Bacteriological evidence of antibiotic failure in pneumococcal lower respiratory tract infections.

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.