Paranos Paschalis, Vourli Sophia, Pournaras Spyros, Meletiadis Joseph
Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece.
Department of Medical Microbiology and Infectious Diseases, Erasmus MC, 3015 CN Rotterdam, The Netherlands.
Pharmaceuticals (Basel). 2022 Nov 30;15(12):1501. doi: 10.3390/ph15121501.
In the light of increasing antimicrobial resistance among gram-negative bacteria and the lack of new more potent antimicrobial agents, new strategies have been explored. Old antibiotics, such as colistin, temocillin, fosfomycin, mecillinam, nitrofurantoin, minocycline, and chloramphenicol, have attracted the attention since they often exhibit in vitro activity against multi-drug-resistant (MDR) gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. The current review provides a summary of the in vitro activity, pharmacokinetics and PK/PD characteristics of old antibiotics. In silico modelling was then performed using Monte Carlo simulation in order to combine all preclinical data with human pharmacokinetics and determine the probability of target (1-log kill in thigh/lung infection animal models) attainment (PTA) of different dosing regimens. The potential of clinical efficacy of a drug against severe infections by MDR gram-negative bacteria was considered when PTA was >95% at the epidemiological cutoff values of corresponding species. In vitro potent activity against MDR gram-negative pathogens has been shown for colistin, polymyxin B, temocillin (against E. coli and K. pneumoniae), fosfomycin (against E. coli), mecillinam (against E. coli), minocycline (against E. coli, K. pneumoniae, A. baumannii), and chloramphenicol (against E. coli) with ECOFF or MIC90 ≤ 16 mg/L. When preclinical PK/PD targets were combined with human pharmacokinetics, Monte Carlo analysis showed that among the old antibiotics analyzed, there is clinical potential for polymyxin B against E. coli, K. pneumoniae, and A. baumannii; for temocillin against K. pneumoniae and E. coli; for fosfomycin against E. coli and K. pneumoniae; and for mecillinam against E. coli. Clinical studies are needed to verify the potential of those antibiotics to effectively treat infections by multi-drug resistant gram-negative bacteria.
鉴于革兰氏阴性菌的耐药性不断增强且缺乏新的更有效的抗菌药物，人们探索了新的策略。一些旧抗生素，如黏菌素、替莫西林、磷霉素、美西林、呋喃妥因、米诺环素和氯霉素，因其通常对多重耐药（MDR）革兰氏阴性菌，如大肠杆菌、肺炎克雷伯菌、铜绿假单胞菌和鲍曼不动杆菌具有体外活性而受到关注。本综述总结了旧抗生素的体外活性、药代动力学和药代动力学/药效学特征。然后使用蒙特卡洛模拟进行计算机建模，以便将所有临床前数据与人体药代动力学相结合，并确定不同给药方案达到目标（大腿/肺部感染动物模型中1-log杀灭）的概率（PTA）。当在相应菌种的流行病学临界值下PTA>95%时，考虑药物对MDR革兰氏阴性菌引起的严重感染的临床疗效潜力。黏菌素、多黏菌素B、替莫西林（对大肠杆菌和肺炎克雷伯菌）、磷霉素（对大肠杆菌）、美西林（对大肠杆菌）、米诺环素（对大肠杆菌、肺炎克雷伯菌、鲍曼不动杆菌）和氯霉素（对大肠杆菌）对MDR革兰氏阴性病原体显示出体外强效活性，其ECOFF或MIC90≤16mg/L。当临床前药代动力学/药效学目标与人体药代动力学相结合时，蒙特卡洛分析表明，在所分析的旧抗生素中，多黏菌素B对大肠杆菌、肺炎克雷伯菌和鲍曼不动杆菌具有临床潜力；替莫西林对肺炎克雷伯菌和大肠杆菌具有临床潜力；磷霉素对大肠杆菌和肺炎克雷伯菌具有临床潜力；美西林对大肠杆菌具有临床潜力。需要进行临床研究以验证这些抗生素有效治疗多重耐药革兰氏阴性菌感染的潜力。
