Clinical relevance, mechanisms, and evolution of polymyxin B heteroresistance carbapenem-resistant Klebsiella pneumoniae: A genomic, retrospective cohort study

ObjectivesTo study the clinical relevance, mechanisms, and evolution of polymyxin B (POLB) heteroresistance in carbapenem-resistant Klebsiella pneumoniae (PHR-CRKP), potentially leading to a significant rise in POLB full resistant (FR) CRKP.Methods544 CRKP isolates from 154 patients treated with POLB were categorized into PHR and NHR (POLB non-heteroresistance) groups. We conducted statistical analysis to compare clinical implications and treatment responses. We employed whole-genome sequencing, bioinformatics, and PCR to study the molecular epidemiology, mechanisms behind PHR, and its evolution into FR.ResultsWe observed a considerable proportion (118/154, 76.62%) of clinical undetected PHR strains prior to POLB exposure, with a significant subset of them (33/118, 27.97%) evolved into FR after POLB treatment. We investigated the clinical implications, epidemiological characteristics, mechanisms and evolutionary patterns of PHR strains in the context of POLB treatment. 92.86% (39/42) of patients had PHR isolates before FR, highlighting the clinical importance of PHR. ST15 exhibited a notably lower PHR rate (1/8, 12.5% vs. 117/144, 81.25%; P < 0.01). ST11 PHR strains showing significantly higher rate of mgrB mutations by endogenous insertion sequences in their resistant subpopulation (RS) compared to other STs (78/106, 73.58% vs. 4/12, 33.33%; P < 0.01). The mgrB insertional inactivation rate was lower in FR isolates than in the RS of PHR isolates (15/42, 35.71% vs. 84/112, 75%; P < 0.01), while the pmrAB mutation rate was higher in FR isolates than in the RS of PHR isolates (8/42, 19.05% vs. 2/112, 1.79%; P < 0.01). The evolution from PHR to FR was influenced by subpopulation dynamics and genetic adaptability due to hypermutability.ConclusionsWe highlight significant genetic changes as the primary driver of PHR to FR in CRKP, underscoring polymyxins complexity. To study the clinical relevance, mechanisms, and evolution of polymyxin B (POLB) heteroresistance in carbapenem-resistant Klebsiella pneumoniae (PHR-CRKP), potentially leading to a significant rise in POLB full resistant (FR) CRKP. 544 CRKP isolates from 154 patients treated with POLB were categorized into PHR and NHR (POLB non-heteroresistance) groups. We conducted statistical analysis to compare clinical implications and treatment responses. We employed whole-genome sequencing, bioinformatics, and PCR to study the molecular epidemiology, mechanisms behind PHR, and its evolution into FR. We observed a considerable proportion (118/154, 76.62%) of clinical undetected PHR strains prior to POLB exposure, with a significant subset of them (33/118, 27.97%) evolved into FR after POLB treatment. We investigated the clinical implications, epidemiological characteristics, mechanisms and evolutionary patterns of PHR strains in the context of POLB treatment. 92.86% (39/42) of patients had PHR isolates before FR, highlighting the clinical importance of PHR. ST15 exhibited a notably lower PHR rate (1/8, 12.5% vs. 117/144, 81.25%; P < 0.01). ST11 PHR strains showing significantly higher rate of mgrB mutations by endogenous insertion sequences in their resistant subpopulation (RS) compared to other STs (78/106, 73.58% vs. 4/12, 33.33%; P < 0.01). The mgrB insertional inactivation rate was lower in FR isolates than in the RS of PHR isolates (15/42, 35.71% vs. 84/112, 75%; P < 0.01), while the pmrAB mutation rate was higher in FR isolates than in the RS of PHR isolates (8/42, 19.05% vs. 2/112, 1.79%; P < 0.01). The evolution from PHR to FR was influenced by subpopulation dynamics and genetic adaptability due to hypermutability. We highlight significant genetic changes as the primary driver of PHR to FR in CRKP, underscoring polymyxins complexity.