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(1) Background: Infections caused by multidrug-resistant (MDR) bacteria represent one of the major global public health problems of the 21st century. Beta-lactam antibacterial agents are commonly used to treat infections due to Gram-negative pathogens. New β-lactam/β-lactamase inhibitor combinations are urgently needed. Combining relebactam (REL) with imipenem (IMI) and cilastatin (CS) can restore its activity against many imipenem-nonsusceptible Gram-negative pathogens. (2) Methods: we performed a systematic review of the studies reporting on the use of in vivo REAL/IPM/CS. (3) Results: A total of eight studies were included in this review. The primary diagnosis was as follows: complicated urinary tract infection (n = 234), complicated intra-abdominal infections (n = 220), hospital-acquired pneumonia (n = 276), and ventilator-associated pneumonia (n = 157). Patients with normal renal function received REL/IPM/CS (250 mg/500 mg/500 mg). The most frequently reported AEs occurring in patients treated with imipenem/cilastatin plus REL/IPM/CS were nausea (11.5%), diarrhea (9.8%), vomiting (9.8%), and infusion site disorders (4.0%). Treatment outcomes in these high-risk patients receiving REL/IPM/CS were generally favorable. A total of 70.6% of patients treated with REL/IPM/CS reported a favorable clinical response at follow-up. (4) Conclusions: this review indicates that REL/IPM/CS is active against important MDR Gram-negative organisms.

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BackgroundMultiple randomized controlled studies have compared numerous antibiotic regimens, including new, recently commercialized antibiotics in the treatment of nosocomial pneumonia (NP). The objective of this Bayesian network meta-analysis (NMA) was to compare the efficacy and the safety of different antibiotic treatments for NP.MethodsWe conducted a systematic search of PubMed, Medline, Web of Science, EMBASE and the Cochrane Library databases from 2000 through 2021. The study selection included studies comparing antibiotics targeting Gram-negative bacilli in the setting of NP. The primary endpoint was 28 day mortality. Secondary outcomes were clinical cure, microbiological cure and adverse events.ResultsSixteen studies encompassing 4993 patients were included in this analysis comparing 13 antibiotic regimens. The level of evidence for mortality comparisons ranged from very low to moderate. No significant difference in 28 day mortality was found among all beta-lactam regimens. Only the combination of meropenem plus aerosolized colistin was associated with a significant decrease of mortality compared to using intravenous colistin alone (OR = 0.43; 95% credible interval [0.17-0.94]), based on the results of the smallest trial included. The clinical failure rate of ceftazidime was higher than meropenem with (OR = 1.97; 95% CrI [1.19-3.45]) or without aerosolized colistin (OR = 1.40; 95% CrI [1.00-2.01]), imipemen/cilastatin/relebactam (OR = 1.74; 95% CrI [1.03-2.90]) and ceftazidime/avibactam (OR = 1.48; 95% CrI [1.02-2.20]). For microbiological cure, no substantial difference between regimens was found, but ceftolozane/tazobactam had the highest probability of being superior to comparators. In safety analyses, there was no significant difference between treatments for the occurrence of adverse events, but acute kidney failure was more common in patients receiving intravenous colistin.ConclusionsThis network meta-analysis suggests that most antibiotic regimens, including new combinations and cefiderocol, have similar efficacy and safety in treating susceptible Gram-negative bacilli in NP. Further studies are necessary for NP caused by multidrug-resistant bacteria. Registration PROSPERO CRD42021226603.

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BackgroundImipenem is a broad-spectrum carbapenem antibiotic for severe infections with significant pharmacokinetic (PK) variability. This review systematically synthesized published population pharmacokinetic (popPK) studies to identify key covariates and guide individualized dosing for patients with various conditions.MethodsA systematic PubMed and Web of Science search identified imipenem popPK models. Studies employing nonlinear mixed-effects modeling in patients with various conditions were included, and data were extracted independently by two reviewers via a standardized form. The study characteristics and PK parameter estimates were compared.ResultsThis systematic review of 18 popPK studies revealed that imipenem PKs were predominantly characterized by two-compartment models. The clearance of imipenem varied from 4.79 to 16.2 L/h in adults. Creatinine clearance (CLcr) was the most consistent and significant covariate for imipenem clearance, whereas body weight (BW) was frequently identified for volume of distribution. Other clinically relevant covariates, including the glomerular filtration rate (GFR), age, and serum ALB level, were also incorporated into the final models for specific patient subpopulations. All models applied internal validations, such as bootstrap and visual predicative check, but only three studies performed external validation.ConclusionThis review systematically integrates existing popPK models of imipenem, highlighting renal function and BW as key covariates. This study provides valuable insights for individualized dosing while identifying critical research gaps, particularly the need for external validation and focused studies in special populations.

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BackgroundCarbapenem-resistant Gram-negative bacteria (CRGNB) pose a severe global health threat, yet comprehensive bibliometric analyses in this field remain limited. This systematic review employs a bibliometric methodology to identify research hotspots and emerging trends from 2020 to 2025.MethodLiterature published between January 1, 2020, and October 31, 2025, was retrieved from the Web of Science Core Collection (WoSCC), Scopus, and PubMed for bibliometric analysis. Analytical tools, including VOSviewer, CiteSpace, and the Bibliometrix package, were used to assess publications by number, country, institution, journal, author, and keywords.ResultsThe bibliometric analysis revealed that global CRGNB research has experienced a fluctuating growth trend. China was the leading contributor, with 2,950 publications (25.5% of the total), and demonstrated significant collaboration with the USA and the UK. Major research clusters encompassed hypervirulent CRGNB strains (particularly carbapenem-resistant Klebsiella pneumoniae and Escherichia coli), resistance mechanisms (particularly carbapenemase-producing), antibiotic resistance, emerging therapeutic strategies (such as novel β-lactam/β-lactamase inhibitors, siderophore antibiotics, phage therapy, and antimicrobial peptides) and One Health perspectives (addressing environmental reservoirs). Thematic analysis identified evolving research priorities, including hypervirulent CRGNB strains, artificial intelligence, and early diagnosis and rapid screening of carbapenem resistance, exemplified by clustered regularly interspaced short palindromic repeats-based detection and artificial intelligence-driven matrix assisted laser desorption ionization-time of flight analysis. Randomized controlled trials indicated promising outcomes for several new antimicrobial agents, such as cefiderocol, sulbactam-durlobactam, and imipenem-relebactam. However, safety concerns, particularly in critically ill patients, remain a significant challenge.ConclusionCRGNB research is increasingly directed toward elucidating resistance mechanisms, improving diagnostic tools, and exploring non-antibiotic therapeutic options. Strengthening international collaboration and fostering multidisciplinary approaches are imperative to advance high-quality research and address this growing threat.

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Guideline-based combination therapy achieves sputum culture conversion rates in 23%-34% of patients with Mycobacterium abscessus-complex lung disease. Thus, new therapies are needed. We performed a systematic review to validate and benchmark the hollow fiber system model of M. abscessus lung disease for drug development. We performed a literature search to identify all published hollow fiber system pharmacokinetic-pharmacodynamic studies. Preferred Reporting Items for Systematic Reviews and Meta-Analyses was used for bias minimization. A total of 12 studies were identified. The average quality score was 13.7 out of 21. Eight were monotherapy (exposure-effect and dose-fractionation), one double β-lactam, and three guideline-based therapy studies. For omadacycline and imipenem, hollow fiber system data were accompanied by clinical real-world evidence confirmation. Microbial kill was always terminated by antimicrobial resistance. We used quantitative analyses to rank drugs' efficacy based on CFU/mL kill below day 0 bacterial burden normalized to multi-drug guideline-based therapy kill. The highest-ranked drugs were sulbactam-durlobactam-ceftriaxone (177-fold), epetraborole (15-fold), and omadacycline (7-fold) better than guideline-based therapy. We used the target exposures identified in the systematic analysis in Monte Carlo experiments to identify optimal doses for inhaled formulations. The optimal inhalational dose of imipenem was 250 mg/day, for tigecycline 4 mg/day, for cefoxitin 50 mg/day, and for amikacin liposome inhalation suspension 590 mg once weekly. The hollow fiber system model of M. abscessus lung disease is tractable for exposure-effect, dose-fractionation, and factorial design combination studies. It could also be used to rank drugs and inform on which drugs to test in novel combinations.IMPORTANCECurrent treatments for Mycobacterium abscessus lung disease fail in 70%-80% of patients and are toxic. The hollow fiber system has been used to study old and new potential treatments for this disease. We performed a systematic review of this methodology, for lessons learned. We found 12 studies, which were of adequate quality. Efficacy was always terminated by antimicrobial resistance. The top three drugs in terms of efficacy were sulbactam-durlobactam-ceftriaxone, epetraborole, and omadacycline, which were 7 to 177 times better than standard of care. These drugs could be combined into a new treatment regimen better than current treatments. We also calculated new doses for imipenem, tigecycline, cefoxitin, and amikacin when administered as inhalational therapy. The inhaled doses were multiple-fold lower than intravenous ones, which could be less toxic. The hollow fiber system model is an easily managed system from drug development and dose finding for M. abscessus lung disease.

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Abstract Background Pneumonia, a serious lung infection caused by bacteria, viruses, or fungi, often results in severe complications such as acute respiratory failure and sepsis, especially in ICU settings with high mortality rates. Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are notable forms, frequently caused by multidrug-resistant (MDR) bacteria like Pseudomonas aeruginosa, Klebsiella, and methicillin-resistant Staphylococcus aureus. We aimed to conduct a systematic literature review (SLR) of randomized control trials (RCTs) published up to July 15, 2024 of IMI/REL to evaluate its efficacy and safety for treating HABP/VABP compared to other interventions.Figure 1.Flow diagram of study selection according to PRISMA guidelinesFigure 2.Efficacy of IMI/RELAbbreviations: ARC: Augmented Renal Clearance; APACHE II: Acute Physiology and Chronic Health Evaluation II; CI: Confidence Interval; EFU: Early Follow-Up; EOT: End of Treatment; ESBL: Extended-Spectrum Beta-Lactamase; ICU: Intensive Care Unit; h: Hour; HABP: Hospital-Acquired Bacterial Pneumonia; MITT: Modified Intent-to-Treat; mMITT: Microbiological Modified Intent-to-Treat; mL/min: Milliliters Per Minute; NA: Not Applicable; NRF: Normal Renal Function; RI: Renal Impairment; SmMITT: Supplemental Microbiological Modified Intent-to-Treat; spp: Species; VABP: Ventilator-Associated Bacterial Pneumonia*Klebsiella spp. included Klebsiella aerogenes, Klebsiella oxytoca, and Klebsiella pneumoniae.Note: Only unique data reported for each study in the table above. Any results from primary publications that were repeated in secondary publications were considered duplicates and, therefore, not reported. Data for the APACHE score subgroup from the Ignacio Martin-Loeches (2023)(12) study was already reported in the primary publication; therefore, it was not included in the table above. References in the table: 8. Titov I, Wunderink RG, Roquilly A, Rodríguez Gonzalez D, David-Wang A, Boucher HW, et al. A randomized, double-blind, multicenter trial comparing efficacy and safety of imipenem/cilastatin/relebactam versus piperacillin/tazobactam in adults with hospital-acquired or ventilator-associated bacterial pneumonia (RESTORE-IMI 2 Study). Clinical Infectious Diseases. 2021;73(11):e4539-e48. 9. Roberts JA, Nicolau DP, Martin-Loeches I, Deryke CA, Losada MC, Du J, et al. Imipenem/cilastatin/relebactam efficacy, safety and probability of target attainment in adults with hospital-acquired or ventilator-associated bacterial pneumonia among patients with baseline renal impairment, normal renal function, and augmented renal clearance. JAC-Antimicrobial Resistance. 2023;5(2):dlad011. 10. Martin-Loeches I, Shorr AF, Kollef MH, Du J, Losada MC, Paschke A, et al., editors. Participant-and Disease-Related Factors as Independent Predictors of Treatment Outcomes in the RESTORE-IMI 2 Clinical Trial: A Multivariable Regression Analysis. Open Forum Infectious Diseases; 2023: Oxford University Press US. 11. Chen LF, Losada MC, Mahoney KA, Du J, Brown ML, Tipping R, et al., editors. 1460. Imipenem/Cilastatin (IMI)/Relebactam (REL) in Hospital-Acquired/Ventilator-Associated Bacterial Pneumonia (HABP/VABP): Subgroup Analyses of Critically Ill Patients in the RESTORE-IMI 2 Trial. Open Forum Infectious Diseases; 2020: Oxford University Press US. 12. EUCTR. IMI/REL (MK-7655A) vs. PIP/TAZ in Treatment of Subjects with HABP/VABP. European Union Clinical Trials Register. 2018. 13. Losada MC, Maniar A, Du J, Brown ML, Young K, Hilbert DW, et al., editors. 1230. Clinical and Microbiologic Outcomes by Causative Pathogen in Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia (HABP/VABP) Treated with Imipenem/Cilastatin (IMI)/Relebactam (REL) Versus Piperacillin/Tazobactam (PIP/TAZ). Open Forum Infectious Diseases; 2020: Oxford University Press. 14. Losada MC, Du J, Brown ML, Young K, Moise P, Tipping R, et al., editors. Efficacy and safety of imipenem/cilastatin/relebactam versus piperacillin/tazobactam in patients with hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia by geographic region. Intensive Care Medicine Experimenta; 2020. 15. Clinicaltrial.gov. Imipenem/Cilastatin/Relebactam (MK-7655A) Versus Piperacillin/Tazobactam in Participants With Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia (MK-7655A-016). Clinicaltrialgov registry. 2018. Methods PICOTS included patients aged ≥18yrs, requiring hospitalizations and treatment for a bacterial infection for HABP/VABP and receiving IMI/REL (Table 1). Systematic literature searches were conducted in Medline, Embase, and Cochrane databases up to July 15, 2024. Additionally, relevant conferences, HTA websites, and bibliographies of identified systematic reviews were hand-searched. Study selection involved two independent reviewers, with conflicts resolved by a third reviewer. Quality assessment was conducted using the Cochrane Risk-of-Bias Tool.Table 1.PICOTS Results From 2,406 database records, 12 publications were included after title/abstract and full-text screening (Figure 1). These encompassed three unique trials: RESTORE-IMI 1, RESTORE-IMI 2, and NCT03583333. The trials consistently demonstrated the efficacy of IMI/REL in all-cause mortality and clinical responses for HABP/VABP. The safety profile of IMI/REL was comparable (Figure 2). Conclusion The SLR provides strong evidence of IMI/REL's efficacy and safety for treating HABP/VABP, particularly benefiting critically ill patients, including those with severe infections and compromised renal function as shown in the RESTORE-IMI-1 and 2 trials. Facing significant multidrug-resistant (MDR) challenges, imipenem/relebactam may be effective where pathogens may be resistant to existing therapies. These findings will contribute to health technology assessments and facilitate integration of IMI/REL into treatment guidelines in additional geographic regions. Disclosures Carolyn Cameron, MPH, MSD: Stocks/Bonds (Public Company) Shalini Bagga, TBD, Amgen: Work in a consultancy that works with Pharma companies|BI: Work in a consultancy that works with Pharma companies|BMS: Work in a consultancy that works with Pharma companies|Merck: Work in a consultancy that works with Pharma companies|Pfizer: Work in a consultancy that works with Pharma companies|Sanofi: Work in a consultancy that works with Pharma companies|Takeda: Work in a consultancy that works with Pharma companies Vaneet Pal Kaur Khurana, Masters in Pharmacy, Merck & Co., Inc.: I work for a consultancy that contracts with Pharma companies|P'fizer: I work for a consultancy that contracts with Pharma companies|Takeda: I work for a consultancy that contracts with Pharma companies|Vasomune Therapeutics: I work for a consultancy that contracts with Pharma companies Prashant Soni, Masters in Pharmacy, BMS: I work in a consultancy that contracts with Pharma companies|Merck: I work in a consultancy that contracts with Pharma companies|Pfizer: I work in a consultancy that contracts with Pharma companies|Sanofi: I work in a consultancy that contracts with Pharma companies|Takeda: I work in a consultancy that contracts with Pharma companies|Vasomune: I work in a consultancy that contracts with Pharma companies Sachin Kumar, TBD, BMS: I work for a company that contracts with Pharma companies|Merck: I work for a company that contracts with Pharma companies|Pfizer: I work for a company that contracts with Pharma companies|Sanofi: I work for a company that contracts with Pharma companies|Takeda: I work for a company that contracts with Pharma companies Emre Yucel, PhD, Merck & Co., Ltd: Stocks/Bonds (Public Company)

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BackgroundGram-negative bacteria is a global public health problem. Treatment options include novel beta-lactamase inhibitors.ObjectivesThe objective of this study was to collect information on the efficacy and safety of novel β-lactamase inhibitor combinations such as imipenem-cilastatin/relebactam (IMI/REL).MethodsIn order to comprehensively evaluate the clinical, microbiological, and adverse events outcomes, a meta-analysis was conducted on clinical trials comparing novel β-lactamase inhibitor combinations with existing comparator therapies.ResultsFour studies comprising 948 patients were included in the analysis. IMI/REL therapy demonstrated similar clinical responses to comparators across various treatment visits, including discontinuation of intravenously administered therapy visits [DCIV, RR = 1.00 (0.88, 1.12)], early follow-up visits [EFU, RR = 1.00 (0.89, 1.14)], late follow-up visits [LFU, RR = 1.00 (0.88, 1.13)]. Moreover, no significant difference in the microbiologic response of MITT patients was observed between IMI/REL and comparators across DCIV [RR = 0.99 (0.89, 1.11)], EFU [RR = 1.01 (0.95, 1.07)], and LFU visits [RR = 1.00 (90.94, 1.07)]. In terms of safety, therapy with IMI/REL and comparators exhibited similar risks of at least one adverse event (AE), drug-related AEs, and discontinuation due to AEs. The incidence of serious AEs (SAEs) was significantly lower in the IMI/REL group compared to the comparison groups. The predominant AEs were gastrointestinal disorders, with no significant difference observed between the IMI/REL group and comparators.ConclusionThe clinical and microbiologic response to IMI/REL in the treatment of bacterial infection was comparable to that of the comparator. Furthermore, the incidence of AEs and the tolerability of IMI/REL were similar among the comparators. Based on these findings, IMI/REL can be considered as a viable alternative treatment option.

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Relebactam is a new inhibitor of class A and class C β-lactamases. The FDA has approved combining IMI/CS/REL to treat some infectious diseases. This study systematically reviews the efficacy and safety of IMI/CS/REL based on existing clinical trials so as to provide a reference for follow-up research. Researchers comprehensively searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov for randomised controlled trials published up to Mar 28, 2025, with “Imipenem/Cilastatin/Relebactam” or “IMI/CS/REL” as keywords, and screened the results according to the proposed exclusion and inclusion criteria. Data extraction was performed on the included randomized controlled trials (RCTs), while the day 28/30 all-cause mortality, clinical response rate, microbiological response rate, the adverse event response rate and drug-related adverse reaction rate were evaluated using R (4.4.3). The evaluation results were expressed in terms of relative risk with 95% confidence limit (RR, 95%CI). Six RCTs (1606 subjects) were involved in this meta-analysis. The meta-analysis showed no significant differences between IMI/CS/REL and comparators in day 28/30 all-cause mortality (RR = 0.82, 95% CI 0.39–1.72, P = 0.10), in clinical response rate during the early follow-up period (EFU) (RR = 1.02, 95%CI 0.96–1.08, P = 0.67) and in microbiological response at EFU (RR = 1.02, 95%CI 0.95–1.09, P = 0.76). The adverse events (AEs) rate also showed no statistical difference in each study’s arms (RR = 1.02, 95%CI 0.95–1.08, P = 0.87). IMI/CS/REL demonstrates a non-inferior efficacy and safety profile compared to standard comparators in treating carbapenem-susceptible or carbapenem-resistant pathogens. Nevertheless, more robust clinical evidence—especially in resistant, polymicrobial, and pathogen-defined infections—is needed to fully establish its role in real-world practice.

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