Abstract：
OBJECTIVE: To study the clinical relevance, mechanisms, and evolution of polymyxin B (POLB) heteroresistance (PHR) in carbapenem-resistant Klebsiella pneumoniae (CRKP), potentially leading to a significant rise in POLB full resistant (FR) CRKP.
METHODS: Total of 544 CRKP isolates from 154 patients treated with POLB were categorized into PHR and POLB non-heteroresistance (NHR) groups. We performed 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.
RESULTS: We observed a considerable proportion (118 of 154, 76.62%) of clinically undetected PHR strains before POLB exposure, with a significant subset of them (33 of 118, 27.97%) evolving 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. About 92.86% (39 of 42) of patients had PHR isolates before FR, highlighting the clinical importance of PHR. the ST15 exhibited a notably lower PHR rate (1 of 8, 12.5% vs. 117 of 144, 81.25%; p < 0.01). The ST11 PHR strains showing significantly higher rate of mgrB mutations by endogenous insertion sequences in their resistant subpopulation (RS) compared with other STs (78 of 106, 73.58% vs. 4 of 12, 33.33%; p < 0.01). The mgrB insertional inactivation rate was lower in FR isolates than in the RS of PHR isolates (15 of 42, 35.71% vs. 84 of 112, 75%; p < 0.01), whereas the pmrAB mutation rate was higher in FR isolates than in the RS of PHR isolates (8 of 42, 19.05% vs. 2 of 112, 1.79%; p < 0.01). The evolution from PHR to FR was influenced by subpopulation dynamics and genetic adaptability because of hypermutability.
CONCLUSIONS: We highlight significant genetic changes as the primary driver of PHR to FR in CRKP, underscoring polymyxin complexity.
METHODS: Total of 544 CRKP isolates from 154 patients treated with POLB were categorized into PHR and POLB non-heteroresistance (NHR) groups. We performed 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.
RESULTS: We observed a considerable proportion (118 of 154, 76.62%) of clinically undetected PHR strains before POLB exposure, with a significant subset of them (33 of 118, 27.97%) evolving 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. About 92.86% (39 of 42) of patients had PHR isolates before FR, highlighting the clinical importance of PHR. the ST15 exhibited a notably lower PHR rate (1 of 8, 12.5% vs. 117 of 144, 81.25%; p < 0.01). The ST11 PHR strains showing significantly higher rate of mgrB mutations by endogenous insertion sequences in their resistant subpopulation (RS) compared with other STs (78 of 106, 73.58% vs. 4 of 12, 33.33%; p < 0.01). The mgrB insertional inactivation rate was lower in FR isolates than in the RS of PHR isolates (15 of 42, 35.71% vs. 84 of 112, 75%; p < 0.01), whereas the pmrAB mutation rate was higher in FR isolates than in the RS of PHR isolates (8 of 42, 19.05% vs. 2 of 112, 1.79%; p < 0.01). The evolution from PHR to FR was influenced by subpopulation dynamics and genetic adaptability because of hypermutability.
CONCLUSIONS: We highlight significant genetic changes as the primary driver of PHR to FR in CRKP, underscoring polymyxin complexity.
摘要：
目的：研究临床相关性，机制,耐碳青霉烯类肺炎克雷伯菌（PHR-CRKP）中多粘菌素B（POLB）异质抗性的演变，可能导致POLB完全耐药(FR)CRKP显著上升。
方法：将来自154例接受POLB治疗的患者的544株CRKP分离株分为PHR和NHR（POLB非异质耐药）组。我们进行了统计分析，以比较临床意义和治疗反应。我们采用了全基因组测序，生物信息学，和PCR来研究分子流行病学，PHR背后的机制，以及它向FR的演变。
结果：在POLB暴露之前，我们观察到相当比例的临床未检测到的PHR菌株（118/154，76.62％），POLB治疗后，其中一个重要子集（33/118，27.97％）演变成FR。我们调查了临床意义，流行病学特征，在POLB处理的背景下PHR菌株的机制和进化模式。92.86%(39/42)的患者在FR之前有PHR分离株，强调PHR的临床重要性。ST15的PHR率明显较低（1/8，12.5%与117/144,81.25%;P<0.01)。与其他STs相比，ST11PHR菌株在其抗性亚群（RS）中通过内源性插入序列显示mgrB突变率显着更高（78/106，73.58％vs.4/12,33.33%;P<0.01)。FR分离株的mgrB插入失活率低于PHR分离株的RS（15/42，35.71％vs.84/112，75%；P<0.01），而FR分离株的pmrAB突变率高于PHR分离株的RS(8/42，19.05%vs.2/112,1.79%;P<0.01)。由于超突变性，从PHR到FR的进化受到亚群动态和遗传适应性的影响。
结论：我们强调显著的遗传变化是CRKP中PHR到FR的主要驱动因素，强调多粘菌素的复杂性。
方法：将来自154例接受POLB治疗的患者的544株CRKP分离株分为PHR和NHR（POLB非异质耐药）组。我们进行了统计分析，以比较临床意义和治疗反应。我们采用了全基因组测序，生物信息学，和PCR来研究分子流行病学，PHR背后的机制，以及它向FR的演变。
结果：在POLB暴露之前，我们观察到相当比例的临床未检测到的PHR菌株（118/154，76.62％），POLB治疗后，其中一个重要子集（33/118，27.97％）演变成FR。我们调查了临床意义，流行病学特征，在POLB处理的背景下PHR菌株的机制和进化模式。92.86%(39/42)的患者在FR之前有PHR分离株，强调PHR的临床重要性。ST15的PHR率明显较低（1/8，12.5%与117/144,81.25%;P<0.01)。与其他STs相比，ST11PHR菌株在其抗性亚群（RS）中通过内源性插入序列显示mgrB突变率显着更高（78/106，73.58％vs.4/12,33.33%;P<0.01)。FR分离株的mgrB插入失活率低于PHR分离株的RS（15/42，35.71％vs.84/112，75%；P<0.01），而FR分离株的pmrAB突变率高于PHR分离株的RS(8/42，19.05%vs.2/112,1.79%;P<0.01)。由于超突变性，从PHR到FR的进化受到亚群动态和遗传适应性的影响。
结论：我们强调显著的遗传变化是CRKP中PHR到FR的主要驱动因素，强调多粘菌素的复杂性。
