nacubactam (RG6080) / Roche, Meiji Seika - LARVOL DELTA

Cefepime 2.0: Upgrading β-Lactamase Inhibitor Use. (PubMed, Microorganisms) - "Combining cefepime with novel β-lactamase inhibitors (enmetazobactam, taniborbactam, zidebactam, and nacubactam) revitalizes the role of this fourth-generation cephalosporin in contemporary therapy. Because they possess distinct microbiological spectra, these agents serve complementary rather than interchangeable roles. Their clinical success demands targeted integration into antimicrobial stewardship programs to optimize efficacy and safely reduce carbapenem dependence."

Journal • Review • Infectious Disease

Efficacy of new antimicrobial agents against carbapenemase-producing and non-carbapenemase-producing carbapenem-resistant Enterobacterales in Japan: national genomic surveillance (JARBS 2.0) study. (PubMed, J Antimicrob Chemother) - "Nacubactam-based combinations, cefiderocol and aztreonam/avibactam show promise against MBL-producing Enterobacterales in Japan, whereas cefepime/nacubactam demonstrated the greatest activity against non-CP CRE. The upgraded JARBS 2.0 framework enables high-resolution genomic and phenotypic surveillance, bridging the gap between molecular resistance mechanisms and the clinical efficacy of emerging antimicrobial agents. These findings highlight the value of integrating genomic surveillance into routine monitoring to guide antimicrobial therapy and inform infection prevention and control strategies."

Journal • Infectious Disease

In vitro activities of aztreonam/nacubactam and cefepime/nacubactam against a global collection of molecularly characterized Enterobacterales isolates carrying carbapenemases: a global antimicrobial resistance surveillance study from 2021 to 2023. (PubMed, JAC Antimicrob Resist) - "Meropenem-non-susceptible Enterobacterales isolates were sequenced by nanopore technology to identify resistance mechanisms...Aztreonam/nacubactam at ≤4/4 mg/L was active against 98.7% of the 307 NDM-producing isolates, more than aztreonam/avibactam (95.1% susceptible) or cefiderocol [85.7% susceptible (CLSI breakpoints)], while cefepime/nacubactam was active against 94.1% at ≤8/8 mg/L...Aztreonam/nacubactam and cefepime/nacubactam demonstrated potent in vitro activity against Enterobacterales that carried serine-carbapenemases and MBLs, including those with chromosomal resistance mechanisms that compromise the current best-in-class β-lactam antibiotics for treating infections caused by MBL-positive organisms. The percentage of NDM-positive E. coli with insertions in PBP3 is alarming and warrants continued surveillance."

Journal • Preclinical • Infectious Disease

Characterizing the V516M penicillin-binding protein 2 (PBP2) mutation causing zidebactam resistance in Pseudomonas aeruginosa. (PubMed, Antimicrob Agents Chemother) - "Nacubactam showed cross-resistance with zidebactam but showed a much lower basal binding affinity against PBP2, explaining its lower intrinsic antipseudomonal activity...Zidebactam resistance did not affect its activity as an AmpC inhibitor, restoring cefepime susceptibility in the dacB mutant. The PBP2V516M mutation was associated with cell morphology changes, but it did not affect growth rate or virulence. Antibiotic resistance and PBP IC50 profiling of PBP2V516M mutation help to understand the impact of target modification resistance mechanisms on existing DBOs and provide clues for guiding the development of novel derivatives."

Journal

Evaluation of drug-drug interaction between nacubactam and β-lactam antibiotic (cefepime, aztreonam, meropenem, or piperacillin) in Japanese healthy participants. (PubMed, Antimicrob Agents Chemother) - "All treatment emergent adverse events were mild in severity and resolved without treatment. Our results support the further clinical development of nacubactam coadministered with these β-lactam antibiotics."

Journal

Nacubactam: a review on mechanistic insights and therapeutic promise for combating β-lactam resistance among multidrug-resistant Gram-negative pathogens. (PubMed, Ann Med Surg (Lond)) - "Preclinical in vitro and in vivo studies demonstrate that NAC, when combined with β-lactams such as cefepime, aztreonam, or meropenem, produces substantial reductions in minimum inhibitory concentrations against multidrug-resistant Gram-negative pathogens, including carbapenemase-producing and metallo-β-lactamase (MBL)-coexpressing Enterobacterales. NAC represents a promising investigational BLI with a mechanistically innovative profile and broad β-lactam-potentiating capacity. While preclinical and early clinical findings support its translational potential, further clinical validation is required to define its therapeutic role, optimal combinations, and long-term impact in the management of multidrug-resistant Gram-negative infections."

Journal • Review • Infectious Disease

Pharmacokinetic analysis of nacubactam, a novel β-lactamase inhibitor, co-administered with meropenem in patients with a complicated urinary tract infection. (PubMed, JAC Antimicrob Resist) - "Predicted PK/PD indices suggested that all 20 patients would achieve exposure targets for meropenem (minimum inhibitory concentration of 4 mg/L) and nacubactam (8 mg/L). The consistent PK and safety profiles of nacubactam, and the ability to align the dosing regimen with partner antibiotics, confirm the suitability of nacubactam for further clinical development in patients with Gram-negative infections."

Journal • PK/PD data • Infectious Disease • Nephrology

In vitro activity of the novel β-lactamase inhibitor nacubactam against a nationwide collection of carbapenem-resistant Enterobacterales in Japan. (PubMed, JAC Antimicrob Resist) - "Cefepime-nacubactam and aztreonam-nacubactam demonstrated potent activity against CPE, with MIC50/90 of 2/4 and 0.5/2 mg/L, respectively, which were lower than those for ceftazidime-avibactam (64/>64 mg/L) and imipenem-relebactam (2/16 mg/L). Both combinations exhibited potent antibacterial activity against non-carbapenemase-producing carbapenem-resistant Enterobacterales (non-CP-CRE), with MIC50/90 of 0.25/4 and 0.5/4 mg/L, respectively. Cefepime-nacubactam and aztreonam-nacubactam have excellent antibacterial activities against CPE and non-CP-CRE, supporting their potential as therapeutic options for CRE infections."

Journal • Preclinical • Infectious Disease • Pneumonia

Effects of Nacubactam and Its Metabolites on QTc Interval: A Pooled Analysis of Two Randomized Phase 1 Studies. (PubMed, Clin Transl Sci) - "While certain confidence intervals from Mixed models for repeated measures straddled 10 ms at 3 h after 1000/2000 mg doses, these inconsistencies were not sustained and not evident at higher doses. Overall, findings support the safety of nacubactam and justify evaluation in larger, multidose, combination-therapy studies and provide regulatory-relevant evidence supporting progression to multidose and combination therapy trials without the need for a dedicated thorough QT study."

Clinical • Journal • P1 data • Retrospective data

Efficacy and safety of cefepime-nacubactam and aztreonam-nacubactam compared with imipenem-cilastatin for complicated urinary tract infection or acute uncomplicated pyelonephritis (Integral-1): a double-blind, randomised phase 3 trial. (PubMed, Lancet) - P3 | "Cefepime-nacubactam and aztreonam-nacubactam are potential treatment options for Gram-negative cUTI and acute uncomplicated pyelonephritis, including infections caused by antimicrobial-resistant strains."

Clinical • Journal • P3 data • Infectious Disease • Nephrology

In vitro activity of aztreonam-nacubactam and cefepime-nacubactam against a global collection of clinically important Gram-negative Bacilli collected in 2021-2023. (PubMed, JAC Antimicrob Resist) - "Aztreonam-nacubactam and cefepime-nacubactam were active against the majority of Enterobacterales isolates that were resistant to aztreonam-avibactam, ceftazidime-avibactam, imipenem-relebactam, meropenem-vaborbactam and cefiderocol. The MIC90s for aztreonam-nacubactam and cefepime-nacubactam were 16 and 8 mg/L for P. aeruginosa and >64 and 64 mg/L for A. baumannii. The results of this study support the continued development of aztreonam-nacubactam and cefepime-nacubactam as potential therapies for infections caused by CRE where resistance or potential toxicity to marketed antimicrobial agents excludes their use."

Journal • Preclinical • Infectious Disease • Nephrology

Overview of novel cefepime-based β-Lactam/β-lactamase inhibitor combinations. (PubMed, Expert Rev Anti Infect Ther) - "This review summarizes approved and investigational cefepime-based BL/BLI combinations, including cefepime/enmetazobactam (FEP/EMT), cefepime/taniborbactam (FTB), cefepime/zidebactam (FPZ), and cefepime/nacubactam (FEP/NAC)...FPZ combines β-lactamase inhibition and β-lactam - enhancer activity, retaining activity against XDR Enterobacterales and P. aeruginosa, including cefiderocol- or aztreonam/avibactam (ATM/AVI)-resistant strains. FEP/NAC shows promise against carbapenem- and MBL-producing strains, though clinical data remain limited. Optimal use relies on rapid molecular diagnostics, susceptibility testing, and antimicrobial stewardship to maximize efficacy and limit the emergence of resistance."

Journal • Review • Infectious Disease

A multi-center, open-label, two-part study to investigate the effect of renal function and hemodialysis on the pharmacokinetics of the novel β-lactamase inhibitor nacubactam. (PubMed, Antimicrob Agents Chemother) - P1 | "Renal impairment had no apparent effect on the safety profile of nacubactam, and a single 1 g dose was well tolerated in all groups. These data can be used to underwrite nacubactam dosing recommendations for patients with impaired renal function, including those receiving renal replacement therapy.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT02975388."

Journal • PK/PD data • Chronic Kidney Disease • Nephrology • Renal Disease

Evidence of intrapulmonary penetration of nacubactam, a novel β-lactamase inhibitor, following coadministration of nacubactam with meropenem in healthy adults. (PubMed, Antimicrob Agents Chemother) - P1 | "The treatment combination was well tolerated, and no significant safety signals were identified. These data support further consideration of nacubactam/β-lactam combinations for the treatment of serious nosocomial pneumonia.CLINICAL TRIALSThis study was registered with ClinicalTrials.gov as NCT03182504."

Journal • Infectious Disease • Pneumonia • Respiratory Diseases

Phase I studies assessing safety and pharmacokinetics of nacubactam administered alone or in combination with cefepime or aztreonam in Japanese healthy participants. (PubMed, Antimicrob Agents Chemother) - "In both studies, nacubactam, whether administered alone or combined with cefepime or aztreonam, was generally well tolerated. These favorable findings support further clinical development of nacubactam."

Clinical • Journal • P1 data • PK/PD data

Outcomes of cefepime/nacubactam and aztreonam/nacubactam for treatment of cUTI/AP patients with CRE: subgroup analysis of integral-1 study (ESCMID Global 2026) - No abstract available

Clinical

The in vitro activity of aztreonam/nacubactam and cefepime/nacubactam against molecularly characterised Enterobacterales isolates including those with ceftazidime-avibactam and aztreonam/avibactam resistance mechanisms collected globally from 2021-2023 (ESCMID Global 2026) - No abstract available

Preclinical

Activity of the novel combination therapy cefepime/nacubactam against 17,220 clinical isolates of Enterobacterales collected worldwide during 2021-2024 (ESCMID Global 2026) - No abstract available

Clinical • Combination therapy

Efficacy and safety of cefepime/nacubactam and aztreonam/nacubactam compared with imipenem/cilastatin for complicated urinary tract infection or acute uncomplicated pyelonephritis: integral-1, a double-blind, randomised phase III trial (ESCMID Global 2026) - No abstract available

Clinical • P3 data • Infectious Disease • Nephrology

Outcomes of cefepime/nacubactam and aztreonam/nacubactam in cUTI/AP patients with ESBL-producing bacteria enrolled into prospective phase III randomised clinical study (Integral-1) (ESCMID Global 2026) - No abstract available

Clinical • P3 data

Outcomes of cefepime/nacubactam and aztreonam/nacubactam for treatment of cUTI/AP patients with CRE: subgroup analysis of integral-1 study (ESCMID Global 2026) - No abstract available

Clinical

Probability of target attainment of cefepime/nacubactam and aztreonam/nacubactam for carbapenem-resistant Enterobacterales infections (ESCMID Global 2026) - No abstract available

Infectious Disease

Determination of the nonclinical PK/PD target value for nacubactam in a mouse thigh infection model using carbapenem-resistant Enterobacterales under co-administration of cefepime or aztreonam (ESCMID Global 2026) - No abstract available

PK/PD data • Preclinical • Infectious Disease

Population pharmacokinetic analysis of nacubactam, cefepime, and aztreonam and exposure–response analysis of efficacy results from phase III clinical trials (ESCMID Global 2026) - No abstract available

Clinical • P3 data • PK/PD data

In vitro activity of nacubactam against broad-spectrum-ß-lactamases (ESCMID Global 2026) - No abstract available

Preclinical