Ceftazidime-avibactam activity against a challenge set of carbapenem-resistant Enterobacterales: Ompk36 L3 alterations and β-lactamases with ceftazidime hydrolytic activity lead to elevated MIC values

Castanheira, Mariana; Doyle, Timothy B; Hubler, Cory; Sader, Hélio S.; Mendes, Rodrigo E.

doi:10.1016/j.ijantimicag.2020.106011

Cited by 24 publications

(11 citation statements)

References 23 publications

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“…In keeping with our findings, a comparable study observed elevated MICs of CZA amongst a panel of carbapenem-resistant Enterobacterales secondary to Ompk36 L3 alterations and production of β-lactamases. 45 Also, a former study by Shen and his colleagues reported that mending of OmpK35 resulted into more reduction of the MIC of ceftazidime as opposed to OmpK36, but without a considerable decrease in the MIC of avibactam. 46 …”

Section: Discussionmentioning

confidence: 98%

Molecular Mechanisms Mediating Ceftazidime/Avibactam Resistance Amongst Carbapenem-Resistant Klebsiella pneumoniae Isolates from Cancer Patients

El-Kady¹,

Elbaiomy²,

Elnagar³

2022

IDR

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Background A growing body of evidence suggests that ceftazidime/avibactam (CZA) is a potential therapeutic option for carbapenem-resistant Klebsiella pneumoniae (CRKP) infections; however, resistant strains are increasingly emerged worldwide. Herein, we deemed to investigate the susceptibility profile of CRKP isolates from cancer patients to CZA and to identify the underlying resistance mechanisms. Methods Clinical samples were obtained from adult patients admitted to the Oncology Center of Mansoura University, Mansoura, Egypt. The antibiotic susceptibility pattern of K. pneumonia e isolates to different antibiotics was tested by the modified Kirby Bauer’s disc diffusion method. Minimum inhibitory concentrations of CZA were assessed using broth microdilution method. Screening for carbapenemase-producing strains was achieved by the modified Hodge test. Multiplex polymerase chain reactions (PCRs) were conducted for uncovering of carbapenemase-encoding genes ( bla KPC , bla VIM , bla IMP , bla NDM-1 , and bla OXA-48 ), and outer membrane porin genes ( ompK35 and ompK36 ). Results A total of 12 CZA-resistant isolates were identified out of 47 CRKP isolates (25.5%). The MIC 50 and MIC 90 of CZA against CRKP were 1 and 64 µg/mL, respectively. Risk factors for CZA resistance included chronic kidney disease, mechanical ventilation, longer length of hospital stay, and ICU admission. The multivariate logistic regression demonstrated that longer length of hospital stay ( P =0.03) was the only independent predictor for acquisition of CZA-resistant isolates. The leading mechanism for CZA resistance was sustained by bla KPC (50%), meanwhile 16.7% and 8.3% of the CZA-resistant isolates harbored bla OXA-48 and bla OXA-48 / bla NDM-1 , respectively. The MBL-encoding genes bla NDM-1 and bla IMP were detected in 16.7% and 8.3% of the isolates, respectively. Absence of both ompK35 and ompK36 was observed in 58.3% of the CZA-resistant isolates. Conclusion CZA has displayed superior in vitro activity against CRKP isolates in comparison to other antibiotics; however, thorough molecular characterization of resistant strains is highly recommended in future studies to detect and monitor the emergence of further tackling strains.

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Section: Discussionmentioning

confidence: 98%

Molecular Mechanisms Mediating Ceftazidime/Avibactam Resistance Amongst Carbapenem-Resistant Klebsiella pneumoniae Isolates from Cancer Patients

El-Kady¹,

Elbaiomy²,

Elnagar³

2022

IDR

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“…In a study by Tsai et al ( 16 ), K. pneumoniae isolates harboring a deletion of ompK36 or both ompK35 and ompK36 were more resistant to ceftazidime than those of the wild type or a construct carrying only an ompK36 deletion. Subsequent studies had also found that the mutant ompK35 (premature termination) and ompK36 (134 to 135 GD insertion) were related to reduced susceptibility to CAZ/AVI ( 17 – 19 ). Combined with our current results, we speculate that perhaps it is the deficiency of outer membrane proteins that results in the diminished penetration of ceftazidime through OmpK35/36 porins in the presence of ESBL and KPC enzymes with good hydrolytic profiles for ceftazidime, which could be the reason for the elevated CAZ/AVI MIC results in our study.…”

Section: Discussionmentioning

confidence: 99%

Increased Expression and Amplification of bla _KPC-2 Contributes to Resistance to Ceftazidime/Avibactam in a Sequence Type 11 Carbapenem-Resistant Klebsiella pneumoniae Strain

Zhang

Yang

et al. 2022

Microbiol Spectr

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“… 13 Ninety-two of 97 nonCP CRE K. pneumoniae isolates were also analysed for their multilocus sequence type (ST) as previously described. 23 …”

Section: Methodsmentioning

confidence: 99%

Activity of meropenem/vaborbactam and comparators against non-carbapenemase-producing carbapenem-resistant Enterobacterales isolates from Europe

Shortridge

Deshpande

Streit

et al. 2022

JAC-Antimicrobial Resistance

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Background Carbapenem-resistant Enterobacterales (CRE) isolates have disseminated worldwide. CREs usually produce a carbapenemase; however, some isolates are negative for known carbapenemases. In this study, we evaluated the activity of meropenem/vaborbactam and comparators against CREs without a carbapenemase (nonCP CREs) collected from European hospitals from 2016 to 2019. Materials and methods 23 043 Enterobacterales clinical isolates were collected in 41 hospitals located in 20 countries. Susceptibility (S) testing was performed using the broth microdilution method. CLSI/EUCAST (2021) interpretive criteria were used. 978 CREs were identified with MICs >2 mg/L to meropenem or imipenem. Whole-genome sequencing was performed on each CRE isolate. 125 isolates were negative for carbapenemase genes, including blaKPC, blaNDM, blaIMP, blaVIM and blaOXA-48-like. NonCP CRE isolates were analysed for the presence of other β-lactamases, multilocus sequence types (ST) and mutations in outer membrane protein (OMP) sequences. Results Most nonCP CRE were Klebsiella pneumoniae (KPN; n = 97/125). 84.0% of nonCP CRE (n = 105) were from Poland, including 88 KPN. The most common β-lactamase was blaCTX-M-15 in 92/125 isolates. OMP disruptions or alterations were noted among 76 KPN. Among KPN isolates that had MLST typing, 30 belonged to ST11, 18 to ST152 and 17 to ST147, while 13 other STs were observed. Susceptibility to meropenem/vaborbactam was 96.0/97.6% (CLSI/EUCAST) while meropenem was 2.4/8.0%S. Conclusions Meropenem/vaborbactam had potent in vitro activity against CRE isolates that lacked known carbapenemases. Resistance mechanisms observed among nonCP CREs included acquired β-lactamases and OMP alterations. These results indicate that meropenem/vaborbactam may be a useful treatment for infections caused by nonCP CREs.

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Ceftazidime-avibactam activity against a challenge set of carbapenem-resistant Enterobacterales: Ompk36 L3 alterations and β-lactamases with ceftazidime hydrolytic activity lead to elevated MIC values

Cited by 24 publications

References 23 publications

Molecular Mechanisms Mediating Ceftazidime/Avibactam Resistance Amongst Carbapenem-Resistant Klebsiella pneumoniae Isolates from Cancer Patients

Molecular Mechanisms Mediating Ceftazidime/Avibactam Resistance Amongst Carbapenem-Resistant Klebsiella pneumoniae Isolates from Cancer Patients

Increased Expression and Amplification of bla _KPC-2 Contributes to Resistance to Ceftazidime/Avibactam in a Sequence Type 11 Carbapenem-Resistant Klebsiella pneumoniae Strain

Activity of meropenem/vaborbactam and comparators against non-carbapenemase-producing carbapenem-resistant Enterobacterales isolates from Europe

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Ceftazidime-avibactam activity against a challenge set of carbapenem-resistant Enterobacterales: Ompk36 L3 alterations and β-lactamases with ceftazidime hydrolytic activity lead to elevated MIC values

Cited by 24 publications

References 23 publications

Molecular Mechanisms Mediating Ceftazidime/Avibactam Resistance Amongst Carbapenem-Resistant Klebsiella pneumoniae Isolates from Cancer Patients

Molecular Mechanisms Mediating Ceftazidime/Avibactam Resistance Amongst Carbapenem-Resistant Klebsiella pneumoniae Isolates from Cancer Patients

Increased Expression and Amplification of bla KPC-2 Contributes to Resistance to Ceftazidime/Avibactam in a Sequence Type 11 Carbapenem-Resistant Klebsiella pneumoniae Strain

Activity of meropenem/vaborbactam and comparators against non-carbapenemase-producing carbapenem-resistant Enterobacterales isolates from Europe

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Increased Expression and Amplification of bla _KPC-2 Contributes to Resistance to Ceftazidime/Avibactam in a Sequence Type 11 Carbapenem-Resistant Klebsiella pneumoniae Strain