enmetazobactam (AAI101) / Allecra - LARVOL DELTA

Classification and applicability of new beta-lactamase inhibitors. (PubMed, Rev Esp Quimioter) - "This non-exhaustive minireview describes the main characteristics of the new beta-lactamase inhibitors (enmetazobactam, avibactam, relebactam, durlobactam, zidebactam, nacubactam, vaborbactam, taniborbactam, and xeruborbactam), their spectrum of inhibition, their activity in combination with different beta-lactams, the main resistance mechanisms that can compromise their activity and the main applications of the different beta-lactam-beta-lactamase inhibitor combinations depending on the type of beta-lactamase/carbapenemase and the microorganism involved."

Journal • Review

Mechanistic basis for inhibition of the extended-spectrum β-lactamase GES-1 by enmetazobactam and tazobactam. (PubMed, FEBS Lett) - "We find no evidence for lysinoalanine formation, with mass spectrometry indicating active enzyme regeneration, behaviour previously observed for carbapenem-hydrolysing enzymes, but not ESBLs. This work establishes that PAS inhibitors interact with diverse β-lactamases by differing mechanisms, which should inform development of future compounds."

Journal • Infectious Disease

Beta-lactams and beta-lactamase inhibitors-current developments (PubMed, Inn Med (Heidelb)) - "These included MRSA-active cephalosporins (ceftaroline and ceftobiprole), new, broadly effective combinations of beta-lactams with beta-lactamase inhibitors, and cefiderocol, a new siderophore cephalosporin that uses the bacteria's own iron uptake systems of gram-negative bacteria to better reach the site of action through the outer membrane.In addition to cefiderocol, the most important active ingredients or fixed combinations already available on the German market include ceftazidime-avibactam, ceftolozane-tazobactam, and aztreonam-avibactam. Imipenem-relebactam and meropenem-vaborbactam are also available; Cefepim-enmetazobactam was recently added...However, interesting new combinations, such as ceftibutene-avibactam for oral use, are in development. Such combinations could also enable the oral treatment of infections by some carbapenemase producers in the future."

Journal • Review • Infectious Disease

Clinical efficacy, safety and pharmacokinetics of novel β-lactam/β-lactamase inhibitor combinations: a systematic review. (PubMed, JAC Antimicrob Resist) - "A total of 191 articles addressing clinical research regarding the efficacy, safety, tolerability, and PK of new BL/BLI combinations with avibactam, durlobactam, enmetazobactam, nacubactam, relebactam, taniborbactam, tazobactam, vaborbactam and zidebactam were included...In spite of that, the development of new BLI effective for class B metallo-β-lactamases (MBL) is still challenging, being aztreonam/avibactam the only approved combination active against MBL-producing bacteria. Although there has been extensive research to develop new BLI and BL/BLI combinations, only a few have reached the market. More evidence of its usefulness in the real world is still needed."

Journal • PK/PD data • Review • Infectious Disease • Nephrology • Pneumonia • Respiratory Diseases

Focus on enmetazobactam chemical stability in association with cefepime for prolonged infusions, in syringe and elastomeric diffusers (ESCMID Global 2025) - No abstract available

Re: 'In vitro activity of cefepime-enmetazobactam on carbapenem resistant Gram negatives' by Bonnin et al. (PubMed, Clin Microbiol Infect) - No abstract available

Journal • Preclinical • Infectious Disease

Invention of Enmetazobactam: An Indian Triumph in Antimicrobial Drug Discovery. (PubMed, ACS Infect Dis) - "It is a novel beta-lactamase inhibitor invented by scientists at Orchid Pharma in Chennai, India, and has garnered international attention for its potential to address antimicrobial resistance. It became the first new chemical entity invented in India, clinically developed by Allecra Therapeutics GmbH, to be approved by the U.S. Food & Drug Administration, with additional approvals from the European Medical Agency, the U.K.'s Medicine & Healthcare Products Regulatory Agency, and the Drug Controller General of India."

Journal

In vivo efficacy of enmetazobactam combined with cefepime in a murine pneumonia model induced by OXA-48-producing Klebsiella pneumoniae. (PubMed, Microbiol Spectr) - "The combination showed a bacteriostatic effect using the 2-h controls as reference. Compared to 24-h controls, and to cefepime or meropenem monotherapies, the co-administration of enmetazobactam with cefepime demonstrated a pronounced in vivo bactericidal activity against cefepime-non-susceptible K. pneumoniae isolates with cefepime/enmetazobactam MICs up to 8 µg/mL in this model."

Journal • Preclinical • Infectious Disease • Pneumonia • Respiratory Diseases

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

Discovery of Enmetazobactam (IDWeek 2024) - No abstract available

Infectious Disease

Evaluation of the activity of cefepime/enmetazobactam against Enterobacterales bacteria collected in Europe from 2019 to 2021, including third-generation cephalosporin-resistant isolates. (PubMed, J Glob Antimicrob Resist) - "Cefepime/enmetazobactam was highly active against Enterobacterales isolates, especially those resistant to third-generation cephalosporins. These data suggest that cefepime/enmetazobactam could be used as a carbapenem sparing agent to replace piperacillin/tazobactam."

Journal • Infectious Disease • Pneumonia

In vivo efficacy of enmetazobactam combined with cefepime in a neutropenic murine OXA-48 Klebsiella pneumoniae pneumonia model (ECCMID 2024) - No abstract available

Preclinical • Infectious Disease • Pneumonia • Respiratory Diseases

Impact of Acquired Broad Spectrum β-Lactamases on Susceptibility to Novel Combinations Made of β-Lactams (Aztreonam, Cefepime, Meropenem, and Imipenem) and Novel β-Lactamase Inhibitors in Escherichia coli and Pseudomonas aeruginosa. (PubMed, Antimicrob Agents Chemother) - "Cefepime-zidebactam displayed low MICs, mainly due to the significant intrinsic antibacterial activity of zidebactam. Cefepime-taniborbactam showed excellent activity against recombinant E. coli strains, including metallo-β-lactamase producers, whereas aztreonam-avibactam remained the best therapeutic option against class B β-lactamase-producing P. aeruginosa."

Journal

Understanding the Breakdown of Enmetazobactam by the Extended Spectrum β-Lactamase GES-1 (ASM Microbe 2023) - "These are properties previously associated with carbapenem-hydrolysing class A β-lactamases, but not with ESBLs. Taken together, this work further establishes the basis for enmetazobactam inhibition of diverse class A β-lactamases and may guide the development of future related β-lactamase inhibitors."

Infectious Disease

Activity of aztreonam in combination with novel β-lactamase inhibitors against metallo-β-lactamase-producing Enterobacterales from Spain. (PubMed, Int J Antimicrob Agents) - "Aztreonam, aztreonam/avibactam, aztreonam/relebactam, aztreonam/zidebactam, aztreonam/taniborbactam, aztreonam/vaborbactam and aztreonam/enmetazobactam MICs were determined. Combinations of aztreonam with new BLIs show promising activity against Enterobacterales co-producing MBLs and SBLs, particularly the aztreonam/zidebactam, aztreonam/avibactam and aztreonam/taniborbactam combinations. Our results show that these novel drugs may represent innovative therapeutic strategies by their use in yet unexplored combinations as solutions for difficult-to-treat infections."

Combination therapy • Journal • Infectious Disease

Impact of surfactants and other body fluids on in vitro activity of a novel β-lactamase inhibitor enmetazobactam in combination with cefepime against clinical isolates of Klebsiella pneumoniae. (PubMed, J Antibiot (Tokyo)) - "Therefore, the impact of surfactants, urine, and serum on the antibacterial activity of the novel β-lactam/β-lactamase inhibitor combination of cefepime-enmetazobactam (FPE) was determined...Minimal Inhibitory Concentration (MIC) determinations (all strains) and Time Kill Curves (TKC) (one clinical isolate) were determined for FPE and piperacillin-tazobactam (TZP) with and without surfactant formulations Survanta® (SUR; 1%v/v) and Curosurf® (CUR; 1 mg ml). Determination of daptomycin MIC against Staphylococcus aureus ATCC 29213 in the presence and absence of surfactants was used as a positive control...These results demonstrate that the antibacterial activity of FPE is unaffected in the presence of lung surfactant. Moreover, FPE was not impacted by media supplemented with urine or serum."

Combination therapy • Journal • Preclinical • Infectious Disease • Pneumonia • Respiratory Diseases

Penicillanic Acid Sulfones Inactivate the Extended-Spectrum β-Lactamase CTX-M-15 through Formation of a Serine-Lysine Cross-Link: an Alternative Mechanism of β-Lactamase Inhibition. (PubMed, mBio) - "Enmetazobactam (formerly AAI101) and tazobactam are penicillanic acid sulfone (PAS) β-lactamase inhibitors that differ by an additional methyl group on the triazole ring of enmetazobactam, rendering it zwitterionic...High-resolution X-ray crystal structures showed that PAS exposure induces formation of a cross-link between Ser70 and Lys73, two residues critical to β-lactamase function. This previously undescribed mechanism of inhibition furthers our understanding of β-lactamase inhibition by classical PAS inhibitors and provides a basis for further, rational inhibitor development."

Journal • Infectious Disease

Development of Broth Microdilution MIC and Disk Diffusion Antimicrobial Susceptibility Test Quality Control Ranges for the Combination of Cefepime and the Novel β-lactamase Inhibitor Enmetazobactam. (PubMed, J Clin Microbiol) - "Enmetazobactam (formerly AAI101) is a novel penicillanic sulfone β-lactamase inhibitor active against a wide range of ESBLs. Quality control ranges were approved by the CLSI in 2017 (broth microdilution MIC) and 2019 (disk diffusion). The established QC ranges will ensure that appropriate assay performance criteria are attained using CLSI reference methodology when determining the susceptibility of clinical isolates to cefepime-enmetazobactam."

Journal • Infectious Disease • Nephrology • Pneumonia • Respiratory Diseases

Lung Pharmacokinetics (PK) in Epithelial Lining Fluid (ELF) (clinicaltrials.gov) - P1; N=19; Completed; Sponsor: Allecra; Recruiting ➔ Completed

Clinical • Trial completion

In vitro activity of the extended-spectrum beta-lactamase inhibitor AAI101, in combination with cefepime, against 90 molecularly characterized Enterobacteriaceae isolates expressing a variety of non-beta-lactam resistance mechanisms (ECCMID 2019) - "Materials/ Clinical isolates of Enterobacteriaceae resistant to gentamicin, ciprofloxacin, tetracycline and/or colistin were molecularly characterized by whole genome sequencing to identify encoded resistance genes. The novel extended-spectrum β-lactamase inhibitor AAI101, in combination with cefepime, was highly active in vitro against 90 recent, molecularly characterized clinical isolates of Enterobacteriaceae expressing a variety of non-β-lactam resistance mechanisms. Cefepime‑AAI101 activity was unaffected by resistance mechanisms targeting aminoglycoside, fluoroquinolone, colistin and tetracycline classes of antibacterial agents. Cefepime-AAI101 was as potent as meropenem and overcame resistance to piperacillin-tazobactam and therefore may represent a suitable alternative for empiric therapy in settings where resistance to piperacillin-tazobactam is increasing and carbapenem-sparing strategies are employed."

Combination therapy • Preclinical • Infectious Disease • Pneumonia • Respiratory Diseases

In vitro activity of cefepime-enmetazobactam against Gram-negative isolates collected from United States and European hospitals during 2014-2015. (PubMed, Antimicrob Agents Chemother) - "Enmetazobactam, formerly AAI101, is a novel penicillanic acid sulfone extended-spectrum β-lactamase (ESBL) inhibitor...Enmetazobactam at a fixed concentration of 8 μg/ml lowered the cefepime MIC from 16 to 0.12 μg/ml for Escherichia coli, from >64 to 0.5 μg/ml for Klebsiella pneumoniae, from 16 to 1 μg/ml for Enterobacter cloacae, and from 0.5 to 0.25 μg/ml for Enterobacter aerogenes Enmetazobactam did not enhance the potency of cefepime against P. aeruginosa Applying the Clinical and Laboratory Standards Institute susceptible-dose-dependent (SDD) breakpoint of 8 μg/ml to cefepime-enmetazobactam for comparative purposes resulted in cumulative inhibitions of 99.9% for E. coli, 96.4% for K. pneumoniae, 97.0% for E. cloacae, 100% for E. aerogenes, 98.1% for all Enterobacteriaceae assessed, and 82.8% for P. aeruginosa Comparator susceptibilities for all Enterobacteriaceae were 99.7% for ceftazidime-avibactam, 96.2% for meropenem, 90.7% for ceftolozane-tazobactam, 87% for..."

Journal • Immunology • Infectious Disease • Nephrology • Pneumonia • Respiratory Diseases

Analysis highlights troubles in the antibiotic pipeline (Center for Infectious Disease Research and Policy) - "A new analysis of the antibiotic pipeline indicates there aren't enough antibiotics in development to meet current and anticipated patient needs....An example of one of the candidates in the pipeline is cefepime plus enmetazobactam, which combines a beta-lactam antibiotic with an ESBL inhibitor....While the drug has produced encouraging results and could be an important new option for treating infections caused by these pathogens, beta-lactam/beta-lactamase inhibitor combinations aren't novel."

Clinical

Pharmacokinetics-pharmacodynamics of enmetazobactam combined with cefepime in a neutropenic murine thigh infection model. (PubMed, Antimicrob Agents Chemother) - "Enmetazobactam (formerly AAI101) is a novel ESBL inhibitor developed in combination with cefepime for empiric treatment of serious Gram-negative infections in settings where ESBLs are prevalent...Nine ESBL-producing isolates of K. pneumoniae, resistant to cefepime and piperacillin-tazobactam, were included in enmetazobactam dose-ranging studies...Sigmoid curve fitting across the combined set of isolates identified enmetazobactam PK-PD targets for stasis and for a 1-log bioburden reduction of 8% and 44% fT > 2 μg/ml, respectively, with a concomitant cefepime PK-PD target of 40 - 60% fT > cefepime-enmetazobactam MIC. These findings support clinical dose selection and breakpoint setting for cefepime-enmetazobactam."

Journal • PK/PD data • Preclinical

Beyond piperacillin-tazobactam: cefepime and AAI101 as a potent β-lactam-β-lactamase inhibitor combination. (PubMed, Antimicrob Agents Chemother) - "Impeding, as well as reducing, the burden of antimicrobial resistance in Gram-negative pathogens is an urgent public health endeavor. Additionally, upon reaction with AAI101, CTX-M-15 was modified to an inactive state. Notably, the in vivo efficacy of cefepime-AAI101 was demonstrated using a mouse septicemia model indicating the ability of AAI101 to bolster significantly the therapeutic efficacy of cefepime in vivo The combination of AAI101 with cefepime represents a potential carbapenem-sparing treatment regimen for infections suspected to be caused by Enterobacteriaceae expressing ESBLs."

Journal

Safety and Efficacy Study of Cefepime-AAI101 in the Treatment of Complicated Urinary Tract Infections (clinicaltrials.gov) - P3; N=1043; Completed; Sponsor: Allecra; Recruiting ➔ Completed

Clinical • Trial completion