The safety and efficacy of relebactam/imipenem/cilastatin in Japanese patients with complicated intra-abdominal infection or complicated urinary tract infection: A multicenter, open-label, noncomparative phase 3 study

Kohno, Shigeru; Bando, Hiroyuki; Yoneyama, Fumihiko; Kikukawa, Hiroaki; Kawahara, Kazuya; Shirakawa, Masayoshi; Aoyama, Norihiro; Brown, Michelle; Paschke, Amanda; Takase, Akiko

doi:10.1016/j.jiac.2020.09.032

Cited by 17 publications

(13 citation statements)

References 26 publications

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“…A phase 3 non-randomized, not controlled, open-label clinical study investigated the safety and efficacy of imipenem/relebactam in 81 Japanese subjects with cIAIs or cUTIs (14 bacteremic, 7 septic). Microorganisms were mostly non-MDR, and the results were in line with registration studies, showing comparable favorable efficacy and safety [137]. The microbiological features of the study may not add informative data for MDR pathogens.…”

Section: Imipenem/relebactamsupporting

confidence: 70%

Microbiological, Clinical, and PK/PD Features of the New Anti-Gram-Negative Antibiotics: β-Lactam/β-Lactamase Inhibitors in Combination and Cefiderocol—An All-Inclusive Guide for Clinicians

et al. 2022

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Bacterial resistance mechanisms are continuously and rapidly evolving. This is particularly true for Gram-negative bacteria. Over the last decade, the strategy to develop new β-lactam/β-lactamase inhibitors (BLs/BLIs) combinations has paid off and results from phase 3 and real-world studies are becoming available for several compounds. Cefiderocol warrants a separate discussion for its peculiar mechanism of action. Considering the complexity of summarizing and integrating the emerging literature data of clinical outcomes, microbiological mechanisms, and pharmacokinetic/pharmacodynamic properties of the new BL/BLI and cefiderocol, we aimed to provide an overview of data on the following compounds: aztreonam/avibactam, cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, cefiderocol, ceftaroline/avibactam, ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/relebactam, meropenem/nacubactam and meropenem/vaborbactam. Each compound is described in a dedicated section by experts in infectious diseases, microbiology, and pharmacology, with tables providing at-a-glance information.

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Section: Imipenem/relebactamsupporting

confidence: 70%

Microbiological, Clinical, and PK/PD Features of the New Anti-Gram-Negative Antibiotics: β-Lactam/β-Lactamase Inhibitors in Combination and Cefiderocol—An All-Inclusive Guide for Clinicians

et al. 2022

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“…Briefly, participants were randomized 1:1 to receive IPM/cilastatin/REL 500 mg/500 mg/250 mg or piperacillin/tazobactam 4 g/500 mg, adjusted for renal function (Table S2), every 6 h; efficacy end points included day 28 all‐cause mortality and clinical response 7–14 days after completing therapy 14 . In addition to PN014, data from another global, phase III study completed after finalization of the previous PopPK model, PN017 (ClinicalTrials.gov identifier: NCT03293485; protocol MK‐7655A‐017 [PN017]), were added to this analysis 22 . Additional details regarding the PN014 methodology and the PopPK dataset can be found in the Supplementary Methods.…”

Section: Methodsmentioning

confidence: 99%

“… 14 In addition to PN014, data from another global, phase III study completed after finalization of the previous PopPK model, PN017 (ClinicalTrials.gov identifier: NCT03293485; protocol MK‐7655A‐017 [PN017]), were added to this analysis. 22 Additional details regarding the PN014 methodology and the PopPK dataset can be found in the Supplementary Methods.…”

Section: Methodsmentioning

confidence: 99%

Population pharmacokinetic/pharmacodynamic assessment of imipenem/cilastatin/relebactam in patients with hospital‐acquired/ventilator‐associated bacterial pneumonia

Patel

Bellanti²,

Daryani

et al. 2021

Clinical Translational Sci

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In the phase III RESTORE‐IMI 2 study (ClinicalTrials.gov: NCT02493764), the combination antibacterial agent imipenem/cilastatin/relebactam (IMI/REL) demonstrated noninferiority to piperacillin/tazobactam for the end points of all‐cause mortality at day 28 and favorable clinical response at the early follow‐up visit in adult participants with gram‐negative hospital‐acquired bacterial pneumonia/ventilator‐associated bacterial pneumonia (HABP/VABP). Existing population pharmacokinetic models for imipenem (IPM) and REL were updated using data from patients with HABP/VABP from RESTORE‐IMI 2. Creatinine clearance (CrCl), body weight, infection type, and ventilation status were significant covariates in the updated model. The following simulations were performed to calculate the pharmacokinetic/pharmacodynamic joint probability of target attainment among patients with HABP/VABP and varying degrees of renal function: augmented renal clearance (CrCl ≥150 ml/min), normal renal function (CrCl ≥90 to <150 ml/min), renal impairment (mild, CrCl ≥60 to <90 ml/min; moderate, CrCl ≥30 to <60 ml/min; or severe, CrCl ≥15 to <30 ml/min), and end‐stage renal disease (CrCl <15 ml/min). At the recommended IMI/REL dosing regimens across renal categories, greater than 90% of patients in all renal function groups were predicted to achieve joint pharmacokinetic/pharmacodynamic targets at a minimum inhibitory concentration breakpoint of ≤2 μg/ml, regardless of ventilation status. This modeling and simulation analysis supports use of the recommended IMI/REL dosing regimens, adjusted based on renal function, in patients with HABP/VABP.

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“…In recent studies, carbapenem and non-beta-lactam beta-lactamase inhibitors, such as imipenem-relebactam, have been found to be effective against most strains of CR-KP and clinical trials show favorable responses to imipenem/cilastatin/relebactam. 8 , 9 However, the in vivo study of imipenem-relebactam against CREs still showed poor activity against 23 metallo-carbapenemase producers out of 660 isolates. 9 An analysis of CR-KP strains in Chongqing, China, found that among carbapenems, 100% of the CR-KP isolates were resistant to ertapenem, 37.2% were resistant to imipenem, 30.8% were resistant to meropenem 2 Resistance to cephalosporins were relatively high among 52.5%, 75.6% and 78.2% isolates against cefepime, CAZ and ceftriaxone, respectively.…”

Section: Discussionmentioning

confidence: 99%

Carbapenem-Resistant Klebsiella pneumoniae Osteomyelitis Treated with Ceftazidime-Avibactam in an Infant: A Case Report

Ji¹,

Sun²,

Li³

et al. 2021

IDR

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Increasing cases of carbapenem-resistant Klebsiella pneumoniae (CR-KP) infections have been observed globally where multi-drug resistance to CR-KP can make the infection difficult to treat. In recent years, the β-lactam/β-lactamase inhibitor, ceftazidime-avibactam (CAZ-AVI), has been developed to treat complicated urinary tract infections and complicated intra-abdominal infections. CAZ-AVI is approved for children over 3-month old but has yet to be investigated for cases of osteomyelitis. Only three case reports exist in literature on the use of CAZ-AVI for CR-KP osteomyelitis in adults. In this report, we present an infant with primary hematogenous osteomyelitis and septic arthritis in the right shoulder following surgical treatment for a heart murmur. Bacterial isolation revealed a strain of CR-KP, which was successfully treated with CAZ-AVI after initial administration of imipenem-based treatments.

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The safety and efficacy of relebactam/imipenem/cilastatin in Japanese patients with complicated intra-abdominal infection or complicated urinary tract infection: A multicenter, open-label, noncomparative phase 3 study

Cited by 17 publications

References 26 publications

Microbiological, Clinical, and PK/PD Features of the New Anti-Gram-Negative Antibiotics: β-Lactam/β-Lactamase Inhibitors in Combination and Cefiderocol—An All-Inclusive Guide for Clinicians

Microbiological, Clinical, and PK/PD Features of the New Anti-Gram-Negative Antibiotics: β-Lactam/β-Lactamase Inhibitors in Combination and Cefiderocol—An All-Inclusive Guide for Clinicians

Population pharmacokinetic/pharmacodynamic assessment of imipenem/cilastatin/relebactam in patients with hospital‐acquired/ventilator‐associated bacterial pneumonia

Carbapenem-Resistant Klebsiella pneumoniae Osteomyelitis Treated with Ceftazidime-Avibactam in an Infant: A Case Report

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