, skin and genital ulcers, encephalitis,
(HHV-1) type 1 (HSV-1) disseminated infection in newborn and
FIG 30.1 Electron micrograph of a
i mmunocompromised
herpesvirus
Human herpesvirus 2 Herpes simplex Same as HSV-1 but more common cause of
(HHV-2) ( HSV-2) genital ulcers
EA, early antigen; D, diffuse; R, restricted; EBNA, Epstein-Bart virus-associated nuclear antigen;
VCA, viral capsid antigen
73
M E D I C A L
MICROBIOLOGY
Infections of the
immunocompromised host
An i mmunocompromised or immunodeficient It is important to have this background
person is lacking in some aspects of innate information because it allows the development of
and/or adaptive immunity. This may be due protocols for the prevention, investigation and
to a primary deficiency or, far more commonly, treatment of infections in immunocompromised
a deficiency secondary to some other condition. patients, which present a number of particular
If induced deliberately through medical problems for clinical management:
intervention, during tumour therapy or after
• Antibiotic prophylaxis or immunisation may
transplant, for example, the person is described as
reduce the frequency of infection, e.g. penicillin
being immunosuppressed. Whatever the route,
and pneumococcal vaccine to decrease
the net result is that the immunocompromised
pneumococcal infections after splenectomy.
individual becomes susceptible to:
In highly susceptible bone marrow transplant
• infection with a range of opportunistic patients, exposure to fungal spores may be
pathogens, such as the commensal flora diminished by treating their air supply with
in addition to more conventional agents high-efficiency particulate air (HEPA) filters.
• infections that may be more severe than in Patients should be made aware of the
a 'normal' host. infections to which they are particularly
susceptible so that they can reduce their
Although it is important to recognise when a risk of exposure (e.g. by more careful food
patient is immunocompromised, in some ways preparation to decrease the potential for
this very broad term is unhelpful because it does Salmonella and Cam pylobacter infection) and
not allow an estimate of the most likely causes obtain medical advice if they are exposed
of infection. This depends on how the patient's (e.g. exposure to varicella-zoster virus by
condition affects each limb of the immune system, contact with a case of chickenpox).
as shown in Table 31.1, which in turn controls • Accurate diagnosis of infection can be difficult
the most likely pathogens (Table 31.2). It should because of an unusual presentation: the
be noted that immunity varies throughout life disease may be more extensive than normal
and not just in 'disease' states. and the characteristic symptoms/signs may be
lacking without an immune response. In cases
The details are beyond the scope of this book,
where there is little inflammation, the focus of
but chronic renal failure is given as an example:
infection may be unknown, making it difficult
• Chronic renal failure leads to a moderate but to guess the most probable pathogens.
broad suppression of adaptive immunity and • Antibiotic prophylaxis may make culture from
phagocytic function so that the number of patient samples difficult within the laboratory.
infections is increased slightly and agents Because these patients may have had so many
such as Legionella, Salmonella and Listeria can antibiotics in the past, infection with
be problematic. However, the chief concern antibiotic-resistant bacteria is more likely.
arises from breaching the skin for CAPD or • Opportunistic pathogens may require unusual
haemodialysis, and staphylococcal infections diagnostic methods within the laboratory
are therefore frequent ( Table 31.1 and 31.2). (and also unusual treatments). Serology as a
• If a renal transplant is undertaken, the diagnostic method is unhelpful because it
i mmediate potential infective problems are presumes an effective immune response
those relating to major surgery: pneumonia as within the patient. Laboratory culture
a result of intubation and artificial ventilation; results may be difficult to interpret, as the
line-related sepsis with intensive care support; commensal flora, which are usually regarded
wound infection secondary to surgery; and as contaminants that were inadvertently
serious infection relating to manipulation of picked up when the sample was taken,
the urinary tract. may be opportunistic pathogens in the
• Long-term post-transplant, infective i mmunocompromised host.
problems are determined by the degree of • Treatment may have to/ be more aggressive
immunosuppression required to prevent than for the same pathogen in a host with a
transplant rejection, with opportunistic normal immune system and may need to be
pathogens reflecting a decrease in cellular extended for longer periods, possibly even
immunity (Tables 31.1 and 31.2). for life.
74
Urinary
E. toll Toxoplasma
Gram-negatives Cryptosporidium
Strongyloides
Genital
Anaerobes (bacterial vaginosis)
Candida
75
M E D I C A L
MICROBIOLOGY
Zoonoses
Zoonoses are infections transmitted from animals transmitted from man to animals, or in either
to man. They are caused by various bacteria, direction. These are termed:
viruses, fungi, protozoa and helminths. Animals
• anthropozoonoses: transmission from animals
serve as natural reservoirs for the micro-organisms
to man
and do not usually show signs of disease.
• zooanthropozoonoses: transmission from
Domestic and farm animals are the predominant
man to animals
reservoirs of disease in Europe, and wild animals
• amphixenoses: infection maintained in both
in the tropics.
man and animals, and may be naturally
Many zoonoses are occupational diseases affecting transmitted in either direction.
farmers, vets, animal breeders, slaughterhouse
I mpact of zoonoses Zoonoses represent some
and laboratory workers.
of the most prevalent and serious infections
Zoonoses result from: world-wide. Examples of common zoonoses are
shown in Table 32.1. In the United Kingdom
• direct contact with animals, their excreta
zoonotic infections are uncommon, and many
and saliva
that were once endemic have declined or been
• indirect contact though food and water
eradicated in recent years (e.g. rabies, anthrax
contaminated with excreta or saliva
and brucellosis). However, the 'new' zoonoses
• arthropod vectors through the bite of an
of campylobacter enteritis, Escherichia coli ( VTEC
insect, louse or tick.
strains) and cryptosporidiosis are being reported
Within these groups, zoonoses may be further with increasing frequency (Table 32.2). Changes
classified by the mode of transmission, in farming practices, reflecting the increased
intermediate host and whether infection is part demands of the consumer, have undoubtedly
of the life cycle: contributed to the greater incidence of such
infections.
• cyclozoonoses: require more than one
vertebrate host, but no invertebrate host for Emerging zoonoses In recent years, many
transmission (e.g. tapeworm) of the newly recognised infectious diseases
• metazoonoses: infectious organisms must of man have been traced to animal reservoirs
multiply or develop in an invertebrate host (e.g. campylobacter enteritis, cryptosporidiosis,
before transmission to a vertebrate host is Lassa fever). It therefore seems probable
possible (e.g. plague and schistosomiasis) that future human pathogens will be identified
• saprozoonoses: development outside of a as zoonotic in origin rather than through
vertebrate host is required, such as on the appearance of a completely new
vegetation or in soil (e.g. Toxocara spp.). pathogenic agent.
Direction of transmission Although zoonoses Factors influencing such events might include
are usually considered to be diseases transmitted microbial changes at the molecular level, such as
from animals to man, they may also be acquisition of virulence factors, and modification
of the immunological status of individuals and
populations. The impact of AIDS has seen the
emergence of many 'new' opportunistic
infections as well as the increased prevalence
I ncidence of zoonoses in the United Kingdom
of other recognised pathogens. Social and
Disease Organism I ncidence per annum ecological conditions that influence population
Brucellosis Bruce/la abortus <10 growth and movement, farming and dietary
Leptospirosis Leptospira interrogans 50 habits, and the environment may also play a
Lyme disease Borrelia burgdorferi <10 significant role.
Salmonellosis Salmonella 30 000
Campylobacter Campylobacter 50 000 (rising) Diagnosis As with other microbial infections,
Haemorrhagic colitis and Escherichia coli (VTEC) 1500 (rising)
zoonotic diseases can be diagnosed by standard
haemolytic uraemic syndrome
Psittacosis Chlamydia pslttaci 600 laboratory techniques of culture, microscopy,
o fever Coxiella burnet ii 200 (underestimated) i mmunological and molecular analysis. When
Orf Orf virus 50 performing such investigations it is important
Toxoplasmosis Toxoplasma gondii 500 congenital infections
to determine the occupation and hobbies of a
Cryptosporidiosis Cryptosporidium parvum 5000
Ringworm Tinea (dermatophyte fungi) Unknown but common patient, as a history of animal contact may
i ndicate a zoonotic infection.
76
Examples of common zoonoses
Bacteria
Brucellosis Bruce/la Cattle, goats, pigs Birth products, food and PUO, lymphadenopathy, splenomegaly, World-wide
dairy produce nausea,weight loss
Salmonellosis Salmonella Most animals Food and dairy produce Acute diarrhoea, abdominal pain, World-wide
low-grade fever
Campylobacteriosis Campylobacter Most animals, Food and dairy produce Actue, diarrhoea, pain and fever World-wide
notably chickens
Verotoxigenic Escherichia toll Cattle Food and dairy produce Acute diarrhoea, renal failure World-wide
Escherichia toll
( VTEC)
Bubonic plague Yersinia pestis Wild rodents Flea bite Fever, swollen, tender lymph nodes South-western
(' Black Death') (especially rats) (buboes), pneumonia, black skin USA, Africa
necrosis and Asia
Leptospirosis Leptospira Rats Urine contamination of Myalgia, malaise, chills, fever, renal World-wide
( Well's disease) interrogans wound or eye and hepatic failure
Anthrax Bacillus anthracis Most mammals Animal hides Cutaneous pustules, fever, malaise, World-wide
headache, sepsis, pneumonia
('woolsorter's disease')
Pasteurella multocida Oral cavity of most Saliva from animal bite Inflammation at bite or scratch, World-wide
mammals ( especially dog or cat) abscess and cellulitis
Lyme disease Borrelia burgdorferi Most animals, Tick bite Rash, flu-like symptoms, arthritis World-wide
(especially deer
and rodents)
Psittacosis Chlamydia psittaci Birds I nhalation of bird Atypical pneumonia (flu-like, dry cough) World-wide
respiratory secretions
0-Fever Coxiella burnetii Wild and domestic Birth products, urine, Atypical pneumonia, febrile illness, World-wide
( Query fever) animals, especially faeces and milk subacute endocarditis
sheep and cattle
Endemic typhus Rickettsia typhi Rodents Louse bite Fever, flu-like symptoms, rash, World-wide
meningoencephalitis, coma
Viruses
Oil Parapoxvirus Sheep and goats Direct animal contact Large painful nodules usually on hands World-wide
Rabies Rhabdovirus All mammals Saliva from bite, scratch Severe pain at bite site, hydrophobia, World-wide
or abrasion muscle spasms, laryngospasm, extreme (some
excitability: high mortality rate exceptions)
Ebola Filovirus Unknown: possibly Person to person Fever, headache, malaise, chest Northern Zaire
monkeys discomfort, diarrhoea and vomiting: and Southern
fatality rate is 50-90%. Sudan
Lasso fever Arenavirus Rodents Rat excreta contamination Fever, haemorrhaging, renal failure West Africa
of skin abrasions, food,
water, or airborne
Yellow fever Flavivirus Monkeys Aedes mosquito bite Fever, jaundice, haemorrhaging Central and
South America
and Africa
Fungi
Taenia ('ringworm') Microsporum canis Dogs and cats Direct contact with animal Skin, hair, nail infections World-wide
Cryptococcosis and Cryptococcus Possibly birds Inhalation of spores from Pneumonia and meningitis World-wide
histoplasmosis neoformans and bird droppings
f-list oplasma
capsulatum
Protozoa
and helminths
Toxoplasmosis Toxoplasma gondii All mammals (cats Ingestion of cat faeces or Mild (flu-like), severe (mufti-organ World-wide
are definitive host) contaminated meat i nfection)
African Trypanosome Domestic cattle Tsetse fly bite General febrile illness followed by East and West
trypanosomiasis and pigs CNS invasion and coma Africa
American Domestic and wild Triatomid bug excreta, Fever, lymphadenopathy, Mexico, Central
trypanosomiasis animals contamination of bite hepatosplenomegaly, cardiac and and South
or eye CNS involvement America
Cryptosporidiosis Crypt osporidiosis Most mammals Contaminated water Mild to severe diarrhoea World-wide
parvum and food
Toxocariasis Toxocara canis Dogs ( canis) Ingestion of faeces Fever, cough, hepatomegaly, World-wide
and call and cats (call) splenomegaly and lymphadenopathy;
granuloma of the retina
Tapeworm: Taenia saginata Cattle (saginata) Ingestion of contaminated Abdominal pain, diarrhoea and weight World-wide (rare
cysticercosis and solium and pigs ( solium) meat loss: cysticerci in muscles i n developed
countries)
77
M E D I C A L
MICROBIOLOGY
Malaria
Malaria is an infection of liver and red blood Clinical features The repeated rounds of
cells caused by protozoan parasites of the genus erythrocyte invasion and rupture release toxins
Plasmodium. Malaria is one of the most serious that cause bouts of high fever. Classic symptoms
health problems facing humanity today, affecting include:
four hundred million people world-wide and
• cycles of shaking chills followed by fever and
causing 2 million deaths each year. Four species
profuse sweating
infect man: P. falciparum (the most common and
• anaemia and jaundice due to erythrocyte
dangerous), P. malariae, P. ovate and P. vivax.
destruction
Life cycle • dark pigmented urine ('blackwater fever')
from erythrocyte destruction
Malaria is spread by the bite of an infected
• liver and spleen enlargement and renal failure.
Anopheles mosquito. Only females of the species
bite humans and transmit the disease. The The time between these fever episodes can be
parasite has a complex life cycle involving characteristic of the infecting Plasmodium species
sexual reproduction in the mosquito and (Table 33.1). With P. falcipa rum this is every
asexual reproduction in liver parenchymal cells 36-48 h (malignant tertian malaria) compared
and erythrocytes (red blood cells) in humans with 72 h for P. malariae ( quartan malaria). The
(Fig. 33.1): cycle is also 48 h for P. vivax but the symptoms
are less severe (benign tertian malaria).
1. In the mosquito:
(a) Male and female gametocytes from Cerebral involvement is a serious consequence
an infected human are ingested when of falciparum malaria. The high levels of
mosquito feeds. parasitaemia lead to the schizont-containing
(b) Gametocytes undergo sexual reproduction erythrocytes blocking brain capillaries. The
in stomach to form an oocyst containing resulting hypoxia causes confusion, coma
sporozoites. and death.
(c) Oocyst penetrates the gut wall and the
The dormant liver hypnozoites formed in ovate
sporozoites enter salivary glands.
and vivax malaria can result in relapse many
(d) Sporozoites infect human when mosquito
years after the initial infection.
next feeds.
Diagnosis Malaria should be suspected in any
2. In humans:
case of fever associated with travel to endemic
(e) Sporozoites enter the blood and infect
areas. Diagnosis is made by clinical symptoms
parenchymal liver cells.
and microscopic examination of blood to
(f) Asexual reproduction (schizogony) forms
identify the erythrocytic forms. This permits
schizonts in which thousands of
the differentiation of Plasmodium species which
merozoites develop.
is vital in the correct choice of treatment.
(g) Merozoites rupture from the liver
schizonts and enter erythrocytes. Treatment Malaria can normally be cured by
(h) Ring-form trophozoites, then sporozoites antimalarial drugs (Table 33.1). Chloroquine
and finally merozoites develop. is the drug of choice, although resistance by
(i) Merozoites rupture from the cells to P. falciparum has restricted its effectiveness in
invade other erythrocytes. many parts of the world. Alternative drugs are
(j) Some merozoites form gametocytes that quinine, mefloquine and the combination of
infect the female mosquito at next feed sulfadoxine plus pyrimethamine. However,
and continue life cycle. resistance to these agents is also being reported.
Primaquine is included in ovate and vivax
In P. ovate and P. vivax infection, some
malaria to destroy the liver hypnozoites.
sporozoites remain dormant as hypnozoites in
the parenchymal cells, only starting the process Prevention Vaccines are being developed but
of schizogony months or years later. are not yet available against malaria. Travellers
to endemic areas must protect themselves
Epidemiology In spite of intensive control
from infection and seek expert advice about
measures, malaria remains widely distributed
antimalarial prophylaxis before embarking.
in the tropics and subtropics of Africa, Asia
The regimen for drug prophylaxis depends
and Latin America (Fig. 33.2). P. falciparum and
on whether resistance is present in the area.
P. vivax account for 95% of all malaria cases,
Examples include chloroquine, fansidar,
and 80% of these occur in tropical Africa.
pyrimethamine plus dapsone and chloroquine
• P. falciparum and P. malariae are the plus proguanil. Preventing mosquito bites by
predominant species in the tropics. covering limbs, using insect repellents and
• P. vivax is common in the tropics, subtropics sleeping under mosquito nets is also essential.
and some temperate regions. Stagnant water, the breeding ground of
• P. ovate is common in West Africa. mosquitoes, should also be avoided.
80
P falciparum West, East and Central 7-14 days 36-48 h Malignant tertian Cerebral malaria, Chloroquine,
Africa, Middle East, malaria haemolytic anaemia quinine, mefloquine,
Far East, South America ('blackwater fever'), sulfadoxine and
j aundice, hypoglycaemia pyrimethamine
P vivax I ndia, North and East 1 2-17 days 48 h Benign tertian Relapse due to liver Chloroquine
Africa, South America, (with relapse malaria hypnozoites with primaquine
Far East up to 3 years)
P malariae Tropical Africa, India, 13-40 days 72 h Quartan malaria Nephrotic syndrome Chloroquine
Far East (with rare relapse) with primaquine
P ovate Tropical Africa 9-18 days (with 48 h Ovale tertian Relapse due to liver Chloroquine
relapse up to 20 years) malaria hypnozoites with primaquine
81
M E D I C A L
MICROBIOLOGY
Tropical infections affect millions of people • parasites: amoebic liver abscess, early
world-wide, causing considerable human schistosomiasis, visceral leishmaniasis,
suffering and economic hardship. Far from African and American trypanosomiasis.
declining, the incidence of many tropical
infections is increasing throughout the world.
The impact of human immunodeficiency virus Diarrhoea
( HIV) and AIDS has seen the emergence of 'new'
Diarrhoea is a common complaint after foreign
opportunistic pathogens as well as the increased
travel, and acute cases will be caused by
prevalence of other recognised types. Climatic
food-poisoning organisms found also in the
changes induced through global warming have
West (e.g. salmonella, shigella, campylobacter,
aided the spread of many diseases, whilst
enteric viruses). Tropical causes are likely to be
starvation and the breakdown in sanitation that
protozoa or helminths. Infections are usually
accompanies war has seen the re-emergence of
asymptomatic in the native population but can
others. In addition, the development of drug
be severe when acquired by the non-indigenous
resistance has also dramatically influenced the
visitor.
ability to treat and control many diseases, notably
parasitic infections. Bacteria Cholera causes severe diarrhoea that
Clinicians in the West will encounter tropical may be fatal because of extensive electrolyte and
infections. The ease and speed with which the water depletion. It is endemic where standards of
globe can be traversed by air travel and the quest sanitation and hygiene are low. Up to 10% of the
for ever more exotic holiday destinations means patient's body weight can be lost in a few hours
patients can become infected and return home through the 'rice-water stool' that arises from the
infection.
before symptoms have developed. Refugees and
i mmigrants can also import infections into the
Protozoa and helminths Amoebiasis and
country or acquire them on visits home. giardiasis are the commonest infective causes
Tropical infections may be broadly classified as of chronic diarrhoea. Persistent eosinophilia
those causing fever, diarrhoea and skin diseases. implicates a worm infection, most commonly
They are caused by a variety of bacteria, viruses filariasis, schistosomiasis and occasionally
and parasites as summarised in Table 34.1. strongyloidiasis. Other causes are:
More common examples are described below. • ascariasis (the large roundworm)-heavy
infections may cause a variety of complications,
Fever including intestinal obstruction
• trichuriasis (whipworm)-chronic bloody
Malaria is the prime suspect in any patient
diarrhoea, anaemia and rectal prolapse when
presenting with fever after returning from a risk
very large numbers are present
area (e.g. the tropics and subtropics of Africa, Asia • hookworms-can cause significant blood loss
and Latin America). A blood film examination for resulting in iron deficiency anaemia
the parasite is an urgent investigation. • tapeworms-infections are common,
Typhoid and paratyphoid fevers are highly but autoinfection by the pig tapeworm
infectious bacterial causes and present as fever (cysticerosis) can be life-threatening.
with abdominal discomfort or vague abdominal
pains, rose spots on the trunk and splenomegaly.
Infected persons may become asymptomatic
Skin conditions
excretors of the organism. Ulcers are the most common skin lesions in the
tropics. The cause is usually unknown, although
Tuberculosis (TB) in the United Kingdom is
Vincent's organisms (a fusiform and a spirochaete)
30-200 times as common in immigrants as in the
and (3-haemolytic streptococci are often isolated
indigenous population. This is probably because
on culture. Mycobacteria, corynebacteria and
of increased susceptibility to the infection and
the protozoan parasite Leishmania are also
can take a form unfamiliar to doctors not
important causes.
educated in third-world countries. HIV infection
greatly increases the risk of TB, and the AIDS Leprosy is caused by an acid-fast mycobacterium
pandemic has seen a resurgence of the disease. and spread by person-to-person contact. The
condition is characterised by a variety of
Other causes of subacute or chronic imported
symptoms, but the most important is thickening
fever include:
of peripheral nerves leading to localised areas
• viruses: viral hepatitis, Lassa fever, rabies of anaesthesia in the affected tissues. Some ten
• bacteria: tick typhus, brucellosis, relapsing fever million people are affected world-wide.
84
Disease Organism Symptoms Mode of transmission Distribution Treatment
Bacteria
Cholera Vibrio cholera Copious watery diarrhoea Faecal-oral from World-wide: India, Fluid + electrolyte
('rice-water stool') contaminated water South-east Asia and replacement; oral
South America tetracycline
Bubonic plague Yersinia pestis Fever, swollen lymph nodes Rodent fleas South-western USA, Streptomycin +
('Black Death') ('buboes'), pneumonia, black Africa and Asia tetracycline
skin necrosis
Endemic typhus Rickettsia typhi Fever, flu-like symptoms, rash, Louse bite World-wide Tetracycline
meningoencephalitis, coma
Leprosy Mycobacterium Lepromatous: (progressive) Person-to-person contact Africa, India, South-east Dapsone + rifampicin
leprae skin nodules, nerve i nvolvement Asia and South America
Tuberculoid: skin lesions
( benign), severe nerve and
tissue destruction
Tropical ulcer Mycobacterium Buruli ulcer: gross, necrotising Unknown Tropical areas in all Clofazimine or rifampicin
ulcerans ulceration of the skin continents
Tuberculosis Mycobacterium Pulmonary: cough, chest pain, Person to person through World-wide Ethambutol, isoniazid,
tuberculosis fever, dyspnoea, haemoptysis respiratory secretions; milk rifampicin, pyrazinamide
and weight loss from infected cattle (in combination)
Glandular involvement
(in tropics) associated with
HIV infection
Typhoid and Salmonella typhi Fever and systemic infection Faecal-oral World-wide Co-trimoxazole,
paratyphoid fever and paratyphi from invasion of bloodstream ciprofloxacin, ceftriaxone
85
M E D I C A L
MICROBIOLOGY
Viruses
Rabies Rhabdovirus Severe pain at bite, hydrophobia, Saliva via bite, scratch, World-wide None
muscle spasms, laryngospasm, or abrasion (some exceptions)
extreme excitability
Ebola Filovirus Fever, headache, malaise, chest Person to person Northern Zaire and None
discomfort, diarrhoea and vomiting southern Sudan
Lassa fever Arenavirus Fever, haemorrhage, renal Rat excreta contamination West Africa None
failure of skin abrasions, food,
water, or airborne
Yellow fever Flavivirus Fever, jaundice, haemorrhage Aedes mosquito Central and South None
America and Africa
Protozoa
Amoebiasis Entamoeba Bloody diarrhoea and Faecal-oral via cysts Common in tropics Metronidazole,
histolytica occasionally liver infection in food and water tinidazole
Balantidiasis Balantidium coli Mild to severe diarrhoea Faecal-oral from cysts Common in tropics Tetracycline, iodoquinol
i n food and water
Malaria Plasmodium Liver, blood and CNS infection Mosquito Africa, Asia and Chloroquine, quinine,
species Latin America mefloquine, sulfadoxine
+ pyrimethamine,
primaquine
African Trypanosoma General febrile illness followed Tsetse fly East and west Africa Pentamidine,
t rypanosomiasis gambiense and by CNS invasion melarsoprol
rhodesiense
American T cruzii Fever, lymphadenopathy, Triatomid bug Mexico, Central and Nifurtimox and
trypanosomiasis hepatosplenomegaly, cardiac South America benznidazole
and CNS involvement
Leishmaniasis Leishmania Skin sores (cutaneous) nose, Sandfly North Africa, Stibogluconate,
mouth, palate destruction I ndia (cutaneous); meglumine antimonate,
( mucocutaneous) Mexico, Central amphotericin B or
and South America pentamidine
( mucocutaneous)
86
M E D I C A L
MICROBIOLOGY
Helminths
Hookworms and Ancylostoma Gut, lungs and heart infection; Larval infection Mediterranean, Mebendazole,
Strongyloidiasis duodenalis, malnutrition, pneumonitis, through skin southern USA, Central albendazole;
Necator americanus anaemia and South America, thiabendazole,
and Strongyloides Africa, Asia ivermectin
stercoralis (strongyloidiasis)
Ascariasis Ascaris As for hookworms Faecal-oral ingestion Southern USA, Central Mebendazole or
('roundworm') lumbricoides of eggs and South America, albendazole
Africa, Asia, Australia
Trichuris Trichuris trichiura Gut infection, malnutrition Faecal-oral ingestion As for Ascaris Albendazole or
('whipworm') of eggs mebendazole
Bancroftian Wuchereria Fever and lymphangitis leading Mosquito South America, I vermectin or DEC
filariasis bancrofti to obstruction of the lymphatics Central Africa,
Far East
Loaiasis Loa loa Migration of worm in eyelid, Mango fly Central and West Africa Ditto
('eyeworm') vitreous and anterior chamber
Cysticercosis Taenia solium Cysticercosis (pork tapeworm): I ngestion of cysticerci South and Central Ditto
(pork tapeworm) larvae penetrate gut and form in pork America, China,
cysticerci in muscles I ndonesia
Schistosomiasis Schistosoma Liver and bladder Burrowing into skin of South America, Praziquantel
('bilharzia') ( S. haematobium) or rectum schistosome cercariae West Indies, Africa,
( S. mansoni, S. japonicum) from aquatic snails Middle East, Egypt,
Far East
87
M E D I C A L
MICROBIOLOGY
The majority of patients present with particular care concerning travel, occupational
symptom/physical sign complexes compatible history and hobbies, pets and animal contact,
with only a few diseases, and they require little drug prescriptions and other drug intake,
investigation. Other clinical presentations, such familial diseases, previous illness and alcohol
as pyrexia or fever of unknown origin (PUO or consumption.
FUO), are more difficult because they have few
A complete examination should include
signs and symptoms, so that the list of differential
examination of the teeth, ears, fundoscopy and
diagnoses is large and the need for investigation
review of the skin in good light for faint rashes.
correspondingly greater. 'Classic' PUO has three
This must be repeated at frequent intervals to
features:
spot important developing or fleeting physical
• an illness of more than 3 weeks' duration signs. Temperature should be recorded
• a temperature greater than 38.3°C (101°F) on methodically, although the great majority of
several occasions patients never display the characteristic patterns
• no specific diagnosis after a week of hospital of fever described in the textbooks.
inpatient investigation.
Investigation may include: samples sent for
With the changing pattern in hospital admissions, laboratory testing; non-invasive tests such as
shorter inpatient times and more use of diagnostic radiology and ultrasound and
community and outpatient services, and also radionuclide scanning; skin testing, essentially
the development of a greater range of powerful the tuberculin test for infection with
diagnostic procedures, the third criterion may Mycobacterium tuberculosis; and invasive testing
be replaced by a minimum set of investigations such as biopsy, endoscopy and surgical
(Table 35.1) rather than a timed period in exploration. A possible minimum set of
hospital. There are over two hundred reported investigations is listed in Table 35.1; further
diverse causes of PUO, which vary slightly investigation will depend upon what has already
according to age (Fig. 35.1). As the number of been done, and clues that may be obtained from
conditions that has to be considered is so large, the history and examination, working through
some clinicians divide patients into further all the possible differential diagnoses.
categories such as neutropaenic PUO, nosocomial
PUO and HIV associated PUO, to focus on Causes Some well-recognised causes of PUO
particular causes and therefore streamline their are given in Table 35.2. However, in the majority
investigation. of cases, the cause is a familiar disease with an
unusual presentation, rather than a rare disorder:
It is important to get a prompt diagnosis, as
this may improve the prognosis for the patient • Infections are the single most common cause
through early treatment, and also prevent of PUO, particularly in the young. They may
the risk of transmission to others in the case of be difficult to diagnose because the patient
communicable infections such as tuberculosis. was on antibiotics when the sample was
Investigation is expensive both in time and taken, because the site of infection is hidden
resources, and it is equally important to ensure or because the infectious agent is difficult or
that the patient does indeed have a pyrexia and i mpossible to culture in the laboratory.
that it is not a factitious fever. Body temperature • Neoplasms are an important cause of PUO,
is normally higher in the evening than the particularly in the elderly. Certain tumours
morning, but some healthy individuals have seem to cause pyrexia themselves, others may
an exaggerated circadian temperature rhythm. produce it because of necrosis or secondary
Others may invent physical diseases to gain infection.
medical attention ( Munchausen syndrome), • Collagen-vascular disease.
and an unexplained temperature is one means • Miscellaneous.
of doing this, either by manipulating the • Undiagnosed: this category is largely made
temperature recording device or even injection up of patients who recovered from a benign
of contaminated materials. febrile illness before a specific diagnosis
was made.
I nvestigation Every case requires a
comprehensive history, careful and repeated Management There is no treatment for the
physical examination, as well as a range of clinical presentation of PUO itself; success lies in
diagnostic tests and procedures. History should finding the cause of the PUO and then managing
include a thorough systems review with that condition.
88
Undiagnosed ???
89
M E D I C A L
MICROBTOLOGY
90
Emerging problems of drug resistance
Scabies Lindane
91
Principles of hospital
i nfection control
Hospital infection increases patient morbidity, • Staff should have health checks before
mortality, length of stay and treatment costs. employment and have necessary
It is estimated that about five thousand patients immunizations.
die as a result of hospital-acquired infection in • Staff should report infections (e.g. diarrhoea)
Britain each year. Control of infection is therefore and needlestick injuries.
an essential element of hospital practice.
II: Prevent transmission Blocking routes of
transmission may reduce the risk of hospital-
Definitions
acquired infection. Organisms may be transferred
Infections acquired by patients or staff in hospital by the airborne route or by contact spread. Few
are termed hospital-acquired or nosocomial organisms exist as isolated particles in air but
(Figs 37.1 and 37.2). The source of infection may many are carried on dust particles, which largely
be other people (cross-infection), the patient's consist of skin scales. Staphylococci and other
own organisms (endogenous infection) or via Gram-positive bacteria may be spread by air,
contaminated food, fluids equipment or the particularly from patients or staff with infected
environment. In England the prevalence of lesions or those who shed increased numbers of
hospital-acquired infection is approximately epithelial cells. The airborne route may also
10%, whereas the annual incidence is nearer 5%. spread respiratory viruses and bacteria during
The sources of hospital-acquired infections are coughing or sneezing. Airborne spread may be
shown in Fig. 37.3. controlled in two ways:
• the use of filtered air in ventilation systems,
Control of hospital infection e.g. operating theatres
Each hospital has an infection control officer • isolation rooms or wards.
(usually a consultant microbiologist) and Patients with organisms that pose a risk for others
infection control nurse(s) who together constitute are placed in source isolation to minimise spread.
the infection control team. This team advises on Protective isolation is provided for highly
the prevention and control of hospital infection, susceptible patients (e.g. immunosuppressed
utilising policies provided and updated by the
hospital infection control committee. The team patients immediately following organ
transplants). Ideally, isolation rooms should
also monitors infection by surveillance - have pressurised ventilation systems which
typically this involves tracking so-called alert direct airflow in (for source isolation) or out of
organisms from sites such as wounds (e.g. Staph. the room (for protective isolation).
aureus (including MRSA) and Strep. pyogenes),
faeces (e.g. Salmonella spp. and Clostridium Contact spread is transmission of organisms by
difficile) and respiratory tract (e.g. Mycobacterium direct contact between the patient and equipment
tuberculosis). Another important function of the or staff. This route is minimised by aseptic
infection control team is education for all groups technique, taking particular care when handling
of staff to update them on new issues and dressings, secretions and excretions that may
improve compliance with policies. transmit organisms directly by hands or via
contaminated equipment. However, any clinical
The three principles of infection control are: contact with infected or colonised patients
I: Exclude the source of infection Inanimate (or their immediate environment) may transfer
sources of infection can be identified and in many organisms to the hands of staff. It is therefore
cases excluded from hospitals by ensuring the very important that all staff are aware of the
provision of: importance of hand hygiene - the single most
i mportant aspect of infection control (Table 37.1
• sterile instruments, dressings and
and rig. 37.4).
intravenous fluids
• clean linen III: Improve the patient's resistance to
• uncontaminated food and drink i nfection This may be achieved by:
• cleaned and disinfected or disposable
equipment • meticulous technique during surgery -
• a safe and clean environment including water haemostasis, removal of dead tissue and foreign
and air of appropriate quality bodies, avoiding wound drains where possible
• clear policies for safe disposal of hospital waste. • care of invasive devices, e.g. intravascular
lines, urinary catheters and endotracheal tubes
Both patients and staff may act as a source of • control of underlying disease, e.g. diabetes
infection, so: • enhancing immunity by immunisation,
• Infected and colonised patients should be e.g. tetanus
identified by adequate microbiological • avoiding unnecessary antimicrobial treatment
investigations and infections treated with • appropriate use of antimicrobial prophylaxis.
appropriate antimicrobials.
Hand hygiene
Social handwashing
Wet hands, wash with soap Routine duties and before eating
Rinse and dry thoroughly Visible contamination with excretions/secretions
FIG 37.1 Main hospital-acquired infections FIG 37.2 Specialities with higher prevalence rates of
hospital-acquired infections
95
M E D I C A L
MICROBIOLOGY
Sterilisation and disinfection are routinely used irradiation or chemical treatment are used.
in hospitals and laboratories to eliminate or Examples include:
control the presence of potentially pathogenic
• gamma irradiation
micro-organisms for the protection of patients
• ultraviolet light
and staff. The two procedures are distinct and
• glutaraldehyde liquid
should not be confused:
• ethylene oxide gas
• Sterilisation is the process by which all micro- • formaldehyde gas.
organisms are removed or killed.
Micro-organisms can also be physically removed
• Disinfection is the process by which
from solutions by trapping them on porous
vegetative, but not all, micro-organisms are
membrane filters. However, viruses may pass
removed or killed.
through the pores.
The choice of sterilisation or disinfection is
Control of sterilisation In dry and moist heat
dictated by the infection risk and may be defined
sterilisation, it is critical that adequate temperature
as high, intermediate or low (Table 38.1).
and exposure times are attained. This will vary
Physical cleaning with detergents (sanitisers) is with the nature and size of the load:
often sufficient to remove microbes and organic
• Thermocouples with chart recorders give a
material on which they thrive. It is also a
visual record that the correct temperature and
prerequisite to effective sterilisation or disinfection.
holding time were achieved during the
sterilisation cycle.
Sterilisation
• Browne's tubes and autoclave tape contain a
Sterilisation is used when the inactivation of all chemical that changes colour when exposed
micro-organisms is an absolute requirement. This to various temperatures.
is achieved by physical, chemical or mechanical • Paper strips impregnated with heat-resistant
means (Table 38.2). Dry or moist heat are the most Bacillus stearothermophilis spores can be placed
commonly used methods in hospitals and inside autoclave loads: spore survival indicates
laboratories. a problem with the autoclave process.
Dry heat Dry heat is only suitable for items able to
withstand temperatures of at least 160°C and is Disinfection
used to sterilise glassware and metal instruments. Disinfection is used to contain the presence of
Complete combustion in high-temperature micro-organisms, usually for the purpose of
incinerators is used for the disposal of human infection control. Disinfectants have a limited
tissues and contaminated waste: spectrum of antimicrobial activity, notably the
• hot air ovens at 160-180°C for 1 h inability to kill bacterial spores, and cannot be
• incineration at >1000°C used to guarantee sterility. The efficacy of many
Moist heat Moist heat sterilisation uses lower disinfectants is also limited by their corrosive and
temperatures than dry heat and can better potentially toxic nature, and rapid inactivation by
penetrate porous loads. The most effective and organic matter.
commonly used method is autoclaving.
Disinfectants that can be applied directly to
Autoclaves are similar to domestic pressure
human skin to prevent, or possibly treat,
cookers, operating on the principle that water
infections are termed antiseptics. Others, termed
under pressure boils at a higher temperature.
biocides, are used in industrial applications to
For example, at 15 psi the steam forms at 121°C
control microbial fouling and the presence of
and is sufficient to kill all micro-organisms,
potentially pathogenic micro-organisms such as
including spores.
Legionella pneumophila in water-cooling towers.
Boiling at 100°C for 5 min will kill vegetative
Chlorine-and phenolic-based disinfectants are
organisms, but spores can survive.
most widely used in hospitals and laboratories.
Pasteurisation at 63°C for 30 min or 72°C for Appendix 7, p. 131 lists some common
20 s is used in the food industry to eliminate disinfectants and antiseptics, their spectrum of
vegetative pathogenic micro-organisms that can microbial activity and application.
be transmitted in milk and other dairy products ( Examples of disinfectant use include:
e.g. Mycobacteria, Salmonella, Campylobacter and
Brucella). It also prolongs the shelf-life of • surface and floor cleaners
products by removing spoilage organisms • containment of potentially infectious spillages
(see also ultra-heat treated (UHT) milk, Table 38.2). • skin and wound cleansing (antiseptics)
• treatment of drinking and bathing waters
Chemical and physical For items that would be
• contact lens hygiene
damaged by heat, other methods employing
• industrial processes (biocides).
1
Risk Application Requirement Examples
Thermometers, respiratory
Intermediate Contact with mucous Disinfection
membranes (although sterilisation apparatus, gastroscopes,
may be desirable) endoscopes
Dry heat Heating in a flame: hot air oven at Direct oxidisation Inoculating loops; metal instruments and glassware;
160-180°C for 1 h; incineration at >1000°C disposal of infectious waste
Moist heat Autoclaving: 121'C for 15 minor 134°C Protein denaturation Preparation of surgical instruments and dressings;
for 3 min production of laboratory culture media and reagents;
disposal of infectious waste
Boiling: 100°C for 5 min Spores will survive; not suitable for sterilisation
Steaming: 100°C for 5 min on Named after its originator: in a suitable liquid, spores
3 consecutive days (Tyndallisation) will germinate on cooling and are then killed by the next
day's steaming (the third heating is for extra security)
Pasteurisation: 63°C for 30 min or 72°C Treatment of milk to remove pathogenic and food
for 20 s spoilage micro-organisms
Ultra-heat treated (UHT) milk: 135-150°C Treatment of milk to give indefinite shelf-life
Irradiation Cobalt-60 gamma irradiation Damage of DNA through Heat-labile items such as plastic syringes, needles and
free-radical formation other small single-use items
Chemical Ethylene oxide gas Alkylating agents causing protein Toxic and potentially explosive; used for items that
and nucleic acid damage cannot withstand autoclaving (e.g. heart valves)
Filtration Passing solutions through a defined Physical removal of microbes Preparation of laboratory culture media, reagents
pore-sized membrane (e.g. 0.2 pm-0.45 pm) and some pharmaceutical products
2
M E D I C A L
MICROBIOLOGY
10 0
Basic measures used in food preservation General measures for the prevention
of infectious disease
Method Example
• Education
Complete removal of food-spoilage Canning involves temperatures of • Adequate nutrition
micro-organisms with maintenance 115°C for 25-100 min intervals; • Hygienic living conditions
of asepsis not absolutely effective
• High level of water sanitation
Low temperature Refrigeration, freezing • Effective waste disposal
' Cook-chill' • I mmunisation
• Prompt control of outbreaks of infection
High temperature Pasteurisation
10 1
M E D I C A L
MICROBIOLOGY
102
Classes of antibacterials
Target site Antibacterial class Example agents Comments/adverse reactions
Protein synthesis Aminoglycosides Gentamicin, amikacin Potential nephro- and oto-toxicity; assay required
Tetracyclines Tetracycline, doxycycline Stain teeth and bone
Chloramphenicol Chloramphenicol Potential marrow toxicity
Macrolides Erythromycin Often used in penicillin-allergic patients
Lincosamides Clindamycin Associated with pseudomembranous colitis
Fusidic acid Fusidic acid May cause jaundice
Nucleic acid synthesis Sulphonamides Sulphamethoxazole Rarely used because of toxic reactions
Trimethoprim Trimethoprim Mainly used in treatment of UTI
Quinolones Nalidixic acid, ciprofloxacin Early quinolones have limited Gram-positive activity
Rifamycins Rifampicin Stains tears/urine, may cause jaundice
Nitroimidazoles Metronidazole Antabuse effect with alcohol
Cell membrane function Polymyxins Colistin Used for bowel decontamination or by inhalation
FIG 40.1 Antibacterial sites of action FIG 40.2 Mutational and transmissible resistance
103
M E D I C A L
MICROBIOLOGY
The aim of successful antibacterial therapy is to resistance. Following the significant increase in
select the right agent, dose, route and duration resistance rates in Gram-negative bacteria, we
using laboratory data where and when available. have now seen a recent increase in multiply
The reality is that up to 30% of antibacterial resistant Gram-positive bacteria - notably
prescriptions may be unnecessary because: methicillin-resistant Staph. aureus ( MRSA) and
vancomycin-resistant enterococci (VRE). This
• there is no clear evidence of infection
has lead to the fear of a post-antibiotic era where
• the infection does not require antibacterials,
many infections may be untreatable.
e.g. viral respiratory tract infections
• the wrong agent has been chosen. The recommended duration of antibacterial
therapy has decreased over recent years. For
There are now over 80 antibacterials available
many acute infections, treatment for 5-7 days is
on the British market, and making a rational
often adequate, and many uncomplicated urinary
selection for a particular patient requires a logical
tract infections will respond to 3 day regimens.
approach. In practice many prescriptions are
In endocarditis and infections of bone and joints,
based simply on the suspected site of infection,
therapy is continued for several weeks, and
e.g. respiratory or urinary tract. A more
successful treatment of tuberculosis requires at
appropriate selection is based on a combination
least 6 months of combination therapy.
of clinical and laboratory findings, refining the
choice by considering specific patient and drug
factors as shown in Fig. 41.1. Whenever possible,
Laboratory aspects
appropriate specimens should be collected before
antibacterial therapy is started. Susceptibility testing is readily available for most
antibacterial agents and generally distinguishes
Rational antibacterial usage can be categorised as
isolates as sensitive or resistant (although the
• initial empirical therapy ('best guess' or 'blind') term intermediate is sometimes used) (Fig. 41.2).
• specific or definitive treatment (generally In some circumstances (e.g. infective endocarditis)
directed by laboratory reports) a quantitative result is required and this is
• prophylaxis (see below). usually reported as a minimum inhibitory
concentration (MIC). Such reports are helpful
In the following situations it may be appropriate
when comparing the susceptibility of the isolate
to consider combined therapy:
with antibiotic concentrations achievable in the
• broad-spectrum cover when blood or at the specific site of infection.
(a) the pathogen is unknown, e.g. septicaemia
Some antibacterials such as gentamicin and
(b) multiple pathogens are possible,
vancomycin have a narrow therapeutic index -
e.g. perforated large bowel
the margin between therapeutic and potentially
• to prevent emergence of resistance,
toxic concentrations is small. To ensure that safe
e.g. anti-tuberculous therapy
and effective concentrations are achieved with
• to provide enhanced activity, e.g. treatment
these agents, antibacterial assays are performed
of infective endocarditis with penicillin and
(Fig. 41.3).
gentamicin. Such a combination is said to be
synergistic - the activity is greater than the Prophylaxis is defined as the use of antimicrobial
sum of the individual activities. When two agents to prevent infection in susceptible patients.
antibacterials significantly interfere with each The majority of antibacterial prophylaxis is
other the combination is antagonistic. employed in surgery, although there are a few
medical indications (Table 41.1). The principles
It is important to minimise unnecessary
of surgical prophylaxis are:
prescriptions, because all antibacterial usage may
be associated with • It must be an adjunct to good surgical
technique.
• unwanted effects, e.g. rash, diarrhoea
• The infection to be prevented occurs
• increasing costs - antibacterials typically
(a) frequently (e.g. large bowel surgery)
account for around 15% of the drug costs of a
(b) rarely but with disastrous consequences,
teaching hospital.
e.g. cardiac valve surgery.
• increasing resistance in both Gram-positive
• Likely pathogens and susceptibilities are
and Gram-negative species.
predictable.
Antibacterials are unique in that they have an • Agents have proven efficacy.
i mpact on the population as well as the individual • Route and timing ensure adequate
patient for whom they were prescribed. Increasing concentrations at time of procedure.
(and frequently unnecessary) use of antibacterials • Duration of prophylaxis is generally < 24 h
is leading to a corresponding increase in bacterial - usually a single dose.
104
FIG 41.1 Rational antibiotic selection
Vascular surgery
Orthopaedic implant surgery
Gynaecological surgery
Lower-limb amputation
Cardiac surgery
105
L
M E D I C A L
MICROBIOLOGY
The replication of viruses depends on the use This area of drug development is particularly
of the biochemical machinery of the host cell. rapid, and new classes of drugs are anticipated.
Selectivity of antiviral drugs is, therefore,
harder to achieve than with antibacterial drugs.
There are, however, several aspects of the virus
Other antiviral agents
replication cycle that can be targeted (Fig. 42.1). Ribavirin is a nucleoside analogue that has
Optimal therapy depends on rapid diagnosis, broad-spectrum in-vitro activity. Its main use
and this is particularly difficult when the virus has been for severe RSV infections in children,
has a long incubation period or prodrome. particularly those with congenital
Latent viruses also prove relatively resistant to cardiopulmonary disorders. It is also useful
antiviral therapy. clinically in patients with severe influenza B
and Lassa fever.
Nucleoside analogues have also been developed Phosphonoformate is an anti-herpes drug which
for the treatment of asymptomatic and is used as an alternative to aciclovir if resistance
symptomatic AIDS, and post-exposure to the latter develops or to ganciclovir in
prophylaxis (Table 42.1). These act as inhibitors cytomegalovirus treatment. It has an unusual
of viral reverse transcriptase (RT). Specificity is side effect of causing penile ulcers.
poor, so that all these drugs are toxic: bone
There have been many drugs, such as pirodavir
marrow suppression, pancreatitis and myositis
for rhinovirus and antisense therapy for human
are not uncommon and may be dose-related.
papillomavirus infections, which have an in-vitro
Rapid evolution of the virus has also meant that
but not in-vivo effect. Drug engineering is likely,
resistance inevitably develops. As resistance to a
however, to produce chemical derivatives which
specific drug is coded for by particular genetic
enhance the latter.
mutations, this has been minimised by the use of
combination of nucleoside analogues. Optimal
combination therapy also uses other classes of Monitoring of antiviral therapy
drugs which interfere with different parts of the
Antiviral resistance has emerged with the more
replication cycle.
widespread use of antivirals. Antiviral
Non-nucleoside RT inhibitors and drugs that susceptibility testing methods are now available
inhibit the action of the viral protease have also if clinical resistance occurs, and, in future,
been developed for use in combination with antiviral load measurements will be developed.
nucleoside analogues (Table 42.1). They are not Clinical resistance does not, however, equate
without serious side effects, and resistance also with lack of in-vitro susceptibility of an isolate to
develops to these drugs. the drug.
10 8
FIG 42.1 Targets for drug therapy in viral replication cycle, FIG 42.2 Postulated antiviral effects of interferons
with examples of drugs
10 9
M E D I C A L
MICROBIOLOGY
Antifungal therapy
Fungi are eukaryotic organisms and share many Azoles These are synthetic compounds that
common biological and metabolic features with inhibit ergosterol biosynthesis. They are an
human cells. As a consequence, antifungal agents important class of antifungal agents, being
are potentially toxic to our own cells in their mode effective in both superficial and systemic fungal
of action. This limits the number of compounds infections, whilst showing reduced toxicity
available for the treatment of human mycoses. compared with amphotericin B:
In addition, many fungi also have detoxification
• fluconazole - effective in the treatment of
mechanisms that remove the drugs.
systemic candidiasis and cryptococcosis
Fungal infections are termed mycoses and these • itraconazole - superficial, subcutaneous and
may be either superficial (localised to the systemic infections, including aspergillosis.
epidermis, hair and nails), subcutaneous
The following azoles are also sometimes used but
(confined to the dermis and subcutaneous tissue)
have largely been superseded by the introduction
or systemic (deep infections of the internal organs).
of fluconazole and itraconazole:
Superficial mycoses caused by dermatophytes
• ketoconazole - topical therapy for
are usually treated by application of creams or
dermatophyte and cutaneous candidiasis
ointments to the infected area (topical therapy).
• miconazole - topical therapy for
Subcutaneous and systemic mycoses require oral
dermatophyte and cutaneous candidiasis.
or intravenous administration (systemic therapy).
In vaginal candidiasis ('thrush'), treatment may The following azole antifungals are also used in
be given using antifungal pessaries. Some the topical treatment of superficial mycoses:
antifungal agents are too toxic for systemic use
• clotrimazole - dermatophyte, oral,
but can be used safely in topical therapy of
cutaneous and vaginal candidiasis
superficial mycoses. Antifungal agents are also
• econazole nitrate - dermatophyte, cutaneous
used prophylactically in patients receiving
and vaginal candidiasis
immunosuppressive therapy to prevent infection
• isoconazole - vaginal candidiasis
by opportunistic fungi from the environment
• sulconazole nitrate - fungal skin infections.
and the normal flora of the body. Examples are
given below, and their uses are summarised in Pyrimidines Synthetic analogues of pyrimidine,
Table 43.1. they are converted inside fungi to compounds
that replace uracil in RNA synthesis and interfere
As with antibacterial drugs, many antifungal
with protein production:
agents are derived from the fermentation
products of certain fungi (e.g. Streptomyces and • Flucytosine (5-fluorocytosine) is converted to
Penicillium). The principal targets and mode of 5-fluorouracil which becomes incorporated
action of antifungal drugs are through the into the RNA, causing abnormalities in
disruption or inhibition of fungal: protein synthesis. Mainly used in the
treatment of yeast infections. Drug resistance
• cell wall integrity
can arise during treatment. Usually used in
• cell wall biosynthesis
combination with amphotericin B for the
• RNA synthesis
treatment of cryptococcosis, disseminated
• cell division and nucleic acid biosynthesis.
candidiasis and fungal endocarditis.
Polyenes These bind to sterol components
Benzofurans These act principally through the
(notably ergosterol) of the fungal cell membrane,
inhibition of cellular microtubule formation
causing increased permeability, leakage of
preventing mitosis (cell division). They also
cellular components and cell death:
inhibit nucleic acid biosynthesis:
• Nystatin is not absorbed by the gut and is too
• Griseofulvin is the only medically useful
toxic for parenteral use. It is used as a topical
agent of the group. Given orally, the drug is
preparation in the treatment of ophthalmic,
concentrated from the blood-stream into the
oral and vaginal candidiasis.
stratum corneum of the skin. Hence it is used
• Amphotericin B is the most important
in the treatment of dermatophyte infections.
member of the polyene antifungals. It is
active against a wide range of fungi but not Allyamines These are new synthetic agents that
dermatophytes. It is the drug of choice in act on fungal ergosterol synthesis:
the treatment of systemic fungal infections.
• Terbinafine can be administered orally or
However, amphotericin B is potentially toxic
topically in the treatment of dermatophyte
and can result in renal damage. It is now
and superficial candidiasis.
commonly given as a liposomal preparation
in which the drug is encapsulated in Cotrimoxazole Cotrimoxazole (trimethoprim
phospholipid-containing liposomes, thereby plus sulphamethoxazole) is used in the treatment
reducing toxicity. and prophylaxis of pneumocystis pneumonia.
110
Summary of antifungal therapy
Superficial mycoses
Dermatophytes (ringworm); Griseofulvin Oral Low toxicity but should not be used in patients with
pityriasis versicolor li ver disease
Terbinafine Oral or topical Low toxicity and highly effective
Itraconazole Oral Minor side effects: headache, nausea, vomiting
Candidiasis Fluconazole Oral Some Candida species, other than C. albicans, show
innate resistance
Nystatin Topical
Clotrimazole Topical
Itraconazole Oral
Subcutaneous mycoses
Sporotrichosis Amphotericin B Oral, i.v. infusion High risk of toxic reactions: fever, rigors, headache,
vomiting, nephrotoxicity (long-term); reduced toxicity
with liposomal preparations
Terbinafine Oral or topical
Itraconazole Oral
Systemic mycoses
Candidiasis and cryptococcosis Amphotericin B Oral, i.v. infusion
Flucytosine + amphotericin B Oral, i.v. infusion Flucytosine is not used alone, as drug resistance can
arise during treatment; may cause nausea, vomiting,
neutropenia and jaundice
Fluconazole i.v. infusion
Aspergillosis Amphotericin B Oral, i.v. infusion
Histoplasmosis; blastomycosis; Ketoconazole (amphotericin B for Oral
coccidioidomycosis; coccidioidomycosis CNS involvement)
paracoccidioidomycosis
Pneumocystis Cotrimoxazole (trimethoprim Oral Effective only against Pneumocystis carinii
+ sulphamethoxazole)
Pentamidine i .m. and aerosolised Toxic reactions when given i.m.
i.v., intravenous; i.m., intramuscular
11 1
M E D I C A L
MICROBIOLOGY
Antiprotozoal and
antihelminthic therapy
Recent years have seen many advances in the antimonial compounds in the treatment of
parasitology; however, the treatment of many leishmaniasis. It is thought to alter parasite
infections remains unsatisfactory. Effective surface membrane permeability, causing leakage
therapeutic agents are limited and of of intracellular components.
disappointing activity because:
Antimalarial agents are discussed elsewhere
• Similarities between parasite and human cells (see Chapter 33).
can result in drug side effects.
• Drugs may not be active against all biological Antihelminthic agents ( Table 44.2)
forms of an organism (cyst and eggs are
particularly resistant). Protozoa and helminths are physically and
• Drug resistance has limited the effectiveness biologically distinct. Drugs active against one
of many agents, particularly in malaria. are not usually active against the other.
• There are no vaccines available against human Albendazole is an antibiotic chemically related
parasites. to metronidazole that has antihelminthic activity
by conversion in the liver to the active form
Antiprotozoal agents ( Table 44.1) of albendazole sulphoxide. It is used to treat
hookworms, strongyloidiasis, ascariasis,
Metronidazole is one of the nitro-imidazole
enterobiasis and trichuriasis. It has also proved
antibiotics active only against anaerobic
effective in some microsporidial infections.
organisms. It is highly effective in the treatment
of amoebiasis due to Entamoeba histolytica, Mebendazole is a synthetic benzimidazole that
trichomoniasis and giardiasis. It is also used to is highly effective against hookworms, ascariasis,
treat anaerobic bacterial infections. Inside the enterobiasis and trichuriasis. It acts by selectively
organism it is reduced to the active form, binding to helminthic tubulin, preventing
producing DNA damage. The related compound microtubule assembly. This results in parasite
tinidazole is also effective against these protozoa. i mmobilisation and death. The related compound,
thiabendazole is used in strongyloidiasis.
Metronidazole is less effective against the cyst
form of E. histolytica, and alternative agents Diethylcarbamazine (DEC) is active against the
such as diloxanide furoate are used to treat microfilaria: bancroftian filariasis ('elephantiasis'),
asymptomatic cyst excretors. loaiasis ('eyeworm') and onchocerciasis ('river
blindness'). DEC causes paralysis of the worms
Melarsoprol is a trivalent arsenical active against
and also alters the surface membranes, resulting
African trypanosomiasis ('sleeping sickness'). It
in enhanced killing by the host's immune system.
is thought to inhibit parasite pyruvate kinase and
However, therapy usually causes severe itching
possibly other enzymes involved in glycolysis.
( Mazzotti reaction), and DEC is now considered
Melarsoprol crosses the blood-brain barrier and
too toxic for use.
is therefore effective in late stage disease when
the trypanosomes have infected the central Ivermectin has replaced DEC in the treatment of
nervous system. the microfilariae because of reduced toxicity. It is
a macrolytic lactone which blocks the parasite
Pentamidine is a diamidine compound used
neurotransmitter GABA, preventing nerve
in the early stages of African trypanosomiasis,
signalling and resulting in paralysis. The
some forms of leishmaniasis and pneumocystis
introduction of ivermectin has been a major
pneumonia. It is thought to act by interacting
advance in the treatment of onchocerciasis. It has
with parasite DNA (particularly kinetoplast DNA
also been shown to have good activity against
of Trypanosoma and Leishmania), preventing cell
nematodes and is increasingly being used in the
division.
treatment of strongyloidiasis.
Nifurtimox is a nitrofuran active against
Praziquantel is an isoquinoline derivative active
American trypanosomiasis (Chagas' disease) in
against trematodes (flukes) and cestodes
the acute phase of infection. It acts by forming
(tapeworms). In causes increased cell permeability
toxic oxygen radicals within the parasite. The
to calcium ions, resulting in contraction and
nitroimidazole derivative benznidazole is used
paralysis. In schistosomiasis, the trematodes are
as an alternative treatment.
then swept to the liver where they are attacked
Pentavalent antimony compounds by phagocytes. With cestodes, the tapeworm
(stibogluconate and meglumine antimonate) are detaches from the gut wall and is expelled with
used to treat leishmaniasis. However, sensitivity the faeces.
varies among species and geographic location.
Niclosamide is also used in the treatment of
Their mode of action is uncertain but is thought
adult tapeworms although praziquantel is
to affect parasite metabolism.
preferred as it is active against both larvae and
Amphotericin B is an antifungal agent active adults of Taenia solium (pork tapeworm) and may
against Leishmania and is used as an alternative to prevent cysticercosis autoinfection.
112
Common antiprotozoal drugs
Amoebae
Entamoeba histolytica Amoebiasis Metronidazole, tinidazole, diloxanide furoate (asymptomatic cyst excretors)
Flagellates
Giardia lamblia giardiasis Metronidazole, tinidazole
Ttrypanosmoma African trypanosomiasis (sleeping sickness) Pentamidine isethionate (early stages), melarsoprol (late stages when
CNS involved)
American trypanosomiasis (Chagas' disease) Nifurtimox, benznidazole
Apicomplexa
Toxoplasma gondii Toxoplasmosis Pyrimethamine + sulphadiazine, spiramycin (in pregnancy and neonatal
infection), azithromycin, atovaquone (cysticidal)
Nematodes (worms)
Necata americanis Hookworm Mebendazole, albendazole
Ancylostoma duodenale
Strongyloides stericoralis Strongyloidiasis Thiabendazole, ivermectin
Ascaris lumbricoides Ascariasis ('roundworm') Mebendazole, albendazole
Toxocara canis and T cati Toxocariasis: visceral or ocular larval migrans Diethylcarbamazine (DEC), mebendazole, albendazo
Trichuris trichiura Trichurias ('whipworm') Albendazole, mebendazole
Enterobius vermicularis Enterobiasis ('pinworm'/'threadworm') Albendazole, mebendazole
Filaria
Wuchereria bancrofti Bancroftian filariasis ('elephantiasis') I vermectin, DEC
Onchocerca volvulus Onchocerciasis ('river blindness') I vermectin, DEC
Loa loa Loaiasis ('eyeworm') Ivermectin, DEC
Cestodes (tapeworms)
Taenia saginata Taeniasis ( beef tapeworm) niclosamide
Praziquantil,
Taenia solium Cysticercosis (pork tapeworm) niclosamide
Praziquantil,
Echinococcus granulosus Echinococcosis, hydatidosis, hydatid cyst (dog tapeworm) Albendazole and surgical removal of cysts
Trematodes (flukes)
Schistosoma spp. Schistosomiasis ('bilharzia') Praziquantel
Fasciola hepatica Fascioliasis Bithionol
11 3
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Infectious disease is an area in which derived from the Digitalis plant is a well-known
pharmaceutical medicines allow treatment with example. A standard therapy for warts has been
eradication of the disease rather than mere podophyllin from the herb Podophyllum peltatum.
palliation which occurs with other common Artemeter and sodium artenusate (new treatments
disorders such as rheumatic and cardiovascular for malaria) have been derived from artemisin,
diseases. In the developing world, pharmaceutical a natural product from Artemesia annua used as a
medicines have prohibitive costs, and alternative herbal remedy for centuries. Phyllanthrus amarus,
remedies are used. Even in developed countries, duckweed plant, has been the source of a remedy
when diseases are chronic or recurrent, alternative for jaundice in Asia for centuries; case-control
remedies may have a role as adjunctive or studies of its use for treating chronic hepatitis B
replacement therapy. Some infections are, in have shown benefit and offer prospects for the
any case, already difficult to treat with known treatment for a disease that is not well-managed
antibiotics, and others are due to organisms by currently licensed drugs. A component of
that have become resistant, such as VRE, MRSA chilli peppers, capsaicin, has antiviral properties
and VRSA. Common colds are the commonest but is now used in herpes zoster infections
infections for which non-prescription medicines because of its ability to control zoster-associated
are taken: most treatments are for symptomatic pain. There are many pharmaceutical companies
relief only, but vitamin C and zinc tablets have now exploring this area of phytopharmacy, also
been used in an attempt to treat or prevent the known as ethnobotany if based on traditional
infection. The practice of evidence-based medicine remedies. Evaluation and control of such
is being applied to these forms of therapy. therapies is likely to be subject to the same
stringency as other drugs, with the recognition
Psychotherapy The science of
that such treatments are not without side effects.
psychoneuroimmunology has shown that the
systems of the body do not work in isolation. Other strategies Many viruses are temperature
Psychological status, and moods, have been sensitive and do not replicate outside a defined
shown to have effects on the immune system, range. This has been exploited for the treatment
possibly via neural and endocrine networks. of common colds, as the two commonest causes,
There is good evidence that a positive emotional rhinoviruses and coronaviruses, replicate best
outlook leads to lower frequency and severity of at 33°C. Devices that raise the temperature
common colds irrespective of other known risk inside the nose to above 35°C abort replication.
factors. Supporting this is the finding that these Unfortunately for this approach, there are other
same people have an enhanced cell-mediated viruses that cause the common cold which
i mmunity. Decades ago, psychotherapy was replicate well at the higher temperature.
described in the medical literature as successful
therapy for common colds but was not pursued. Controlling bacteria-bacteria communication,
Use of psychological manipulation is now used which occurs through substances known as
for control of recurrent infections, such as genital homoserine lactones, is a strategy that is under
herpes, with reported success, but has yet to be exploration. This approach may have the
fully evaluated in case-controlled studies. inherent advantage, if successful, of encouraging
Similarly, there needs to be a full evaluation of pathogens to be commensals and beneficial.
the role of mood on vaccine response, as there is Natural antimicrobial peptides from insects,
a suggestion that a positive mood enhances it. plants and animals are also under investigation
in an era where resistance to known antibiotics
Herbal and `natural' remedies In the is on the increase and the rising cost of
developing world there are many 'natural
development of new drugs is commercially
therapies' used to treat infections. Even in Europe
prohibitive for the pharmaceutical companies.
it is estimated that the herbal remedy market is
worth £1.5 billion, with herbal remedies being The principles of evidence-based medicine have
freely available for public consumption. The not been applied to the use of other approaches,
use of plant-derived remedies in allopathic such as homeopathy and acupuncture, or if
medicine is also well established; digoxin applied have not yet shown benefit.
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Genetically modified
micro-organisms (GMOS) in the
environment and biotechnology
Micro-organisms should not be viewed solely as GMOs in the environment There are now
harmful, as many of them fulfil vital roles in our over forty separate microbial 'biocontrol' agents
industrialised society (Table 46.1). The process of available for use as pesticides, some with a
continuously selecting yeast strains that produce history of use going back to the 1940s. This
the best bread or beer is an example of how the area is likely to expand with the development of
genes of micro-organisms have been modified as genetically engineered plants and other microbes
part of a 'natural' process, but the possibilities for industrial uses. Controls on this work are in
(and concerns) have increased enormously with place as there are a number of potential concerns,
recent advances in genetic engineering. The as yet unproven:
principal problem then is trying to predict how
• Some of these products were generated using
an organism will behave with a gene that has
bacterial host/vector systems which include
never existed in that environment before and
the use of antibiotic resistance genes as
how to ensure that the novel gene cannot spread
selectable markers during cloning. As these
any further to other micro-organisms.
resistance genes were not subsequently
GMOs in the laboratory The use of antibiotics removed, there is a risk of increased spread
encourages antibiotic-resistant organisms, of antibiotic resistance.
including those that arise through mutation. • These novel products are introduced into an
Clinical laboratories will grow these strains environment in which they may not normally
up to large numbers from patient samples as be found, and therefore the effects are
part of the diagnostic process, but their working somewhat unpredictable. They may have a
practices are controlled by strict guidelines deleterious effect on the homeostasis of that
to prevent the spread of infections. Similar environment themselves, or some of their
restrictions are placed upon research laboratories DNA may be taken up into other organisms,
that may purposely create hybrid strains of with unknown consequences.
pathogens through gene cloning for the study • Humans might be exposed to greater levels
of pathogenesis or vaccine production; here, a of these agents than previously. Should a
gene of interest is transferred into a 'laboratory' problem arise, it is most likely to be one of
bacterium where it may be easier to study its allergy, but some of these agents could
activity, where it is simpler to generate and potentially act as pathogens. For example,
monitor the effects of gene mutation, and where Burkholderia (Pseudomonas) cepacia type
it may be possible to produce much larger amounts Winconsin is currently used agriculturally
of the factor of interest than in the 'wild' strain. for 'damping-off' disease in some countries,
and some strains of this species are known
GMOs in humans/animals There is a long
to be an infective problem in patients with
history of giving GMOs to humans and animals
cystic fibrosis.
through the process of immunisation. However,
this movement is now more focused because
of molecular biology, with engineered
vaccines planned for many infectious diseases
(e.g. Hepatitis B, H. influenzae b) and also some
tumours (e.g. cervical carcinoma, malignant
Microbiology in biotechnology
melanoma). In addition, some engineered viruses
(e.g. adenovirus and canary pox) will probably be Food/drug production
used as vectors during gene therapy, for example
• 'Traditional' foods Cheese, yoghurt, wine, beer, bread and other
in cystic fibrosis, delivering a fully functional fermented products
copy of the cftr gene to the affected individual. • Protein supplements Fungi, Spirulina
There is also some concern that mutated or • Antibiotics Streptomyces, Bacillus, fungi
• Organic acid production e.g. acetic acid, citric acid
hybrid micro-organisms might arise accidentally
• Complex steroid production
as a result of xenotransplantation: an animal • Amino acid production e.g. monosodium glutamate
pathogen might be transferred along with the • Bacterial enzymes Biological detergents, diagnostic reagents
donor organ. Particularly as the host would be
Environmental effects
deliberately immunosuppressed, there might be • I nsect control Bacillus thuringiensis, cytoplasmic
sufficient time for the agent to multiply and polyhedrosis viruses
adapt to the human host, with implications then • Biohydrometallergy Leach pile mining of copper
• Bioremediation Oil spill deqradation, sewage treatment
for the entire population.
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When Edward Jenner demonstrated, in 1796, that the injection site. However, now that more is
inoculation with material from cowpox-infected understood about the way that vaccines work,
tissue could protect against subsequent exposure those currently under development will be
to smallpox, the science of immunisation was engineered using molecular biological techniques
born; preparations that induce immunity are now so that they direct the immune response in the
commonly known as vaccines, derived from the manner appropriate to each agent; they should be
name of the cowpox agent (the vaccinia virus). more immunogenic, have fewer side effects and
Vaccines are important against diseases that may be less likely to revert to the harmful wild type
have serious consequences and where treatments than traditional vaccines. Simple DNA vaccines
are less than optimal, particularly when infection are effective because the host cell takes up free
is common. Fig. 47.1 shows how effective they DNA, expresses it and so induces an immune
can be: the decline in cases of whooping cough response against the foreign protein(s).
coincided with the introduction of the pertussis
vaccine in the 1950s, but notifications rose again
when fears over safety of the vaccine led to
Problems with vaccines
decreased uptake in the 1970s. The adverse effects that might be expected after
i mmunisation depend on which vaccine was
Adaptive immunity may be produced by two
given, but local pain and inflammation, headache,
methods:
malaise and temperature (even febrile convulsions)
• Passive immunisation produces immunity are reasonably common. Serious problems, such as
by giving preparations of specific antibody encephalopathy, are extremely rare and certainly
collected from individuals convalescing from less than the morbidity/mortality that might be
infection or post-immunisation, or human expected from natural infection. Contrary to
normal immunoglobulin from pooled blood popular belief, there are few contra-indications
donor plasma if the infectious agent is to vaccination: it is not recommended for those
prevalent (Table 47.1). with a significant acute infection or with
• Active immunisation involves the hypersensitivity to the same vaccine previously;
administration of vaccines to induce a response some live vaccines are contra-indicated in the
from the host's own immune system. It is the i mmunocompromised, almost all in the pregnant.
most powerful method, effective against a Very rarely, a vaccine such as oral polio will
wide range of pathogens (Appendix 8, p. 132) revert back towards the wild virus and may
and, as in most parts of the world, now used cause disease in susceptible contacts. Whilst the
routinely in the UK (Table 47.2). goal of immunisation is the protection of the
vaccinated, it also has implications for the whole
population (Fig. 47.2). If immunisation produces
Vaccine design high levels of herd immunity (case A), infection
Historically, vaccines have been produced by cannot spread, and a small number of susceptible
inactivating the infectious agent or else individuals will be safe; if herd immunity is
attenuating it by multiple passage through a maintained by global immunisation together with
non-human host. Some work via a Th2-type case isolation, a solely human virulent pathogen
response to stimulate the production of antibody, may be eradicated, as happened with smallpox.
for example against the pathogen's adhesins or As the number of vaccine failures/refusers
toxin-binding regions; even the low levels of slowly builds up (case B - C - D), a critical
antibody found years later are sufficient either point is reached when infection can again spread
to abort the infection or prevent severe disease; widely. However, many susceptible individuals
i n this context, it may be particularly important will now be relatively old, and therefore the
to induce mucosal antibody. Vaccines that frequency of severe complications is much
increase cell-mediated immunity promote a increased compared with the pattern of disease
Th1-type response, producing memory T cells prior to the introduction of vaccination. The
that will respond more rapidly and effectively quality control of vaccine production must be
on subsequent exposure to the pathogen. flawless; if a pathogen is incompletely
Many vaccines require oily adjuvants that inactivated or a vaccine becomes contaminated,
non-specifically boost the immune response at the consequences may be disastrous.
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Case study 1
A 22 year old sociology student feels mildly unwell over the weekend and thinks
that she may be coming down with a cold. However, she rallied sufficiently to go
out drinking on Sunday night (5 pints of lager in the Semantics & Firkin) followed
by a fish supper and a pickled egg. The next morning she feels much worse than
she usually does on a Monday - she is drowsy, feels hot and has a headache
(particularly when the curtains are opened).
Questions
2. If you were the GP called to see her, what must you particularly look for in your examination?
3. She has three small reddish-purple non-blanching patches on her back and has a positive Kernig's
sign. What is your diagnosis and what are you going to do about it?
4. You are the house officer and this is your first suspected case of meningococcal meningitis.
How would you investigate this patient to confirm your diagnosis?
5. Analysis of the CSF is as shown below. Does this confirm or exclude a diagnosis of meningococcal
infection?
• red cell count - 50 x 10 6 cells/µL (normal = 0)
• white cell count
-1250 x 106 cells/µL (normal <_ 5)
- 90% polymorphs
-10% lymphocytes
• protein - 0.8 g/L (normal range 0.15-0.45 g/L)
• glucose
- CSF 1.2 mmol/L (normal range CSF glucose ? 60% serum glucose)
- serum 5.8 mmol/L
• no organisms seen by Gram stain and microscopy.
6. What antibiotics would you choose to treat this woman - justify your choice!
7. Do you need to inform anybody about this case - explain your answer.
8. What immunological deficit would you look for in a patient with repeated episodes of
meningococcal infection?
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Case study 2
A 19 year old male presents to his GP with a 2 day history of urethral discharge and
severe pain on passing urine. He has no history of previous genitourinary problems
and is normally fit and healthy. On examination, he is apyrexial; there is a creamy
discharge from his urethra, with slight reddening of the surrounding glans penis,
but otherwise his genitals appear normal.
Questions
1. If you are his GP, what would you want to know in his history?
He is referred to the local genitourinary medicine clinic where a Gram stain of the urethral
discharge shows intracellular Gram-negative diplococci (i.e. coed in pairs).
The urethral discharge is subsequently reported as positive for Chlamydia trachomatis, and a 7 day
course of doxycycline is commenced.
His regular partner is rather reluctant to attend the clinic because she feels well and has no discharge.
Five days later, she ends up back in the department complaining of a vaginal discharge that she
didn't have before her 'treatment' (her inverted commas!).
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5. It is rather difficult to obtain accurate figures, but the 8. It is important to examine her properly. An endocervicitis
majority of males infected with Neisseria gonorrhoeae will would suggest a relapse or reacquisition of either
probably have a co-existent infection with Chlamydia gonococcal or chlamydial infection. However, a
trachomatis as well. Although it is not invariable, the discharge that originates in the vagina itself would be
presence of one STD should always raise suspicion that new - most likely vaginal Candida overgrowth or
there may be others present too. bacterial vaginosis secondary to antibiotic therapy.
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Case study 3
Questions
2. A catheter specimen of urine (CSU) is taken and reveals white cells and over 10 5 bacteria per ml
of mixed flora. How would you interpret this?
4. This is a 'grey' area in view of the patient's age and 6. The pathogenesis of bacteraemic shock is complex. Some
underlying condition. If her prognosis is generally good, of the recognised pathways are shown in Case Study 3,
then she would be managed 'aggressively' with removal Figure, p. 121.
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Case study 4
A group of thirty primary school children visited a local farm during which they
came into close contact with various animals and were allowed to handle lambs.
Packed lunches, prepared at the homes of the children, were eaten during the visit.
Over the next 3-5 days eight of the children developed severe diarrhoea without
vomiting that persisted for 1-3 weeks. Several family members of the affected
children also subsequently developed the same symptoms.
The local Environmental Health Department was notified, and an investigation into
the possible source of the outbreak was instigated. This revealed that no children
from other classes at the school were absent with similar symptoms nor were there
any reports of similar symptoms in the communities where the children lived.
The farm visit was the only common feature shared by all the infected children.
Questions
Faecal specimens were also taken from the children and sent to the microbiology laboratory for
examination.
2. What tests would you request the laboratory to undertake on the specimens, and why are
investigations for viral causes not indicated here?
Culture results for enteric pathogens were all negative. However, microscopy on stained
preparations of faecal smears showed numerous spherical parasite oocysts.
4. How did infection arise in the children, and why were some family members who did not go on
the farm visit infected?
6. What other pathogens causing diarrhoea can be acquired from contact with animals?
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Case study 5
A 36 year old man visited his general practitioner after sudden onset of fever with
chills, cough and myalgia. A week previously he had returned to England after a
6 month contract working as a civil engineer in Rwanda and Uganda. He told the
doctor that he had returned from Africa the previous day and had not taken
malaria prophylaxis.
Routine haematological tests performed in the surgery showed haemoglobin (Hb)
13.2 g/dL, white blood cell (WBC) count 3.0 x 10 9 /L, platelets 100 x 107L and
erythrocyte sedimentation rate (ESR) 70 mm/h. Blood cultures, urine and faecal
specimens were taken along with thick and thin blood films and sent to the
laboratory.
Questions
Four days later the patient was admitted to hospital because of high fever, mental confusion,
abdominal pain and Iysuria. On examination his temperature was 39.7°C, pulse 112/min and
BP 110/70 mmHg. Laboratory investigations showed Hb 11.0 g/dL, WBC 3.4x 10 9 /L, platelets
80 x 10 9 /L, sodium 143 mmol/L, potassium 3.6 mmol/L, urea 8 mmol/L, creatinine 200 µcool/L.
He remained drowsy and confused but with no neck stiffness and appeared slightly jaundiced.
He described the pattern of fever and chills occurring approximately every 2 days.
The blood, faecal and urine cultures were negative and no intestinal parasites were seen on
microscopy. The blood films were also negative. Repeat thick blood films were prepared and
sent for examination and antimalarial treatment started (quinine in this case).
4. Based on the cycle of the fever and chills what is the probable malaria type?
The laboratory examination of the repeat thick blood films confirmed the diagnosis of malaria,
identifying Plasmodium falciparum as the cause. However, the patient continued to deteriorate,
becoming comatosed and hypotensive. Two days later he had a cardiac arrest from which he
could not be resuscitated.
5. What two major complications associated with falciparum malaria are shown here?
7. Describe the preventive measures this patient should have used to avoid infection?
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Case study 6
A previously fit 63 year old man is admitted for elective repair of an abdominal
aortic aneurysm. Surgery is successful and he is transferred to ITU where his early
postoperative recovery is good. However, he starts to show signs of sepsis - he is
pyrexial, total white cell count has risen from 7.4 to 18.1 x 10 6 /mm' in 24 h and he is
still being ventilated 72 h postoperatively. He had two doses of co-amoxiclav as
prophylaxis for surgery, but is not currently on antibiotics.
Questions
There is an area of erythema surrounding his wound, but no evidence of a collection and only a
slight serous discharge; a swab is taken for bacterial culture. There are a few fine crepitations on
listening to his chest, and an X-ray is reported as 'suggesting left ventricular failure, although not
excluding infection'; an aspirate from his endotracheal tube looks clean, but is sent for bacterial
culture. He is catheterised, but his urine is completely clear; as it is negative for leucocyte esterase
and nitrites on dipstick testing, a sample is not sent to the laboratory.
His condition does not improve and, 48 h later, both blood cultures and the wound swab are
reported as growing 'MRSA'.
6. MRSA has not been isolated on any ITU patient previously - what would you do to assess the
situation?
A patient (AF) who was on the ward when RJ was admitted, was found to be MRSA screen
positive; she had had multiple previous admissions to a number of hospitals with respiratory
failure. Two other patients, admitted after RJ, were also found to be positive.
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5. RJ is systemically infected and should be treated with a 8. The three most important measures in effective
glycopeptide antibiotic such as vancomycin, to which infection control are hand-washing, hand-washing
MRSA is almost always sensitive. However, he may also and hand-washing!
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Case study 7
A previously fit 66 year old widower presents to his GP with a fever and
non-productive cough. He has recently returned from a trip to Spain to visit his son.
Examination confirms a raised temperature and pulse rate but no signs in the chest.
The GP prescribes oral amoxicillin.
The patient phones the next day, as he is feeling worse, and the GP visits. He finds
the patient systemically stable but with a continuing fever. The GP changes the
antibiotic to cephalexin.
Questions
2. If this is a lower respiratory tract infection, was the initial antibiotic choice reasonable?
A neighbour phones the GP later that day. The patient now seems very unwell, and the GP revisits
and immediately arranges hospital admission. Chest X-ray shows right middle lobe infiltration.
A diagnosis of pneumonia is made, and blood cultures and sputum culture are arranged.
Treatment is changed to i.v. cefuroxime and clarithromycin.
A blood gas determination that evening prompts admission to the ITU. Sputum culture the next
day shows Strep. pneumoniae.
Treatment is changed to ceftazidime. The patient's condition stabilises, but 3 days later fever
returns and respiratory function worsens. Cultures of central line blood, peripheral blood and
tracheal aspirate are taken.
Blood cultures taken through the central line grow Enterococcus faecium. The tracheal aspirate now
yields a Ps. aeruginosa isolate resistant to ceftazidime. Vancomycin is started, but the patient dies of
multi-organ failure the next day.
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Questions
2. What is meant by the following terms when applied to the classification of bacteria: taxonomy,
biovars, strains, serovars, phylogeny?
6. What are the taxonomic differences in the terms ' Her pesviridae', 'Alphaherpesvirinae' and
'Simplexvirus'?
7. Order the following viruses in descending order of size: influenza virus, parvovirus B19,
rhinovirus, vaccinia virus.
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M E D I C A L
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Questions
2. Name three infections that are more severe in patients with selective immunoglobulin deficiency
3. List three infections which are associated with deficiency of specific components of complement.
8. Draw a simple diagram of the phagocytosis and intracellular digestion of a microbe by a neutrophil.
10. Cite examples of a virus, a bacterium, a fungus and a protozoon that can replicate in macrophages.
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