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

Abstract

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 µg/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.

Adaptive resistance to cefiderocol in carbapenem-resistant Acinetobacter baumannii (CRAB): microbiological and clinical issues

“…In two correspondences, Choby et al, 2021 [ 9 , 10 ] suggested that these discrepancies might be due to cefiderocol-heteroresistant subpopulations not detected by standard AST. This hypothesis seems to be invalidated by the latest results from the CREDIBLE-CR study presented by Longshaw et al [ 11 ]. However, the apparently high rate of clinical or microbiological failure in some case series cannot be ignored, although other factors, such as clinical severity (septic shock) or strong immunosuppression, may influence these poor patient outcomes [ 6 , 12 ].…”

Heteroresistance to piperacillin/tazobactam in Klebsiella pneumoniae is mediated by increased copy number of multiple β-lactamase genes

“… 9–13 We found the prevalence of HR to be considerable among isolates with a susceptible MIC, with HR more likely among isolates with a higher baseline MIC. Although the impact on clinical outcomes remains unclear, 14–16 animal and some clinical studies have implicated HR in antibiotic failure. 8 Thus, ongoing surveillance for HR is warranted, as is continued investigation into its impact on clinical outcomes.…”

Rates of resistance and heteroresistance to newer β-lactam/β-lactamase inhibitors for carbapenem-resistant Enterobacterales

“… 8 There is conflicting evidence that HR can lead to antibiotic treatment failures, and most of these data come from studies of HR in Staphylococcus aureus 25–27 and Acinetobacter baumannii. 28–30 Furthermore, the lack of standardization of HR definitions and methods of detection, especially for Enterobacterales, has made understanding the relevance of HR in treatment failure problematic. 31 While there are limited data on the clinical implications of HR, animal studies have demonstrated failure of carbapenem therapy in HR Gram-negative bacilli infection models.…”