Heteroresistance to cefiderocol in carbapenem-resistant Acinetobacter baumannii in the CREDIBLE-CR study was not linked to clinical outcomes: a post hoc analysis

This study aimed to determine the proportion of heteroresistance in carbapenem-resistant Acinetobacter calcoaceticus-baumannii complex (CRAB) isolates in the cefiderocol arm of the randomized, Phase 3 CREDIBLE-CR study by population analysis profiling (PAP) and to determine whether there is any correlation between heteroresistance and clinical outcomes. PAP phenotypes [PAP-susceptible (PAP-S), PAP-heteroresistant (PAP-HR), or PAP-resistant (PAP-R)] were determined for baseline CRAB isolates after growing for 72 hours on agar plates containing twofold dilutions of cefiderocol (0.5-64 mu g/mL). Clinical cure, microbiological eradication, and all-cause mortality (ACM) were analyzed by PAP phenotype. Only descriptive statistics were performed. Of the 38 CRAB isolates, 36 were susceptible and 2 were non-susceptible by broth microdilution (reference method), while 18 (47.4%) isolates were PAP-HR, 7 (18.4%) were PAP-S, and 13 (34.2%) were PAP-R. ACM by the end of study (end of treatment + 28 days) was 22.2% (4/18) for patients with PAP-HR isolates, 100% (7/7) with PAP-S isolates, and 61.5% (8/13) with PAP-R isolates. Among patients with PAP-HR isolates, 77.8% (14/18) had clinical cure and 38.9% (7/18) had microbiological eradication at test of cure. Among patients with PAP-S isolates, none had clinical cure or microbiological eradication. For patients with PAP-R isolates, clinical cure [23.1% (3/13)] and microbiological eradication [15.4% (2/13)] rates were low at test of cure. Using the PAP method, heteroresistance was detected in CRAB isolates in the cefiderocol arm in the CREDIBLE-CR study. However, heteroresistance was not associated with increased mortality or worse clinical and microbiological outcomes compared with patients with non-heteroresistant isolates. IMPORTANCE The population analysis profiling (PAP) test is considered the "gold standard" method to detect heteroresistance. It exposes bacteria to increasing concentrations of antibiotics at high cell densities to detect any minority resistant subpopulations that might be missed by the low inoculums used for reference susceptibility tests. However, its clinical relevance has not been well established. In the CREDIBLE-CR study, a numerically increased all-cause mortality was observed in the cefiderocol arm relative to the best available therapy arm for patients with Acinetobacter spp. infections. Heteroresistance has independently been proposed by another research group as a potential explanation of the mortality difference. An analysis of the baseline carbapenem-resistant Acinetobacter calcoaceticus-baumannii complex isolates from patients treated with cefiderocol in the CREDIBLE-CR study showed the highest clinical cure rate and the lowest mortality for patients with PAP-heteroresistant isolates compared with PAP-susceptible or PAP-resistant isolates. These findings contradict the abovementioned hypothesis that heteroresistance contributed to the increased mortality.