Impact of the inoculum size on the activity of the aztreonam-avibactam combination in a murine model of peritonitis due to expressing CTX-M-15 and NDM-1.

The combination of aztreonam (ATM) and avibactam (AVI) is an attractive option to treat infections caused by extended spectrum β-lactamase plus NDM-1-producing . Since ATM activity was shown to be severely impacted by an increase in the inoculum size , we wondered whether ATM-AVI activity could be impaired in high-inoculum infections. We analyzed the impact of the inoculum size on ATM-AVI activity and in a murine model of peritonitis due to susceptible CFT073-pTOPO and its isogenic derivatives producing NDM-1 ( CFT073-NDM1) and CTX-M-15 plus NDM-1 ( CFT073-CTXM15-NDM1). The impact of the inoculum size on bacterial morphology was studied by microscopic examination. , at standard (10) inoculum, CFT073-CTXM15-NDM1 was resistant to ATM but susceptible to the ATM-AVI combination. At high (10) inoculum, MICs of ATM alone and of the ATM-AVI combination reached >512 and 64 mg/L, respectively, against all tested strains. ATM led to bacterial filamentation when active against the bacteria, i.e., in monotherapy or in combination with AVI against susceptible CFT073-pTOPO and only in combination with AVI against CFT073-CTXM15-NDM1. , increase in the inoculum led to a drastic decrease in the activity of ATM alone against CFT073-pTOPO and ATM-AVI against CFT073-CTXM15-NDM1. Our results suggest a high impact of the inoculum increase on the activity of ATM alone against ATM-susceptible and of ATM-AVI against CTX-M-15 plus NDM-1 producing . Clinicians must be aware of the risk of failures when using ATM-AVI in high-inoculum infections.