The activity of 14-hydroxy clarithromycin, alone and in combination with clarithromycin, against penicillin- and erythromycin-resistant Streptococcuspneumoniae

There are no data regarding the activity of clarithromycin's active metabol ite, 14-hydroxy clarithromycin, against penicillin-intermediate, penicillin -resistant or erythromycin-resistant Streptococcus pneumoniae. Agar dilutio n MICs were determined for clarithromycin, 14-hydroxy clarithromycin (hence forth called 'metabolite'), azithromycin, erythromycin and clarithromycin/m etabolite (2:1 and 1:1 ratio) against 24 penicillin-intermediate and 14 pen icillin-resistant strains, including 13 erythromycin-resistant clinical str ains and one ATCC strain of S. pneumoniae. The interaction between clarithr omycin and its metabolite was determined using an agar chequerboard assay a gainst all isolates, and time-kill tests were performed against five penici llin-intermediate (macrolide-susceptible) and five penicillin-resistant (tw o macrolide-resistant) strains of S, pneumoniae using all antibiotics alone at simulated peak serum concentrations, and clarithromycin/metabolite in a 2:1 ratio (physiological). MICs were as follows: clarithromycin, 0.008-> 6 4 mg/L; metabolite, 0.015-> 64 mg/L; erythromycin, 0.015->64 mg/L; azithrom ycin, 0.125-> 64 mg/L; clarithromycin/metabolite (1:1 and 2:1 combinations) , 0.001-> 64 mg/L. The MIC of the clarithromycin/metabolite combination was one or more tube dilution lower than the MIC of clarithromycin in 28 of th e isolates tested. In chequerboard testing, 13 strains (seven erythromycin susceptible and six erythromycin resistant) demonstrated synergy, 18 additi vity and seven indifference. In time-kill testing, bacterial eradication be low detection limits occurred with clarithromycin and metabolite in seven o f 10 organisms. The combination of parent and metabolite was more rapidly b actericidal than clarithromycin alone in six of the seven isolates (P = 0.0 26). The metabolite has potent activity against S. pneumoniae and enhances the activity of the parent compound against this organism. The metabolite's activity must be considered in evaluating clarithromycin in vitro to avoid underestimation of clarithromycin's activity against the pneumococcus.