Chemotherapy of bacterial infections

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Chapter 14 Chemotherapy of bacterial infections

Mark Farrington, Surender K. Sharma

Infection of the blood

Septicaemia

is a medical emergency that moves clinically from sepsis (systemic inflammatory response syndrome, ‘SIRS’) via organ dysfunction (‘severe sepsis’) to septic shock as the associated mortality rates progress from 16% to 46%. In a shocked patient (i.e. with low blood pressure that does not promptly respond to circulatory volume enhancement) survival rates fall by over 7% for each hour of delay in commencing effective antibiotics. Urgent support of the circulation and other organs is necessary for survival, and rapid assessment by senior medical staff and early involvement of infection specialists have also been associated with an improved outcome and lowest antibiotic costs during treatment.

Usually, the infecting organism(s) is not known at the time of presentation and treatment must be instituted on the basis of a ‘best guess’ (i.e. ‘empirical therapy’). The clinical circumstances and knowledge of local resistance patterns may provide clues. Examples of suitable choices are given in the list below: patients who have been in hospital for some time before presenting with septicaemia need antibiotic regimens that provide more reliable cover for multiply resistant pathogens, and examples of these are given in square brackets:

• Septicaemia accompanied by a spreading rash that does not blanch with pressure should be assumed to be meningococcal, and the patient must be referred to hospital urgently (after an immediate parenteral dose of benzylpenicillin): ceftriaxone.

• Community-acquired pneumonia: co-amoxiclav + clarithromycin.

• When septicaemia follows gastrointestinal or genital tract surgery, Escherichia coli (or other coliforms), anaerobic bacteria, e.g. Bacteroides, streptococci or enterococci are likely pathogens: piperacillin-tazobactam or gentamicin plus benzylpenicillin plus metronidazole [meropenem, plus vancomycin if MRSA is a risk].

• Septicaemia related to urinary tract infection usually involves Escherichia coli (or other Gram-negative bacteria), enterococci: gentamicin plus benzylpenicillin or piperacillin-tazobactam alone [meropenem plus vancomycin].

• Neonatal septicaemia is usually due to Lancefield Group B streptococcus or coliforms: benzylpenicillin plus gentamicin [vancomycin + ceftazidime].

• 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 [vancomycin]. Uncomplicated Staphylococcus aureus bacteraemia should be treated for 14 days to reduce the risk of metastatic infection: patients with prolonged bacteraemia or who fail to settle promptly should be considered for treatment as for staphylococcal endocarditis.

• Severe cellulitis, bites and necrotising fasciitis accompanied by septicaemia should be treated with optimal cover for Lancefield Group A streptococcus, anaerobes and coliforms: piperacillin-tazobactam + clindamycin [meropenem + clindamycin].

• Septicaemia in patients rendered neutropenic by cytotoxic drugs frequently involves coliforms and Pseudomonas spp. translocating to the circulation directly from the bowel, while coagulase-negative staphylococci also commonly arise from central venous catheter infection: piperacillin-tazobactam, sometimes plus vancomycin.

• Staphylococcal toxic shock syndrome occurs in circumstances that include healthy women using vaginal tampons, in abortion or childbirth, and occasionally with skin and soft tissue infection and after packing of body cavities, such as the nose. Flucloxacillin is used, and elimination of the source by removal of the tampon and drainage of abscesses is also important.

Antimicrobials are given i.v. initially, and their combination with optimal circulatory and respiratory support and glycaemic control, and administration of hydrocortisone and recombinant human activated protein C for severe cases, provides the best outcome.

Patients who have had a splenectomy

are at risk of fulminant septicaemia especially from capsulate bacteria, e.g. Streptococcus pneumoniae, Neisseria meningitidis. The risk is greatest in the first 2 years after splenectomy (but is lifelong), in children, and in those with splenectomy for haematological malignancy. Patients must be immunised against appropriate pathogens and receive continuous low-dose oral prophylaxis with phenoxymethylpenicillin (penicillin V), or erythromycin in those allergic to penicillin.

Infection of paranasal sinuses and ears

Sinusitis

As 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(s) – Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes, Moraxella (Branhamella) catarrhalis – usually respond to oral amoxicillin (with or without clavulanic acid) or doxycycline if serious. It is necessary to treat around 15 patients with antibiotic to cure one patient faster than the natural resolution rate.

In chronic sinusitis, correction of the anatomical abnormalities (polypi, nasal septum deviation) is often important, and diverse organisms, many of them normal inhabitants of the upper respiratory tract, may be cultured, e.g. anaerobic streptococci, Bacteroides spp. 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.

Otitis media

Mild cases are normally viral and often resolve spontaneously, needing only analgesia and observation. 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 small in controlled trials and good outcomes with reduced use of antibiotics have been demonstrated if patients are given a prescription which they only fill if they worsen or fail to improve after 48 h (sometimes known as a ‘WASP’ – a ‘wait and see’ prescription). Children under the age of 2 years with bilateral otitis, and those with acute aural discharge (otorrhoea) benefit most from antibiotic treatment. 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. Pneumococcal vaccination is modestly effective at reducing recurrences in children who are prone to them.

Infection of the throat

Pharyngitis is usually viral but the more serious cases may be due to Streptococcus pyogenes (Group A) (always sensitive to benzylpenicillin), which cannot be differentiated clinically from virus infection with any certainty. Prevention of complications is more important than relief of the symptoms, which seldom last long and corticosteroids are much more effective than antibiotics at shortening the period of pain.

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

Vincent’s infection

(microbiologically complex, including 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 3 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.

Whooping cough

(Bordetella pertussis). Chemotherapy is needed in unvaccinated children whose defences are compromised, have damaged lungs or are less than 3 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, and certainly within 21 days of exposure to a known case) 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 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

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