Laboratory detection and clinical implication of oxacillinase-48 like carbapenemase: The hidden threat

Bakthavatchalam, Yamuna Devi; Anandan, Shalini; Veeraraghavan, Balaji

doi:10.4103/0974-777x.176149

Cited by 77 publications

(44 citation statements)

References 103 publications

(82 reference statements)

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“…Regarding the serine ␤-lactamases, taniborbactam had potent inhibitory activity against class A and C enzymes, with K i values ranging from 0.002 to 0.017 M for SHV-5, KPC-2, CTX-M-15, and P99 AmpC, similar to the values for avibactam. Against the class D OXA-48 enzyme, taniborbactam had a K i of 0.35 M, similar to the values for avibactam and vaborbactam ( Table 2), and that level of potency was sufficient to protect cefepime from this ␤-lactamase subtype, which exhibits weak cefepimase activity and, consequently, which contributes minimally to cefepime resistance (Table 3) (35,36).…”

Section: Resultssupporting

confidence: 54%

VNRX-5133 (Taniborbactam), a Broad-Spectrum Inhibitor of Serine- and Metallo-β-Lactamases, Restores Activity of Cefepime in Enterobacterales and Pseudomonas aeruginosa

Hamrick

Docquier

Uehara

et al. 2020

Antimicrob Agents Chemother

146

109

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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.

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Section: Resultssupporting

confidence: 54%

VNRX-5133 (Taniborbactam), a Broad-Spectrum Inhibitor of Serine- and Metallo-β-Lactamases, Restores Activity of Cefepime in Enterobacterales and Pseudomonas aeruginosa

Hamrick

Docquier

Uehara

et al. 2020

Antimicrob Agents Chemother

146

109

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“…Our study has some limitations. We might have underestimated the prevalence of OXA-48 producers that weakly hydrolyze carbapenems (MIC for meropenem lower than 1 mg/L) because of the selective media we used for the culture (55). Moreover, our study lacks enough power to establish a causal relationship between possible risk factors and MDRO carriage, since the study design was cross-sectional.…”

Section: Discussionmentioning

confidence: 96%

Gastrointestinal Carriage of Vancomycin-Resistant Enterococci and Carbapenem-Resistant Gram-Negative Bacteria in an Endemic Setting: Prevalence, Risk Factors, and Outcomes

Vasilakopoulou

Karakosta

Vourli

et al. 2020

Front. Public Health

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Background: Gastrointestinal carriage of vancomycin-resistant enterococci (VRE) and carbapenem-resistant Gram-negative bacteria (CRGN) constitutes a major public health concern as it may be followed by clinical infection development or lead to intra-hospital dissemination. Detection of carriers and implementation of infection control measures are essential in every hospital. In this study we determined the point prevalence of VRE and CRGN in the fecal flora of the inpatients of a tertiary university hospital in Greece. We determined risk factors for carriage and examined the impact of carriage on hospital outcomes. Materials/Methods: A point prevalence study of VRE/CRGN rectal carriage of inpatients was conducted on March 2018. Specimens were selectively cultured for VRE/CRGN, microorganisms were biochemically identified, submitted to antibiotic susceptibility testing, and tested for carbapenemase production. Data on potential risk factors and hospital outcomes were collected at the time of culture and until hospital discharge. Multivariable logistic and linear regression models were used, adjusting for confounders.Results: Four hundred ninety-one patients were enrolled in the study. Of them, 64 (13.0%) were positive for VRE carriage, 40 (8.2%) for CRGN, and 10 patients (2.1%) for both VRE and CRGN. VRE carriage was independently associated with age over 65 years (adjusted OR: 2.4 [95%CI: 1.3, 4.5]) and length of stay (LOS) before rectal sampling (OR: 1.1 [95%CI: 1.0, 1.1]). Carriage of CRGN was associated with 11 days increase of LOS after rectal sampling (β-coef: 11.4 [95%CI: 1.6, 21.2]), with a 3.5-fold increased risk of acquiring a resistant pathogen after rectal swabbing (RR: 3.5 [95%CI 1.2, 9.9]) and with a 6-fold increased risk of mortality (RR: 6.1 [95%CI: 2.1, 17.9]), after adjusting for sex, age, and comorbidity index. Vasilakopoulou et al. Gastrointestinal Carriage: Prevalence, Risk-Factors, Outcomes Conclusions: High prevalence rates were found for VRE and CRGN carriage among the inpatients of our hospital. Prolonged hospitalization and age were independent risk factors for VRE carriage, while CRGN carriage was associated with increased risk of acquiring a resistant pathogen, prolonged hospital stay, and increased mortality.

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“…Since 2012, the proportion of the OXA-181 variant is increasing in the class D carbapenemases, from less than 1% in 2012 to 8% in 2015 (however, it is far behind OXA-48, which was found in ϳ90% of the class D carbapenemases in 2015; L. Gauthier, personal data). Furthermore, this variant may be underestimated since carbapenem hydrolytic activity is very low, with sometimes false-negative results obtained with phenotypic methods such as the Carba NP test (21).…”

Section: Discussionmentioning

confidence: 99%

Diversity of Carbapenemase-Producing Escherichia coli Isolates in France in 2012-2013

Gauthier

Dortet

Cotellon

et al. 2018

Antimicrob Agents Chemother

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With the dissemination of carbapenemase-producing (CPE) strains worldwide, carbapenem-hydrolyzing enzymes are increasingly reported among isolates of, the first hospital and community-acquired opportunistic pathogen. Here, we have performed an epidemiological survey of carbapenemase-producing (CP-) isolates received at the French National Reference Centre (F-NRC) in 2012 and 2013. Antimicrobial susceptibilities for last-resort antibiotics and antimicrobial compounds commonly used to treat urinary tract infections were determined by broth microdilution. Clonal relationship was assessed using repetitive sequence-based PCR (rep-PCR) and multilocus sequence typing (MLST). From this collection of 140 carbapenemase-producing isolates, 74% produced an OXA-48-like carbapenemase and 21% produced an NDM carbapenemase. A link with a foreign country was suspected for 37% of infected/colonized patients. Most of the isolates were from screening (56%) and from urine samples (26%). Colistin, fosfomycin, and nitrofurantoin possessed the most consistent activity, with 100%, 95%, and 96% isolates susceptible, respectively. A wide diversity of carbapenemase-producing isolates has been found (50 different sequence types [STs]). The most prevalent clones were (i) sequence type 38 (ST38) producing OXA-48 ( = 21), a clone linked to Turkey and North African countries, (ii) ST-90 producing OXA-204 ( = 9), which was responsible for an outbreak related to a contaminated duodenoscope, and (iii) ST-410 producing OXA-181 ( = 5), which was recovered from patients of different geographical origins. These specific clones might be considered high-risk clones for the dissemination of carbapenemases in The wide diversity of STs, combined with the increasing number of CP- isolates received by the F-NRC, suggests a likely dissemination of CP- isolates in the community.

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Laboratory detection and clinical implication of oxacillinase-48 like carbapenemase: The hidden threat

Cited by 77 publications

References 103 publications

VNRX-5133 (Taniborbactam), a Broad-Spectrum Inhibitor of Serine- and Metallo-β-Lactamases, Restores Activity of Cefepime in Enterobacterales and Pseudomonas aeruginosa

VNRX-5133 (Taniborbactam), a Broad-Spectrum Inhibitor of Serine- and Metallo-β-Lactamases, Restores Activity of Cefepime in Enterobacterales and Pseudomonas aeruginosa

Gastrointestinal Carriage of Vancomycin-Resistant Enterococci and Carbapenem-Resistant Gram-Negative Bacteria in an Endemic Setting: Prevalence, Risk Factors, and Outcomes

Diversity of Carbapenemase-Producing Escherichia coli Isolates in France in 2012-2013

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