title: Exposure-response analyses of tigecycline efficacy in patients with complicated intra-abdominal infections.
abstract: 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.
authors.affiliation: Cognigen Corporation, 395 Youngs Road, Buffalo, NY 14221, USA. Julie.Passarell@cognigencorp.com
authors.forename: J A
authors.initials: JA
authors.lastname: Passarell
authors.forename: A K
authors.initials: AK
authors.lastname: Meagher
authors.forename: K
authors.initials: K
authors.lastname: Liolios
authors.forename: B B
authors.initials: BB
authors.lastname: Cirincione
authors.forename: S A
authors.initials: SA
authors.lastname: Van Wart
authors.forename: T
authors.initials: T
authors.lastname: Babinchak
authors.forename: E J
authors.initials: EJ
authors.lastname: Ellis-Grosse
authors.forename: P G
authors.initials: PG
authors.lastname: Ambrose
mesh_terms: D034841:Abdominal Cavity / Q000382:microbiology*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D001421:Bacteria, Anaerobic / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D006090:Gram-Negative Bacteria / Q000145:classification / Q000187:drug effects; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D006094:Gram-Positive Bacteria / Q000145:classification / Q000187:drug effects; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests / Q000592:standards; D008875:Middle Aged; D008911:Minocycline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000078304:Tigecycline; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D000078304:Tigecycline; D008911:Minocycline