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PubMed1977

Temperature-sensitive cell division mutants of Escherichia coli with thermolabile penicillin-binding proteins.

The thermostability of the penicillin-binding proteins (PBPs) of 31 temperature-sensitive cell division mutants of Escherichia coli has been examined. Two independent cell division mutants have been found that have highly thermolabile PBP3. Binding of [(14)C]benzylpenicillin to PBP3 (measured in envelopes prepared from cells grown at the permissive temperature) was about 30% of the normal level at 30 degrees C, and the ability to bind [(14)C]benzylpenicillin was rapidly lost on incubation at 42 degrees C. The other PBPs were normal in both mutants. At 30 degrees C both mutants were slightly longer than their parents and on shifting to 42 degrees C they ceased dividing, but cell mass and deoxyribonucleic acid synthesis continued and long filaments were formed. At 42 degrees C division slowly recommenced, but at 44 degrees C this did not occur. The inhibition of division at 42 degrees C was suppressed by 0.35 M sucrose, and in one of the mutants it was partially suppressed by 10 mM MgCl(2). PBP3 was not stabilized in vitro at 42 degrees C by these concentrations of sucrose or MgCl(2). Revertants that grew as normal rods at 42 degrees C regained both the normal level and the normal thermostability of PBP3. The results provide extremely strong evidence that the inactivation of PBP3 at 42 degrees C in the mutants is the cause of the inhibition of cell division at this temperature and identify PBP3 as an essential component of the process of cell division in E. coli. It is the inactivation of this protein by penicillins and cephalosporins that results in the inhibition of division characteristic of low concentrations of many of these antibiotics.

Carrier Proteins↗

PubMed2026

Outbreak of aztreonam-avibactam-resistant NDM-5-producing Escherichia coli isolates in a hospital of Paris.

The emergence of aztreonam-avibactam resistance among NDM-producing Escherichia coli represents a major therapeutic and infection control concern. Four cases of aztreonam-avibactam-resistant (AZAR) NDM-producing E. coli, recovered from three blood cultures and one rectal surveillance culture in a hospital of Paris, prompted an investigation based on whole-genome sequencing. The three isolates responsible for bloodstream infection, which were clonally related, belonged to the ST405 and produced NDM-5, DHA-1, CTX-M-15, and TEM-1 β-lactamases. They also had a penicillin-binding protein 3 (PBP3) modified by the insertion of four amino acids (YRIK). On the other hand, the isolate recovered from the rectal swab belonged to another sequence type (ST2083). It produced NDM-5, CMY-42, and TEM-1 β-lactamases and had an altered PBP3 by the insertion of four other residues (YRIN). Epidemiological investigation identified endoscopic retrograde cholangiopancreatography as a potential risk factor, leading to the detection of three additional patients infected with the ST405 clone after exposure to the same duodenoscope. The outcome of the bloodstream infections was favorable except for one patient. In total, seven patients infected or colonized by AZAR NDM-5-producing E. coli were identified over a 5-month period in 2025, six with duodenoscope exposure.IMPORTANCEThis study underlines the emergence of aztreonam-avibactam resistance among NDM-producing Escherichia coli isolates in France. To our knowledge, this report describes the first clonal outbreak due to aztreonam-avibactam-resistant NDM-producing E. coli.

Humans↗

PubMed2026

Aztreonam-avibactam Activity against Enterobacterales from Asia Pacific and Latin American Medical Centres: Summary of 5 years of Surveillance prior to Clinical Use (2020-2024).

OBJECTIVES: To assess the in vitro activity of aztreonam-avibactam against Enterobacterales from the Asia Pacific region (APAC) and Latin America (LATAM) during a 5-year period prior to its approval for clinical use in these regions. METHODS: 12,039 Enterobacterales isolates were consecutively collected in 2020-2024 from 17 medical centres in APAC (n=7,369) and 10 in LATAM (n=4,670) then susceptibility tested by broth microdilution. Carbapenem-resistant Enterobacterales (CRE) and isolates with elevated aztreonam-avibactam MICs (>4 mg/L) were submitted to whole genome sequencing. RESULTS: Aztreonam-avibactam was active against 99.9% of Enterobacterales from APAC and LATAM and exhibited potent activity against CRE isolates (MIC50/90, 0.25/2 mg/L; 97.3% susceptible in APAC and MIC50/90, 0.25/0.5 mg/L; 99.4% susceptible in LATAM). Cefiderocol was active against 91.2% of CREs from APAC and LATAM. Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam showed limited activity against CRE isolates from LATAM (53.5% to 64.8% susceptibility) and APAC (27.3% to 38.8% susceptible). The occurrence of carbapenemases varied clearly among the countries evaluated. In general, metallo-β-lactamases (MBLs) prevailed in APAC and KPCs predominated in LATAM, but with great variability among countries within a region. Decreased susceptibility to aztreonam-avibactam was largely due to PBP3 alterations plus the production of CMY and/or CTX-M β-lactamases among Escherichia coli, and decreased membrane permeability associated with KPC production among Klebsiella pneumoniae. CONCLUSIONS: The results of this investigation provide a baseline for monitoring the activity of aztreonam-avibactam in APAC and LATAM and emphasize the importance of surveillance programs to monitor the emergence of resistance markers.

Aztreonam-avibactam↗

PubMed2025

Molecular insights into carbapenemase-producing Enterobacterales from Senegal.

BACKGROUND: Carbapenemase-producing Enterobacterales (CPE) are an urgent global health threat, especially in resource-limited countries. Here we determined the prevalence and the molecular characteristics of CPE isolated from infections in Dakar, Senegal. METHOD: From January 2019 to December 2020, Enterobacterales with reduced susceptibility to ertapenem (diameter < 25 mm) from infections were collected at the Pasteur Institute of Dakar. Carbapenemases were detected using biochemical and immunochromatographical assays. WGS was used to determine resistome, MLST, plasmids, virulence genes and genetic relatedness. RESULTS: Of the 1045 Enterobacterales collected during the study period, 86 had a diameter around ertapenem of <25 mm (8%) and 19 were confirmed as CPE (2%). These included Escherichia coli (n = 6) [ST410 (n = 3), ST405 (n = 2) and ST2083], Enterobacter spp. (n = 6) [ST231 (n = 3), ST245, ST760 and ST960] and Klebsiella spp. (n = 5) (ST22, ST25, ST231, ST1535, ST4843), Citrobacter freundii ST22 (n = 1) and Citrobacter koseri with unknown ST (n = 1). blaOXA-48 (n = 7; 35%), blaOXA-181 (n = 7; 35%) and blaNDM-5 (n = 6; 30%) genes were identified. C. freundii ST22 harboured blaNDM-5, blaOXA-48 and blaCTX-M-15 genes. Some E. coli isolates belonging to the high-risk clone ST410 were closely related (<20 SNPs) to isolates recovered in France from patients returning from Senegal, suggesting transnational spread. In addition, 5/6 carbapenemase-producing E. coli isolates possessed a four amino acid insertion in PBP3, conferring reduced susceptibility to aztreonam/avibactam and cefiderocol. CONCLUSIONS: This study highlights the spread of NDM-5 and OXA-181 in Senegal, and reports the first co-occurrence of NDM-5 and OXA-48 in sub-Saharan Africa. The spread of CPE, especially in high-risk clones, underscores the urgent need for continued surveillance and targeted interventions.

Senegal↗

PubMed2025

Mechanisms of resistance to ceftazidime/avibactam in mutants derived in vitro from Klebsiella pneumoniae producing OXA-48-like enzymes.

OBJECTIVES: To generate in vitro ceftazidime-avibactam-resistant mutants derived from Klebsiella pneumoniae producing OXA-48 or OXA-48 derivatives OXA-131 and OXA-232 carbapenemases, to define their antimicrobial susceptibility phenotype and to analyse mutations potentially involved in resistance to ceftazidime-avibactam. METHODS: Mutants were obtained by plating overnight bacterial cultures on Mueller-Hinton agar plates containing increasing concentrations of ceftazidime-avibactam (0.5/4-32/4 mg/L). MICs were determined using Sensititre™ DKMNG panels. Whole-genome sequencing of 8 parental strains and 31 mutant derivatives was performed with Illumina. RESULTS: All parental strains were susceptible to ceftazidime-avibactam (MIC ≤ 0.5/4-2/4 mg/L) and either susceptible or resistant to meropenem (MIC 0.5 to >16 mg/L) and imipenem (MIC ≤ 0.5 to >16 mg/L). MICs of ceftazidime-avibactam for the mutants increased up to 4 to >16 mg/L, while MICs of meropenem and imipenem for most mutants either increased up to >16 mg/L or remained unchanged. Whole-genome sequencing of the mutants identified alterations in genes coding for proteins related to AcrAB-TolC (AcrB, AcrR), PBPs (PBP2, PBP3), porins (OmpK36, EnvZ) or the stress or stringent responses (RseB, CpxA, SpoT). No mutations were detected in genes coding for OXA-48-like enzymes or other β-lactamases. CONCLUSIONS: Ceftazidime-avibactam can select in vitro mutants of OXA-48-like carbapenemase-producing K. pneumoniae resistant to this combination and, in some cases, also to carbapenems. No mutations related to ceftazidime-avibactam resistance were found in genes coding OXA-48-like enzymes, but they were detected in genes related to active efflux, PBPs, permeability or proteins of the stress and stringent responses.

Ceftazidime↗

PubMed2026

In vitro susceptibility testing of aztreonam-avibactam against predominantly NDM-producing Enterobacterales in Peru.

Metallo-β-lactamase-producing Enterobacterales are distributed worldwide, but some Latin American countries show a higher prevalence. Aztreonam-avibactam (ATM-AVI) may be an option for treating these infections. To evaluate in vitro susceptibility to aztreonam (ATM) alone and ATM-AVI in carbapenem-non-susceptible Enterobacterales isolates, based on the type of carbapenemase production, we prospectively collected carbapenem-non-susceptible Enterobacterales isolates from Peruvian hospitals during 2023-2024. Identification and susceptibility testing were performed by commercial panels and disk diffusion. Carbapenemases were detected by immunochromatography. ATM and ATM-AVI MICs were determined using broth microdilution panels with avibactam fixed at 4 µg/mL. The non-susceptible isolates to ATM-AVI and those with double production of carbapenemases underwent whole-genome sequencing. A total of 438 Enterobacterales isolates were analyzed; carbapenemase production was detected in 422 (96.3%) and NDM was the most frequent (61.9%). Coproduction of NDM + KPC in K. pneumoniae and NDM + OXA-48-like in Escherichia coli was observed. Overall, 99.3% were susceptible to ATM-AVI; MIC50 and MIC90 were 0.12 and 2 µg/mL, respectively. Overall, K. pneumoniae isolates had lower MIC50 and MIC90 values to ATM-AVI (0.12 and 0.5 µg/mL) compared to E. coli (0.5 and 4 µg/mL). Three E. coli isolates were resistant to ATM-AVI (MIC ≥ 8 µg/mL), they belonged to ST410, ST167, and ST10 and harbored a YRIN insertion in PBP3 along with CYM-type, PER-type, and CTX-M-type beta-lactamase genes. ATM-AVI demonstrated potent activity against carbapenem-non-susceptible Enterobacterales, including those producing NDM, which is the carbapenemase most frequently detected in Peruvian hospitals.IMPORTANCEEnterobacterales isolates cause common illnesses in humans. Carbapenems are the antibiotics used to treat several of these infections, and increasingly, isolates resistant to these antibiotics are found. The most important mechanism of resistance to carbapenem among Enterobacterales is the production of enzymes called carbapenemases. Our results allowed us to recognize that NDM is the most frequent type of carbapenemase detected. Most of the antimicrobials available do not cover the Enterobacterales carrying NDM carbapenemase. In this scenario, we found that the new combination of drugs, aztreonam-avibactam, has high in vitro efficacy against most of the carbapenem-resistant isolates and against those isolates carrying NDM carbapenemase.

Aztreonam↗