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Antimicrobial Agents and Chemotherapy, January 2008, p. 204-210, Vol. 52, No. 1
0066-4804/08/$08.00+0     doi:10.1128/AAC.00813-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Exposure-Response Analyses of Tigecycline Efficacy in Patients with Complicated Intra-Abdominal Infections{triangledown}

J. A. Passarell,1* A. K. Meagher,1 K. Liolios,1 B. B. Cirincione,1 S. A. Van Wart,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 22 June 2007/ Returned for modification 13 August 2007/ Accepted 17 October 2007

Exposure-response analyses were performed to test the microbiological and clinical efficacies of tigecycline in complicated intra-abdominal infections where Escherichia coli and Bacteroides fragilis are the predominant pathogens. Data from evaluable patients enrolled in three clinical trials were pooled. Patients received intravenous tigecycline (100-mg loading dose followed by 50 mg every 12 h or 50-mg loading dose followed by 25 mg every 12 h). At the test-of-cure visit, microbiological and clinical responses were evaluated. Patients were prospectively classified into cohorts based on infection with a baseline pathogen(s): E. coli only (cohort 1), other mono- or polymicrobial Enterobacteriaceae (cohort 2), at least one Enterobacteriaceae pathogen plus an anaerobe(s) (cohort 3), at least one Enterobacteriaceae pathogen plus a gram-positive pathogen(s) (cohort 4), and all other pathogens (cohort 5). The cohorts were prospectively combined to increase sample size. Logistic regression was used to evaluate ratio of steady-state 24-hour area under the concentration-time curve (AUC) to MIC as a response predictor, and classification-and-regression-tree (CART) analyses were utilized to determine AUC/MIC breakpoints. Analysis began with cohorts 1, 2, and 3 pooled, which included 71 patients, with 106 pathogens. The small sample size precluded evaluation of cohorts 1 (34 patients, 35 E. coli pathogens) and 2 (16 patients, 24 Enterobacteriaceae). CART analyses identified a significant AUC/MIC breakpoint of 6.96 for microbiological and clinical responses (P values of 0.0004 and 0.399, respectively). The continuous AUC/MIC ratio was also borderline predictive of microbiological response (P = 0.0568). Cohort 4 (21 patients, 50 pathogens) was evaluated separately; however, an exposure-response relationship was not detected; cohort 5 (31 patients, 60 pathogens) was not evaluated. The prospective approach of creating homogenous populations of pathogens was critical for identifying exposure-response relationships in complicated intra-abdominal infections.

* Corresponding author. Mailing address: Cognigen Corporation, 395 Youngs Road, Buffalo, NY 14221. Phone: (716) 633-3463, ext. 266. Fax: (716) 633-7404. E-mail: Julie.Passarell{at}cognigencorp.com

{triangledown} Published ahead of print on 22 October 2007.

Antimicrobial Agents and Chemotherapy, January 2008, p. 204-210, Vol. 52, No. 1
0066-4804/08/$08.00+0     doi:10.1128/AAC.00813-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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