Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 15) pdf

13 Chemotherapy of bacterial infections SYNOPSIS We live in a world heavily populated by microorganisms of astonishing diversity Most of these exist in our external environment but certain classes are normally harboured within our bodies, especially colonising mucosal surfaces Depending on the circumstances, infectious disease can arise from organisms living exogenously or endogenously, and a knowledge of common pathogens at specific sites often provides a good basis for rational initial therapy This chapter considers the bacteria that cause disease in individual body systems, the drugs that are used to combat them, and how they are best used It discusses infection of: Blood Paransal sinuses and ears Throat Bronchi, lungs and pleura Endocardium Meninges Intestines Urinary tract Genital tract Bones and joints Eye Also mycobacteria, that infect many sites Table I I I (p 21 I) is a general reference for this chapter Infection of the blood Septicaemia is a medical emergency Accurate microbiological diagnosis is of the first importance and blood cultures should be taken before starting antimicrobial therapy Usually, the infecting organism^) is not known at the time of presentation and treatment must be instituted on the basis of a 'best guess' The clinical circumstances may provide some clues Patients who have been in hospital for some time before presenting with septicaemia may need antibiotic regimens that provide more reliable cover for multiply resistant pathogens, and examples of suitable choices are given in the list below in brackets • When septicaemia follows gastrointestinal or genital tract surgery, Escherichia coll (or other Gram-negative bacteria), anaerobic bacteria, e.g Bacteroides, streptococci or enterococci are likely pathogens and the following combinations are effective: cefuroxime plus metronidazole or gentamicin plus benzylpenicillin plus metronidazole (meropenem plus vancomycin) • Septicaemia related to urinary tract infection usually involves Escherichia coli (or other Gramnegative bacteria), enterococci: gentamicin plus benzylpenicillin or cefotaxime alone (ciprofloxacin plus vancomycin) • Neonatal septicaemia is usually due to streptococci or coliforms: benzylpenicillin plus gentamicin 237 13 CHEMOTHERAPY OF BACTERIAL INFECTIONS • Staphylococcal septicaemia may be suspected where there is an abscess, e.g of bone or lung, or with acute infective endocarditis or infection of intravenous catheters: high dose flucloxacillin is indicated (vancomycin) • Toxic shock syndrome occurs in circumstances that include healthy women using vaginal tampons, abortion or childbirth, and occasionally with skin and soft tissue infection The clinical problem is due to systemic effects of toxins produced by staphylococci: while this is not strictly an infection of the blood, flucloxacillin is used to eliminate the source Elimination of the source by removal of the tampon and drainage of abscesses, and circulatory support are also important Antimicrobials should be given i.v initially in septicaemia Infection of paranasal sinuses and ears SINUSITIS Acute infection of the paranasal sinuses causes significant morbidity Since oedema of the mucous membrane hinders the drainage of pus, a logical first step is to open the obstructed passage with a sympathomimetic vasoconstrictor, e.g ephedrine nasal drops Antibiotic therapy produces limited additional clinical benefit, but the common infecting organism—Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes, Moraxella (Branhamella) catarrhalis—usually respond to oral amoxicillin (with or without clavulanic acid) or doxycycline, if the case is serious enough to warrant antibiotic therapy In chronic sinusitis, correction of the anatomical abnormalities (polypi, nasal septum deviation) is often important Very diverse organisms, many of them normal inhabitants of the upper respiratory tract, may be cultured, e.g anaerobic streptococci, Bacteroides spp., and a judgement is required as to whether any particular organism is acting as a pathogen Choice of antibiotic should be guided by culture and sensitivity testing; therapy may need to be prolonged 238 OTITIS MEDIA Mild cases, characterised by pinkness or infection of the eardrum, often resolve spontaneously and need only analgesia and observation They are normally viral A bulging, inflamed eardrum indicates bacterial otitis media usually due to Streptococcus pneumoniae, Haemophilus influenzae, Moraxella (Branhamella) catarrhalis, Streptococcus pyogenes (Group A) or Staphylococcus aureus Amoxicillin or co-amoxiclav is satisfactory, but the clinical benefit of antibiotic therapy is very small when tested in controlled trials Chemotherapy has not removed the need for myringotomy when pain is very severe, and also for later cases, as sterilised pus may not be completely absorbed and may leave adhesions that impair hearing Chronic infection presents a similar problem to that of chronic sinus infection, above Infection of the throat Pharyngitis is usually viral but the more serious cases may be caused by Streptococcus pyogenes (Group A) which is always sensitive to benzylpenicillin Unfortunately, streptococcal sore throats cannot be clinically differentiated from non-streptococcal with any certainty Prevention of complications is more important than relief of the symptoms which seldom last long There is no general agreement whether chemotherapy should be employed in mild sporadic sore throat and expert reviews on the subject reflect the resulting diversity of clinical views.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 Severe sporadic or epidemic sore throat is likely to be strepto1 Cooper R J, Hoffman J R, Bartlett J G et al 2001 Principles of appropriate antibiotic use for acute pharyngitis in adults: background Annals of Internal Medicine 134: 506 Del Mar C B, Glasziou P P, Spinks A B 2001 Antibiotics for sore throat (Cochrane Review) The Cochrane Library Oxford: Update Software Thomas M, Del Mar C, Glasziou P 2000 How effective are treatments other than antibiotics for acute sore throat? British Journal of General Practice 50: 817 INFECTION OF THE coccal and phenoxymethylpenicillin by mouth (or erythromycin/clarithromycin or an oral cephalosporin in the penicillin allergic) should be given to prevent these complications Ideally, it should be continued for 10 days, but compliance is bad once the symptoms have subsided and days should be the minimum objective If there is a possibility that the pharyngitis is due to infectious mononucleosis, amoxicillin must not be used as the patient is very likely to develop a rash (see p 220) In a closed community, chemoprophylaxis of unaffected people to stop an epidemic may be considered, for instance with phenoxymethylpenicillin 125 mg 12-hourly orally, for a period depending on the course of the epidemic 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 should be undertaken in patients who have had one attack of rheumatic fever It is continued for at least years, or until aged 20, whichever is the longer period (although some hold that it should continue for life, for histological study of atrial biopsies shows that the cardiac lesions may progress despite absence of clinical activity) 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 but in the rare cases of nephritis in which recurrent haematuria occurs after sore throats, chemoprophylaxis should be used Ideally, chemoprophylaxis should continue throughout the year but, if the patient is unwilling to submit to this, at least the colder months should be covered (see also p 207) Adverse effects are uncommon Patients taking penicillin prophylaxis are liable to have penicillinresistant 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 The same risk applies to urinary, abdominal and chest surg- BRONCHI, LUNGS AND PLEURA 13 ery, and patients need special chemoprophylaxis (see Endocarditis) Patients taking penicillins are also liable to be carrying resistant staphylococci and pneumococci Other causes of pharyngitis Vincent's infection (microbiologically complex, includes anaerobes, spirochaetes) responds readily to benzylpenicillin; a single i.m dose of 600 mg is often enough except in a mouth needing dental treatment, when relapse may follow Metronidazole 200 mg 8-hourly by mouth for days is also effective Diphtheria (Corynebacterium diphtheriae) Antitoxin 10 000-100 000 units i.v in two divided doses 0.5-2 h apart is given to neutralise toxin already formed according to the severity of the disease Erythromycin or benzylpenicillin is also used, to prevent the production of more toxin by destroying the bacteria Whooping-cough (Bordetella pertussis) Chemotherapy is needed in children who are weak, have damaged lungs or are under years old Erythromycin is usually recommended at the catarrhal stage and should be continued for 14 days (also as prophylaxis in cases of special need) It may curtail an attack if given early enough (before paroxysms have begun) but is not dramatically effective; it also reduces infectivity to others A corticosteroid, salbutamol, and physiotherapy may be helpful for relief of symptoms, but reliable evidence of efficacy is lacking 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 if there is role for antimicrobials in uncomplicated acute bronchitis but 239 13 CHEMOTHERAPY OF BACTERIAL INFECTIONS amoxicillin, a tetracycline or trimethoprim are appropriate if treatment is considered necessary In chronic bronchitis, suppressive chemotherapy, generally needed only during the colder months (in temperate, colder regions), may be considered for patients with symptoms of pulmonary insufficiency, recurrent acute exacerbations or permanently purulent sputum Amoxicillin or trimethoprim is suitable for treatment For intermittent therapy, the patient is given a supply of the drug and is told to take it in full dose at the first sign of a 'chest' cold, e.g purulent sputum, and to stop it after 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, although in seriously ill patients cover for both 'typical' and 'atypical' pathogens should be included from the beginning It is not possible reliably to differentiate between pneumonias caused by 'typical' and 'atypical' pathogens on clinical grounds alone Pneumonia in previously healthy people (community acquired) Disease that is segmental or lobar in its distribution is usually caused by 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 p.o are the treatments of choice if pneumococcal pneumonia is very likely; alternatively, use erythromycin/clarithromycin in a penicillin-allergic patient Seriously ill patients are best given benzylpenicillin (to cover the pneumococcus) plus ciprofloxacin (to cover Haemophilus and 'atypical' pathogens) Where penicillin-resistant pneumococci are prevalent, i.v cefotaxime is a reasonable 'best guess' choice 240 Pneumonia following influenza is often caused by Staphylococcus aureus, and 'best guess' therapy is usually achieved by adding flucloxacillin to one of the regimens above When staphylococcal pneumonia is proven, sodium fusidate p.o plus flucloxacillin i.v should be used in combination 'Atypical' cases of pneumonia may be caused by Mycoplasma pneumoniae which may be epidemic, or more rarely Chlamydia pneumoniae or psittaci (psittacosis/ornithosis) Legionella pneumophilia or Coxiella burnetii (Q fever) and a tetracycline or erythromycin/ clarithromycin should be given by mouth Treatment of ornithosis should continue for 10 days after the fever has settled and in mycoplasma pneumonia and Q fever a total of weeks treatment may be needed to prevent relapse At the earliest possible stage, once a clinical improvement has been seen, initial i.v administration of antibiotics for pneumonia should be switched to the oral route Pneumonia acquired in hospital Pneumonia is usually defined as being nosocomial (Greek: nosokomeian, hospital) if it presents after at least days in hospital It occurs primarily among patients admitted with medical problems or recovering from abdominal or thoracic surgery or on mechanical ventilators The common pathogens are Staphylococcus aureus, Enterobacteriaceae, Streptococcus pneumoniae, Pseudomonas aeruginosa, and Haemophilus influenzae It is reasonable to initiate therapy with ciprofloxacin, meropenem or ceftazidime (plus vancomycin if the local prevalence of MRSA is high) until the results of sputum culture and antimicrobial susceptibility tests are known Pneumonia in people with chronic lung disease Normal commensals of the upper respiratory tract proliferate in damaged lungs especially following viral infections, pulmonary congestion or pulmonary infarction Mixed infection is therefore common, and since Haemophilus influenzae and Streptococcus pneumoniae are often the pathogens, amoxicillin or trimethoprim are reasonable choices, but if ENDOCARDITIS response is inadequate co-amoxiclav or a quinolone should be substituted Klebsiella pneumoniae rarely causes lung infection (Triedlander's pneumonia') in the alcoholic and debilitated elderly Abscesses form, particularly in the upper lobes: cefotaxime possibly with 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 B-lactamase, co-amoxiclav or erythromycin/clarithromycin should be used Pneumonia in immunocompromised patients Pneumonia is common, e.g in acquired immunodeficiency 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 strenuous efforts should be made 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 cefotaxime or ceftazidime Pseudomonas aeruginosa may also cause pneumonia in these patients; for treatment see Reference data on antimicrobial drugs of choice, page 211, Table 11.1 • An important respiratory pathogen in patients with deficits in cell-mediated immunity is the fungus Pneumocystis carinii, which should be treated with co-trimoxazole 120 mg/kg/d by mouth or i.v in 2-4 divided doses for 14 days, or with pentamidine (see p 276) Legionnaires' disease Legionella pneumophila responds to erythromycin 13 2-4 g/d i.v in divided doses but rifampicin may be added in more severe infections Ciprofloxacin is also effective Pneumonia due to anaerobic microorganisms Pneumonia is often caused by aspiration of material from the oropharynx, or due to the presence of other lung pathology such as pulmonary infarction or bronchogenic carcinoma As well as conventional microbial causes, the pathogens include anaerobic and aerobic streptococci, Bacteroides spp and Fusobacterium, and the diagnosis may be missed unless anaerobic cultures of fresh material are performed Treatment for several weeks with cefuroxime plus metronidazole may be needed to prevent relapse Pulmonary abscess is treated according to the organism identified and with surgery if necessary Empyema is treated according to the organism isolated and with aspiration and drainage Endocarditis When suspicion is high enough, three blood cultures should be taken over a few hours and antimicrobial treatment commenced; it can 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 the most common pathogens In intravenous drug users, Staphylococcus aureus is the most likely organism Culture-negative endocarditis (up to 20% of cases) is usually due to prior antimicrobial therapy or to special culture requirements of the microbe; it is best regarded as being due to streptococci and treated accordingly PRINCIPLES FORTREATMENT • High doses of bactericidal drugs are needed because the organisms are difficult to access in avascular vegetations on valves and the protective host reaction is negligible • Drugs should be given parenterally at least 241 13 CHEMOTHERAPY OF BACTERIAL INFECTIONS initially and preferably by intravenous bolus injection which achieves the necessary high peak concentration to penetrate the relatively avascular vegetations • The infusion site should be examined daily and changed regularly to prevent opportunistic infection, which is usually with coagulasenegative staphylococci or fungi Alternatively, use may be made of a central subclavian venous catheter sited with meticulous attention to aseptic technique • Prolonged therapy is needed, usually weeks, and in the case of infected prosthetic valves at least weeks The patient should be reviewed one month after completing the antimicrobial treatment Valve replacement may be needed at any time during and after antibiotic therapy if cardiovascular function deteriorates or if the infection proves impossible to control • Dosage must be adjusted according to the sensitivity of the infecting organism This is established by the Minimum Inhibitory Concentration test (p 203), rather than by testing dilutions of the patient's serum against the organism (the Serum Bactericidal Titre which was formally recommended, but which has not been proved useful) • • • • DOSE REGIMENS The following regimens are those commonly recommended: Initial (best guess) treatment should comprise benzylpenicillin 1.2-2.4 g 4-hourly, plus gentamicin in low dose, e.g 80 mg 12-hourly, by i.v injection (synergy allows this dose of gentamicin and minimises risk of adverse effects) Regular serum gentamicin assay is vital: trough concentrations should be below mg/1 and peak concentrations about mg/1; if Staphylococcus aureus is suspected, high-dose flucloxacillin plus either gentamicin or sodium fusidate should be used Patients allergic to penicillin should be treated with vancomycin When an organism has been identified and its sensitivity to drugs determined: • Viridans group streptococci: benzylpenicillin plus gentamicin i.v for at least weeks or, if 242 • • the organism is very sensitive, for weeks, followed by amoxicillin p.o for weeks Some patients with uncomplicated endocarditis caused by very sensitive strains may be managed as outpatients; for these patients ceftriaxone may be suitable, with its prolonged t1/2 allowing convenient once-daily administration Enterococcus faecalis (Group D): benzylpenicillin 1.8-3g 4-hourly plus gentamicin 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 Staphylococcus aureus: flucloxacillin g 4-hourly by i.v injection for at least weeks plus either gentamicin by i.v injection or sodium fusidate by mouth for the first 1-2 weeks Staphylococcus epidermidis and other coagulase negative staphylococci infecting native heart valves should be managed as for Staphylococcus aureus if the organism is sensitive These organisms, however, have a predilection for prosthetic valves and such cases should be treated with vancomycin plus rifampicin for at least weeks with gentamicin for the first weeks Coxiella or Chlamydia: tetracycline by mouth for at least 4-6 weeks Valve replacement is advised in most cases, but some may continue indefinitely on tetracycline Fungal endocarditis: amphotericin plus flucytosine are used 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, surgical incision of the skin, instrumentation of the urinary tract, parturition and even seemingly innocent activities such as brushing the teeth or chewing toffee Experience shows that people with acquired or congenital heart defects are at risk from bacteraemia and may be protected by antimicrobials used prophylactically (although there is no scientific proof of the efficacy of this) The drugs are given as a short course in high dose at the time of MENINGITIS the procedure to coincide with the bacteraemia and avoid emergence of resistant organisms There follow general recommendations4'5'6 on antimicrobial prophylaxis; not every contingency is covered because prophylaxis may be needed for patients with cardiac defects whenever surgery or instrumentation is undertaken on tissue that is heavily colonised or infected, e.g in surgery or instrumentation of the upper respiratory or genitourinary tracts, or obstetric, gynaecological or gastrointestinal procedures Different national Working Parties have recommended differing prophylactic measures,4'5'6 and the physician should consult special sources and exercise a clinical judgement that relates to individual circumstances All oral drugs should be taken under supervision Dental procedures Under local or no anaesthesia • 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, but not if they have had endocarditis in the past) should receive amoxicillin g by mouth 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 h before the procedure Under general anaesthesia • Patients who are not allergic to penicillins and who have not taken penicillin more than once in the previous month should receive amoxicillin g i.m or i.v at induction then 0.5 g by mouth h later Alternatively amoxicillin g may be taken by mouth together with probenecid g by Simmons N A1993 Recommendations for endocarditis prophylaxis Journal of Antimicrobial Chemotherapy 31: 437 Littler W A, McGowan D A, Shanson D C 1997 Changes in recommendations about amoxycillin prophylaxis for prevention of endocarditis Lancet 350:1100 Dajani A S, Taubert K Wilson W et al 1997 Prevention of bacterial endocarditis Recommendations by the American Heart Association Journal of the American Medical Association 277:1794 13 mouth h before the procedure (probenecid delays renal excretion and thus maintains a high blood concentration of amoxicillin), or amoxicillin g may be followed by another g dose as soon as possible after the procedure • Special risk patients, i.e with prosthetic valves or with previous endocarditis, should receive amoxicillin g i.m or i.v and gentamicin 120 mg at induction, then amoxicillin 0.5 g by mouth h later Patients who are penicillin-allergic or have received penicillin more that once in the previous month should receive vancomycin g i.v over 100 then gentamicin 120 mg i.v at induction or 15 before the procedure; or teicoplanin 400 mg i.v plus gentamicin 120 mg i.v at induction or 15 before the procedure; or clindamycin 300 mg over at least 10 at induction or 15 before the procedure then clindamycin 150 mg i.v or by mouth h later Special sources should be consulted for prophylactic regimens recommended for children and for other procedures, such as instrumentation of the urogenital or gastrointestinal tracts Meningitis Speed of initiating treatment and accurate bacteriological diagnosis are the major factors determining the fate of the patient When meningococcal disease is suspected (and unless the patient has a history of penicillin anaphylaxis) treatment with benzylpenicillin should be started by the general practitioner before transfer to hospital; benefit to the patient outweighs the reduced chance of identifying the causative organism Newly introduced diagnostic methods such as the Polymerase Chain Reaction (PCR) for bacterial DNA in CSF or blood enable accurate and 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 Intrathecal therapy is now considered unnecessary, and can be dangerous, e.g encephalopathy with penicillin 243 13 CHEMOTHERAPY OF BACTERIAL INFECTIONS INITIALTHERAPY SUBSEQUENTTHERAPY Initial therapy should be sufficient to kill all pathogens, which are likely to be: When the infecting organism has been identified, specific therapy is chosen as follows Intravenous administration should continue until the patient is capable of taking drugs by mouth, and whether continuation therapy should be given by mouth 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 is reduced The following are recommended (adult doses) All ages over years For Neisseria meningitidis and Streptococcus pneumoniae benzylpenicillin 2-4 g 4-6-hourly should be given, followed, in the case of Neisseria meningitidis, by rifampicin for days prior to discharge from hospital (to eradicate persisting organisms) Some prefer to use cefotaxime 2-3 g 6-8-hourly in all cases until the results of susceptibility tests are known, and this may be the generally preferred choice if penicillin resistance in pneumococci and meningococci rises in prevalence Optimal therapy for penicillin-resistant pneumococcal meningitis may comprise cefotaxime 2-3 g 6-8-hourly plus vancomycin g 12-hourly plus rifampicin 600 gm 12-hourly Children under years Neisseria meningitidis is now commonest and Haemophilus influenzae, formerly a frequent pathogen, is much less often isolated (as a result of immunisation programmes) Streptococcus pneumoniae is also less commonly found than in older patients Give a cephalosporin, e.g cefotaxime When Haemophilus influenzae is isolated give rifampicin for days before discharge from hospital to clear naso-pharyngeal carriage Neisseria meniningitidis: benzylpenicillin 2.4 g 4-6-hourly or cefotaxime 2-3 g 6-8-hourly is given Treatment should continue for a minimum of days Streptococcus pneumoniae: cefotaxime 2-3 g 6-8hourly is given or benzylpenicillin 2.4 g 4-6-hourly if the organism is penicillin-sensitive Treatment should continue for 10 days after the patient has become afebrile and the physician should be aware of the possibility of relapse Haemophilus influenzae: cefotaxime 2-3 g 6-8hourly or chloramphenicol 100 mg/kg/d is given Treatment should continue 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 Neonates Chemoprophylaxis 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 for neonates Ampicillin must be added if Listeria monocytogenes is suspected Dexamethasone given i.v and early appears to reduce long-term neurological sequelae, especially sensorineural deafness, in infants and children There is not, however, general agreement about the use of dexamethasone for meningitis in adults Chloramphenicol remains a good alternative for 'blind' therapy in patients giving a history of B-lactam anaphylaxis The three common pathogens (below) are spread by respiratory secretions Asymptomatic nasopharyngeal carriers seldom develop meningitis but they may transmit the pathogens to close personal contacts Rifampicin by mouth is effective at reducing carriage rates 244 Meningococcal meningitis often occurs in epidemics in closed communities, but also in isolated cases Close personal contacts should receive oral rifampicin 600 mg 12-hourly for days Single doses of oral ciprofloxacin (500 mg) or i.m ceftriaxone (2 g) are alternatives, the latter of particular value for pregnant women NFECTION OFTHE Haemophilus influenzae type b has an infectivity similar to that of the meningococcus Rifampicin 600 mg daily should be given for days Pneumococcal meningitis tends to occur in isolated cases and chemoprophylaxis of contacts is not recommended Infection of the intestines (For Helicobacter pylori see p 630.) Antimicrobial therapy should be reserved for specific conditions with identified pathogens where benefit has been shown; not all acute diarrhoea is infective for it can be caused by bacterial toxins in food, dietary indiscretions, anxiety and by drugs Even if diarrhoea is infective, it may be due to viruses; or, if it is 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 Maintenance of water and electrolyte balance, either by i.v infusion or orally with a glucose-electrolyte solution together with an antimotility drug (except in small children) are the mainstays of therapy in such cases (see Oral rehydration therapy, p 643) Some specific intestinal infections benefit from chemotherapy: Campylobacter jejuni Erythromycin or ciprofloxacin by mouth will eliminate the organism from the stools and a 5-day course is worth giving early in the illness if it is severe Shigella Mild disease requires no specific antimicrobial therapy but toxic shigellosis with high fever should be treated with ciprofloxacin or amoxicillin by mouth Salmonella An antimicrobial should be used for severe salmonella gastroenteritis, or for bacteraemia or salmonella enteritis in an immunocompromised patient The choice lies between ciprofloxacin, amoxicillin or co-trimoxazole, according to the sensitivity of the pathogen Typhoid fever is a generalised infection and requires treatment with ciprofloxacin Chloramphenicol, amoxicillin or co-trimoxazole are less effective alternatives The i.v route should be used at INTESTINES 13 least initially, followed by oral administration 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.7 Organsims 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 Cholecystectomy or investigation of urinary tract abnormalities may be needed 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, is the drug of choice in most high-risk parts of the world for a severe attack (see Travellers' diarrhoea, p 644) Antimicrobials are not generally given for prophylaxis but, when it is indicated, a quinolone should be used 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, perhaps by releasing more toxin from dying bacteria An antimicrobial should generally therefore be avoided for bloody diarrhoea unless the diagnosis has been confirmed bacteriologically not to be VTEC Vibrio cholerae The cause of death in cholera is electrolyte and fluid loss in the stools and this may exceed 1/h The most important aim of treatment is prompt replacement and maintenance of water and electrolytes with oral or intravenous electrolyte solutions 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) Carriers may be treated by doxycycline by mouth in high dose for days Ciprofloxacin may be given for resistant organisms The most famous carrier was Mary Mallon (Typhoid Mary') who worked as a cook in New York City, USA, using various assumed names and moving through several different households She caused at least 10 outbreaks with 51 cases of typhoid fever and deaths To protect the public, she was kept in detention for 23 years 245 13 CHEMOTHERAPY OF BACTERIAL INFECTIONS 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 lead to cerebral symptoms and even to coma In acute coma, neomycin g/d should be given by gastric tube; as prophylaxis, 1-4 g/d may be given to patients with protein intolerance who fail to respond to dietary protein restriction (see also lactulose, p 640) Selective decontamination of the gut reduces 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 nonabsorbable (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 An alternative is to administer oral ciprofloxacin alone Peritonitis is usually a mixed infection and antimicrobial choice must take account of coliforms, anaerobes and streptococci; a combination of gentamicin, benzylpenicillin plus metronidazole or of cefuroxime plus metronidazole, or meropenem alone is usually appropriate Surgical drainage of peritoneal collections and abscesses is usually required as well Chemoprophylaxis in surgery: see p 208 Antibiotic-associated colitis: see p 210 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 Staphylococcus saprophyticus Patients with abnormal urinary tracts (e.g renal 246 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 are 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 Elimination of infection is hastened by a large urine volume (over 1.5 I/d) and by frequent micturition Drug treatment of urinary tract infection falls into several categories: Lower urinary tract infection Initial treatment with an oral cephalosporin (e.g cefalexin), trimethoprim, amoxicillin or coamoxiclav is usually satisfactory, although current resistance rates of 20-50% among common pathogens for trimethoprim and amoxicillin threaten their value for empirical therapy Therapy should normally last 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 it is advisable to start with gentamicin plus amoxicillin i.v or alternatively cefotaxime i.v alone If oral therapy is considered suitable, ciprofloxacin or norfloxacin is recommended for weeks This is an infection of the kidney substance and so needs adequate blood as well as urine concentrations 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, GENITALTRACT 7-14 days of high-dose treatment may be given, following which continuous low-dose prophylaxis may be needed 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 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/d), nalidixic acid (0.5-1.0 g/d) or trimethoprim (100 mg/d) are 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 (p 249) INFECTIONS 13 SPECIAL DRUGS FOR URINARYTRACT INFECTIONS General antimicrobials are used for urinary tract infections and described elsewhere A few agents are used solely for infection of the urinary tract: Nitrofurantoin, a synthetic antimicrobial, is active against the majority of urinary pathogens except pseudomonads It is well absorbed from the gastrointestinal tract and is concentrated in the urine (t1/, 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 The main use of nitrofurantoin is now for prophylaxis 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 It is safe in pregnancy, except near to term because it may cause neonatal haemolysis, and it must be avoided in patients with glucose-6phosphate dehydrogenase deficiency (see p 123) Nalidixic acid: see page 233 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 Screening of contacts plays a vital part in controlling spread and reducing reinfection GONORRHOEA The problems of (3-lactam and quinolone resistance in Neisseria gonorrhoeae are increasing, and selection of a particular drug will depend on sensitivity testing and a knowledge of resistance patterns in different geographical locations Effective treatment 247 13 CHEMOTHERAPY OF BACTERIAL INFECTIONS requires exposure of the organism briefly to a high concentration of the drug Single-dose regimens are practicable as well as being obviously desirable for social reasons, including compliance The following schedules are effective: Uncomplicated anogenital infections: amoxicillin with probenecid by mouth; spectinomycin i.v, cefotaxime i.m or ciprofloxacin by mouth may be used for penicillin-allergic patients Pharyngeal gonorrhoea responds less reliably, and i.m cefotaxime is recommended Coexistent infection Chlamydia tmchomatis is frequently present with Neisseria gonorrhoeae; tetracycline by mouth for days or a single oral dose of azithromycin Ig will treat the chlamydial urethritis Nongonococcal 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 and sometimes Ureaplasma urealyticum Tetracycline or azithromycin by mouth is effective 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 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 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 days or a single dose of ceftriaxone or azithromycin Pelvic inflammatory disease Several pathogens are 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 metronidazole plus doxycycline by mouth SYPHILIS Treponema pallidum is known to be invariably sensitive to penicillin Primary and secondary syphilis are effectively treated by benzylpenicillin or procaine penicillin i.m daily for 10-21 days Tetracycline or erythromycin orally may be used for penicillin-allergic patients Tertiary syphilis should have the same treatment, ensuring that it continues for weeks Congenital syphilis in the newborn should be 248 GRANULOMA INGUINALE Calymmatobacterium granulomatis infection is treated with ampicillin or co-trimoxazole or a tetracycline for weeks BACTERIALVAGINOSIS (BACTERIAL VAGINITIS,ANAEROBICVAGINOSIS) 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 There is evidence to associate the condition with overgrowth of several normal commensals of the vagina including Gardnerella vaginalis, Gram-negative curved bacilli, and anaerobic organisms, especially of the Bacteroides genus, the latter being responsible for the characteristic fishy odour of the vaginal discharge The condition responds well to a single g oral dose of metro- MYCOBACTERIAL INFECTIONS nidazole, with topical clindamycin offering an alternative Candida vaginitis: see page 263 Trichomonas vaginitis: see page 234 Infection of bones and joints Osteomyelitis may be acute or chronic and the causative bacteria arrive in the bloodstream or are 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 but Haemophilus influenzae is frequently seen in children (much reduced now by the Hib vaccine), 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 species) 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) The outcome of chronic osteomyelitis is improved if dead bone can be removed surgically Definitive therapy is guided by the results of culture but commonly used regimens include flucloxacillin with or without fusidic acid (for Staphylococcus aureus), cefotaxime or co-amoxiclav (in children), and ciprofloxacin (for coliforms) Short courses of therapy (3 weeks) may suffice for acute osteomyelitis 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 Aspiration of the joint allows specific microbiological diagnosis, differentiation from noninfectious 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 13 Eye infections Superficial infections, caused by a variety of organisms, are treated by chloramphenicol, fusidic acid, framycetin, gentamicin, ciprofloxacin, ofloxacin or neomycin in drops or ointments Ciprofloxacin, ofloxacin, gentamicin or tobramycin are 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 make the disease worse 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 should be treated with systemic erythromycin and topical tetracycline Herpes keratitis (see p 258) It is essential that a corticosteroid should never be put on the eye; the disease is exacerbated and permanent blindness can result Mycobacterial infections PULMONARYTUBERCULOSIS 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 strains of Mycobacterium tuberculosis (MDRTB) in developed 249 13 CHEMOTHERAPY OF BACTERIAL INFECTIONS countries will disturb this optimistic view Chemotherapy was formerly protracted, but a better understanding of the mode of action of antituberculous drugs has allowed the development of effective short-course regimens Principles of antituberculosis therapy • A large number of actively multiplying bacilli must be killed: isoniazid achieves this • Treat persisters, i.e semidormant 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-drugresistant mutants that may exist de novo or emerge during therapy in all large bacterial populations: 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 phase with administration of at least three drugs to reduce the bacterial load as rapidly as possible (usually for months), followed by a continuation phase with usually two drugs given for months All short-course regimens include isoniazid, pyrazinamide and rifampicin After extensive clinical trials, the following three have been found satisfactory: An unsupervised regimen of daily dosing comprising isoniazid and rifampicin for months, plus pyrazinamide for the first months A supervised (directly observed) regimen for patients who cannot be relied upon to comply with treatment, comprising thrice-weekly dosing with isoniazid and rifampicin for months, plus pyrazinamide for the first months (isoniazid and pyrazinamide are given in higher dose than in the unsupervised regimen) With both the above regimens, ethambutol by mouth or streptomycin i.m should be added for the first months if there is a likelihood of drugresistant organisms, or if the patient is severely ill with extensive active lesions A less costly, yet still effective, regimen favoured 250 by some countries comprises supervised daily administration of isoniazid, rifampicin, pyrazinamide and either ethambutol or streptomycin for months followed by months of unsupervised daily isoniazid and thiacetazone All the regimens are highly effective, with relapse rates of 1-2% in those who continue for months; even if patients default after, say, months, tuberculosis can be expected to recur in only 10-15% Drug resistance seldom develops with any of these regimens Although compliance is often a concern with multiple drug therapy given for long periods, especially in the Developing World, directly observed therapy (DOT) has surprisingly not been proven to improve relapse rates in many trials Combination therapy is assumed to improve compliance: some commonly used combinations include Rifater (rifampicin, isoniazid plus pyrazinamide), and Rifinah or Rimactazid (rifampicin plus isoniazid) Special problems Resistant organisms Initial resistance occurs in about 4% of isolates in the UK, usually to isoniazid Multiple-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 should extend for 12-24 months after cultures become negative Treatment of such cases requires expert management Atypical 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 clarithromycin or a quinolone, often in combination Chemoprophylaxis may be either • primary, i.e the giving of antituberculosis 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 because they have a high risk MYCOBACTERlAL INFECTIONS of disseminated disease; isoniazid alone for months may be used since there is little risk of resistant organisms emerging because the organism load is low 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 (1 above) is best Streptomycin should be excluded from any regimen (danger of fetal eighth cranial nerve damage) Nonrespiratory tuberculosis The principles of treatment, i.e multiple therapy and prolonged followup, are the same as for respiratory tuberculosis In only a few cases is surgery now necessary It should always be preceded and followed by chemotherapy Many chronic tuberculous lesions may be relatively inaccessible to drugs as a result of avascularity of surrounding tissues; 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 enters inflamed meninges well but noninflamed meninges less so An effective regimen is isoniazid, rifampicin, pyrazinamide and streptomycin Treatment may need to continue for much longer than modern short-course chemotherapy for pulmonary tuberculosis Adrenal steroid and tuberculosis In pulmonary tuberculosis a corticosteroid may be given to severely ill patients It reduces the injurious reaction of the body to tuberculoprotein and buys time for the chemotherapy to take effect It also causes the patient to feel better much more quickly In the absence of effective chemotherapy, an adrenal steroid will cause tuberculosis to extend and it should never be used alone, e.g for another disease, if tuberculosis is suspected Tuberculosis in the immunocompromised Immunocompromised patients require special measures because they may be infected more readily when exposed, their infections usually involve large 13 numbers of tubercle bacilli (multibacillary disease), and in the case of patients with AIDS, are more likely to be infected with multiply antibiotic resistant strains Usually at least four drugs are started, and patients are isolated until bacteriological results are 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 nondividing 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, readily crossing tissue barriers and entering cells and cerebrospinal fluid 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 (see Pharmacogenetics, p 123) The tl/2 is h in fast and h in slow acetylators; steadystate plasma concentration in fast acetylators is less than half that in slow acetylators but standard oral doses (300 mg/d) 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 which may range from moderate elevation of hepatic enzymes to severe hepatitis and death It is probably caused by a chemically reactive metabolite^), e.g acetylhydrazine Most cases develop within the first weeks of therapy and liver function tests should be monitored monthly during this period at least 251 13 CHEMOTHERAPY OF BACTERIAL INFECTIONS 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 and alcoholism Such patients should receive pyridoxine 10 mg/d 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 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 semidormant 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 well into 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 or 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 tl/2 is 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 252 and itching with or without a rash, and thrombocytopenia Rises in plasma 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 certain effects that probably have an immunological basis, namely, 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 Red discolouration of urine, tears and sputum is a useful indication that the patient is taking the drug Rifampicin also causes an orange discolouration 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 287) Rifabutin (t1/2 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 nontuberculous mycobacterial infection in combination with other drugs 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 semidormant, 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 It is inactive against Mycobacterium bovis Pyrazinamide is well absorbed from the gastrointestinal tract and metabolised in the liver, very little unchanged drug MYCOBACTERIAL INFECTIONS appearing in the urine (il/2 h) CSF concentrations are almost identical to those in the blood, hence the drug is valuable in tuberculous meningitis Experience in several countries indicates that 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 an NSAID is usually sufficient and it is rarely necessary to discontinue pyrazinamide because of arthralgia Hepatitis, which was particularly associated with high doses, is not a problem with modern short-course schedules Sideroblastic anaemia and urticaria also occur Ethambutol Ethambutol, being bacteriostatic, is used in conjunction with other antituberculosis 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 cross into the CSF if the meninges are not inflamed Excretion is mainly by the kidney, by tubular secretion as well as by glomerular filtration (t l / h); the dose should be reduced when renal function is impaired 13 (with each eye separately) and if there is any deterioration to stop the drug immediately and seek advice Patients who cannot understand and comply (especially children) should be given alternative therapy, if possible The need for repeated specialist ophthalmological monitoring is controversial Peripheral neuritis occurs but is rare Streptomycin: see page 225 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 (t1/213 h) Adverse reactions include gastrointestinal symptoms, conjunctivitis and vertigo More serious effects are erythema multiforme, haemolytic anaemia, agranulocytosis, cerebral oedema and hepatitis Alternative or reserve drugs are used where there are problems of drug intolerance and bacterial resistance They are in this class because of either greater toxicity or of lesser efficacy and include: ethionamide (gastrointestinal irritation, allergic reactions), capreomycin (nephrotoxic), and cycloserine (effective but neurotoxic) Quinolone antibiotics such as ciprofloxacin and the more recently introduced macrolides such as clarithromycin and azithromycin also have useful activity against mycobacteria LEPROSY Adverse effects In recommended oral doses (15 mg/kg per day) (taking account of reduced renal function), ethambutol is relatively nontoxic The main problem is optic neuritis (unilateral or bilateral) causing loss of visual acuity, central scotomata, occasionally also peripheral vision loss and red-green colour blindness The changes reverse if treatment is stopped promptly; if not, the patient may go blind It is prudent to note any history of eye disease and to get baseline tests of vision before starting treatment with ethambutol The drug should not be given to a patient whose vision is much reduced and who may not notice further minor deterioration Patients should be told to make a point of reading small print in newspapers 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 months • for multibacillary disease: dapsone, rifampicin and clofazimine for years Follow-up for 4-8 years may be necessary Dapsone, a bacteriostatic sulphone (related to sulphonamides, and acting by the same mechanism, see p 231), has for many years been the standard drug for the treatment of all forms of leprosy 253 13 CHEMOTHERAPY OF BACTERIAL INFECTIONS Irregular and inadequate duration of treatment with a single drug have allowed the emergence of resistance, both primary and secondary, to become a major problem Dapsone is also used to treat dermatitis herpetiformis, and is given for Pneumocystis carinii and (with pyrimethamine) malaria prophylaxis The t1/2 is 27 h Adverse effects range from gastrointestinal symptoms to agranulocytosis, haemolytic anaemia and generalised allergic reactions that include exfoliative dermatitis Rifampicin (see above) is bactericidal, and is safe and effective when given once monthly This long interval renders feasible the directly observed administration of rifampicin which the above regimens require Clofazimine has a leprostatic action and an antiinflammatory effect that prevents erythema nodosum leprosum It causes gastrointestinal symptoms Reddish discolouration of the skin and other cutaneous lesions also occur, and may persist for months after the drug has been stopped The tl/2 is 70 days Other antileprotics include ethionamide and prothionamide Thalidomide (see Index), despite its notorious past, still finds a use with corticosteroid in the control of allergic lepromatous reactions OTHER BACTERIAL INFECTIONS Burns Infection may be reduced by application of silver sulphadiazine cream Substantial absorption can occur from any raw surface and use of aminoglycoside, e.g neomycin, preparations can cause ototoxicity Gas gangrene The skin between the waist and the knees is normally contaminated with anaerobic faecal organisms However assiduous the skin preparation for orthopaedic operations or thigh amputations, this will not kill or remove all the spores Surgery done for vascular insufficiency where tissue oxygenation may be poor is likely to be followed by infection Gas gangrene (Clostridium perfringens) may occur; it may be prevented by benzylpenicillin or metronidazole prophylaxis 254 Wounds Systemic chemoprophylaxis is necessary for several days at least in dirty wounds where sutures have to be left below the skin, and in penetrating wounds of body cavities Flucloxacillin is probably best, but in the case of penetrating abdominal wounds, metronidazole should be added, and consideration given to adding an agent active against aerobic Gram-negative bacteria, e.g gentamicin (see also Tetanus) Abscesses and infections in bone and serous cavities are treated according to the antimicrobial sensitivity of the organism concerned but require high doses because of poor penetration Local instillation of the drug may be needed Actinomycosis The anaerobe Actinomyces israelii is sensitive to several drugs, but not metronidazole, and access is poor because of granulomatous fibrosis High doses of benzylpenicillin or amoxicillin are given for several weeks; the infections are often mixed with other anaerobic bacteria so metronidazole is often given in addition to ensure activity against all components of the mixture Co-amoxiclav may be a convenient alternative Surgery is likely to be needed Leptospirosis To be maximally effective, chemotherapy should be started within days of the onset of symptoms Benzylpenicillin is recommended; a Herxheimer reaction may be induced (see Syphilis) General supportive management is important, including attention to fluid balance and observation for signs of hepatic, renal or cardiac failure Lyme disease Keeping the skin covered and use of insect repellants are effective to prevent tick bites and tick removal shortly after attachment (within 24 h) will prevent infection In most manifestations of the disease, Borrelia burgdorferi responds to amoxicillin or doxycycline orally for up to 21 days but when the central nervous system is invaded large doses of cefotaxime should be given i.v for 14 days GUIDETO FURTHER READING Adachi J A, Ostrosky-Zeichner L, DuPont H L, Ericsson C D 2000 Empirical antimicrobial therapy MYCOBACTERlAL INFECTIONS for traveler's diarrhea Clinical Infectious Diseases 31:1079-1083 Arroll B, Knealy T 2001 Antibiotics for acute bronchitis British Medical Journal 322: 939-940 Bisno A L 2001 Acute pharyngitis New England Journal of Medicine 344: 205 Brown P D, Lerner S A1998 Community-acquired pneumonia Lancet 352:1295-1302 Campion E W 1999 Liberty and the control of tuberculosis New England Journal of Medicine 340: 385-386 Del Mar C et al 1997 Are antibiotics indicated as initial treatment for children with acute otitis media? A meta-analysis British Medical Journal 314: 1526-1529 Dixon T C et al 1999 Anthrax New England Journal of Medicine 341: 815-826 Goldenberg D L1998 Septic arthritis Lancet 351: 197-202 Gorbach S L 1999 Antibiotics and Clostridium difficile New England Journal of Medicine 341:1690-1691 Jacobson R R, Krahenbuhl J L 1999 Leprosy Lancet 353: 655-660 Joint Tuberculosis Committee of the British Thoracic Society 1998 Chemotherapy and management of tuberculosis in the United Kingdom: recommendations Thorax 53: 536 13 Lew D P, Waldvogel F A1997 Osteomyelitis New England Journal of Medicine 336: 999-1007 Marik P E 2001 Aspiration pneumonitis and aspiration pneumonia New England Journal of Medicine 344: 665-671 Mead P S, Griffin P M 1998 Escherichia coli 0157;H7 Lancet 352:1207-1212 Mylonakis E, Calderwood S B 2001 Infective endocarditis in adults New England Journal of Medicine 345:1318-1330 Nicolle L E 2000 Asymptomatic bacteruria—important or not? New England Journal of Medicine 343: 1037-1039 Rosenstein N E et al 2001 Meningococcal disease New England Journal of Medicine 344:1378-1388 Sobel J D 1997 Vaginitis New England Journal of Medicine 337:1896-1903 Steere A C 2001 Lyme disease New England Journal of Medicine 345:115-125 Whitty C J 1999 Erasmus, syphilis, and the abuse of stigma Lancet 354: 2147-2148 Working Party 1996 Guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen British Medical Journal 312: 430 255 ... 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... sympathomimetic vasoconstrictor, e.g ephedrine nasal drops Antibiotic therapy produces limited additional clinical benefit, but the common infecting organism—Streptococcus pneumoniae, Haemophilus influenzae,... pyogenes (Group A) or Staphylococcus aureus Amoxicillin or co-amoxiclav is satisfactory, but the clinical benefit of antibiotic therapy is very small when tested in controlled trials Chemotherapy