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Multidrug-Resistant Infections: What's on the Horizon?

Jasmine R. Marcelin, MD

July 18, 2018

Ceftazidime-Avibactam Resistance 头孢他啶-阿维巴坦耐药

Ceftazidime-avibactam is approved by the US Food and Drug Administration (FDA) for the treatment of complicated intra-abdominal and urinary tract infections, and has activity against carbapenem-resistant Enterobacteriaceae (CRE). Data from the real-world application of this agent, and potential pitfalls, are still emerging. Two recent articles[1,2] illustrate experience with the use of, and emerging resistance to, ceftazidime-avibactam.


In "Pneumonia and Renal Replacement Therapy Are Risk Factors for Ceftazidime-Avibactam Treatment Failures and Resistance Among Patients With Carbapenem-Resistant Enterobacteriaceae Infections," investigators reported their single-center, retrospective experience of treatment outcomes using ceftazidime-avibactam for CRE infections.[1] Among 77 patients receiving this antibiotic, 30-day and 90-day survival outperformed the predicted survival rates of 81% and 62%, respectively. Clinical success was achieved in 55% of patients. On a multivariable analysis, the presence of pneumonia (odds ratio [OR], 4.78; confidence interval [CI], 1.03-22.2; P = .046) and need for renal replacement therapy (OR, 3.09; CI, 1.03-9.34; P = .045) were independent risk factors for treatment failure. Poorer outcomes among patients with pneumonia are troubling, given that 43% of the 77 patients had pneumonia.

在“肺炎及肾脏替代治疗是头孢他啶-阿维巴坦治疗CRE感染患者失败及耐药的危险因素”一文中,研究者报告了采用头孢他啶-阿维巴坦治疗CRE感染的单中心回顾性研究结果。在接受这种抗生素的77名患者中,30天及90天生存率分别为81%和62%,均高于预期。55%的患者临床治疗成功。在多因素分析中,肺炎(比数比 [OR], 4.78; 可信区间 [CI], 1.03-22.2; P = .046)及需要肾脏替代治疗 (OR, 3.09; CI, 1.03-9.34; P = .045) 是治疗失败的独立危险因素。由于77名患者中43%罹患肺炎,因此,肺炎患者的不良预后令人担忧。

Resistance to ceftazidime-avibactam developed in 10% of patients; all were Klebsiella pneumoniae carbapenemase (KPC)-3 subtypes. The need for renal replacement therapy independently predicted risk for resistance among patients who developed microbiologic failure (OR, 26.67; CI, 2.24-317.1, P = .009). The pharmacokinetics/pharmacodynamics of this antibiotic in critically ill patients with nosocomial pneumonia and renal replacement therapy needs further evaluation. Optimal dosing of ceftazidime-avibactam in these situations still needs to be determined, because it is possible that those patients did not achieve adequate drug concentrations to be effective.

10%的患者发生头孢他啶-阿维巴坦的耐药;所有患者均为肺炎克雷白杆菌KPC-3亚型。需要肾脏替代治疗是细菌学治疗失败患者发生耐药的独立预测因素 (OR, 26.67; CI, 2.24-317.1, P = .009)。这种抗生素在医院获得性肺炎患者及接受肾脏替代治疗的患者的药代动力学/药效学需要进一步评估。在这些情况下,头孢他啶-阿维巴坦的适宜剂量仍需确定,因为这些患者可能无法达到有效的药物浓度。

In the second article, the authors reported a case of emergence of resistance to colistin during treatment of a KPC-producing K pneumoniae bloodstream infection. The patient's index isolate demonstrated reduced susceptibility to ceftazidime-avibactam (minimum inhibitory concentration, 4 ug/mL), despite being naive to it. He was treated with meropenem, tigecycline, and colistin combination therapy, but his bloodstream infection relapsed after 8 days of treatment. The second isolate was typed and found to be clonally related to the first but had developed colistin resistance. The authors hypothesized that, induced by antibiotic pressure, the ST258 strain of KPC-K pneumoniae that infected the patient was likely to have developed colistin resistance by random transposition of the mgrB gene sequence.

在第二篇文章中,作者报告了一例产KPC的肺炎克雷白杆菌血行性感染患者治疗过程中发生粘菌素耐药的病例。尽管患者从未使用头孢他啶-阿维巴坦,但初始分离菌株即显示对头孢他啶-阿维巴坦敏感性降低(最小抑菌浓度 4 ug/mL)。患者接受了美罗培南、替加环素和粘菌素的联合治疗,但治疗8天后血行性感染礽持续存在。研究者对第二个分离菌株进行分型,发现与第一株为相关克隆,但已发生粘菌素的耐药。作者由此作出假设,在抗生素压力的诱导下,感染患者的产KPC肺炎克雷白杆菌ST258株通过mgrB基因序列的随机转座而产生对粘菌素的耐药性。

Viewpoint 视点

With CRE resistance to "last-line" agents such as colistin, what is the next frontier for treatment of these infections? There are European reports of bacteriophage research for use in multidrug-resistant infections but a paucity of data demonstrating clinical effectiveness in large-scale studies.


In a brief report, LaVergne and colleagues[3] described a case of treatment of a multidrug-resistant Acinetobacter baumannii posttraumatic cerebritis with bacteriophage therapy. The patient demonstrated susceptibility to colistin in vitro but did not improve clinically on a combination regimen of colistin, azithromycin, and rifampin. The use of bacteriophage therapy was conducted under an emergency investigational new drug application. The isolate had to be screened to determine which phage had the most virulence against it and was individualized for the specific bacterial isolate. The local craniotomy site infection appeared to heal with phage therapy, but the patient did poorly and eventually care was withdrawn. It was concluded that the patient's death was not necessarily a result of phage failure; potential considerations included intravenous administration rather than local phage therapy, baseline critical illness with poor chance of recovery, and perhaps inadequate serum bacteriophage levels.


Time and effort to individualize and administer bacteriophages means that significant research is still needed to determine whether, and when, this therapy would be useful in clinical care. Meanwhile, given the slow drug discovery pipeline, modification of our current use patterns and antimicrobial stewardship remain the cornerstone strategies to prevent us from toppling off the proverbial cliff of antimicrobial resistance.



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