There is no general agreement as to whether chemotherapy should be employed in mild sporadic sore throat, and expert reviews reflect this diversity of opinion.^1,^2,³ The disease usually subsides in a few days, septic complications are uncommon and rheumatic fever rarely follows. It is reasonable to withhold penicillin unless streptococci are cultured or the patient develops a high fever: some primary care physicians take a throat swab and give the patient a WASP prescription for penicillin which is only filled if streptococci are isolated. Severe sporadic or epidemic sore throat is likely to be streptococcal and the risk of these complications is limited by phenoxymethylpenicillin by mouth (clarithromycin or an oral cephalosporin in the penicillin-allergic), given, ideally, for 10 days, although compliance is bad once the symptoms have subsided and 5 days should be the minimum objective. Azithromycin (500 mg daily p.o.) for 3 days is effective as long as the streptococci are susceptible, with improved compliance, and 5-day courses of oral cephalosporins are as effective as 10 days of penicillin. Do not use amoxicillin if the circumstances suggest pharyngitis due to infectious mononucleosis, as the patient is very likely to develop a rash (see p. 176). In a closed community, chemoprophylaxis of unaffected people to stop an epidemic may be considered, for instance with oral phenoxymethylpenicillin 125 mg 12-hourly.

In scarlet fever and erysipelas, the infection is invariably streptococcal (Group A), and benzylpenicillin should be used even in mild cases, to prevent rheumatic fever and nephritis.

Chemoprophylaxis

Chemoprophylaxis of streptococcal (Group A) infection with phenoxymethylpenicillin is necessary for patients who have had one attack of rheumatic fever. Continue for at least 5 years or until aged 20 years, whichever is the longer period (although some hold that it should continue for life). Chemoprophylaxis should be continued for life after a second attack of rheumatic fever. A single attack of acute nephritis is not an indication for chemoprophylaxis. Ideally, chemoprophylaxis should continue throughout the year but, if the patient is unwilling to submit to this, cover at least the colder months (see also footnote p. 167).

Adverse effects

are uncommon. Patients taking penicillin prophylaxis are liable to have penicillin-resistant viridans type streptococci in the mouth, so that during even minor dentistry, e.g. scaling, there is a risk of bacteraemia and thus of infective endocarditis with a penicillin-resistant organism in those with any residual rheumatic heart lesion. Patients taking penicillins are also liable to be carrying resistant staphylococci and pneumococci.

Other causes of pharyngitis

Infection of the bronchi, lungs and pleura

Bronchitis

Most cases of acute bronchitis are viral; where bacteria are responsible, the usual pathogens are Streptococcus pneumoniae and/or Haemophilus influenzae. It is questionable whether there is a role for antimicrobials in uncomplicated acute bronchitis, but amoxicillin, a tetracycline or trimethoprim is appropriate if treatment is considered necessary. Whether newer antimicrobials, e.g. moxifloxacin, confer significant outcome advantages to justify their expense is debatable.

In chronic bronchitis,

suppressive chemotherapy with amoxicillin or trimethoprim may be considered during the colder months (in temperate, colder regions), for patients with symptoms of pulmonary insufficiency, recurrent acute exacerbations or permanently purulent sputum.

For intermittent therapy,

the patient is given a supply of the drug and told to take it in full dose at the first sign of a ‘chest’ cold, e.g. purulent sputum, and to stop the drug after 3 days if there is rapid improvement. Otherwise, the patient should continue the drug until recovery takes place. If the exacerbation lasts for more than 10 days, there is a need for clinical reassessment.

Pneumonias

The clinical setting is a useful guide to the causal organism and hence to the ‘best guess’ early choice of antimicrobial. It is not possible reliably to differentiate between pneumonias caused by ‘typical’ and ‘atypical’ pathogens on clinical grounds alone and most experts advise initial cover for both types of pathogen in seriously ill patients. However, there is no strong evidence that adding ‘atypical’ cover to empirical parenteral treatment with a β-lactam antibiotic improves the outcome. Published guidelines often recommend hospital admission and parenteral and broader-spectrum therapy for the most severely affected patients as assessed by the ‘CURB-65’ score (one point is scored for each of Confusion, elevated serum Urea, Respiratory rate > 30 breaths per minute, low Blood pressure, and age of 65 or above). Delay of 4 hours or more in commencing effective antibiotics in the most seriously ill patients is associated with increased mortality.

Pneumonia in previously healthy people (community acquired)

Disease that is segmental or lobar

in its distribution is usually due to Streptococcus pneumoniae (pneumococcus). Haemophilus influenzae is a rare cause in this group, although it more often leads to exacerbations of chronic bronchitis and does cause pneumonia in patients infected with HIV. Benzylpenicillin i.v. or amoxicillin or clarithromycin p.o. are the treatments of choice if pneumococcal pneumonia is very likely; use clarithromycin, doxycycline or moxifloxacin in a penicillin-allergic patient. Seriously ill patients should receive benzylpenicillin (to cover the pneumococcus) plus ciprofloxacin (to cover Haemophilus and ‘atypical’ pathogens), and co-amoxiclav plus clarithromycin is an alternative that may have a lower propensity to promote Clostridium difficile diarrhoea. Where penicillin-resistant pneumococci are common, i.v. cefotaxime is a reasonable ‘best guess’ choice pending confirmation of susceptibilities from the laboratory, with vancomycin as an alternative. A wide variety of new antibiotics is under investigation for use in penicillin-resistant pneumococcal infections, including cephalosporins, e.g. ceftobiprole, penicillin relatives, e.g faropenem, quinolones, glycopeptides, e.g. oritavancin, and ketolides, e.g. cethromycin.

Pneumonia following influenza

is often caused by Staphylococcus aureus, and ‘best guess’ therapy usually involves adding flucloxacillin to one of the regimens above. When staphylococcal pneumonia is proven, sodium fusidate or rifampicin p.o. plus flucloxacillin i.v. should be used in combination. Staphylococcal pneumonia that involves strains producing Panton-Valentine leucocidin toxin is frequently necrotising in nature, and linezolid or clindamycin have been shown to reduce toxin production at the ribosomal level so are recommended for inclusion when this condition is suspected.

‘Atypical’ cases

of pneumonia may be caused by Mycoplasma pneumoniae or more rarely Chlamydia pneumoniae or psittaci (psittacosis/ornithosis), Legionella pneumophila or Coxiella burnetii (Q fever), and doxycycline or clarithromycin should be given by mouth. Treatment of ornithosis should continue for 10 days after the fever has settled, and that of mycoplasma pneumonia and Q fever for 3 weeks to prevent relapse.

At an early stage (i.e. at 24–48 h),

once there is clinical improvement, i.v. administration should change to oral.

Pneumonia acquired in hospital

Pneumonia is usually defined as being nosocomial

(Greek: nosokomeian, hospital) if it presents after at least 48 h in hospital. It occurs primarily among patients admitted with medical problems or recovering from abdominal or thoracic surgery and those who are on mechanical ventilators. The common pathogens are Staphylococcus aureus, Enterobacteriaceae, Streptococcus pneumoniae, Pseudomonas aeruginosa and Haemophilus influenzae, and anaerobes after aspiration. Mild cases can be given co-amoxiclav unless they are known to be colonised with resistant bacteria, but for severe cases it is reasonable to initiate therapy with piperacillin-tazobactam (plus vancomycin if the local prevalence of MRSA is high) pending the results of sputum culture and susceptibility tests. Vancomycin or teicoplanin are equally effective for MRSA pneumonia as linezolid, and have an overall lower rate of adverse reactions.

Pneumonia in people with chronic lung disease

Normal commensals

of the upper respiratory tract proliferate in damaged lungs especially following virus infections, pulmonary congestion or pulmonary infarction. Antibiotics should not be given to patients who do not demonstrate two or more of increased dyspnoea, sputum volume and sputum purulence. Mixed infection is common, and as Haemophilus influenzae and Streptococcus pneumoniae are often the pathogens, amoxicillin or trimethoprim is a reasonable choice in domiciliary practice; if response is inadequate, co-amoxiclav or a quinolone should be substituted, but there is no evidence that they are superior first line to the older choices.

Klebsiella pneumoniae

is a rare cause of lung infection (Friedlander’s pneumonia) in the alcoholic and debilitated elderly. Cefotaxime or piperacillin-tazobactam, possibly plus an aminoglycoside, is recommended.

Moraxella

(previously Branhamella) catarrhalis, a commensal of the oropharynx, may be a pathogen in patients with chronic bronchitis; because many strains produce β-lactamase, co-amoxiclav or clarithromycin is used.

Pneumonia in immunocompromised patients

Pneumonia is common, e.g. in acquired immune deficiency syndrome (AIDS) or in those who are receiving immunosuppressive drugs.

Common pathogenic bacteria may be responsible (Staphylococcus aureus, Streptococcus pneumoniae), but often organisms of lower natural virulence (Enterobacteriaceae, viruses, fungi) are causal and necessitate strenuous efforts to identify the microbe including, if feasible, bronchial washings or lung biopsy.

• Until the pathogen is known the patient should receive broad-spectrum antimicrobial treatment, such as an aminoglycoside plus ceftazidime.

• Aerobic Gram-negative bacilli, e.g. Enterobacteriaceae, Klebsiella spp., are pathogens in half of the cases, especially in neutropenic patients, and respond to piperacillin-tazobactam or ceftazidime. These and Pseudomonas aeruginosa may respond better with addition of an aminoglycoside.

• The fungus Pneumocystis carinii is an important respiratory pathogen in patients with deficient cell-mediated immunity; treat with co-trimoxazole 120 mg/kg daily by mouth or i.v. in two to four divided doses for 14 days, as modified by serum assay, or with pentamidine (see p. 236).

Legionnaires’ disease

Legionella pneumophila responds to erythromycin 4 g/day i.v. in divided doses, or clarithromycin, with the addition of rifampicin in more severe infections. Ciprofloxacin is probably a little more effective, although at the expense of a higher risk of adverse reactions.

Pneumonia due to anaerobic microorganisms

Pneumonia often follows aspiration of material from the oropharynx, or accompanies other lung pathology such as pulmonary infarction or bronchogenic carcinoma. In addition to conventional microbial causes, pathogens include anaerobic and aerobic streptococci, Bacteroides spp. and Fusobacterium. Co-amoxiclav or piperacillin-tazobactam may be needed for several weeks to prevent relapse.

Pulmonary abscess: treat the identified organism and employ aspiration or formal surgical drainage if necessary.

Empyema: aspiration or drainage is essential, followed by antibiotic treatment of the isolated organism.

Endocarditis

When there is suspicion, two or three blood cultures should be taken over a few hours and antimicrobial treatment commenced, to be adjusted later in the light of the results. Delay in treating only exposes the patient to the risk of grave cardiac damage or systemic embolism. Streptococci, enterococci and staphylococci are causal in 80% of cases, with viridans group streptococci having recently been overtaken by Staphylococcus aureus as the most common pathogens. In intravenous drug users, Staphylococcus aureus is particularly likely, although the potential list of pathogens is extensive in this group. Culture-negative endocarditis (in 8–10% of cases in contemporary practice) is usually due to previous antimicrobial therapy or to special culture requirements of the microbe; it is best regarded as being due to streptococci and treated accordingly.

Endocarditis on prosthetic valves presenting in the first few months after the operation usually involves Staphylococcus aureus, coagulase-negative staphylococci or Gram-negative rods. The infecting flora then becomes progressively more characteristic of native valve infections as time progresses.

Principles for treatment

• Use high doses of bactericidal drugs because the organisms are difficult to access in avascular vegetations on valves.

• Give drugs parenterally and preferably by i.v. bolus injection to achieve the necessary high peak concentration to penetrate the vegetations.

• Examine the infusion site daily and change it regularly to prevent opportunistic infection, which is usually with coagulase-negative staphylococci or fungi. Alternatively, use a central subclavian venous catheter.

• Continue therapy, usually for 2–4 weeks, and, in the case of infected prosthetic valves, 6 weeks. Prolonged courses may also be indicated for patients infected with enterococci or other strains with penicillin minimum inhibitory concentrations (MICs) above 0.5 mg/L, whose presenting symptoms have been present for over 6 weeks, for those with large vegetations, and those whose clinical symptoms and signs are slow to settle after treatment has started. Highly susceptible streptococcal endocarditis (penicillin MIC of 0.1 mg/L or below) can be treated successfully with 2 week courses.

• Valve replacement may be needed at any time during and after antibiotic therapy if cardiovascular function deteriorates or the infection proves impossible to control.

• Adjust the dose according to the sensitivity of the infecting organism – use the minimum inhibitory concentration test (MIC: see p. 163).

Dose regimens

The following regimens are commonly recommended (the reader is referred to the British Society for Antimicrobial Chemotherapy treatment guidelines 2006; currently under review, the European Society of Cardiology (2009) or to other published references for detailed advice):

1. Initial (‘best guess’) treatment should comprise benzylpenicillin (7.2 g i.v. daily in six divided doses), plus gentamicin (1 mg/kg body-weight 8-hourly – synergy allows this dose of gentamicin and minimises risk of adverse effects). Regular serum gentamicin assay is vital: trough concentrations should be below 1 mg/L and peak concentrations 3–5 mg/L; if Staphylococcus aureus is suspected, high-dose flucloxacillin plus rifampicin should be used. Patients allergic to penicillin and those with intracardiac prostheses or suspected MRSA infection should receive vancomycin plus rifampicin plus gentamicin. Patients presenting acutely (suggesting infection with Staphylococcus aureus) should receive flucloxacillin (8–12 g/day in four to six divided doses) plus gentamicin.

2. When an organism is identified and its sensitivity determined:

• Viridans group streptococci: the susceptibility of the organism determines the antimicrobial(s) and its duration of use, ranging from benzylpenicillin plus gentamicin for 2 weeks, to vancomycin plus gentamicin for 6 weeks. Patients with uncomplicated endocarditis caused by very sensitive strains may be managed as outpatients; for these patients ceftriaxone 2 g/day for 4 weeks may be suitable.

• Enterococcus faecalis (Group D): ampicillin 2 g 4-hourly or benzylpenicillin 2.4 g 4-hourly plus gentamicin 1 mg/kg 8–12-hourly i.v. for 4–6 weeks. The prolonged gentamicin administration carries a significant risk of adverse drug reactions, but is essential to assure eradication of the infection. Streptococci from endocarditis are checked for high-level gentamicin resistance (MIC above 128 mg/L) because cidal synergy is not seen with β-lactams in such strains. Alternative regimens for such infections include ampicillin plus streptomycin (if not similarly high-level resistant) or high-dose ampicillin alone.

• Staphylococcus aureus: flucloxacillin 2 g 4–6-hourly i.v. for at least 4 weeks. In the presence of intracardiac prostheses, flucloxacillin is combined with rifampicin orally (or fusidic acid) for at least the first 2 weeks, and MRSA may be treated with vancomycin plus rifampicin plus fusidic acid (or gentamicin) for 4–6 weeks.

• Staphylococcus epidermidis infecting native heart valves is managed as for Staphylococcus aureus if the organism is sensitive.

• Coxiella or Chlamydia: give doxycycline 100 mg once daily orally, plus ciprofloxacin 500 mg 8-hourly for at least 3 years. Valve replacement is advised in many cases.

• Fungal endocarditis: amphotericin plus flucytosine has been used, although experience is growing with the new azoles and echinocandins, and specialist advice should be sought. Valve replacement is usually essential.

• Culture-negative endocarditis: benzylpenicillin plus gentamicin i.v. are given for 4–6 weeks.

Prophylaxis

Transient bacteraemia is provoked by dental procedures that induce gum bleeding, surgical incision of the skin, instrumentation of the urinary tract and parturition. However, even seemingly innocent activities such as brushing the teeth result in bacteraemia and are lifelong risks, whereas medical interventions are usually single. Adding this to the fact that even single antibiotic doses carry inevitable risks and the evidence base for their efficacy is lacking, expert working parties have re-evaluated the traditional wisdom of advocating prophylactic antibiotics for many procedures in patients with acquired or congenital heart defects.

If used, the drugs are given as a short course in high dose at the time of the procedure to coincide with the bacteraemia and avoid emergence of resistant organisms. The following recommendations on antimicrobial prophylaxis are based on those published in 2006 by the British Society for Antimicrobial Chemotherapy (see Guide to further reading); they are abbreviated and not every contingency is covered. The guidelines are based on a careful assessment of the risks of bacteraemia and reported cases of endocarditis after each procedure. Other national working parties may recommend different measures, and the physician should consult special sources and their local microbiologist, and exercise a clinical judgement that relates to individual circumstances. All oral drugs should be taken under supervision.

Adults who are not allergic to penicillins and who have not taken penicillin more than once in the previous month (including those with a prosthetic valve) require amoxicillin 3 g by mouth 1 h before the procedure.

Patients allergic to penicillins or who have taken penicillin more than once in the previous month should receive clindamycin 600 mg by mouth 1 h before the procedure. Azithromycin 500 mg is an alternative, available as a suspension for those unable to swallow capsules. If parenteral prophylaxis is required, use amoxicillin 1 g i.v. or clindamycin 300 mg i.v.

Patients having a series of separate procedures all requiring prophylaxis should receive amoxicillin or clindamycin alternately. Where practicable, a preoperative mouthwash of the antiseptic chlorhexidine gluconate (0.2%) should be used to reduce oral bacterial numbers.

Consult the guideline publication (above) for prophylactic regimens for children and other procedures, including instrumentation of the urogenital or gastrointestinal tracts, which are now recognised to carry a greater risk of endocarditis than dental procedures.

Meningitis

Speed of initiating treatment and accurate bacteriological diagnosis are the major factors determining the fate of the patient, especially with invasive meningococcal disease where fulminant meningococcal septicaemia still carries a 20–50% mortality rate (and supporting the circulation in the intensive care unit is as important a determinant of outcome as the rapid commencement of antibiotic therapy). With suspected meningococcal disease, unless the patient has a history of penicillin anaphylaxis, benzylpenicillin should be started by the general practitioner before transfer to hospital; the benefit of rapid treatment outweighs the reduced chance of identifying the causative organism. Molecular diagnostic methods such as the polymerase chain reaction (PCR) for bacterial DNA in CSF or blood enable rapid diagnosis even when the causative organisms have been destroyed by antibiotics.

Drugs must be given i.v. in high dose

The regimens below provide the recommended therapy, with alternatives for patients allergic to first choices, and septic shock requires appropriate management (see p. 191). Intrathecal therapy is now considered unnecessary (except for neurosurgical infections in association with indwelling CSF drains and shunts) and can be dangerous, e.g. encephalopathy with penicillin.

Initial therapy

Initial therapy should be sufficient to kill all pathogens, which are likely to be:

All ages over 5 years

For Neisseria meningitidis and Streptococcus pneumoniae, give benzylpenicillin 2.4 g 4-hourly followed, in the case of Neisseria meningitidis, by rifampicin for 2 days prior to discharge from hospital (to eradicate persisting organisms). Some prefer cefotaxime 2–3 g 6–8-hourly or ceftriaxone 2 g i.v. 12-hourly in all cases pending the results of susceptibility tests, and this may be generally preferred depending upon the local prevalence of penicillin resistance. In such cases, in elderly, pregnant or immunocompromised patients it is prudent to add amoxicillin initially to cover the possibility of listeria involvement. Optimal therapy for known or suspected penicillin-resistant pneumococcal meningitis comprises ceftriaxone 2 g i.v. 12-hourly plus vancomycin 15 mg/kg i.v. 12-hourly plus rifampicin 300 mg i.v. 12-hourly.

Children under 5 years

Neisseria meningitidis is now commonest and Haemophilus influenzae, formerly a frequent pathogen, is much less often isolated following immunisation programmes. Streptococcus pneumoniae is also less common than in older patients. Give a cephalosporin, e.g. ceftriaxone.

Neonates

For Escherichia coli, give cefotaxime or ceftazidime perhaps with gentamicin. For Group B streptococci, give benzylpenicillin plus gentamicin. Consult a specialist text for details of doses. Add ampicillin if Listeria monocytogenes is suspected.

Dexamethasone given i.v. (0.15 mg/kg 6-hourly for 4 days) and early appears to reduce long-term neurological sequelae, especially sensorineural deafness, in infants and children. In adults there is evidence to support dexamethasone therapy in pneumococcal meningitis, but outcome is not affected in meningitis caused by other pathogens.

Chloramphenicol remains a good alternative for ‘blind’ therapy in patients giving a history of β-lactam anaphylaxis.

Subsequent therapy

Necessarily, i.v. administration should continue until the patient can take drugs by mouth, but whether or when continuation therapy should be oral or i.v. is a matter of debate. Antimicrobials (except aminoglycosides) enter well into the CSF when the meninges are inflamed; relapse may be due to restoration of the blood–CSF barrier as inflammation reduces. The following are recommended (adult doses).

Neisseria meningitidis

Give benzylpenicillin 2.4 g 4-hourly or ceftriaxone 2 g i.v. 12-hourly for a minimum of 5 days.

Streptococcus pneumoniae

Give ceftriaxone 2 g i.v. 12-hourly or benzylpenicillin 2.4 g 4-hourly if the organism is penicillin-sensitive and continue for 10 days after the patient has become afebrile.

Haemophilus influenzae

Give ceftriaxone 2 g i.v. 12-hourly or chloramphenicol 100 mg/kg daily for 10 days after the temperature has settled. Subdural empyema, often presenting as persistent fever, is relatively common after haemophilus meningitis and may require surgical drainage.

Chemoprophylaxis

The three common pathogens (below) are spread by respiratory secretions. Asymptomatic nasopharyngeal carriers seldom develop meningitis but may transmit the pathogens to close personal contacts. Rifampicin by mouth is effective at reducing carriage rates.

Meningococcal meningitis

often occurs in epidemics in closed communities, but also in isolated cases. Patients and close personal contacts should receive rifampicin 600 mg 12-hourly by mouth for 2 days. Single doses of ciprofloxacin (500 mg by mouth) or ceftriaxone (2 g i.m.) are alternatives, the latter of particular value for pregnant women.

Haemophilus influenzae

Pneumococcal meningitis

tends to occur in isolated cases and contacts do not need chemoprophylaxis.

Infection of the intestines

(For Helicobacter pylori, see p. 533)

Both wit and truth are contained in the aphorism that ‘travel broadens the mind but opens the bowels’. Antimicrobial therapy should be reserved for specific conditions with identified pathogens where benefit has been shown; acute diarrhoea can be caused by bacterial toxins in food, dietary indiscretions, anxiety and by drugs as well as by infection. Even if diarrhoea is infective, it may be due to viruses; or, if bacterial, antimicrobial agents may not reduce the duration of symptoms and may aggravate the condition by permitting opportunistic infection and encouraging Clostridium difficile-associated diarrhoea. Maintaining water and electrolyte balance either orally or by i.v. infusion with a glucose–electrolyte solution, and administration of an antimotility drug (except in small children, and those with with bloody, dysenteric stools, and in Clostridium difficile infection), are the mainstays of therapy in such cases (see Oral rehydration therapy, p. 537). Some specific intestinal infections do benefit from chemotherapy:

Campylobacter jejuni

Clarithromycin, azithromycin or ciprofloxacin by mouth eliminates the organism from the stools but is only clinically effective if commenced within the first 24–48 h of the illness and if is the patient is severely affected. Ciprofloxacin resistance has become common in parts of the world (e.g. Thailand).

Shigella

Mild disease requires no specific antimicrobial therapy but toxic shigellosis with high fever should be treated with ciprofloxacin or azithromycin by mouth for 5 days.

Salmonella

Give an antimicrobial for severe salmonella gastroenteritis, or for bacteraemia or salmonella enteritis in an immunocompromised patient. The choice lies between ciprofloxacin, azithromycin or a parenteral cephalosporin: ciprofloxacin resistance is rising in incidence in salmonella (including in S. typhi), especially in the Indian subcontinent.

Typhoid fever

is a generalised infection and requires treatment with 14 days of i.v. ceftriaxone, oral or i.v. ciprofloxacin, or oral azithromycin. Chloramphenicol, amoxicillin or co-trimoxazole are less effective alternatives. Initial parenteral therapy can be switched to oral once the patient has improved and susceptibility of the causative pathogen determined. A longer period of treatment may be required for those who develop complications such as osteomyelitis or abscess.

A carrier state

develops in a few individuals who have no symptoms of disease but who can infect others.⁴ Organisms reside in the biliary or urinary tracts. Ciprofloxacin in high dose by mouth for 3–6 months may be successful for what can be a very difficult problem, requiring investigation for urinary tract abnormalities or even cholecystectomy.

Escherichia coli

is a normal inhabitant of the bowel but some enterotoxigenic strains are pathogenic and are frequently a cause of travellers’ diarrhoea. A quinolone, e.g. ciprofloxacin, azithromycin or the non-absorbable rifampicin-relative rifaximin are alternatives (see Travellers’ diarrhoea, p. 537). Prophylactic use of an antimicrobial is not usual but, should it be deemed necessary, a quinolone or rifaximin is effective.

Verotoxic Escherichia coli (VTEC; O157) may cause severe bloody diarrhoea and systemic effects such as the haemolytic uraemic syndrome (HUS); antibiotic therapy has been shown in some trials to worsen the prognosis. In general, avoid using an antibiotic for bloody diarrhoea unless VTEC has been excluded bacteriologically.

Vibrio cholerae

Death in cholera is due to electrolyte and fluid loss in the stools, and this may exceed 1 L/h. Prompt replacement and maintenance of water and electrolyte balance with i.v. and oral electrolyte solutions is vital. A single dose of doxycycline, given early, significantly reduces the amount and duration of diarrhoea and eliminates the organism from the faeces (thus lessening the contamination of the environment). Ciprofloxacin or a macrolide (clarithromycin or azithromycin) are alternatives for resistant organisms. Oral zinc acetate supplements have been shown modestly to reduce the volume and duration of cholera diarrhoea in combination with antibiotics, probably by improving gut mucosal integrity and function in malnourished patients. Carriers may be treated by doxycycline by mouth in high dose for 3 days.

Suppression of bowel flora

is thought by some to be useful in hepatic encephalopathy. Here, absorption of products of bacterial breakdown of protein (ammonium, amines) in the intestine leads to cerebral symptoms and even to coma. In acute coma, neomycin 6 g daily should be given by gastric tube; as prophylaxis, 1–4 g/day may be given to patients with protein intolerance who fail to respond to dietary protein restriction (see also Lactulose, p. 551).

Selective decontamination

of the gut may reduce the risk of nosocomial infection from gut organisms (including fungi) in patients who are immunocompromised or receiving intensive care (notably mechanical ventilation). The commonest regimen involves combinations of topical non-absorbable (framycetin, colistin, nystatin and amphotericin) and i.v. (cefotaxime) antimicrobials to reduce the number of Gram-negative bacilli and yeasts while maintaining a normal anaerobic flora. Alternatives include using the topical agents alone, or administering oral ciprofloxacin. Selective decontamination should be used with great care in hospitals with a high incidence of multiply resistant bacteria or Clostridium difficile diarrhoea.

Peritonitis

is usually a mixed infection and antimicrobial choice must take account of coliforms and anaerobes, although the need to include cover for the other major component of the bowel flora, streptococci, is less certain. Piperacillin-tazobactam or a combination of gentamicin, benzylpenicillin plus metronidazole, or meropenem alone is usually appropriate, and can be stopped after the patient is clinically improved and their inflammatory markers (e.g. C-reactive protein) have normalised. Short courses of antibiotics (5–7 days) are associated with a good outcome for intestinal perforations that are surgically corrected within a day or two. Surgical drainage of peritoneal collections and abscesses may need to be repeated.

Chemoprophylaxis in surgery

See page 167.

Antibiotic-associated colitis and Clostridium difficile diarrhoea

See page 170.

Traveller’s diarrhoea

See page 537.

Infection of the urinary tract

(Excluding sexually transmitted infections)

Common pathogens include Escherichia coli (commonest in all patient groups), Proteus spp., Klebsiella spp., other Enterobacteriaceae, Pseudomonas aeruginosa, Enterococcus spp. and Staphylococcus saprophyticus.

Patients with abnormal urinary tracts, e.g. renal stones, prostatic hypertrophy, indwelling urinary catheters, are likely to be infected with a more varied and antimicrobial-resistant microbial flora. Identification of the causative organism and of its sensitivity to drugs is important because of the range of organisms and the prevalence of resistant strains.

For infection of the lower urinary tract a low dose may be effective, as many antimicrobials are concentrated in the urine. Infections of the substance of the kidney require the doses needed for any systemic infection. A large urine volume (over 1.5 L/day) and frequent micturition hasten elimination of infection.

Drug treatment of urinary tract infection falls into several categories:

Lower urinary tract infection

This is most commonly seen in young women with normal urinary tracts. Antibiotic treatment shortens the duration of symptoms but may cause adverse reactions, and 20–30% are free of symptoms at 5–7 days even without antibiotics. Initial treatment with co-amoxiclav, an oral cephalosporin (e.g. cefalexin) or trimethoprim, is usually satisfactory. Current resistance rates of 20–50% among common pathogens for trimethoprim and amoxicillin threaten their value for empirical therapy in many parts of the world. Therapy should normally last for 3 days and may need to be altered once the results of bacterial sensitivity are known.

Upper urinary tract infection

Acute pyelonephritis may be accompanied by septicaemia and is usually marked by fever and loin pain. In such patients it is advisable to start with co-amoxiclav i.v. or alternatively gentamicin (perhaps plus amoxicillin) i.v. If oral therapy is considered suitable, co-amoxiclav or ciprofloxacin is recommended for 2 weeks. This is an infection of the kidney substance and so needs adequate blood as well as urine concentrations, although a switch to an oral agent (guided by the results of susceptibility testing) to complete the course is recommended after the patient has clinically improved.

Upper or lower tract infection with extended-spectrum β-lactamase (ESBL) coliform strains has become more common in some locales, even in patients with no prior hospital contact (see page 185). Such bacteria are usually resistant also to ciprofloxacin, parenteral cephalosporins and gentamicin. Parenteral meropenem, ertapenem or amikacin, or oral pivmecillinam or fosfomycin may be effective.

Recurrent urinary tract infection

Attacks following rapidly with the same organism may be relapses and indicate a failure to eliminate the original infection. Attacks with a longer interval between them and produced by differing bacterial types may be regarded as due to reinfection, most often by ascending infection from the perineal skin. Repeated short courses of antimicrobials should overcome most recurrent infections but, if these fail, 7–14 days of high-dose treatment may be given, following which continuous low-dose prophylaxis may be needed with trimethoprim, nitrofurantoin or an oral cephalosporin. There is some evidence that daily ingestion of cranberry juice may reduce the frequency of relapse in women, perhaps by sugars within the juice interfering with adhesion of bacteria to the urinary epithelium. Vesicoureteric reflux (passage of bladder urine back up the ureter to the kidney) accounts for about a third of urinary tract infections in children, and causes progressive renal damage. Long-term oral antibiotic prophylaxis in such patients is modestly effective at reducing symptomatic infections.

Asymptomatic infection (‘asymptomatic bacteriuria’)

This may be found by routine urine testing of pregnant women or patients with known structural abnormalities of the urinary tract. Such infection may explain micturition frequency or incontinence in the elderly. Appropriate antimicrobial therapy should be given, chosen on the basis of susceptibility tests, and normally for 7–10 days. Amoxicillin or a cephalosporin is preferred in pregnancy, although nitrofurantoin may be used if imminent delivery is not likely (see below).

Prostatitis

The commonest pathogens here are Gram-negative aerobic bacilli, although chlamydia may also be involved. A quinolone such as ciprofloxacin is commonly used, although trimethoprim, doxycycline or erythromycin are also effective. Being lipid soluble, these drugs penetrate the prostate in adequate concentration; they may usefully be combined. Response to a single, short course is often good, but recurrence is common and a patient can be regarded as cured only if he has been symptom-free without resort to antimicrobials for a year. Four weeks of oral therapy is often given for recurrent attacks.

Chemoprophylaxis

Chemoprophylaxis is sometimes undertaken in patients liable to recurrent attacks or acute exacerbations of ineradicable infection. It may prevent progressive renal damage in children who are found to have asymptomatic bacteriuria on routine screening. Nitrofurantoin (50–100 mg/day), nalidixic acid (0.5–1.0 g/day) or trimethoprim (100 mg/day) is satisfactory. The drugs are best given as a single oral dose at night.

Tuberculosis of the genitourinary tract

is treated on the principles described for pulmonary infection (see p. 203).

Special drugs for urinary tract infections

General antimicrobials used for urinary tract infections are described elsewhere. A few agents find use solely for infection of the urinary tract:

Nitrofurantoin,

a synthetic antimicrobial, is active against the majority of urinary pathogens except pseudomonads, and has increased in importance recently because it has retained activity against a useful proportion of urinary tract coliforms that have acquired resistance to trimethoprim, oral β-lactams and quinolones. It is well absorbed from the gastrointestinal tract and is concentrated in the urine (t_½ 1 h), but plasma concentrations are too low to treat infection of kidney tissue. Excretion is reduced when there is renal insufficiency, rendering the drug both more toxic and less effective. Adverse effects include nausea and vomiting (much reduced with the macrocrystalline preparation) and diarrhoea. Peripheral neuropathy occurs especially in patients with significant renal impairment, in whom the drug is contraindicated. Allergic reactions include rashes, generalised urticaria and pulmonary infiltration with lung consolidation or pleural effusion. Nitrofurantoin is safe in pregnancy, except near to term (because it may cause neonatal haemolysis), and it must be avoided in patients with glucose-6-phosphate dehydrogenase deficiency (see p. 101).

Nalidixic acid

See page 188.

Pivmecillinam

400 mg p.o. initially, then 200–400 mg p.o. three or four times daily.

Fosfomycin trometamol

3 g p.o. in a single dose.

Genital tract infections

A general account of orthodox literature is given below, but treatment is increasingly the prerogative of specialists, who, as is so often the case, get the best results. Interested readers are referred to specialist texts. Sexually transmitted infections are commonly multiple. Tracing and screening of contacts plays a vital part in controlling spread and reducing re-infection. Recommended treatment regimens vary to some extent among countries, and this is in response to differences in antimicrobial susceptibility of the relevant pathogens and availability of antimicrobial agents.

Gonorrhoea

The problems of β-lactam and quinolone resistance in Neisseria gonorrhoeae infection are increasing (ciprofloxacin resistance rates rose from 2.1% in 2000 to 9.8% in 2002 in England and Wales, reaching over 60% in ethnic white patients in 2009), and selection of a particular drug will depend on sensitivity testing and a knowledge of resistance patterns in different locations. Cefixime and ceftriaxone resistance on testing in vitro are increasing, but not yet to levels that compromise therapeutic efficacy. Effective treatment requires exposure of the organism briefly to a high concentration of the drug. Single-dose regimens are practicable and improve compliance. The following schedules are effective:

Uncomplicated anogenital infections

High-dose cefixime 400 mg by mouth; spectinomycin i.v., or ceftriaxone 250 mg i.m. UK resistance rates for oral ciprofloxacin or ofloxacin are now considered too high for recommendation unless the isolate is known to be susceptible.

Pharyngeal gonorrhoea

responds less reliably, and i.m. ceftriaxone is recommended.

Coexistent infection

Chlamydia trachomatis is frequently present with Neisseria gonorrhoeae; tetracycline by mouth for 7 days or a single oral dose of azithromycin 1 g or ofloxacin 400 mg will treat the chlamydial urethritis.

Non-gonococcal urethritis

The vast majority of cases of urethritis with pus in which gonococci cannot be identified are due to sexually transmitted organisms, usually Chlamydia trachomatis (the most common bacterial sexually-transmitted infection worldwide) and sometimes Ureaplasma urealyticum. Tetracycline for 1 week, or single-dose azithromycin by mouth are effective.

Pelvic inflammatory disease

Several pathogens are usually involved, including Chlamydia trachomatis, Neisseria gonorrhoeae and Mycoplasma hominis, and there may be superinfection with bowel and other urogenital tract bacteria. A combination of antimicrobials is usually required, e.g. ceftriaxone plus doxycycline plus metronidazole i.v. for severe, acute infection where chlamydia involvement is likely, or co-amoxiclav alone for post-partum chorioamnionitis.

Syphilis

Primary and secondary syphilis are effectively treated by a single dose of 2.4 million units (MU) benzathine penicillin i.m. Doxycycline or erythromycin orally for 2 weeks may be used for penicillin-allergic patients, and a single oral dose of 2 g azithromycin appears to have equivalent efficacy. Treponema pallidum is invariably sensitive to penicillin but macrolide resistance has been reported worldwide rarely except in infections in men who have sex with men.

Tertiary syphilis responds to doxycycline for 28 days or to 3 weekly doses of 2.4 MU benzathine penicillin i.m. Neurosyphilis requires higher serum concentrations for cure and should be treated with procaine penicillin 2.4 megaunits i.m. once daily for 17 days with oral probenecid 500 mg four times a day.

Congenital syphilis in the newborn should be treated with benzylpenicillin for 10 days at least. Some advocate that a pregnant woman with syphilis should be treated as for primary syphilis in each pregnancy, in order to avoid all danger to children. Therapy is best given between the third and sixth month, as there may be a risk of abortion if it is given earlier.

Results of treatment

of syphilis with penicillin are excellent. Follow-up of all cases is essential, for 5 years if possible.

The Herxheimer (or Jarisch–Herxheimer) reaction is probably caused by cytokine (mainly tumour necrosis factor) release following massive slaughter of spirochaetes. Presenting as pyrexia, it is common during the few hours after the first penicillin injection; other features include tachycardia, headache, myalgia and malaise, which last for up to a day. It cannot be avoided by giving graduated doses of penicillin. Prednisolone may prevent it and should probably be given if a reaction is specially to be feared, e.g. in a patient with syphilitic aortitis.

Chancroid

The causal agent, Haemophilus ducreyi, normally responds to erythromycin for 7 days or a single dose of ceftriaxone or azithromycin.

Granuloma inguinale

Calymmatobacterium granulomatis infection responds to co-trimoxazole or doxycycline for 2 weeks or a single dose of azithromycin weekly for 4 weeks.

Bacterial vaginosis (bacterial vaginitis, anaerobic vaginosis)

Bacterial vaginosis is a common form of vaginal discharge in which neither Trichomonas vaginalis nor Candida albicans can be isolated and inflammatory cells are not present: it is diagnosed from the characteristic Gram’s stain appearances of a vaginal swab. The condition is associated with overgrowth of several normal commensals of the vagina including Gardnerella vaginalis, Gram-negative curved bacilli and anaerobic organisms, the latter being responsible for the characteristic fishy odour of the vaginal discharge. The condition responds well to a single dose of metronidazole 2 g or 400 mg thrice daily for a week by mouth, with 7 days of topical clindamycin cream offering an alternative.

Candida vaginitis

See page 223.

Trichomonas vaginitis

See page 236.

Infection of bones and joints

Causative bacteria of osteomyelitis may arrive via the bloodstream or be implanted directly (through a compound fracture, chronic local infection of local tissue, or surgical operation). Staphylococcus aureus is the commonest isolate in all patient groups, and Salmonella species in the tropics. Chronic osteomyelitis of the lower limbs (especially when underlying chronic skin infection in the elderly) frequently involves obligate anaerobes (such as Bacteroides spp.) and coliforms.

Strenuous efforts should be made to obtain bone for culture because superficial and sinus cultures are poorly predictive of the underlying flora, and prolonged therapy is required for chronic osteomyelitis (usually 6–8 weeks, sometimes longer). Surgical removal of dead bone improves the outcome of chronic osteomyelitis.

Definitive therapy is guided by the results of culture but commonly used regimens include co-amoxiclav (community-acquired cases in adults), flucloxacillin with or without fusidic acid (for Staphylococcus aureus), cefotaxime or co-amoxiclav (in children), and ciprofloxacin (for coliforms). Short courses of therapy (3–6 weeks) may suffice for acute osteomyelitis, but vertebral body osteomyelitis requires at least 8 weeks’ treatment.

Septic arthritis

is a medical emergency if good joint function is to be retained. Staphylococcus aureus is the commonest pathogen, but a very wide range of bacteria may be involved including streptococci, coliforms and Neisseria spp. Aspiration of the joint allows specific microbiological diagnosis, differentiation from non-infectious causes such as crystal synovitis, and has therapeutic benefit, e.g. for the hip joint, where formal drainage is recommended. Initial therapy is as for chronic osteomyelitis, and continuation guided by culture results for 4–6 weeks is usually required. Switching to oral therapy is often possible with satisfactory progress.

Infection of prosthetic joints may also involve a range of bacteria, but is most commonly staphylococcal. Debridement of the prosthesis and culture of adjacent bone biopsy samples fulfils both therapeutic and diagnostic needs, and prolonged antibiotic therapy guided by culture is successful (with retention of the prosthesis in situ) in 60% of cases or more as long as it is commenced within a few weeks of first presentation of the infection and the prosthesis is stable.

Eye infections

Superficial infections,

caused by a variety of organisms, are treated by chloramphenicol, fusidic acid, framycetin, gentamicin, ciprofloxacin, levofloxacin, ofloxacin or neomycin in drops or ointments. Ciprofloxacin, ofloxacin, levofloxacin, gentamicin or tobramycin is used for Pseudomonas aeruginosa, and fusidic acid principally for Staphylococcus aureus. Preparations often contain hydrocortisone or prednisolone, but the steroid masks the progress of the infection, and should it be applied with an antimicrobial to which the organism is resistant (bacterium or virus) it may aggravate the disease by suppressing protective inflammation. Local chemoprophylaxis without corticosteroid is used to prevent secondary bacterial infection in viral conjunctivitis. A variety of antibiotics may be given by direct injection to the chambers of the eye for treatment of bacterial endophthalmitis.

Chlamydial conjunctivitis

In the developed world, the genital (D–K) serotypes of the organism are responsible, and the reservoir and transmission is maintained by sexual contact. Endemic trachoma in developing countries is usually caused by serotypes A, B and C. In either case, oral tetracycline is effective. Pregnant or lactating women may receive systemic erythromycin. Neonatal ophthalmia responds to systemic erythromycin and topical tetracycline.

Herpes keratitis

See page 217.

Mycobacterial infections

Pulmonary tuberculosis

Nearly one-third of the world’s population is infected with Mycobacterium tuberculosis, and it is the second leading cause of death due to an identified pathogen, after HIV infection. Drug therapy has transformed tuberculosis from a disabling and often fatal disease into one in which almost 100% cure is obtainable, although the recent emergence of multiple drug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) strains and their interaction with HIV infection has disturbed this optimistic view. Chemotherapy was formerly protracted, but a better understanding of the mode of action of antituberculosis drugs and of effective immune reconstitution in HIV infection has allowed the development of shorter-course regimens.

Principles of antituberculosis therapy

• Kill a large number of actively multiplying bacilli: isoniazid achieves this.

• Treat persisters, i.e. semi-dormant bacilli that metabolise slowly or intermittently: rifampicin and pyrazinamide are the most efficacious.

• Prevent the emergence of drug resistance by multiple therapy to suppress single-drug-resistant mutants that may exist de novo or emerge during therapy: isoniazid and rifampicin are best.

• Combined formulations are used to ensure that poor compliance does not result in monotherapy with consequent drug resistance.

Most contemporary regimens employ an initial intensive phase with rifampicin, isoniazid, pyrazinamide with or without ethambutol, to reduce the bacterial load as rapidly as possible (usually for 2 months), followed by a continuation phase with rifampicin and isoniazid given for at least 4 months (Fig. 14.1).

Fig. 14.1 Treatment of drug-sensitive pulmonary and extrapulmonary tuberculosis. Daily supervised treatment is preferred. Intermittent, thrice-weekly treatment administered under direct observation equally effective. Monitor adverse effects (hepatic functions, serum uric acid) periodically.

All short-course regimens include isoniazid, pyrazinamide and rifampicin. After extensive clinical trials, the following have been found satisfactory:

1. An unsupervised regimen of daily dosing comprising isoniazid and rifampicin for 6 months, plus pyrazinamide for the first 2 months.

2. A supervised (directly observed therapy, DOT) regimen for patients who cannot be relied upon to comply with treatment, comprising thrice-weekly dosing with isoniazid and rifampicin for 6 months, plus pyrazinamide for the first 2 months (isoniazid and pyrazinamide are given in higher dose than in the unsupervised regimen). With both of the above regimens, ethambutol by mouth or streptomycin i.m. should be added for the first 2 months if there is a likelihood of drug-resistant organisms, or if the patient is severely ill with extensive active lesions. Ethambutol should not be administered in small children as they are unable to report visual side-effects.

All of the regimens are highly effective, with relapse rates of 1–2% in those who continue for 6 months; even if patients default after, say, 4 months, tuberculosis can be expected to recur in only 10–15%. Drug resistance seldom develops with any of these regimens.

Compliance is often a concern with multiple drug therapy given for long periods, especially in the developing world, and (surprisingly) DOT did improve relapse rates in many trials. Fixed-dose combination therapy is assumed to improve compliance; however, bio-availability of rifampicin remains a matter of concern in fixed-dose combinations; some commonly used fixed-dose combinations include Rifater (rifampicin, isoniazid plus pyrazinamide), and Rifinah or Rimactazid (rifampicin plus isoniazid). In all cases, effective control of tuberculosis in a population requires optimal therapy of index cases combined with careful screening and case finding among their contacts.

Special problems

Drug resistant organisms

Initial drug resistance occurs in about 4% of isolates in the UK, usually to isoniazid. Patients with multiply drug-resistant tuberculosis, i.e. resistant to rifampicin and isoniazid at least, should be treated with three or four drugs to which the organisms are sensitive, and treatment should extend for 12–24 months after cultures become negative (Table 14.1 and Fig. 14.2). Treatment of such cases requires expert management.

Table 14.1 General principles for MDR-TB and XDR-TB drug regimen according to drug-susceptibility testing

Fig. 14.2 Treatment of MDR-TB. The number and category of drugs in the intensive phase may vary according to country’s national programme. Monitor adverse effects (neuropsychiatric, renal, hepatic and thyroid functions) periodically. MDR-TB, multidrug-resistant tuberculosis.

Non-tuberculous mycobacteria are often resistant to standard drugs; their virulence is low but they can produce serious infection in immunocompromised patients which may respond, e.g. to macrolide (clarithromycin), ethambutol or rifabutin, often in combination.

Chemoprophylaxis

may be either:

• primary, i.e. the giving of antituberculous drugs to uninfected but exposed individuals, which is seldom justified, or

• secondary, which is the treatment of infected but symptom-free individuals, e.g. those known to be in contact with the disease and who develop a positive tuberculin reaction. Secondary chemoprophylaxis may be justified in children under the age of 3 years because they have a high risk of disseminated disease; isoniazid alone for 6–9 months may be used as there is little risk of resistant organisms emerging because the organism load is low. Shorter treatment regimens with an alternative drug (rifampicin for 4 months or 3 months) or drug combinations (rifampicin plus isoniazid for 3 months) have better adherence rates. Combined use of rifampicin and pyrazinamide for 2 months in HIV-negative contacts is not recommended as it produces severe drug induced hepatitis.

Pregnancy

Drug treatment should never be interrupted or postponed during pregnancy. On the general principle of limiting exposure of the fetus, the standard three-drug, 6-month course (no. 1 above) is best. Exclude streptomycin from any regimen (danger of fetal eighth cranial nerve damage). Treatment of MDR-TB is not contraindicated during pregnancy. While treating MDR-TB, risks and benefits should be discussed with the mother. Treatment should be started in the second trimester or earlier if the disease is severe; to avoid teratogenic effects drugs should not be administered in the first trimester. Injectables should be avoided. Capreomycin is the injectable of choice in an unavoidable situation but carries the risk of ototoxicity. Ethionamide should be avoided as it aggravates nausea and vomiting and also has teratogenic effects.

Extrapulmonary tuberculosis

The principles of treatment, i.e. multiple therapy and prolonged follow-up, are the same as for pulmonary tuberculosis (see Fig. 14.1). Many chronic tuberculosis lesions may be relatively inaccessible to drugs as a result of avascularity, so treatment frequently has to be prolonged and dosage high, especially if damaged tissue cannot be removed by surgery, e.g. tuberculosis of bones.

Meningeal tuberculosis

It is essential to use isoniazid and pyrazinamide, which penetrate well into the CSF. Rifampicin and streptomycin enter inflamed meninges well, but non-inflamed meninges less so, whereas ethambutol has poor penetration. An effective regimen is isoniazid, rifampicin, pyrazinamide and streptomycin. Treatment may need to continue for much longer (9–12 months) than modern short-course chemotherapy for pulmonary tuberculosis.

Bone and joint tuberculosis

Six to nine months drug regimens containing rifampicin are effective (see Fig. 14.1). Surgery is indicated when chemotherapy fails with evidence of ongoing infection and for relief of cord compression with persistent or recurrent neurological deficits or instability of the spine.

Lymph node tuberculosis

In drug-susceptible lymph node tuberculosis a 6-month regimen is adequate. Affected lymph nodes may enlarge while the patient is on treatment or after the end of treatment without any evidence of mycobacterial relapse (immune reconstitution inflammatory syndrome (IRIS)). Cold abscesses of lymph nodes require needle drainage.

Adrenal steroid and tuberculosis

Corticosteroids are administered in adrenal gland involvement with Addison’s disease, in meningeal and pericardial tuberculosis (see Fig. 14.1).

Tuberculosis in the immunocompromised

Such patients require special measures because they may be infected more readily when exposed; their infections usually involve large numbers of tubercle bacilli (multibacillary disease), and patients with AIDS are more likely to be infected with multiply antibiotic-resistant strains. While treating patients co-infected with HIV and tuberculosis, antituberculosis treatment (ATT) is started first and antiretroviral treatment (ART) is started subsequently. ART-naïve HIV/AIDS patients should be started on ART between 2 weeks and 2 months after anti-TB drugs, depending on CD4 cell counts. Patients already on ART require some modification in treatment; efavirenz should be used in place of nevirapine. Rifabutin should be preferred over rifampicin while using protease inhibitors. Patients while on ART and ATT may develop IRIS (within 3 months of treatment). In this paradoxical reaction, patients initially show some improvement and subsequently reveal either aggravation of existing lesions or appearance of fresh lesions. Development of IRIS does not require stopping of ART and usually non-steroidal anti-inflammatory drugs (NSAIDs) are sufficient. Drug-resistant TB should be ruled out. Usually at least four drugs are started, and patients are isolated until bacteriological results have been obtained and they have shown clinical improvement. If infections are proved to involve antibiotic-susceptible mycobacteria, therapy can continue with a conventional 6-month regimen with careful follow-up. Particular problems may occur with multiple drug interactions during antituberculous treatment of patients receiving antiretroviral therapy.

Antituberculosis drugs

Isoniazid

Isoniazid (INH, INAH, isonicotinic acid hydrazide) is selectively effective against Mycobacterium tuberculosis because it prevents the synthesis of components that are unique to mycobacterial cell walls. Hence it is bactericidal against actively multiplying bacilli (whether within macrophages or at extracellular sites) but is bacteriostatic against non-dividing bacilli; it has little or no activity against other bacteria. Isoniazid is well absorbed from the alimentary tract and is distributed throughout the body water, including CSF. It should always be given in cases where there is special risk of meningitis (miliary tuberculosis and primary infection). Isoniazid is inactivated by conjugation with an acetyl group and the rate of the reaction is bimodally distributed. The t_½ is 1 h in fast and 4 h in slow acetylators; fast acetylators achieve less than half the steady-state plasma concentration of slow acetylators but standard oral doses (300 mg/day) on daily regimens give adequate tuberculocidal concentrations in both groups.

Adverse effects

Isoniazid is in general well tolerated. The most severe adverse effect is liver damage, ranging from a moderate rise in hepatic enzymes to severe hepatitis and death. Liver histology in isoniazid hepatitis is indistinguishable from acute viral hepatitis. It is probably caused by a chemically reactive metabolite(s), e.g. acetylhydrazine. Most cases are in patients aged over 35 years, and develop within the first 8 weeks of therapy; liver function should be monitored monthly during this period at least. High-dose isoniazid (16–20 mg/kg/day) may be useful in DR-TB.

Isoniazid is a structural analogue of pyridoxine and accelerates its excretion, the principal result of which is peripheral neuropathy with numbness and tingling of the feet, motor involvement being less common. Neuropathy is more frequent in slow acetylators, malnourished people, the elderly and those with HIV infection, liver disease, diabetes mellitus and alcoholism, chronic renal failure, malnutrition, pregnant and breast-feeding women. Such patients should receive pyridoxine 10 mg/day by mouth, which prevents neuropathy and does not interfere with the therapeutic effect; some prefer simply to give pyridoxine to all patients. Other adverse effects include mental disturbances, incoordination, optic neuritis and convulsions.

Isoniazid inhibits the metabolism of phenytoin, carbamazepine and ethosuximide, increasing their effect. Ideally, blood levels of these drugs should be monitored (therapeutic drug monitoring).

Rifampicin

Rifampicin has bactericidal activity against the tubercle bacillus, comparable to that of isoniazid. It is also used in leprosy.

It acts by inhibiting RNA synthesis, bacteria being sensitive to this effect at much lower concentrations than mammalian cells; it is particularly effective against mycobacteria that lie semi-dormant within cells. Rifampicin has a wide range of antimicrobial activity. Other uses include leprosy, severe legionnaires’ disease (with erythromycin or ciprofloxacin), the chemoprophylaxis of meningococcal meningitis, and severe staphylococcal infection (with flucloxacillin or vancomycin).

Rifampicin is well absorbed from the gastrointestinal tract. It penetrates most tissues. Entry into the CSF when meninges are inflamed is sufficient to maintain therapeutic concentrations at normal oral doses but transfer is reduced as inflammation subsides in 1–2 months.

Enterohepatic recycling takes place, and eventually about 60% of a single dose is eliminated in the faeces; urinary excretion of unchanged drug also occurs. The t_½ is 4 h after initial doses, but shortens on repeated dosing because rifampicin is a very effective enzyme inducer and increases its own metabolism (as well as that of several other drugs; see below).

Adverse reactions

Rifampicin rarely causes any serious toxicity. Adverse reactions include flushing and itching with or without a rash, and thrombocytopenia. Rises in plasma levels of bilirubin and hepatic enzymes may occur when treatment starts, but are often transient and are not necessarily an indication for stopping the drug; fatal hepatitis, however, has occurred. Hepatic function should be checked before starting treatment and at least for the first few months of therapy. Intermittent dosing, i.e. less than twice weekly, either as part of a regimen or through poor compliance, promotes an influenza-like syndrome (malaise, headache and fever, shortness of breath and wheezing), acute haemolytic anaemia and thrombocytopenia, and acute renal failure sometimes with haemolysis. These may have an immunological basis. Red discoloration of urine, tears and sputum is a useful indication that the patient is taking the drug. Rifampicin also causes an orange discoloration of soft contact lenses.

Interactions

Rifampicin is a powerful enzyme inducer and speeds the metabolism of numerous drugs, including warfarin, steroid contraceptives, narcotic analgesics, oral antidiabetic agents, phenytoin and dapsone. Appropriate increase in dosage, and alternative methods of contraception, are required to compensate for increased drug metabolism (see also paracetamol overdose, p. 246).

Rifabutin

(t_½ 36 h) has similar activity and adverse reactions, and is used for prophylaxis of Mycobacterium avium infection in patients with AIDS, and for treatment of tuberculous and non-tuberculous mycobacterial infection in combination with other drugs. All rifamycins have high levels of cross-resistance. It is preferred over rifampicin when protease inhibitors are used for treating HIV-TB co-infection. Rifabutin and saquinavir should not be used together. Rifabutin and protease inhibitors are costlier drugs; dose reduction of rifabutin is required, as most protease inhibitors are inhibitors of CYP3A4 isoenzyme and significantly reduce clearance of rifabutin. The dose of rifabutin should be increased from 300 mg/day to 450–600 mg/day when it is co-administered with efavirenz. Adverse effects include gastrointestinal intolerance, bone marrow suppression, hepatotoxicity, uveitis and skin discoloration with normal serum bilirubin (pseudojaundice).

Rifaximin

is a semi-synthetic rifamycin that is not absorbed from the gastrointestinal tract (less than 0.4%). Because of the very high faecal concentrations achieved after a 400-mg oral dose (about 8000 micrograms/g faeces), it has broad activity against the common bacterial causes of travellers’ diarrhoea and has proved as effective as an oral quinolone or azithromycin (see p. 537), and adverse effects are rare. Efficacy of rifaximin treatment in acute hepatic encephalopathy is well documented. Its protective effect against breakthrough episodes of hepatic encephalopathy along with lactulose on a long-term basis is being evaluated, as rifaximin has a low risk of inducing bacterial resistance.

Pyrazinamide

Pyrazinamide is a derivative of nicotinamide and is included in first-choice combination regimens because of its particular ability to kill intracellular persisters, i.e. mycobacteria that are dividing or semi-dormant, often within cells. Its action is dependent on the activity of intrabacterial pyrazinamidase, which converts pyrazinamide to the active pyrazinoic acid; this enzyme is most effective in an acidic environment such as the interior of cells. In drug-sensitive tuberculosis it should not be administered beyond 2 months. It is inactive against Mycobacterium bovis. Pyrazinamide is well absorbed from the gastrointestinal tract and metabolised in the liver, very little unchanged drug appearing in the urine (t_½ 9 h). CSF concentrations are almost identical to those in the blood. Pyrazinamide is safe to use in pregnancy.

Adverse effects

include hyperuricaemia and arthralgia, which is relatively frequent with daily but less so with intermittent dosing and, unlike gout, affects both large and small joints. Pyrazinoic acid, the principal metabolite of pyrazinamide, inhibits renal tubular secretion of urate. Symptomatic treatment with a non-steroidal anti-inflammatory drug is usually sufficient and it is rarely necessary to discontinue pyrazinamide because of arthralgia. Incidence of hepatitis which occurred with high doses has decreased with modern short-course schedules, but still requires close clinical and laboratory monitoring. Sideroblastic anaemia and urticaria also occur.

Ethambutol

Ethambutol, being bacteriostatic, is used in conjunction with other antituberculous drugs to delay or prevent the emergence of resistant bacilli. It is well absorbed from the gastrointestinal tract and effective concentrations occur in most body tissues including the lung; in tuberculous meningitis, sufficient may reach the CSF to inhibit mycobacterial growth but insignificant amounts enter CSF if the meninges are not inflamed. Excretion is mainly by the kidney, by tubular secretion as well as by glomerular filtration (t_½ 4 h); the dose should be reduced when renal function is impaired.

Adverse effects

Antituberculosis drug-induced hepatitis

Among the first-line antituberculosis drugs, rifampicin, isoniazid and pyrazinamide are potentially hepatotoxic drugs. Additionally, rifampicin can cause asymptomatic jaundice without evidence of hepatitis. Rifampicin rarely causes hepatitis when administered alone and rifampicin and isoniazid are ~ 3 times less toxic in the absence of pyrazinamide. It is essential to rule out acute viral hepatitis by performing markers for viral hepatitis before diagnosing antituberculosis drug-induced hepatitis in developing nations. Drug-induced hepatitis can be life-threatening if drugs are continued despite its occurrence. All hepatotoxic drugs should be immediately stopped until complete biochemical recovery occurs. In the interim period, ethambutol, streptomycin and one of the fluoroquinolones should be administered. The best approach to reintroducing antituberculosis drugs is still debatable. The approach could be sequential or simultaneous. Some advocate reintroduction of all three drugs one by one as it allows identification of the culprit drug, while others prefer to use rifampicin first followed by isoniazid and if the patient tolerates both drugs avoid pyrazinamide.

Streptomycin

See page 180.

Thiacetazone

Thiacetazone is tuberculostatic and is used with isoniazid to inhibit the emergence of resistance to the latter drug. It is absorbed from the gastrointestinal tract, partly metabolised and partly excreted in the urine (t_½ 13 h). Usual adult dose is 150 mg/day. It is not used in HIV-TB co-infection because of severe cutaneous reactions; Asian patients may have higher incidence of Stevens–Johnson syndrome.

Adverse reactions

include gastrointestinal symptoms, conjunctivitis and vertigo. More serious effects are erythema multiforme, haemolytic anaemia, agranulocytosis, cerebral oedema and hepatitis.

Second-line antituberculosis drugs

Kanamycin and amikacin

Both kanamycin (t_½ 2–4 h) and amikacin (t_½ 2–4 h) are bactericidal drugs of the aminoglycoside class, valuable in patients with resistance to streptomycin. Cross-resistance between kanamycin and amikacin is usual. The optimal dose is 15 mg/kg body-weight, usually 0.75–1.0 g/day i.m. Adverse effects are similar to streptomycin.

Capreomycin

Capreomycin (t_½ 4–6 h) is a bactericidal aminoglycoside derived from Streptomyces capreolus. There is no cross-resistance with other aminoglycosides. The usual dose is 20 mg/kg/day up to 1 g in a single dose daily i.m. for 40–120 days; the dose is then reduced to 2–3 times weekly as the risk of adverse effects increases sharply. Adverse effects are similar to streptomycin. Hypokalaemia, hypocalcaemia and hypomagnesaemia have been reported. Rarely, hepatitis and general cutaneous reactions may occur.

Thioamides

Ethionamide and prothionamide

Ethionamide (t_½ 2–3 h) and prothionamide (t_½ 2–3h) are bactericidal drugs. Their chemical structure resembles thioacetazone and there is frequent partial cross-resistance. The maximum optimum dose is 15–20 mg/kg/day up to 1 g/day and the usual dose is 750 mg/day in patients weighing 50 kg or more (or can be split in two doses: 500 mg in the morning and 250 in the evening) and 500 mg/day in patients weighing < 50 kg. These drugs are more acceptable when administered with orange juice or milk. Adverse reactions include gastrointestinal side-effects, depression, hallucinations, hepatitis, hypothyroidism and peripheral neuropathy. The drugs should be avoided during pregnancy.

Cycloserine and terizidone

Cycloserine (t_½ 10 h) is bacteriostatic at the usual dosage and terizidone is a combination of two molecules of cycloserine. The maximum daily dose is 15–20 mg/kg; the usual dose of cycloserine and terizidone is 500–750 mg/day (250 mg in the morning and 500 mg 12 hours later). Main adverse effects are related to the central nervous system (less with terizidone) and include headache, tremors, insomnia, depression, convulsions, altered behaviour and suicidal tendencies. Addition of pyridoxine (50 mg/250 mg of cycloserine and terizidone is recommended) decreases these adverse effects.

Fluoroquinolones

Ciprofloxacin (t_½ 3–5 h) is no longer recommended to treat drug-susceptible or drug-resistant tuberculosis. The most potent available fluoroquinolones, in descending order, include: moxifloxacin (t_½ 9–10 h) (400 mg/day) or gatifloxacin (t_½ 8 h) (400 mg/day) > levofloxacin (t_½ 6–8 h) (750 mg/day) > ofloxacin (t_½ biphasic: 4–5 h and 20–25 h (accounts for < 5%)) (800 mg/day). Though moxifloxacin and gatifloxacin have equal potency, the latter is not favoured in those with diabetes mellitus because of the risk of hyperglycaemia, hypoglycaemia and new-onset diabetes mellitus. Later-generation fluoroquinolones have some efficacy against ofloxacin-resistant strains and are recommended for the treatment of XDR-TB. Close monitoring is required as safety data on long-term use are limited. Prolonged QT interval occurs with moxifloxacin.

Para-aminosalicylic acid (PAS)

Usual dose of para-aminosalicylic acid (PAS) (t_½ 1 h) is 8–12 g/day in divided doses. Commonly observed adverse effects include gastrointestinal upset, hepatic dysfunction, hypothyroidism; it should be administered cautiously in patients with cardiac and renal insufficiency because of the sodium load.

Leprosy

Effective treatment of leprosy is complex and requires much experience to obtain the best results. Problems of resistant leprosy now require that multiple drug therapy be used and involve:

• For paucibacillary disease: dapsone and rifampicin for 6 months.

• For multibacillary disease: dapsone, rifampicin and clofazimine for 2 years. Follow-up for 4–8 years may be necessary.

Dapsone

is a bacteriostatic sulphone (related to sulphonamides, acting by the same mechanism; see p. 187). It has long been the standard drug for all forms of leprosy. Irregular and inadequate duration of treatment with a single drug has allowed the emergence of primary and secondary resistance to become a major problem. Dapsone is also used to treat dermatitis herpetiformis and Pneumocystis carinii pneumonia, and (with pyrimethamine) for malaria prophylaxis. The t_½ is 27 h. Adverse effects range from gastrointestinal symptoms to agranulocytosis, haemolytic anaemia and generalised allergic reactions that include exfoliative dermatitis.