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

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 mug/ml, t(1/2) of 6 h; in ELF, C-ELF(total) maximum of 35 mug/ml, t(1/2) of 6 h; C-ELF(free) maximum of 14 mug/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 greater than or equal to90% (AUC(0-24)/MIC ratio, greater than or equal to61) resulted in bacterial eradication, while T>MIC values of 40 to 56% (AUC(0-24)/MIC ratios of greater than or equal to30.5 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 less than or equal to8% (AUC(0-24)/MIC ratio, less than or equal to17.3) 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 mug/ml. However, mef(A) isolates for which MICs are greater than or equal to16 mug/ml along with erm(B) may result in bacteriological failures.