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Antimicrobial Agents and Chemotherapy, June 2007, p. 1939-1945, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.01084-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Exposure-Response Analyses of Tigecycline Efficacy in Patients with Complicated Skin and Skin-Structure Infections{triangledown}

A. K. Meagher,1 J. A. Passarell,1* B. B. Cirincione,1 S. A. Van Wart,1 K. Liolios,1 T. Babinchak,2 E. J. Ellis-Grosse,2 and P. G. Ambrose3,4

Cognigen Corporation, Buffalo, New York,1 Wyeth Research, Collegeville, Pennsylvania,2 ICPD/Ordway Institute, Albany, New York,3 School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York4

Received 28 August 2006/ Returned for modification 1 December 2006/ Accepted 7 March 2007

Exposure-response analyses were performed for the microbiological and clinical efficacy of tigecycline in the treatment of complicated skin and skin-structure infections, where Staphylococcus aureus and streptococci are the predominant pathogens. A prospective method was developed to create homogeneous patient populations for PK-PD analyses. Evaluable patients from three clinical trials were pooled for analysis. Patients received a tigecycline 100-mg loading dose/50 mg every 12 h or a 50-mg loading dose/25 mg every 12 h. At the test-of-cure visit, microbiologic and clinical responses were evaluated. Patients were prospectively evaluated and classified into cohorts based on baseline pathogens: S. aureus only (cohort 1), monomicrobial S. aureus or streptococci (cohort 2), two gram-positive pathogens (cohort 3), polymicrobial (cohort 4), or other monomicrobial infections (cohort 5). A prospective procedure for combining cohorts was used to increase the sample size. Logistic regression evaluated steady-state 24-h area under the concentration-time curve (AUC24)/MIC ratio as a predictor of response, and classification and regression tree (CART) analyses were utilized to determine AUC/MIC breakpoints. Analysis began with pooled cohorts 2 and 3, the focus of these analyses, and included 35 patients with 40 S. aureus and/or streptococcal pathogens. CART analyses identified a significant AUC/MIC breakpoint of 17.9 (P = 0.0001 for microbiological response and P = 0.0376 for clinical response). The continuous AUC/MIC ratio was predictive of microbiological response based on sample size (P = 0.0563). Analysis of all pathogens combined decreased the ability to detect exposure-response relationships. The prospective approach of creating homogeneous populations based on S. aureus and streptococci pathogens was critical for identifying exposure-response relationships.

* Corresponding author. Mailing address: Cognigen Corp., 395 Youngs Rd., Buffalo, NY 14221. Phone: (716) 633-3463. Fax: (716) 633-7404. E-mail: julie.passarell{at}cognigencorp.com

{triangledown} Published ahead of print on 12 March 2007.

Antimicrobial Agents and Chemotherapy, June 2007, p. 1939-1945, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.01084-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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