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aztreonam

aztreonam

Overview

Aztreonam is a synthetic monocyclic beta-lactam antibiotic (monobactam) first approved in the 1980s, notable for its narrow-spectrum activity exclusively targeting aerobic Gram-negative bacteria. Unlike penicillins and cephalosporins, aztreonam lacks the bicyclic ring structure of classical beta-lactams and is therefore non-cross-reactive in most patients with penicillin allergy. Its mechanism of action involves binding to penicillin-binding protein 3 (PBP3) in Gram-negative organisms, inhibiting cell wall transpeptidation and triggering bacterial lysis. Because aztreonam has no intrinsic activity against anaerobes or Gram-positive bacteria, it exerts minimal disruption on the anaerobic components of human gut flora, a property that distinguishes it from broader-spectrum beta-lactams and carries meaningful implications for colonization resistance.

Aztreonam is used clinically to treat serious infections caused by susceptible Gram-negative pathogens, including Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Stenotrophomonas maltophilia complex. Its utility has been substantially extended in the era of multidrug-resistant (MDR) pathogens through combination with beta-lactamase inhibitors. Aztreonam is intrinsically stable to metallo-beta-lactamases (MBLs) such as NDM, making it an important backbone for combination regimens against carbapenem-resistant Enterobacterales. Its contemporary research profile reflects this role: aztreonam is increasingly studied in partnership with inhibitors such as avibactam, nacubactam, and ceftazidime-avibactam to overcome complex resistance mechanisms including MBL co-production and PBP3 mutations.

Focus of Latest Publications

Recent publications highlight aztreonam as an active subject of investigation across several intersecting areas: novel beta-lactam/inhibitor combinations, the management of MDR Gram-negative infections, gut microbiome preservation, and clinical pharmacology in diverse populations.

Novel combination regimens with beta-lactamase inhibitors

A central theme in 2025–2026 literature is pairing aztreonam with next-generation beta-lactamase inhibitors to restore activity against MBL-producing organisms. The Integral-1 trial (PMID 42134354), a double-blind randomized phase 3 study published in The Lancet, evaluated aztreonam-nacubactam alongside cefepime-nacubactam against imipenem-cilastatin as the comparator for complicated urinary tract infections (cUTI) and acute uncomplicated pyelonephritis. This represents a pivotal efficacy and safety assessment of aztreonam combined with nacubactam — a novel diazabicyclooctane inhibitor active against serine-beta-lactamases — in a well-controlled clinical setting.

Parallel to this, Phase 1 pharmacokinetic studies (PMID 41973073) conducted in healthy Japanese male participants assessed the safety, tolerability, and pharmacokinetics of nacubactam administered either alone or in combination with cefepime or aztreonam (2 g per dose each, intravenously over 60 minutes for 7 days). These studies established foundational PK/PD data for the aztreonam-nacubactam combination in a Japanese population, supporting broader international development.

The combination of aztreonam with avibactam (aztreonam-avibactam, AZA) also featured prominently. A comparative in vitro study (PMID 41874381) assessed the activity of aztreonam-avibactam and aztreonam plus ceftazidime-avibactam against the Stenotrophomonas maltophilia complex — an intrinsically MDR pathogen. The study exploited the complementary inhibitory spectrum of aztreonam (stable to L1 metallo-beta-lactamase) and avibactam (an L2 serine-beta-lactamase inhibitor), rationalizing their pairing for this organism where both resistance mechanisms co-exist.

Resistance emergence and genomic determinants

A retrospective clinical and genomic analysis (PMID 41870042) at a tertiary cancer center examined ceftazidime-avibactam-resistant E. coli isolates collected between 2017 and 2024. The study investigated patient- and isolate-level factors associated with reduced susceptibility to the aztreonam/ceftazidime-avibactam (ATM/CZA) combination as well as aztreonam-avibactam. Oxford Nanopore Technologies long-read sequencing was employed to characterize genomic determinants of resistance, providing high-resolution insight into resistance gene context and mobile genetic elements. These findings are particularly relevant for oncology patients with Gram-negative infections, a population with high antibiotic exposure and elevated risk of resistance selection.

A complementary case-level study (PMID 41718487) described treatment optimization for a patient with MDR E. coli harboring both NDM metallo-beta-lactamase and PBP3 mutations — a combination that undermines both aztreonam monotherapy (via MBL hydrolysis of aztreonam's partner agents) and ceftazidime-avibactam alone (via PBP3 alteration reducing target engagement). Post-surgical administration of ceftazidime-avibactam combined with aztreonam was used, exploiting the MBL-stability of aztreonam and the serine-beta-lactamase inhibition provided by avibactam, illustrating the rational basis for such "hybrid" combinations.

Gut microbiome and colonization resistance

A murine model study (PMID 42224177) compared the microbiome impact of extended antibiotic courses. Notably, 5 or 10 days of aztreonam treatment did not alter colonization resistance, in stark contrast to piperacillin/tazobactam, which caused prolonged disruption of human gut flora even at shorter durations. This finding reinforces aztreonam's ecological advantage as a narrow-spectrum agent preserving anaerobic gut communities, relevant to infection prevention and antimicrobial stewardship decisions.

Contextual note on co-published research

One publication co-indexed in this dataset (PMID 41661672) concerns FASN inhibition in colorectal cancer and mentions ATM only in the context of the ATM kinase (ataxia-telangiectasia mutated) rather than aztreonam; it also involves BRCA1 pathway biology, PARP inhibitor olaparib, and TVB-2640 (a FASN inhibitor). While this publication does not involve aztreonam the antibiotic, its co-occurrence reflects database overlap between the abbreviation "ATM" (aztreonam) and the ATM kinase gene symbol.

Key Publications

  • Jun A Case Report: A Rare Casr Mutation Associated with HER2-Positive Breast Cancer. (Experimental oncology, 2026, PMID 42290554): "Although highly penetrant genes such as BRCA1, BRCA2, TP53, PALB2, CHEK2, and ATM are well known in hereditary breast cancer, genes with low penetrance may also contribute to the disease risk."
  • Jun Longer durations of piperacillin/tazobactam treatment cause more prolonged alteration of colonization resistance in mice. (PloS one, 2026, PMID 42224177): "In contrast, 5 or 10 days of treatment with aztreonam, a narrow-spectrum antibiotic with no activity against anaerobes, did not alter colonization resistance."
  • May 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. (Lancet (London, England), 2026, PMID 42134354): "We assessed the efficacy and safety of cefepime-nacubactam and aztreonam-nacubactam versus imipenem-cilastatin in complicated urinary tract infection (cUTI) or acute uncomplicated pyelonephritis."
  • May FASN Inhibition Enhances the Efficacy of Chemotherapy in Colorectal Cancer by Inhibiting the DNA Damage Response. (Cancer research, 2026, PMID 41661672): "In addition, FASN inhibitor treatment blocked DDR by decreasing ATM expression and CHK2 phosphorylation."
  • May Phase I studies assessing safety and pharmacokinetics of nacubactam administered alone or in combination with cefepime or aztreonam in Japanese healthy participants. (Antimicrobial agents and chemotherapy, 2026, PMID 41973073): "In the OP0595-4 study, 2 g of nacubactam was administered intravenously over 60 min for 7 days in combination with cefepime or aztreonam (2 g per dose each)."
  • May Optimizing target inactivation to treat multidrug-resistant Escherichia coli with NDM and PBP3 mutations: "going the extra mile". (Antimicrobial agents and chemotherapy, 2026, PMID 41718487): "After surgery, ceftazidime-avibactam/aztreonam was administered."
  • May Clinical and genomic determinants associated with emergent ceftazidime-avibactam plus aztreonam non-susceptibility in ceftazidime-avibactam resistant Escherichia coli. (Antimicrobial agents and chemotherapy, 2026, PMID 41870042): "We performed a comprehensive clinical and genomic analysis of ceftazidime-avibactam-resistant Escherichia coli (CZA-R-Ec) collected at a tertiary cancer center (2017-2024) to identify patient- and isolate-level factors associated with reduced susceptibility to ATM/CZA and aztreonam-avibactam (AZA)."
  • May Comparative in vitro activity of aztreonam-avibactam and aztreonam plus ceftazidime-avibactam against Stenotrophomonas maltophilia complex. (Antimicrobial agents and chemotherapy, 2026, PMID 41874381): "Aztreonam (ATM; stable to L1 β-lactamase) with avibactam (AVI; an L2 β-lactamase inhibitor)."
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