Dataset Information

Acetylcysteine increases sensitivity of ceftazidime-avibactam-resistant enterobacterales with different enzymatic resistance to ceftazidime-avibactam in vitro and in vivo.

ABSTRACT:

Background

Ceftazidime-avibactam (CZA) improves treatment outcomes for infections caused by carbapenem-resistant organisms, but has led to serious bacterial resistance. Acetylcysteine (NAC) is an approved medication that protects the respiratory tract through antioxidant and anti-inflammatory effects.

Results

This study found that NAC combined with CZA effectively inhibits the growth of CZA-resistant clinical Enterobacterales strains. The CZA/NAC combination inhibits biofilm formation in vitro and decreases bacterial burden in a mouse thigh infection model. The combination is biocompatible and primarily increases cell membrane permeability to cause bacterial death.

Conclusions

These findings prove that the CZA/NAC combination has potential as a treatment for CZA-resistant Enterobacterales infections.

SUBMITTER: Huang Z

PROVIDER: S-EPMC10623744 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Acetylcysteine increases sensitivity of ceftazidime-avibactam-resistant enterobacterales with different enzymatic resistance to ceftazidime-avibactam in vitro and in vivo.

Huang Zeyu Z Han Yijia Y Zhang Xiaotuan X Sun Yao Y Lin Yuzhan Y Feng Luozhu L Zhou Tieli T Wang Zhongyong Z

BMC microbiology 20231103 1

<h4>Background</h4>Ceftazidime-avibactam (CZA) improves treatment outcomes for infections caused by carbapenem-resistant organisms, but has led to serious bacterial resistance. Acetylcysteine (NAC) is an approved medication that protects the respiratory tract through antioxidant and anti-inflammatory effects.<h4>Results</h4>This study found that NAC combined with CZA effectively inhibits the growth of CZA-resistant clinical Enterobacterales strains. The CZA/NAC combination inhibits biofilm forma ...[more]

PMID: 37923985

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Project description:Background: Avibactam, relebactam and vaborbactam are β-lactamase inhibitors that proved their efficiency against KPC-producing Enterobacterales. Regarding their inhibitor activity towards Ambler’s class A extended spectrum β-lactamases (ESBL) and Ambler’s class C cephalosporinase (AmpC), they should be active on most of the carbapenem-resistant non-carbapenemase-producing Enterobacterales (CR non-CPE). Objectives: Determine the in vitro activity of ceftazidime-avibactam, imipenem-relebactam and meropenem-vaborbactam and comparators against CR non-CPE. Methods: MICs to ceftazidime/avibactam, imipenem/relebactam, meropenem/vaborbactam, but also temocillin, ceftolozane/tazobactam, ertapenem, colistin, eravacycline and tigecycline were determined by broth microdilution (ThermoFisher) on a collection of 284 CR non-CPE (inhibition zone diameter < 22 mm to meropenem). Whole genome sequencing was performed on 90 isolates to assess the genetic diversity as well as resistome. Results: According to EUCAST breakpoints, susceptibility rates of ceftazidime, imipenem, meropenem and ertapenem used at standard dose were 0.7%, 45.1%, 14.8% and 2.5%, respectively. Increased exposure of ceftazidime, imipenem and meropenem led to reach 3.5%, 68.3% and 67.7% susceptibility, respectively. Using the EUCAST clinical breakpoints, susceptibility rates of ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam were 88.4%, 81.0% and 80.6%, respectively. Susceptibility rates of temocillin, ceftolozane/tazobactam, tigecycline, eravacycline, and colistin were 0%, 4.6%, 27.8%, 54.9% and 90.1%. MICs distributions with and without the presence of the inhibitor demonstrated a better ability of avibactam and relebactam compared to vaborbactam to restore susceptibility to the associated β-lactam. Conclusions: This study demonstrated the in vitro efficacy of ceftazidime/avibactam, imipenem/relebactam and to a lesser extent meropenem/vaborbactam against CR non-CPE. Moreover, to test all β-lactams/β-lactamases inhibitors combinations without a priori for CRE, non-CPE is crucial since resistance to one of the β-lactam/β-lactamase inhibitor combinations does not predict resistance to another molecule, depending on the resistance mechanisms involved.

Project description:Oxacillinases (OXA)-48-like β-lactamases are one of the most common resistance determinants among carbapenem-resistant Enterobacterales reported globally. Moreover, there is no standard treatment available against organisms producing OXA-48-like enzymes, and they are sometimes difficult to detect, making treatment challenging. The objective of this study was to evaluate the distribution and antimicrobial susceptibility of blaOXA-48-like Enterobacterales isolates against ceftazidime-avibactam (CAZ-AVI) and a panel of comparators collected worldwide from 2016 to 2020 as a part of the Antimicrobial Testing Leadership and Surveillance program. Among all the Enterobacterales isolates collected, 1.8% (1,690/94,052) carried blaOXA-48-like, and a majority of those were identified as K. pneumoniae (86.5%, 1,462/1,690). Among all the blaOXA-48-like isolates, 88.9% (1,502/1,690) were extended-spectrum β-lactamase (ESBL)-positive, 20.7% (350/1,690) were metallo-β-lactamase (MBL)-positive, and 8.9% (150/1,690) were ESBL- and MBL-negative. There were 10 different variants of the OXA-48-like family of enzymes detected, with the major variant being blaOXA-48 (50.2%, 848/1,690), blaOXA-232 (29.3%, 496/1,690), and blaOXA-181 (18.0%, 304/1,690). Overall, all the blaOXA-48-like isolates showed a susceptibility of 78.6% to CAZ-AVI. Importantly, high susceptibility to CAZ-AVI was shown by all the blaOXA-48 type, MBL-negative isolates (n = 1,380, ≥99.0%), and all the MBL-negative isolates (n = 1,300, ≥97.6%) of the major variants (blaOXA-48, blaOXA-232, and blaOXA-181) studied. Among the comparator agents, all isolates showed good susceptibility to only tigecycline (>95.0%) and colistin (>78.6%). Considering the limited treatment options available, CAZ-AVI could be considered as a potential treatment option against blaOXA-48-like Enterobacterales. However, routine surveillance and appropriate stewardship strategies for these organisms may help identify emerging resistance mechanisms and effective treatment of infections.ImportanceResistance to carbapenems among Enterobacterales is often due to the production of enzymes that are members of the oxacillinases (OXA)-48-like family. These organisms can also be resistant to other classes of drugs and are difficult to identify and treat. This study evaluated the activity of the drug ceftazidime-avibactam (CAZ-AVI) and other comparator agents against a global collection of Enterobacterales that produce OXA-48-like enzymes. CAZ-AVI was active against blaOXA-48-like Enterobacterales, and only colistin and tigecycline were similarly active among the comparator agents, highlighting the limited treatment options against these organisms. Continued surveillance of the distribution of these OXA 48-like producing Enterobacterales and monitoring of resistance patterns along with the implementation of antimicrobial stewardship measures to guide antibiotic use and appropriate treatment are necessary to avoid drug resistance among these organisms.

Dataset Information

Acetylcysteine increases sensitivity of ceftazidime-avibactam-resistant enterobacterales with different enzymatic resistance to ceftazidime-avibactam in vitro and in vivo.

Background

Results

Conclusions

Publications

Acetylcysteine increases sensitivity of ceftazidime-avibactam-resistant enterobacterales with different enzymatic resistance to ceftazidime-avibactam in vitro and in vivo.

Similar Datasets

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