Abstract
The global pandemic of antimicrobial resistance, particularly in the pneumococcus, has had a major impact on the management of community-acquired pneumonia. A number of prospective and retrospective studies have analysed the impact of penicillin resistance on clinical outcome in pneumonia. Pharmacodynamic principles predicting success when the antibiotic dose exceeds the minimum inhibitory concentration (MIC) for 40-50% of the dosing interval have proved remarkably accurate. There is no evidence of bacteriological failure of penicillins active against resistant strains. There is a single report of the failure of the less active agent, ticarcillin. High dose oral and intravenous amoxicillin should treat strains with MICs < or = 4 microg x mL(-1), as should high doses of intravenous penicillin, ceftriaxone and cefotaxime. Strains of pneumococci resistant to these agents at an MIC > or = 8 microg x mL(-1) are rare at the present time. Most other cephalosporins are less active and should not be used empirically for drug-resistant Streptococcus pneumoniae. Bacteriological failures of cefazolin, cefuroxime and ceftazidime have been reported. There is increasing evidence of bacteriologically confirmed macrolide failure of pneumonia therapy at MICs > or = 4 microg x mL(-1). The molecular basis of the resistance is irrelevant if the MIC is in that range or higher. Double mutants in the parC and gyrA genes lead to fluoroquinolone resistance that has been found to cause bacteriological failure of the fluoroquinolones, particularly levofloxacin and ciprofloxacin, in the management of pneumonia and exacerbations of chronic bronchitis. Two mutations in these genes can greatly increase the MICs of all the marketed fluoroquinolones, and raise the prospect of failure of therapy even with the more active ones. However, demonstration of bacteriological failure of gatifloxacin or moxifloxicin has not yet been reported. High dose, active beta-lactams or fluoroquinolones with enhanced activity against Gram positive pathogens remain the drugs of choice for the management of community-acquired pneumonia caused by the drug-resistant pneumococcus.
Highlights
Bacteriological evidence of antibiotic failure in pneumococcal lower respiratory tract infections
The global dissemination of antimicrobial resistance in the pneumococcus has lead to a number of therapeutic dilemmas in the management of pneumococcal pneumonia
Available evidence suggests that highly-active b-lactam agents, such as penicillin, amoxicillin, the extended-spectrum cephalosporins, cefotaxime or ceftriaxone, and the carbapenems, meropenem and imipenem, all retain useful clinical activity for the treatment of pneumococcal pneumonia
Summary
A retrospective analysis by FEIKEN et al [22] revealed an intriguing association of late mortality (deaths after 4 days of therapy) in patients infected with pneumococci highly resistant to penicillin (MIC o4 mg?mL-1). GARAU [34] has recently described a series of both adults and children in whom macrolide-resistant pneumococci were grown from blood while they were receiving macrolides or azithromycin therapy [34] An analysis of these failures documents a threshold for bacteriological failure of y8 mg?mL-1, a level unachievable for 50% of the dosing interval in patients treated with intravenous erythromycin. As there have been bacteriologically documented failures in patients infected with pneumococci expressing mefA resistance when the MIC is o8 mg?mL-1 [34], the level of MIC is, a more important predictor of the clinical relevance of macrolide resistance than is the presence of the mefA gene While this agent is rarely used for the management of pneumonia in developed countries, it remains the recommended drug of choice for the management of pneumonia in children in developing countries. Table 2. – Bacteriological failures of macrolide therapy of respiratory tract infections caused by drug-resistant pneumococci
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