Exposure-Response Analysis Of The Efficacy Of Tigecycline In Patients With Complicated Skin And Skin-Structure Infections

Authors: Meagher AK, Passarell JA, Cirincione B, Van Wart S, Liolios K, Babinchak T, Ellis-Grosse EJ, Ambrose PG
Conference: ECCMID
Keywords: anti-infectives, antibiotic, AUC:MIC ratio, CART, classification and regression tree, cSSSI, dermatology, exposure-response, GEE, infectious disease, IV, logistic regression, pharmacodynamic, PK/PD, S-Plus, s.aureus, SAS, staphylococcus, steady state, streptococcus
Division: Clinical Pharmacology and Pharmacometrics (CPP)

Abstract

Objectives: Tigecycline, the first glycylcycline to reach clinical trials, is in development for the treatment of patients with serious infections, including complicated skin and skin-structure infections (cSSSI). Pharmacokinetic/pharmacodynamic (PK/PD) relationships, including patient covariates, for microbiological and clinical efficacy of tigecycline were evaluated in patients with cSSSI.

Methods: Patients from 3 cSSSI clinical trials (one phase 2 and two phase 3), with PK data and classified as both clinically and microbiologically evaluable, were pooled for analysis. A prospective approach for categorizing patients into cohorts was used and patients with infections due to Staphylococcus aureus and/or streptococci, the predominant pathogens in cSSSI, were the focus of this evaluation. Patients received 100-mg loading dose and 50 mg q12h (100/50) or 50-mg loading dose and 25 mg q12h (50/25). At the test of cure visit, microbiological (eradication or persistence) and clinical (cure or failure) outcomes were assessed. Indeterminate responses were excluded. Steady-state 24-hour area under the concentration-time curve (AUC) and AUC/MIC ratio were evaluated as predictors of response. Patient covariates included: age, weight, country, baseline Pseudomonas aeruginosa or anaerobes, and comorbidities (diabetes, peripheral vascular disease). Classification and regression tree (CART) analyses determined AUC/MIC breakpoints. Logistic regression (one observation/patient) was performed to determine predictors of efficacy.

Results: The dataset included 35 patients with 40 S. aureus and/or streptococcal baseline pathogens. MIC values ranged from 0.06 to 0.5 g/mL. Clinical cure was achieved in 30 (85.7%) patients and 35 (87.5%) pathogens were successfully eradicated. The median AUC/MIC ratio was 13.5 and 29 for the 50/25 and 100/50 mg dose groups, respectively. Covariates were not significant predictors of efficacy. CART identified a significant AUC/MIC breakpoint of 12.5 (p=0.0177 for microbiological and 0.0341 for clinical response). The continuous AUC/MIC ratio was marginally significant based on sample size (p=0.0563 for microbiological and 0.1960 for clinical response) and was deemed the most informative model. For each unit increase in AUC/MIC, within the observed range, patients were 3.7% more likely to have a successful clinical response and 17.1% more likely to have a successful microbiological response.

Conclusion: Patients with AUC/MIC ratios ≥ 12.5 were 13 times more likely to have successful microbiological response. At the median AUC/MIC ratio of 13.5 and 29 for the 50/25 and 100/50 dose groups, the model-predicted probability of clinical success was 0.6597 and 0.9570, respectively. Tigecycline is likely to be an important treatment option for cSSSI.

European Congress of Clinical Microbiology and Infectious Disease (ECCMID), Copenhagen, Denmark, April 2005

By AK Meagher, Julie A. Passarell, BB Cirincione, SA Van Wart, K Liolios, T Babinchak, EJ Ellis-Grosse, PG Ambrose