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

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.