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Johann Motsch, Katherine Young, Michelle L Brown, Joan R Butterton, Amanda Paschke, Reply to Sfeir, Clinical Infectious Diseases, Volume 72, Issue 8, 15 April 2021, Pages 1485–1486, https://doi.org/10.1093/cid/ciaa881
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To the Editor—We thank Dr Sfeir for his feedback on our clinical trial comparing imipenem/cilastatin/relebactam (IMI/REL) with imipenem/cilastatin plus colistin for treating imipenem-nonsusceptible infections [1]. We specifically wish to address his comments on the choice of breakpoints for the trial and on the need to accelerate availability of antimicrobial susceptibility testing (AST) for novel agents.
Both the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) approved susceptibility interpretative criteria for IMI/REL in January 2020, 6 months after first approval [2, 3]. When the RESTORE-IMI 1 trial was conducted, official breakpoints for IMI/REL were not available. To ensure that all enrolled patients had causative pathogens susceptible to study therapy, we applied the existing IMI breakpoints to IMI/REL [1]. This approach was appropriate for several reasons, based on data that had been presented publicly prior to study initiation. First, pharmacokinetics of IMI and REL are complementary, and clinical trials showed that neither component of the IMI/REL combination affects the other’s plasma and pulmonary pharmacokinetic parameters [4–6]. Thus, for the IMI component of IMI/REL, we could use the identical dosing regimen approved for IMI alone [7]. This differs from the other β-lactam/β-lactamase combinations noted by Dr Sfeir. Ceftazidime/avibactam and meropenem/vaborbactam employ longer infusion times (along with other differences in dosing regimen) than the respective parent β-lactam alone, altering exposure parameters along with susceptibility breakpoints [8–11]. Second, in vitro susceptibility and surveillance studies showed that REL can restore IMI susceptibility to the existing IMI breakpoints [12–16]. Finally, preclinical studies and pharmacokinetic/pharmacodynamic simulations based on phase 2 dose-finding trials also supported the IMI/REL dosing regimen and conditional breakpoints used in RESTORE-IMI 1 [16–19]. Of note, the recently approved “susceptible” breakpoints for IMI/REL [2, 3] match those for IMI in use at the time the study was conducted [20, 21]. This confirms that the patient eligibility criteria, which considered “intermediate susceptible” pathogens as nonsusceptible, were appropriate.
We agree with Dr Sfeir regarding the need to overcome the challenges facing AST for novel antimicrobials. To improve patient access to medically important new antibacterial agents with activity against resistant pathogens, it is imperative that interpretative criteria for susceptibility testing, along with commercial AST for such novel drugs, become available as quickly as possible. Merck & Co, Inc (Kenilworth, New Jersey), the company that markets IMI/REL, has engaged with the US Food and Drug Administration (FDA) and multiple other stakeholders to accelerate development, approval, and commercialization of AST devices. For instance, the company works closely with device manufacturers, providing both funding and material support, to expedite the inclusion of its antibiotics on AST panels. In the case of IMI/REL, Merck & Co, Inc helped to make manual AST available within 1 month of approval, by supporting multiple manufacturers to implement the FDA’s guidance on coordinated development of antimicrobial drugs and devices. As part of its commitment to antimicrobial stewardship, the company continues to collaborate with regulators and AST developers to make AST for future antibacterial agents available sooner than in the past, thus enabling more patients to receive timely access to appropriate treatment for drug-resistant infections.
Notes
Acknowledgments. Medical writing assistance was provided by Dominik Wolf, MSc, of Merck & Co, Inc. Editorial assistance was provided by Michele McColgan, BA, of Merck & Co, Inc.
Financial support. Funding for the RESTORE-IMI 1 trial was provided by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, New Jersey.
Potential conflicts of interest. J. M.’s institution (University Clinics Heidelberg) received research support from Merck & Co, Inc. K. Y., M. L. B., J. R. B., and A. P. are employees of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, and own stock and/or hold stock options in Merck & Co, Inc. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
