Clinical use of ampicillin-sulbactam/ceftazidime-avibactam combination therapy for carbapenem-resistant Acinetobacter baumannii complex infections

S ulbactam-durlobactam is a key drug in the treatment of carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (CRAB) infections; however, access is limited due to cost and availability (1,2).There is increasing in vitro, but limited clinical data supporting the utility of avibactam instead of durlobactam in "sulbactam-avibac tam" combinations (3-11).Three patients received ampicillin-sulbactam/ceftazidime-avibactam (AS/CA) for CRAB infections-ventilator-associated pneumonia, infected burns, and bacteremia.Table 1 summarizes clinical features, antimicrobial dosing, and outcomes; case descrip tions are provided in the supplemental material.There was no attributable drug toxicity.Isolates underwent whole-genome sequencing with Oxford Nanopore (supplemental material and Table S2).All isolates carried acquired bla OXA-23 , with ISAba1 detected as the upstream promoter for intrinsic bla OXA-51-like and bla ADC genes.Additionally, a PBP3 mutation (A515V) associated with increased sulbactam-durlobactam MICs was present in all isolates (12).Broth microdilution MIC measurements were performed for all components for AS/CA (Table 2 and supplemental material).The median sulbactam MIC of 32 mg/L was reduced to a median of 8 mg/L with the addition of avibactam.Synergy checkerboard assays were performed to calculate the fractional inhibitory concentration index (FICi).F min is the lowest determined FICi value, and F min ≤ 0.5 indicates synergy (Table 3 and supplemen tal material) (13).The sulbactam-avibactam combination showed synergy for all isolates (F min , 0.188-0.125).Testing of ampicillin-sulbactam with ceftazidime-avibactam when sulbactam and avibactam concentrations were both fixed at 2 mg/L and 4 mg/L did not demonstrate further synergy from the partner drugs (F min , 1.001-0.501),but some additive benefit was observed.We demonstrate potential clinical efficacy and tolerability of AS/CA for the treatment of serious CRAB infections.Case 1 did not clearly demonstrate clinical response, and the cause of death was progressive metastatic mesothelioma.Microbiological response could not be evaluated due to lack of follow-up cultures.Cases 2 and 3 had no growth on burn cultures while on treatment, despite having been consistently culture-positive before treatment.With discontinuation of AS/CA, both cases re-isolated CRAB from burn samples, though neither required re-treatment for clinical infection.The contribution of concomitant antimicrobials in our cases was likely limited.In Case 1, initial therapy included aztreonam for possible concurrent infection with MBL-pro ducing Enterobacterales.Case 3 developed bacteremia while receiving trimethoprimsulfamethoxazole (to which it tested susceptible), resulting in the addition of AS/CA, suggesting that trimethoprim-sulfamethoxazole alone was insufficient.