Pharmacokinetic-pharmacodynamic analyses of efficacy using estimates of serum and effect site tigecycline exposures in patients with complicated intra-abdominal infections

Abstract number: o361

Bhavnani  S.M., Rubino  C.M., Ambrose  P.G., Korth-Bradley  J., Speth  J., Ellis-Grosse  E.J., Drusano  G.L.

Introduction: 

Tigecycline has demonstrated efficacy in the treatment of complicated intra-abdominal infections (cIAI).These analyses were designed to examine the relationship between tigecycline exposure, as measured by the ratio of the area under the concentration-time curve to the minimum inhibitory concentration of the drug to the organism (AUC: MIC) in two matrices, serum and colon wall, and outcome.

Methods: 

PK analyses used drug concentrations from Phase 1 (serum and colon wall concentrations in non-infected patients) and Phase 2/3 cIAI (serum) studies, (n = 420). Drug concentration data were co-modelled using NPAG. PK-PD analyses utilized clinical outcome, patient covariates, and serum- and colon wall-based AUC: MIC estimates (which were based on the infecting organism with the highest MIC value). Univariate and multivariate logistic regression with backwards stepping were performed. Covariates with p values < 0.1 in univariate analyses were considered for inclusion in the multivariate models. Tree-based modelling was used to identify PK-PD breakpoints predictive of clinical cure. PK-PD breakpoints were used to evaluate potential susceptibility breakpoints using Monte Carlo simulation.

Results: 

The median tissue penetration (AUCcolon wall:AUCserum) ratio was 1.3 and 2.6 in Phase 1 and Phase 2/3 patients, respectively. 121 patients were included in the PK-PD analyses. MIC values driving AUC: MIC estimates were primarily based on those from Enterobacteriaceae (70%) followed by anaerobes (21%) and gram positive organisms (9%). The final model evaluating serum exposures included diagnosis, weight, APACHE II breakpoint (>= 13), presence of Pseudomonas and AUCserum:MIC breakpoint (7.24) (McFadden's rho-squared = 0.403; p < 0.001). The final model evaluating colon wall exposures included race, weight, APACHE II breakpoint (>= 13), presence of Pseudomonas and AUCcolon wall:MIC breakpoint (4.06) (McFadden's rho-squared = 0.256; p < 0.001). Based on Monte Carlo simulations, the probability of PK-PD target attainment for serum exposures exceeded 0.9 for MIC values up to 0.5 mg/L. For colon wall exposures, the probability of PK-PD target attainment was 0.99 and 0.83 for MIC values of 1 and 2 mg/L, respectively.

Conclusion: 

Patient outcome is multi-faceted. One component, tigecycline exposure, is directly linked to outcome. In addition to considerations of patient status (clinical assessment) and microbiology milieu, effect-site exposure adds to our understanding of drug effect in deep-seated infections.