Johns Hopkins University School of Medicine, Department of Pediatrics, Division of Pediatric Infectious Diseases, Baltimore, Maryland USA.
Ares Genetics, Head of Bioinformatics & Analytics, Vienna, Austria.
Clin Infect Dis. 2021 Dec 6;73(11):e4599-e4606. doi: 10.1093/cid/ciaa1306.
Ceftolozane-tazobactam (TOL-TAZ) affords broad coverage against Pseudomonas aeruginosa. Regrettably, TOL-TAZ resistance has been reported. We sought to identify modifiable risk factors that may reduce the emergence of TOL-TAZ resistance.
Twenty-eight consecutive patients infected with carbapenem-resistant P. aeruginosa isolates susceptible to TOL-TAZ, treated with ≥72 hours of TOL-TAZ , and with P. aeruginosa isolates available both before and after TOL-TAZ exposure between January 2018 and December 2019 in Baltimore, Maryland, were included. Cases were defined as patients with at least a 4-fold increase in P. aeruginosa TOL-TAZ MICs after exposure to TOL-TAZ. Independent risk factors for the emergence of TOL-TAZ resistance comparing cases and controls were investigated using logistic regression. Whole genome sequencing of paired isolates was used to identify mechanisms of resistance that emerged during TOL-TAZ therapy.
Fourteen patients (50%) had P. aeruginosa isolates which developed at least a 4-fold increase in TOL-TAZ MICs(ie, cases). Cases were more likely to have inadequate source control (29% vs 0%, P = .04) and were less likely to receive TOL-TAZ as an extended 3-hour infusion (0% vs 29%; P = .04). Eighty-six percent of index isolates susceptible to ceftazidime-avibactam (CAZ-AVI) had subsequent P. aeruginosa isolates with high-level resistance to CAZ-AVI, after TOL-TAZ exposure and without any CAZ-AVI exposure. Common mutations identified in TOL-TAZ resistant isolates involved AmpC, a known binding site for both ceftolozane and ceftazidime, and DNA polymerase.
Due to our small sample size, our results remain exploratory but forewarn of the potential emergence of TOL-TAZ resistance during therapy and suggest extending TOL-TAZ infusions may be protective. Larger studies are needed to investigate this association.
头孢他唑巴坦（TOL-TAZ）对铜绿假单胞菌具有广泛的覆盖范围。遗憾的是，已经报道了 TOL-TAZ 耐药性。我们试图确定可能降低 TOL-TAZ 耐药性出现的可修改的危险因素。
2018 年 1 月至 2019 年 12 月期间，马里兰州巴尔的摩市连续收治了 28 例碳青霉烯类耐药铜绿假单胞菌感染患者，这些患者的铜绿假单胞菌分离株对 TOL-TAZ 敏感，接受了≥72 小时的 TOL-TAZ 治疗，并且在 TOL-TAZ 暴露前后均有铜绿假单胞菌分离株。病例定义为在接触 TOL-TAZ 后铜绿假单胞菌 TOL-TAZ MIC 至少增加了 4 倍的患者。使用逻辑回归分析比较病例和对照组，确定在接触 TOL-TAZ 期间出现 TOL-TAZ 耐药的独立危险因素。使用全基因组测序对配对分离株进行分析，以确定在 TOL-TAZ 治疗期间出现的耐药机制。
14 名患者（50%）的铜绿假单胞菌分离株 MIC 至少增加了 4 倍（即病例）。病例组更可能存在不充分的源头控制（29%比 0%，P=0.04），并且不太可能接受 TOL-TAZ 作为 3 小时的延长输注（0%比 29%；P=0.04）。86%的指数分离株对头孢他啶-阿维巴坦（CAZ-AVI）敏感，在接触 TOL-TAZ 后，且没有任何 CAZ-AVI 暴露的情况下，后续铜绿假单胞菌分离株对 CAZ-AVI 具有高水平耐药性。在 TOL-TAZ 耐药分离株中发现的常见突变涉及 AmpC，AmpC 是头孢他唑巴坦和头孢他啶的已知结合位点，以及 DNA 聚合酶。
由于我们的样本量较小，我们的结果仍然是探索性的，但警告在治疗过程中 TOL-TAZ 耐药性可能出现，并提示延长 TOL-TAZ 输注可能具有保护作用。需要更大的研究来调查这种关联。
