COMMENTARY

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

Jasmine R. Marcelin, MD

Disclosures

July 18, 2018

Editorial Collaboration

Medscape &

Ceftazidime-Avibactam Resistance

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.

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.

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.

Viewpoint

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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