Durability and mechanistic performance of aztreonam/avibactam versus aztreonam plus ceftazidime/avibactam against Stenotrophomonas maltophilia complex

BACKGROUND: Stenotrophomonas maltophilia complex infections are difficult to treat because of intrinsic resistance mediated by the L1 metallo-β-lactamase and L2 serine β-lactamase. Although aztreonam/avibactam is clinically available, aztreonam combined with ceftazidime/avibactam remains an alternative, but comparative pharmacodynamic data under clinically relevant exposures are limited. We compared aztreonam/avibactam and aztreonam + ceftazidime/avibactam under prolonged human-simulated dosing. METHODS: Three clinical S. maltophilia complex isolates (17061, 17639 and 16852) were studied in 96-h hollow fibre infection models. Human-simulated aztreonam/avibactam and aztreonam + ceftazidime/avibactam regimens were administered as 3-h extended or continuous infusions at total daily aztreonam doses of 6 g or 8 g. blaL1 and blaL2 expression was quantified by RT-qPCR, and population pharmacokinetic modelling with Monte Carlo simulation (n = 1000) verified target exposures. RESULTS: At 6 g/day of aztreonam, neither aztreonam/avibactam nor aztreonam + ceftazidime/avibactam achieved sustained bactericidal activity; extended infusions failed to produce killing, and continuous infusion produced only transient bactericidal effects followed by regrowth. In contrast, continuous-infusion aztreonam/avibactam at 8 g/day produced rapid and durable bactericidal activity across all isolates through 96 h with stable minimum inhibitory concentrations (MICs), whereas aztreonam + ceftazidime/avibactam at the same dose achieved early killing followed by regrowth. Transcriptionally, aztreonam/avibactam limited or uncoupled blaL1 and blaL2 induction even at intensified dosing, while aztreonam + ceftazidime/avibactam more consistently promoted blaL1 up-regulation and greater β-lactamase variability. CONCLUSIONS: Under human-simulated conditions, only continuous-infusion aztreonam/avibactam with intensified aztreonam exposure (8 g/day) achieved durable bactericidal activity against S. maltophilia complex, whereas adding ceftazidime did not improve pharmacodynamic outcomes and was associated with greater β-lactamase induction.