Post Hoc of RESTORE

In the treatment of hospital-acquired bacterial pneumonia (HABP)/ventilator-associated bacterial pneumonia (VABP), a greater risk of day-28 all-cause mortality is associated with the severity of critical illness, bacteremia at baseline, renal impairment, and vasopressor use, according to a post hoc analysis of the RESTORE-IMI 2 trial (ClinicalTrials.gov Identifier: NCT02493764) published in Open Forum Infectious Diseases.

The phase 3 RESTORE-IMI 2 trial compared IMI/REL with PIP/TAZ for the treatment of HABP/VABP in adults, finding IMI/REL to be noninferior. The current post hoc analysis of this trial reassessed trial findings, taking into account baseline pathogen susceptibility, and identified clinically relevant factors that independently predicted clinical and microbiologic outcomes/responses to treatment among patients with HABP/VABP who took part in RESTORE-IMI 2.

RESTORE-IMI 2, which was completed in 2020, involved inpatients severely ill with HABP/VAPB from 27 countries (43% ≥65 years of age; 48% with Acute Physiologic Assessment and Chronic Health Evaluation [APACHE] II scores ≥15; 49% mechanically ventilated; 66% in the intensive care unit). Participants, who were randomized to PIP/TAZ (piperacillin 4g, tazobactam 500mg) or IMI/REL (imipenem 500 mg, cilastatin 500 mg, relebactam 250 mg), received 30-minute intravenous infusions every 6 hours for 7 to 14 days. Trial findings showed that IMI/REL treatment was noninferior for both the primary efficacy outcome of day-28 all-cause mortality (ACM) and the secondary outcome of favorable clinical response at early follow-up (7 to 14 days following end of treatment).

In the post hoc analysis, the investigators performed stepwise multivariable regression analysis to identify variables independently associated with day-28 ACM, favorable microbiologic response at end of treatment, and favorable clinical response at early follow-up. The post hoc analysis also accounted for in vitro susceptibility to randomized treatment and the number of baseline infecting pathogens.

Investigators found that a greater risk of day-28 ACM was associated with APACHE II scores of at least 15, bacteremia at baseline, renal impairment, and vasopressor use. Absence of Acinetobacter calcoaceticus-baumannii complex at baseline, monomicrobial infections at baseline, intensive care unit admission at randomization, nonventilated pneumonia at baseline, no vasopressor use, normal renal function, and IMI/REL treatment were associated with a favorable microbiologic response at end of treatment in the microbiologic modified intention-to-treat (MITT) population, consistent with the MITT population. No bacteremia at baseline, no vasopressor use, an APACHE II score less than 15, and normal renal function were associated with a favorable clinical response at early follow-up in the microbiologic MITT population, consistent with the MITT population. After accounting for in vitro susceptibility to assigned treatment and polymicrobial infection, these factors remained significant.

Study limitations include the hypothesis-generating and nonconfirmatory nature of post hoc analyses.

"This analysis, which accounted for baseline pathogen susceptibility, validated well recognized patient- and disease-related factors as independent predictors of clinical outcomes. These results lend further support to the noninferiority of IMI/REL to piperacillin/tazobactam and suggests that pathogen eradication may be more likely with IMI/REL," the investigators concluded.

Disclosure: This research was supported by Merck Sharp & Dohme LLC. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.