RESTORE-IMI 1 showed a safety difference IMI-REL and IMI+CST when it comes to nephrotoxicity. The team behind a new retrospective study has applied acute kidney injury assessments to the results.
In July 2019, the US Food and Drug Administration announced the approval of Imipenem-cilastatin + relebactam (IMI-REL) for the treatment of complicated urinary tract infections and complicated intra-abdominal infections in adults with limited or no alternative treatments available.
In a multicenter, randomized, double-blind, comparator-controlled phase 3 trial, RESTORE-IMI 1, IMI-REL was evaluated versus imipenem-cilastatin + colistin (IMI+CST) in patients with bacterial infections. The trial determined noninferiority for IMI-REL and found notable safety advantages, particularly with respect to nephrotoxicity.
While differences in nephrotoxicity favorable to IMI-REL were observed between the 2 treatment arms, there is no standard definition of nephrotoxicity used in clinical trials.
In light of this deficit, the investigators of a new retrospective study, published in Open Forum Infectious Diseases, conducted an in-depth analysis to explore the renal safety profile of IMI-REL and IMI+CST. Their findings bolster earlier evidence that IMI-REL had a more favorable renal safety profile.
The retrospective evaluation used 2 acute kidney injury assessment criteria, Kidney Disease Improving Global Outcomes [KDIGO] and Risk, Injury, Failure, Loss, and End-stage Kidney Disease [RIFLE]. The study team also examined the time to onset of protocol-defined nephrotoxicity and the incidence of renal adverse events.
Out of 47 participants, 45 had adequate data to assess nephrotoxicity. Of these participants, 29 were in the IMI-REL group and 16 were in the IMI+CST group.
Under KDIGO criteria, no participants in the IMI-REL experienced stage 3 acute kidney injury. In comparison, 31.3% of the IMI+CST treated participants experienced stage 3 acute kidney injury, according to KDIGO.
Similarly, none of the IMI-REL group participants experienced renal failure by RIFLE criteria versus 25% for IMI+CST.
Overall, time to onset of nephrotoxicity varied considerably from 2 to 22 days.
In the IMI-REL group, 12.9% of patients experienced renal adverse events compared with 37.5% of patients in the IMI+CST treatment arm. The IMI-REL group experienced no discontinuations due to drug-related renal adverse events, compared with 12.5% of patients discontinuing treatment in the IMI+CST group.
The study authors noted that their findings were consistent with a pattern when it comes to colistin relative to newer antibacterial agents.
“As in RESTORE-IMI 1, recent clinical studies of other new antibacterial agents compared with colistin-based therapy have suggested that colistin has a higher rate of nephrotoxicity than these newer therapies. The consistency of this observation across recent clinical trials is notable for clinicians managing complex infections,” the study team wrote.