1951. Nephrotoxicity associated with imipenem/cilastatin/relebactam (IMI/REL) versus imipenem/cilastatin plus colistin (IMI+CST) in patients with imipenem-nonsusceptible (NS) bacterial infections
Session: Poster Abstract Session: Clinical Trials
Saturday, October 6, 2018
Room: S Poster Hall
  • 18-1315-C MRPAB18304 IDWeek Nephrotoxicity_final.pdf (414.5 kB)
  • Background: Nephrotoxicity is a common complication of CST-based therapy, limiting its use to treat carbapenem-resistant bacterial infections. REL is a novel β-lactamase inhibitor that restores imipenem activity against many imipenem-NS strains of gram-negative pathogens. IMI/REL was shown to be as effective but better tolerated than IMI+CST in the phase 3 RESTORE-IMI 1 study (NCT02452047), including a lower incidence of treatment-emergent nephrotoxicity (prespecified secondary endpoint). Here we present additional renal safety data from that trial.


    Methods: Randomized, active-controlled, double-blind, phase 3 trial in adults with infections caused by ≥1 imipenem-NS (but CST- and IMI/REL-susceptible) pathogen. Treatment (2:1) was IMI/REL or IMI+CST for 5-21 days in complicated intra-abdominal infection and complicated urinary tract infection and 7-21 days in hospital-acquired/ventilator-associated bacterial pneumonia. For baseline serum creatinine (Cr) <1.2 mg/dL, nephrotoxicity was defined as a doubling of serum Cr to >1.2 mg/dL OR decrease in Cr clearance [CrCl] ≥50%; for Cr ≥1.2 mg/dL, nephrotoxicity was defined as an increase in serum Cr ≥1 mg/dL OR decrease from baseline in CrCl ≥20% OR need for renal replacement therapy. KDIGO and RIFLE criteria of acute kidney injury (AKI) were applied to the data; renal-related adverse events (AEs) were analyzed.


    Results: A total of 47 patients were randomized, treated (31 IMI/REL, 16 IMI+CST), and included in this analysis. A significantly smaller percentage of patients in the IMI/REL than the IMI+CST group experienced protocol-defined nephrotoxicity (% difference: -45.9 [95% CI: -69.1, -18.4]; P=.002) during study treatment and the 14-day follow-up period (Table). These results were confirmed by applying KDIGO and RIFLE criteria, with no patients in the IMI/REL group in stage 3 AKI or failure compared with 31.3% and 25.0%, respectively, in the IMI+CST group. Fewer renal AEs, including discontinuations due to renal events, were observed in the IMI/REL group.


    Conclusion: IMI/REL demonstrates a more favorable renal safety profile compared with CST-based therapy, as demonstrated by a lower incidence of treatment-emergent nephrotoxicity and AKI with IMI/REL across several different analyses.

    Michelle Brown, RN1, Johann Motsch, MD2, Keith Kaye, MD, MPH3, Thomas File, MD4, Helen W. Boucher, MD, FIDSA5, Neika Vendetti, MPH1, Angela Aggrey, PhD1, Hee-Koung Joeng, PhD1, Robert Tipping, MS1, Jiejun Du, PhD1, Daryl D. Depestel, PharmD, BCPS-ID1, Joan Butterton, MD1, Nicholas A. Kartsonis, MD1 and Amanda Paschke, MD, MSCE1, (1)Merck & Co., Inc., Kenilworth, NJ, (2)Universitätsklinikum Heidelberg, Heidelberg, Germany, (3)University of Michigan, Ann Arbor, MI, (4)Summa Health System, Akron, OH, (5)Infectious Diseases, Tufts Medical Center, Boston, MA


    M. Brown, Merck & Co., Inc.: Employee , Salary .

    J. Motsch, Heidelberg University: Research Contractor , Research grant .

    K. Kaye, Merck & Co., Inc.: Consultant and Research Contractor , Research grant . Melinta, Achaogen, Allergan: Consultant , Consulting fee .

    T. File, Bio Merieux, Curetis, Melinta, Merck, MotifBio, Nabriva, Paratek, Pfizer: Consultant , Consulting fee .

    H. W. Boucher, Merck & Co., Inc.: Scientific Advisor , Consulting fee .

    N. Vendetti, Merck & Co., Inc.: Employee , Salary .

    A. Aggrey, Merck & Co., Inc.: Employee , Salary .

    H. K. Joeng, Merck & Co., Inc.: Employee , Salary .

    R. Tipping, Merck & Co., Inc.: Employee , Salary .

    J. Du, Merck & Co., Inc.: Employee , Salary .

    D. D. Depestel, Merck & Co., Inc.: Employee , Salary .

    J. Butterton, Merck & Co., Inc.: Employee , Salary and Stock .

    N. A. Kartsonis, Merck & Co., Inc.: Employee , Salary and Stocks .

    A. Paschke, Merck & Co., Inc.: Employee and Shareholder , Salary .

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