Dataset Information

Activity of cefepime/taniborbactam and comparators against whole genome sequenced ertapenem-non-susceptible Enterobacterales clinical isolates: CANWARD 2007-19.

ABSTRACT:

Objectives

This study assessed in vitro activities of cefepime/taniborbactam and comparator antimicrobial agents against ertapenem-non-susceptible Enterobacterales (ENSE) clinical isolates collected from the CANWARD study 2007-19, and associations between MIC and various mechanisms of β-lactam resistance identified using WGS.

Methods

A total of 179 ENSE (MIC ≥ 1 mg/L) isolates underwent susceptibility testing using reference CLSI broth microdilution. WGS was performed using the Illumina NextSeq platform. Carbapenemases, ESBLs and other β-lactamases were identified using ResFinder 4.0. Alterations in ompC/F and ftsI (PBP3) were identified by comparing extracted sequences to the appropriate NCBI reference gene. Porin alterations were analysed with Provean v1.1.3. Specific alterations of interest in PBP3 included a YRIN or YRIK insertion after P333.

Results

Cefepime/taniborbactam was highly active (MIC₅₀/MIC₉₀, 0.5/2 mg/L; 177/179 isolates inhibited at ≤ 8 mg/L) against ENSE with various antimicrobial resistance phenotypes. Thirteen (7.3%) of the 179 ENSE isolates demonstrated cefepime/taniborbactam MIC values ≥ 4 mg/L and possessed combinations of β-lactam resistance mechanisms, including a carbapenemase and/or ESBL and/or other β-lactamase genes, as well as alterations in OmpC and/or OmpF and/or PBP3. Of the two Escherichia coli isolates that demonstrated a cefepime/taniborbactam MIC of 32 mg/L, one possessed NDM-5, OXA-181 and TEM-1B, an OmpC alteration and P333_Y334insYRIN in PBP3, while the second contained CTX-M-71, a truncated OmpF and a large alteration in OmpC (F182_R195delinsMTTNGRDDVFE).

Conclusions

Cefepime/taniborbactam was highly active against ENSE with various antimicrobial resistance phenotypes/genotypes. ENSE isolates with cefepime/taniborbactam MIC values ≥ 4 mg/L possessed combinations of β-lactam resistance mechanisms, including β-lactamase genes, as well as alterations in OmpC and/or OmpF and/or PBP3.

SUBMITTER: Golden AR

PROVIDER: S-EPMC8826793 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

Activity of cefepime/taniborbactam and comparators against whole genome sequenced ertapenem-non-susceptible Enterobacterales clinical isolates: CANWARD 2007-19.

Golden Alyssa R AR Baxter Melanie R MR Karlowsky James A JA Mataseje Laura L Mulvey Michael R MR Walkty Andrew A Bay Denice D Schweizer Frank F Lagace-Wiens Philippe R S PRS Adam Heather J HJ Zhanel George G GG

JAC-antimicrobial resistance 20220207 1

<h4>Objectives</h4>This study assessed <i>in vitro</i> activities of cefepime/taniborbactam and comparator antimicrobial agents against ertapenem-non-susceptible Enterobacterales (ENSE) clinical isolates collected from the CANWARD study 2007-19, and associations between MIC and various mechanisms of β-lactam resistance identified using WGS.<h4>Methods</h4>A total of 179 ENSE (MIC ≥ 1 mg/L) isolates underwent susceptibility testing using reference CLSI broth microdilution. WGS was performed using ...[more]

PMID: 35156028

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Project description:BackgroundCefepime/taniborbactam is a cephalosporin/bicyclic boronate β-lactamase inhibitor combination in clinical development for nosocomial pneumonia due to MDR Gram-negative bacteria. A murine pneumonia model was used to characterize cefepime/taniborbactam in vivo pharmacodynamics against Enterobacterales and Pseudomonas aeruginosa strains.MethodsClinical cefepime-non-susceptible Enterobacterales and P. aeruginosa strains expressing serine carbapenemases and/or other cefepime-hydrolysing β-lactamases with cefepime/taniborbactam combination MICs of 0.12-16 mg/L were used. Cefepime and taniborbactam human-simulated regimens equivalent to clinical doses (i.e. 2/0.5 g q8h) were established in the pneumonia model. The in vivo activity of the cefepime human-simulated regimen given alone or concomitantly with escalating taniborbactam exposures against eight Enterobacterales and four P. aeruginosa strains was assessed. Taniborbactam pharmacokinetics were evaluated to determine systemic exposures of regimens used; taniborbactam fAUC0-24/MIC values required for efficacy were estimated using the Hill equation. In addition, the in vivo activity of the cefepime/taniborbactam combination human-simulated regimen was assessed against 18 strains.ResultsAmong Enterobacterales, median taniborbactam fAUC0-24/MIC values associated with stasis and 1 log kill were 0.96 and 4.03, respectively, while for P. aeruginosa, requirements were 1.35 and 3.02 for stasis and 1 log kill, respectively. The cefepime/taniborbactam human-simulated regimen produced >2 log kill in 14/18 strains and >1 log kill in 18/18 strains.ConclusionsCefepime/taniborbactam produced marked in vivo bactericidal activity against cefepime-non-susceptible Enterobacterales and P. aeruginosa isolates with cefepime/taniborbactam MICs up to and including 16 mg/L in the pneumonia model. Assessments of the probability of clinical attainment of the identified targets should be undertaken to support the selected cefepime/taniborbactam dose for treatment of nosocomial pneumonia.

Project description:ObjectivesTaniborbactam is a boronate-based β-lactamase inhibitor in clinical development in combination with cefepime.MethodsCefepime-taniborbactam and comparator broth microdilution MICs were determined for patient isolates of Enterobacterales (n = 20 725) and Pseudomonas aeruginosa (n = 7919) collected in 59 countries from 2018 to 2022. Taniborbactam was tested at a fixed concentration of 4 mg/L. Isolates with cefepime-taniborbactam MICs ≥ 16 mg/L underwent WGS. β-Lactamase genes were identified in additional meropenem-resistant isolates by PCR/Sanger sequencing.ResultsTaniborbactam reduced the cefepime MIC90 value for all Enterobacterales from >16 to 0.25 mg/L (>64-fold). At ≤16 mg/L, cefepime-taniborbactam inhibited 99.5% of all Enterobacterales isolates; >95% of isolates with MDR and ceftolozane-tazobactam-resistant phenotypes; ≥ 89% of isolates with meropenem-resistant and difficult-to-treat-resistant (DTR) phenotypes; >80% of isolates with meropenem-vaborbactam-resistant and ceftazidime-avibactam-resistant phenotypes; 100% of KPC-positive, 99% of OXA-48-like-positive, 99% of ESBL-positive, 97% of acquired AmpC-positive, 95% of VIM-positive and 76% of NDM-positive isolates. Against P. aeruginosa, taniborbactam reduced the cefepime MIC90 value from 32 to 8 mg/L (4-fold). At ≤16 mg/L, cefepime-taniborbactam inhibited 96.5% of all P. aeruginosa isolates; 85% of meropenem-resistant phenotype isolates; 80% of isolates with MDR and meropenem-vaborbactam-resistant phenotypes; >70% of isolates with DTR, ceftazidime-avibactam-resistant and ceftolozane-tazobactam-resistant phenotypes; and 82% of VIM-positive isolates. Multiple potential mechanisms of resistance, including carriage of IMP, or alterations in PBP3 (ftsI), porins (decreased permeability) and efflux (up-regulation) were present in most isolates with cefepime-taniborbactam MICs ≥ 16 mg/L.ConclusionsCefepime-taniborbactam exhibited potent in vitro activity against Enterobacterales and P. aeruginosa, and inhibited most carbapenem-resistant isolates, including those carrying serine carbapenemases or NDM/VIM MBLs.

Project description:Novel β-lactam-β-lactamase inhibitor combinations currently approved for clinical use are poorly active against metallo-β-lactamase (MBL)-producing strains. We evaluated the in vitro activity of cefepime-taniborbactam (FTB [formerly cefepime-VNRX-5133]) and comparator agents against carbapenemase-producing Enterobacterales (n = 247) and carbapenem-resistant Pseudomonas species (n = 170) clinical isolates prospectively collected from different clinical origins in patients admitted to 8 Spanish hospitals. FTB was the most active agent in both Enterobacterales (97.6% MICFTB, ≤8/4 mg/L) and Pseudomonas (67.1% MICFTB, ≤8/4 mg/L) populations. The MICFTB was >8 mg/L in 6/247 (2.4%) Enterobacterales isolates (3 KPC-producing Klebsiella pneumoniae isolates, 1 VIM-producing Enterobacter cloacae isolate, 1 IMP-producing E. cloacae isolate, and 1 NDM-producing Escherichia coli isolate) and in 56/170 (32.9%) Pseudomonas isolates, 19 of them carbapenemase producers (15 producers of VIM, 2 of GES, 1 of GES+VIM, and 1 of GES+KPC). Against the Enterobacterales isolates with meropenem MICs of >2 mg/L (138/247), FTB was the most active agent against both serine-β-lactamases (107/138) and MBL producers (31/138) (97.2 and 93.5% MICFTB, ≤8/4 mg/L, respectively), whereas the activity of comparators was reduced, particularly against the MBL producers (ceftazidime-avibactam, 94.4 and 12.9%, meropenem-vaborbactam, 85.0 and 64.5%, imipenem-relebactam, 76.6 and 9.7%, ceftolozane-tazobactam, 1.9 and 0%, and piperacillin-tazobactam, 0 and 0%, respectively). Among the meropenem-resistant Pseudomonas isolates (163/170; MIC, >2 mg/L), the activities of FTB against serine-β-lactamase (35/163) and MBL (43/163) producers were 88.6 and 65.1%, respectively, whereas the susceptibilities of comparators were as follows: ceftazidime-avibactam, 88.5 and 16.0%, meropenem-vaborbactam, 8.5 and 7.0%, imipenem-relebactam, 2.9 and 2.3%, ceftolozane-tazobactam, 0 and 2.3%, and piperacillin-tazobactam, 0 and 0%, respectively. Microbiological results suggest FTB as a potential therapeutic option in patients infected with carbapenemase-producing Enterobacterales and carbapenem-resistant Pseudomonas isolates, including MBL producers.

Project description:In recent times, discovery efforts for novel antibiotics have mostly targeted carbapenemase-producing Gram-negative organisms. Two different combination approaches are pertinent: β-lactam-β-lactamase inhibitor (BL/BLI) or β-lactam-β-lactam enhancer (BL/BLE). Cefepime combined with a BLI, taniborbactam, or with a BLE, zidebactam, has been shown to be promising. In this study, we determined the in vitro activity of both these agents along with comparators against multicentric carbapenemase-producing Enterobacterales (CPE). Nonduplicate CPE isolates of Escherichia coli (n = 270) and Klebsiella pneumoniae (n = 300), collected from nine different tertiary-care hospitals across India during 2019 to 2021, were included in the study. Carbapenemases in these isolates were detected by PCR. E. coli isolates were also screened for the presence of the 4-amino-acid insert in penicillin binding protein 3 (PBP3). MICs were determined by reference broth microdilution. Higher MICs of cefepime/taniborbactam (>8 mg/L) were linked to NDM, both in K. pneumoniae and in E. coli. In particular, such higher MICs were observed in 88 to 90% of E. coli isolates producing NDM and OXA-48-like or NDM alone. On the other hand, OXA-48-like-producing E. coli or K. pneumoniae isolates were nearly 100% susceptible to cefepime/taniborbactam. Regardless of the carbapenemase types and the pathogens, cefepime/zidebactam showed potent activity (>99% inhibited at ≤8 mg/L). It seems that the 4-amino-acid insert in PBP3 (present universally in the study E. coli isolates) along with NDM adversely impact the activity of cefepime/taniborbactam. Thus, the limitations of the BL/BLI approach in tackling the complex interplay of enzymatic and nonenzymatic resistance mechanisms were better revealed in whole-cell studies where the activity observed was a net effect of β-lactamase inhibition, cellular uptake, and target affinity of the combination. IMPORTANCE The study revealed the differential ability of cefepime/taniborbactam and cefepime/zidebactam in tackling carbapenemase-producing Indian clinical isolates that also harbored additional mechanisms of resistance. NDM-expressing E. coli with 4-amino-acid insert in PBP3 are predominately resistant to cefepime/taniborbactam, while the β-lactam enhancer mechanism-based cefepime/zidebactam showed consistent activity against single- or dual-carbapenemase-producing isolates including E. coli with PBP3 inserts.

Project description:Carbapenem-resistant Enterobacterales (CRE), specifically those resistant to only ertapenem among carbapenems (ETP-mono-resistant), are increasingly reported, while the optimal therapy options remain uncertain. To investigate the prevalence and characteristics of ETP-mono-resistant CRE, CRE strains were systematically collected from 102 hospitals across China between 2018 and 2021. A 1:1 randomized matching study was conducted with ETP-mono-resistant strains to meropenem- and/or imipenem-resistant (MEM/IPM-resistant) strains. Antimicrobial susceptibility testing, whole-genome sequencing, carbapenem-hydrolysing activity and the expression of carbapenemase genes were determined. In total, 18.8% of CRE strains were ETP-mono-resistant, with relatively low ertapenem MIC values. ETP-mono-resistant strains exhibited enhanced susceptibility to β-lactams, β-lactam/β-lactamase inhibitor combinations, levofloxacin, fosfomycin, amikacin and polymyxin than MEM/IPM-resistant strains (P < 0.05). Phylogenetic analysis revealed high genetic diversity among ETP-mono-resistant strains. Extended-spectrum β-lactamases (ESBLs) and/or AmpC, as well as porin mutations, were identified as potential major mechanisms mediating ETP-mono-resistance, while the presence of carbapenemases was found to be the key factor distinguishing the carbapenem-resistant phenotypes between the two groups (P < 0.001). Compared with the MEM/IPM-resistant group, limited carbapenemase-producing CRE (CP-CRE) strains in the ETP-mono-resistant group showed a significantly lower prevalence of ESBLs and porin mutations, along with reduced expression of carbapenemase. Remarkably, spot assays combined with modified carbapenem inactivation method indicated that ETP-mono-resistant CP-CRE isolates grew at meropenem concentrations eightfold above their corresponding MIC values, accompanied by rapidly enhanced carbapenem-hydrolysing ability. These findings illustrate that ETP-mono-resistant CRE strains are relatively prevalent and that caution should be exercised when using meropenem alone for treatment. The detection of carbapenemase should be prioritized.

Project description:As shifts in the epidemiology of β-lactamase-mediated resistance continue, carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) are the most urgent threats. Although approved β-lactam (BL)-β-lactamase inhibitor (BLI) combinations address widespread serine β-lactamases (SBLs), such as CTX-M-15, none provide broad coverage against either clinically important serine-β-lactamases (KPC, OXA-48) or clinically important metallo-β-lactamases (MBLs; e.g., NDM-1). VNRX-5133 (taniborbactam) is a new cyclic boronate BLI that is in clinical development combined with cefepime for the treatment of infections caused by β-lactamase-producing CRE and CRPA. Taniborbactam is the first BLI with direct inhibitory activity against Ambler class A, B, C, and D enzymes. From biochemical and structural analyses, taniborbactam exploits substrate mimicry while employing distinct mechanisms to inhibit both SBLs and MBLs. It is a reversible covalent inhibitor of SBLs with slow dissociation and a prolonged active-site residence time (half-life, 30 to 105 min), while in MBLs, it behaves as a competitive inhibitor, with inhibitor constant (Ki ) values ranging from 0.019 to 0.081 μM. Inhibition is achieved by mimicking the transition state structure and exploiting interactions with highly conserved active-site residues. In microbiological testing, taniborbactam restored cefepime activity in 33/34 engineered Escherichia coli strains overproducing individual enzymes covering Ambler classes A, B, C, and D, providing up to a 1,024-fold shift in the MIC. Addition of taniborbactam restored the antibacterial activity of cefepime against all 102 Enterobacterales clinical isolates tested and 38/41 P. aeruginosa clinical isolates tested with MIC90s of 1 and 4 μg/ml, respectively, representing ≥256- and ≥32-fold improvements, respectively, in antibacterial activity over that of cefepime alone. The data demonstrate the potent, broad-spectrum rescue of cefepime activity by taniborbactam against clinical isolates of CRE and CRPA.

Project description:This study evaluated the in vitro activity of cefepime-zidebactam in comparison with that of ceftazidime-avibactam and other comparators against clinically significant Gram-negative bacillus isolates. A total of 3,400 nonduplicate Gram-negative clinical isolates were collected from 45 medical centers across China in the CHINET Program in 2018, including Enterobacterales (n = 2,228), Pseudomonas aeruginosa (n = 657), and Acinetobacter baumannii (n = 515). The activities of cefepime-zidebactam and 20 comparators were determined by broth microdilution as recommended by the Clinical and Laboratory Standards Institute. Cefepime-zidebactam demonstrated potent activity against almost all Enterobacterales (MIC50/90, 0.125/1 mg/liter) and good activity against P. aeruginosa (MIC50/90, 2/8 mg/liter). Among the 373 carbapenem-resistant Enterobacteriaceae isolates, 57.3% (213/373) and 15.3% (57/373) were positive for blaKPC-2 and blaNDM, respectively. Cefepime-zidebactam showed a MIC of ≤2 mg/liter for 92.0% (196/213) of blaKPC-2 producers and 79.7% (47/59) of blaNDM producers. Ceftazidime-avibactam showed good in vitro activity against Enterobacterales (MIC50/90, 0.25/2 mg/liter; 94.0% susceptible) and P. aeruginosa (MIC50/90, 4/16 mg/liter; 86.9% susceptible). Ceftazidime-avibactam was active against 9.1% of carbapenem-resistant Escherichia coli isolates (63.6% were blaNDM producers) and 84.6% of Klebsiella pneumoniae isolates (74.3% were blaKPC producers). Most (90.1%) blaKPC-2 producers were susceptible to ceftazidime-avibactam. Cefepime-zidebactam demonstrated limited activity (MIC50/90, 16/32 mg/liter) against the 515 A. baumannii isolates (79.2% were carbapenem resistant), and ceftazidime-avibactam was less active (MIC50/90, 64/>64 mg/liter). Cefepime-zidebactam was highly active against clinical isolates of Enterobacterales and P. aeruginosa, including blaKPC-2-positive Enterobacterales and blaNDM-positive Enterobacterales and carbapenem-resistant P. aeruginosa And ceftazidime-avibactam was highly active against blaKPC-2-positive Enterobacterales and carbapenem-resistant P. aeruginosa.

Dataset Information

Activity of cefepime/taniborbactam and comparators against whole genome sequenced ertapenem-non-susceptible Enterobacterales clinical isolates: CANWARD 2007-19.

Objectives

Methods

Results

Conclusions

Publications

Activity of cefepime/taniborbactam and comparators against whole genome sequenced ertapenem-non-susceptible Enterobacterales clinical isolates: CANWARD 2007-19.

Similar Datasets

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