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

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Abstract
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 10 6 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 log 10 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.