AbstractInfections caused by metallo-β-lactamase (MBL)-producing gram-negative pathogens represent a formidable and emerging threat to public health. MBLs compromise the activity of carbapenems and many newly developed β-lactam/β-lactamase inhibitor agents, leaving few treatment options. Remarkably, these enzymes have disseminated globally at an unprecedented rate. Therapeutic management of MBL-producing pathogens remains a major challenge because the enzymes are not inhibited by currently available β-lactamase inhibitors, and most pathogens that harbour MBLs are equipped with mechanisms of resistance to all available antibiotic classes. Recent advances have elucidated the biochemical and structural function of diverse MBLs thereby improving the development of future antibiotics. In this review, we summarize the contemporary global epidemiology of clinically relevant MBLs, describe the molecular mechanisms driving their dissemination and evaluate current and emerging therapeutic strategies for infections caused by MBL-producing gram-negative pathogens including Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia.

Extended-spectrum β-lactamase (ESBL)–producing Enterobacterales are an increasing cause of complicated urinary tract infections (UTIs). Reliance on carbapenems to treat these infections accelerates resistance, underscoring the urgent need for effective oral transition options to preserve last-line agents and lessen healthcare burden.MethodsWe conducted a multicenter, open-label, randomized, noninferiority trial at four tertiary hospitals in South Korea (November 2022–June 2025). Adults hospitalized with complicated UTIs due to ESBL-producing Enterobacterales who improved after 3–7 days of intravenous antibiotics were randomized (1:1) to either continue intravenous carbapenem or β-lactam/β-lactamase inhibitor therapy or switch to oral fosfomycin trometamol (3 g once daily). The primary outcome was clinical cure, defined as resolution of urinary tract infection–related symptoms and signs within 4 days after completion of treatment. Secondary outcomes included microbiological cure, readmission, adverse events, and 30-day recurrence.ResultsOf the 344 screened patients, 299 were randomized (152 oral fosfomycin; 147 intravenous therapy). Clinical cure occurred in 92.8% of the oral fosfomycin group and 95.2% of the intravenous group (risk difference, −2.47%; 95% CI −7.84 to 2.89), confirming noninferiority. Microbiological cure was similarly high in both groups: urine (98.0% vs 96.6%) and blood (97.3% vs 97.5%). Safety profiles and 30-day outcomes were also comparable.ConclusionsOral fosfomycin was noninferior to continued intravenous therapy when used as oral transition therapy for complicated UTIs caused by ESBL-producing Enterobacterales. These findings provide evidence to support oral fosfomycin transition as a carbapenem-sparing antibiotic stewardship strategy for patients with complicated UTIs caused by ESBL-producing Enterobacterales.Clinical Trials RegistrationKCT0007669.

A 40-year-old woman presented with fever and painless decreased vision. Vitritis and a large, yellow, elevated subretinal lesion accompanied by Roth spots and retinal hemorrhages (A) were found. B-scan ultrasonography showed a dome-shaped, moderately reflective lesion measuring 2.24 × 8.16 mm at the superior posterior pole (B). Aqueous humor next-generation sequencing and culture were negative, whereas vitreous next-generation sequencing identified an extended-spectrum β-lactamase–producing Klebsiella pneumoniae strain.

Abstract. Carbapenem-resistant Pseudomonas aeruginosa (CRPA), a World Health Organization high-priority pathogen, represents a major clinical threat due to

Patients with bloodstream infections (BSIs) with antimicrobial resistant bacteria often receive ineffective empirical therapy (IET). The implications are still uncertain.MethodsWe performed a retrospective, multicenter, study of patients with BSIs caused by extended-spectrum β-lactamase (ESBL)-producing gram-negative bacteria in southern Sweden from 2013 to 2022. Patients were categorized based on time to effective therapy: ≤24 hours (EET) and >24 hours (IET). Therapy was considered effective if the agent was active in susceptibility testing and administered intravenously at an appropriate dose. The primary outcome was 30-day mortality. Secondary outcomes were ICU admission and hospital length of stay.ResultsA total of 289/644 (44.9%) patients received IET within the first 24 hours after the index blood culture collection. No significant impact of IET on 30-day mortality was found in univariable (Hazard ratio 0.66; P = .15) or multivariable Cox regression analysis (Hazard ratio 0.64; P = .13). Patients receiving EET were more likely to receive intensive care (Odds ratio 0.38; P = .008), but the association was nonsignificant after adjusting for severity of illness and comorbidities. IET was not associated with a longer hospital stay in Fine–Gray competing risks regression analysis (univariable: sHR 1.15; P = .082; multivariable: sHR 1.11; P = .20).ConclusionsIET was not associated with 30-day mortality, in patients with BSIs with ESBL-producing Enterobacterales. If confirmed in prospective studies, our findings could support antimicrobial stewardship efforts by reducing unnecessary empirical carbapenem use without compromising short-term clinical outcomes, particularly in low-prevalence settings.

Abstract. Antimicrobial resistance (AMR) is a global health threat, yet, despite this, antibiotic drug discovery has stagnated. Most compounds entering the

Phylogenomic and functional analyses suggest that predatory myxobacteria had a key role in the early evolution of B1 metallo-β-lactamases and revealed the adaptations required for expression of resistance in enterobacterial pathogens.

Importance  Understanding how neonatal unit colonization pressure, the proportion of infants carrying resistant bacteria on a unit, is associated with antibiotic-resistant bacterial acquisition risk can inform the design and implementation of effective infection prevention and control (IPC) interventions.Objectives  To describe resistant bacterial gene prevalence in European neonatal units and to assess the association between unit-level extended-spectrum β-lactamase (ESBL) colonization pressure and infant-level ESBL acquisition.Design, Setting, and Participants  Multicenter study in 24 tertiary neonatal units in 8 European countries (Estonia, Greece, Germany, Italy, Poland, Spain, Switzerland, and the United Kingdom) using repeated cross-sectional surveys collecting stool samples from infants over 4 surveys with 4-, 7-, and 14-day intervals, analyzed using real-time quantitative polymerase chain reaction (PCR) between January 2022 and June 2024 as part of the NeoIPC project. All infants present on the neonatal unit at 8:00 am on the day of the survey were eligible; infants could contribute to multiple surveys.Exposure  ESBL colonization pressure at previous survey.Main Outcome and Measure  Incident infant gut colonization with ESBL-harboring bacteria (ESBL-colonized). Bayesian hierarchical logistic regression modeling was used to assess the association between colonization pressure and infant-level acquisition risk on the neonatal unit.Results  Overall, 943 infants (547 of 943 male [58.0%]; median [IQR] gestational age, 34 [30-38] weeks, and median [IQR] birth weight, 2130 [1254-3084] g) contributed to 1847 infant-survey observations. Stool samples were collected and PCR results obtained in 1448 of 1847 infant surveys (78.4%). The most common genes detected were those encoding ESBLs (205 of 1448 samples [14.2%]), with high unit-level variation. In the colonization acquisition analysis, we included 829 samples from 533 infants hospitalized since birth who were either newly admitted since or not colonized at the previous survey time point; 90 of 533 infants (16.9%) became ESBL-colonized. Their median (IQR) gestational age was 34 (30-37) weeks, and median (IQR) length of stay at survey was 14 (5-32) days. Colonization pressure was associated with increased odds of becoming ESBL-colonized for all survey intervals (4-day interval: mean odds ratio [OR], 1.89; 95% credible interval [CrI], 1.22-2.94; 7-day interval: OR, 1.76; 95% CrI, 1.26-2.63; 14-day interval: OR, 1.73; 95% CrI, 1.15-2.52 per 10% increase of colonization pressure).Conclusions and Relevance  In this cross-sectional study, ESBL colonization pressure was associated with individual risk of acquiring ESBL on the neonatal unit. Unit-level interventions targeting colonization rather than infection may have important direct and indirect benefits in units with high colonization pressure.

Importance  Cefepime is recommended for the treatment of febrile neutropenia and gram-negative infections at moderate risk of ampicillin resistance locus C β-lactamase production. Concerns regarding cefepime’s safety have been raised in the literature without firm conclusions.Objective  To conduct a systematic review and bayesian random-effects meta-analysis of all randomized clinical trials (RCTs) comparing cefepime with other β-lactams for all-cause mortality.Data Sources  Cochrane Central Register of Controlled Trials, Medline, Embase, Web of Science, World Health Organization–International Clinical Trials Registry Platform, ClinicalTrials.gov, and LILACS were searched from inception to May 25, 2026.Study Selection  Randomized clinical trials of children and adults comparing either (1) cefepime monotherapy vs any β-lactam monotherapy or (2) combination therapy of cefepime and a second drug vs β-lactam and the same second drug. Studies of prophylactic cefepime or cefepime and β-lactamase inhibitor combinations were excluded.Data Extraction and Synthesis  This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline. Two independent reviewers extracted data and assessed the risk of bias using the Cochrane risk-of-bias tool, version 2.0.Main Outcomes and Measures  The main outcome was all-cause mortality (30-day or closest reported). Odds of mortality were synthesized using a hierarchical bayesian random-effects model on the log-odds scale. The posterior probabilities of increased mortality (odds ratio [OR] >1) with cefepime for the overall analysis and relevant subgroups were examined. Certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations framework.Results  Synthesis of 110 trials including 22 608 patients (cefepime: 11 726 patients [approximately 56% male]; comparator β-lactam: 10 882 patients [approximately 56% male]) showed a 94.4% posterior probability that the pooled OR mortality exceeded 1 with cefepime use compared with other β-lactams (778 [6.6%] vs 674 [6.2%]; OR, 1.10, 95% credible interval, 0.98-1.24). Meta-analysis of published peer-reviewed RCTs (73 trials, 15 411 patients) showed that cefepime was associated with a 98.6% posterior probability of higher mortality compared with other β-lactams (OR, 1.17; 95% credible interval, 1.02-1.34). Posterior distributions generally favored higher odds of mortality across all comparator β-lactams, across all clinical indications, and with doses of 2 g or more every 12 hours.Conclusions and Relevance  This systematic review and bayesian meta-analysis found that cefepime was associated with higher odds of all-cause mortality compared with other β-lactams. These findings support a nuanced discussion of cefepime’s safety in guidance statements.

Proceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences (NAS) - an authoritative source of high-impact, original research that broadly spans...

Background: The Citrobacter genus harbors class C (AmpC) and class A β-lactamases. Citrobacter freundii produces an inducible AmpC β-lactamase controlled by the LysR-type transcriptional regulator Amp...

SUMMARY AmpC β-lactamases are clinically important cephalosporinases encoded on the chromosomes of many of the Enterobacteriaceae and a few other organisms, where they mediate resistance to cephalothin, cefazolin, cefoxitin, most penicillins, and β-lactamase inhibitor-β-lactam combinations. In many bacteria, AmpC enzymes are inducible and can be expressed at high levels by mutation. Overexpression confers resistance to broad-spectrum cephalosporins including cefotaxime, ceftazidime, and ceftriaxone and is a problem especially in infections due to Enterobacter aerogenes and Enterobacter cloacae, where an isolate initially susceptible to these agents may become resistant upon therapy. Transmissible plasmids have acquired genes for AmpC enzymes, which consequently can now appear in bacteria lacking or poorly expressing a chromosomal blaAmpC gene, such as Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis. Resistance due to plasmid-mediated AmpC enzymes is less common than extended-spectrum β-lactamase production in most parts of the world but may be both harder to detect and broader in spectrum. AmpC enzymes encoded by both chromosomal and plasmid genes are also evolving to hydrolyze broad-spectrum cephalosporins more efficiently. Techniques to identify AmpC β-lactamase-producing isolates are available but are still evolving and are not yet optimized for the clinical laboratory, which probably now underestimates this resistance mechanism. Carbapenems can usually be used to treat infections due to AmpC-producing bacteria, but carbapenem resistance can arise in some organisms by mutations that reduce influx (outer membrane porin loss) or enhance efflux (efflux pump activation).

We read with great interest the recent Correspondence by Warecki and colleagues.1 Antimicrobial resistance is one of the most urgent global health threats, and the spread of metallo-β-lactamase (MBL)-...