Efficacy of human-simulated aztreonam-avibactam against Stenotrophomonas maltophilia in the neutropenic murine thigh infection model

BACKGROUND: Stenotrophomonas maltophilia causes severe infections with limited treatment options. Aztreonam-avibactam demonstrates in vitro activity against this important pathogen with an MIC90 of 4/4 mg/L, but the efficacy of this agent is unknown. Herein, we used the neutropenic thigh infection model to assess in vivo efficacy against S. maltophilia. METHODS: S. maltophilia isolates (n = 27) resistant to aztreonam (MIC ≥64 mg/L) and with aztreonam-avibactam MICs between 2/4 and >16/4 mg/L were examined using a neutropenic murine thigh infection model. Pharmacokinetic studies were performed for the development of a human-simulated regimen (HSR) of aztreonam-avibactam (1.5-0.5 g q6h, 3h infusion) to mimic the human free plasma exposure profile. Efficacy of the aztreonam-avibactam HSR was defined as ≥1 log10 cfu/thigh reduction at 24 h compared with baseline bacterial burden. RESULTS: Among investigated isolates, the mean baseline bacterial burden in the model was 6.22 ± 0.16 log10 cfu/thigh. Without treatment, isolates grew on average to 7.81 ± 0.44 log10 cfu/thigh at 24 h. With aztreonam-avibactam HSR administration, 78% (7/9), 67% (6/9), 29% (2/7) and 0% (0/2) reached ≥1 log10 cfu/thigh reduction at MICs of 2/4, 4/4, 8/4 and ≥16/4 mg/L, respectively. CONCLUSIONS: Aztreonam-avibactam HSR demonstrated in vivo efficacy against the majority of S. maltophilia isolates with MIC ≤4/4 mg/L in a neutropenic murine thigh infection model. These results provide decision support to standards development organizations for determination of susceptibility breakpoints for aztreonam-avibactam against S. maltophilia.