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      Clinical and Microbiologic Efficacy and Safety of Imipenem/Cilastatin/Relebactam in Complicated Infections: A Meta-analysis

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          Abstract

          Background

          Antimicrobial resistance is on the rise. The use of redundant and inappropriate antibiotics is contributing to recurrent infections and resistance. Newer antibiotics with more robust coverage for Gram-negative bacteria are in great demand for complicated urinary tract infections (cUTIs), complicated intra-abdominal infections (cIAIs), hospital-acquired bacterial pneumonia (HABP), and ventilator-associated bacterial pneumonia (VABP).

          Materials and Methods

          We performed this meta-analysis to evaluate the efficacy and safety profile of a new antibiotic, Imipenem/cilastatin/relebactam, compared to other broad-spectrum antibiotics for complicated infections. We conducted a systemic review search on PubMed, Embase, and Central Cochrane Registry. We included randomized clinical trials-with the standard of care as comparator arm with Imipenem/cilastatin/relebactam as intervention arm. For continuous variables, the mean difference was used. For discrete variables, we used the odds ratio. For effect sizes, we used a confidence interval of 95%. A P-value of less than 0.05 was used for statistical significance. Analysis was done using a random-effects model irrespective of heterogeneity. Heterogeneity was evaluated using the I 2 statistic.

          Results

          The authors observed similar efficacy at clinical and microbiologic response levels on early follow-up and late follow-up compared to the established standard of care. The incidence of drug-related adverse events, serious adverse events, and drug discontinuation due to adverse events were comparable across both groups.

          Conclusion

          Imipenem/cilastatin/relebactam has a non-inferior safety and efficacy profile compared to peer antibiotics to treat severe bacterial infections (cUTIs, cIAIs, HABP, VABP).

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          Most cited references40

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          Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis

          The spread of antibiotic-resistant bacteria poses a substantial threat to morbidity and mortality worldwide. Due to its large public health and societal implications, multidrug-resistant tuberculosis has been long regarded by WHO as a global priority for investment in new drugs. In 2016, WHO was requested by member states to create a priority list of other antibiotic-resistant bacteria to support research and development of effective drugs.
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            Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America.

            The Infectious Diseases Society of America (IDSA) continues to view with concern the lean pipeline for novel therapeutics to treat drug-resistant infections, especially those caused by gram-negative pathogens. Infections now occur that are resistant to all current antibacterial options. Although the IDSA is encouraged by the prospect of success for some agents currently in preclinical development, there is an urgent, immediate need for new agents with activity against these panresistant organisms. There is no evidence that this need will be met in the foreseeable future. Furthermore, we remain concerned that the infrastructure for discovering and developing new antibacterials continues to stagnate, thereby risking the future pipeline of antibacterial drugs. The IDSA proposed solutions in its 2004 policy report, "Bad Bugs, No Drugs: As Antibiotic R&D Stagnates, a Public Health Crisis Brews," and recently issued a "Call to Action" to provide an update on the scope of the problem and the proposed solutions. A primary objective of these periodic reports is to encourage a community and legislative response to establish greater financial parity between the antimicrobial development and the development of other drugs. Although recent actions of the Food and Drug Administration and the 110th US Congress present a glimmer of hope, significant uncertainly remains. Now, more than ever, it is essential to create a robust and sustainable antibacterial research and development infrastructure--one that can respond to current antibacterial resistance now and anticipate evolving resistance. This challenge requires that industry, academia, the National Institutes of Health, the Food and Drug Administration, the Centers for Disease Control and Prevention, the US Department of Defense, and the new Biomedical Advanced Research and Development Authority at the Department of Health and Human Services work productively together. This report provides an update on potentially effective antibacterial drugs in the late-stage development pipeline, in the hope of encouraging such collaborative action.
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              The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria.

              From early this decade, Enterobacteriaceae that produce Klebsiella pneumoniae carbapenemases (KPC) were reported in the USA and subsequently worldwide. These KPC-producing bacteria are predominantly involved in nosocomial and systemic infections; although they are mostly Enterobacteriaceae, they can also be, rarely, Pseudomonas aeruginosa isolates. KPC beta lactamases (KPC-1 to KPC-7) confer decreased susceptibility or resistance to virtually all beta lactams. Carbapenems (imipenem, meropenem, and ertapenem) may thus become inefficient for treating enterobacterial infections with KPC-producing bacteria, which are, in addition, resistant to many other non-beta-lactam molecules, leaving few available therapeutic options. Detection of KPC-producing bacteria may be difficult based on routine antibiotic susceptibility testing. It is therefore crucial to implement efficient infection control measures to limit the spread of these pathogens.
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                Author and article information

                Journal
                Infect Chemother
                Infect Chemother
                IC
                Infection & Chemotherapy
                The Korean Society of Infectious Diseases; Korean Society for Antimicrobial Therapy; The Korean Society for AIDS
                2093-2340
                2092-6448
                June 2021
                18 June 2021
                : 53
                : 2
                : 271-283
                Affiliations
                [1 ]Staten Island University Hospital, Staten Island, NY, USA.
                [2 ]King Edward Medical University, Lahore, Pakistan.
                Author notes
                Corresponding Author: Syeda Sahra, MD. Resident Physician-Internal Medicine, Staten Island University Hospital, 475-Seaview Avenue, Staten Island, NY 10305 USA. Tel: +1 7182269000, Fax: +1 7742094381, ssahra@ 123456northwell.edu
                Author information
                https://orcid.org/0000-0003-0119-3329
                https://orcid.org/0000-0001-9782-2446
                https://orcid.org/0000-0002-8817-1247
                https://orcid.org/0000-0002-7758-3318
                https://orcid.org/0000-0001-9125-9533
                Article
                10.3947/ic.2021.0051
                8258290
                34216121
                39f91f3a-7ee1-4ced-9170-d36601334474
                Copyright © 2021 by The Korean Society of Infectious Diseases, Korean Society for Antimicrobial Therapy, and The Korean Society for AIDS

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 15 May 2021
                : 08 June 2021
                Categories
                Original Article

                bacterial pneumonia,complicated intra-abdominal infections,complicated urinary tract infection,imipenem,imipenem/cilastatin/relebactam

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