Optimization of Synergistic Combination Regimens against Carbapenem- and Aminoglycoside-Resistant Clinical Pseudomonas aeruginosa Isolates via Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling
Optimization of Synergistic Combination Regimens against Carbapenem- and Aminoglycoside-Resistant Clinical Pseudomonas aeruginosa Isolates via Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling
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通过基于机制的药代动力学/药效学模型优化抗碳青霉烯类和氨基糖苷类临床铜绿假单胞菌分离株的协同组合方案
DOI：
10.1128/aac.01011-16
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发表时间：
2016
影响因子：
4.9
通讯作者：
C. Landersdorfer
中科院分区：
文献类型：
--
作者：
Rajbharan Yadav;J. Bulitta;R. Nation;C. Landersdorfer
摘要优化抗生素组合有望对抗多重耐药铜绿假单胞菌。本研究旨在系统评价碳青霉烯和氨基糖苷类抗生素联合用药的协同杀菌和耐药预防作用，并通过基于作用机制的数学模型（MBM）合理优化联合用药方案。我们研究了亚胺培南与妥布霉素或阿米卡星的单药治疗和联合治疗对三种难治性双重耐药铜绿假单胞菌的临床分离株。在48小时静态浓度时间杀灭研究（接种物，107.5 CFU/ml）中定量总种群和耐药种群的活菌计数概况。我们通过MBM和Monte Carlo模拟针对分离株FADDI-PA 088合理优化了联合给药方案（亚胺培南[MICimipenem]的MIC为16 mg/L，MICtobramycin为32 mg/L，即，根据EUCAST数据库的第98届世界杯）。针对该分离株，亚胺培南（1.5× MIC）与1至2 mg/L妥布霉素（MIC，32 mg/L）或阿米卡星（MIC，4 mg/L）联合使用，在48 h时比最有效的单药治疗产生≥2-log 10的杀灭率，并防止耐药性。对于所有3种菌株，≥0.88× MICimipenem联合中位0.75× MICtobramycin（范围：0.032×至2.0× MICtobramycin）或0.50× MICamikacin（范围：0.25×至0.50× MICamikacin）可实现协同杀灭而无耐药性。MBM表明，氨基糖苷类药物显著提高亚胺培南靶点浓度高达3倍;达到50%的协同效应需要氨基糖苷类药物浓度为1.34 mg/L（如果氨基糖苷类药物MIC为4 mg/L）和4.88 mg/L（MIC为8 - 32 mg/L）。预计优化的联合方案（亚胺培南5 g/天持续输注加妥布霉素7 mg/kg输注0.5 h）可在48 h时达到>2.0-log 10杀灭率，并在90.3%的患者中防止再生（中位数细菌杀灭率>4.0 log 10 CFU/ml），因此非常有前景。
ABSTRACT Optimizing antibiotic combinations is promising to combat multidrug-resistant Pseudomonas aeruginosa. This study aimed to systematically evaluate synergistic bacterial killing and prevention of resistance by carbapenem and aminoglycoside combinations and to rationally optimize combination dosage regimens via a mechanism-based mathematical model (MBM). We studied monotherapies and combinations of imipenem with tobramycin or amikacin against three difficult-to-treat double-resistant clinical P. aeruginosa isolates. Viable-count profiles of total and resistant populations were quantified in 48-h static-concentration time-kill studies (inoculum, 107.5 CFU/ml). We rationally optimized combination dosage regimens via MBM and Monte Carlo simulations against isolate FADDI-PA088 (MIC of imipenem [MICimipenem] of 16 mg/liter and MICtobramycin of 32 mg/liter, i.e., both 98th percentiles according to the EUCAST database). Against this isolate, imipenem (1.5× MIC) combined with 1 to 2 mg/liter tobramycin (MIC, 32 mg/liter) or amikacin (MIC, 4 mg/liter) yielded ≥2-log10 more killing than the most active monotherapy at 48 h and prevented resistance. For all three strains, synergistic killing without resistance was achieved by ≥0.88× MICimipenem in combination with a median of 0.75× MICtobramycin (range, 0.032× to 2.0× MICtobramycin) or 0.50× MICamikacin (range, 0.25× to 0.50× MICamikacin). The MBM indicated that aminoglycosides significantly enhanced the imipenem target site concentration up to 3-fold; achieving 50% of this synergistic effect required aminoglycoside concentrations of 1.34 mg/liter (if the aminoglycoside MIC was 4 mg/liter) and 4.88 mg/liter (for MICs of 8 to 32 mg/liter). An optimized combination regimen (continuous infusion of imipenem at 5 g/day plus a 0.5-h infusion with 7 mg/kg of body weight tobramycin) was predicted to achieve >2.0-log10 killing and prevent regrowth at 48 h in 90.3% of patients (median bacterial killing, >4.0 log10 CFU/ml) against double-resistant isolate FADDI-PA088 and therefore was highly promising.
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一些糖部分修饰的新型紫红霉素衍生物的制备及其细胞毒活性。
DOI：
10.7164/antibiotics.55.181
发表时间：
2002
期刊：
The Journal of antibiotics
影响因子：
--
作者：
Algiannis,Nectarios;Pouli,Nicole;Marakos,Panagiotis;Skaltsounis,Alexios-Leandros;Florent,Jean-Claude;Perchellet,ElisabethM;Sperfslage,BonnieJ;McIlvain,CorbinJ;Perchellet,Jean-Pierre
通讯作者：
Perchellet,Jean-Pierre
影响因子：
11.8
作者：
Guidos, Robert J.;Spellberg, Brad;Gilbert, David N.
通讯作者：
Gilbert, David N.
影响因子：
11.8
作者：
Boucher, Helen W.;Talbot, George H.;Gilbert, David
通讯作者：
Gilbert, David
影响因子：
5.2
作者：
Ly, Neang S.;Bulitta, Juergen B.;Tsuji, Brian T.
通讯作者：
Tsuji, Brian T.