Association of blaVIM-2, blaPDC-35, blaOXA-10,&nbsp;blaOXA-488 and blaVEB-9 β-Lactamase Genes with Resistance to Ceftazidime-Avibactam and Ceftolozane-Tazobactam in Multidrug-Resistant Pseudomonas aeruginosa.

Mazen A Sid Ahmed,Hamad Abdel Hadi,Ali A Sultan,Ali S Omrani,Emad Bashir Ibrahim,Bo Söderquist,Jana Jass,Abdul Salam,Abdul Latif Al Khal,Faisal Ahmad Khan,Sini Skariah

doi:10.3390/antibiotics11020130

Abstract

Ceftazidime–avibactam and ceftolozane–tazobactam are approved for the treatment of complicated Gram-negative bacterial infections including multidrug-resistant (MDR) Pseudomonas aeruginosa. Resistance to both agents has been reported, but the underlying mechanisms have not been fully explored. This study aimed to correlate β-lactamases with phenotypic resistance to ceftazidime–avibactam and/or ceftolozane–tazobactam in MDR-P. aeruginosa from Qatar. A total of 525 MDR-P. aeruginosa isolates were collected from clinical specimens between 2014 and 2017. Identification and antimicrobial susceptibility were performed by the BD PhoenixTM system and gradient MIC test strips. Of the 75 sequenced MDR isolates, 35 (47%) were considered as having difficult-to-treat resistance, and 42 were resistant to ceftazidime–avibactam (37, 49.3%), and/or ceftolozane–tazobactam (40, 53.3%). They belonged to 12 sequence types, with ST235 being predominant (38%). Most isolates (97.6%) carried one or more β-lactamase genes, with blaOXA-488 (19%) and blaVEB-9 (45.2%) being predominant. A strong association was detected between class B β-lactamase genes and both ceftazidime–avibactam and ceftolozane–tazobactam resistance, while class A genes were associated with ceftolozane–tazobactam resistance. Co-resistance to ceftazidime–avibactam and ceftolozane–tazobactam correlated with the presence of blaVEB-9, blaPDC-35, blaVIM-2, blaOXA-10 and blaOXA-488. MDR-P. aeruginosa isolates resistant to both combination drugs were associated with class B β-lactamases (blaVIM-2) and class D β-lactamases (blaOXA-10), while ceftolozane–tazobactam resistance was associated with class A (blaVEB-9), class C (blaVPDC-35), and class D β-lactamases (blaOXA-488).

Highlights

Gram-negative bacteria (GNB) represent a major healthcare burden due to their association with a variety of community and healthcare-associated infections (HAIs) [1,2]
Of the 525 MDR-P. aeruginosa tested against ceftazidime–avibactam and ceftolozane– tazobactam, 75 isolates were sent for whole-genome sequencing (WGS), and of these 37 (49.3%) were resistant to ceftazidime–avibactam, 40 (53.3%) were resistant to ceftolozane–tazobactam, 35 (46.7%) were resistant to both, and 33 (44%) were susceptible to both
The present study reported 42 MDR-P. aeruginosa isolates that were phenotypically resistant to ceftazidime–avibactam and/or ceftolozane–tazobactam, and many were considered as difficult-to-treat resistance (DTR)

Summary

Introduction

Gram-negative bacteria (GNB) represent a major healthcare burden due to their association with a variety of community and healthcare-associated infections (HAIs) [1,2]. Pathogens have multiple mechanisms of resistance, it has been established that β-lactamase genes are the cornerstone of antimicrobial resistance (AMR), in GNB [5]. To overcome these challenges, parallel critical measures are needed, including the prevention of AMR spread, while simultaneously developing new therapeutic modalities [3,6]. Ceftazidime–avibactam and ceftolozane–tazobactam have been approved by the United States Food and Drug Administration (US-FDA) and the European Medicines Agency (EMA) for the treatment of complicated infections caused by GNB, including ventilation-associated pneumonia, urinary tract and intra-abdominal infections [7]. The addition of tazobactam to ceftolozane extended its activity against many, but not all, extended-spectrum β-lactamase (ESBL)-producing GNB [10]

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