Strukova Elena N, Portnoy Yury A, Romanov Andrey V, Edelstein Mikhail V, Zinner Stephen H, Firsov Alexander A
Department of Pharmacokinetics and Pharmacodynamics, Gause Institute of New Antibiotics, Moscow, Russia.
Institute of Antimicrobial Chemotherapy, Smolensk State Medical University, Smolensk, Russia.
Antimicrob Agents Chemother. 2015 Dec 7;60(3):1208-15. doi: 10.1128/AAC.02334-15.
There is growing evidence of applicability of the hypothesis of the mutant selection window (MSW), i.e., the range between the MIC and the mutant prevention concentration (MPC), within which the enrichment of resistant mutants is most probable. However, it is not clear if MPC-based pharmacokinetic variables are preferable to the respective MIC-based variables as interstrain predictors of resistance. To examine the predictive power of the ratios of the area under the curve (AUC24) to the MPC and to the MIC, the selection of ciprofloxacin-resistant mutants of three Klebsiella pneumoniae strains with different MPC/MIC ratios was studied. Each organism was exposed to twice-daily ciprofloxacin for 3 days at AUC24/MIC ratios that provide peak antibiotic concentrations close to the MIC, between the MIC and the MPC, and above the MPC. Resistant K. pneumoniae mutants were intensively enriched at an AUC24/MIC ratio of 60 to 360 h (AUC24/MPC ratio from 2.5 to 15 h) but not at the lower or higher AUC24/MIC and AUC24/MPC ratios, in accordance with the MSW hypothesis. AUC24/MPC and AUC24/MIC relationships with areas under the time courses of ciprofloxacin-resistant K. pneumoniae (AUBCM) were bell shaped. These relationships predict highly variable "antimutant" AUC24/MPC ratios (20 to 290 h) compared to AUC24/MIC ratios (1,310 to 2,610 h). These findings suggest that the potential of the AUC24/MPC ratio as an interstrain predictor of K. pneumoniae resistance is lower than that of the AUC24/MIC ratio.
突变选择窗(MSW)假说,即最小抑菌浓度(MIC)与突变预防浓度(MPC)之间的范围,在此范围内耐药突变体最有可能富集,其适用性的证据越来越多。然而,基于MPC的药代动力学变量作为耐药性的菌株间预测指标是否优于基于相应MIC的变量尚不清楚。为了研究曲线下面积(AUC24)与MPC和MIC的比值的预测能力,对三株肺炎克雷伯菌菌株(具有不同的MPC/MIC比值)的环丙沙星耐药突变体的选择进行了研究。每种菌株每天两次暴露于环丙沙星中,持续3天,AUC24/MIC比值使抗生素峰值浓度接近MIC、在MIC和MPC之间以及高于MPC。根据MSW假说,耐药肺炎克雷伯菌突变体在AUC24/MIC比值为60至360小时(AUC24/MPC比值为2.5至15小时)时大量富集,但在较低或较高的AUC24/MIC和AUC24/MPC比值时则没有。AUC24/MPC和AUC24/MIC与环丙沙星耐药肺炎克雷伯菌(AUBCM)时间进程下的面积之间的关系呈钟形。与AUC24/MIC比值(1310至2610小时)相比,这些关系预测“抗突变”AUC24/MPC比值(20至290小时)变化很大。这些发现表明,AUC24/MPC比值作为肺炎克雷伯菌耐药性的菌株间预测指标的潜力低于AUC24/MIC比值。