Teo Jocelyn Qi-Min, Fauzi Nazira, Ho Jayden Jun-Yuan, Tan Si Hui, Lee Shannon Jing-Yi, Lim Tze Peng, Cai Yiying, Chang Hong Yi, Mohamed Yusoff Nurhayati, Sim James Heng-Chiak, Tan Thuan Tong, Ong Rick Twee-Hee, Kwa Andrea Lay-Hoon
Department of Pharmacy, Singapore General Hospital, Singapore, Singapore.
Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
Front Microbiol. 2021 Dec 13;12:779988. doi: 10.3389/fmicb.2021.779988. eCollection 2021.
Carbapenem-resistant (CRKP) is becoming increasingly problematic due to the limited effectiveness of new antimicrobials or other factors such as treatment cost. Thus, combination therapy remains a suitable treatment option. We aimed to evaluate the bactericidal activity of various antibiotic combinations against CRKP with different carbapenemase genotypes and sequence types (STs). Thirty-seven CRKP with various STs and carbapenemases were exposed to 11 antibiotic combinations (polymyxin B or tigecycline in combination with β-lactams including aztreonam, cefepime, piperacillin/tazobactam, doripenem, meropenem, and polymyxin B with tigecycline) in static time-kill studies (TKS) using clinically achievable concentrations. Out of the 407 isolate-combination pairs, only 146 (35.8%) were bactericidal (≥3 logCFU/mL decrease from initial inoculum). Polymyxin B in combination with doripenem, meropenem, or cefepime was the most active, each demonstrating bactericidal activity in 27, 24, and 24 out of 37 isolates, respectively. Tigecycline in combination with β-lactams was rarely bactericidal. Aside from the lower frequency of bactericidal activity in the dual-carbapenemase producers, there was no apparent difference in combination activity among the strains with other carbapenemase types. In addition, bactericidal combinations were varied even in strains with similar STs, carbapenemases, and other genomic characteristics. Our findings demonstrate that the bactericidal activity of antibiotic combinations is highly strain-specific likely owing to the complex interplay of carbapenem-resistance mechanisms, i.e., carbapenemase genotype alone cannot predict bactericidal activity. The availability of WGS information can help rationalize the activity of certain combinations. Further studies should explore the use of genomic markers with phenotypic information to predict combination activity.
由于新型抗菌药物疗效有限或治疗成本等其他因素，耐碳青霉烯类肺炎克雷伯菌（CRKP）正变得越来越棘手。因此，联合治疗仍然是一种合适的治疗选择。我们旨在评估各种抗生素联合用药对具有不同碳青霉烯酶基因型和序列类型（STs）的CRKP的杀菌活性。在静态时间杀菌研究（TKS）中，使用临床可达到的浓度，将37株具有不同STs和碳青霉烯酶的CRKP暴露于11种抗生素联合用药（多粘菌素B或替加环素与包括氨曲南、头孢吡肟、哌拉西林/他唑巴坦、多利培南、美罗培南在内的β-内酰胺类药物联合，以及多粘菌素B与替加环素联合）。在407个菌株-联合用药对中，只有146个（35.8%）具有杀菌作用（相对于初始接种菌量减少≥3 logCFU/mL）。多粘菌素B与多利培南、美罗培南或头孢吡肟联合是最具活性的，分别在37株菌株中有27株、24株和24株表现出杀菌活性。替加环素与β-内酰胺类药物联合很少具有杀菌作用。除了双碳青霉烯酶产生菌的杀菌活性频率较低外，其他碳青霉烯酶类型的菌株在联合活性方面没有明显差异。此外，即使在具有相似STs、碳青霉烯酶和其他基因组特征的菌株中，杀菌联合用药也各不相同。我们的研究结果表明，抗生素联合用药的杀菌活性具有高度菌株特异性，这可能是由于碳青霉烯耐药机制的复杂相互作用，即仅碳青霉烯酶基因型不能预测杀菌活性。全基因组测序（WGS）信息的可用性有助于使某些联合用药的活性合理化。进一步的研究应探索使用基因组标记与表型信息来预测联合活性。
