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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Influence of inoculum size and marbofloxacin plasma exposure on the amplification of resistant subpopulations of Klebsiella pneumoniae in a rat lung infection model.
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Influence of inoculum size and marbofloxacin plasma exposure on the amplification of resistant subpopulations of Klebsiella pneumoniae in a rat lung infection model.

机译：接种量和马尔福沙星血浆暴露量对大鼠肺部感染模型中肺炎克雷伯菌耐药亚群扩增的影响。

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摘要

We tested the hypothesis that the bacterial load at the infection site could impact considerably on the pharmacokinetic/pharmacodynamic (PK/PD) parameters of fluoroquinolones. Using a rat lung infection model, we measured the influence of different marbofloxacin dosage regimens on selection of resistant bacteria after infection with a low (10(5) CFU) or a high (10(9) CFU) inoculum of Klebsiella pneumoniae. For daily fractionated doses of marbofloxacin, prevention of resistance occurred for an area-under-the-concentration-time-curve (AUC)/MIC ratio of 189 h for the low inoculum, whereas for the high inoculum, resistant-subpopulation enrichment occurred for AUC/MIC ratios up to 756 h. For the high-inoculum-infected rats, the AUC/MIC ratio, C(max)/MIC ratio, and time within the mutant selection window (T(MSW)) were not found to be effective predictors of resistance prevention upon comparison of fractionated and single administrations. An index corresponding to the ratio of the time that the drug concentrations were above the mutant prevention concentration (MPC) over the time that the drug concentrations were within the MSW (T(>MPC)/T(MSW)) was the best predictor of the emergence of resistance: a T(>MPC)/T(MSW) ratio of 0.54 was associated with prevention of resistance for both fractionated and single administrations. These results suggest that the enrichment of resistant bacteria depends heavily on the inoculum size at the start of an antimicrobial treatment and that classical PK/PD parameters cannot adequately describe the impact of different dosage regimens on enrichment of resistant bacteria. We propose an original index, the T(>MPC)/T(MSW) ratio, which reflects the ratio of the time that the less susceptible bacterial subpopulation is killed over the time that it is selected, as a potentially powerful indicator of prevention of enrichment of resistant bacteria. This ratio is valid only if plasma concentrations achieve the MPC.
机译：我们检验了以下假设，即感染部位的细菌载量可能会严重影响氟喹诺酮类药物的药代动力学/药效学（PK / PD）参数。使用大鼠肺部感染模型，我们测量了低剂量（10（5）CFU）或高浓度（10（9）CFU）肺炎克雷伯菌感染后不同马尔波沙星剂量方案对耐药菌选择的影响。对于每日分次剂量的马西沙星，低接种量的浓度-时间-曲线下面积（AUC）/ MIC比为189 h可以预防耐药，而高接种量的耐药菌亚群富集发生在AUC / MIC比长达756小时。对于高接种量感染的大鼠，在比较分级分离时，未发现AUC / MIC比，C（max）/ MIC比和突变选择窗内的时间（T（MSW））是预防耐药的有效预测指标和单一主管部门。对应于药物浓度高于突变预防浓度（MPC）的时间与药物浓度在MSW范围内的时间之比的指数（T（> MPC）/ T（MSW））是最佳的预测指标耐药性的出现：T（> MPC）/ T（MSW）比为0.54与分次给药和单次给药的耐药性预防相关。这些结果表明，耐药菌的富集在很大程度上取决于抗菌剂治疗开始时的接种量，并且经典的PK / PD参数不能充分描述不同剂量方案对耐药菌富集的影响。我们提出了一个原始指标，即T（> MPC）/ T（MSW）比率，该比率反映了较不易感染的细菌亚群在被选择的时间内被杀死的时间的比率，作为潜在的强有力的预防指标抵抗细菌的富集。仅当血浆浓度达到MPC时，该比率才有效。

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