Pharmacodynamic Evaluation of the Potential Clinical Utility of Fosfomycin and Meropenem in Combination Therapy against KPC-2-Producing Klebsiella pneumoniae
Pharmacodynamic Evaluation of the Potential Clinical Utility of Fosfomycin and Meropenem in Combination Therapy against KPC-2-Producing Klebsiella pneumoniae
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DOI：
10.1128/aac.03099-15
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发表时间：
2016-07-01
影响因子：
4.9
通讯作者：
Bronharo Tognim, Maria Cristina
中科院分区：
文献类型：
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作者：
Albiero, James;Sy, Sherwin K. B.;Bronharo Tognim, Maria Cristina
产KPC的肺炎克雷伯氏菌在全球范围内引起与高死亡率相关的严重感染。由磷霉素和碳青霉烯组成的联合治疗比单药治疗更好地对抗多重耐药微生物，但尚未确定联合治疗的剂量。评价了美罗培南和磷霉素对18株产KPC-2克雷伯菌的MIC。肺炎。还用棋盘法测定了组合抗菌剂的活性。每种药物单独和联合的MIC 50和MIC 90针对短美罗培南（1.5小时）或延长（3小时）输注方案（每8小时1 g [q8 h]，每6小时1.5 g，每8小时2 g）和磷霉素（每8小时4克，每6小时6克，8 g q8 h），以评价游离药物浓度高于MIC的时间作为给药间隔的百分比（fT > MIC）。美罗培南单药治疗的MIC（50）s和MIC（90）s分别为32和256 mg/L，磷霉素分别为64和512 mg/L。抗菌药物联合用药使细菌敏感性增加至单药MIC（50）的1/4和MIC（90）的1/8至1/16。抗微生物组合对至少三分之二的分离株表现出协同效应。在联合治疗中，磷霉素方案6 g q6 h和8 g q8 h作为3 h输注，对MIC 50和MIC 90有更好的机会实现>= 90%的目标实现概率（PTA）70% fT > MIC。美罗培南1.5 g q6 h和2 g q8 h延长输注方案可达到接近90% PTA，MIC 50为40% fT > MIC，但MIC 90则不是。MIC值的显著降低和适当PTA的实现表明，含有磷霉素和美罗培南的方案可以有效地对抗产生KPC-2的K。肺炎。
KPC-producing Klebsiella pneumoniae causes serious infections associated with high death rates worldwide. Combination therapy consisting of fosfomycin and a carbapenem is better than monotherapy to combat multidrug-resistant microorganisms, but no dosages for the combination have been defined. The MICs of meropenem and fosfomycin were evaluated against 18 clinical isolates of KPC-2-producing K. pneumoniae. The activities of combination antimicrobials were also determined by the checkerboard method. The MIC50 and MIC90 of each agent alone and in combination were challenged against short (1.5-h) or prolonged (3-h) infusion regimens of meropenem (1 g every 8 h [q8h], 1.5 g q6h, 2 g q8h) and fosfomycin (4 g q8h, 6 g q6h, 8 g q8h) by Monte Carlo simulation to evaluate the time above the MIC of the free drug concentration as a percentage of the dosing interval (fT > MIC). The monotherapy MIC(50)s and MIC(90)s were 32 and 256 mg/liter for meropenem and 64 and 512 mg/liter for fosfomycin, respectively. Antimicrobial combination increased bacterial susceptibility to 1/4 the MIC(50)s and to 1/8 to 1/16 the MIC(90)s of monotherapy. The antimicrobial combination demonstrated a synergistic effect for at least two-thirds of the isolates. In combination therapy, fosfomycin regimens of 6 g q6h and 8 g q8h as a 3-h infusion against the MIC50 and MIC90 had better chances of achieving >= 90% probability of target attainment (PTA) of 70% fT > MIC. Meropenem regimens of 1.5 g q6h and 2 g q8h in prolonged infusion can achieve close to 90% PTA of 40% fT > MIC for MIC50 but not MIC90. The significant reduction in the MIC values and the achievement of appropriate PTA demonstrated that regimens containing fosfomycin with meropenem can be effective against KPC-2-producing K. pneumoniae.