Imipenem/Cilastatin/Relebactam Efficacious for Hospital-Acquired Pneumonia

Study results published in JAC-Antimicrobial Resistance support the use of imipenem/cilastatin/relebactam among patients with hospital-acquired/ventilator-associated pneumonia, with full dosing recommended for those with normal kidney function and augmented renal clearance (ARC) and lower dosing for those with kidney impairment.

The RESTORE-IMI 2 trial was a phase 3, randomized, double-blinded, active-controlled, multicenter study. Researchers examined the relationship between kidney function and the efficacy and safety of imipenem/cilastatin/relebactam (intervention) among patients with hospital-acquired/ventilator-associated pneumonia. Patients were randomly assigned 1:1 to receive either the intervention (1.25 g) or piperacillin-tazobactam (4.5 g), administered every 6 hours for 7 to 14 days.  The primary outcomes were 28-day all-cause mortality, clinical and microbiologic response, and adverse event occurrence.

Among 531 patients included in the modified intention-to-treat population, 188 (35.4%) had normal renal function, 88 (16.6%) had augmented kidney clearance, 124 (23.4%) had mild kidney impairment, and 109 (20.5%) had severe kidney impairment. Overall, the majority of patients were men (69.1%) and White (77.8%), and the median age was 62 (range, 18-98) years.

All-cause mortality rates at 28 days were similar between patients with normal kidney function and those with augmented renal clearance, as well as comparable across all baseline kidney categories. Of note, the rate of 28-day mortality was highest among patients with moderate kidney impairment.

Irrespective of treatment group, comparisons against patients with moderate to severe kidney impairment showed higher and similar clinical response rates among patients with either mild kidney impairment, normal renal function, or augmented kidney clearance (creatinine clearance [CL_Cr], >150 to <250 mL/min).

Of patients with augmented kidney clearance with CL_Cr levels of more than 250 mL/min, those who received the intervention (n=12) vs piperacillin-tazobactam (n=9) were more likely to have a favorable clinical response (91.7% vs 44.4%).

Overall, favorable microbiologic response rates in patients with normal kidney function or augmented kidney clearance with CL_Cr levels at or above 90 mL/min were higher among those who received the intervention vs piperacillin-tazobactam (86.6% vs 67.2%). Consistent with 28-day all-cause mortality and clinical response outcomes, the overall rate of favorable microbiologic responses was decreased among patients in both groups with moderate to severe kidney impairment.

Overall, the most commonly reported adverse events were anemia, diarrhea, increased aspartate aminotransferase levels, hypokalemia, and pyrexia.

Limitations of this study include insufficient power and the possibility that some patients with augmented kidney clearance at baseline may have attained normal kidney function or developed kidney impairment during the study period.

According to the researchers, “These results contrast with those of previous studies that suggested that antibacterial drug failure rates are higher in patients with ARC [augmented renal clearance] than in those without ARC.””

Disclosures: Multiple authors declared affiliations with pharmaceutical, biotech, and/or device companies. Please see the original reference for a full list of disclosures.