Developing countries	Specific geographical areas (see text)
Malaria	Histoplasmosis
Schistosomiasis	Brucellosis
Dengue	World-wide
Tick typhus	Influenza
Typhoid	Pneumonia
Tuberculosis	Upper respiratory tract infection
Dysentery	Urinary tract infection
Hepatitis A	Traveller’s diarrhea
Amoebiasis	Viral infection

Fever of unknown origin (FUO)

One definition of a fever of unknown origin is ‘a fever persisting for more than 2 weeks, with no clear diagnosis despite intelligent and intensive investigation’. The definition of FUO has also been refined to include classical FUO, nosocomial FUO, neutropenic FUO and HIV-related FUO.

The causes of FUO, when determined, are infections (20–40%), e.g. endocarditis, TB, Lyme disease; connective tissue disease, e.g. polymyalgia (15–20%); malignancy, e.g. lymphoma (10–30%); and miscellaneous (e.g. drugs).

Fever and rash

The presentation of fever and rash in an adult has many potential causes. These range from severe life-threatening infections, such as meningococcal sepsis or toxic shock syndrome, to the usually mild infections of parvovirus or enterovirus. Travel-related illnesses include dengue, typhus or typhoid. Illnesses such as syphilis or HIV seroconversion illness can also present with a fever and rash.

Investigations

Initial investigations should include the following:

• FBC, LFTs, CRP

• blood cultures (repeated)

• skin biopsy for microscopy (Gram stain), culture or PCR if appropriate

• appropriate imaging.

A low platelet count would tend to indicate either a viral infection or possibly malaria. A lymphopenia may also indicate a viral infection, whereas a neutrophilia occurs in a bacterial infection. Treatment may be delayed until a diagnosis is made or appears highly likely. However, if serious infection, such as meningococcal sepsis, is suspected, then antimicrobial therapy must be started immediately.

Systemic multi-system infections

Sepsis

Sepsis is a leading cause of death worldwide and is usually the result of an overwhelming bacterial infection. Most infections, whether bacterial, fungal or viral, initiate a systemic inflammatory response with the release of vasodilatory and pro-inflammatory substances, including cytokines, histamine and prostaglandins. This results in endothelial damage, capillary leak and vasodilatation, causing tissue hypoperfusion. Additionally, the coagulation pathway is activated by a number of cytokines, resulting in microthrombi and further tissue ischaemia. The mortality rate for severe sepsis remains about 30%.

Clinical features

Patients are pyrexial (occasionally hypothermic) and often hypotensive, and have rigors, warm peripheries and a bounding pulse. Hypotension may not be present, particularly in children and young adults. They can be hyperglycaemic or, in severe cases, hypoglycaemic.

A consensus definition (1991) of sepsis immune response syndrome (SIRS) for adults considers two or more of the following features to be present:

• heart rate > 90 beats per min

• body temperature < 36°C or > 38°C

• respiratory rate > 20 breaths per min or PaCO₂ < 4.3 kPa

• white blood cell count < 4 × 10⁹/L or > 12 × 10⁹/L, or > 10% immature (band) forms on film.

Septicaemia is defined as SIRS plus the detection of a positive blood culture. Bacteraemia is the presence of bacteria in the bloodstream without SIRS or in an asymptomatic patient.

Severe sepsis is sepsis complicated by organ dysfunction or hypotension.

Septic shock is sepsis with hypotension in adults with a systolic BP < 90 mmHg, a mean arterial pressure < 60 mmHg, or a reduction of > 40 mmHg in the systolic BP from baseline.

Management

Sepsis and septic shock should be treated urgently, as should the bacterial cause of the infection.

• Patients should have close monitoring (intensive care) and be adequately supported with IV fluid volume replacement, inotropes and adequate oxygenation.

• Therapy to optimize the mixed venous oxygen saturation has been shown to improve survival from sepsis significantly.

• Adjunctive therapy of severe sepsis with activated protein C (drotrecogin alfa activated) may be of benefit. Evidence for other adjunctive therapies, such as the use of steroids, is disappointing. Tight glycaemic control is now not recommended (p. 539).

• Blood tests should include FBC, U&E, LFTs and CRP.

• Blood cultures × 2 (at least) should be taken from different sites prior to antibiotic therapy.

• Early IV antibiotic therapy should be given. The exact choice of antibiotic depends on the probable source of sepsis. If the source of sepsis is completely unknown, then choose antibacterial agents that treat a broad range of Gram-positive and Gram-negative bacteria (such as co-amoxiclav 1.2 g IV 3 times daily, cefotaxime 1 g twice daily IV to maximum of 8 g daily, plus gentamicin 5–7 mg/kg IV daily).

• Neutropenic sepsis may often be caused by Pseudomonas aeruginosa and these patients should be treated with an antipseudomonal β-lactam antibiotic (such as piperacillin/tazobactam 4.5 g 6-hourly IV infusion or meropenem 1 g 8-hourly) plus an aminoglycoside. If there is a permanent IV line in situ, then glycopeptides may need to be added. Failure of fever to resolve should indicate the need to investigate the possibility of a fungal or viral infection and/or to use a glycopeptide to treat resistant gram negative infections.

• Asplenic patients can develop sepsis from encapsulated organisms, e.g. Streptococcus pneumoniae, Neisseria meningitidis or Haemophilus influenzae. Give a third-generation cephalosporin (ceftriaxone IV infusion 2–4 g daily ± vancomycin 1–1.5 g IV infusion 12-hourly).

Meningococcal septicaemia

Neisseria meningitidis is found worldwide. There are five major serogroups. The organism is carried asymptomatically in the nasopharynx of 5–20% of the general population. Invasion into the bloodstream (septicaemia-causing disease) depends on both host and bacterial factors.

Presentation is with the classic triad of headache, fever and neck stiffness, though this is not always the case (p. 54). Septicaemia causes septic shock with fever, myalgia and hypotension, and may be accompanied by a petechial or haemorrhagic rash. The case fatality rate is approximately 10%.

N.B. If not treated immediately, patients can deteriorate rapidly, with shock, disseminated intravascular coagulation, multi-organ failure and death.

Diagnosis

Diagnosis is frequently clinical with:

• presence of a rash (Fig. 2.1)

• Gram stain showing diplococci in CSF (not always necessary) or aspirate of petechiae

• culture of blood, CSF or aspirate

• PCR of above samples if necessary.

Fig. 2.1 Meningococcal septicaemia showing a purpuric rash.

Management (Box 2.1)

Start antibiotics immediately.

• cefotaxime 2 g 6-hourly IV for 7 days or

• benzyl penicillin 2.4 g 4-hourly by IV infusion.

Box 2.1 Meningococcal meningitis and meningococcaemia emergency treatment

Suspicion of meningococcal infection is a medical emergency requiring treatment immediately

Clinical features

• Petechial or non-specific blotchy red rash

• Fever, headache, neck stiffness

All these features may not be present — and meningococcal infection may sometimes begin like any apparently non-serious infection

Immediate treatment for suspected meningococcal meningitis at first contact before transfer to hospital or investigation

• Benzylpenicillin 1200 mg (adult dose) slow IV injection or intramuscularly

• Alternative if penicillin allergy — cefotaxime 2 g IV ×4 daily

In meningitis, minutes count; delay is unacceptable

On arrival in hospital

• Routine tests including blood cultures immediately

• Watch out for septicaemic shock

Patient contacts in the household and ‘kissing’ contacts should be given prophylaxis with oral rifampicin 600 mg 6-hourly for 2 days or ciprofloxacin 500 mg single dose to eradicate bacteria from the nasopharynx. Group C disease contacts should be offered immunization.

Malaria

Malaria in humans is caused by Plasmodium falciparum (most severe form), Plasmodium vivax, Plasmodium ovale, Plasmodium malariae or rarely Plasmodium knowlesi, which are transmitted by the Anopheles mosquito. P. vivax and P. malariae may recur after many years, but P. falciparum and P. malariae do not recur, although individuals may be reinfected. P. falciparum causes a potentially fatal malaria that results in about 1–2 million deaths annually, most in children in sub-Saharan Africa. The other causes of malaria are very rarely fatal and may be regarded as the benign malarias.

Type of malaria	Drug treatment
Plasmodium vivax, P. ovale, P. malariae	Chloroquine 600 mg 300 mg 6 hours later 300 mg 24 hours later 300 mg 24 hours later
P. falciparum (almost all are resistant to chloroquine)	Quinine 600 mg 3 times daily for 7 days Plus Doxycycline 200 mg once daily for 7 days Or Clindamycin 450 mg 3 times daily for 7 days (Fansidar (SP) (pyrimethamine and sulfadoxine) 3 tablets as single dose with or following quinine) Or Malarone 4 tablets daily for 3 days Or Riamet (artemether with lumefantrine) 4 tablets 12-hourly for 3 days
	Alternative therapy
	Artesunate-mefloquine 12/25 mg/kg daily for 3 days Or Dihydroartemisinin/piperaquine 6.3 mg/kg daily for 3 days

Management of severe falciparum malaria (Box 2.2)

• In non-endemic countries, all cases of falciparum malaria should be admitted to hospital for at least 1–2 days to ensure there is no immediate deterioration. It can be a medical emergency and require intensive care therapy.

• Artesunate 2.4 mg/kg single bolus by IV injection can be given if available, then at 12 and 24 hours, thereafter daily until oral medication can be tolerated. It does not cause hypoglycaemia. A recent trial found a lower death rate in patients with severe malaria treated with artesunate compared to quinine-treated patients. Artemisinin resistance has been reported in Cambodia. Artesunate is also available as rectal suppositories. However, if artesunate is difficult to obtain then quinine therapy should not be delayed.

• Quinine salts is an alternative. 20 mg/kg IV loading dose (max. 1.2 g) given over 4 hours, followed by 10 mg/kg IV over 4 hours 3 times daily should be used to treat severe malaria. IV administration may induce hypoglycaemia, and any patient receiving IV quinine should have a glucose infusion and regular (4-hourly) blood glucose monitoring. Quinine may be given orally as soon as the patient is able to tolerate oral medication (600 mg 3 times daily) to complete a week of therapy.

• Exchange transfusion is of unproven benefit in the treatment of severe malaria; it has a number of complications and should only be used in adults with a parasitaemia of > 10% after specialist advice has been sought.

Management of non-falciparum malaria

Non-falciparum malarias can be treated with oral chloroquine 600 mg, then 300 mg after 8 hours, then 300 mg daily for 2 days. There is some reported chloroquine-resistant malaria in Papua New Guinea and treatment can be with riamet or malarone (dosages in Table 2.2). P. vivax and P. ovale have hypnozoites that may persist and cause a recurrence of infection many years later. Patients with vivax or ovale infection should receive primaquine 15 mg daily for 2–3 weeks following successful treatment, to eradicate hepatic hypnozoites and prevent relapse. Anyone who is about to receive primaquine should have their glucose-6-phosphate dehydrogenase (G6PD) status checked, as primaquine use is associated with haemolysis in patients with G6PD deficiency (p. 216). WHO guidelines www.who.int/topics/malaria/en.

Prevention of malaria

• Avoidance of mosquito bites with mosquito repellants and permethrin-impregnated bed-nets can reduce transmission of malaria by similar amounts to chemoprophylaxis. The advice given to travellers to the tropics about the risks of malaria at their destinations and the need for malaria chemoprophylaxis should be up to date, as it changes over time.

• Currently available alternatives for chemoprophylaxis in adults are atovaquone/proguanil (malarone 1 tablet daily), mefloquine 250 mg weekly and doxycycline 100 mg daily.

• Chloroquine-resistant P. falciparum is so common that there are very few places where chloroquine 300 mg weekly/proguanil 200 mg daily prophylaxis can currently be recommended.

• Prophylaxis should usually be started a week (malarone — only 1 day) before travel and continued for 4 weeks after return. It should also be stressed in advice to patients that malaria chemoprophylaxis is not 100% effective; should they become febrile after return from a malarial area, they should still suspect malaria.

Dengue

Dengue is caused by a flavivirus that is carried by the daytime-biting Aedes mosquito. It is found throughout most of the tropics and is particularly common in South-East Asia and the Caribbean. The incubation period is about 5–7 days.

Clinical features

An acute febrile illness with very severe musculoskeletal pain, severe headache with retro-orbital pain, severe malaise, lymphadenopathy and sometimes a maculo-papular rash occur. The fever subsides after 3–4 days and then returns.

Dengue haemorrhagic fever (DHF) may occur as a result of a second or subsequent infection with a different dengue serotype and may be caused by an abnormal immune response to dengue infection. It presents with severe bleeding (haematemesis and melaena), a severe capillary leak and hypotension.

Investigations

Investigations show a low platelet count, normal white cell count and sometimes mildly abnormal liver biochemistry. See Figure 2.2 for the course and timing of diagnosis.

Fig. 2.2 Dengue infection: course and timing of diagnosis.

(From Halstead SB 2007, with permission.)

Treatment

There are no specific antiviral therapies currently available for the treatment of dengue fever but adequate fluid replacement in DHF is essential; blood transfusion is given if necessary. Corticosteroids are of no proven benefit. Convalescence is slow.

Leptospirosis

Leptospirosis is a zoonosis caused by a number of species of the genus Leptospira. Leptospirosis is found worldwide, but is particularly common in South-East Asia. A chronic renal infection in the animal reservoir (usually rodents) is the usual source of infection in humans, disease in humans being acquired through contact with water contaminated with rodent urine. Around 90% of infections are thought to result in a self-limiting febrile illness, but some result in a severe and potentially fatal illness. The incubation period is 5–14 days.

Clinical features

The main features of severe leptospirosis are fever, anorexia, jaundice, myalgia, conjunctival suffusion, and hepatic and renal failure. The case fatality rate of severe leptospirosis is about 5–40%.

Diagnosis

Diagnosis of leptospirosis is by culture or serological tests. There should be early liaison with the laboratory, as specialized culture techniques improve diagnosis.

Treatment

Treatment of severe disease is with benzyl penicillin 1.2 g IV 4 times daily or ceftriaxone 1 g IV daily. Doxycycline 100 mg twice daily may be used in mild disease. Jarisch–Herxheimer reactions have been reported after treatment.

Plague

Sporadic cases (as well as occasional epidemics) of plague occur worldwide, the majority in sub-Saharan Africa, although disease is occasionally seen in the southern states of the USA. Plague is caused by a Gram-negative bacillus, Yersinia pestis. The main reservoirs are rodents. The usual vector is the rat flea.

Clinical features

Clinical manifestations of plague are bubonic, septicaemic, pneumonic, pharyngeal and meningitis.

Diagnosis

Diagnosis is by clinical suspicion and culture of Y. pestis from blood, sputum or aspirate of a bubo. A rapid immunodermatographic dipstick test is also available, and has high sensitivity and specificity.

Treatment

The treatment of choice is streptomycin 15 mg/kg IM twice daily for at least 7 days or gentamicin 5 mg/kg IV daily for 10 days. Oral tetracycline, quinolones and chloramphenicol are also effective. Post-exposure prophylaxis is with doxycycline or ciprofloxacin.

Brucellosis

Brucellosis is a zoonosis and nearly all human infections result from direct or indirect exposure to animals. Farmers, veterinarians and abattoir workers are particularly at risk. Spread is following direct contact with infected animals or by the consumption of unpasteurized dairy products from cows, goats or sheep. The pathogens are members of the genus Brucella: in humans usually B. abortus, B. melitensis and B. canis. Brucellosis has a worldwide distribution, although it has been eliminated from the UK. It is especially common in the Mediterranean, India and the Arabian Peninsula.

Clinical features

The onset is insidious, with an incubation period about 2–4 weeks. Symptoms are initially non-specific, although specific ones include an ‘undulant’ fever, malodorous sweat and a peculiar taste in the mouth. Brucellosis can affect nearly any organ of the body and includes lymphadenopathy, hepatosplenomegaly, sacro-iliitis, arthritis, osteomyelitis and meningoencephalitis. Chronic brucellosis can last over a year. Symptoms may also recur over long periods.

Investigations

• White cell count is normal/low. CRP and ESR are variable.

• Blood and bone marrow cultures (which have a higher yield) should be performed. Brucella may also be cultured from CSF, lymph nodes or liver biopsies. There should be liaison with the laboratory, as a prolonged incubation is required and laboratory transmission of Brucella should be prevented.

• Serological tests with rising antibody titres on ELISA may aid diagnosis if culture results remain negative.

Treatment

• WHO recommends treatment for 6 weeks with doxycycline 200 mg daily and rifampicin 600–900 mg daily, but relapses occur.

• Doxycycline 200 mg daily for 6 weeks and streptomycin 1 g IM daily for 2–3 weeks or gentamicin are also used.

Listeriosis

Listeria monocytogenes causes an infection of many animal species. It is also widespread in the environment in soil and decayed matter. The organism can grow at low temperatures and may be transmitted in foods such as unpasteurized cheeses and pâtés.

Clinical features

• In healthy adults, Listeria causes a self-limiting febrile gastroenteritis, the incidence of which is unknown. A brainstem encephalitis can occur in healthy adults; CSF examination may be normal, although these patients are often bacteraemic and MRI may be useful.

• In pregnant women, neonates, and elderly or immunosuppressed patients, Listeria can cause serious problems.

• In pregnancy bacteraemia usually occurs in the last trimester and presents as a flu-like illness, but infection of the fetus can lead to septic abortion, premature labour and stillbirth. Early treatment may prevent fetal loss but the rate remains about 50%.

• In neonates Listeria may manifest as an early-onset sepsis in the premature infant, acquired in utero. A second, late-onset form occurs about 2 weeks after birth and usually presents as a meningitis.

• In the elderly and the immunocompromised Listeria usually causes meningitis or bacteraemia; a variety of other focal infections have been described.

Investigations

Listeriosis is established by culture of blood, CSF or other body fluids.

Treatment

The treatment of choice for adult listeriosis is ampicillin plus gentamicin. Co-trimoxazole is also effective.

Q fever

Infection with the obligate intracellular pathogen Coxiella burnetii, which is widespread in many animals, is the cause of Q fever. Transmission to humans is usually via dust, aerosol and unpasteurized milk; spore formation means that the infection can remain in the environment for long periods.

The incubation period is 2–4 weeks. Onset is insidious, with fever, myalgia and headache, but pneumonia and hepatitis may occur. Occasionally, endocarditis or other focal infections may cause chronic illness.

• Diagnosis is made serologically or by nested PCR (low sensitivity).

• Treatment is with doxycycline 200 mg daily for 14 days. The addition of chloroquinine is used in chronic infection.

Lyme disease

Lyme disease is found in North America, Europe and Asia, and is caused by infection with the spirochaete Borrelia burgdorferi, of which there are several genomic species. It is a zoonosis transmitted to man by ixodid ticks, the main animal reservoir being deer or occasionally other mammals. Infections usually occur after visiting woodland.

There are three stages of Lyme infection:

• Stage 1 disease is a localized infection, presenting about a week after the tick bite with erythema migrans (a macular rash), lymphadenopathy, and associated fever and headache.

• Stage 2 disease occurs several days to weeks after the appearance of erythema migrans. Some patients may develop a more widespread rash, and after several weeks or months around 15% of untreated cases develop neurological complications such as meningitis, encephalitis, cranial or peripheral neuritis, or radiculopathies. About 5% of patients develop cardiac involvement. Myalgia and arthritis may also occur at this stage.

• Stage 3 disease commonly causes a chronic arthritis (usually of the knees), but may also cause chronic encephalomyelitis and other neurological disorders or acrodermatitis chronica atrophicans. The evidence for persistent infection at this stage is lacking.

Diagnosis

This may occasionally be established by finding spirochaetes in CSF or skin samples. Serodiagnosis is usually performed to confirm the diagnosis, with an IgM response detectable in the first month. Some care should be taken in interpreting results, as false positives may occur.

Treatment

• Amoxicillin 500 mg 3 times daily for 14–21 days or doxycycline 100 mg twice daily for 14–21 days can be used to treat early infection or isolated facial palsies. The duration of amoxicillin or doxycycline treatment should be increased to 30–60 days for stage 2 disease.

• Ceftriaxone 2 g IV daily for 14–28 days should be used if there is neurological involvement or cardiac involvement, e.g. second- or third-degree atrioventricular block.

• Prevention is necessary in tick-infested areas with repellants and protective clothing. Ticks must be removed promptly.

Visceral leishmaniasis

Visceral leishmaniasis (kala-azar) is caused by Leishmania donovani, L. infantum or L. chagasi, and is present in India, Asia, Africa, the Mediterranean and South America. In central India, humans are the main host and the disease occurs in epidemics. In most other areas, it is a zoonosis; the main animal reservoirs are dogs and foxes, although in Africa it is carried by rodents. Visceral leishmaniasis is a common opportunistic infection of advanced HIV disease in Mediterranean coastal regions.

Clinical features

The incubation period is usually 1–2 months but may be much longer. Fever and splenomegaly are common features, pancytopenia and hepatomegaly are often present, and lymphadenopathy is common in Africa. If the infection is untreated, death usually occurs within a year with worsening pancytopenia and weight loss.

Diagnosis

This is confirmed by finding the parasite in aspirates of bone marrow, liver, lymph node or spleen, though in inexperienced hands these can occasionally be mistaken for histoplasmosis.

• Nucleic acid amplification and specialized culture techniques are available from specialist centres.

• Serology can be useful.

Treatment

• The drug of choice is IV amphotericin B (preferably given in the liposomal form), but this is expensive and is not widely available in many areas where the disease is prevalent.

• Miltefosine may be an oral alternative to amphotericin B.

• In areas where resources are limited, pentavalent antimony salts are used, but these are toxic drugs and should be given after specialist advice.

Rickettsial diseases

Rickettsia and the closely related species, Orientia, are small intracellular bacteria that are spread by arthropods (ticks, lice, mites). The reservoir of infection is usually mammalian (often rodent) but may be human. The incubation period is 4–21 days and rickettsial illnesses are characterized by fever, rash and headache. A black spot or eschar may be present at the site of the tick bite, which is painless. Renal failure and haematological, neurological or cardiovascular abnormalities may complicate the illness, but these are rare.

Treatment

• Doxycycline 100 mg twice daily for 5–7 days and rifampicin 600 mg daily are also effective if tetracyclines cannot be used.

• Prophylaxis for scrub typhus is with weekly oral doxycycline 200 mg, but only in highly endemic areas.

Epstein–Barr virus (EBV)

This herpes virus commonly causes infections, mainly in adolescents and young adults worldwide. It is probably transmitted in saliva and by aerosol.

Clinical features

• Infectious mononucleosis (sometimes referred to as glandular fever) produces a fever, headache, malaise, lymphadenopathy and sore throat. A transient macular rash is common if amoxicillin is given. Mild hepatitis and splenomegaly are common. Severe complications, such as meningoencephalitis, myocarditis and splenic rupture, are rare.

• A post-viral syndrome may occasionally occur after the acute infection, with patients feeling lethargic for a number of months. Like other herpes viruses, EBV remains latent for life but reactivation in the immunocompetent is controversial.

EBV is implicated in the aetiology of a number of malignancies, including Burkitt’s lymphoma, nasopharyngeal carcinoma and post-transplant lymphoma, and in HIV disease with primary cerebral lymphoma, Hodgkin’s lymphoma and oral leucoplakia.

Investigations

• Specific IgG and IgM EBV antibodies detect the infection.

• PCR is available for the detection of EBV DNA in CSF and other body fluids; this may be particularly useful in the diagnosis of meningoencephalitis or primary cerebral lymphoma in HIV infection.

Treatment

Most cases of EBV infection require no specific treatment. The efficacy of antiviral treatment of EBV-associated tumours or EBV in immunosuppressed patients remains unproven; steroids may be of use in some complications, such as thrombocytopenia or haemolysis.

Skin and soft-tissue infections

Skin infections result in a number of different conditions. The most common organisms causing skin infections are group A streptococci and Staphylococcus aureus.

• Impetigo — weeping exudative area, often on the face, with a honey-coloured crust on the surface due to Staph. aureus or group A streptococci.

• Cellulitis — confluent erythema of the skin, often tender. Cellulitis affects the lower leg or sometimes the face, and is associated with a high temperature. It is commonly caused by a streptococcus, or less frequently a staphylococcus.

• Folliculitis — inflammation of hair follicles, presenting as tender papules and pustules. Folliculitis is very commonly caused by Staph. aureus.

• Boils — deep-seated inflammation of the skin, causing painful red swellings, sometimes with pus. Boils are usually caused by staphylococci.

Treatment

Treatment should be started empirically and should cover both Staph. aureus and streptococcal infections. If oral therapy is appropriate, then flucloxacillin 500 mg 4 times daily and amoxicillin 500 mg 3 times daily are reasonable choices; the duration of therapy depends on response, but is usually around a week. Clindamycin 300–450 mg 4 times daily, clarithromycin 500 mg orally 2 times daily for 7 days or another macrolide is used in penicillin-allergic patients.

In severe or extensive infections, high-dose IV benzyl penicillin 1.2–1.8 g IV 4-hourly and flucloxacillin 1–2 g IV 6-hourly will be required. High-dose IV clindamycin or a macrolide is used in penicillin-allergic patients. Collections of pus may need to be drained, and in cellulitis elevation of the affected limb speeds recovery.

Meticillin-resistant Staph. aureus (MRSA)

The mec-A gene in Staph. aureus makes it resistant to meticillin, oxacillin, flucloxacillin and nearly all other β-lactam antibiotics. The incidence of MRSA has increased over the last 25 years and in some hospitals more than 50% of Staph. aureus are MRSA; the prevalence of community-acquired MRSA is increasing.

Like meticillin-sensitive Staph. aureus (MSSA), MRSA is usually a harmless skin colonizer, particularly in hospital inpatients. However, both can cause a variety of invasive infections, e.g. soft-tissues infections, bacteraemias, pneumonias and line infections. The case fatality rate of invasive MRSA infections is greater than that of MSSA. Eradication of MRSA carriage is possible, though sometimes difficult. Isolation of patients, strict hand washing, good IV catheter care and other infection control procedures should be observed. Control of the use of antibiotics in hospitals and good infection control policies are vital to prevent spread.

Community-acquired MRSA (CA-MRSA) may have different resistance profiles to hospital strains (often retaining sensitivities) as regards tetracycline, clindamycin and co-trimoxazole. It often produces the exotoxin Panton–Valentine leucocidin and is an increasingly common cause of soft-tissue infections, particularly in the USA (USA300 strain).

Treatment

Treatment of MRSA infection depends on the source of the infection and the sensitivity of the MRSA.

Antibiotics active against MRSA include the glycopeptides (vancomycin and teicoplanin), rifampicin, the tetracyclines and fusidic acid.

• Serious invasive MRSA infections should, in general, be treated with a glycopeptide (e.g. vancomycin 1 g IV twice daily), and often a second agent is added, such as rifampicin for MRSA pneumonia, fusidic acid for MRSA osteomyelitis, or gentamicin or rifampicin for MRSA endocarditis.

• MRSA bacteraemia should be treated for at least 2 weeks but, for example, MRSA endocarditis or osteomyelitis must be treated for longer.

• Less serious infections, such as mild cellulitis, can be treated with two oral agents, such as a tetracycline, co-trimoxazole or a combination of fusidic acid and rifampicin.

• Newer agents include linezolid, quinupristin/dalfopristin, daptomycin and tigecycline. Linezolid may have advantages over vancomycin; linezolid has better penetration into lung tissue and skin, but the clinical benefit is yet to be confirmed. These new drugs should not yet be used as first-line treatment for MRSA infections.

Glycopeptide-intermediate Staph. aureus (GISA) and vancomycin-resistance in Staph. aureus (VRSA)

• GISA develops because of changes in cell wall synthesis.

• VRSA, which has acquired the van A gene from vancomycin-resistant enterococci, has also been reported but is rare.

Staphylococcal toxic shock syndrome (TSS)

TSS is an acute febrile illness characterized by a generalized erythematous rash that nearly always starts within the first 24 hours of illness, desquamating after about 1 week. The most common symptoms include fever (>40° C), hypotension, and diffuse rash with desquamation. TSS ranges in severity from a mild disease to a severe life-threatening illness. It is due to toxin production by Staph. aureus. TSS toxin-1 (TSST-1) acts as a superantigen that stimulates non-specific T-cell proliferation. For streptococcal toxic shock syndrome, see below.

In the early 1980s, most cases of TSS were in menstruating females and associated with retained tampons. Recently, TSS has been less often associated with menstruation.

• Treatment is by removal of the source of the staphylococcal infection and treatment with flucloxacillin 1–2 g IV 4 times daily.

Post-streptococcal syndromes

Strep. pyogenes infections usually cause localized throat or skin infections. However, there are a number of immune-associated, generalized complications of Strep. pyogenes.

Rheumatic fever

This is a multi-system inflammatory disorder, occurring in children and young adults as a result of a pharyngeal infection with a group A streptococcus. It is due to molecular mimicry between cell wall M proteins of some group A streptococcus strains, and cardiac laminin and myosin and synovial membrane. Rheumatic fever is much less common in Western Europe and the USA than in other parts of the world; this may be due in part to the treatment of streptococcal infections, e.g. sore throats. The diagnosis of rheumatic fever is made according to the revised Duckett–Jones criteria. The major criteria are carditis, polyarthritis, chorea, erythema marginatum and subcutaneous nodules, while the minor criteria include fever and arthralgia.

• Diagnosis. This is made on the basis of two or more major criteria, or one major criterion plus two or more minor criteria, with evidence of recent streptococcal infection, e.g. positive throat cultures or raised antistreptolysin O titre.

• Treatment

• Aspirin/NSAIDs produce a dramatic response.

• Bed rest is advised. Steroids are used if carditis is present but their efficacy remains unproven.

• Streptococcal infections should be eradicated with oral phenoxymethylpenicillin 500 mg 4 times daily for 10 days.

• Prophylaxis. Oral phenoxymethylpenicillin 250 mg twice daily, until the age of 20 years or for 5 years after the latest attack, is used for prophylaxis against further episodes of rheumatic fever. This is most common after an episode of carditis. Erythromycin is used if the patient is allergic to penicillin.

• Complications. Chronic rheumatic valvular disease develops in just over half of those who have acute rheumatic fever complicated by carditis (after 10–20 years). The mitral and aortic valves are mainly affected.

Cat scratch fever

This is caused by Bartonella henselae. Regional lymphadenopathy occurs 1–2 weeks after infection. This resolves after weeks or months and is not accompanied by systemic symptoms. Doxycycline can be used.

Herpes simplex (HSV)

HSV1 is spread by direct contact and droplet infection. The primary illness produces a fever with painful blisters on the face or a painful gingivostomatitis. Recrudescence of HSV blisters appears as cold sores.

• Treatment is with topical aciclovir; if infection is severe, use oral aciclovir 200 mg 5 times daily for 5 days.

Myositis

Pyomyositis is an acute bacterial infection of skeletal muscle that is usually caused by Staph. aureus and occasionally by streptococci or other organisms.

• Treatment is with prompt surgical debridement with benzyl penicillin 1.2 g IV 4 times daily and flucloxacillin 500 mg 4 times daily.

Gas gangrene

Gas gangrene is caused by infection with Clostridium perfringens or occasionally with other species of Clostridia. It is characterized by the absence of pus and the presence of gas in the tissues. It may be difficult to distinguish from necrotising fasciitis, except during surgery, though the presence of gas on X-ray and crepitation in the tissues is useful.

• Treatment is with prompt surgical debridement and high-dose benzyl penicillin 2.4 g IV 6 times daily and clindamycin 1.2 g IV 4 times daily. Hyperbaric oxygen therapy is also advised, although there is no RCT to support the use of this therapy.

Necrotising skin and soft-tissue infections

These are defined as soft-tissue infections spreading along the fascial planes with or without an overlying cellulitis. They are serious infections with mortality as high as 40%. Clinically, these patients are very unwell and pain is a prominent symptom, out of proportion to the skin findings. The causative organism is usually group A streptococcus, though other organisms can cause this syndrome; if the infection follows abdominal surgery or a testicular infection (Fournier’s gangrene), then mixed infections with anaerobic and aerobic organisms (synergistic gangrene) occur. Vibrio vulnificans infection may be contracted from sea water.

• Diagnosis is made clinically and these patients should be rapidly assessed by a specialist surgeon. High white cell count and high CRP are usually present. US/CT may be helpful but should not delay early surgery.

• Treatment is with wide and aggressive surgical debridement, which may need to be repeated on a number of occasions.

• Antibiotic therapy for group A streptococcus is with high-dose benzyl penicillin 2.4 g IV 6 times daily and clindamycin 1.2 g IV 4 times daily.

• If a synergistic infection is suspected, then treatment should cover anaerobes and Gram-negative organisms; suitable drugs could include ampicillin, gentamicin and metronidazole; ampicillin, gentamicin and clindamycin; or co-amoxiclav, gentamicin and metronidazole.

Bite wounds

The major problem resulting from bite wounds is infection, but this will depend on the site, extent and cause.

• Dog bites. These are the commonest type of bite (80%) but only a few become infected. The oral flora of dogs contains streptococci, staphylococci, Pasteurella multocida and Capnocytophaga canimorsus.

• Treatment. If the bite is infected, give co-amoxiclav 500 mg 8-hourly for 7 days. This can also be used as prophylaxis for 3–5 days.

• Cat bites. Most of these become infected and prophylaxis with co-amoxiclav should always be given.

• Treatment. If the bite is infected, give co-amoxiclav or doxycycline 100 mg daily. Increase the duration to 2 weeks for cellulitis and longer for osteomyelitis.

• Wild animal bites. The danger here is rabies and vaccination must be given (p. 56). Co-amoxiclav is a reasonable choice for prophylaxis.

General measures for bite wounds

• Investigations include culture of swabs from wounds.

• Foreign bodies should be removed and the wound irrigated.

• Do not suture unless the bite is on the face.

• Elevate if possible.

• Give antibiotics as above.

• If there is a fracture, X-ray the relevant area. Vaccinate against rabies (p. 57).

Varicella zoster virus (VZV) infection

Primary infection with VZV is in childhood in Europe and the Americas. In some countries (e.g. in South Asia) transmission is different, with more infections in adults.

The primary infection with VZV causes chickenpox, which almost never occurs again in the same person. Chickenpox is infectious from 2 days before the start of the rash until all the vesicles have crusted. The incubation period of chickenpox is 14–21 days. There is a brief ‘flu-like prodromal illness, which may be absent in the young. A rash then develops, with macules rapidly progressing to vesicles, mainly on the head and trunk. The rash occurs in ‘crops’, with skin lesions in all stages typically present on the body. Eventually, the vesicles crust and heal without scarring. Chickenpox is highly infectious and is spread from infected lesions and by the respiratory route. After recovery, VZV remains latent for life in spinal nerve roots. The illness tends to be more severe in adults, particularly pregnant women, smokers and the immunosuppressed. Complications of chickenpox include pneumonia, bacterial superinfection of skin lesions and meningo-encephalitis. VZV can cross the placenta and infection in pregnancy leads to fetal damage in about 2% of cases, mostly in infections before 20 weeks’ gestation.

Shingles is a secondary reactivation of latent VZV infection in the distribution of one or sometimes two dermatomes. The vesicles of shingles are identical to those in chickenpox. Shingles mainly affects the elderly but can occur at any age. Post-herpetic neuralgia may occur after herpes infection and causes severe debilitating pain. Shingles involving the ophthalmic division of the trigeminal nerve has a high rate of complications. Disseminated shingles infection can occur in the immunosuppressed patients (particularly in late HIV infection), when the rash is seen over many dermatomes and appears similar to chickenpox. Shingles lesions may transmit infection to non-immune individuals.

Diagnosis

Diagnosis is clinical but, if necessary, can be confirmed with immunofluorescence, electron microscopy or viral culture of vesicle fluid.

Treatment

• Healthy children with chickenpox usually require no treatment and infection results in lifelong immunity.

• Adults with chickenpox should be given antiviral treatment, if they present within 72 hours of onset, with aciclovir (800 mg oral 5 times daily for 7 days) or oral valaciclovir or famciclovir.

• Severe VZV infection, particularly in the immunosuppressed or pregnant women, should be treated with IV aciclovir (10 mg/kg IV 3 times daily).

• Zoster immune immunoglobulin (ZIG) can be used as post-exposure prophylaxis in the immunocompromised or pregnant, with no past infection with chickenpox who has been exposed to VZV.

• An effective varicella vaccine is available but is not recommended as routine in all countries.

• Shingles is also treated with aciclovir (800 mg orally 5 times daily for 7 days), as early treatment reduces the duration of symptoms and the occurrence of neuralgia.

• Prophylactic therapy with aciclovir can be used to prevent HSV and VZV in immunocompromised patients. In the USA varicella zoster vaccine is recommended for all people over 65 years.

Leprosy (Hansen’s disease)

Leprosy is caused by Mycobacterium leprae, an acid-fast bacillus. The majority of cases are in India and Brazil. The prevalence of leprosy has decreased since a successful WHO treatment campaign.

The incubation period is very variable but is usually 2–6 years. The signs of leprosy are usually skin lesions, usually anaesthetic and thickened peripheral nerves. Leprosy is classified between two polar extremes of tuberculoid (high degree of cell-mediated immunity (CMI)) and lepromatous (impaired CMI), depending on the host’s immune reaction to the infection (Ridley–Jopling system).

Diagnosis and treatment

It is not possible to culture M. leprae but diagnosis is made clinically and on microscopic examination of tissue. The type of treatment and its duration depend on the type of leprosy. Rifampicin, clofazimine and dapsone are the main drugs used (p. 87).

Respiratory infections

Upper respiratory tract infections

Pharyngitis

Most throat infections are caused by viruses and do not need antimicrobial therapy, but it is difficult to differentiate between viral and bacterial causes in all patients. Patients with three of the following are more likely to have bacterial rather than viral infection: fever, purulent tonsils, cervical lymphadenopathy and absence of cough. Strep. pyogenes (Lancefield group A β-haemolytic streptococcus) is the major bacterial cause of pharyngitis and is commoner in the age group 5–15. A history of contact with a patient with proven Strep. pyogenes infection is helpful in diagnosis.

• Investigations. Rapid antigen detection tests may be helpful but, like throat cultures, will also be positive in those who have throat colonization with Strep. pyogenes.

• Treatment. If antibacterial treatment is given, the first choice should be oral phenoxymethylpenicillin 500 mg 4 times daily for 10 days. Amoxicillin and ampicillin should not be given unless infection with EBV can be ruled out. For penicillin-allergic patients, a macrolide (e.g. erythromycin 250 mg 4 times daily or 500 mg twice daily) or an oral cephalosporin can be given for 10 days. Rarer bacterial causes of pharyngitis include Arcanobacterium haemolyticum, which can be treated with erythromycin.

Acute laryngo-tracheobronchitis (croup)

This causes paroxysms of cough with breathlessness and stridor. It is caused initially by viral infections, e.g. parainfluenza, complicated by bacterial infection. The voice is hoarse with a barking cough (croup) and audible laryngeal stridor.

• Treatment. Oral corticosteroids and nebulized adrenaline (epinephrine) are helpful. Oxygen with adequate rehydration is necessary.

Epiglottitis

This presents with a sudden onset of fever, sore throat and stridor, which may rapidly progress to complete airway obstruction. In children, the bacterial causes of epiglottitis include group A streptococcus, Strep. pneumoniae and Staph. aureus. Capsulated strains of H. influenzae, e.g. type b, are now rare in countries that immunize against this pathogen (Hib vaccine). A swab from the epiglottis may reveal the causative organism, but this could potentially provoke airway obstruction and should only be carried out if facilities for intubation are present. Blood cultures should also be taken.

• Treatment. Cefotaxime 50 mg/kg IV 4 times daily or ceftriaxone 50 mg/kg IV daily is the first-choice agent. For patients who are allergic to cephalosporins, chloramphenicol 25 mg/kg IV 4 times daily is used. Epiglottitis is rare in adults but the spectrum of bacteria is similar to that seen in children and cefotaxime, ceftriaxone or chloramphenicol can be used at adult doses.

Coryza

Coryza (the common cold) is caused by viruses. There are currently no effective antimicrobial treatments.

Sinusitis

Most episodes of sinusitis are viral and will resolve without antimicrobial therapy. The symptoms of bacterial infection are maxillary/facial pain, and purulent discharge after 7–10 days. The likely organisms are Strep. pneumoniae, H. influenzae, Moraxella catarrhalis, group A streptococcus, Staph. aureus and anaerobes in chronic infection.

• Treatment. Appropriate antibacterials include amoxicillin 500 mg 3 times daily for 7 days, oral doxycycline 200 mg, followed by 100 mg daily for 7 days or erythromycin 250 mg 4 times daily or 500 mg twice daily for 7 days. If there is a failure to respond or the patient has recently received antibacterial treatment, co-amoxiclav 625 mg 3 times daily for 7 days or ciprofloxacin 500 mg twice daily for 7 days, combined with metronidazole 400 mg twice daily for 7 days, can be used. Chronic infection usually requires surgery.

Otitis media

This is predominantly an infection of children. Most episodes are viral and will resolve without antimicrobial treatment. Although bacterial infection may occur with Strep. pneumoniae, H. influenzae, group A streptococcus and Staph. aureus, use of antibacterials is of questionable value, as most cases get better without treatment.

• Treatment. If the child remains unwell for more than 3 days, antibacterials can be used, including amoxicillin (< 2 years, 125 mg 3 times daily; 2–10 years, 250 mg 3 times daily; > 10 years, 500 mg 3 times daily, all for 5 days). If the patient is allergic to penicillin, erythromycin (< 2 years, 125 mg 4 times daily; 2–8 years, 250 mg 4 times daily; > 8 years, 250–500 mg 4 times daily) can be given for 5 days or azithromycin (15–25 kg, 200 mg daily; 26–35 kg 300 mg; 36–45 kg 400 mg daily) for 3 days.

Diphtheria

Diphtheria is caused by pharyngeal or cutaneous infection with toxigenic strains of Corynebacterium diphtheriae and, rarely, toxigenic strains of C. ulcerans. Classical diphtheria presents with a membranous pharyngitis, cervical lymphadenopathy and oedema of the surrounding soft tissues. The membrane, which is not always present, is typically grey, thick and adherent. Laryngeal involvement also occurs, and causes hoarseness and stridor. Nasal diphtheria may present as a bloody nasal discharge. Cutaneous diphtheria is commoner in tropical countries and usually affects the legs. The lesions start as vesicles and progress to form ulcers.

• Diagnosis. Diagnosis relies on a combination of clinical and laboratory findings, with the demonstration of a toxigenic isolate of C. diphtheriae from throat, nose or skin swabs.

• Treatment. A combination of antitoxin to neutralize the toxin and antibacterials to eradicate the organism is needed, though the benefit of antitoxin in cutaneous infection is uncertain. Appropriate antibacterials include IV erythromycin 40 mg/kg a day, until the patient can swallow, when oral erythromycin 500 mg 4 times daily or oral phenoxymethylpenicillin 250 mg 4 times daily can be given. Antibacterials should be given for 14 days and a throat swab taken to check for elimination of the organism. If the culture is still positive, a further 10 days’ treatment is needed. Cases should also be immunized in the convalescent stage. Close contacts require antibacterial prophylaxis with erythromycin 500 mg 4 times daily for 7 days. If cultures are positive from close contacts, a further 10 days’ treatment is needed. Those contacts who have not been immunized in the preceding 12 months require vaccine. Non-toxigenic strains of C. diphtheriae may cause severe pharyngitis, which can be treated with oral erythromycin 500 mg 4 times daily for 7 days or phenoxymethylpenicillin 250 mg 4 times daily for 7 days.

Measles

This is a vaccine-preventable viral infection and no specific antiviral treatment is available. The incubation period ranges from 7 to 18 days. There is a prodromal illness with fever, conjunctivitis, cough and often diarrhoea. This is followed, usually 2 or 3 days later, with a rash that starts on the face and spreads to the trunk, lasting for 4–7 days. Measles is a self-limiting illness but complications are relatively frequent. Diagnosis is by demonstration of viral antigen on PCR in nasopharyngeal aspirates or urine, or by demonstration of IgM antibody in blood or saliva. Otitis media and pneumonia may follow and antibacterials can be used for these complications. Inosine pranobex has been used to treat the rare complication, subacute sclerosing panencephalitis, but there is little evidence of any benefit.

Mumps

This is a vaccine-preventable viral infection and no specific antiviral treatment is available. The incubation ranges from 18 to 21 days. Mumps is a febrile illness characterized by inflammation of the salivary glands, particularly the parotids, which are swollen and tender. It is a self-limiting illness and complications are rare. Aseptic meningitis, orchitis and oophoritis and pancreatitis may occur. Diagnosis is usually by demonstration of IgM antibody in blood or saliva.

Rubella (German measles)

Rubella is a worldwide viral disease spread by droplets. The incubation is 14–21 days; the rash begins 7 days after the onset of malaise, fever, conjunctivitis and lymphadenopathy. The rash is pinkish red, macular and discrete. Treatment is supportive and complications are rare. Congenital rubella syndrome affects fetuses in ~80% of women who contract the disease in the first trimester.

Prevention is with the MMR vaccine.

Lower respiratory tract infections

Influenza

Influenza A and influenza B viruses are a cause. The incubation period is from 1 to 4 days, and patients present with fever, headache, malaise, generalized aches, cough and sore throat. Secondary bacterial infection is common and secondary pneumonia caused by Staph. aureus has a mortality of 20%. Rapid diagnosis can be made by antigen detection or the nucleic acid amplification test (NAAT) from nasopharyngeal aspirate or throat washings, and acute and convalescent serology. Prevention by immunization is necessary in people over 65 years of age, those who are immunosuppressed, those with chronic respiratory, cardiac, renal and liver disease, and those with diabetes mellitus.

• Treatment. The neuraminidase inhibitors, oseltamivir 75 mg twice daily for 5 days and zanamivir 10 mg by inhalation twice daily for 5 days, can shorten duration of illness and may reduce complications if started as soon as possible after symptoms start (no more than 48 hours after onset).

• Prophylaxis. Oseltamivir 75 mg orally once daily for 7 days following exposure, or for up to 6 weeks during an epidemic, is used if current vaccine does not cover the circulating strain of the virus. Amantadine and rimantadine may also be used for treatment and prophylaxis, although adverse effects are common.

• H1N1. A variant H1N1 virus, originally seen only in pigs, caused an influenza in humans initially in 2009, with mostly mild symptoms. However, deaths have occurred and many countries have been affected. This virus is susceptible to oseltamivir, although resistance is found.

• Avian flu. In 1997 and again in 2004 and 2005, the avian H5N1 strain of influenza A was found in humans, initially transmitted from poultry but also spreading from human to human. The illness is similar to but more severe than that caused by other influenza viruses.

Pertussis (whooping cough)

Whooping cough is a vaccine-preventable acute bacterial infection caused by Bordetella pertussis. The incubation period ranges from 7 to 13 days. Clinically, three stages of illness are recognized: a catarrhal stage, a paroxysmal stage and a convalescent stage. In infants, adolescents and adults, these stages may not be so obvious. In adults, a chronic cough may the only symptom. Complications of infection include bronchopneumonia and seizures, which are more likely in infants.

• Diagnosis. This can be confirmed by culture of B. pertussis from a pernasal swab or by PCR from the same specimen. Cultures and PCR are more likely to be positive in the early stages of infection. Serology can also be useful for diagnosis later in the infection.

• Treatment. Treatment should be confined to those who are diagnosed within 21 days of onset of symptoms. Antibacterials have little effect on resolution of symptoms but can reduce infectivity of the case. Erythromycin (< 2 years, 125 mg 4 times daily; 2–8 years, 250 mg 4 times daily; others, 500 mg 4 times daily, all for 7 days) is given. Cases are likely to be no longer infectious after 5 days of treatment. Patients should complete their immunization schedule for pertussis. Unimmunized or partly immunized contacts of infectious cases can be given prophylaxis with erythromycin (< 2 years, 125 mg 4 times daily; 2–8 years, 250 mg 4 times daily; others, 500 mg 4 times daily, all for 7 days). Azithromycin (15–25 kg, 200 mg daily; 26–35 kg, 300 mg daily; 36–45 kg, 400 mg daily; adults, 500 mg daily, for 5 days) can also be used. Contacts should also be immunized unless it is certain that they have completed a full schedule previously.

Lung abscess

The pathogenesis of lung abscess is variable. It may follow pneumonia (especially aspiration pneumonia), bacteraemic spread (e.g. IV drug users), foreign body, or bronchial obstruction with a tumour. Bacteria include anaerobes, enteric Gram-negative bacilli, Strep. milleri, Strep. pneumoniae and Staphylococcus aureus, especially in right-sided endocarditis. Lung abscess presents with fever, night sweats, breathlessness, and a cough with foul-smelling sputum.

• Investigations

• CXR — cavity formation

• Blood and sputum culture

• Treatment. Treatment will be led by culture results but suitable agents include clindamycin 450 mg 4 times daily or 600 mg IV 4 times daily, or cefotaxime 1 g IV 3 times daily and metronidazole 500 mg IV 3 times daily, or co-amoxiclav 1.2 g IV 4 times daily. If Staph. aureus is isolated, flucloxacillin 500 mg IV 4 times daily and oral sodium fusidate 500 mg 3 times daily are used. The duration of treatment will depend on response and many patients will need surgical drainage or bronchoscopic relief of obstruction.

Cardiological infections

Infective endocarditis (IE)

IE is a severe life-threatening infection that still has a high mortality despite advances in cardiac surgery and antibacterial therapy. It predominantly affects individuals with structural abnormalities of the cardiac valves, which may be congenital or acquired. IE occurs following a bacteraemic spread to the valve. Bacteraemia may follow dental or other surgical procedures or as a result of infection at another site. IV drug users are also at risk. Endocarditis may also result from infected intravascular devices in hospital patients. The commonest bacterial causes of IE are α-haemolytic streptococci, enterococci and Staph. aureus; in prosthetic valve IE, coagulase-negative staphylococci are most common.

Clinical features

Symptoms include fever, malaise and weight loss. Embolic phenomena and vasculitic lesions may also be evident. A new valvular murmur may be heard. The duration of symptoms often reflects the bacterial aetiology. IE caused by Staph. aureus usually has an acute presentation, often with neurological complications, e.g. cerebrovascular events. IE caused by α-haemolytic streptococci has a more indolent presentation over weeks or months. Patients with right-sided endocarditis may present with a lung abscess.

Diagnosis

The Duke Criteria are the established way of making the diagnosis clinically.

• Blood cultures are the key diagnostic investigation. At least three sets of samples should be taken and there should be liaison with the microbiology department.

• Trans-thoracic echocardiogram is a rapid, non-invasive investigation and has a high specificity for visualizing vegetations, although sensitivity is 60–75%.

• Trans-oesophageal echocardiography (TOE) has a higher sensitivity and specificity for abscess formation because of the physical proximity of the transducer to the aortic root. A negative echo does not exclude the diagnosis in a patient with a fever but it does lower the probability.

• Inflammatory markers, e.g. ESR and CRP, are raised and liver biochemistry is usually mildly deranged.

• Microscopic haematuria is almost always present.

Treatment

High concentrations of IV antibiotics are required for prolonged periods to achieve successful treatment, as IE still carries a substantial morbidity and mortality. Empirical antibiotic treatment is started only after cultures are taken and is then adjusted according to the culture results. The treatment should continue for 4–6 weeks.

• Clinical endocarditis culture results awaited with no suspicion of staphylococci: benzyl penicillin 1.2 g 4-hourly, gentamicin 80 mg every 12 hours.

• If suspected staphylococcal endocarditis: vancomycin 1 g 12-hourly, gentamicin 80 mg 8-hourly.

• If cardiac prosthesis, penicillin allergy or MRSA: vancomycin and rifampicin.

• When culture is confirmed:

• Streptococcal endocarditis: penicillin-sensitive: treatment as above.

• Enterococcal endocarditis: amoxicillin 2 g 4-hourly, gentamicin 80 mg 12-hourly.

• Staphylococcal endocarditis: vancomycin 1 g 12-hourly, or flucloxacillin 2 g 4-hourly or benzyl penicillin 1.2 g 4-hourly plus gentamicin 80–120 mg 8-hourly. Vancomycin and gentamicin levels must be monitored. Choice will depend on sensitivities. Liaise with an infectious diseases expert.

• Prophylactic therapy prior to invasive procedure: not necessary unless there is an infection at the site of the proposed intervention (see national guidelines).

Pericarditis

Pericarditis is inflammation of the pericardium, giving rise to chest pain and a pericardial friction rub, with concave upward elevation of the ST segment in all leads on the ECG. Acute infective pericarditis is caused by viruses, e.g. Coxsackie B and echovirus, and by a variety of bacteria, including Strep. pneumoniae (following pneumonia), Staph. aureus, group A streptococcus and N. meningitidis. In acute bacterial pericarditis, fever and signs of heart failure due to tamponade occur. TB presents less acutely! Diagnosis of bacterial pericarditis including TB can be confirmed by culture of pericardial fluid. Pericardial biopsy may be needed to diagnose TB.

• Treatment will be guided by culture findings but empirical therapy with cefotaxime 1 g IV 3 times daily is suitable. If Staph. aureus is suspected, flucloxacillin 2 g IV 4 times daily should be added.

Non-infective pericarditis occurs following a myocardial infarct (p. 445), in malignant disease (lung cancer, lymphoma), in uraemia and after surgery.

Myocarditis

Acute inflammation of the myocardium is commonly due to viruses, e.g. Coxsackie, adenoviruses or influenza viruses. It can also be caused by rickettsial, fungal, bacterial or parasitic infections, drug hypersensitivity, autoimmunity and other factors. Presentation is with palpitations, chest pain, breathlessness and fatigue.

• Investigations: CXR, ECG, viral antibodies, PCR, echo and nasopharyngeal swab. A myocardial biopsy may be helpful.

• Treatment: depends on the cause. Antiviral agents are not usually helpful.

Rheumatological infections

Neurological infections

Meningitis

Meningitis is inflammation of the meninges; it is usually caused by infection, although rarely it results from a non-infectious cause. Infectious causes of meningitis include bacterial (including TB), viral and fungal (e.g. cryptococcal). Acute bacterial meningitis is a medical emergency and should be considered in any patient with fever and neurological symptoms, especially if there is a history of other infections or head trauma.

Clinical features

• Meningitis usually presents with headache, neck stiffness, photophobia and fever. Vomiting, myalgia, impaired consciousness and rash are often present, particularly in bacterial meningitis. In acute bacterial infection there is usually intense malaise, fever, rigors, severe headache, photophobia and vomiting.

• Signs of meningitis include fever, rash, a positive Kernig’s sign, neck stiffness and head jolt; of these signs, the head jolt is one of the more reliable.

Investigations

In bacterial meningitis there is usually a neutrophilia and a raised CRP.

• CT should be performed immediately if raised intracranial pressure (ICP) is suspected (e.g. loss of consciousness).

• CSF examination by lumbar puncture (LP) is carried out in the absence of contraindications (e.g. signs of raised ICP, papilloedema or impaired consciousness). N.B. If a petechial rash is present, indicating meningococcal infection, IV penicillin or cefotaxime must be given IMMEDIATELY and an LP is not necessary. In cases without a meningococcal rash, CSF examination confirms the diagnosis and gives information about cause, prognosis and antibiotic sensitivities. An LP is still useful even if antibiotics are given beforehand, or if the LP is deferred until the patient is stabilized.

• PCR of blood for N. meningitidis is helpful if LP is not possible or the CSF is culture-negative.

• Viral stool and throat cultures, as well as viral PCR of CSF, will often detect the viral cause of meningitis.

Treatment

Treatment is with antimicrobial therapy and supportive measures, including maintenance of airways and electrolyte balance. Dexamethasone 0.15 mg/kg 4 times daily for 4 days is given, especially if Strep. pneumoniae meningitis is suspected, although corticosteroids should be avoided if septic shock is a factor.

• Initial therapy with ‘unknown cause’ should be with cefotaxime 2 g IV 4 times daily or ceftriaxone 2 g IV twice daily. Alternative antibiotics (if the patient is allergic) include benzyl penicillin 2.4–4.8 g daily IV in 4 divided doses and chloramphenicol oral or IV infusion 50 mg/kg in 4 divided doses for β-lactam allergy.

• N. meningitidis (see also p. 33 and Box 2.1) is treated with IV benzyl penicillin. Alternatively, high-dose cefotaxime 2 g IV 4 times daily or ceftriaxone 2 g IV twice daily for about 7 days (at least 5 days after the patient is febrile) is given. For close contacts, prophylaxis and eradication, see p. 33.

• Strep. pneumoniae is treated with cefotaxime 2 g IV 4 times daily for 10–14 days or benzyl penicillin (see above). Vancomycin 1 g IV twice daily, though CSF penetration may be poor, and rifampicin can be given if there is known or suspected resistance. Dexamethasone 0.15 mg/kg 4 times daily for 4 days should also be given.

• L. monocytogenes (suspect in patients > 55 years old or the immunosuppressed) is treated with ampicillin 2 g IV 4 times daily or with gentamicin slow IV infusion 3–5 mg/kg/day in 2 divided doses for 3–4 weeks. Listeria is resistant to cephalosporins.

Other forms of meningitis

• Tuberculous meningitis presents with vague headaches, lassitude, anorexia and vomiting. Evidence of meningism takes weeks to develop. LP shows high protein and low glucose levels.

• Treatment with anti-TB drugs (p. 87) is often on a presumptive basis. A glucocorticoid should also be given (adults, equivalent to prednisolone 20–40 mg if on rifampicin; otherwise 10–20 mg).

• Viral meningitis This presents with fever, headache, photophobia and meningism similar to bacterial meningitis but often less severe. Viral meningitis is usually a self-limiting condition lasting 4–10 days, although a headache may persist for some time. The CSF usually contains lymphocytes.

• Treatment is symptomatic.

Encephalitis

Encephalitis is inflammation of the brain that usually results in fever, impaired consciousness, confusion and occasionally convulsions. The cause is usually viral; the most common causes of encephalitis in Europe are HSV, enterovirus, mumps, EBV, VZV and influenza. Often, viral aetiology is presumed but never confirmed. Bacterial causes of encephalitis include listeria, syphilis, mycoplasma, and Lyme disease. There are a number of causes of encephalitis that occur in certain specific areas, which include Japanese B encephalitis and enterovirus in South-East Asia, Ross River fever in Australia, rabies in many countries, and West Nile encephalitis in Egypt and Sudan. Outbreaks of encephalitis occur, such as a West Nile virus outbreak in the USA.

Investigations

• CT or MRI may show areas of oedema, particularly temporal lobe changes in HSV encephalitis.

• EEG usually shows typical slow waves.

• CSF shows a raised lymphocytic count.

• CSF PCR may be diagnostic.

• Viral serology (blood and CSF) is helpful.

• Brain biopsy is occasionally performed.

Treatment

Herpes simplex encephalitis has a high case fatality rate and high-dose aciclovir 10 mg/kg IV 3 times daily, infused over 1 hour, should be given for 2–3 weeks if it is suspected. Seizures are treated with anticonvulsants.

Prophylaxis

Vaccines are available against Japanese encephalitis for travellers to endemic areas in Asia. Tick-borne encephalitis vaccine is also available.

Brain abscess

Brain abscesses present with fever, headache and features of raised ICP and a space-occupying lesion. Abscesses usually develop over weeks but can develop more quickly (particularly cerebellar abscesses). Brain abscesses arise by local spread from the paranasal sinuses and teeth (streptococci and anaerobes), and are occasionally caused by Pseudomonas infection from otitis externa or staphylococcal infection from penetrating trauma. Haematological spread of bacteria causes brain abscesses, usually from endocarditis. Brain abscesses are often the result of infections with mixed organisms. Immunosuppressed patients develop abscesses with unusual organisms such as Toxoplasma or Nocardia.

Investigations

• Neutrophilia and raised CRP are usual, though not invariable.

• MRI or CT with contrast will identify brain abscesses as ring enhancing lesions. These scans will also identify focal collections in the skull or sinuses.

Treatment

Expert advice should be sought from neurosurgeons on the need for surgical drainage and there should be close liaison with the laboratory for appropriate antibiotic advice. The site of the infection and likely infecting agents will guide empiric therapy, e.g. cefuroxime 2 g IV 6 hourly plus metronidazole 500 mg IV 8 hourly (add flucloxacillin if staphyloccus suspected).

Cerebral malaria

See p. 34.

Rabies

Rabies is a Lyssavirus, which causes an infection that is nearly always fatal in humans. Rabies is found in most countries, though it is absent from a number including the UK, Australia and New Zealand. Nearly any mammal may carry rabies and bites should be considered as potential sources of infection. The incubation period ranges from a few weeks to several years; in general, it is inversely related to the distance from the bite to the brain. Rabies may present as either paralytic rabies, which takes the form of an ascending paralysis (similar to Guillain–Barré syndrome) or furious rabies. Furious rabies initially presents with tingling at the site of the bite, along with fever and headache. About 2 weeks later, there is an encephalitic illness marked by hyperexcitability, precipitated by sounds or visual stimuli. Pharyngeal spasms (hydrophobia) when trying to drink or eat occur in about half the cases of furious rabies. On examination there is hyperreflexia and evidence of sympathetic over-activity. The patient goes on to develop convulsions, respiratory paralysis and cardiac arrhythmias. Death usually occurs about 10–14 days later.

• Diagnosis. This is clinical but can be confirmed by detecting the virus in blood, saliva or CSF by PCR, viral culture or immunofluorescence. Skin biopsies can show histological, immunofluorescence or PCR evidence of rabies.

• Treatment. There is no known treatment for rabies once the disease is established and therapy should be to keep the patient comfortable.

• Prophylaxis. Both pre- and post-exposure prophylaxis are available. Human diploid cell vaccine (HDCV) is relatively safe (though expensive) and may be given if there is any doubt of an exposure to rabies. HDCV given at 0 and 1 month provides protection against rabies, with booster doses given at 1 year and then every 1–3 years. For post-exposure prophylaxis the wound should be cleaned carefully and left open. Human rabies immunoglobulin should be given immediately if the patient had not been previously immunized (20 U/kg half infiltrated around the wound and half IM). HDCV 1 mL IM on days 0, 3, 7, 14 and 28 should then be given.

Tetanus

Clostridium tetani is found in soil and disease results from a contaminated wound. Neonatal tetanus can result from contamination of the umbilical stump. Following an incubation of a few days to several weeks, there is malaise and spasm of the masseter muscle (lockjaw) and of the facial muscles, giving a grinning expression (risus sardonicus). Painful reflex spasms occur, with arching of the neck and back (opisthotonus), respiratory impairment and autonomic dysfunction (tachycardia, labile BP, sweating and cardiac arrhythmias). Death is from aspiration, hypoxia, respiratory failure, cardiac arrest or exhaustion.

Diagnosis

• Diagnosis is clinical.

• Rarely, C. tetani is isolated from wounds.

Management

• Suspected tetanus

• Clean/debride the wound.

• Give human tetanus immunoglobulin (HTIG) 250–500 U.

• Give an IM injection of tetanus toxoid.

Gastrointestinal infections

Gastroenteritis (see also p. 135)

Diarrhoea as a result of infectious intestinal disease is common and is caused by a wide variety of viruses, bacteria and protozoa. The majority of infections worldwide are viral and these are responsible for high infant mortality rates in the developing world. Viruses include rotavirus, adenoviruses, astrovirus and calicivirus (norovirus and sapoviruses).

• Diagnosis. This is usually clinical but, if necessary, electron microscopy, antigen detection tests or PCR on stools can be used. Protozoa can be identified by microscopy of stool specimens.

• Treatment. There are no specific antiviral treatments available but rehydration therapy is often necessary (see below).

Common bacterial causes include non-typhoidal Salmonellae, Campylobacter spp., and strains of Escherichia coli, which have been classified according to their pathogenic mechanisms, e.g. enterotoxigenic E. coli (ETEC), enteropathogenic E. coli (EPEC), enteroinvasive E. coli (EIEC), enteroaggregative E. coli (EaggEC) and enterohaemorrhagic E. coli, which produce verocytoxin (VTEC). Cholera caused by Vibrio cholerae is still common in many parts of the world. Shigella spp. cause bacillary dysentery with bloody stools.

• Treatment. The major risks with bacterial infections are dehydration and, in some cases, malnutrition. Rehydration can be accomplished by use of an oral rehydration solution (ORS) (Table 2.3). There is overwhelming evidence that this is life-saving; IV fluids are required only in severe cases or when there is excessive vomiting.

• Antibiotics. In most cases, symptoms will resolve without antibiotics. If symptoms are severe, e.g. ≥ 6 unformed stools per day and/or fever, tenesmus or blood, antibacterials are given (Table 2.4).

• Shigella infections are treated with co-trimoxazole 960 mg twice daily for 3 days or ciprofloxacin 500 mg twice daily for 3 days.

• ETEC, EPEC and EIEC infection can be treated with the same antibiotics, but they should not be used for infection with VTEC strains such as E. coli O157, as there is evidence that antibacterials increase the risk of complications such as haemolytic uraemic syndrome.

• Campylobacter infection can be treated effectively with oral erythromycin 500 mg twice daily for 5 days, but increasing resistance with quinolones means that ciprofloxacin will be less helpful.

• Non-typhoidal Salmonella does not usually need treatment unless the symptoms are severe or there are the following risk factors: patient < 6 or > 50 years, prosthesis present, valvular heart disease, severe atherosclerosis, immune suppression or malignancy. Ciprofloxacin 500 mg twice daily for 5–7 days or ceftriaxone 60 mg/kg IV daily dose can then be used.

• Cholera usually responds to doxycycline 300 mg single dose, tetracycline 500 mg 4 times daily for 3 days and co-trimoxazole 960 mg twice daily, or a single dose of a quinolone, e.g. oral ciprofloxacin 1 g or azithromycin 1 g, which help to shorten duration of diarrhoea and also reduce the infectivity of the patient.

• Giardia intestinalis diarrhoea is treated with metronidazole 2 g daily for 3 days or tinidazole 2 g as a single dose.

• Entamoeba histolytica infection is treated with oral metronidazole 800 mg 3 times daily for 5 days or tinidazole 2 g daily for 2–3 days, followed by diloxanide furoate 500 mg 3 times daily for 10 days to eradicate cysts.

• Cyclospora cayetanensis infection is treated with co-trimoxazole 960 mg twice daily for 7 days.

• Cryptosporidium hominis infection lacks effective treatments.

Table 2.3 Oral rehydration solutions (ORS) and IV solutions used in moderate and severe diarrhoea

Table 2.4 Antibiotics in adult acute bacterial gastroenteritis

Clostridium difficile-associated diarrhoea

C. difficile-associated diarrhoea (CDAD) occurs most frequently after exposure to cephalosporins, quinolones and clindamycin, but most antibiotics have been causal. Elderly hospitalized patients are often affected. Hospital-acquired infections remain frequent. Severity ranges from mild diarrhoea to severe pseudomembranous colitis with development of a toxic megacolon and bowel perforation. Diarrhoea may be the only symptom, whereas in severe disease there is fever as well. Severe disease may be defined as including the following features:

• white cell count > 15 × 10⁹/L

• acute rising creatinine (> 50% of baseline)

• fever > 38.5°C

• evidence of severe colitis.

• Diagnosis. Diagnosis of CDAD can be made by detection of C. difficile toxins in the stool on ELISA or cell culture. Pseudomembranous colitis is seen at sigmoidoscopy.

• Treatment. Fluid loss can be severe, requiring IV rehydration (p. 611). Some patients will improve when the offending precipitating antibacterial is stopped. For non-severe disease, oral metronidazole 400 mg 3 times daily for 7–10 days is the treatment of choice. An alternative is oral vancomycin 125 mg 4 times daily for 7–10 days. In severe disease oral vancomycin is recommended 125–500 mg oral 4 times daily for 10–14 days. If the patient cannot take oral medication, metronidazole may be given by the IV route, 500 mg 3 times daily for 7–10 days. Relapse of diarrhoea after treatment is common. IVIG may be considered in severe disease. Some patients may respond simply to repeat treatment but many do not. Pulsed tapering courses of metronidazole or vancomycin have been used. Toxic megacolon may require colectomy.

• Prevention. Prevention requires isolation of infected patients and good hygiene, including hand washing with soap and water by patients and healthcare workers. Reduction in the hospital use of cephalosporins reduces the risk.

Enteric fever (typhoid and paratyphoid fever)

Typhoid fever is a systemic bacterial infection caused by Salmonella typhi. The incubation period ranges from 1 to 3 weeks. Presentation is variable and the severity of symptoms can range from mild to severe toxaemia. Common symptoms are fever, headache, malaise, nausea and a dry cough, with constipation or diarrhoea.

Diagnosis

Blood culture is usually positive in the first 2 weeks. S. typhi may also be isolated from bone marrow. Culture of faeces and urine can also be performed, although it should be noted that these cultures may also be positive in chronic carriers. Several rapid antibody detection tests have been developed with good sensitivity, though relatively poor specificity.

The symptoms of paratyphoid fever are similar but usually less severe. Paratyphoid fever is caused by Salmonella paratyphi A, S. paratyphi B and S. paratyphi C.

Treatment

Treatment is governed by the severity of illness and the susceptibility of the organism. Quinolones are the most effective antibacterial treatment for both adults and children when the organism is susceptible. In many parts of the world, patients will not be admitted to hospital and for mild illness ciprofloxacin 15 mg/kg daily for 5–7 days is commonly used. Quinolones are not licensed for use in children but the benefit in this situation outweighs the risk. For severe illness requiring hospital admission, ciprofloxacin 15 mg/kg daily for 10–14 days is recommended. In the case of reduced quinolone susceptibility (demonstrated by nalidixic acid resistance), alternatives for mild disease include azithromycin 8–10 mg/kg daily for 7 days and cefixime 20 mg/kg daily for 7–14 days. For severe disease with nalidixic acid-resistant isolates, cefotaxime 80 mg/kg IV daily or ceftriaxone 60 mg/kg IV daily for 10–14 days is given.

Gastrointestinal tuberculosis

TB can affect the intestine as well as the peritoneum. Intestinal TB is due to reactivation of primary disease caused by Mycobacterium tuberculosis. Bovine TB occurs in areas where milk is unpasteurized and is rare in Western countries.

Clinical features

These are abdominal pain, weight loss, anaemia, fever with night sweats, obstruction, right iliac fossa pain or a palpable mass. The ileocaecal area is most commonly affected, but the colon and, rarely, other parts of the gastrointestinal tract can be involved.

Diagnosis

• Small bowel follow-through will show transverse ulceration and diffuse narrowing of the bowel, with shortening of the caecal pole.

• US or CT shows additional mesenteric thickening and lymph node enlargement.

• Histology and culture of tissue is desirable but not always possible. Specimens can be obtained by colonoscopy or laparoscopy, but laparotomy is required in some cases.

Treatment

Drug treatment is similar to that of pulmonary TB: rifampicin, isoniazid, ethambutol and pyrazinamide (p. 87). In gastrointestinal TB treatment should last 1 year.

Peritonitis

Spontaneous bacterial peritonitis (SBP)

The yearly risk of developing spontaneous bacterial peritonitis (SBP) for patients with ascites and cirrhosis has been estimated to be as high as 29%. See Chapter 6 (p. 189) for Diagnosis and Treatment.

Peritonitis secondary to large bowel perforation, ruptured appendix or ruptured diverticulum

This is caused by organisms that are part of the normal bowel flora, namely enteric Gram-negative bacilli, anaerobes and enterococci.

• Treatment. An antibacterial combination such as amoxicillin 1 g IV 4 times daily, metronidazole 500 mg IV 3 times daily and gentamicin 5 mg/kg IV daily is suitable, as is monotherapy with meropenem 1 g IV 3 times daily, co-amoxiclav 1.2 g IV 3 times daily or piperacillin/tazobactam 4.5 g IV 3 times daily. A combination of a cephalosporin, e.g. cefotaxime 2 g IV 3 times daily, and metronidazole 500 mg IV 3 times daily can also be used, but cephalosporins have no activity against enterococci. Antibacterials alone are often insufficient therapy and appropriate surgical drainage or peritoneal washouts must be performed.

Peritonitis with continuous peritoneal dialysis (CAPD)

Peritonitis is also a risk for patients undergoing CAPD. Infection usually occurs as a result of bacteria entering the peritoneum via the dialysis catheter or following an exit site infection. The common bacterial causes are coagulase-negative staphylococci, Staph. aureus and Gram-negative bacilli, including P. aeruginosa. Fungal infection with Candida spp. also occurs. Patients usually present with a ‘cloudy bag’, often without other symptoms.

• Diagnosis. Peritoneal fluid should be sent for cell count, Gram stain and culture. Infection has been defined as > 100 white blood cells per microlitre, with > 50% neutrophils seen on microscopy. Culture is improved if large volumes of peritoneal dialysate are concentrated by centrifugation. Around 20% of cultures are sterile despite raised cell counts.

• Treatment. Empiric treatment is usually intraperitoneal and includes vancomycin (< 60 kg body weight 1.5 g; > 60g body weight 2 g, and left in bag for 6 hours) and an aminoglycoside, e.g. gentamicin 0.6 mg/kg and left in bag for 6 hours, or vancomycin and oral ciprofloxacin 500 mg orally twice daily for 4 days. Once a pathogen is identified, treatment can be more specific. Infection with coagulase-negative staphylococci is usually treatable, but an exit site infection with Staph. aureus and Candida peritonitis usually requires removal of the dialysis catheter. Cultures yielding enteric Gram-negative bacilli are suggestive of peritonitis following bowel perforation and urgent surgical intervention will be required.

Tuberculous peritonitis

This is the second most common form of abdominal TB.

• In the wet type, ascitic fluid should be examined for protein concentration (> 20 g/L) and tubercle bacilli (rarely found).

• In the dry form, patients present with subacute intestinal obstruction, which is due to tuberculous small bowel adhesions.

• In the fibrous form, patients present with abdominal pain, distension and ill-defined irregular tender abdominal masses.

• Diagnosis. The diagnosis of peritoneal TB can be supported by findings on US or CT screening (mesenteric thickening and lymph node enlargement). A histological diagnosis is not always required before instituting treatment.

• Treatment. Drug treatment is similar to that of pulmonary TB (p. 87).

Hepatobiliary and pancreatic infections

Pancreatitis

See p. 170.

Hepatitis

See p. 179.

Cholecystitis

See p. 172.

Cholangitis

See p. 173.

Liver abscess (see also p. 194)

A liver abscess may occur following intestinal sepsis, e.g. appendicitis, biliary sepsis or, more rarely, bacteraemic spread from a more distant focus. The bacteria most frequently involved are enteric Gram-negative bacilli, Streptococcus milleri, enterococci and anaerobes. Blood cultures may yield the organism.

Treatment

• Percutaneous or surgical drainage is sometimes required.

• Suitable antibacterials are a combination of amoxicillin 1 g IV 4 times daily, metronidazole 500 mg IV 3 times daily and gentamicin 5 mg/kg IV daily, or monotherapy with meropenem 1 g 3 times daily, co-amoxiclav 1.2 g 3 times daily or piperacillin/tazobactam 4.5 g IV 3 times daily.

• Entamoeba histolytica liver abscess can be diagnosed serologically. Treatment is with metronidazole 400 mg or 500 mg IV 3 times daily for 5–10 days. Tinidazole 1.5–2 g daily for 3–6 days is an alternative.

• Aspiration of an amoebic abscess is indicated if rupture is suspected or there is failure to improve after 72 hours of metronidazole. Aspiration can improve penetration of metronidazole and may need to be repeated.

• Diloxanide furoate 500 mg orally 3 times daily for 10 days should be given after metronidazole or tinidazole to eradicate intestinal cysts.

Genitourinary infections

Lower urinary tract infection (LUTI)

LUTI is common in women, in whom it usually occurs in a normal urinary tract. In contrast, LUTI is rare in men and children, and these patients should be investigated for anatomical urinary tract abnormalities. LUTI may occasionally result in a potentially life-threatening Gram-negative bacteraemia. LUTI is characterized by dysuria, urgency, fever, polyuria, suprapubic tenderness or frequency.

Diagnosis

Urinary dipsticks for both white cells and nitrites together are highly sensitive and provides a quick, simple confirmation of a LUTI. Bacteriuria and pyuria correlate well with the presence of infection. Quantitative culture often yields more than 10⁸ bacteria/L, but lower counts may indicate infection in the presence of pyuria or acute dysuria.

Treatment

The most common causative organism of LUTI is E. coli; the next most common are Proteus mirabilis, Klebsiella aerogenes, Staphylococcus saprophyticus and Enterococcus. The sensitivities of these organisms vary greatly across the world. In particular, sensitivities to amoxicillin and trimethoprim vary greatly and the empirical treatment of LUTI must be based on local antibiotic sensitivities. In the UK, the empirical treatment of uncomplicated LUTI may be with trimethoprim 200 mg twice daily for 3–7 days, nitrofurantoin 50 mg 4 times daily for 7 days or an oral cephalosporin for 7 days. A urine culture should be obtained and antibiotic changes based on culture results.

In pregnancy, asymptomatic bacteriuria requires treatment. Women should have their urine routinely dipstick-tested in the first trimester; with a positive result, urine should be sent for microscopy and culture, and appropriate antibiotics that are safe in pregnancy should be started e.g. cefadroxil 500 mg × 2 for 7 days.

Upper urinary tract infections (UUTI)

UUTI presents with fever, flank pain and LUTI symptoms. These infections are severe and often require hospital admission.

Diagnosis

Urine specimens are similar to those in LUTI, showing significant bacteriuria and pyuria. Blood cultures are also frequently positive. Causative agents are similar to those of LUTI. Non-invasive studies, such as US or CTKUB, should be performed to rule out intrarenal abscess, anatomical abnormalities or renal stones.

Treatment

Patients with mild to moderate illness who are able to take oral medication can be safely treated as outpatients with quinolones, e.g. ciprofloxacin 250–500 mg twice daily for 10–14 days. Patients with a more severe or systemic illness and those unable to tolerate oral treatment should be initially given parenteral therapy, with an appropriate empirical therapy based on local antibiotic sensitivities. The choice would include co-amoxiclav, third-generation cephalosporins, fluoroquinolones or aminoglycosides. As with LUTI, changes to antibiotic therapy should be guided by the results of a urine culture if there is no response to the initial empirical therapy. In pregnant women give cefuroxime 750 mg–1.5 g IV 3 times daily for 48 h, switching to oral amoxicillin 500 mg 8 hourly.

Urinary catheter-related infections

Urinary tract infection is one of the most common causes of healthcare-associated infections and indwelling urinary catheters are linked with a greatly increased risk of a urinary tract infection. Urinary catheters are commonly colonized with bacteria, and the presence of bacteria in a urine sample from a catheterized patient does not necessarily imply that treatment should be given. If there are symptoms of a urinary tract infection, then treatment should be prescribed, the choice of the most appropriate antibiotic varying according to local antibiotic sensitivities. If the catheter can be removed, then this should be done. There is no agreement as to whether an aminoglycoside antibiotic should be given during a urinary tract infection to ‘cover’ a catheter change.

Epididymitis

Epididymitis is usually caused by Neisseria gonorrhoeae or Chlamydia trachomatis in sexually active men, or by enteric organisms or TB in older men. Diagnosis and therapy should be directed accordingly.

Prostatitis

Acute prostatitis presents as fever, dysuria, and an extremely tender prostate on examination. Chronic prostatitis is usually asymptomatic, but occasionally lower back pain, testicular discomfort and dysuria are noted. Quantitative urine cultures performed both before and after prostatic massage and NAAT on urine or swab are performed for diagnosis. Prostatitis is usually the result of Gram-negative infection. Treatment is with quinolones, e.g. ciprofloxacin 500 mg twice daily for 28 days.

Systemic fungal infections

Candidiasis

This is the most common fungal infection in humans. Candida albicans is the major pathogen. This and other species that are pathogenic to humans are commensals in the oropharynx and gastrointestinal tract.

• Clinical features. Vaginal infection (p. 72) and oral thrush are common. They are seen in the very young and the elderly, and in patients who have had antibiotic therapy. Any organ in the body can be invaded in the immunosuppressed. Candidal oesophagitis presents with painful dysphagia. Cutaneous candidiasis typically occurs in intertriginous areas. It is also a cause of paronychia. Chronic mucocutaneous candidiasis is a rare manifestation, usually occurring in children, and is associated with a T-cell defect.

• Diagnosis. Scrapings from infected lesions, tissue secretions or blood cultures (in invasive disease) can demonstrate the fungus.

Treatment

• Oral lesions respond to nystatin 500 000 U every 6 hours, oral amphotericin B 10 mg lozenge dissolved in the mouth 4 times daily for up to 2 weeks, or fluconazole 50 mg daily for 2 weeks.

• Systemic infections require parenteral therapy; possible treatment includes fluconazole 400 mg daily, or caspofungin 70 mg on the first day then 50 mg daily. In neutropenic patients liposomal amphotericin 3–5 mg/kg/day or caspofungin or voriconazole are recommended.

Histoplasmosis

Histoplasma capsulatum infection occurs worldwide but the disease is commonly seen in Ohio and the Mississippi river valley, where over 80% of the population have been subclinically exposed. Transmission is mainly by inhalation of the spores, which can survive in moist soil for years.

Clinical features

• Primary pulmonary histoplasmosis is usually asymptomatic, with radiological features similar to those seen with the Ghon primary complex of TB (p. 512). Calcification in the lungs, spleen and liver occurs in patients from areas of high endemicity. When symptomatic, primary pulmonary histoplasmosis generally presents as a mild ‘flu-like illness, with fever, chills, myalgia and cough. The systemic symptoms are pronounced in severe disease.

• Chronic pulmonary histoplasmosis produces pulmonary cavities, infiltrates and characteristic fibrous streaking from the periphery towards the hilum on X-ray.

• Disseminated histoplasmosis resembles disseminated TB clinically. Fever, lymphadenopathy, hepatosplenomegaly, weight loss, leucopenia and thrombocytopenia are common.

• Diagnosis. Diagnosis is made by culturing the fungi or by demonstrating them on histological sections. The histoplasmin skin test is only of diagnostic value when it converts from a negative to a positive result.

• Management. Only symptomatic patients require therapy. Itraconazole or ketoconazole is indicated for moderate disease. Severe infection is treated with IV amphotericin B for 1–2 weeks, followed by oral itraconazole 200 mg twice daily for 6 months

Aspergillosis

This is caused by Aspergillus fumigatus (the most common), A. flavus and A. niger. These fungi are ubiquitous in the environment and are often found on decaying leaves and trees. Humans are infected by inhalation of the spores. Three major forms of the disease are recognized:

• Allergic bronchopulmonary aspergillosis (rare) is an exaggerated immune response to aspergillus which leads to proximal bronchiectasis. Eosinophilic pneumonia occurs, particularly in late autumn and winter, with a wheeze, cough, fever and malaise. Peripheral blood eosinophil count is usually raised. Total levels of IgE are usually extremely high (both that specific to Aspergillus and also the non-specific type). Skin-prick testing to protein allergens from A. fumigatus gives rise to positive immediate skin tests. Sputum may show eosinophils and mycelia, and precipitating antibodies are usually, but not always, found in the serum.

• Treatment. Prednisolone 30 mg daily produces rapid clearing of the pulmonary infiltrates; intermittent long-term treatment with prednisolone 10–15 mg daily is usually required. Itraconazole 200 mg daily is also used and improves pulmonary function.

• Aspergilloma and invasive aspergillosis. A. fumigatus grows within previously damaged lung tissue, forming a ball of mycelium within lung cavities (called an aspergilloma). A round lesion, with an air ‘halo’ above it, is seen on CXR. With continuing antigenic stimulation, large quantities of precipitating antibody are seen in the serum. Massive haemoptysis may occur and requires resection of the area of damaged lung containing the aspergilloma. Antifungal agents are not helpful. Invasive aspergillosis is seen with immunosuppression and requires aggressive antifungal Voriconazole 6 mg/kg × 2 for 24 hours then 4 mg/kg IV or orally is the treatment of choice. Caspofungin and amphotericin B is used liposomal 3–5 mg/kg day (p. 89).

Cryptococcosis

Cryptococcus neoformans has a worldwide distribution and is spread via the droppings of birds, especially pigeons. Transmission is by inhalation of the spores into the lungs, which produces a granulomatous reaction; pulmonary symptoms are uncommon. Pulmonary lesions include lung cavitation, hilar lymphadenopathy and pleural effusions. Meningitis usually occurs in immunocompromised patients with AIDS or lymphoma and often develops subacutely.

• Diagnosis. A positive Indian ink stain or latex cryptococcal antigen test performed on the CSF is diagnostic. Tissue biopsies may demonstrate characteristic encapsulated yeasts.

• Treatment. Amphotericin B 0.7–1.0 mg/kg daily IV, alone or in combination with flucytosine 100–200 mg/kg daily for 2 weeks, is followed by fluconazole 400 mg daily. Therapy should be continued for 8 weeks with meningitis. Fluconazole has greater CSF penetration and is used when toxicity is encountered with amphotericin B and flucytosine, and as maintenance therapy in immunocompromised patients, especially those with HIV (p. 114).

Coccidioidomycosis

Coccidioides immitis, a soil saprophyte, is found in the southern USA, Central America and parts of South America. Transmission is by inhalation of spores.

• Clinical features. The majority of patients are asymptomatic. Acute pulmonary coccidioidomycosis presents with fever, malaise and cough, after an incubation period of about 10 days. Erythema nodosum, erythema multiforme, phlyctenular conjunctivitis and, less commonly, pleural effusions may occur. Complete recovery is usual.

• Diagnosis. The organism can be identified in respiratory secretions or tissue samples by histopathology. Cultures are not usually performed. Tests include the highly specific latex agglutination and precipitin tests (IgM), which are positive within 2 weeks of infection and decline thereafter. Other tests include complement fixation, ELISA and radioimmunoassay. A complement-fixation test (IgG) performed on the CSF is diagnostic of coccidioidomycosis meningitis; it becomes positive within 4–6 weeks and remains so for many years.

• Treatment. Mild pulmonary infections are self-limiting and require no treatment, but progressive and disseminated disease require urgent therapy. Itraconazole 200 mg for 6 months or fluconazole 400–600 mg for 6 months is the treatment of choice for primary pulmonary disease, with more prolonged courses for cavitating or fibronodular disease. Fluconazole in high dose (600–1000 mg daily) is given for meningitis.

Blastomycosis

Blastomycosis is caused by Blastomyces dermatitidis and is found in North America.

• Clinical features. Blastomycosis primarily involves the skin, presenting as non-itchy papular lesions that later develop into ulcers with red verrucous margins. Pulmonary solitary lesions are found and are radiologically similar to the Ghon focus of TB. Fever, malaise and cough occur, and bone lesions are common.

• Diagnosis. The organism is found in histological sections or by culture from lesions; results can be negative in up to 50% of patients. ELISA may be helpful in the diagnosis but there is some cross-reactivity between Blastomyces and Histoplasma antibodies.

• Treatment. Itraconazole 200–400 mg is used for mild to moderate disease for up to 6 months. Fluconazole is also used. In severe or unresponsive disease and in the immunocompromised, amphotericin B 0.7–1.0 mg/kg/day (max. 2.5 g) or liposomal amphotericin for several weeks followed by oral azole therapy is recommended.

Pneumocystis jiroveci infection

This is seen in adults associated with immunodeficiency states, particularly AIDS, and is discussed on page 112.

Helminthic infections

Worm infections are very common in developing countries. Multiple infections with different helminths are common in endemic areas. Mass treatment programmes are carried out, usually annually, to keep the total worm load down (see Table 2.5). Treatment of trematodes and intestinal nematodes is shown in Tables 2.6 and 2.7 respectively.

Table 2.5 Drugs used in mass treatment programmes for helminth infections (alone or in combination)

Drug	Infection
Diethylcarbamazine (DEC)	Loiasis
Diethylcarbamazine (DEC)	Filariasis
Ivermectin	Loiasis
	Filariasis
	Onchocerciasis
	Strongyloidiasis
Albendazole	Filariasis (with DEC)
Albendazole	Intestinal helminths
Praziquantel	Schistosomiasis

Table 2.6 Treatment of trematode infections

Parasite	Drug and dose
Schistosoma mansoni	Praziquantel 40 mg/kg single dose*
S. haematobium	Praziquantel 40 mg/kg single dose*
S. japonicum	Praziquantel 60 mg/kg single dose*
Paragonimus spp.	Praziquantel 25 mg/kg 8-hourly for 3 days
Chlonorchis sinensis	Praziquantel 25 mg/kg 8-hourly for 2 days
Opisthorcis spp.	Praziquantel 25 mg/kg 8-hourly for 1 day
Fasciolopsis buski	Praziquantel 25 mg/kg 8-hourly for 1 day
Fasciola hepatica	Triclabendazole 10 mg/kg single dose^†

* May be split to minimize nausea.

^† Repeated if necessary.

Table 2.7 Drugs used for treating human intestinal nematodes (single dose unless otherwise stated)

Sexually transmitted infections

Sexually transmitted infections (STIs) are very common worldwide.

Risk factors for most STIs are similar and therefore multiple infections frequently coexist, some of which may be asymptomatic. Because of this, all patients presenting with a possible STI should be screened for syphilis, chlamydia, gonorrhoea and trichomoniasis, and should be offered HIV testing.

People seeking advice for STIs are usually anxious and concerned about confidentiality, and are sometimes embarrassed. The clinic setting should ensure privacy and adhere to strict confidentiality. STIs should ideally be treated in a genitourinary clinic.

In addition to a history of both genital and generalized symptoms, a travel and drug history will aid diagnosis and allow contact tracing to be carried out. Treatment of sexual partners is an essential part of the control of STIs.

Investigations

In general, send urethral, vaginal, urine, and sometimes oral and rectal swabs for culture and NAAT, along with appropriate serological tests for diagnosis. Investigations should also include screening for hepatitis (A, C and B), and HIV screening should be offered.

Herpes simplex virus (HSV)

Genital herpes is caused by the human herpes simplex virus (usually type 2). It is characterized by painful genital vesicles and ulceration. Like other human herpes viruses, herpes simplex virus remains dormant but can reactivate with recurrences. The diagnosis of genital herpes is made clinically but should be confirmed by viral culture or immunofluorescence. As herpes infection is so common, all genital ulcers should be cultured for herpes virus. Antiviral therapy is effective if begun within 5 days of the start of the infection, whilst there are new lesions.

Treatment

Treatment should be with aciclovir 200 mg 5 times a day, famciclovir 250 mg 3 times daily or valaciclovir 500 mg twice daily for 5 days; IV therapy is necessary to treat complications if the patient is unable to tolerate oral therapy. HIV-positive patients need to be treated for 10 days. Suppressive therapy with aciclovir 400 mg twice daily for recurrent confirmed genital herpes infections is used for severe or frequent recurrences.

Syphilis

Treponema pallidum infection causes syphilis. The natural history of syphilis is divided into the following entities:

• Primary syphilis develops within several weeks of exposure and involves a chancre (painless, indurated, superficial ulceration).

• Secondary syphilis is characterized by multi-system involvement within the first 2 years following infection: generalized polymorphic, (usually) non-itchy rash, often affecting the palms and soles, mucocutaneous lesions and generalized lymphadenopathy. Less commonly, other complications such as meningitis occur.

• Tertiary syphilis includes cardiovascular, gummatous and neurological disease (tabes dorsalis, meningovascular syphilis or general paresis), which occurs after a period of latency (early or late).

Investigations

Microscopic diagnosis of primary syphilis is made by dark-field microscopy of exudates from a chancre. Serology is the mainstay of the diagnosis of syphilis. A cardiolipin (non-treponemal) serological test, such as the rapid plasma reagin (RPR) test or the Venereal Disease Research Laboratory (VDRL) test, detects non-specific treponemal antigens and becomes positive a few weeks into the infection; it then becomes negative again after several months. Specific treponemal serological tests, such as the fluorescent treponemal antibody absorption test (FTA), the Treponema pallidum haemagglutination test (TPHA) and the Treponema pallidum particle agglutination assay (TPPA), become positive after several months and remain positive for life. The treponemal enzyme immunoassay (EIA) (IgG and IgM) is also available; the IgM becomes positive after about 2 weeks and the IgG after 5 weeks. Screening with an EIA (IgG and IgM) or both a non-specific (RPR/VDRL) and a specific test (FTA/TPPA) is recommended. The serology cannot differentiate between syphilis and other treponemal diseases such as yaws and pinta. CSF serology is necessary to diagnose neurosyphilis.

Treatment

• Early syphilis is treated with procaine penicillin G 750 mg IM daily for 10 days. Doxycycline 100 mg twice daily for 14 days, erythromycin 500 mg 4 times orally daily for 14 days or azithromycin 500 mg daily for 10 days is also used in cases of penicillin allergy.

• Late latent syphilis is treated with procaine penicillin 750 mg IM daily for 17 days or doxycycline 200 mg twice daily for 28 days.

• Neurosyphilis is treated with procaine penicillin 2 g IM daily for 17 days plus probenecid 500 mg 4 times daily for 17 days, or in case of penicillin allergy doxycycline 200 mg twice daily for 28 days. Patients with neurological syphilis should be given prednisolone at the start of the therapy to avoid the Jarisch–Herxheimer reaction), although the evidence for its efficacy is poor.

Chancroid

Chancroid is caused by Haemophilus ducreyi. It is relatively uncommon in Europe and North America, but a common cause of ulcerative genital lesions in Africa and Asia. Chancroid presents as painful, non-indurated genital ulcers with tender inguinal lymphadenopathy that suppurates.

• Diagnosis. Diagnosis of chancroid requires culture and microscopy of H. ducreyi from a genital lesion or lymph node aspirate.

• Treatment. Treatment regimens are ceftriaxone 250 mg IM single dose, azithromycin 1 g daily single dose, ciprofloxacin 500 mg twice daily for 3 days or erythromycin 500 mg 4 times daily for 7 days.

Trichomoniasis

Trichomonas vaginalis is a flagellated protozoan that causes a vaginitis. Clinical symptoms include a foul-smelling frothy vaginal discharge, dysuria and genital inflammation (cervical petechiae), though many infections are asymptomatic. Men are usually asymptomatic but may present with discharge or dysuria.

• Diagnosis. Microscopy of vaginal fluid shows motile trichomonads on a saline wet mount of discharge.

• Treatment. Metronidazole 2.0 g single dose or metronidazole 400–500 mg twice daily for 5–7 days is used. Metronidazole is contraindicated in pregnancy so intravaginal clotrimazole 100 mg (suppositories) daily for 7 days may be used for symptomatic relief, although definitive treatment later is usually required.

Candidiasis

Vulvovaginal candidiasis is a common cause of an itchy vaginitis caused by Candida spp. and is not sexually transmitted. It presents with a thick, white vaginal discharge and intense vulvar inflammation, pruritus and occasionally dysuria. In men, candidiasis is often asymptomatic but can cause a balanitis.

• Diagnosis is usually made clinically, but is supported by microscopy and culture.

• Treatment with topical clotrimazole (cream or suppository) or fluconazole 150 mg oral single dose is usually effective, but infections are often recurrent.

Bacterial vaginosis

Bacterial vaginosis (BV) is the most frequent cause of vaginal discharge in women of childbearing age. It is characterized by a replacement of vaginal lactobacilli leading to overgrowth of predominantly anaerobic organisms (Gardnerella vaginalis, Prevotella and Mobiluncus spp.) and a rise in vaginal pH; it is not, strictly speaking, an STI. BV presents as a homogeneous, thin, vaginal discharge that smoothly coats the vaginal walls. There is minimal genital inflammation. Clue cells are found on microscopy; the pH of vaginal fluid is > 4.5 and there is a fishy odour on adding 10% KOH.

• Treatment is with metronidazole 400–500 mg twice daily for 5–7 days, metronidazole 2 g single dose, clindamycin (2% cream) 4 times daily for 7 days or clindamycin 300 mg twice daily for 7 days. Recurrence is common.

Human papilloma virus

Anogenital warts are caused by the human papilloma virus (HPV), of which over 100 genotypes have been identified. Warts may be single or multiple, and are usually easy to diagnose on naked eye examination, but if in doubt diagnosis may be confirmed histologically. There may be occult lesions and HPV (not all types) is associated with carcinoma.

• Treatment is with cryotherapy, chemical applications such as podophyllin, podophyllotoxin, imiquimod and interferon, or surgical removal. No single therapy is always effective and recurrences are common. An effective vaccine is now available and should be given to females aged 12–13 years.

Gonorrhoea

Gonorrhoea is caused by infection with Neisseria gonorrhoeae, a Gram-negative diplococcus. Men usually present with urethral discharge and/or dysuria but infection may be asymptomatic. Rectal infection may cause anal discharge or pain but pharyngeal infection is usually asymptomatic. In women gonorrhoea is often asymptomatic but vaginal discharge and lower abdominal pain occur.

On examination men usually have a purulent urethral discharge, and rarely, epididymal tenderness or balanitis is seen. In women examination is often normal, but there may be a mucopurulent cervical discharge and cervical contact bleeding, and rarely, lower abdominal tenderness.

• Diagnosis. Diagnosis is by NAAT (PCR-based) on urine or microscopy and culture of urethral and cervical samples.

• Treatment. There is increasing resistance of N. gonorrhoeae to commonly used antibiotics, especially in South-East Asia. The antibiotic treatment of gonorrhoea should reflect local resistance patterns. Cefixime 400 mg as a single dose or ciprofloxacin 500 mg as a single dose are common first-line therapies; ofloxacin 400 mg as a single dose is an alternative. Quinolone resistance is becoming increasingly common. Patients should return 72 hours after completing treatment for a test of cure.

Chlamydia

Genital infection with Chlamydia trachomatis is very common. Approximately 40% of non-gonococcal urethritis is caused by C. trachomatis. This infection is maintained at such high rates because it may be symptomless in both men and women. Most infections are asymptomatic but in men may present as dysuria or urethral discharge. In women chlamydia presents as vaginal discharge, intermenstrual bleeding or lower abdominal pain. Rectal infection may occasionally cause proctitis.

• Diagnosis is often made on clinical suspicion (after excluding other diagnoses), as tests are not completely sensitive. Diagnosis may be made by culture, immunofluorescence or NAAT.

• Treatment is with doxycycline 100 mg twice daily for 7 days, azithromycin 1 g orally as a single dose. Erythromycin 500 mg 4 times daily for 14 days is an alternative although test of cure at 28 days is recommended as there is a significant rate of treatment failure.

Antimicrobial drugs

These drugs are categorized as antibacterials, antivirals, antifungals, antiprotozoals and antihelminthics.

Mode of action

Antimicrobials have many and varied mechanisms of action, e.g. inhibition of an organism’s cell wall or inhibition of protein or nucleic acid synthesis. The essential property is selective toxicity to the microbe rather than the host. In the case of bacteria, the result is either death of the bacterium (bactericidal) or inhibition of the bacterium’s growth (bacteriostatic). Though the terms bacteriostatic and bactericidal are defined in vitro, their applicability to treatment has been questioned.

General principles of use

Antimicrobials are widely used for treatment or for prophylaxis, but are also widely misused. Overuse can lead to resistance. The following general principles should be followed to guide the use of these agents:

• Necessity for treatment should be decided on the clinical evidence of infection, the availability of other more appropriate therapy (e.g. surgical drainage of an abscess) and an evaluation of whether the benefits of treatment outweigh the risks (e.g. side-effects).

• Cultures of appropriate sites and sensitivities must be obtained prior to commencing antibiotics, except in certain circumstances (e.g. meningococcal disease).

• Choice of antimicrobial will depend on sensitivity to the causative bacterium and whether the agent will reach the site of infection. More than one drug may be required but any contraindications and possible drug reactions should be checked.

• Dose will vary with the patient’s age and weight, the presence or absence of renal and liver dysfunction, and the site and severity of infection.

• Route of administration depends on the absorption kinetics.

• Oral therapy is cost-effective and non-invasive but depends on good gastrointestinal absorption.

• Intramuscular injections are painful and may be contraindicated in bleeding disorders.

• Intravenous therapy is used in severe infections, particularly when high concentrations in the blood are required quickly.

• Switch from IV to oral therapy. This should be as soon as possible when the signs and symptoms of infection have improved and the patient is haemodynamically stable and able to take oral fluids. N.B. Remember IV therapy is extremely expensive e.g. IV metronidazole is approximately 15 times the oral cost.

• Topical antibiotics can be used for skin, eye or ear infections.

• Rectal (suppositories or foam) antibiotics are usually cheaper but are not always appropriate.

• Duration of therapy depends on the nature of the infection and the clinical response. The optimum duration of therapy is not known for many infections. Good evidence exists for treatment of TB, bacterial pharyngitis, urinary tract infection and endocarditis.

Antimicrobial prophylaxis

Prophylaxis is the use of a drug to prevent infection. The antimicrobial used should be given at the appropriate time, by the appropriate route and for the appropriate duration. The choice of antibacterial agent is also dictated by the likely sensitivity of the organisms expected to be encountered.

Situations in which prophylaxis is needed include the following:

• before a surgical procedure with a risk of infection, e.g. bowel or gynaecological surgery or implantation of surgical prostheses

• after an individual has been exposed to an infectious agent, e.g. N. meningitidis

• before an individual has been exposed to an infectious agent but is not yet ill, e.g. antimalarial prophylaxis for P. falciparum infection

• when post-splenectomy chemoprophylaxis is required (see Box 7.1, p. 205).

Chemoprophylaxis to prevent endocarditis after procedures in patients with high-risk heart lesions is controversial. Procedures can introduce a bacterium but there is no evidence that this leads to endocarditis. The UK is unusual in that it has issued guidance that chemoprophylaxis is never required; most other countries recommend chemoprophylaxis in high-risk cases.

Adverse effects

• Toxicity. Antimicrobials may be harmful to the patient. Minor side-effects, such as nausea, are common. Antimicrobials may be ototoxic, nephrotoxic, hepatotoxic or neurotoxic. Some are contraindicated in pregnancy because of potential teratogenicity, and in breast feeding because the agent is present in the milk. N.B. Always check the dose and route of administration.

• Interactions. Antimicrobials may interact with a wide range of other drugs, e.g. rifampicin, warfarin or the oral contraceptive pill (p. 11).

Failure of antimicrobial therapy

Antimicrobials may fail for a variety of reasons and this does not always indicate resistance or necessitate a change in antimicrobial therapy. The common reasons for failure of antimicrobial therapy are:

• poor compliance

• wrong diagnosis, wrong choice of drug, failure of drug to reach the site of infection

• inadequate dose, duration or route of administration

• bacterium has become resistant, superinfection with resistant organism

• antimicrobial started too late

• antimicrobial is inactivated by another drug, or metabolized or excreted more quickly than normal

• other treatment such as surgery is required, e.g. drainage of an abscess, removal of an infected intravascular device.

Antimicrobial resistance

Resistance may be due to there being no active site for the antimicrobial agent, cell wall impermeability or the destruction or modification of the antimicrobial itself. Reduced drug uptake and increased drug excretion (efflux) can also play a part.

Not all organisms are sensitive to all antimicrobial agents; some are intrinsically resistant. Antimicrobial resistance may also develop (acquired resistance) in organisms that were previously sensitive, as a result either of mutation or of horizontal transferral of resistance genes by conjugation, transfer of plasmids or other mobile genetic elements.

Antimicrobials are commonly prescribed drugs and resistance can easily develop with overuse. It is imperative that they should be prescribed rationally and only when necessary. A number of resistant organisms already exist, e.g. meticillin-resistant staphylococci, ESKAPE organisms (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, and Enterobacter species). A recent resistance in Klebsiella pneumoniae contains NDm-1 (New Delhi metallo-beta-lactamase-1), a transmissable genetic element encoding multiple resistant genes. The worrying factor is that it can spread across many bacterial genes.

Antimicrobial policies/guidelines

Most hospitals operate an antibacterial policy to reduce the development of resistance, to achieve economy and to reduce the frequency of hospital-acquired infections. The latter has been achieved by the reduction in use of broad-spectrum antibiotics.

Antibacterial drugs

These drugs may be classified according to their chemical structure (e.g. β-lactam agents, aminoglycosides, quinolones), their mode of action (e.g. inhibitors of cell wall synthesis, inhibitors of protein synthesis) or their spectrum of activity (e.g. antituberculous agents, antistaphylococcal agents).

Below is a brief description of the commonly used antibacterial agents listed according to chemical structure; some are listed by mode of action and some by spectrum of activity.

β-lactams

These antibiotics contain a β–lactam ring structure; they interfere with bacterial cell wall synthesis and are bactericidal. They include the penicillins, cephalosporins, carbapenems and monobactams.

Penicillins

Patients should always be asked if they are sensitive to penicillin prior to its administration. In general, patients with a history of atopy (asthma, eczema and hay fever) have a higher risk of anaphylactic reactions to penicillins.

Penicillin is active against streptococci, including most pneumococci, meningococci, Corynebacterium diphtheriae and treponemes. Most strains of Staphylococcus aureus and Neisseria gonorrhoeae are now resistant because of the production of β-lactamase. IM preparations, e.g. benzyl penicillin, procaine penicillin and the derivatives of benzyl penicillin, such as benthamine penicillin or benzathine penicillin, are less frequently used but are still useful in the treatment of syphilis (p. 72).

• Benzyl penicillin (penicillin G). Dose 2.4–4.8 g daily in 4 divided doses IM or by slow IV infection or infusion.

• Phenoxymethylpenicillin (penicillin V). This is poorly absorbed enterally and oral bioavailability is low. It is mainly used for streptococcal sore throats and prophylaxis against recurrent rheumatic fever (250 mg twice daily).

• Broader-spectrum penicillins. Ampicillin 250 mg to 1 g 6-hourly orally or 500 mg 4–6-hourly IV and amoxicillin 250–500 mg 8-hourly orally or 0.5–1 g 6–8-hourly IV. The spectrum of activity includes that of basic penicillins but also covers enterococci and some Gram-negative bacteria, e.g. Haemophilus influenzae, some Enterobacteriaceae. However, these antibiotics are hydrolysed by β-lactamase enzymes, e.g. those found in Staph. aureus, N. gonorrhoeae and some H. influenzae. Thus almost all staphylococci, 20% of H. influenzae and 60% of Escherichia coli are resistant.

• Penicillinase-resistant penicillins. The first semisynthetic β-lactamase-stable compound to be used was meticillin, which has been replaced by the isoxazolyl penicillins. These are β-lactamase-stable penicillins that are active against Staph. aureus, e.g. flucloxacillin orally 500 mg 6-hourly or IM or IV infusion 0.5–1 g 6-hourly. Meticillin-resistant Staph. aureus (MRSA — see p. 43) is also resistant to this agent. Strains of Staph. aureus that remain sensitive to isoxazolyl penicillins are often referred to as MSSA (meticillin-sensitive Staph. aureus). Nafcillin has a spectrum of activity similar to the isoxazolyl penicillins and is used mostly in North America (2 g IV 4–6-hourly). Temocillin 1–2 g 12-hourly IM or IV infusion is active against Gram-negative bacteria and is stable to many β-lactamases. It is best reserved for treating β-lactamase-producing Gram-negative bacteria, those isolates resistant cephalosporins such as cefotaxime and ceftazidime.

• Antipseudomonal penicillins. These are semi-synthetic derivatives that have an expanded spectrum of activity against Gram-negative bacteria, including Pseudomonas aeruginosa. Examples include the ureidopenicillins such as piperacillin (combined with tazobactam 4.5 g 8-hourly IV), and the carboxypenicillins such as ticarcillin (combined with clavulanic acid 3.2 g 6–8-hourly IV). These agents are often used as empirical therapy in neutropenic sepsis. They are usually used in combination with a β-lactamase inhibitor, as the latter broadens the spectrum of activity.

• β-lactam/β-lactamase inhibitor combinations. These include co-amoxiclav 500 mg 8-hourly orally, a combination of amoxicillin and the β-lactamase inhibitor clavulanic acid; piperacillin and the inhibitor tazobactam; ampicillin and the inhibitor sulbactam; ticarcillin and clavulanic acid. The spectrum of activity is that of the β-lactams plus expanded activity against Gram-negatives, including Pseudomonas, MSSA and also most anaerobic organisms.

• Mecillinams. Pivmecillinam 200–400 mg 8-hourly orally is active against Gram-negative bacteria, including Klebsiella, Enterobacter, Salmonella and E. coli, but not Pseudomonas.

Cephalosporins

These β-lactams have an advantage over penicillins in that they are more resistant to hydrolysis by β-lactamases but are still inactive against MRSA and enterococci. Cephalosporins are often classified by ‘generations’, with succeeding generations having a wider Gram-negative spectrum. This classification is not always helpful, as not all cephalosporins of the same generation have the same activity. For example, some have less activity against Gram-positive organisms, particularly staphylococci. Cephalosporins also produce adequate CSF concentrations in the presence of meningeal inflammation.

Oral cephalosporins are used frequently for treatment of urinary tract infections, but because of extremely poor oral bioavailability most are usually used parenterally.

The IV agents are commonly used for empirical treatment of septicaemia and neutropenic sepsis. They are often used in combination with an aminoglycoside and metronidazole, in abdominal sepsis. In severe community-acquired pneumonia they are usually combined with a macrolide. These drugs are also widely misused when an antimicrobial with a narrower spectrum may be better. Patients on these broad-spectrum agents are prone to the development of Clostridium difficile-associated diarrhoea.

• First generation. These oral agents are active against staphylococcal and streptococcal infections. They include cefalexin 250 mg 4 times daily increasing to 1–1.5 g 6–8-hourly for severe infections, and cefadroxil 0.5–1 g twice daily for skin and soft-tissue infections and 1 g daily for urinary tract infections.

• Second generation. These are more effective than first-generation agents against E coli, Klebsiella spp. and Proteus mirabilis, but less effective against Gram-positive organisms. They include cefuroxime 250 mg orally twice daily for mild upper respiratory tract infections, or 750 mg 3 times daily IM or IV, rising to 1.5 g 6–8-hourly for severe infections. For meningitis, use 3 g IV 8-hourly. This drug is also useful for community-acquired pneumonia, urinary tract infections, and soft-tissue and skin infections. Cefaclor 250 mg oral 8-hourly, or 500 mg 8-hourly for severe infections, is used for sensitive Gram-positive and Gram-negative bacteria.

• Third generation. These penetrate the CSF better than the second-generation drugs. They are broad-spectrum and more potent against anaerobic Gram-negative bacteria. They are useful in severe septicaemia and can also be used for urinary tract infections, pneumonia and intra-abdominal infections, usually combined with metronidazole. They include cefotaxime 1 g twice daily IM or IV, increased in severe infections, e.g. meningitis, to 2 g 6-hourly. It has greater activity against many Gram-negatives and also retains some anti-Gram-positive activity, e.g. for streptococci. Ceftriaxone IV 1 g daily over 2–4 mins or by IV infusion, rising to 2–4 g in severe infections, has similar activity to cefotaxime but a longer half-life, allowing once-a-day dosing. Ceftazidime 1 g 3 times daily IV, 2 g IM 8-hourly for broad-spectrum cover in meningitis, is a parenteral third-generation agent with a spectrum of activity extended to include P. aeruginosa. Cefoperazone 2–4 g IV 12-hourly has similar activity to ceftazidime. Cefixime 200 mg twice daily and cefpodoxime 200 mg twice daily are the only orally available third-generation drugs and are used for upper and lower respiratory and urinary tract infections.

• Fourth generation. Cefepime 0.5–2 g IV 8–12-hourly has good activity against Gram-negatives, including P. aeruginosa. It has better activity against Gram-positive bacteria such as MSSA than the third-generation agents, and is used in febrile neutropenic infections.

• Fifth generation. Ceftobiprole (IV and oral) and Ceftaroline have a similar broad spectrum action but also include MRSA, pseudomonas and enterococcei.

Carbapenems

These agents are stable to many β-lactamases, including extended spectrum β-lactamases (ESBLs) and AmpC-producing organisms. Currently available carbapenems are not active against MRSA. The Gram-negative organism, Stenotrophomonas maltophilia, which may cause sepsis in immunocompromised patients, is also resistant by virtue of the production of a metallo-β-lactamase enzyme. Such enzymes have also been found in some other Gram-negatives, including some isolates of P. aeruginosa. Examples of carbapenems include:

• Imipenem 0.5 mg 4 times daily IV infusion has a broad spectrum of activity, including aerobic and anaerobic Gram-positive and Gram-negative bacteria. It is used in combination with a specific enzyme inhibitor, cilastatin, which blocks its renal inactivation. It is slightly more active against enterococci compared to the others in this group. Imipenem and meropenem are used in the empirical treatment of sepsis, including neutropenic sepsis, and polymicrobial infections, e.g. abdominal sepsis, or when ESBL-producing organisms are suspected, or in infections with multi-resistant Acinetobacter, when they are sensitive. Imipenem should not be used for the treatment of CNS infection or in people prone to fitting, as it is neurotoxic in high doses or in patients with chronic kidney disease.

• Meropenem 500 mg 8-hourly IV infusion is similar to imipenem but, as it is stable to the renal enzyme, it does not require cilastatin. It is the preferred antibiotic in this class for CNS infections.

• Ertapenem 1 g once daily IV infusion has a longer half-life but has no activity against P. aeruginosa. It is used for community-acquired pneumonia.

• Doripenem 500 g 4 times daily IV infusion is used for hospital-acquired pneumonia and complicated urinary tract and abdominal sepsis.

• Monobactams. Aztreonam 2 g twice daily IV infusion, a parenteral drug, is the only member of this class of drug that has been used widely. Monobactams are active against a wide range of Gram-negative organisms but not active against Gram-positive or anaerobic organisms, meaning that aztreonam should not be used on its own empirically.

• Toxicity of β-lactams. Generally β–lactams are very safe. Hypersensitivity reaction occurs in 1–10% of patients, causing rashes, urticaria and anaphylaxis (< 0.05%). Hypersensitivity is to the basic penicillin structure and therefore occurs with all penicillins and all β-lactam antibiotics. Rarely, an encephalopathy occurs. Intrathecal injections should not be given, as they can cause a fatal encephalopathy. Ampicillin produces a rash in 90% of patients with infective mononucleosis who receive the drug. Co-amoxiclav causes a cholestatic jaundice six times more frequently than amoxicillin itself; this is commoner in patients over 65 years. Flucloxacillin rarely causes a cholestatic jaundice, which can occur several weeks after the drug is stopped.

Aminoglycosides

Aminoglycosides bind to the 30S subunit of the bacterial ribosome and interfere with protein synthesis. They are bactericidal. This group includes gentamicin, netilmicin, amikacin, tobramycin and streptomycin. These agents are poorly absorbed from the gut and must be given parenterally. They are active predominantly against Gram-negative bacteria, including P. aeruginosa. Many strains of Staph. aureus are sensitive to aminoglycosides. There are differences in the activity of the different agents, with bacteria resistant to some of the aminoglycosides as a result of the production of aminoglycoside-modifying enzymes. The substrate range of these enzymes varies so, for example, an organism that is resistant to gentamicin may still be sensitive to amikacin. These drugs are rarely used as monotherapy and are usually given in combination with a β-lactam. Streptococci and enterococci are resistant to aminoglycosides, but when used in combination with a β-lactam, synergy occurs. Thus many regimens for treatment of infective endocarditis include an aminoglycoside. Gentamicin and amikacin are now commonly given as a single daily dose.

• Gentamicin is given by slow IV injection over 3 mins, or by slow IV infusion, either 5 mg/kg as a single daily dose or 3–5 mg/kg/day in divided doses 8-hourly.

• Amikacin is used in serious Gram-negative infections resistant to gentamicin. It is given by slow IV injection or infusion 15 mg/kg as a single daily dose or in 2 divided doses. For severe infections use a maximum of 22.5 mg/kg/day in 3 divided doses. Amikacin is also used occasionally for the treatment of TB or infections caused by non-tuberculous mycobacteria.

• Streptomycin IM 0.5–1 g daily is mainly used for treatment of TB when other drugs cannot be used, e.g. because of resistance.

• Tobramycin 1 mg/kg daily every 8 hours by slow IV injection or infusion, increasing to 5 mg/kg daily for severe infections has similar activity to gentamicin. It can also be used by inhaler for treatment of P. aeruginosa in cystic fibrosis (can cause bronchospasm).

• Netilmicin 4–6 mg/kg daily in 2 or 3 divided doses has a similar spectrum of activity to gentamicin.

Side-effects: aminoglycosides are nephrotoxic and therapeutic drug monitoring is essential (p. 365). Nephrotoxicity is reversible if detected early but permanent damage can occur. Use cautiously in liver disease. Ototoxicity can be vestibular or due to cochlear damage. Aminoglycosides should not be used along with ototoxic diuretics, e.g. furosemide.

• Neomycin is used as a topical agent for the treatment of eye and ear infections.

Macrolides

Macrolides and ketolides inhibit protein synthesis by binding to the 50S subunit of the bacterial ribosome and interfere with protein synthesis. They are bacteriostatic.

• Erythromycin has a similar range of activity to penicillin and thus is often used to treat infections where β-lactams are contraindicated because of allergy, e.g. those caused by streptococci and Staph. aureus. However, resistance in these organisms is becoming commoner. Some isolates of MRSA remain sensitive. Erythromycin is commonly used to treat community-acquired pneumonia, as it is active against Mycoplasma pneumoniae and Legionella pneumophila. Erythromycin can be given orally 250–500 mg 6-hourly, rising to 4 g daily in severe infections. It can also be given by IV infusion in severe infections, 50 mg/kg daily in divided doses 6-hourly.

• Clarithromycin, e.g. 250–500 mg twice daily orally, is an erythromycin derivative that has a similar spectrum to erythromycin but greater activity. Tissue concentrations are higher. It is used for respiratory tract infections and otitis media. It is also given in combination with other drugs (e.g. amoxicillin and omeprazole) for the eradication of Helicobacter pylori.

• Azithromycin, e.g. 500 mg once daily for 3 days orally, has better activity than erythromycin against some Gram-negative organisms such as H. influenzae but less activity against Gram-positive bacteria. It is also used for the treatment of upper and lower respiratory tract infections and otitis media. Macrolides have good intracellular penetration and azithromycin is useful for the treatment of Salmonella typhi and S. paratyphi infections (500 mg once daily for 7 days). It is also useful for genital Chlamydia infections and non-gonococcal urethritis (1 g single dose). It is used in the WHO SAFE approach (p. 93) for trachoma (20 mg/kg as a single dose) and also in the treatment and prophylaxis of Mycobacterium avium intracellulare in patients with HIV infection (p. 117).

• Telithromycin is a ketolide derivative of erythromycin with a similar spectrum of activity to the other macrolides. It is used in the treatment of respiratory tract infections (800 mg daily for 5 days).

Nausea, vomiting and diarrhoea are common gastrointestinal side-effects, which are less frequent with clarithromycin and azithromycin. Rashes and abnormal liver biochemistry occur, as does prolongation of the QT interval.

Glycopeptides

Glycopeptides interfere with bacterial cell wall synthesis and are bactericidal.

• Vancomycin is active only against Gram-positive organisms. Absorption from the gut is poor so it is only used parenterally, except when it is given orally to treat C. difficile-associated diarrhoea (125 mg 6-hourly). Vancomycin IV infusion 1 g 12-hourly is reserved for situations when other agents cannot be used, e.g. against MRSA. It is also used for the treatment of neutropenic sepsis and also IV line-associated infections. Some strains of enterococci are now resistant to glycopeptides, so-called glycopeptide-resistant enterococci (GRE), and reduced susceptibility has also developed in some strains of MRSA, which are termed glycopeptide-intermediate Staphylococcus aureus (GISA).

• Teicoplanin is used once daily 200–400 mg by IV infusion.

Side-effects: vancomycin is nephrotoxic and therapeutic drug monitoring is needed. Trough levels are most useful, aiming for 5–10 mg/L. With normal renal function the level should be measured before the fourth dose, but if there are renal problems wait for the result before giving the next dose. Vancomycin causes histamine release, leading to the red man syndrome if given rapidly. Teicoplanin is less nephrotoxic but still requires monitoring in patients with poor renal function or to check that therapeutic concentrations have been achieved.

Tetracyclines

Tetracyclines bind to the 30S subunit of the bacterial ribosome; they interfere with protein synthesis and are bacteriostatic. Tetracyclines are natural microbial products or semisynthetic derivatives. They are broad-spectrum agents with activity against many commonly encountered Gram-positive and Gram-negative organisms, as well as Chlamydia spp., M. pneumoniae, rickettsia, Coxiella burnetii (Q fever), and the agents of Lyme disease and syphilis. The majority of preparations are for oral administration. In terms of microbiological activity there is little to choose between the various tetracyclines. Use of these agents for the treatment of common bacterial infection has been limited due to the development of resistance, but they are still commonly employed in the treatment of infections caused by chlamydiae, i.e. urethritis, cervicitis and lymphogranuloma venereum. Minocycline, in particular, has also found a role in the treatment of acne and rosacea. In combination with other drugs, tetracyclines can be used for brucellosis. Tetracyclines can also be used to treat syphilis, and in the treatment and prophylaxis of malaria.

• Tetracycline 250–500 mg 4 times daily is also used in some H. pylori eradication regimens if other treatments have failed. Its absorption can be inhibited by chelation with cations in milk, milk products, iron, aluminium, magnesium and zinc.

• Doxycycline is given as 200 mg 1st day, then 100 mg daily orally.

• Minocycline 100 mg twice daily can occasionally cause irreversible pigmentation.

• Demeclocycline hydrochloride is given as 150 mg 6-hourly or 300 mg 12-hourly.

• Lymecycline is given as 408 mg 12-hourly (for at least 8 weeks in acne). Higher doses are used for severe infections.

• Oxytetracycline is given as 250–500 mg 6-hourly.

• Tigecycline 50 mg IV infusion 12-hourly is a glycylcycline agent, structurally related to the tetracyclines. It is a derivative of minocycline. It has a similar mechanism of action to the tetracyclines but remains active against some organisms that are resistant to tetracycline, as well as having activity against MRSA and GRE. It is currently reserved for complicated abdominal and soft-tissue infections caused by multiple antibacterial-resistant organisms.

Side-effects: nausea and photosensitivity are common. Tetracyclines should not be given to children and breast feeding mothers because of deposition in growing bone and teeth, causing yellowing and enamel defects. Demeclocycline can cause reversible nephrogenic diabetes insipidus and acute kidney injury. Hypersensitivity is common.

Quinolones

Quinolones affect bacterial DNA synthesis by inhibiting the action of bacterial topoisomerases. They are bactericidal and are active against Gram-positive and Gram-negative bacteria. Oral and IV preparations are available for most of these agents. MRSA is commonly resistant to the quinolones and there is increasing resistance to many bacteria, as the agents are widely used.

• Ciprofloxacin 250–750 mg twice daily oral, IV infusion 200–400 mg twice daily over 30–60 mins (for severe infections) is active mostly against Gram-negatives and useful for complicated urinary tract infections, gastrointestinal infections and gonorrhoea. It does have some activity against Gram-positive organisms but is not adequate for the treatment of pneumococcal infections. Ciprofloxacin can be used as prophylaxis for close contacts of meningococcal infection and following exposure to Bacillus anthracis.

• Norfloxacin 400 mg twice daily has a similar spectrum of activity but its use has been confined mainly to the treatment of urinary tract infections. For prophylaxis to prevent recurrent urinary infections norfloxacin may be given for up to 12 weeks.

• Ofloxacin 200–400 mg daily is used for urinary tract infections and for gonorrhoea, genital chlamydia and pelvic inflammatory disease. It is also available as a topical agent for the treatment of eye and ear infections.

• Moxifloxacin 400 mg once daily for 5–10 days is used for the treatment of pneumonia caused by β-lactam-resistant pneumococci, sinusitis and chronic bronchitis, and is also playing an increasing role in the treatment of TB, especially multi-drug-resistant TB.

• Levofloxacin 250–750 mg daily for 7–10 days; infusion 50 mg once to twice daily given over 60 mins is active against Gram-positive and Gram-negative organisms, and is used as second-line therapy in community-acquired pneumonia.

• Nalidixic acid 900 mg 6-hourly for 7 days was the first quinolone and is used in urinary tract infections only.

Gastrointestinal side-effects include nausea, vomiting, abdominal pain and diarrhoea; skin problems include rash, pruritus and, rarely, toxic epidermal necrolysis; neurological disturbances include headaches, drowsiness and dizziness, particularly in the elderly and confused. Prolongation of the QT interval occurs, particularly with moxifloxacin and levofloxacin, and these should not be used in patients taking class I or III anti-arrhythmics. Nalidixic acid should not be used in porphyria. There is an age-related tendon inflammation/rupture and those with tendonitis or taking corticosteroids should not be given the drug. The young and pregnant/breast feeding women can develop an arthropathy. Patients on these agents are also prone to the development of C. difficile-associated diarrhoea. There are many drug interactions.

Sulphonamides and trimethoprim

• Sulphonamides are bacteriostatic by competitive inhibition of folate synthesis; they have a broad range of activity. However, because of resistance they are now rarely used for treatment of bacterial infections, other than for urinary tract infections in many parts of the world. Sulfadiazine and sulfadoxine are combined with pyrimethamine and used as treatment for the protozoal infections, toxoplasmosis and malaria (p. 35) respectively. Sulfamethoxazole is combined with trimethoprim as co-trimoxazole. Sulfasalazine is a combination of 5-aminosalicylic acid and sulfapyridine and is used in inflammatory bowel disease (p. 157)

• Trimethoprim is a synthetic diaminopyrimidine drug with a broad range of bactericidal activity against Gram-positive and Gram-negative bacteria, but not anaerobes. It exerts its action by inhibiting bacterial dihydrofolate reductase, an enzyme required for folate synthesis. It is mostly used for the treatment of urinary tract infections and respiratory tract infections (200 mg 12-hourly).

• Co-trimoxazole is a combination of trimethoprim and sulfamethoxazole, and is bactericidal. It is available orally 960 mg 12-hourly. It can also be given by IV infusion 980 mg, rising to 1.44 g 12-hourly in severe infections. It penetrates the tissues well, including the CNS, bone and prostate. Its use for bacterial infections should be limited to treatment of nocardiosis, Whipple’s disease, some atypical mycobacterial infections, and infections with Stenotrophomonas maltophilia. Co-trimoxazole has a major role in the treatment and prophylaxis of Pneumocystis pneumonia in HIV infection (p. 112). However, since HAART therapy, its use has declined. Side-effects include nausea, vomiting, headache and a variety of rashes. Prolonged use causes folate deficiency and megaloblastic anaemia. Stevens–Johnson syndrome, toxic epidermolysis and blood dyscrasias (e.g. thrombocytopenia) preclude its common usage. Avoid in elderly patients, as deaths have been reported.

Nitroimidazoles

• Metronidazole 500 mg 3 times daily orally or by IV infusion is active against anaerobic bacteria and some protozoa. Its antibacterial effect works by breaking or causing destabilization of DNA. Metronidazole has no activity against aerobic bacteria and is used for the treatment of suspected or proven anaerobic infections, e.g. abdominal or dental infections and brain abscesses. It is also used for C. difficile-associated diarrhoea, bacterial vaginosis and tetanus, and in combination with other drugs for the eradication of H. pylori. It has a major use as prophylaxis for abdominal surgery, and is also used for the treatment of protozoal infections, e.g. amoebiasis (p. 136) and Giardia (p. 136). A topical formulation is useful for reducing the odour caused by anaerobic infection of ulcers.

• Tinidazole 500 mg twice daily has a longer half-life than metronidazole but is used similarly.

Side-effects are vomiting, a metallic taste in the mouth and a peripheral neuropathy after prolonged use. There is also a disulfiram-like reaction with alcohol. Both drugs enhance the anticoagulant effect of warfarin.

Chloramphenicol

Chloramphenicol orally or by IV infusion 50 mg/kg in 4 divided doses inhibits protein synthesis by binding to the 50S subunit. It is well absorbed and used for life-threatening infections. It has a broad spectrum of activity against many Gram-positive and Gram-negative bacteria, including anaerobes. It is now rarely given systemically but is still used occasionally for the treatment of brain abscesses, typhoid and some complicated respiratory tract infections or meningitis, when other agents are not suitable. A topical preparation is very useful for the treatment of eye and ear infections.

Side-effects can be serious and include irreversible aplastic anaemia, limiting its use. Gastrointestinal (nausea, vomiting, diarrhoea) and neurological (peripheral neuropathy, optic neuritis, headaches, depression) side-effects occur.

Fusidic acid

Sodium fusidate 500 mg 3 times daily orally or IV inhibits bacterial protein synthesis and is bacteriostatic. It is active predominantly against Gram-positive organisms, and Staph. aureus in particular. If used as a single agent resistance can develop and therefore it should always be combined with another drug when treating serious staphylococcal infection such as osteomyelitis or infective endocarditis. The oral preparation, sodium fusidate, is well absorbed and is less likely to cause disturbance of liver function than the IV fusidic acid. The oral suspension of fusidic acid is less well absorbed and therefore higher doses are required. Topical preparations can also be used for skin infections and eye infections, although there are concerns over the development of resistance.

Side-effects include occasional hepatic toxicity.

Oxazolidinone

Linezolid oral 600 mg 12-hourly for 10–14 days or IV infusion over 30–120 mins is one of the newest antibacterial agents. It inhibits protein synthesis by binding to the bacterial 50S ribosomal subunit at its interface with the 30S subunit. It is bacteriostatic. It is active against Gram-positive infections only. Its use should be reserved for multi-resistant Gram-positive infections, such as those caused by MRSA or GRE. Oral and IV preparations are available.

Side-effects: diarrhoea, nausea, vomiting, taste disturbances and tongue discoloration occur. Linezolid is a reversible non-selective monoamine oxidase inhibitor and thus has many potential drug interactions. Patients treated for over 28 days are also at risk of developing thrombocytopenia, anaemia, leucopenia and severe optic neuropathy (patients should report eye symptoms immediately).

Polymyxins

These are cyclic peptides that are active against Gram-negative bacteria only. They disrupt bacterial cell membranes and are bactericidal. Polymyxin B and colistin (polymyxin E) are the two agents in use. Neither is absorbable as an oral drug. Polymyxin B is mainly used topically for ear infections. Colistin is also used topically for ear infections but is also available as an IV preparation (slow IV infusion 1–2 million U 8-hourly). Because of toxicity, this is reserved for infections when other agents cannot be used, e.g. multiple-resistant Acinetobacter. Nebulized colistin is also used for treatment of cystic fibrosis infections. Colistin can be given orally 1.5–3 million U 8-hourly, in combination with other drugs, for gastrointestinal decontamination in neutropenic patients and in some patients on the ICU.

Side-effects are dose-related neuro- and nephrotoxicity and polymyxins should not be given with aminoglycosides or other nephrotoxic agents.

Other antibiotics

• Clindamycin is given as 150 mg 6-hourly up to 450 mg 6-hourly in severe infections; IV infusion 0.6–2.7 g daily in 2–4 divided doses. The mode of action is similar to that of the macrolides. Clindamycin is active against Gram-positive bacteria, in particular Staph. aureus and streptococci, as well as having good activity against anaerobes. It is used mainly in the treatment of bone and joint infections, serious Streptococcus pyogenes infections and mixed infections where anaerobes are suspected. Topical clindamycin can be used for the treatment of bacterial vaginosis. The major side-effect is C. difficile diarrhoea, which limits its usage. It also causes rashes, nausea, vomiting and abnormal liver biochemistry.

• Streptogrammins inhibit protein synthesis as a result of binding to the 50S subunit of the bacterial ribosome and interfering with transfer RNA function. They are bacteriostatic. Quinupristin and dalfopristin are given together and are active mostly against Gram-positive organisms, with the exception of Enterococcus faecalis. Use is limited to treatment of infections caused by MRSA or vancomycin-resistant enterococci (VRE) (not E. faecalis). They do not cross the blood–brain barrier. The combined drugs (7.5 mg/kg IV 8-hourly) must be given by IV infusion via a central line. Virginiamycin and pristinamycin are other drugs in this class. Side-effects include nausea, diarrhoea, myalgia and arthralgia.

• Rifamycins include rifampicin (p. 87), which has a wide spectrum of activity against Gram-positive and Gram-negative bacteria, and even some protozoa and viruses. However, its main role is as an antituberculous agent. This drug is sometimes used in combination with others for the treatment of brucellosis and also serious infections caused by Staph. aureus, including MRSA. It is also used as prophylaxis in close contacts of meningococcal and invasive H. influenzae type b infections.

• Daptomycin 4 mg/kg IV infusion daily is a lipopeptide with activity against Gram-positive bacteria similar to vancomycin. It is bactericidal as a result of disrupting the bacterial cell membrane potential. It is used for complicated skin and soft-tissue infections, and for infections caused by multiple-resistant bacteria such as MRSA and VRE. Side-effects are gastrointestinal disturbances (nausea, vomiting, diarrhoea and occasionally abdominal pain and constipation), and hepatic and renal impairment. Myalgia, muscle weakness and myositis are uncommon but the creatine phosphokinase should be monitored. Daptomycin interferes with the assay for the prothrombin time.

• Nitrofurans include nitrofurantoin 50 mg 3 times daily, the only commonly used antibacterial of this group. It has activity against a wide variety of bacteria but is used almost exclusively as an oral preparation for the treatment and prevention of urinary tract infections. Proteus spp. and P. aeruginosa are resistant. Side-effects include nausea, brown urine and, rarely, pulmonary complications (e.g. pneumonitis and fibrosis) and peripheral neuropathy.

• Methenamine 1 g 12-hourly orally for 3 weeks at a time is converted to formaldehyde in acidic urine in the bladder and is used for lower urinary tract infections. Side-effects include dysuria and haematuria; the drug is contraindicated in glaucoma and renal impairment.