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Pharmacodynamic Modeling of Clarithromycin against Macrolide-Resistant [PCR-Positive mef(A) or erm(B)] Streptococcus pneumoniae Simulating Clinically Achievable Serum and Epithelial Lining Fluid Free-Drug Concentrations

Department of Medical Microbiology, Faculty of Medicine, University of Manitoba,² Departments of Clinical Microbiology,³ Medicine, Health Sciences Centre, Winnipeg, Manitoba, Canada¹

Received 11 October 2001/ Returned for modification 22 April 2002/ Accepted 10 August 2002

The association between macrolide resistance mechanisms and clinical outcomes remains understudied. The present study, using an in vitro pharmacodynamic model, assessed clarithromycin (CLR) activity against mef(A)-positive and erm(B)-negative Streptococcus pneumoniae isolates by simulating free-drug concentrations in serum and both total (protein-bound and free) and free drug in epithelial lining fluid (ELF). Five mef(A)-positive and erm(B)-negative strains, one mef(A)-negative and erm(B)-positive strain, and a control [mef(A)-negative and erm(B)-negative] strain of S. pneumoniae were tested. CLR was modeled using a one-compartment model, simulating a dosage of 500 mg, per os, twice a day (in serum, free-drug C_p maximum of 2 µg/ml, t_1/2 of 6 h; in ELF, C_ELF(total) maximum of 35µg/ml, t_1/2 of 6 h; C_ELF(free) maximum of 14 µg/ml, t_1/2 of 6 h). Starting inocula were 10⁶ CFU/ml in Mueller-Hinton broth with 2% lysed horse blood. With sampling at 0, 4, 8, 12, 20, and 24 h, the extent of bacterial killing was assessed. Achieving CLR T/MIC values of 90% (AUC_0-24/MIC ratio, 61) resulted in bacterial eradication, while T>MIC values of 40 to 56% (AUC_0-24/MIC ratios of 30.5 to 38) resulted in a 1.2 to 2.0 log₁₀ CFU/ml decrease at 24 h compared to that for the initial inoculum. CLR T/MIC values of 8% (AUC_0-24/MIC ratio, 17.3) resulted in a static effect or bacterial regrowth. The high drug concentrations in ELF that were obtained clinically with CLR may explain the lack of clinical failures with mef(A)-producing S. pneumoniae strains, with MICs up to 8 µg/ml. However, mef(A) isolates for which MICs are 16 µg/ml along with erm(B) may result in bacteriological failures.

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