Vostrov S N, Kononenko O V, Lubenko I Y, Zinner S H, Firsov A A
Division of Infectious Diseases, Roger Williams Medical Center, Rhode Island Hospital, Brown University, Providence, Rhode Island, USA.
Antimicrob Agents Chemother. 2000 Apr;44(4):879-84. doi: 10.1128/AAC.44.4.879-884.2000.
To demonstrate the impact of the pharmacokinetics of gatifloxacin (GA) relative to those of ciprofloxacin (CI) on the antimicrobial effect (AME), the killing and regrowth kinetics of two differentially susceptible clinical isolates each of Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae were studied. With each organism, a series of monoexponential pharmacokinetic profiles of GA (half-life [t(1/2)], 7 h) and CI (t(1/2) = 4 h) were simulated to mimic different single doses of GA and two 12-h doses of CI. The respective eightfold ranges of the ratios of the area under the concentration-time curve (AUC) to the MIC were 58 to 466 and 116 to 932 (microg. h/ml)/(microg/ml). The species- and strain-independent linear relationships observed between the intensity of AME (I(E)) and log AUC/MIC were not superimposed for GA and CI (r(2) = 0.99 in both cases). The predicted AUC/MIC ratio for GA that might be equivalent to a clinically relevant AUC/MIC breakpoint for CI was estimated to be 102 rather than 125 (microg. h/ml)/(microg/ml). The respective MIC breakpoints were 0.32 microg/ml (for a 400-mg dose of GA) and 0.18 microg/ml (for two 500-mg doses of CI). On the basis of the I(E)-log AUC/MIC relationships, equiefficient 24-h doses (D(24h)s) of GA and CI were calculated for hypothetical strains of S. aureus, E. coli, and K. pneumoniae for which the MICs were equal to the MICs at which 50% of isolates are inhibited. To provide an "acceptable" I(E) equal to 200 (log CFU/ml). h, i.e., the I(E) provided by AUC/MIC of 125 (microg. h/ml)/(microg/ml) for ciprofloxacin, the D(24h)s of GA for all three organisms were much lower (115, 30, and 60 mg) than the clinically proposed 400-mg dose. Although the usual dose of CI (two doses of 500 mg) would be in excess for E. coli and K. pneumoniae (D(24h) = two doses of 40 mg and two doses of 115 mg, respectively), even the highest clinical dose of CI (two doses of 750 mg) might be insufficient for S. aureus (D(24h), > two doses of 1,000 mg). The method of generalization of data obtained with specific organisms to other representatives of the same species described in the present report might be useful for prediction of the AMEs of new quinolones.
为证明加替沙星（GA）相对于环丙沙星（CI）的药代动力学对抗菌效果（AME）的影响，研究了金黄色葡萄球菌、大肠埃希菌和肺炎克雷伯菌各两株药敏不同的临床分离株的杀灭及再生长动力学。对于每种菌株，模拟了一系列GA（半衰期[t(1/2)]为7小时）和CI（t(1/2)=4小时）的单指数药代动力学曲线，以模拟不同的GA单剂量及CI的两个12小时剂量。浓度-时间曲线下面积（AUC）与MIC之比的各自8倍范围为58至466以及116至932（μg·h/ml）/（μg/ml）。GA和CI在AME强度（I(E)）与log AUC/MIC之间观察到的与菌种和菌株无关的线性关系并不重叠（两种情况下r(2)=0.99）。估计GA可能相当于CI临床相关AUC/MIC折点的预测AUC/MIC比为102而非125（μg·h/ml）/（μg/ml）。各自的MIC折点分别为0.32μg/ml（对于400mg剂量的GA）和0.18μg/ml（对于两个500mg剂量的CI）。基于I(E)-log AUC/MIC关系，针对金黄色葡萄球菌、大肠埃希菌和肺炎克雷伯菌的假设菌株计算GA和CI的等效24小时剂量（D(24h)），这些菌株的MIC等于50%分离株被抑制时的MIC。为提供等于200（log CFU/ml）·h的“可接受”I(E)，即环丙沙星AUC/MIC为125（μg·h/ml）/（μg/ml）时提供的I(E)，所有三种菌株的GA的D(24h)远低于临床建议的400mg剂量（分别为115mg、30mg和60mg）。尽管CI的常用剂量（两个500mg剂量）对大肠埃希菌和肺炎克雷伯菌会过量（D(24h)分别为两个40mg剂量和两个115mg剂量），但即使CI的最高临床剂量（两个750mg剂量）对金黄色葡萄球菌可能也不足（D(24h)>两个1000mg剂量）。本报告中描述的将特定菌株获得的数据推广到同一菌种其他代表菌株的方法可能有助于预测新型喹诺酮类药物的AME。
