摘要
目的 通过蒙特卡洛模拟评价头孢哌酮/舒巴坦(CSL,2∶1)对不同肾功能患者革兰阴性菌血流感染给药方案的合理性.方法 应用琼脂稀释法测定CSL对革兰阴性菌的最低抑制浓度(MIC),并通过蒙特卡洛模拟(MCS)计算不同肾功能患者CSL不同给药方案对不同敏感性细菌的达标概率(PTA)和累积反应分数(CFR),评估给药方案的合理性.结果 CSL对血流感染来源肠杆菌、鲍曼不动杆菌和铜绿假单胞菌的MIC90分别为32/16、128/64和64/32 mg/L.对MIC＞16mg/L的肠杆菌,对不同肾功能患者即使CSL以4.5 g q6 h 15 min输注,获得的PTA仍低于90％,CFR最高为77.82％,对产ESBL肠杆菌血流感染CFR仍低于80％.对ESBL阴性肠杆菌感染患者,CLCR＞60mL/min时,CSL 3.0 g q6 h(说明书最大剂量)、3.0gq8h、4.5 g q6 h和4.5 g q8 h 4种给药方案获得的CFR分别为90.2％、83.15％、91.4％和87.09％;CLCR≤60 mL/min时,所有给药方案均可使CFR大于80％.对鲍曼不动杆菌感染患者,当CLCR＞60 mL/min,CSL各给药方案所获CFR均低于40％;CLCR为31～60 mL/min,CSL 4.5 g q6 h给药获得CFR为85.27％;CLCR为 10～30 mL/min,3.0gq6h、4.5 g q6 h和4.5 g q8 h获得的CFR分别为88.05％、91.86％和82.61％;CLCR＜10 mL/min时(非透析患者),各给药方案所获得CFR均大于80％.对铜绿假单胞菌感染患者,当患者CLCR在10～30或≤10 mL/min时,CSL以4.5 g q6h给药所获得的CFR分别为80.09％和81.68％.结论 CSL治疗革兰阴性菌血流感染时,需要根据细菌敏感性和患者肾功能等情况制定个体化给药方案,目前推荐的给药方案可能存在剂量不足情况.针对鲍曼不动杆菌敏感性折点可能需要进一步调整.
Abstract
Objective This study evaluated the rationality of cefoperazone/sulbactam(CSL,2∶1)dosing regimens for patients with Gram-negative bacterial bloodstream infection with various renal functions by Monte Carlo simulation.Methods The agar dilution method was used to determine the minimum inhibitory concentration(MIC)of CSL against Gram-negative bacteria.Monte Carlo simulations were conducted to calculated the probability of target attainment(PTA)and cumulative fraction of response(CFR)of different CSL dosing regimens for evaluating of the rationality of the administration regimen.Results The MIC90 of CSL against Enterobacteriaceae,Acinetobacter baumannii and Pseudomonas aeruginosa from bloodstream infections were 32/16,128/64,and 64/32 mg/L,respectively.For Enterobacteriaceae with MIC＞16 mg/L,even if CSL was administered in 15 min at a dose of 4.5 g q6h,the PTA achieved was still less than 90％,with a maximum CFR of 77.82％.For patients with ESBL-producing Enterobacteriaceae infections,CFR achieved was still less than 80％.While for those with ESBL-negative Enterobacteriaceae infections,when CLCR＞60 mL/min,CFR obtained of four dosing regimens of CSL,3.0 g q6h(maximum recommended dose in instructions),3.0 g q8h,4.5 g q6h,and 4.5 g q8h,were 90.2％,83.15％,91.4％,and 87.09％,respectively;when CLCR ≤ 60 mL/min,all dosing regimens could achieve CFR higher than 80％.For patients with A.baumannii infections,when CLCR＞60 mL/min,CFR obtained were all less than 40％;when CLCR was 31-60 mL/min,a CFR of 85.27％was obtained after administration of 4.5 g q6h;when CLCR was 10～30 mL/min,CFR obtained for 3.0 g q6h,4.5 g q6h,and 4.5 g q8h were 88.05％,91.86％,and 82.61％,respectively;when CLCR＜10 mL/min(non-dialysis patients),CFR obtained for each dosing regimen was higher than 80％.For patients infected with P.aeruginosa,when the patient had a CLCR of 10～30 or≤10 mL/min,CFR obtained for 4.5 g q6h were 80.09％and 81.68％,respectively.Conclusion The recommended dosages of CSL might be suboptimal,and relative higher dosages should be used for the treatment of Gram-negative bacterial bloodstream infections in accordance with the level of renal function of patients.The breakpoint of A.baumannii might need to be adjusted.
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