Infectious diseases

Infection remains the main cause of morbidity and mortality in humans, particularly in developing areas where it is associated with poverty and overcrowding. Although the prevalence of infectious disease has reduced in the developing world as a result of increasing prosperity, immunization and antibiotic availability, antibiotic-resistant strains of microorganisms and dis-eases such as human immunodeficiency virus (HIV) infection have emerged. Increasing global mobility and climate change has aided the spread of infec-tious disease world-wide. In the elderly and immunocompromised the pres-entation of infectious disease may be atypical with few localizing signs and the normal physiological responses to infection (fever and sometimes neu-trophilia) may be diminished or absent. A high index of suspicion is required in these populations.

The widespread use of antibiotics has led to bacterial resistance and changing patterns of disease, e.g. meticillin-resistant Staphylococcus aureus (MRSA), which is a bacterium commonly found on the skin and/or in the noses of healthy people (they are ‘colonized'). Infection is a result of MRSA spread (either from the same patient or between patients) from a site of colonization to a wound, burn or indwelling catheter where it causes clinical disease. The bacteria are resistant to multiple antibiotics, and infections are usually treated with vancomycin or teicoplanin. The risk of infection with MRSA is reduced by hospital staff washing their hands with antibacterial soap or alcohol hand scrub after contact with all patients, side-room isolation of colonized and infected patients (hospital staff wear disposable gowns and gloves before contact) and topical antibiotics for individuals colonized (identified by nasal and skin swabs) with MRSA.

Notification of specific infectious diseases is a legal requirement in the UK (Table 2.1) and these are indicated in the text by the superscripted abbrevia-tion nd where appropriate. However, recognizing and reporting certain infec-tions is international practice. Notification includes reporting of patient demographic details along with the disease that is being reported. This allows analyses of local and national trends, tracing of the source and the prevention of spread to others. Notification is in the first instance to the appropriate

Table 2.1 Notifiable diseases in England & Wales under the Public Health (Control of Diseases) Act 1984 and the Public Health (Infectious Diseases) Regulations 1988






Typhoid fever





Typhus fever


Meningitis; all types


Viral haemorrhagic fever


Meningococcal septicaemia (without meningitis)

Relapsing fever

Viral hepatitis; all types




Whooping cough




Scarlet fever

Yellow fever

Food poisoning






officer (usually a consultant in communicable disease control) Via the local health protection unit.

Common investigations in infectious disease

■ Blood tests. Full blood count, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), biochemical profile, urea and electrolytes are performed in the majority of cases.

■ Imaging. X-ray, ultrasound, echocardiography, computed tomography (CT) and magnetic resonance imaging (MRI) are used to identify and localize infections. Positron emission tomography (PET) (p. 828) and single photon emission computed tomography (SPECT) have proved useful in localizing infection, especially when combined with CT. Biopsy or aspiration of tissue for microbiological examination may also be facili-tated by ultrasound or CT guidance.

■ Radionuclide scanning after injection of indium- or technetium-labelled white cells (previously harvested from the patient) may occasionally help to localize infection. It is most effective when the peripheral white cell count (WCC) is raised, and is of particular value in localizing occult abscesses.

■ Microbiological investigations

■ Microscopy and culture of blood, urine, cerebrospinal fluid (CSF) and faeces should be performed as clinically indicated. Detection of a specific clostridial toxin is a more reliable test for diarrhoea caused by Clostridium difficile than culture of the organism itself.

Infectious diseases

■ Immunodiagnostic tests. These detect either a viral/bacterial antigen using a polyvalent antiserum or a monoclonal antibody or the sero-logical response to infection.

■ Nucleic acid detection. Nucleic acid probes can be used to detect pathogen-specific nucleic acid in body fluids or tissue. The utility of this approach has been enhanced by amplification techniques such as the polymerase chain reaction (PCR), which increases the amount of target DNA/RNA in the sample to be tested.

Pyrexia of unknown origin

Pyrexia (or fever) of unknown origin (PUO) is defined as ‘a documented fever persisting for >2 weeks, with no clear diagnosis despite intelligent and intensive investigation'. Occult infection remains the most common cause in adults (Table 2.2).


A detailed history and examination is essential, and the examination should be repeated on a regular basis in case new signs appear. First-line investiga-tions are usually repeated as the results may have changed since the tests were first performed:

■ Full blood count, including a differential WCC and blood film

■ ESR and CRP

■ Serum urea and electrolytes, liver biochemistry and blood glucose

■ Blood cultures - several sets from different sites at different times

■ Microscopy and culture of urine, sputum and faeces

■ Baseline serum for virology

■ Chest X-ray

■ Serum rheumatoid factor and antinuclear antibody.

Second-line investigations are performed in conditions that remain undiag-nosed and when repeat physical examination is unhelpful:

■ Abdominal imaging with ultrasound, CT or MRI to detect occult abscesses and malignancy

■ Echocardiography for infective endocarditis

■ Biopsy of liver and bone marrow occasionally; temporal artery biopsy (p. 777) should be considered in the elderly

■ Determination of HIV status (after counselling).

Table 2.2 Causes of pyrexia of unknown origin

Infection (20-40%)

Pyogenic abscess, e.g. liver, pelvic, subphrenic


nfective endocarditis


Viruses: Epstein-Barr, cytomegalovirus

Primary human immunodeíiciency virus (HIV) nfection


Lyme disease

Malignant disease (10-30%)



Renal cell carcinoma

Hepatocellular carcinoma

Vasculitides (15-20%)

Adult Still’s disease

Rheumatoid arthritis

Systemic lupus erythematosus

Wegener’s granulomatosis

Giant cell arteritis

Polymyalgia rheumatica

Miscellaneous (10-25%)

Drug fevers


nflammatory bowel disease


Granulomatous hepatitis, e.g. tuberculosis, sarcoidosis

Factitious fever (switching thermometers, njection of pyogenic material)

Familial Mediterranean fever

Undiagnosed (5-25%)


The treatment is of the underlying cause. Blind antibiotic therapy should not be given unless the patient is very unwell. In a few patients no diagnosis is reached after thorough investigation and in most of these the fever will resolve on follow-up.


■ Bacteraemia refers to the transient presence of organisms in the blood (generally without causing symptoms) as a result of local infection or penetrating injury.

■ Septicaemia is reserved for the clinical picture that results from the systemic inflammatory response to infection (p. 577).

Inflammation is normally intended to be a local and contained response to infection. Activated polymorphonuclear leucocytes, macrophages and lym-phocytes release inflammatory mediators including tumour necrosis factor, interleukin-1 (IL-1), platelet-activating factor, IL-6, IL-8, interferon and eicosanoids. In some cases, mediator release exceeds the boundaries of the local environment leading to a generalized response that affects normal tissues. Clinical features include fever, tachycardia, an increase in respiratory rate and hypotension. Septicaemia has a high mortality without treatment, and demands immediate attention. The pathogenesis and management of septic shock is discussed on pages 574 and 577.


Overall, about 40% of cases are the result of Gram-positive organisms and 60% of Gram-negative ones. Fungi are much less common but can occur, particularly in the immunocompromised. In the previously healthy adult, septicaemia may occur from a source of infection in the chest (e.g. with pneumonia), urinary tract (often Gram-negative rods) or biliary tree (com-monly Enterococcus taecalis, Escherichia colì). Intravenous drug users develop septicaemia as a result of Staph. aureus and Pseudomonas sp. infection. Hospitalized patients are susceptible to infection from wounds, indwelling urinary catheters and intravenous cannulae.

Clinical features

Fever, rigors and hypotension are the cardinal features of severe septicaemia. Lethargy, headache and a minor change in conscious level may be preceding features. In elderly and immunocompromised patients the clinical features may be quite subtle and a high index of suspicion is needed. Certain bacteria are associated with a particularly fulminating course:

■ Staphylococci that produce an exotoxin called toxic shock syndrome toxin-1. The toxic shock syndrome is characterized by an abrupt onset of fever, rash, diarrhoea and shock. It is associated with infected tampons in women but may occur in anyone, including children.

■ The Waterhouse-Friderichsen syndrome is most commonly caused by Neisserìa meningitidis. This is a rapidly fatal illness (without treatment) with a purpuric skin rash and shock. Adrenal haemorrhage (and hypo-adrenalism) may or may not be present.


In addition to blood count, serum electrolytes and liver biochemistry:

■ Blood cultures

■ Cultures from possible source: urine, abscess aspirate, sputum

■ In some cases: chest radiography, abdominal ultrasonography and CT.


Antibiotic therapy should be started immediately the diagnosis is suspected and after appropriate culture samples have been sent to the laboratory. The probable site of origin of sepsis will often be apparent, and knowledge of the likely microbial flora can be used to choose appropriate treatment. In cases where ‘blind' antibiotic treatment is necessary, a reasonable combination would be intravenous gentamicin and piperacillin, or cefotaxime, with or without metronidazole for anaerobes. Therapy may subsequently be altered on the basis of culture and sensitivity results. Activated protein C is an endogenous protein that modulates the inflammatory cascade and has anti-inflammatory actions. Recombinant human activated protein C is added to full supportive treatment in patients with severe sepsis and multiorgan failure, but it is expensive and can increase bleeding.


Viral infections that are confined to a single organ (or system) are discussed in the relevant chapter, e.g. the common cold caused by one of the rhino-viruses is discussed in Chapter 11 on respiratory diseases.


Measles is caused by infection with an RNA paramyxovirus. With the introduc-tion of aggressive immunization policies, the incidence fell in the West (when immunization schedules were adhered to), but it remains common in devel-oping countries, where it is associated with a high morbidity and mortality. One attack confers lifelong immunity. It is spread by droplet infection and the period of infectivity is from 4 days before and up to 4 days after the onset of the rash (after which the infected person can return to work or school).

Clinical features

The incubation period is 8-14 days. Two distinct phases of the disease can be recognized.

The pre-eruptive and catarrhal stage There is fever, cough, rhinor-rhoea, conjunctivitis and pathognomonic Koplik's spots in the mouth (small, grey, irregular lesions on an erythematous base, commonly on the inside of the cheek).

Eruptive or exanthematous stage Characterized by the presence of a maculopapular rash which starts on the face and spreads to involve the whole body. The rash becomes confluent and blotchy. It fades in about a week.


These are uncommon in the healthy child but carry a high mortality in the malnourished or those with other diseases. Complications include gastroen-teritis, pneumonia, otitis media, encephalitis and myocarditis. Rarely, persist-ence of the virus with reactivation pre-puberty results in subacute sclerosing panencephalitis with Progressive mental deterioration and death.


The diagnosis is usually clinical and treatment is symptomatic. Measles vaccine is given to children of 13 months (9 months in developing countries) to prevent infection. In some countries, including the UK, it is given in com-bination with mumps and rubella vaccines (MMR).


Mumps is also caused by infection with a paramyxovirus, spread by droplets. The incubation period averages 18 days.

Clinical features

It is primarily an infection of school-aged children and young adults. There is fever, headache and malaise, followed by painful parotid gland swelling. Less common features are orchitis, meningitis, pancreatitis, oophoritis, myo-carditis and hepatitis.


Diagnosis is usually clinical. In doubtful cases demonstration of a rise in serum antibody titres is necessary for diagnosis. Treatment is symptomatic. The disease is prevented by administration of a live attenuated mumps virus vaccine (as MMR, see above). Children can return to school 5 days after the onset of the swelling.


Rubella (‘German measles') is caused by an RNA virus and has a peak age of incidence of 15 years. The incubation period is 14-21 days. During the prodrome the patient complains of malaise, fever and lymphadenopathy (suboccipital, post-auricular, posterior cervical nodes). A pinkish macular rash appears on the face and trunk after about 7 days and lasts for up to 3 days.


The diagnosis may be suspected clinically and a definitive diagnosis is made by demonstrating a rising serum antibody titre in paired samples taken 2 weeks apart, or by the detection of rubella-specific IgM.


Treatment is symptomatic. Complications are uncommon but include arthralgia, encephalitis and thrombocytopenia. Prevention is with a live vaccine (see Measles). Children can return to school 6 days after the onset of the rash.

Congenital rubella syndrome

Maternal infection during pregnancy may affect the fetus, particularly if infec-tion is acquired in the first trimester. Congenital rubella syndrome is charac-terized by the presence of fetal cardiac defects, eye lesions (particularly cataracts), microcephaly, mental handicap and deafness. There may also be persistent viral infection of the liver, lungs and heart, with hepatomegaly, pneumonitis and myocarditis. The teratogenic effects of rubella underlie the importance of preventing maternal infection with immunization.

Herpes viruses

Herpes simplex virus (HSV)

HSV-1 causes:

■ Herpetic stomatitis with buccal ulceration, fever and local lymphadenopathy

■ Herpetic whitlow: damage to the skin over a finger allows access of the virus, with the development of irritating vesicles

■ Keratoconjunctivitis

■ Acute encephalitis

■ Disseminated infection in immunocompromised patients.

HSV-2 is transmitted sexually and causes genital herpes, with painful genital ulceration, fever and lymphadenopathy. Anorectal infection may occur in male homosexuals. There may be systemic infection in the immunocompro-mised host, and in severe cases death may result from hepatitis and encephalitis. These divisions are not rigid, because HSV-1 can also give rise to genital herpes.

Recurrent HSV infection occurs when the virus lies dormant in ganglion cells and is reactivated by trauma, febrile illnesses and ultraviolet irradiation. This leads to recurrent labialis (‘cold sores') or recurrent genital herpes.


The diagnosis is often clinical. A firm diagnosis is made by detection of virus from the lesions usually by HSV DNA detection by PCR. Herpes simplex encephalitis is discussed on page 768.


Oral aciclovir, famciclovir and valaciclovir for 5 days are useful if started while lesions are still forming; after this time there is little clinical benefit. Long-term suppressive therapy for 6-12 months reduces the frequency of attacks in recurrent genital herpes. Aciclovir and penciclovir is used topically as a cream for herpes labialis.

Varicella zoster virus

Varicella (chickenpox) Primary infection with this virus causes chickenpox, which may produce a mild childhood illness, although this can be severe in adults and immunocompromised patients.

Clinical features

After an incubation period of 14-21 days there is a brief prodromal period of fever, headache and malaise. The rash, predominantly on the face, scalp and trunk, begins as macules and develops into papules and vesicles, which heal with crusting. Complications include pneumonia and central nervous system involvement, presenting as acute truncal cerebellar ataxia.


The diagnosis is usually clinical but is confirmed by detection of viral DNA in vesicular fluid by PCR, electron microscopy or immunofluorescence.


Healthy children require no treatment. Anyone over the age of 16 is given antiviral therapy with aciclovir (if they present within 72 hours) because they are more at risk of severe disease. Because of the risk to both mother and fetus during pregnancy, pregnant women exposed to varicella zoster virus should receive prophylaxis with zoster-immune immunoglobulin (ZIG), and treatment with aciclovir if they develop chickenpox. Immunocompro-mised patients are treated in a similar manner. A live attenuated varicella vaccine is licensed for children in the USA and on a named patient basis in the U.K.

Herpes zoster (shingles) After the primary infection, herpes zoster remains dormant in dorsal root ganglia and/or cranial nerve ganglia, and reactivation causes shingles. A person with shingles (particularly if the rash is weeping) could cause chickenpox in a non-immune person after close contact and touch.

Clinical features

Pain and tingling in a dermatomal distribution precede the rash by a few days. The rash consists of papules and vesicles in the same dermatome. The most common sites are the lower thoracic dermatomes and the ophthalmic division of the trigeminal nerve.


Treatment is with oral acyclovir, valaciclovir or famciclovir given as early as possible. The main complication is post-herpetic neuralgia (PHN), which can be severe and last for years. Treatment is with carbamazepine or phenytoin. The development of PHN is reduced by prompt treatment with aciclovir or similar. Vaccination of all adults over the age of 60 years with varicella vaccine also reduces PHN.

Infectious mononucleosis and Epstein-Barr virus infection

Infectious mononucleosis (glandular fever) is caused by the Epstein-Barr virus (EBV) and predominantly affects young adults. EBV is transmitted in saliva and by aerosol. EBV is also the major aetiological agent responsible for hairy leukoplakia in patients with acquired immune deficiency syndrome (AIDS), Burkitt's lymphoma, nasopharyngeal carcinoma, post-transplant lymphoma and the immunoblastic lymphoma of AIDS patients.

Clinical features

The predominant symptoms of infectious mononucleosis are fever, headache, sore throat and a transient macular rash (more common following administra-tion of amoxicillin given inappropriately for a sore throat). There may be palatal petechiae, cervical lymphadenopathy, splenomegaly and mild hepa-titis. Rare complications include splenic rupture, myocarditis and meningitis. Cytomegalovirus (CMV), toxoplasmosis and acute HIV infection produce a similar illness.


Atypical lymphocytes (activated CD8-positive T lymphocytes) on a peripheral blood film strongly suggest EBV infection. Detection of heterophile antibodies is the diagnostic test of choice. The antibodies react to antigens from phylogenetically unrelated species and agglutinate sheep red cells (the Paul-Bunnell reaction) and horse red blood cells (the ‘Monospot test'). Measurement of EBV-specific antibodies may be necessary in the few patients with suspected infectious mononucleosis and negative heterophile antibodies.


Most cases require no treatment. Corticosteroids are given if there is neuro-logical involvement (encephalitis, meningitis), when there is tonsillar enlarge-ment causing respiratory obstruction and if there is severe thrombocytopenia or haemolysis.


Most of the bacterial infections are discussed under the relevant system, e.g. meningitis in Chapter 17 and pneumonia in Chapter 11.

Lyme borreliosis (Lyme disease)

Lyme disease is a multisystem inflammatory disease caused by the spiro-chaete Borrelia burgdorferi and occasionally other Borrelia species. Infection is spread from deer and other wild mammals by Ixodes ticks. It is widespread in Europe and North America and recently has been reported in Africa and South America. It is most likely to occur in rural wooded areas in the spring and summer months.

Clinical features

■ The first stage follows 7-10 days after infection and is characterized by erythema migrans (EM) at the site of the tick bite and the associated non-specific complaints of fever, malaise, headache or myalgia. EM is pathognomic of Lyme disease and characterized by an erythematous rash expanding to 5-6 cm over several days with central clearing (‘bull's eye' appearance).

■ The second stage follows weeks to months later when some patients develop neurological problems (meningoencephalitis, cranial or poly-neuropathies), cardiac problems (myocarditis or conduction defects) or arthritis.

■ Patients may continue to have fatigue and musculoskeletal pain for months to years (sometimes called chronic Lyme disease) after the acute infection is treated, but there is no objective evidence that this is due to persistent infection with Borrelia.


The diagnosis can be made on the basis of typical clinical features in a patient living or visiting an endemic area.

Serology will show IgM antibodies in the first month and IgG antibodies late in the disease.


Amoxicillin or doxycycline are the treatments of choice in early-stage disease. Intravenous benzylpenicillin or cettriaxone is given for later stages of disease. To prevent infection in tick-infested areas, repellents and protective clothing should be worn and ticks removed promptly from the site of a bite.


This zoonosis is caused by a Gram-negative organism, Leptospira interro-gans, which is excreted in animal urine and enters the host through a skin abrasion or intact mucous membranes. Individuals who work with animals or take part in water sports which bring them into close contact with rodents (e.g. boating lakes, diving) are most at risk.

Clinical features

Following an incubation period of about 10 days, the initial leptospiraemic phase is characterized by fever, headache, malaise and myalgia, followed by an immune phase, which is most commonly manifest by meningism. Most recover uneventfully at this stage. A small proportion go on to develop hepatic and renal failure, haemolytic anaemia, and circulatory collapse (Weil's disease).


Blood or CSF culture can identify the organisms in the first week of the disease. The organism may be detected in the urine during the second week. Serology will show specific IgM antibodies by the end of the first week.


Oral doxycycline is given for mild disease and intravenous penicillin or eryth-romycin for more severe disease. The complications of the disease should be treated appropriately.

Fever in the returned traveller

Fever is a common problem in people travelling between countries. Malaria is the single most common cause of fever in recent travellers from the tropics to the UK. Falciparum malaria has the potential to be rapidly fatal, and so evaluation of fever in this group of patients is often regarded as a medical emergency. Table 2.3 lists the causes of fever in travellers from the tropics; in about 25% of cases no specific cause is found. The most common causes are discussed in greater detail below.

Viral haemorrhagic fever (VHF)nd is a rare cause of fever in travellers. Presentation with high fever and other symptoms occurs before the onset of

Table 2.3 Causes of fever after travel to the tropics

Malaria Viral hepatitis

Febrile illness unrelated to foreign travel Dengue fever

Enteric fever (typhoid and paratyphoid fevers)

80% of speciíic infections*





Amoebic liver abscess


Acute HIV infection


*Includes respiratory and urinary tract infection

spontaneous haemorrhage (into skin, gut, lung). In suspected cases patients must be immediately isolated to prevent transmission and notification must be made to the laboratory handling any specimens. Lassa fever, Marburg virus and Ebola virus disease are mainly seen in sub-Saharan Africa and Congo-Crimean haemorrhagic fever in Asia and Africa.

Approach to diagnosis

An accurate history and physical examination will help formulate an appropri-ate differential diagnosis and guide initial investigations. In addition to a full medical history, an accurate travel history must be obtained:

■ A detailed travel history: dates (for assessment of incubation period; Table 2.4), countries visited, travel in rural (where infection may be more common) or urban areas, exposure to vectors (mosquitoes, ticks, flies, fresh water infested with snails containing schistosomes).

■ Needle and blood exposure, e.g. blood transfusion or surgery, shared needles, acupuncture.

■ Vaccination and prophylaxis: recent vaccination against yellow fever and hepatitis A and B is extremely effective; subsequent infection with these agents is very unlikely. Vaccination against typhoid is only partially effec-tive; therefore infection is still a possibility. Malaria is always a possibility, even in those who have taken chemoprophylaxis and used anti-mosquito precautions.

■ History of unprotected sexual intercourse may suggest an acute HIV (p. 45) or hepatitis B seroconversion illness (p. 153).

Table 2.4 Typical incubation periods for tropical infections

Incubation period


Short (<10 days)

Arboviral infections (including dengue fever), enteric bacterial infections, paratyphoid, plague, typhus, haemorrhagic fevers

Medium (10-21 days)

Malaria (but may be much longer), typhoid fever (rarely 3-60 days) scrub typhus, Lassa fever, African trypanosomiasis, brucellosis, leptospirosis

Long (>21 days)

Viral hepatitis, tuberculosis, HIV, schistosomiasis, amoebic liver abscess, visceral leishmaniasis, filariasis

The initial work-up of a febrile patient who has recently travelled is listed below. Additional studies depend on exposure and other factors:

■ Full blood count with ditferential WCC

■ Thick and thin blood malaria films and malaria rapid antigen test; repeat after 12-24 hours if initial films negative and malaria suspected

■ Liver biochemistry, urea and electrolytes, blood glucose

■ Cultures of blood and stool

■ Urine dip sticks ± microscopy and culture

■ Chest X-ray

■ ‘Acute' serum for storage and subsequent antibody detection with paired convalescent serum at a later date.


Malaria is a protozoan parasite widespread in the tropics and subtropics (Fig. 2.1). Each year 500 million people are affected, with a mortality rate of 0.2%. In endemic areas mortality is principally in infants, and those who survive to adulthood acquire significant immunity. In hyperendemic areas an exagger-ated immune response to repeated malarial infections leads to massive splenomegaly, anaemia and elevated IgM levels (hyperreactive malarial splenomegaly, tropical splenomegaly syndrome). Malaria parasites are scanty or absent in this syndrome and the disease responds to prolonged antimalarial treatment.


Malaria is transmitted by the bite of infected female anopheline mosquitoes. Occasionally it is transmitted in contaminated blood (transfusions,

Fig. 2.1 Malaria- geographical distribution

contaminated equipment, injecting drug users sharing needles). Rarely the parasite is transmitted by importation of infected mosquitoes by air (airport malaria).

Four malaria parasites infect humans; by far the most hazardous is Plas-modium falciparum, and the symptoms of infection with this virus can rapidly progress from an acute fever with rigors to severe multiorgan failure, coma and death. Once successfully treated this form does not relapse. The other malaria parasites, P. vivax, P. ovale and P. malariae, cause a more benign illness. However, P. ovale and P. vivax may relapse and P. malariae may run a chronic course over months or years.


The infective form of the parasite (sporozoites) passes through the skin and via the bloodstream to the liver. Here they multiply inside hepatocytes as merozoites. After a few days the infected hepatocytes rupture, releasing merozoites into the blood where they are taken up by erythrocytes and pass through further stages of development, which terminate with the rupture of the red cell. Rupture of red blood cells contributes to anaemia and releases pyrogens, causing fever. Red blood cells infected with P. falciparum adhere to the endothelium of small vessels and the consequent vascular occlusion causes severe organ damage, chiefly in the gut, kidney, liver and brain. P. ovale and P. vivax remain latent in the liver, and this is responsible for the relapses that may occur.

Clinical features

The incubation period varies:

■ 10-14 days in P. vivax, P. ovale and P. falciparum infection

■ 18 days to 6 weeks in P. malariae infection.

The onset of symptoms may be delayed (up to 3 months, 1 year in vivax malaria) in the partially immune or after prophylaxis. There is an abrupt onset of fever (>40° C), tachycardia and rigors, followed by profuse sweating some hours later. This may be accompanied by anaemia and hepatosplenomegaly.

P. falciparum infection (Table 2.5) is a medical emergency because patients may deteriorate rapidly. The following clinical forms are recognized and are more likely to occur when more than 1% of the red blood cells (RBCs) are parasitized:

■ Cerebral malaria- diminished consciousness, confusion, convulsions, coma and eventually death. Hypoglycaemia, a complication of severe malaria, may present in a similar way and must be excluded.

■ Blackwater fever - dark brown-black urine (haemoglobinuria) resulting from severe intravascular haemolysis.

Table 2.5 Possible features of p. falciparum malaria

Central nervous system

mpaired consciousness, convulsions


Haemoglobinuria (blackwater fever)


Uraemia (acute tubular necrosis)


Anaemia (haemolysis, dyserythropoiesis)

Disseminated intravascular coagulation

Bleeding, e.g. retinal haemorrhages



Acute respiratory distress syndrome


Hypoglycaemia (particularly in children)

Metabolic acidosis




Splenic rupture



Shock and Gram-negative septicaemia


The conventional method for diagnosing malaria is light microscopy of a Giemsa-stained thick and thin blood smear. Thick smears are most useful for diagnosis of malaria and thin smears for quantification of the percentage of parasitized red cells and for species identification. Three smears should be taken over 48 hours before the diagnosis of malaria is ruled out. Rapid antigen tests are available for near-patient use. Full blood count, serum urea and electrolytes, liver biochemistry and blood glucose are checked in falci-parum malaria to detect complications (Table 2.5).


Parasitological testing and confirmation of the diagnosis should be performed before antimalarial treatment is started except in remote rural areas (see below).

Treatment of uncomplicated malaria i.e. symptomatic malaria without signs of severity or evidence (clinical or laboratory) of vital organ dysfunction and parasite count <2%. Artemisinin-based combination therapies (ACT) are the recommended treatments for uncomplicated P. falciparum malaria and for treatment of P. vivax from chloroquine-resistant areas (Indonesia, Papua New Guinea, Timor Leste and other parts of Oceania) (Table 2.6). Fixed-dose

Table 2.6 Treatment of acute uncomplicated malaria in adults

Type of malaria

Oral drug treatment


Chloroquine: 600 mg followed by 300 mg at 6, 24 and 48 hours


ACT (except AS + SP) tor chloroquine-resistant p. vivax malaria

P. falciparum

First-line is ACT plus single dose primaquine (0.75 mg/kg)

a) Artemether plus lumetantrine (co-artemether/Riamet): 4 tablets twice a day tor 3 days


b) Artesunate (AS, 4 mg/kg daily) plus one ot amodiaquine (10 mg/kg daily), meíloquine (8.3 mg/kg daily) or sultadoxine-pyrimethamine (SP, 25/1.25 mg/kg on day 1)


  c) Dihydroartemisinin (4 mg/kg daily) plus piperaquine (18 mg/kg daily)
In p. vivax and p. ovale atter treatment ot acute intection to eradicate liver cysts
  Oral primaquine* (15 mg base/day tor p. ovale, 30 mg/ day tor p. vivax) tor 14 days

Chloroquine doses quoted are for the base drug.
*Check for glucose-6-phosphate dehydrogenase deficiency first (p. 207). Primaquine
contraindicated in severe deficiency. In mild to moderate deficiency give 0.75 mg base/
kg body weight once a week for 8 weeks.

ACT, artemisinin-based combination therapy.

combinations are preferred to the loose individual medicines co-dispensed. Antipyretics such as aspirin and paracetamol are given as necessary, and intravenous fluids may be required to combat dehydration and shock.

Severe falciparum malaria (indicated by the presence of any of the complications listed in Table 2.5) is a medical emergency, and optimal management may require admission to the intensive care unit (ITU). Expert advice should be sought from a malaria reference centre.

■ Parenteral artesunate 2.4 mg/kg body weight i.v. or im given at diag-nosis (time 0) and then at 12 hours and 24 hours, then once a day until patient able to tolerate oral medication and complete treatment by a course of an ACT (Table 2.6).

■ Quinine if artesunate is unavailable. Quinine 20 mg/kg loading dose in 5% dextrose intravenously over 4 hours, then 10 mg/kg over 4 hours every 8 hours plus oral doxycycline 200 mg daily for 7 days. Omit loading dose if patient taking quinine or mefloquine already as prophylaxis. Treat-ment can be switched to oral quinine when the patient is stable and responding to treatment.

■ Rectal artesunate is given in remote rural areas of some countries (Africa and Asia) to patients with suspected severe malaria before referral to a health facility for definitive treatment. Intramuscular artesunate or quinine are also used in this setting.

Intravenous glucose is given for hypoglycaemia and benzodiazepines for seizures. Early dialysis for acute kidney injury should be commenced and positive-pressure ventilation for non-cardiogenic pulmonary oedema.

Prevention and control

Effective prevention of malaria includes the following elements (ABC):

■ Awareness of risk

■ Bite avoidance - using mosquito repellents, covering up with permethrin-impregnated clothing, sleeping under impregnated bednets

■ Chemoprophylaxis.

As a result of changing patterns of resistance, advice about chemoprophy-laxis should be sought before leaving for a malaria-endemic area. Further details can be found in national formularies or from travel advice centres. Prophylaxis does not afford full protection. Drug regimens should be started at least 1 week before departure and continued without interruption for 4 weeks after return. The rationale for this advice is to ensure therapeutic drug levels before travelling and to enable unwanted effects to be dealt with before departure. The continued use of drugs after returning home will deal with infection contracted on the last day of exposure. With the now widespread geographical prevalence of chloroquine resistant P. falciparum, mefloquine (250 mg weekly) is for many travellers the mainstay of malarial chemo-prophylaxis. Malarone (proguanil/atovaquone) or doxycycline are alternatives to mefloquine.

Dengue fever

Dengue viruses (a member of the Flaviridae family) are transmitted to humans through bites of infected female Aedes aegypti mosquitoes. These are found mainly in Asia, Africa, Central and South America, where it is a common cause of fever and may be fatal. After an incubation period of 5-6 days there is an abrupt onset of fever, headache, retro-orbital pain and severe myalgia, often with a skin rash. Dengue haemorrhagic fever is a severe form with thrombocytopenia and spontaneous bleeding. The additional signs of circula-tory failure (hypotension, tachycardia, poor peripheral perfusion) indicate dengue shock syndrome. Diagnosis during the acute phase is by detection of the virus (by cell culture, reverse transcription PCR) or its components (non-structural protein, NS1) in the blood. Treatment is supportive particularly with adequate fluid resuscitation.


Schistosomiasis is virtually confined to travellers in southern and sub-Saharan Africa, especially those who undertake water sports in Lake Malawi. Acute symptoms are more common in non-immune individuals such as travellers. Parasite penetration through the skin may cause a localized pruritic papular rash (‘swimmer's itch'). Parasite migration through the lungs and hepatic circulation 3-4 weeks after infection may cause fever, arthralgia and dry cough (Katayama fever). Chronic complications of Schistosoma infection usually occur only in endemic areas where there is a high parasite load (Table 2.10).

Enteric fevernd

Typhoid fever and paratyphoid fever are caused by Salmonella typhi and S. paratyphi (types A, B and C), respectively. Humans are the only reservoir of infection and spread is faecal-oral. The incubation period is 10-14 days.

Clinical features

There is an insidious onset of intermittent fever, headache and dry cough. In the second week of the illness there is an erythematous maculopapular rash (‘rose spots') on the upper abdomen and thorax, splenomegaly, cervical lymphadenopathy and hepatomegaly. Diarrhoea may develop. Complications, usually occurring in the third week, are pneumonia, meningitis, acute chole-cystitis, osteomyelitis, intestinal perforation and haemorrhage. Recovery occurs in the fourth week.


Diagnosis requires the culture of S. typhi or S. paratyphi from the patient. Organisms can be cultured from the blood, faeces and urine depending on the stage in the illness that individuals present for medical attention. Where the diagnosis is in doubt, bone marrow cultures may be positive even after starting antibiotics. A blood count shows non-specific leucopenia.

Management and prevention

Treatment is with oral ciprofloxacin 500 mg twice daily for 7-14 days. Infec-tions from the Indian subcontinent, Middle-East, and South-East Asia may be resistant to ciprofloxacin and treatment is with azithromycin 500 mg daily for 7 days. Infection is cleared when consecutive cultures of urine and faeces are negative. A few patients become chronic carriers, with the focus of infection in the gall bladder and prolonged antibiotic treatment is indicated. Vaccination with injectable inactivated or oral live attenuated vaccines gives partial protection.


Other Salmonella species (S. choleraesuis and S. enteritidis) cause a self-limiting infection presenting with diarrhoea and vomiting (Table 2.7) and are a cause of traveller's diarrhoea.


Most causes of acute diarrhoea (lasting less than 14 days) with or without vomiting are due to a gastrointestinal infection with bacteria, virus or proto-zoa. Not all cases of gastroenteritis are food poisoning as the pathogens are not always food- or water-borne, e.g. C. difficile as a complication of antibi-otic use (see below). Individuals at increased risk of infection include infants and young children, the elderly, travellers (principally to developing coun-tries), the immunocompromised and those with reduced gastric acid secre-tion (e.g. individuals using proton pump inhibitors or with pernicious anaemia). Viral gastroenteritis is a common cause of diarrhoea and vomiting in young children. Helminthic gut infections are rare in the West but relatively common in developing countries.

Bacteria can cause diarrhoea in three different ways resulting in two broad clinical syndromes: watery diarrhoea and bloody diarrhoea, i.e. dysentery (Table 2.7).

The clinical features based on the principal presenting symptom associated with the causative organisms of food poisoning are summarized in Table 2.8. Listeriosis (infection with Listeria monocytogeneầ) is associated with contaminated coleslaw, non-pasteurized soft cheeses and other pack-aged chilled foods. The most serious complication of listerial infection is meningitis, occurring perinatally and in immunocompromised adults. Hepa-titis A (p. 149) and Toxoplasma gondii (p. 20) are also acquired from infected foods and their major effects are extraintestinal.

Most infectious causes of diarrhoea are self-limiting. Routine stool exami-nation for culture and microscopy for ova and parasites (three samples, since excretion is intermittent) and stool testing for C. difficile toxin is not usually necessary other than in the following groups of patients: immunosuppressed, patients with inflammatory bowel disease (to distinguish a flare from infec-tion), certain employees such as food handlers, bloody diarrhoea, persistent diarrhoea (>7 days, possible Giardia, Cryptosporidium, Cyclospora), severe symptoms (fever, volume depletion) or recent antibiotic treatment or hospi-talization. The management of patients with acute diarrhoea includes ade-quate hydration and antimotility agents such as loperamide (other than those with bloody diarrhoea or fever). Antibiotic therapy is not given in most cases

Table 2.7 Pathogenic mechanisms of bacterial gastroenteritis where established
Pathogenesis Mode of action Clinical
Effacement of
intestinal mucosa
Enteropathogenic E. coli
Enteroaggregative E. coli
Diffusely adhering E.
coli (DAEC)
Penetration +
destruction of
Shigella spp.
Campylobacter spp.
Enteroinvasive E. coli
Toxin production
Enterotoxin Fluid secretion
without mucosal
Profuse watery
Vibrio cholera
Salmonella spp.
Campylobacter spp.
Enterotoxigenic E. coli
Bacillus cereus
Staph. aureus producing
enterotoxin B
Clostridium perfringens
type A
Cytotoxin Damage to
Salmonella spp.
Campylobacter spp.
Enterohaemorrhagic E.
coli (EHEC)

since the illness is usually self-limited. Antibiotics are avoided in patients with suspected or proven enterohaemorrhagic E. coli infection as they may increase the risk of haemolytic uraemic syndrome. Empirical antibiotic therapy, e.g. ciprofloxacin and metronidazole, is given to patients with severe symptoms or bloody diarrhoea, pending the results of stool testing.

Clostridium difficile

C. ditíicile is responsible for some cases of antibiotic-related diarrhoea and nearly all cases of pseudomembranous colitis. It may also induce a relapse in patients with inflammatory bowel disease.

Pathology and clinical features

C. difficile can be cultured from the stool of 3% of healthy adults and about one-third of hospital inpatients. Most colonized patients remain asymptomatic. Clinical disease develops when the normal colonic microbiota is altered, usually by antibiotics, and creates an environment which favours the proliferation of C. difficile. Infection with toxigenic strains of C. difficile causes colonic inflammation and diarrhoea by secretion of toxins A and B, which induces expression of cytokines such as IL-8 (chemoattractant for neutrophils) in intestinal epithelial cells, causes loss of barrier function and causes cell death by apoptosis. There is focal epithelial ulceration and an inflammatory exudate that appears as a pseudomembrane on endo-scopic examination. The clinical picture varies from mild diarrhoea to life-threatening severe disease with profuse diarrhoea, abdominal pain and toxic megacolon.

Diagnosis is by demonstration of toxins A and/or B in stool samples (may be false negative) or the characteristic appearance of pseudomembranes at endoscopy.


Treatment of the acute episode is to prevent cross-infection (isolate hos-pitalized patients in a side-room, disposable gloves and aprons for staff having patient contact, washing hands with soap and water before and after patient contact), stop offending antibiotics where possible and treat with oral metronidazole (500 mg three times daily) for 10-14 days. Vancomycin (125 mg four times a day) is given for severe disease. Recurrent disease (relapse of diarrhoea after initial resolution of infection) occurs in 15-35% of cases and is usually treated with pulsed tapering doses of vancomycin. Treatment options for refractory disease, particularly if severe, are escalating doses of oral vancomycin (up to 500 mg four times a day), vancomycin administered as a retention enema, rifampicin, intravenous immunoglobulin (400 mg/kg) or occasionally colectomy but post-operative mortality is high.

Prevention of C. difficile infection is by preventing cross infection (see above) and by reducing overprescribing and inappropriate antibiotic use (avoid broad spectrum agents, use the shortest treatment course likely to be effective, avoid intravenous antibiotics and use single antibiotic doses for surgical prophylaxis).

Travellers’ diarrhoea

This is one of the most common illnesses in people who travel internationally and affects 20-50% of travellers depending on destination. The risk is highest in people travelling to areas with poor food and water hygiene.

Clinical features

There is diarrhoea (with or without blood), abdominal cramps, fever, nausea and vomiting which usually resolve without treatment over several days. A prolonged illness lasting weeks is more likely to be caused by protozoan parasites (Table 2.9).

Treatment and prevention

To reduce the risk of infection, travellers are advised to drink bottled water, peel fruit before eating it and avoid salads because the ingredients may have been washed in contaminated water. Antibiotic prophylaxis with ciprofloxacin is not indicated for most travellers but is given when a trip is vital or when an underlying medical illness would be compromised by diarrhoea, e.g. patients with an ileostomy, immunosuppression and chronic kidney disease.

Treatment of travellers' diarrhoea is symptomatic with rehydration and antidiarrhoeal agents, e.g. loperamide. Empirical antibiotics are given to patients with moderate to severe symptoms (fever, tenesmus, bloody

Table 2.9 Causes of travellers' diarrhoea

Bacteria- 70-90% of cases

E coli (enterotoxigenic)

E coli (enteroaggregative)

Shigella spp.

Salmonella spp.

Campylobacter jejuni

Aeromonas and Plesimonas spp.

Vibrio cholera

Viruses - 10%



Protozoa- <5%

Giardia intestinalis

Entamoeba histolytica

Cryptosporidium parvum

Cyclospora cayetanensis

Note: Co-infection with multiple pathogens occurs in approximately 10% of cases. *Often associated with outbreaks of diarrhoea or cruise ships and in hoỉiday resoits.

diarrhoea) after obtaining a stool sample. Fluoroquinolones, e.g. oral cipro-floxacin (500 mg twice daily for 1-3 days depending on symptoms) are used in most cases. Rifaximin (poorly absorbed derivative or rifamycin) is used in areas where E. coli predominates and azithromycin is increasingly used due to emergence of fluoroquinolone resistant Campylobacter. Colonoscopy and biopsy are occasionally necessary in patients with persistent diarrhoea, when an alternative diagnosis to travellers' diarrhoea, such as inflammatory bowel disease seems likely. Irritable bowel syndrome (p. 117) can occur after travel-lers' diarrhoea.


Amoebiasis is caused by the protozoal organism Entamoeba histolytica. Infec-tion occurs world-wide, although much higher incidence rates are found in the tropics and subtropics. Transmission of infection is by ingestion of cysts in contaminated food and water or spread directly by person-to-person contact.

Clinical features

Intestinal amoebiasis (amoebic dysentery) E. histolytica invades the colonic epithelium leading to tissue necrosis and ulceration. Ulceration may deepen and progress under the mucosa to form typical flask-like ulcers. The presentation varies from mild bloody diarrhoea to fulminating colitis, with the risk of toxic dilatation, perforation and peritonitis. An amoeboma (inflamma-tory fibrotic mass) may develop, commonly in the caecum or rectosigmoid region, which may bleed, cause obstruction or intussusception, or be mis-taken for a carcinoma.

Amoebic liver abscess An amoebic liver abscess (often single and in right lobe of liver) develops when organisms invade through the bowel serosa, enter the portal vein and pass into the liver. There is tender hepatomegaly, a high swinging fever and profound malaise. There may not be a history of colitis.


Serology Amoebic fluorescent antibody test (FAT) is positive in 90% of patients with liver abscess and in 60-70% of patients with active colitis.

Colonic disease Microscopic examination of fresh stool or colonic exudate obtained at sigmoidoscopy shows the motile trophozoites, which contain red blood cells. E. histolytica must be distinguished by molecular techniques from the non-pathogenic E. dispar, which appears identical and is seen frequently in stools in patients from amoebic areas.

Liver disease Liver abscesses should be considered when the serum alkaline phosphatase is elevated. Liver ultrasonography or CT scan will confirm the presence of an abscess.

Differential diagnosis

Amoebic colitis must be differentiated from the other causes of bloody diar-rhoea: inflammatory bowel disease, bacillary dysentery, E. coli, Campylo-bacter sp., salmonellae and, rarely, pseudomembranous colitis. Amoebic liver abscess must be differentiated from a pyogenic abscess and/or a hydatid cyst.


■ Colitis - oral metronidazole, 800 mg three times daily for 5 days, followed by a luminal amoebicide such as diloxanide furoate to clear the bowel of parasites.

■ Liver abscess - metronidazole 500 mg three times daily for 5 days. A large tense abscess may require percutaneous drainage under ultrasound guidance.

Control and prevention

Improved standards of personal hygiene and water supply are required. Travellers are advised to drink bottled water. Individual chemoprophylaxis is not advised because the risk of acquiring infection is low. There is no effective vaccine.

Shigellosis (bacillary dysentery)nd

Shigellosis is an acute self-limiting intestinal infection which occurs world-wide but is more common in tropical countries and in areas of poor hygiene. Transmission is by the faecal-oral route. The four Shigella species (S. dys-enteriae, S. ílexneri, S. boydiiand S. sonnei) invade and damage the intestinal mucosa (Table 2.8). Some strains of S. dysenteriae secrete a cytotoxin which results in diarrhoea. Differential diagnosis is from other causes of bloody diarrhoea (see above). Sigmoidoscopic appearances may be the same as those in inflammatory bowel disease. Ciprofloxacin 500 mg orally twice daily is the treatment of choice.


Cholera is caused by the Gram-negative bacillus, Vibrio cholerae (Tables 2.7 and 2.8). Infection is common in tropical and subtropical countries in areas of poor hygiene. Infection is by the faecal-oral route, and spread is predomi-nantly by ingestion of water contaminated with the faeces of infected humans. There is no identified animal reservoir.

Pathophysiology and clinical features

Following attachment to and colonization of the small intestinal epithelium, V. cholerae produces its major virulence factor, cholera toxin. The toxin binds to its enterocyte surface receptor (monsialoganglioside G1) which in turn activates cyclic AMP. The increase in cAMP activates intermediates (e.g. protein kinase and Ca2+) which then act on the apical membrane causing chloride ion secretion (with water) and inhibition of sodium and chloride absorption. This produces massive secretion of isotonic fluid into the intes-tinal lumen. Cholera toxin also increases serotonin release from entero-chromaffin cells in the gut, which contributes to the secretory activity and diarrhoea. Additional enterotoxins have been described in V. cholerae which may contribute to its pathogenic effect. Profuse watery diarrhoea (‘rice-water stools') may result in dehydration, hypotension and death.


Management is aimed at effective rehydration, which is mainly oral. Intra-venous fluids are given in severe cases. The mechanism of action of oral rehydration solutions (ORS) depends on the fact that there is a glucose-dependent sodium absorption mechanism not related to cAMP and thus unaffected by cholera toxin. The World Health Organization ORS contains sodium (75 mmol/L) and glucose (75 mmol/L), along with potassium, chlo-ride and citrate. Cereal-based regimens also contain cooked rice. Single dose azithromycin 1 g helps to eradicate the infection, decrease stool output and shorten the duration of the illness.

Prevention and control

Good hygiene and sanitation are the most effective measures for the reduc-tion of infection. Oral live attenuated and killed vaccine are recommended in potential or actual outbreak situations.


Giardia intestinalis is a flagellated protozoan that is found world-wide but is more common in developing countries. It is a cause of travellers' diarrhoea and may cause prolonged symptoms (see later).

Clinical features

The clinical features are the result of damage to the small intestine, with subtotal villous atrophy in severe cases. There is diarrhoea, nausea, abdomi-nal pain and distension, with malabsorption and steatorrhoea in some cases. Repeated infections can result in growth retardation in children.


Treatment is often given based on clinical suspicion. If necessary, the diag-nosis is made by finding cysts on stool examination (but negative stool does not exclude the diagnosis) or parasites in duodenal aspirates or biopsies.


Metronidazole 2 g as a single dose daily for 3 days will cure most infections; some patients need two or three courses. Alternative drugs include tinidazole, mepacrine and albendazole.


The helminths or worms that infect humans are of three classes (Table 2.10). In the UK only three species are commonly encountered: Enterobius vermicu-laris, Ascaris lumbricoides and Taenia saginata. Other species occur in tropi-cal and subtropical countries and may be imported into the UK. A raised blood eosinophil count (eosinophilia) occurs at some stage in nearly all helminth infections.


Sexually transmitted infections (STIs) remain endemic in all societies, and the range of diseases spread by sexual activity continues to increase. The three common presenting symptoms are:

■ Urethral discharge (see below)

■ Genital ulcers (see below)

■ Vaginal discharge - this is caused by Candida albicans, Trichomonas vaginalis, Neisseria gonorrhoeae, Chlamydia trachomatis and herpes simplex. Bacterial vaginosis is also characterized by a vaginal discharge but is not regarded as an STI. It occurs when the normal lactobacilli of the vagina are replaced by a mixed flora of Gardnerella vaginalis and anaerobes, resulting in an offensive discharge. Other causes of vaginal discharge are retained tampon, chemical irritants, cervical polyps and neoplasia.

STIs predominantly seen in the tropics are chancroid (caused by Haemophilus ducrei), donovanosis (Klebsiella g/anulomatis) and lymphogranuloma venereum (Chlamydia trachomatis types LGV 1, 2 and 3). They present with genital ulceration and inguinal lymphadenopathy.

The aspects of management of all the STIs are:

■ Accurate diagnosis and effective treatment

■ Screening for other STIs including HIV and hepatitis viruses

■ Patient education

■ Contact tracing: the patient's sexual partners must be traced so that they can be treated, thereby preventing the disease from spreading further

■ Follow-up to ensure that infection is adequately treated.


Urethritis in men presents with urethral discharge and dysuria. It is often asymptomatic in women. The causes are infection with N. gonorrhoeae, C. trachomatis, Ureaplasma urealyticum, Bacteroides sp. and Mycoplasma sp.


The causative organism, N. gonorrhoeae (gonococcus), is a Gram-negative intracellular diplococcus which infects epithelium, particularly of the urogeni-tal tract, rectum, pharynx and conjunctivae.

Clinical features

The incubation period ranges from 2 to 14 days. In men the symptoms are purulent urethral discharge and dysuria. In men who have sex with men proctitis may produce anal pain, discharge and itch. Women may be asymp-tomatic or complain of vaginal discharge, dysuria and intermenstrual bleed-ing. Complications include salpingitis, Bartholin's abscess and perihepatitis (Fitzhugh-Curtis) in women, epididymitis and prostatitis in men, and systemic spread with a rash and arthritis (p. 297). Infants born to infected mothers may develop ocular infections (ophthalmia neonatorum).


Gram stain and culture of a swab are taken from the urethra in men and the endocervix in women. Blood culture and microscopy of synovial fluid should be performed in cases of disseminated gonorrhoea. Nucleic acid amplification tests (NAATs) using urine specimens are non-invasive and highly sensitive, but may give false-positive results.


Single-dose oral treatment with cefixime (400 mg), ceftriaxone (250 mg i.m.) or spectinomycin (2 g i.m.) successfully treats uncomplicated anogenital infection. Single-dose oral amoxicillin 3 g with probenecid 1 g, ciprofloxacin (500 mg) or ofloxacin (400 mg) is used in areas with a low prevalence of antibiotic resistance. Longer courses are required for complicated infections. Culture tests should be repeated at least 72 hours after treatment is complete.

Chlamydia urethritis

C. trachomatis infection presents in men with urethral discharge and dysuria. In women, infection may be asymptomatic and only found during investiga-tions for infertility (secondary to salpingitis and fallopian tube blockage). The diagnosis of chlamydial urethritis is made by the NAAT. Treatment is with doxycycline (100 mg 12 hourly for 7 days) or single-dose azithromycin 1 g (in pregnancy).

Genital ulcers

The infective causes of genital ulceration in the UK include syphilis, herpes simplex and herpes zoster. Non-infective causes are Behget's disease, toxic epidermal necrolysis (p. 813), Stevens-Johnson syndrome (p. 813), carci-noma and trauma.


Syphilis is a chronic systemic disease which is acquired or congenital (trans-placentally from mother to fetus). The causative organism, Treponema pal-lidum, is a motile spirochaete which enters the new host through breaches in squamous or columnar epithelium.

Early stages

Primary infection After an incubation period of 10-90 days a papule devel-ops at the site of inoculation. This ulcerates to become a painless, firm chancre, which heals spontaneously within 2-3 weeks.

Secondary infection Between 4 and 10 weeks after the appearance of the primary lesion constitutional symptoms with fever, sore throat and arthralgia appear. There may be generalized lymphadenopathy, widespread skin rash (except the face), superficial ulcers in the mouth and on the genitalia (snail-track ulcers) and condylomata lata (warty perianal lesions). Many sites may be affected (hepatitis, nephritis, arthritis, meningitis). In most patients symptoms subside within 3-12 weeks.

Late stages

Tertiary syphilis This occurs after a latent period of 2 years or more. The characteristic lesion is a gumma (granulomatous, sometimes ulcerating lesion) occurring in the skin, bones, liver and testes. Cardiovascular and neurosyphilis are discussed on pages 465 and 770.

Congenital syphilis 30% are stillborn. Otherwise, 2-6 weeks after birth there is nasal discharge, skin and mucous membrane lesions, and failure to thrive. Signs of late syphilis (see above) appear after 2 years of age, when there are also characteristic bone (‘sabre tibia') and teeth abnormalities (Hutchinson's teeth) as a result of earlier damage.


■ Dark ground microscopy of fluid taken from lesions shows organisms in primary and secondary disease. Serological tests may be negative in primary disease.

■ Serology. The T. pallidum enzyme immunoassay (EIA) is the screening test of choice. A positive test is then confirmed with the T. pallidum haemagglutination assay (TPHA) and Venereal Disease Research Labora-tory (VDRL) test. The VDRL test is detectable within 3-4 weeks of infec-tion; it becomes negative in treated patients and in some untreated patients with late tertiary syphilis. Other diseases, e.g. autoimmune disease and malignancy, may give false-positive results. The T. pallidum EIA, TPHA and the fluorescent treponemal antibody test are positive in most patients with primary disease, and remain positive in spite of treat-ment. They do not distinguish between syphilis and other treponemes, e.g. yaws.


■ Early stages - intramuscular procaine benzylpenicillin (procaine penicil-lin) 600 mg for 10 days. Erythromycin or doxycycline if the patient is allergic to penicillin.

■ Late stages - extend early-stage treatment for a further week.

The Jarisch-Herxheimer reaction, characterized by malaise, fever and head-ache, occurs most commonly in secondary syphilis and is the result of release of TNF-a, IL-6 and IL-8 when organisms are killed by antibiotics.


HIV is the cause of AIDS. Estimates for 2007 are that on a world-wide scale, 33 million people are infected with HIV and on a daily basis, 6800 acquire HIV and 5700 die of AIDS. Sub-Saharan Africa remains the most seriously affected and in countries with the highest prevalence 33% of 15-year-olds will die of HIV. However, infection rates are rising exponentially in eastern Europe and parts of Central Asia. Highly active antiretroviral therapy (HAART) has transformed the outcome for individuals with HIV infection but is unavail-able in the poorer parts of the world. The challenge in developed countries is to diagnose HIV infection at an earlier stage (one-third of HIV infections in the UK remain undiagnosed) and thus reduce transmission and avoid late diagnosis, which is associated with an impaired response to HAART.

Routes of acquisition

Transmission is by:

■ Sexual intercourse (vaginal and anal). World-wide, heterosexual inter-course accounts for the vast majority of infections. In the UK sex between men accounts for over half the infections. Coexistent STIs, especially those causing genital ulceration, enhance transmission.

■ Mother to child Transmission can occur in utero, although the majority of infections takes place perinatally or via breast milk.

■ Contaminated blood, bloodproducts and organ donations. The risk is now minimal in developed countries since the introduction of screening blood products in 1985.

■ Contaminated needles. This is a major route of transmission of HIV among intravenous drug addicts who share needles and syringes. Healthcare workers have a risk of approximately 0.3% following a single needle-stick injury with known HIV-infected blood.

HIV infection is not spread by ordinary social or household contact.

Pathogenesis of HIV infection

There are two types, HIV-1 and HIV-2. HIV-2 is mainly confined to West Africa, runs a more indolent course than HIV-1 and may not respond to many of the drugs used in HIV-1. The virus consists of an outer envelope and an inner core. The core contains RNA and the enzyme reverse transcriptase, which allows viral RNA to be transcribed into DNA and then incorporated into the host cell genome (i.e. a retrovirus). The rapid emergence of viral quasispecies (closely related but genetically distinct variants) is due to the high mutation rate of reverse transcriptase and the high rate of viral turnover. This genetic diversification has implications for the evolution of viral variants with resist-ance to antiviral drugs.

HIV surface glycoprotein gp120 binds to the CD4 molecule on host lymphocytes and other cells bearing the CD4 receptor. The interaction between CD4 and HIV surface glycoprotein together with host chemokine co-receptors CCR5 and CXCR4 is responsible for HIV entry into cells and release of viral RNA. There is a Progressive and severe depletion of infected CD4 helper lymphocytes which results in host susceptibility to infections with intracellular bacteria and mycobacteria. The coexisting antibody abnormali-ties predispose to infections with capsulated bacteria, e.g. Streptococcus pneumoniae and Haemophilus influenzae. The clinical illness associated with HIV infection is due to this immune dysfunction, and also to a direct effect of HIV on certain tissues.

Natural history of HIV infection

The typical pattern of HIV infection is shown in Fig. 2.2. Throughout the course of HIV infection, viral load and immunodeficiency progress steadily, despite the absence of observed disease during the latency period.

HIV infection is divided into the following stages:

■ Category A includes primary HIV infection or seroconversion. Illness occurs in most individuals 2-4 weeks after infection. Symptoms are non-specific and include fever, maculopapular rash, myalgia, headache/ aseptic meningitis. The illness lasts up to 3 weeks and recovery is usually complete.

Fig. 2.2 Schematic representation of the course of human immunodeficiency virus (HIV) infection. The effect of antiretroviral therapy is also shown.

■ Clinical latency. Most are asymptomatic. A subgroup of patients have persistent generalized lymphadenopathy defined as lymphadenopathy (>1 cm) at two or more extra inguinal sites for more than 3 months in the absence of causes other than HIV infection. There may be splenomegaly.

■ Category B. Early symptomatic HIV infection is associated with a rise in viral load, a fall in CD4 count and development of symptoms and signs due to direct HIV effects and immunosuppression. Examples of category B conditions include bacillary angiomatosis (Bartonella infection causing subcutaneous nodules), candidiasis (oral pharyngeal), oral hairy leuco-plakia, herpes zoster involving more than one dermatome, idiopathic thrombocytopenic purpura, listeriosis, pelvic inflammatory disease and peripheral neuropathy.

■ Category C includes patients with clinical conditions that indicate that they have severe immunosuppression (AIDS; Table 2.11).

Clinical features

The spectrum of illnesses associated with HIV infection is broad and is the result of direct HIV infection (Table 2.12), infections associated with

Table 2.11 AIDS-defining conditions*

Candidiasis of bronchi, trachea or lungs

Infectious diseases

Candidiasis, oesophageal

Cervical carcinoma, invasive

Coccidioidomycosis, disseminated or extrapulmonary

Cryptococcosis, extrapulmonary

Cryptosporidiosis, chronic intestinal (1 month duration)

Cytomegalovirus (CMV) disease (other than liver, spleen or nodes)

CMV retinitis (with loss of Vision)

Encephalopathy (HlV-related)

Herpes simplex, chronic ulcers (1 month duration); or bronchitis, pneumonitis or oesophagitis Histoplasmosis, disseminated or extrapulmonary Isosporiasis; chronic intestinal (1 month duration)

Kaposi’s sarcoma Lymphoma, Burkitt’s

Lymphoma, immunoblastic (or equivalent term)

Lymphoma (primary) of brain

Mycobacterium avium-intracellulare complex or M. kansasii, disseminated or extrapulmonary Mycobacterium tuberculosis, any site

Mycobacterium, other species or unidentiíied species, disseminated or extrapulmonary Pneumocystis ịiroveci (ormerly P. cariniị pneumonia Pneumonia, recurrent

Progressive multifocal leucoencephalopathy Salmonella septicaemia, recurrent Toxoplasmosis of brain Wasting syndrome, due to HIV

*USA deílnition also includes those with a CD4 count <200 cells/mm3

immunodeficiency (p. 49), co-infections, e.g. hepatitis B (p. 152) and side-effects of the drugs used to treat the condition.


Informed consent and testing for HIV infection should be within the compe-tence of any doctor, nurse, midwife or trained healthcare worker. Recent UK national guidelines for HIV testing are intended to facilitate an increase in testing and prevent late diagnosis (

■ Simple and rapid antibody assays are increasingly available giving results within minutes. Assays that can utilize alternative body fluids to serum/ plasma such as oral fluid, whole blood and urine are now available and home testing kits are being developed. Antibodies may not be detectable for 6-12 weeks (depending on the assay) after infection (window period).

Table 2.12 Direct human immunodeficiency virus (HIV) infection effects

Neurological disease

AIDS dementia complex

Sensory polyneuropathy

Autonomic neuropathy causing diarrhoea and postural hypotension

Aseptic meningitis


Retinal cotton wool spots - rarely troublesome


Dry, itchy flaky skin

Pruritic papular eruption

Aphthous ulceration in the mouth


Anaemia of chronic disease


Autoimmune thrombocytopenia


Anorexia leading to weight loss in advanced disease

HIV enteropathy leading to diarrhoea and malabsorption


Renal impairment

Nephrotic syndrome (due to focal glomerulosclerosis)


Chronic sinusitis and otitis media

Lymphoid interstitial pneumonitis - lymphocytic níiltration of the lung, causing dyspnoea and a dry cough


Reduced adrenal function - infection may precipitate clear adrenal insufficiency


Myocarditis and cardiomyopathy

■ Viral p24 antigen (p24ag) is detectable in serum shortly after infection but 8-10 weeks after exposure.

■ Viral genotype analysis is recommended for all newly diagnosed patients with HIV. Drug-resistant variants of HIV are increasing.


Patients are regularly monitored to assess the progression of the infection and its treatment. Clinical examination will identify signs of immuno-suppression, e.g. oral hairy leucoplakia.

■ Following a diagnosis of HIV infection, the numbers of circulating CD4 lymphocytes are measured approximately 3 monthly; patients with counts below 200 cells are at greatest risk of HIV-related pathology (normal CD4 count in a healthy adult is >500). Rapidly falling CD4 counts and those below 350 are an indication for treatment with antiretroviral drugs.

■ Plasma levels of HIV RNA (‘viral load', measured in copies of RNA per mL) are a measure of viral replication. The viral load is the best indicator of long-term prognosis, e.g. 6 months after seroconversion to HIV patients with a viral load >100 000 copies/mL have a 10 times higher risk of progression to AIDS over the ensuing 5 years than those consistently below 10 000 copies/mL. HIV RNA levels fall with effective antiretroviral medication and a rising viral load, in a patient where compliance is assured, indicates drug failure.

■ The diagnosis of AIDS is made when an HIV-positive patient develops one or more of a defined list of opportunistic infections, malignancies or HIV-associated illnesses (Table 2.10) in the absence of other causes of immunosuppression, e.g. leukaemia, immunosuppressive drugs.


Management involves treatment with antiretroviral drugs, social and psycho-logical care, prevention of opportunistic infections and prevention of trans-mission of HIV. Although HIV infection cannot be cured, the advent of HAART has transformed HIV into a chronic controllable condition. The aims of treat-ment are to maintain physical and mental health, to avoid transmission of the virus, and to provide appropriate palliative support as needed. General health promotion advice on smoking cessation, alcohol, diet, drug misuse and exercise should be given, particularly in light of the cardiovascular, metabolic and hepatotoxic risks associated with HAART. Antiretroviral drugs and indications for starting treatment (UK) are listed in Tables 2.13 and 2.14 respectively.

Treatment regimens for HIV infection are complicated and require a long-term commitment to high levels of adherence. A combination of clinical assessment and laboratory marker data, including viral load and CD4 counts, together with individual circumstances, should guide therapeutic decision-making.

Treatment is initiated with a combination of drugs started simultaneously. The preferred starting regimen is two nucleoside/nucleotide reverse tran-scriptase inhibitors in combination with either a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor. The goal is to suppress the viral load to an undetectable level (<50 copies/mL) and thus secondarily halt the destruction of CD4 T lymphocytes within 3-6 months of starting therapy. Patients may need to change therapy because of drug resistance (indicated by a rise in viral load and falling CD4 count) or intolerance/adverse drug reactions.

Conditions due to immunodeticiency

Immunodeficiency allows the development of opportunistic infections. These are diseases caused by organisms that are not usually considered patho-genic, or are unusual presentations of known pathogens, or the occurrence

Table 2.13 Antiretroviral drugs
Class of drug Mechanism of action Side-effects
Reverse transcriptase inhibitors
1. Nudeoside/nudeotide* reverse transcriptase inhibitors








Inhibit synthesis of DNA by reverse transcription and also act as DNA Chain terminators

Nausea, mitochondrial dysfunction and lactic acidosis,* polyneuropathy, pancreatitis (didanosine), myelosuppression (lamivudine, zidovudine), lipodystrophy+ (stavidudine, zidovudine)

2. Non-nucleoside reverse transcriptase inhibitors




Bind directly to, and inhibit reverse transcriptase

Rash, toxic epidermal necrolysis, elevation of liver enzymes, Central nervous system effects (dreams, hallucinations, depression) with efavirenz

Protease inhibitors









Act competitively on HIV aspartyl protease enzyme, which is involved in production of functional viral proteins and enzymes

Lipodystrophy, hyperlipidaemia, gastrointestinal intolerance, peri-oral paraesthesia (ritonavir), intracranial bleeding (tipranavir)

Fusion inhibitors


Inhibits fusion of HIV with target cell

Reactions at s.c. injections sites

Co-receptor blockers


Blocks the CCR5 chemokine co-receptor

Hepatotoxicity, pyrexia, rash, hypotension

Integrase inhibitors


Prevents insertion of HIV DNA into the human genome

Gastrointestinal side-effects, headache, myopathy, rhabdomyolysis

All are given orally as capsules or tablets except enfuvirtide (s.c. injection)
*Potentially fatal, stop treatment immediately, presents with fatigue, abdominal pain,
nausea, hepatomegaly.
†Peripheral fat loss (face, limbs), central fat accumulation with a ‘buffalo hump’,
hypertriglyceridaemia, insulin resistance.


Table 2.14 UK recommendations for starting antiretroviral therapy

Primary HIV infection

Treatment in clinical trial

or if there is neurological involvement

or if the CD4 <200 for 3/12

or if an AIDS-defining illness is present

Established HIV infection

CD4 <250


CD4 251-350

Treat as soon as patient ready

CD4 >350

Consider enrolment into ‘when to start’ trial

AIDS diagnosis/category C

Treat (except for tuberculosis when CD4 >350)

Modified from Gazzard BG. British HIV Association guidelines for the treatment of
HIV-1-infected adults with antiretroviral therapy 2008. HIV Medicine 2008; 9: 563–608.
Available at:

of tumours that have an oncogenic viral aetiology. Susceptibility increases as the patient becomes more immunosuppressed. When patients are profoundly immunocompromised (CD4 count <100 cells/mm3) disseminated infections with organisms of very low virulence such as M. avium-intracellulare and Cryptosporidium are able to establish themselves. The mortality and morbidity associated with HIV infection have declined dramatically since the introduction of HAART. Similarly, long-term secondary chemoprophylaxis for previously life-threatening infections may not be necessary when HAART maintains the CD4 count above 200 cells/mm3 and the viral load is low.


Pneumocystis jivoreci (tormerly P. carinii) causes pneumonia in severely immunocompromised patients (CD4 count <200). There is an insidious onset of breathlessness, a non-productive cough, fever and malaise. Pneumothorax may complicate P. ịivoreci pneumonia (PCP). The chest X-ray may be normal or show bilateral perihilar interstitial infiltrates, which can progress to more diffuse shadowing. High-resolution CT scans of the chest are abnormal even if there is little on the chest X-ray. Histoplasmosis can produce a similar appearance. Definitive diagnosis is made by demonstrating the organisms (silver staining or immunofluorescent techniques) in samples obtained via bronchoscopy and bronchoalveolar lavage or by PCR amplification of the fungal DNA from a peripheral blood sample. Treatment is usually with intra-venous co-trimoxazole, intravenous pentamidine or dapsone and trimetho-prim for 21 days. Systemic corticosteroids reduce mortality in severe cases (PaO2 <9.5 kPa). Long-term prophylaxis, usually with oral co-trimoxazole, is required in patients whose CD4 count remains below 200 cells/mm3 despite HAART.

Cryptococcus neoíormans most commonly causes meningitis in AIDS patients. There is an insidious onset of fever, nausea and headache, eventu-ally with impaired consciousness and change in affect. Diagnosis is made by CSF microscopy (Indian ink staining shows the organisms directly), demon-stration of cryptococcal antigen, and culture of the organism from CSF and/ or blood. CT scan is performed before lumbar puncture to exclude a space-occupying lesion. Treatment is with intravenous amphotericin B ± flucytosine or fluconazole. Oral fluconazole is continued long term unless the CD4 count is >100 for a 6-month period.

Candida infection (usually Candida albicans) presents as creamy plaques in the mouth, vulvovaginal region and oesophagus (producing odynophagia and dysphagia). Treatment is with fluconazole (preferred if Candida is dis-seminated) or itraconazole. Disseminated infection with Aspergillus tumiga-tus occurs in advanced HIV infection. Treatment is with amphotericin B, voriconazole or caspofungin. The prognosis is poor.

Protozoal infections

Toxoplasma gondii most commonly causes encephalitis and cerebral abscess in AIDS patients. Clinical features include focal neurological signs, fits, fever, headache and possible confusion. Eye involvement with chorioretinitis may also be present. Diagnosis is made on the basis of positive Toxoplasma serology and multiple ring-enhancing lesions on contrast-enhanced CT or MRI of the brain. Treatment is with anticonvulsants and combination pyrimethamine, sulfadiazine and folinic acid (leucovorin) for at least 6 weeks. Lifelong maintenance is required to prevent relapse unless the CD4 count can be restored by HAART. The differential diagnosis of multiple ring-enhancing CNS lesions in these patients includes lymphoma, mycobacterial (e.g. tuberculoma) or focal cryptococcal infection.

Cryptosporidium species (parvum and hominis) cause a self-limiting watery diarrhoea and abdominal cramps in immunocompetent individuals and a severe chronic watery diarrhoea in HIV patients, in whom it also causes sclerosing cholangitis. Diagnosis is made by demonstrating cysts on stool microscopy or on small bowel biopsy specimens obtained at endoscopy. HAART and immune restoration is associated with resolution of symptoms. Treatment is otherwise symptomatic. Paromomycin and nitazoxanide have a limited effect on diarrhoea.

Microsporidia infection (Enterocytozoon bieneusi and Septata intestinalis) cause diarrhoea. Diagnosis is made by demonstrating spores in the stools. Treatment is with HAART and albendazole.

Leishmaniasis occurs in HIV-infected individuals who have been in endemic areas (South America, tropical Africa, Mediterranean). Features are fever, malaise, diarrhoea, splenomegaly, anaemia and thrombocytopenia.

The diagnosis is made by demonstrating the organism in bone marrow biopsy or splenic aspirates. Treatment of choice is liposomal amphotericin.


Cytomegalovirus causes retinitis, colitis, oesophageal ulceration, encepha-litis, pneumonitis, polyradiculopathy and adrenalitis. Retinitis presents with floaters, loss of visual acuity and orbital pain, usually in a patient with CD4 count <100. The diagnosis is made on fundoscopy, which shows a charac-teristic appearance of the retina with haemorrhages and exudate. Colitis presents with bloody diarrhoea and abdominal pain. Diagnosis is made by demonstrating characteristic ‘cytomegalic cells' (large cells containing an intranuclear inclusion and sometimes intracytoplasmic inclusions) on light-microscopic examination of mucosal biopsy specimens. Treatment of CMV infection is with intravenous ganciclovir or foscarnet. Reactivation occurs in CMV retinitis and oral or topical ganciclovir is given long term, unless immune competence can be restored with HAART.

Herpes virus Primary infection with herpes simplex virus causes genital and oral ulceration, and systemic infection. Varicella zoster occurs at any stage of HIV infection, but may be more aggressive and longer lasting than in immunocompetent patients. Treatment is with aciclovir. Human herpes-virus 8 is associated with Kaposi's sarcoma (see below). EBV causes oral hairy leucoplakia, presenting as a pale, ridged lesion on the side of the tongue. EBV is also associated with primary cerebral lymphoma and non-Hodgkin's lymphoma (see below).

Human papilloma virus (HPV) produces genital and plantar warts. HPV infection is associated with the more rapid development of squamous cell cancer of the cervix and anal cancer.

Papovavirus causes progressive multifocal leucoencephalopathy, which presents with intellectual impairment and often hemiparesis and aphasia.

Hepatitis virus B and C Because of the comparable routes of transmis-sion of hepatitis viruses and HIV, co-infection is common, particularly in drug users and those infected by blood products. Hepatitis B does not seem to influence the natural history of HIV, though there is a reduced rate of clear-ance of the hepatitis B e antigen in co-infected patients and thus the risk of developing chronic infection is increased. Hepatitis C, on the other hand, is associated with a more rapid progression of HIV infection, and the progres-sion of hepatitis C is more likely and more rapid.

Bacterial infection

This may present early in HIV infection, is often disseminated and frequently recurs. Mycobacterium tuberculosis can cause disease at all stages of HIV infection, but extrapulmonary tuberculosis (TB) is more common with advanced disease. M. tuberculosis infection usually responds well to standard treatment regimens, although the duration of therapy may be extended, especially in extrapulmonary infection. Treatment of TB in HIV co-infected patients presents specific challenges, particularly with regard to drug inter-actions and multidrug resistance (p. 544), and requires input from a specialist physician.

Mycobacterium avium-intracellulare (MAI) occurs only in the later stages of HIV infection when patients are profoundly immunosuppressed (CD4 cell count <50 /mm3). Clinical features include fever, anorexia, weight loss, diar-rhoea and anaemia with bone marrow involvement. MAI is typically resistant to standard anti-tuberculous therapies. A combination of ethambutol, rifabu-tin and clarithromycin reduces the burden of organisms and provides symp-tomatic benefit. Other infections include Strep. pneumoniae, H. influenzae, staphylococcal skin infection and salmonella.


The commonest tumours are Kaposi's sarcoma and non-Hodgkin's lym-phoma. The incidence of all HIV-related malignancies has fallen dramatically since the introduction of HAART.

■ Kaposi's sarcoma is a vascular tumour that appears as red-purple, raised, well-circumscribed lesions on the skin, hard palate and conjunctivae, and in the gastrointestinal tract. The lungs and lymph nodes may also be involved. Human herpesvirus 8 is implicated in the pathogenesis. Local-ized disease is treated with radiotherapy; systemic disease is treated with chemotherapy. Initiation of HAART may cause regression of lesions and prevent new ones emerging.

■ Non-Hodgkin's lymphoma occurs in the brain, gut and lung.

■ Squamous cell carcinoma of the cervix and anus is associated with HIV. HPV may play a part in the pathogenesis.

Prevention and control

■ The risk of HIV transmission following a needle-stick injury involving contaminated blood is reduced by about 80% with post-exposure prophy-laxis using a combination of zidovudine, lamivudine and indinavir for 4 weeks. Prophylaxis should be started as soon as possible after exposure.

■ Pregnant HIV-positive women should receive antiviral therapy to reduce the risk of vertical transmission. Delivery by caesarean section and the avoidance of breast-feeding dramatically reduces infection for patients not adequately treated with HAART, but access to these interventions is limited in resource-poor countries.

■ The use of condoms reduces sexual transmission of HIV. Male circumci-sion protects those individuals against infection with HIV and also other sexually transmitted diseases, such as syphilis and gonorrhoea.

■ Advise drug addicts not to share needles; some areas provide free sterile needles.


The rate of progression among patients infected with HIV varies greatly. The average life expectancy for an HIV-infected patient in the absence of treat-ment is approximately 10 years. The mean survival following a CD4 count of 200 cells/^L is about 3 years. The introduction of HAART has resulted in a dramatic decrease in mortality and opportunistic infections in patients with HIV.


Antimicrobial agents are natural or synthetic chemical substances that sup-press the growth of, or destroy, microorganisms including bacteria, fungi and viruses. Antimicrobial treatment must be started immediately in patients with life-threatening infection and ‘blind therapy' based on the likely causative organisms. Treatment can be adjusted later based on antimicrobial suscep-tibility data from specimens, e.g. pus, blood, foreign bodies, sent before or coinciding with start of treatment. Treatment should be prescribed for the shortest course likely to be effective and agents selected to minimize col-lateral damage, e.g. hospital-wide policies to restrict use of broad-spectrum antibiotics such as some cephalosporins in favour of narrow-spectrum anti-biotics such as benzylpenicillin, have achieved significant reduction in C. difficile infections. Antimicrobials should always be prescribed in accordance with local policies and guidelines.


The choice of antibacterial is based on patient factors and the known or likely causative organism. Factors related to the patient which must be considered include history of drug allergy (e.g. penicillin), renal and hepatic function, susceptibility to infection (e.g. immunosuppressed), severity of illness, age, ability to take drugs by mouth, and in women use of the contraceptive pill, pregnancy or breast-feeding. Antibacterials can be either bacteriostatic (inhibit bacterial growth but do not destroy it, infection is eliminated by the native immune system) or bactericidal (kill the microorganism). Antibacterials are also grouped according to their mechanism of action.

β-Lactam antibacterials

Mechanism of action

The Inhibit synthesis of the peptidoglycan layer of the cell wall, which sur-rounds certain bacteria and is essential for their survival.


Benzylpenicillin (penicillin G) is effective for many streptococcal and menin-gococcal infections, leptospirosis and treatment of Lyme disease. Phen-oxymethylpenicillin (penicillin V) has a similar antibacterial spectrum to benzyl-penicillin but it should not be used for serious infections because gut absorption is unpredictable. Flucloxacillin is effective for infections due to P-lactamase-producing staphylococci (most staphylococci are resistant to benzyl-penicillin because they produce penicillinases). Ampicillin is princi-pally indicated for the treatment of exacerbations of chronic bronchitis and middle ear infections. Amoxicillin is a derivative of ampicillin and has a similar antibacterial spectrum. It is better absorbed than ampicillin when given by mouth. Co-amoxiclav consists of amoxicillin with the p-lactamase inhibitor clavulanic acid, which extends the spectrum of activity of amoxicillin. Pipera-cillin is an extended spectrum p-lactam antibiotic. It is usually used together with a p-lactamase inhibitor such as tazobactam. The combination has activ-ity against many Gram-positive and Gram-negative pathogens and anaerobes including Pseudomonas aeruginosa.

Preparations and dose


Injection: 600 mg vial.

IM/IV (slow injection or infusion): 2.4-4.8 g daily in four divided doses. Higher doses may be needed in serious infections.


Tablets: 250 mg; Solution: 125 mg/5 mL, 250 mg/mL.

Oral 500 mg every 6 hours increased up to 1 g every 6 hours in severe infections.


Capsules: 250 mg, 500 mg; Solution: 125 mg/5 mL, 250 mg/5 mL;

Inịection: 250 mg vial.

Oral 250-500 mg every 6 hours, at least 30 minutes before food.

IM 250-500 mg every 6 hours.

IV (slow injection or infusion): 0.25-2 g every 6 hours.


Capsules: 250 mg, 500 mg; Suspension: 125 mg/5 mL, 250 mg/5 mL;

Inịection: 250 mg vial.

Oral 250-500 mg depending on infection.

IM/IV (slow injection or infusion): 500 mg every 8 hours increased to 1 g every 6 hours in severe infections.


Capsules: 250 mg, 500 mg; Suspension: 125 mg/5 mL, 250 mg/5 mL;

Injectìon: 500 mg vial.

Oral 0.25-1 g every 6 hours 30 minutes before food.

IM/IV (slow injection or infusion): 500 mg every 4-6 hours increased to 2 g every 6 hours in endocarditis and 2 g every 4 hours in Listeria meningitis.

Piperacillin + tazobactam

Injection 2.25 g (2 g/250 mg) or 4.5 g (4 g/500 mg) vial.

IV (slow injection or infusion): 4.5 g every 8 hours increased to every 6 hours with an aminoglycoside in neutropenia.


Hypersensitivity reactions include urticaria, fever, rashes, and anaphylaxis. Individuals with a history of anaphylaxis, urticaria or rash immediately after penicillin administration are at risk of immediate hypersensitivity to a penicil-lin and should not receive a penicillin or cephalosporin (10% of penicillin-allergic patients are also allergic to cephalosporins). Encephalopathy with fits results from excessively high doses or in patients with severe renal failure. Diarrhoea and C. difficile infection (p. 34) can occur as a result of disturbance of the normal colonic flora. Other effects are interstitial nephritis, hepatitis, cholestatic jaundice, reversible neutropenia and eosinophilia. Amino-penicillins (e.g. amoxicillin) frequently produce a non-allergic maculopapular rash in patients with glandular fever.


Contraindicated in penicillin hypersensitivity (see above); macrolides are an alternative in these patients.

Cephalosporins Mechanism of action

Inhibit bacterial wall synthesis in a manner similar to the penicillins.


Broad-spectrum antibiotics - used for treatment of septicaemia, pneumonia, meningitis, biliary tract infections, peritonitis and urinary tract infections.

Preparations and dose

Cephalosporins are often classified by ‘generations'. The members within each generation share similar antibacterial activity. Succeeding generations tend to have increased activity against Gram-negative bacilli, usually at the expense of Gram-positive activity, and increased ability to cross the blood-brain barrier.

First-generation Cefalexin

Capsules: 250 mg, 500 mg; Suspension: 125 mg/5 mL, 250 mg/5 mL.

Oral 250 mg every 8 hours, doubled for severe infections; maximum 4 g daily.

Second generation Cefaclor

Capsules: 250 mg, 500 mg; Suspension: 125 mg/5 mL, 250 mg/5 mL.

Oral 250 mg every 8 hours, doubled for severe infections; maximum 4 g daily.


Tablets: 125 mg, 250 mg; Suspension: 125 mg/mL; Injection: 250 mg, 750 mg, 1.5 g vial.

Oral 250 mg twice daily in most infections; double dose for pneumonia. Gonorrhoea: 1 g as a single dose; Lyme disease: 500 mg twice daily for 20 days.

IM/IV 750 mg every 6-8 hours; 1.5 g every 6-8 hours in severe infections. Single injected doses over 750 mg by intravenous route only.

Third generation Cefotaxime

Injection: 500 mg, 1 g, 2 g.

IM/IV (injection or infusion): 1 g every 12 hours increased in severe infections (e.g. meningitis) to 8 g daily in four divided doses.


Injection: 250 mg, 500 mg, 1 g, 2 g.

IM/IV (injection or infusion): 1 g every 8 hours or 2 g every 12 hours; 2 g every 8 hours or 3 g every 12 hours in severe infections. Single doses over 1 g by intravenous route only.


Skin rashes, nausea and vomiting, diarrhoea (including C. difficile colitis), hypersensitivity reactions (see penicillin).


Penicillin hypersensitivity other than with a minor rash only.

Aminoglycosides Mechanism of action

Inhibit protein synthesis in bacteria by binding irreversibly to the 30S ribo-somal unit. This inhibits translation from mRNA to protein. Aminoglycosides are bactericidal.


Active against many Gram-negative bacteria (including Pseudomonas species) and some Gram-positive bacteria but are inactive against anaerobes. Often used for serious Gram-negative infections when they have a comple-mentary and synergistic action with agents that disrupt cell wall synthesis (e.g. penicillins).

Preparations and dose

Examples: gentamicin (the most widely used), amikacin, neomycin, netil-micin, streptomycin, tobramycin.


Injection: 40 mg/mL

IM/IV (slow injection over 3 min or infusion): 3-5 mg/kg in divided doses every 8 hours or once daily by intravenous infusion, 5-7 mg/kg, then adjust according to serum gentamicin concentration.


Most unwanted effects are dose related and are probably related to high trough concentrations of the drug. Ototoxicity can lead to both vestibular and auditory dysfunction, which result in often irreversible disturbances of balance or deafness. Other side-effects are renal toxicity, acute neuromuscular blockade, nausea, vomiting, rash and antibiotic-associated colitis.


Contraindicated in myasthenia gravis. Monitor serum concentrations in all patients and reduce dose in renal impairment. In patients with normal renal function, serum aminoglycoside concentrations should be measured after three to four doses (earlier and more frequent measurements in patients with renal failure), 1 hour after i.m. or i.v. administration (‘peak' concentration to ensure bactericidal efficacy) and also just before the next dose ('trough' concentration to minimize the risk of toxic effects). For once-daily dose regimen consult local guidelines on monitoring.


Mechanism of action

Interfere with bacterial protein synthesis by binding reversibly to the 50S subunit of the bacterial ribosome. The action is primarily bacteriostatic unless at high concentrations.


Erythromycin has an antibacterial spectrum that is similar to that of penicillin; it is thus an alternative in penicillin-allergic patients. Indications for erythro-mycin include respiratory infections, whooping cough, legionnaires' disease, Chlamydia infections and Campylobacter enteritis. Erythromycin has poor activity against H. influenzae. Clarithromycin is a derivative of erythromycin with slightly greater activity. Azithromycin has slightly less activity than erythromycin against Gram-positive bacteria but enhanced activity against Gram-negative bacteria.

Preparations and dose

Examples: erythromycin, azithromycin, clarithromycin.


Capsules and tablets: 250 mg; Suspension: 125 mg/5 mL, 250 mg/5 mL, 500 mg/5 mL; Injection: 1 g vial.

Oral 0.5-1 g daily in two or four divided doses; up to 4 g daily in severe infections. Early syphilis: 500 mg four times daily for 14 days. Uncompli-cated genital chlamydia and non-gonococcal urethritis: 500 mg twice daily for 14 days.

IV infusion 25 mg/kg by continuous infusion or in divided doses every 6 hours; 50 mg/kg in severe infections.


Tablets: 250 mg, 500 mg; Injection: 500 mg vial.

Oral 250 mg every 12 hours; increased in severe infections to 500 mg every 12 hours.

IV infusion into larger proximal vein: 500 mg twice daily.


Gastrointestinal upsets (epigastric discomfort, nausea, vomiting and diar-rhoea) are common with the oral preparation of erythromycin; azithromycin and clarithromycin are better tolerated. Skin rashes, cholestatic jaundice (with erythromycin), prolongation of the QT interval on the electrocardiogram (ECG), with a predisposition to ventricular arrhythmias. Erythromycin and clarithromycin inhibit P450 drug-metabolizing enzymes and can elevate levels of drugs (e.g. carbamazepine and ciclosporin) requiring these enzymes for metabolism (see national formulary for list).

Sulphonamides and trimethoprim Mechanism of action

Inhibit the enzyme dihydrofolate reductase in the synthetic pathway to folic acid. Bacteria cannot utilize external folic acid, a nutrient that is essential for cell growth.


The importance of the sulphonamides has decreased as a result of increasing bacterial resistance and their replacement by antibacterials that are generally more active and less toxic. Sulfamethoxazole and trimethoprim are used in combination (as co-trimoxazole) because of their synergistic activity. However, co-trimoxazole is associated with rare but serious side-effects (e.g. Stevens-Johnson syndrome, bone marrow suppression) and its use is limited to the treatment of PCP, toxoplasmosis and nocardiosis. In other infections it is only used when there is evidence of sensitivity and good reason to prefer this combination to a single drug. Trimethoprim is used in urinary tract infec-tions and acute and chronic bronchitis.


Tablets: 100 mg, 200 mg; Suspension: 50 mg/5 mL.

Oral 200 mg every 12 hours.


Nausea, vomiting and diarrhoea, skin rashes. Rarely bone marrow sup-pression, folate deficiency (in patients with depleted folate stores), photo-sensitivity and allergic reactions including anaphylaxis.


Contraindicated in blood dyscrasias.

Metronidazole and tinidazole Mechanism of action

A toxic metabolite inhibits bacterial DNA synthesis and breaks down existing DNA. Only some anaerobes and some protozoa contain the enzyme (nitroreductase) that converts metronidazole to its toxic metabolite. It is bactericidal.


Anaerobic infections, protozoal infections, Helicobacter pylori eradication, C. diííicile colitis. Metronidazole is more commonly used than tinidazole.

Preparations and dose


Tablets: 200 mg, 400 mg; Suspension: 200 mg/5 mL; Intiavenous infusion: 5 g/5 mL; Flagyt® suppositories.

Oral 400 mg every 8 hours; for surgical prophylaxis, 400 mg before surgery and three further doses of 400 mg every 8 hours for high-risk procedures.

IV infusion over 20 minutes: 500 mg every 8 hours; for surgical prophylaxis, 500 mg at induction and up to three further doses of 500 mg every 8 hours for high-risk procedures.

By rectum 500 mg every 8 hours; for surgical prophylaxis, 1 g 2 hours before surgery and up to three further doses of 1 g every 8 hours for high-risk procedures.


Nausea, vomiting, metallic taste, disulfiram-like reaction (unpleasant hang-over symptoms) with alcohol, skin rashes, and abnormal liver biochemistry. With prolonged therapy, peripheral neuropathy, transient epileptiform seizures and leucopenia can occur.


Caution with alcohol ingestion; reduce dose in severe liver disease and avoid in porphyria.


Mechanism of action

Inhibit replication of bacterial DNA. The effect is bactericidal.


Ciprofloxacin has a broad spectrum of activity and is particularly active against Gram-negative bacteria. It has only weak activity against strepto-cocci, staphylococci and anaerobes.

Preparations and dose

Examples: ciprofloxacin, norfloxacin, levofloxacin.


Tablets: 100 mg, 250 mg, 500 mg, 750 mg; Suspension: 250 mg/5 mL;

Intravenous infusion: 2 mg/mL.

Oral 250-750 mg twice daily depending on infection.

IV infusion (over 30-60 minutes): 200-400 mg twice daily.


Gastrointestinal upset (nausea, vomiting, diarrhoea), CNS effects (dizziness, headache, tremors, rarely convulsions), photosensitive skin rashes, tendon damage (pain, inflammation, rupture).


Contraindicated in patients with a history of tendon disorders related to quinolone use; risk of tendon rupture is increased by corticosteroids. If ten-donitis is suspected, stop quinolone immediately.

Ebook Essentials of Kumar and Clark's Clinical Medicine, 5e

1. Ethics and communication

Ethics and communication

2. Infectious diseases

Infectious diseases

3. Gastroenterology and nutrition

Gastroenterology and nutrition

4. Liver, biliary tract and pancreatic disease

Liver, biliary tract and pancreatic disease

5. Haematological disease

Haematological disease
Assessment and treatment of suspected neutropenic sepsis

6. Malignant disease

Malignant disease

7. Rheumatology

Clinical features, Investigations

8. Water, electrolytes and acid–base balance


9. Renal disease

Renal disease

10. Cardiovascular disease


11. Respiratory disease

Respiratory disease

12. Intensive care medicine

Intensive care medicine

13. Drug therapy, poisoning, and alcohol misuse

Drug therapy, poisoning, and alcohol misuse

14. Endocrine disease

Endocrine disease

15. Diabetes mellitus and other disorders of metabolism


16. The special senses


17. Neurology


18. Dermatology