Prediction of the effects of inoculum size on the antimicrobial action of trovafloxacin and ciprofloxacin against Staphylococcus aureus and Escherichia coli in an in vitro dynamic model
Prediction of the effects of inoculum size on the antimicrobial action of trovafloxacin and ciprofloxacin against Staphylococcus aureus and Escherichia coli in an in vitro dynamic model
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DOI：
10.1128/aac.43.3.498
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发表时间：
1999-03-01
影响因子：
4.9
通讯作者：
Portnoy, YA
中科院分区：
文献类型：
--
作者：
Firsov, AA;Vostrov, SN;Portnoy, YA
接种量（N-0）对抗菌作用的影响尚未在体外动态模型中进行广泛研究。为了研究这种效应及其可预测性，在N-0 = 10（6）和10（9）CFU/ml（S.金黄色葡萄球菌（E. aureas）和N-0 = 10（6）、10（7）和10（9）CFU/ml（E. coli）。在不同的浓度-时间曲线下面积（AUC）与MIC的比值下，分别模拟了曲伐他汀和环丙沙星的一系列药代动力学曲线，其半衰期分别为9.2和4 h（单位：[微克×小时/毫升]/[微克/毫升]）曲伐他汀为58 - 466，环丙沙星为116 - 932，金黄色葡萄球菌和大肠杆菌分别为58至233和116至466。N-0对E.与金黄色葡萄球菌相比，两种微生物的N-0的增加仅与存活细菌的最小数量的微小增加以及它们的再生长的几乎可以忽略的延迟有关。N-0诱导的抗菌作用强度的降低（I-E，对照生长曲线和生长-再生长曲线之间的面积）也相对较小，然而，N-0效应既不能通过简单地将在较高N（0）s下获得的时间-希尔曲线移动较高N-0和最低N-0之间的差值来消除，也不能通过使用在N-0范围内确定的I（E）s来消除。采用细菌数上限（I-E's），通过多元相关和回归分析，与各自平均值相关的I-E和log AUC/MIC以及log N-0之间的线性关系[（log AUC/MIC）（平均值）和（log N-0）（平均值）]建立了曲伐夫利和环丙沙星对每种菌株的抑制率（r（2）= 0.97至0.99）。基于关系I-E = a + B [（log AUC/MIC）/log AUC/MIC）（平均值）] - c [（log N-0）/（log N-0）（平均值）]，可以在曲伐他汀或环丙沙星的给定AUC/MIC和给定N-0下准确预测抗微生物效果。此外，可以评估AUC/MIC和N-0对I-E的相对影响。由于曲伐沙星和环丙沙星对大肠埃希菌的db比（0.3 - 0.4）远低于先前检查的氨苄西林-舒巴坦（1.9），因此喹诺酮类的接种物效应可能远不如β-内酰胺类显著。所描述的方法，在体外动态模型中的接种物的影响的分析可能是有用的研究与其他抗生素类。
The effect of inoculum size (N-0) on antimicrobial action has not been extensively studied in in vitro dynamic models. To investigate this effect and its predictability, killing and regrowth kinetics of Staphylococcus aureus and Escherichia coli exposed to monoexponentially decreasing concentrations of trovafloxacin las a single dose) and ciprofloxacin (two doses at a 12-h interval) were compared at N-0 = 10(6) and 10(9) CFU/ml (S. aureas) and at N-0 = 10(6), 10(7), and 10(9) CFU/ml (E. coli). A series of pharmacokinetic profiles of trovafloxacin and ciprofloxacin with respective half-lives of 9.2 and 4 h mere simulated at different ratios of area under the concentration-time curve (AUC) to MIC (in [micrograms x hours/milliliter]/[micrograms/milliliter]) 58 to 466 with trovafloxacin and 116 to 932 with ciprofloxacin fur S, aureus and 58 to 233 and 116 to 466 for E, coli, respectively. Although the effect of N-0 was more pronounced for E. coli than for S, aureus, only a minor increase in minimum numbers of surviving bacteria and an almost negligible delay in their regrowth were associated with an increase of the N-0 for both organisms. The N-0-induced reductions of the intensity of the antimicrobial effect (I-E, area between control growth, and the killing-regrowth curves) were also relatively small, However, the N-0 effect could not be eliminated either by simple shifting of the time-hill curves obtained at higher N(0)s by the difference between the higher and lowest N-0 or by operating with I(E)s determined within the N-0-adopted upper limits of bacterial numbers (I-E's), By using multivariate correlation and regression analyses, linear relationships between I-E and log AUC/MIC and log N-0 related to the respective mean values [(log AUC/MIC)(average) and (log N-0)(average)] were established far both trovafloxacin and ciprofloxacin against each of the strains (r(2) = 0.97 to 0.99). The antimicrobial effect may be accurately predicted at a given AUC/MIC of trovafloxacin or ciprofloxacin and at a given N-0 based on the relationship I-E = a + b [(log AUC/MIC)/log AUC/MIC)(average)] - c [(log N-0)/(log N-0)(average)]. Moreover, the relative impacts of AUC/MIC and N-0 on I-E may be evaluated. Since the db ratios for trovafloxacin and ciprofloxacin against E, coli were much lower (0.3 to 0.4) than that for ampicillin-sulbactam as examined previously (1.9), the inoculum effect with the quinolones may be much less pronounced than with the beta-lactams. The described approach to the analysis of the inoculum effect in in vitro dynamic models might be useful in studies with other antibiotic classes.