Comparative <i>in vitro</i> activity of aztreonam–avibactam and aztreonam plus ceftazidime–avibactam against <i>Stenotrophomonas maltophilia</i> complex

Members of the <i>Stenotrophomonas maltophilia</i> complex are intrinsically multidrug-resistant pathogens that disproportionately affect critically ill patients. Aztreonam-avibactam (ATM-AVI), FDA approved in 2025, combines aztreonam (ATM; stable to L1 β-lactamase) with avibactam (AVI; an L2 β-lactamase inhibitor). Aztreonam plus ceftazidime-avibactam (ATM-CZA) has been used as a surrogate for ATM-AVI, but direct comparisons between the two regimens are lacking. Twenty-three clinical <i>S. maltophilia</i> complex isolates underwent broth microdilution (BMD) testing for ATM, ceftazidime, ATM-AVI, and ATM-CZA, with gradient diffusion performed in parallel for ATM-AVI and ATM-CZA. Static 24-h time-kill assays at humanized steady-state Cmax concentrations evaluated bactericidal activity (≥3-log₁₀ reduction). Semi-mechanistic pharmacodynamic modeling characterized growth kill dynamics by resistance determinants (<i>blaL1</i>, <i>blaL2</i>, <i>smeABC</i>). ATM-CZA and ATM-AVI MIC_50/90 values for BMD were 1/2 and 2/4 mg/L, respectively. Both regimens were bactericidal against most isolates, with a mean paired difference of 0.09 log₁₀ colony-forming units (CFU)/mL (<i>P</i> = 0.83). Isolate-level variation was evident: ATM-AVI sustained killing, whereas ATM-CZA permitted regrowth for MD17639, -4.86 vs 0.13 log₁₀ CFU/mL, <i>P</i> = 0.019; MD17061, -2.61 vs 0.64 log₁₀ CFU/mL, <i>P</i> < 0.001). Conversely, ATM-CZA achieved greater reductions in MD17662 (-3.84 vs -1.95; <i>P</i> = 0.026), MD17047 (-4.27 vs -2.64; <i>P</i> = 0.021), and UK4 (-3.47 vs -1.58; <i>P</i> = 0.017). Modeling predicted ATM-AVI benefit in <i>blaL2</i> and ATM-CZA benefit against <i>blaL1</i> or <i>smeABC</i> dominant isolates, and diminished activity of both when mechanisms coexisted. ATM-AVI and ATM-CZA show comparable <i>in vitro</i> activity against <i>S. maltophilia</i> complex. Isolate-level heterogeneity warrants further study of genotype-phenotype relationships.