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Antimicrobial Agents and Chemotherapy, September 2004, p. 3508-3515, Vol. 48, No. 9
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.9.3508-3515.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Steady-State Plasma and Intrapulmonary Pharmacokinetics and Pharmacodynamics of Cethromycin

John E. Conte Jr.,1,2,3* Jeffrey A. Golden,2 Juliana Kipps,1 and Elisabeth Zurlinden1

Infectious Diseases Research Group, Department of Epidemiology and Biostatistics,1 Department of Medicine,2 Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California3

Received 30 October 2003/ Returned for modification 9 December 2003/ Accepted 25 April 2004

The objective of this study was to determine the steady-state plasma and intrapulmonary pharmacokinetic parameters of orally administered cethromycin in healthy volunteers. The study design included administering 150 or 300 mg of cethromycin once daily to 25 or 35 healthy adult subjects, respectively, for a total of five doses. Standardized and timed bronchoalveolar lavage (BAL) was performed after the last dose. Blood was obtained for drug assay prior to the first and last dose, at multiple time points following the last dose, and at the time of BAL. Cethromycin was measured in plasma, BAL, and alveolar cell (AC) by using a combined high-performance liquid chromatography-mass spectrometric technique. Plasma, epithelial lining fluid (ELF), and AC pharmacokinetics were derived by noncompartmental methods. Cmax/90% minimum inhibitory concentration (MIC90) ratios, area under the concentration-time curve (AUC)/MIC90 ratios, intrapulmonary drug exposure ratios, and percent time above MIC90 during the dosing interval (%T > MIC90) were calculated for recently reported respiratory pathogens. The kinetics were nonlinear, i.e., not proportional to dose. In the 150-mg-dose group, the Cmax (mean ± standard deviations), AUC0-24, and half-life for plasma were 0.181 ± 0.084 µg/ml, 0.902 ± 0.469 µg · h/ml, and 4.85 ± 1.10 h, respectively; for ELF the values were 0.9 ± 0.2 µg/ml, 11.4 µg · h/ml, and 6.43 h, respectively; for AC the values were 12.7 ± 6.4 µg/ml, 160.8 µg · h/ml, and 10.0 h, respectively. In the 300-mg-dose group, the Cmax (mean ± standard deviations), AUC0-24, and half-life for plasma were 0.500 ± 0.168 µg/ml, 3.067 ± 1.205 µg · h/ml, and 4.94 ± 0.66 h, respectively; for ELF the values were 2.7 ± 2.0 µg/ml, 24.15 µg · h/ml, and 5.26 h, respectively; for AC the values were 55.4 ± 38.7 µg/ml, 636.2 µg · h/ml, and 11.6 h, respectively. We concluded that the Cmax/MIC90 ratios, AUC/MIC90 ratios, %T > MIC90 values, and extended plasma and intrapulmonary half-lives provide a pharmacokinetic rationale for once-daily administration and are favorable for the treatment of cethromycin-susceptible pulmonary infections.

* Corresponding author. Mailing address: University of California, San Francisco, 350 Parnassus Ave., Suite 507, San Francisco, CA 94117. Phone: (415) 476-1312. Fax: (415) 476-0760. E-mail: 1jconte99{at}comcast.net.

Antimicrobial Agents and Chemotherapy, September 2004, p. 3508-3515, Vol. 48, No. 9
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.9.3508-3515.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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