PK-PD Evaluation of Doripenem (DOR) Against Extended Spectrum ß-Lactamase (ESBL) Producing Enterobacteraceae

Authors: Andes D, Craig WA, Bhavnani SM, Jones RN, Thye D, Wikler MA, Ambrose PG
Conference: IDSA
Keywords: anti-infectives, antibiotic, bacilli, carbapenem, cefepime, ceftazidime, E coli, Emax, enterobacter, gram-negative, infectious disease, intravenous, IV, Klebsiella, MIC, mice, Monte Carlo, murine, pseudomonas, SC, simulation, subcutaneous, T>MIC
Division: Clinical Pharmacology and Pharmacometrics (CPP)

Abstract

Background: Increasing resistance among ESBL-producing bacteria is a growing concern. We examined the potential utility of DORI against ESBL-producing isolates.

Methods: Physicians and house staff practicing in a 24-bed medical-surgical-trauma ICU are now required to A murine infection model was used to identify the PK-PD measure (T>MIC) associated with efficacy and the impact of ESBL production on the in vivo activity of DORI. Mice were infected with 106.5-7.5 CFU/mL of 3 strains of E. coli (1 non- ESBL & 2 ESBL), 4 K. pneumoniae (2 non-ESBL & 2 ESBL), and 2 E. cloacae (1 non-ESBL & 1 ESBL). The T>MIC necessary to produce a static effect and a 1-log kill were determined using an Emax model. DOR MIC distributions for non-ESBL and ESBL producing E. coli, K. pneumoniae and P. mirabilis strains were determined by NCCLS methods. Mean parameter estimates and a covariance matrix from a population PK model were used for a 5000 patient Monte Carlo Simulation to estimate the probability of DOR attaining target exposure for a static/-log kill for various dosing regimens.

Results: For a static effect, mean free drug T>MIC was 30% (20-38%) and 29% (26-33%) for non-ESBL and ESBL strains, respectively. For a 1-log kill, mean free drug T>MIC was 40% (27-47%) and 35% (30-39%) for non-ESBL and ESBL strains, respectively. The MIC50/90 for combined non-ESBL (80) and ESBL (74) strains was ≤0.015/0.06 and
0.03/0.12, respectively. The table below demonstrates the impact of varying dose, interval, and infusion durations on PKPD target attainment (%) at MICs of 0.12 and 0.25 mg/L.

Conclusions: ESBL production in the strains had no impact on the T>MIC needed for in vivo efficacy nor the DOR MIC distributions against Enterobacteraceae (p values 0.1-0.8). These data suggest that DOR may be useful for the treatment of infections caused by ESBL-producing bacteria.

Infectious Diseases Society of America (IDSA), San Diego, California, October 2003

By D. Andes, W.A. Craig, S.M. Bhavnani R.N. Jones, D. Thye, M.A. Wikler, P.G. Ambrose