Ordway Research Institute, Albany, New York, USA.
Antimicrob Agents Chemother. 2012 Jan;56(1):231-42. doi: 10.1128/AAC.05252-11. Epub 2011 Oct 17.
The panoply of resistance mechanisms in Pseudomonas aeruginosa makes resistance suppression difficult. Defining optimal regimens is critical. Cefepime is a cephalosporin whose 3' side chain provides some stability against AmpC β-lactamases. We examined the activity of cefepime against P. aeruginosa wild-type strain PAO1 and its isogenic AmpC stably derepressed mutant in our hollow-fiber infection model. Dose-ranging studies demonstrated complete failure with resistance emergence (both isolates). Inoculum range studies demonstrated ultimate failure for all inocula. Lower inocula failed last (10 days to 2 weeks). Addition of a β-lactamase inhibitor suppressed resistance even with the stably derepressed isolate. Tobramycin combination studies demonstrated resistance suppression in both the wild-type and the stably derepressed isolates. Quantitating the RNA message by quantitative PCR demonstrated that tobramycin decreased the message relative to that in cefepime-alone experiments. Western blotting with AmpC-specific antibody for P. aeruginosa demonstrated decreased expression. We concluded that suppression of β-lactamase expression by tobramycin (a protein synthesis inhibitor) was at least part of the mechanism behind resistance suppression. Monte Carlo simulation demonstrated that a regimen of 2 g of cefepime every 8 h plus 7 mg/kg of body weight of tobramycin daily would provide robust resistance suppression for Pseudomonas isolates with cefepime MIC values up to 8 mg/liter and tobramycin MIC values up to 1 mg/liter. For P. aeruginosa resistance suppression, combination therapy is critical.
铜绿假单胞菌的耐药机制多种多样，这使得抑制耐药性变得困难。定义最佳治疗方案至关重要。头孢吡肟是一种头孢菌素，其 3'侧链提供了对 AmpCβ-内酰胺酶的一些稳定性。我们在中空纤维感染模型中检查了头孢吡肟对铜绿假单胞菌野生型菌株 PAO1 及其同源 AmpC 稳定去阻遏突变体的活性。剂量范围研究表明，耐药性的出现（两种分离株）完全失败。接种物范围研究表明，所有接种物最终都失败了。较低的接种物最后失败（10 天到 2 周）。即使添加β-内酰胺酶抑制剂，也能抑制耐药性。妥布霉素联合研究表明，在野生型和稳定去阻遏的分离株中均能抑制耐药性。通过定量 PCR 定量 RNA 信息表明，与头孢吡肟单药实验相比，妥布霉素降低了该信息。用 AmpC 特异性抗体进行 Western blot 分析显示，表达降低。我们得出结论，妥布霉素（一种蛋白质合成抑制剂）抑制β-内酰胺酶表达至少是耐药性抑制的部分机制。蒙特卡罗模拟表明，每 8 小时给予 2 g 头孢吡肟和每天 7 mg/kg 体重的妥布霉素的方案将为头孢吡肟 MIC 值高达 8 mg/L 且妥布霉素 MIC 值高达 1 mg/L 的铜绿假单胞菌分离株提供强大的耐药性抑制。对于铜绿假单胞菌的耐药性抑制，联合治疗至关重要。
