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

Integral-2: P3 Study to Assess Efficacy and Safety of Cefepime/Nacubactam and Aztreonam/Nacubactam Versus Best Available Therapy for Adults With Infection Due to Carbapenem Resistant Enterobacterales (clinicaltrials.gov) - P3 | N=150 | Recruiting | Sponsor: Meiji Seika Pharma Co., Ltd. | Trial completion date: Feb 2025 ➔ Sep 2025 | Trial primary completion date: Feb 2025 ➔ Sep 2025

Trial completion date • Trial primary completion date • Infectious Disease • Nephrology • Pneumonia • Respiratory Diseases

In vitro microbiological activity of aztreonam, cefepime and cefiderocol combined with nacubactam against NDM-harbouring Escherichia coli and Klebsiella pneumoniae clinical isolates (ESCMID Global 2025) - No abstract available

Late-breaking abstract • Preclinical • Infectious Disease • Pneumonia

Activity of the novel combination therapies cefepime/nacubactam against 12,613 clinical isolates of Enterobacterales collected worldwide during 2021-2023 (ESCMID Global 2025) - No abstract available

Clinical • Combination therapy

Genomic approach to evaluate the intrinsic antibacterial activity of novel diazabicyclooctanes (zidebactam and nacubactam) against clinical Escherichia coli isolates from diverse clonal lineages in the United Arab Emirates. (PubMed, J Infect Public Health) - "This study provides compelling evidence for the potential of DBOs, particularly zidebactam, as novel antibacterial agents. Their unique characteristics and broad-spectrum activity position them as promising candidates for future antibiotic development. While the inclusion of DBO therapies in the antibiotic arsenal could significantly impact MDR pathogen treatment, realizing their full potential requires further research, clinical evaluation, and vigilant monitoring of resistance mechanisms through integrated genomic approaches."

Journal

Susceptibility of a worldwide collection of 12,613 Enterobacterales isolated during 2021-2023 to the novel combination therapy aztreonam/nacubactam (ESCMID Global 2025) - No abstract available

Combination therapy

In vitro activities of aztreonam/nacubactam and cefepime/nacubactam against carbapenemase-producing Enterobacterales collected as part of a global surveillance study in 2021-2022 (ESCMID Global 2025) - No abstract available

Preclinical

In vitro activity and resistance mechanisms of novel antimicrobial agents against metallo-β-lactamase producers. (PubMed, Eur J Clin Microbiol Infect Dis) - "Cefiderocol and aztreonam/avibactam are already clinically available and recommended by international guidelines. In addition, two new classes of β-lactam/ β-lactamase combinations are under clinical evaluation: (i) combination of β-lactam with novel boronic-derived inhibitors (e.g. taniborbactam and xeruborbactam), (ii) combination of β-lactam with last generation diazabicyclooctane β-lactamase inhibitors (e.g. zidebactam and nacubactam), active on most of serine-β-lactamases but also showing strong intrinsic activity on PBP-2. This review aims to provide up-to-date data on the characteristics, activity and emerging resistance mechanisms of the armamentarium of clinically available or soon-to-be introduced drugs for the treatment of MβL-producing Gram-negative organisms."

Journal • Preclinical • Review • Infectious Disease

The combined dual β-lactams and diazabicyclooctane β-lactamase inhibitor is highly effective against Mycobacterium abscessus species in vitro. (PubMed, J Glob Antimicrob Resist) - "The combination of cefazolin, cefotiam, cefoxitin, or cefuroxime with imipenem and nacubactam was highly effective against MABS. Without nacubactam, the combination of cefoxitin and imipenem was effective."

Journal • Preclinical • Infectious Disease • Pulmonary Disease • Respiratory Diseases

β-Lactam/β-Lactamase Inhibitor Combination Antibiotics Under Development. (PubMed, Pathogens) - "The incorporation of ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, and imipenem/cilastatin/relebactam has provided new therapeutic options in the treatment of patients with infections due to MDR pathogens. Cefiderocol along with cefepime/enmetazobactam, avibactam/aztreonam, and sulbactam/durlobactam have been recently added to these agents as therapeutic choices, particularly for metallo-β-lactamase producing Gram-negative bacteria...However, only a few have advanced through phase 1, 2, and 3 clinical trials. Among them, in this article, we focus on the most promising combinations of cefepime/zidebactam, cefepime/taniborbactam, and imipenem/cilastatin/funobactam, which are currently under investigation in phase 3 trials."

Journal • Review • Infectious Disease

Advancements in the fight against globally distributed OXA-48 carbapenemase: evaluating the new generation of carbapenemase inhibitors. (PubMed, Antimicrob Agents Chemother) - "To assess the potential of these compounds, this study compared the efficacy against OXA-48 of novel β-lactamase inhibitors, specifically the 1,6-diazabicyclo[3,2,1]octanes (DBOs) avibactam, relebactam, zidebactam, nacubactam, and durlobactam, along with the cyclic and bicyclic boronates vaborbactam, taniborbactam, and xeruborbactam...Combinations, such as cefepime/zidebactam, meropenem/nacubactam, and sulbactam/durlobactam, show promising activity against OXA-48-producing Enterobacterales, while ceftazidime/avibactam, cefepime/taniborbactam, and meropenem/xeruborbactam combinations also appear highly active, largely due to the excellent kinetics of these new inhibitors. Overall, this comprehensive analysis provides important insights into the effectiveness of new BLIs against OXA-48-producing Enterobacterales, highlighting xeruborbactam, durlobactam, and avibactam as leading candidates. Additionally, BLIs like zidebactam, nacubactam, and taniborbactam also showed..."

Journal • Infectious Disease

Integral-1: Efficacy and Safety of Cefepime/Nacubactam or Aztreonam/Nacubactam Compared to Imipenem/Cilastatin in Subjects With Complicated Urinary Tract Infections or Acute Uncomplicated Pyelonephritis (clinicaltrials.gov) - P3 | N=614 | Completed | Sponsor: Meiji Seika Pharma Co., Ltd. | Active, not recruiting ➔ Completed

Trial completion • Infectious Disease • Nephrology

In vitro antimicrobial activity of six novel β-lactam and β-lactamase inhibitor combinations and cefiderocol against NDM-producing Enterobacterales in China. (PubMed, Int J Antimicrob Agents) - "Aztreonam/avibactam and aztreonam/nacubactam showed the highest activity against NPE. The potential resistance mechanisms of novel antimicrobial agents against NPE should be under active surveillance."

Journal • Preclinical • Infectious Disease • Pneumonia

Simulated achievement rate of β-lactams/nacubactam treatment in humans using instantaneous MIC-based PK/PD analysis. (PubMed, J Antimicrob Chemother) - "AZT/NAC and CFPM/NAC are bactericidal against CPE at practically achievable dosages."

Journal • PK/PD data • Infectious Disease

Integral-1: Efficacy and Safety of Cefepime/Nacubactam or Aztreonam/Nacubactam Compared to Imipenem/Cilastatin in Subjects With Complicated Urinary Tract Infections or Acute Uncomplicated Pyelonephritis (clinicaltrials.gov) - P3 | N=614 | Active, not recruiting | Sponsor: Meiji Seika Pharma Co., Ltd. | Recruiting ➔ Active, not recruiting

Enrollment closed • Infectious Disease • Nephrology

Assessment of the activity and mechanisms of resistance to cefiderocol and combinations of β-lactams and the novel β-lactamase inhibitors avibactam, taniborbactam, zidebactam, nacubactam, xeruborbactam, and ANT3310 in emerging double-carbapenemase-producing Enterobacterales. (PubMed, Antimicrob Agents Chemother) - "Minimum inhibitory concentration (MIC) values for ceftazidime, ceftazidime/avibactam, aztreonam, aztreonam/avibactam, aztreonam/nacubactam, cefiderocol, cefepime, cefepime/taniborbactam, cefepime/zidebactam, cefepime/nacubactam, imipenem, imipenem/relebactam, meropenem, meropenem/vaborbactam, meropenem/xeruborbactam, and meropenem/ANT3310 were determined by reference broth microdilution. Meropenem/ANT3310 (MIC50/MIC90 = 0.5/≥64 mg/L; 47/57 susceptible) and cefepime/taniborbactam (MIC50/MIC90 = 0.5/16 mg/L; 44/57 susceptible) also retained high levels of activity, although they were affected by NDM-type enzymes in combination with porin deficiency. Our findings highlight that cefiderocol and combinations of β-lactams and the novel β-lactamase inhibitors avibactam, nacubactam, taniborbactam, zidebactam, xeruborbactam, and ANT3310 show promising activity against double-carbapenemase-producing Enterobacterales."

Journal

Rapid Emergence of Resistance to Broad-Spectrum Direct Antimicrobial Activity of Avibactam. (PubMed, bioRxiv) - "Avibactam (AVI) is a diazabicyclooctane (DBO) β-lactamase inhibitor used clinically in combination with ceftazidime...This activity is mechanistically similar to that of more potent novel DBOs (zidebactam, nacubactam) in late clinical development...Although avibactam-resistant strains had increased lag time, suggesting a fitness cost that might render them less problematic in clinical infections, there was no statistically significant difference in growth rates between susceptible and resistant strains. The finding of rapid emergence of resistance to avibactam as the result of a large mutational target has important implications for novel DBOs with potent direct antibacterial activity, which are being developed with the goal of expanding cell wall-active treatment options for multidrug-resistant gram-negative infections but may be vulnerable to treatment-emergent resistance."

Journal • Infectious Disease

Novel agents in development for the treatment of resistant Gram-negative infections. (PubMed, Expert Rev Anti Infect Ther) - "While many of these novel agents demonstrate in vitro activity against carbapenem-resistant GNB, their efficacy has mainly been evaluated in phase-3 randomized controlled trials (RCT) for infections caused by carbapenem-susceptible GNB. Although evidence from real-world observational studies is generally less robust than that from RCT, it could be crucial for updating clinical guidelines on treating carbapenem-resistant GNB with these new agents in the absence of dedicated RCT."

Gram negative • Journal • Review • Infectious Disease

Relative inhibitory activities of newly developed diazabicyclooctanes, boronic acid derivatives, and penicillin-based sulfone β-lactamase inhibitors against broad-spectrum AmpC β-lactamases. (PubMed, Antimicrob Agents Chemother) - "The relative inhibitory activities of diazabicyclooctanes (avibactam, relebactam, zidebactam, nacubactam, durlobactam), boronic acid derivatives (vaborbactam, taniborbactam, xeruborbactam), and penicillin-based sulfone derivative enmetazobactam were evaluated against several intrinsic and acquired class C β-lactamases. Notably, durlobactam exhibited the most pronounced inhibitory effect. Interstingly, the chromosomal AmpC of Acinetobacter baumannii was the least sensitive enzyme to the newly developed β-lactamase inhibitors."

Journal

Impact of chromosomally encoded resistance mechanisms and transferable β-lactamases on the activity of cefiderocol and innovative β-lactam/β-lactamase inhibitor combinations against Pseudomonas aeruginosa. (PubMed, J Antimicrob Chemother) - "Cefiderocol and new β-lactam/β-lactamase inhibitor combinations show promising and complementary in vitro activity against mutational and transferable P. aeruginosa β-lactam resistance. However, the combined effects of efflux pumps, OprD deficiency and efficient β-lactamases could still result in the loss of all therapeutic options. Resistance surveillance, judicious use of new agents and continued drug development efforts are encouraged."

Journal

Integral-1: Efficacy and Safety of Cefepime/Nacubactam or Aztreonam/Nacubactam Compared to Imipenem/Cilastatin in Subjects With Complicated Urinary Tract Infections or Acute Uncomplicated Pyelonephritis (clinicaltrials.gov) - P3 | N=600 | Recruiting | Sponsor: Meiji Seika Pharma Co., Ltd. | Trial completion date: Aug 2024 ➔ Nov 2024 | Trial primary completion date: Aug 2024 ➔ Nov 2024

Trial completion date • Trial primary completion date • Infectious Disease • Nephrology

In vitro activity of nacubactam (OP0595) in combination with β-Lactams against clinical isolates of Enterobacterales collected in four Asian countries from 2017 to 2021 (ECCMID 2024) - No abstract available

Combination therapy • Preclinical

In vitro activity of two aztreonam-based combinations, aztreonam/avibactam and aztreonam/nacubactam against molecularly characterised carbapenemase expressing Enterobacterales collected in India (ECCMID 2024) - No abstract available

Late-breaking abstract • Preclinical

Activity of the novel combination therapies aztreonam/nacubactam and cefepime/nacubactam against 3,694 clinical isolates of Enterobacterales collected worldwide during 2022 (ECCMID 2024) - No abstract available

Clinical • Combination therapy

Post-β-lactamase-inhibitor effect of nacubactam in combination with aztreonam and cefepime on ESBL, AmpC, KPC, or OXA-48-producing Enterobacterales (ECCMID 2024) - No abstract available

Combination therapy

Activity of cefiderocol and innovative β-lactam/β-lactamase inhibitor combinations against isogenic strains of Escherichia coli expressing single and double β-lactamases under high and low permeability conditions. (PubMed, Int J Antimicrob Agents) - "Our finding highlights the promising activity that cefiderocol and new β-lactam/β-lactamase inhibitors have against recombinant E. coli strains expressing widespread β-lactamases, including when these are combined with low permeability or other enzymes. Aztreonam/avibactam, cefiderocol, cefepime/zidebactam and meropenem/nacubactam will help to mitigate to some extent the urgency of new compounds able to resist MBL action, although NDM enzymes represent a growing challenge against which drug development efforts are still needed."

Journal