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Enhanced efficacy of single-dose versus multi-dose azithromycin regimens in preclinical infection models.
J Antimicrob Chemother. 2005 Aug; 56(2):365-71.JA

Abstract

OBJECTIVES

As a result of the prolonged half-life and unique pharmacokinetic and pharmacodynamic (PK-PD) characteristics of azithromycin, shorter dosing regimens are being evaluated for the treatment of community-acquired infections. To provide further support for a shorter dosing regimen, the efficacy of azithromycin was determined in preclinical infection models comparing single- versus multi-dose regimens.

METHODS

The efficacy of single versus multi-dose regimens of azithromycin was compared in mouse pneumonia, acute peritonitis, and neutropenic thigh infection models and in a gerbil model of Haemophilus influenzae acute otitis media. Azithromycin was administered as a single oral dose on the first treatment day, or as two divided doses over 2 treatment days, or as three divided doses over 3 treatment days. The pharmacokinetics of azithromycin was profiled following single and multi-dose regimens with the single dose data fit to an Emax model to characterize the PK-PD of azithromycin.

RESULTS

In the mouse efficacy models, administration of single-dose azithromycin produced superior rates of survival and bacterial clearance compared with the same total dose divided over 2 or 3 days. In the gerbil model, a single dose sterilized the middle ear and more rapidly cleared H. influenzae. The pharmacokinetic evaluation confirmed similar total exposure (AUC) in serum and pulmonary tissue for the three regimens. Correlation of PK-PD parameters and antimicrobial efficacy confirmed a concentration-dependent and dosing-independent relationship for azithromycin.

CONCLUSIONS

These data are consistent with data reported from clinical studies and indicate that a single-dose regimen would be at least as effective as the same dose administered over several days.

Authors+Show Affiliations

Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA. dennis.girard@pfizer.comNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16002421

Citation

Girard, D, et al. "Enhanced Efficacy of Single-dose Versus Multi-dose Azithromycin Regimens in Preclinical Infection Models." The Journal of Antimicrobial Chemotherapy, vol. 56, no. 2, 2005, pp. 365-71.
Girard D, Finegan SM, Dunne MW, et al. Enhanced efficacy of single-dose versus multi-dose azithromycin regimens in preclinical infection models. J Antimicrob Chemother. 2005;56(2):365-71.
Girard, D., Finegan, S. M., Dunne, M. W., & Lame, M. E. (2005). Enhanced efficacy of single-dose versus multi-dose azithromycin regimens in preclinical infection models. The Journal of Antimicrobial Chemotherapy, 56(2), 365-71.
Girard D, et al. Enhanced Efficacy of Single-dose Versus Multi-dose Azithromycin Regimens in Preclinical Infection Models. J Antimicrob Chemother. 2005;56(2):365-71. PubMed PMID: 16002421.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Enhanced efficacy of single-dose versus multi-dose azithromycin regimens in preclinical infection models. AU - Girard,D, AU - Finegan,S M, AU - Dunne,M W, AU - Lame,M E, Y1 - 2005/07/07/ PY - 2005/7/9/pubmed PY - 2005/9/3/medline PY - 2005/7/9/entrez SP - 365 EP - 71 JF - The Journal of antimicrobial chemotherapy JO - J Antimicrob Chemother VL - 56 IS - 2 N2 - OBJECTIVES: As a result of the prolonged half-life and unique pharmacokinetic and pharmacodynamic (PK-PD) characteristics of azithromycin, shorter dosing regimens are being evaluated for the treatment of community-acquired infections. To provide further support for a shorter dosing regimen, the efficacy of azithromycin was determined in preclinical infection models comparing single- versus multi-dose regimens. METHODS: The efficacy of single versus multi-dose regimens of azithromycin was compared in mouse pneumonia, acute peritonitis, and neutropenic thigh infection models and in a gerbil model of Haemophilus influenzae acute otitis media. Azithromycin was administered as a single oral dose on the first treatment day, or as two divided doses over 2 treatment days, or as three divided doses over 3 treatment days. The pharmacokinetics of azithromycin was profiled following single and multi-dose regimens with the single dose data fit to an Emax model to characterize the PK-PD of azithromycin. RESULTS: In the mouse efficacy models, administration of single-dose azithromycin produced superior rates of survival and bacterial clearance compared with the same total dose divided over 2 or 3 days. In the gerbil model, a single dose sterilized the middle ear and more rapidly cleared H. influenzae. The pharmacokinetic evaluation confirmed similar total exposure (AUC) in serum and pulmonary tissue for the three regimens. Correlation of PK-PD parameters and antimicrobial efficacy confirmed a concentration-dependent and dosing-independent relationship for azithromycin. CONCLUSIONS: These data are consistent with data reported from clinical studies and indicate that a single-dose regimen would be at least as effective as the same dose administered over several days. SN - 0305-7453 UR - https://www.unboundmedicine.com/medline/citation/16002421/Enhanced_efficacy_of_single_dose_versus_multi_dose_azithromycin_regimens_in_preclinical_infection_models_ L2 - https://academic.oup.com/jac/article-lookup/doi/10.1093/jac/dki241 DB - PRIME DP - Unbound Medicine ER -