Ceftazidime-Avibactam Susceptibility Breakpoints against Enterobacteriaceae and Pseudomonas aeruginosa

Abstract

Clinical susceptibility breakpoints against Enterobacteriaceae and Pseudomonas aeruginosa for the ceftazidime-avibactam dosage regimen of 2,000/500 mg every 8 h (q8h) by 2-h intravenous infusion (adjusted for renal function) have been established by the FDA, CLSI, and EUCAST as susceptible (MIC, ≤8 mg/liter) and resistant (MIC, >8 mg/liter). The key supportive data from pharmacokinetic/pharmacodynamic analyses, in vitro surveillance, including molecular understanding of relevant resistance mechanisms, and efficacy in regulatory clinical trials are collated and analyzed here.

Trial registration: ClinicalTrials.gov NCT00752219 NCT01499290 NCT01500239 NCT01726023 NCT01595438 NCT01599806 NCT01644643 NCT01808092.

Keywords: MIC breakpoints; ceftazidime-avibactam.

FIG 1

Joint PTA for patients with cIAI and normal renal function receiving ceftazidime-avibactam 2,000/500 mg q8h plotted as a function of ceftazidime-avibactam MIC overlaid with the ceftazidime-avibactam MIC distributions against Enterobacteriaceae (n = 34,062) from the INFORM global surveillance program, 2012 to 2014 (A), overlaid with the ceftazidime-avibactam MIC distributions against Pseudomonas aeruginosa (n = 7,062) from the INFORM global surveillance program, 2012 to 2014 (B), and sensitivity analysis of PTA at different joint PK/PD targets (C). Joint PTA is defined as simultaneous attainment of 50% fT>MIC of ceftazidime-avibactam for ceftazidime and 50% fT>C_T of 1 mg/liter for avibactam, with both targets having to be achieved for a simulated patient to be categorized as achieving the joint target. Ceftazidime-avibactam MICs were evaluated with avibactam tested at a fixed concentration of 4 mg/liter. PTA was evaluated for ceftazidime-avibactam MIC values of 0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64, and 128 mg/liter. The values above the bars are the numbers of isolates tested at each MIC. The arrows show the position of the approved ceftazidime-avibactam-susceptible clinical breakpoint of MIC ≤8 mg/liter (8, 9). This set of isolates of Enterobacteriaceae was also the source of analyses of phenotypically and genotypically defined resistant subpopulations as discussed in the text (3, 4, 6). The isolates of P. aeruginosa were presented and analyzed in detail elsewhere (5).

FIG 2

Distributions of ceftazidime-avibactam MICs against Enterobacteriaceae (n = 2,615) (A) and Pseudomonas aeruginosa (n = 276) (B) across one phase 2 and five phase 3 prospective clinical trials. The ranges of MICs tested were up to 32 mg/liter in the phase 2 trial and up to 256 mg/liter in the phase 3 trials. The upper limit plotted here was >128 mg/liter, for comparability with Fig. 1. Three Enterobacteriaceae isolates and one P. aeruginosa isolate from the phase 2 trial tested with a ceftazidime-avibactam MIC of >32 mg/liter and are excluded from these frequency distributions. Data pooled from the microbiological modified intent-to-treat populations of the following trials: phase 2 cIAI (NCT00752219 [39]), phase 3 cIAI (RECLAIM 1 and 2 [NCT01499290 and NCT01500239] and RECLAIM 3 [NCT01726023] [40, 43]), phase 3 cUTI (RECAPTURE 1 and 2 [NCT01595438 and NCT01599806] [41]), phase 3 cIAI and cUTI caused by ceftazidime-nonsusceptible pathogens (REPRISE [NCT01644643] [42]), and NP, including VAP (REPROVE [NCT01808092] [44]). Ceftazidime-avibactam MICs were evaluated with avibactam tested at a fixed concentration of 4 mg/liter. The values above the bars are the numbers of isolates tested at each MIC. The arrows show the position of the approved ceftazidime-avibactam-susceptible clinical breakpoint of MIC ≤8 mg/liter (8, 9).