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Antimicrobial Agents and Chemotherapy, December 2002, p. 4029-4034, Vol. 46, No. 12
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.12.4029-4034.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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

Ayman M. Noreddin,1 Danielle Roberts,2 Kim Nichol,1,2 Aleksandra Wierzbowski,1 Daryl J. Hoban,1,2 and George G. Zhanel1,2,3*

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 Cp maximum of 2 µg/ml, t1/2 of 6 h; in ELF, CELF(total) maximum of 35µg/ml, t1/2 of 6 h; CELF(free) maximum of 14 µg/ml, t1/2 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% (AUC0-24/MIC ratio, >=61) resulted in bacterial eradication, while T>MIC values of 40 to 56% (AUC0-24/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% (AUC0-24/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.

* Corresponding author. Mailing address: Department of Clinical Microbiology, Health Sciences Centre, MS673-820, Sherbrook St., Winnipeg, Manitoba R3A 1R9, Canada. Phone: (204) 787-4902. Fax: (204) 787-4699. E-mail: ggzhanel{at}pcs.mb.ca.

Antimicrobial Agents and Chemotherapy, December 2002, p. 4029-4034, Vol. 46, No. 12
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.12.4029-4034.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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