Performance in practice: bacteriological efficacy in patients with drug-resistant S. pneumoniae

Using pharmacokinetic/pharmacodynamic principles, pharmacokinetically enhanced amoxicillin/clavulanate 2000/125 mg twice daily was designed to provide adequate levels of amoxicillin over the 12-h dosing interval to eradicate penicillin-resistant Streptococcus pneumoniae (PRSP, penicillin MICs > or = 2 mg/L) with amoxicillin MICs of at least 4 mg/L. The clinical efficacy of amoxicillin/clavulanate 2000/125 mg was evaluated in patients with respiratory tract infections caused by S. pneumoniae, including isolates with elevated penicillin (2-8 mg/L) MICs. Data from 10 clinical studies were combined: seven randomised (1:1), double-blind, controlled trials (efficacy intent-to-treat [ITT]N = 3376): amoxicillin/clavulanate 2000/125 mg twice daily vs. levofloxacin 500 mg once daily in acute bacterial sinusitis (ABS); levofloxacin 500 mg once daily in acute exacerbations of chronic bronchitis (AECB); clarithromycin 500 mg twice daily in AECB; amoxicillin/clavulanate 875/125 mg twice daily/three times daily and 1000/125 mg three times daily in community-acquired pneumonia (CAP) and three noncomparative studies (efficacy ITT N = 3024): two in ABS, one in CAP. The bacteriological per-protocol (PP) population at follow up (days 14-39) comprised 1295 patients for amoxicillin/clavulanate 2000/125 mg and 241 for comparators. With amoxicillin/clavulanate 2000/125 mg at follow-up, outcome was successful (clinical success and eradication/presumed eradication) in 85/90 (94.4%) patients with S. pneumoniae in comparative studies and 421/445 (94.6%) in noncomparative studies, and with comparators 58/70 (82.9%) were successes. In the amoxicillin/clavulanate 2000/125 mg group at follow up, 52/552 S. pneumoniae isolates were resistant to penicillin. At follow up, 50/52 (96.2%) patients with PRSP were successes, including 6/7 with amoxicillin MICs of 4 mg/L and 7/8 with amoxicillin MICs of 8 mg/L. Success rates for amoxicillin/clavulanate 2000/125 mg against PRSP were similar for CAP (96.0%[24/25]), AECB (100%[3/3]) and ABS (95.8%[23/24]). There were six PRSP isolates in the comparator group (two isolates were from one patient), and three of five patients in this group were successes. In conclusion, amoxicillin/clavulanate 2000/125 mg demonstrated combined clinical/bacteriological success against 50/52 patients with PRSP, including 13/15 strains with amoxicillin MICs of 4-8 mg/L. These results for the pharmacokinetic-enhanced formulation of amoxicillin/clavulanate 2000/125 mg are in line with the high efficacy against PRSP predicted using pharmacokinetic/pharmacodynamic parameters.