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JAC Advance Access originally published online on May 29, 2003
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Journal of Antimicrobial Chemotherapy (2003) 52, 83-88
© 2003 The British Society for Antimicrobial Chemotherapy

Pharmacodynamic activity of azithromycin against macrolide-susceptible and -resistant Streptococcus pneumoniae simulating clinically achievable free serum, epithelial lining fluid and middle ear fluid concentrations

George G. Zhanel1,3,*, Mel DeCorby1, Ayman Noreddin1, Chris Mendoza1, Andrew Cumming1, Kim Nichol1,2, Aleksandra Wierzbowski1 and Daryl J. Hoban1,2

1 Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba; Departments of 2 Clinical Microbiology and 3 Medicine, Health Sciences Centre, MS673-820 Sherbrook Street, Winnipeg, Manitoba, Canada R3A 1R9

Received 19 December 2002; returned 6 March 2003; revised 2 April 2003; accepted 6 April 2003

Background: The association between macrolide resistance mechanisms and bacteriological eradication of Streptococcus pneumoniae remains poorly studied. The present study, using an in vitro pharmacodynamic model, assessed azithromycin activity against macrolide-susceptible and -resistant S. pneumoniae simulating clinically achievable free serum (S), epithelial lining fluid (ELF) and middle ear fluid (MEF) concentrations.

Materials and methods: Two macrolide-susceptible [PCR-negative for both mef(A) and erm(B)] and six macrolide-resistant [five mef(A)-positive/erm(B)-negative displaying various degrees of macrolide resistance and one mef(A)-negative/erm(B)-positive] S. pneumoniae were tested. Azithromycin was modelled simulating a dosage of 500 mg/250 mg by mouth, once a day [free S: maximum concentration (Cmax) 0.2 mg/L, t1/2 68 h; free ELF Cmax 1.0 mg/L, t1/2 68 h] and 10 mg/kg by mouth, once a day (free MEF: Cmax 1.0 mg/L, t1/2 68 h) using a one compartment model. Starting inocula were 1 x 106 cfu/mL in Mueller–Hinton broth with 2% lysed horse blood. Sampling at 0, 2, 4, 6, 12, 24 and 48 h assessed the extent of bacterial killing (decrease in log10 cfu/mL versus initial inoculum).

Results: Free azithromycin concentrations in serum, ELF and MEF simulating time above the MIC (T > MIC) of 100% [area under the curve to MIC (AUC0–24/MIC] ≥ 36.7] were bactericidal (≥3 log10 killing) at 24 and 48 h versus macrolide-susceptible S. pneumoniae. Against macrolide-resistant S. pneumoniae, free serum concentrations providing T > MIC of 0% or AUC0–24/MIC ≤ 1.1 demonstrated no bacterial inhibition followed by regrowth at 24 and 48 h, whereas free ELF and MEF providing T > MIC of 0% or AUC0–24/MIC of 4.6 produced a bacteriostatic (0.2–0.5 log10 killing at 24 h) effect with a mef(A) strain with an azithromycin MIC of 2 mg/L. Against mef(A)-positive S. pneumoniae strains with azithromycin MICs ≥ 4 mg/L, no bacterial killing occurred at any time point and rapid regrowth was observed simulating ELF or MEF T > MIC of 0% or AUC0–24/MIC ≤ 2.3.

Conclusion: Azithromycin serum, ELF and MEF concentrations rapidly eradicated macrolide-susceptible S. pneumoniae but did not eradicate macrolide-resistant S. pneumoniae regardless of resistance phenotype.

Keywords: azithromycin, pharmacodynamics, Streptococcus pneumoniae

* Corresponding author. Tel: +1-204-787-4902; Fax: +1-204-787-4699; E-mail: ggzhanel{at}pcs.mb.ca


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