P-1211. Effectiveness of iMIpenem-Relebactam for multidrug-resistant Pseudomonas AeruGinosa in pnEumonia and bloodstream infections in the United States (MIRAGE)

TL;DR

This study evaluates how effective a drug called imipenem/relebactam is in treating severe infections caused by drug-resistant Pseudomonas aeruginosa in U.S. patients.

Contribution

The study provides real-world evidence of imipenem/relebactam's effectiveness in treating multidrug-resistant Pseudomonas aeruginosa infections in critically ill patients.

Findings

80% of patients met clinical success criteria at day 7, and 55% at day 30.

63% of patients completed the full treatment course as planned.

30-day mortality was 17%, and 30% of patients experienced recurrent infections within 90 days.

Abstract

Imipenem/relebactam (I/R) demonstrates potent in vitro activity against multidrug-resistant (MDR) Pseudomonas aeruginosa. The objective of this study was to evaluate the effectiveness of I/R for treatment of MDR P. aeruginosa infections across the U.S.Table 1.Detailed inclusion and exclusion criteria for patients receiving I/R1 Pneumonia was defined as the presence of a new or progressive infiltrate with at least one of the following: purulent tracheal secretions, worsening cough or dyspnea, PaO2/FiO2 < 200 with PEEP ≥5 cm H2O, fever (≥38°C) or hypothermia (≤35°C), leukocytosis (≥10,000 white blood cells per µL), or tachypnea (respiratory rate >30 beats per minute).2 MDR was defined as non-susceptibility to at least one agent in three or more antibiotic classes.Table 2.Patient demographics, underlying diseases, severity of illness, and treatment characteristics of patients treated with I/R for pneumonia or bacteremia.*Other immunocompromising conditions included bone-marrow transplant, chronic steroid use, neutropenia, and AIDS.Abbreviations: IQR = interquartile range

Detailed inclusion and exclusion criteria for patients receiving I/R

1 Pneumonia was defined as the presence of a new or progressive infiltrate with at least one of the following: purulent tracheal secretions, worsening cough or dyspnea, PaO2/FiO2 < 200 with PEEP ≥5 cm H2O, fever (≥38°C) or hypothermia (≤35°C), leukocytosis (≥10,000 white blood cells per µL), or tachypnea (respiratory rate >30 beats per minute).

2 MDR was defined as non-susceptibility to at least one agent in three or more antibiotic classes.

Patient demographics, underlying diseases, severity of illness, and treatment characteristics of patients treated with I/R for pneumonia or bacteremia.

*Other immunocompromising conditions included bone-marrow transplant, chronic steroid use, neutropenia, and AIDS.

Abbreviations: IQR = interquartile range

This was a retrospective, multicenter, observational study of I/R for MDR P. aeruginosa pneumonia and bacteremia. Patients were included if they received I/R for >48h initiated within 7 days of the index MDR P. aeruginosa culture (Table 1). Clinical success was defined as survival, resolution of signs and symptoms of infection, completion of the intended treatment course, and the absence of a recurrent infection due to MDR P. aeruginosa. I/R susceptibility was determined by site-level microbiology labs; non-susceptibility was defined by the Clinical and Laboratory Standards Institute (CLSI) criteria.Table 3.Real-world characteristics of I/R use in pneumonia and bloodstream infections.1 I/R treatment was discontinued in one patient with acute interstitial nephritisTable 4.Clinical outcomes of patients treated with I/R for MDR P. aeruginosa pneumonia or bacteremia1 Non-susceptibility was defined as a categorical change from susceptible to non-susceptible as defined by CLSI interpretive criteria. Among the 16 cases meeting this criteria, non-susceptibility was identified by gradient strip testing and broth microdilution in 25% and 75%, respectively. The median I/R MICs for isolates categorized as susceptible and non-susceptible were 2 and 8 mg/L, respectively.

Real-world characteristics of I/R use in pneumonia and bloodstream infections.

1 I/R treatment was discontinued in one patient with acute interstitial nephritis

Clinical outcomes of patients treated with I/R for MDR P. aeruginosa pneumonia or bacteremia

1 Non-susceptibility was defined as a categorical change from susceptible to non-susceptible as defined by CLSI interpretive criteria. Among the 16 cases meeting this criteria, non-susceptibility was identified by gradient strip testing and broth microdilution in 25% and 75%, respectively. The median I/R MICs for isolates categorized as susceptible and non-susceptible were 2 and 8 mg/L, respectively.

64 patients from 10 centers were included (Table 2); patients from 6 additional centers were screened and did not meet inclusion criteria. The overall cohort was critically-ill; 80%, 75%, and 48% were in the intensive care unit, receiving mechanical ventilation, and on vasopressors, respectively. The median (interquartile range; IQR) SOFA score was 7 (5 – 12). 53% received treatment with another new β-lactam for MDR P. aeruginosa infections prior to I/R. The median time to I/R initiation was 67 hours. I/R treatment was primarily prescribed based on susceptibility results in 75% of patients, including resistance to other novel β-lactam agents (Table 3). 63% of patients completed the intended I/R treatment course as planned. At day 7 and 30, 80% and 55% met criteria for clinical success, respectively (Table 4). The overall 30- and 90-day mortality rates were 17% and 30%, respectively. Recurrent infections were documented in 38% of patients within 90 days.

In this critically-ill patient population we found that I/R was often used following treatment with other novel β-lactams. Clinical outcomes were generally comparable to those previously reported in similar real-world studies for other novel β-lactam agents suggesting that I/R plays a role in treatment of MDR P. aeruginosa infections, particularly when other agents are not available or test resistant.

jason M. Pogue, PharmD, Entasis: Advisor/Consultant|Entasis: Grant/Research Support|GlaxoSmithKline: Advisor/Consultant|Melinta: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support Alexander J. Lepak, MD, FIDSA, BioMerieux: Grant/Research Support William R. Miller, M.D., Merck: Grant/Research Support|UpToDate: Royalties, topic author Jeffrey C. Pearson, PharmD, InflaRx Pharmaceuticals, Inc.: Advisor/Consultant Emre Yucel, PhD, Merck & Co., Ltd: Stocks/Bonds (Public Company)

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