Background Patients infected with difficult-to-treat Pseudomonas aeruginosa are likely to receive meropenem (MEM) empirically before escalation to ceftolozane/tazobactam (C/T). We assessed whether pre-exposure to MEM affected C/T resistance development on C/T exposure. Materials and methods Nine clinical P. aeruginosa isolates were exposed to MEM 16 mg/L for 72 h. Then, isolates were serially passaged in the presence of C/T (concentration of 10 mg/L) for 72 h as two groups: an MEM-exposed group inoculated with MEM pre-exposed isolates and a non-MEM control group. At 24 h intervals, samples were plated on drug-free and drug-containing agar (C/T concentration 16/8 mg/L) and incubated to quantify bacterial densities (log10 cfu/mL). Growth on C/T agar indicated resistance development, and resistant population was calculated by dividing the cfu/mL on C/T plates by the cfu/mL on drug-free agar. Results At 72 h, resistant populations were detected in 6/9 isolates. In five isolates, MEM exposure significantly increased the prevalence of ceftolozane/tazobactam-resistance development; the percentages of resistance population were 100%, 100%, 53.5%, 31% and 3% for the MEM-exposed versus 0%, 0%, 2%, 0.35% and ≤0.0003% in the unexposed groups. One isolate had a similar resistant population at 72 h between the two groups. The remaining isolates showed no development of resistance, regardless of previous MEM exposure. Conclusions MEM exposure may pre-dispose to C/T resistance development and thus limit the therapeutic utility of this β-lactam/β-lactamase inhibitor. Resistance may be a result of stress exposure or molecular-level mutations conferring cross-resistance. Further in vivo studies are needed to assess clinical implications of these findings.

中文翻译：

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使用体外连续传代评估美罗培南暴露对铜绿假单胞菌头孢特洛嗪/他唑巴坦耐药性发展的影响

背景 感染难以治疗的铜绿假单胞菌的患者可能会在升级至噻呋特啰嗪/他唑巴坦 (C/T) 之前根据经验接受美罗培南 (MEM)。我们评估了 MEM 预暴露是否会影响 C/T 暴露时的 C/T 耐药性发展。材料和方法 将 9 个临床铜绿假单胞菌分离株暴露于 16 mg/L 的 MEM 中 72 小时。然后，将分离株在 C/T（浓度为 10 mg/L）存在下连续传代 72 小时，分为两组：接种 MEM 预暴露分离株的 MEM 暴露组和非 MEM 对照组。每隔 24 小时，将样品铺在不含药物和含药物的琼脂（C/T 浓度 16/8 mg/L）上，并孵育以量化细菌密度（log10 cfu/mL）。 C/T 琼脂上的生长表明抗性的发展，抗性群体通过将 C/T 平板上的 cfu/mL 除以无药琼脂上的 cfu/mL 来计算。结果 72 h 时，在 6/9 的分离株中检测到耐药群体。在 5 个分离株中，MEM 暴露显着增加了头孢特洛嗪/他唑巴坦耐药性的发生率； MEM暴露组的耐药人群比例为100%、100%、53.5%、31%和3%，而未暴露组的耐药人群比例为0%、0%、2%、0.35%和≤0.0003%。 72 小时时，两组之间的一种分离株具有相似的耐药群体。无论之前的 MEM 暴露如何，其余分离株均未表现出耐药性。结论 MEM 暴露可能会导致 C/T 耐药性的发展，从而限制这种 β-内酰胺/β-内酰胺酶抑制剂的治疗效用。耐药性可能是应激暴露或分子水平突变导致的交叉耐药性的结果。需要进一步的体内研究来评估这些发现的临床意义。