Determining the optimal dosing of a novel combination regimen of ceftazidime/avibactam with aztreonam against NDM-1-producing Enterobacteriaceae using a hollow-fibre infection model

Abstract

Background: MBL-producing strains of Enterobacteriaceae are a major public health concern. We sought to define optimal combination regimens of ceftazidime/avibactam with aztreonam in a hollow-fibre infection model (HFIM) of MBL-producing strains of Escherichia coli and Klebsiella pneumoniae.

Methods: E. coli ARLG-1013 (blaNDM-1, blaCTX-M, blaCMY, blaTEM) and K. pneumoniae ARLG-1002 (blaNDM-1, blaCTXM-15, blaDHA, blaSHV, blaTEM) were studied in the HFIM using simulated human dosing regimens of ceftazidime/avibactam and aztreonam. Experiments were designed to evaluate the effect of staggered versus simultaneous administration, infusion duration and aztreonam daily dose (6 g/day versus 8 g/day) on bacterial killing and resistance suppression. Prospective validation experiments for the most active combination regimens were performed in triplicate to ensure reproducibility.

Results: Staggered administration of the combination (ceftazidime/avibactam followed by aztreonam) was found to be inferior to simultaneous administration. Longer infusion durations (2 h and continuous infusion) also resulted in enhanced bacterial killing relative to 30 min infusions. The rate of killing was more pronounced with 8 g/day versus 6 g/day aztreonam combination regimens for both tested strains. In the prospective validation experiments, ceftazidime/avibactam with aztreonam dosed every 8 and 6 h, respectively (ceftazidime/avibactam 2/0.5 g every 8 h + aztreonam 2 g every 6 h), or ceftazidime/avibactam with aztreonam as continuous infusions resulted in maximal bacterial killing and resistance suppression over 7 days.

Conclusions: Simultaneous administration of aztreonam 8 g/day given as a continuous or 2 h infusion with ceftazidime/avibactam resulted in complete bacterial eradication and resistance suppression. Further study of this combination is needed with additional MBL-producing Gram-negative pathogens. The safety of this double β-lactam strategy also warrants further study in Phase 1 clinical trials.

Figure 1.

Staggered versus simultaneous dosing regimens for ceftazidime/avibactam (CAZ/AVI) in combination with aztreonam (ATM) against E. coli and K. pneumoniae. Combination administration strategies were either staggered (ceftazidime/avibactam was given first, followed by aztreonam 2 g given later) or simultaneous (ceftazidime/avibactam and aztreonam given together). This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 2.

Effect of infusion duration on bacterial killing and regrowth against E. coli (ARLG 1013). This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 3.

Effects of altering aztreonam dose from 6 g/day to 8 g/day in combination with standard and CI ceftazidime/avibactam. Other regimens included a growth control, aztreonam monotherapy, ceftazidime/avibactam monotherapy and the aztreonam/avibactam regimen [aztreonam/avibactam 1.5/0.5 g IV q6h (2 h infusion)], which is currently being evaluated in a Phase III clinical trial. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 4.

Prospective validation of optimal regimens identified in HFIM studies. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 5.

PAPs of E. coli ARLG-1013 from prospective validation studies. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.