Mechanisms of Resistance to Ceftolozane/Tazobactam in Pseudomonas aeruginosa: Results of the GERPA Multicenter Study

Abstract

Resistance mechanisms of Pseudomonas aeruginosa to ceftolozane/tazobactam (C/T) were assessed on a collection of 420 nonredundant strains non-susceptible to ceftazidime (MIC > 8 μg/ml) and/or imipenem (> 4 μg/ml), collected by 36 French hospital laboratories over a one month period (GERPA study). Rates of C/T resistance (MIC > 4/4 μg/ml) were equal to 10% in this population (42/420 strains), and 23.2% among the isolates resistant to both ceftazidime and imipenem (26/112). A first group of 21 strains (50%) was found to harbor various extended-spectrum β-lactamases (1 OXA-14; 2 OXA-19; 1 OXA-35; 1 GES-9; 3 PER-1), carbapenemases (2 GES-5; 1 IMP-8; 8 VIM-2), or both (1 VIM-2/OXA-35; 1 VIM-4/SHV-2a). All the strains of this group belonged to widely distributed epidemic clones (ST111, ST175, CC235, ST244, ST348, ST654), and were highly resistant to almost all the antibiotics tested except colistin. A second group was composed of 16 (38%) isolates moderately resistant to C/T (MIC from 8/4 to 16/4 μg/ml), of which 7 were related to international clones (ST111, ST253, CC274, ST352, ST386). As demonstrated by targeted mass spectrometry, cloxacillin-based inhibition tests and gene blaPDC deletion experiments, this resistance phenotype was correlated to an extremely high production of cephalosporinase PDC. In part accounting for this strong PDC upregulation, genomic analyses revealed the presence of mutations in regulator AmpR (D135N/G in 6 strains) and enzymes of the peptidoglycan recycling pathway such as AmpD, PBP4, and Mpl (9 strains). Finally, all the 5 (12%) remaining C/T resistant strains (group 3) appeared to encode PDC variants with mutations known to improve the hydrolytic activity of the β-lactamase to ceftazidime and C/T (F147L, ΔL223-Y226, E247K, N373I). Collectively, our results highlight the importance of both intrinsic and transferable mechanisms in C/T resistant P. aeruginosa. Which mutational events lead some clinical strains to massively produce the natural cephalosporinase PDC remains incompletely understood.

XDR-Pseudomonas aeruginosa Outside the ICU: Is There Still Place for Colistin?

“…Further, we observed that 26.3% of our isolates were susceptible only to colistin. These data agree with others already reported in Southern European countries’ literature, suggesting that colistin could represent the only therapeutic option available in these patients, although with some pharmacological and safety concerns [ 1 , 24 , 25 , 26 , 27 ].…”

Activity of ceftolozane/tazobactam against Gram-negative isolates among different infections in Hong Kong: SMART 2017–2019

“…For example, PDC-346 identified in the current study (Table 2), which includes mutations R79Q, T105A and G183D (relative to wild-type PDC-1), was previously demonstrated to confer resistance to ceftolozane/tazobactam and ceftazidime/avibactam [31,32]. A recent study by French investigators characterized a subset of 42 isolates of P. aeruginosa with ceftolozane/tazobactam MICs>4 µg ml −1 and placed each isolate into one of three groups based upon the resistance mechanism identified [14]. The largest group (21 isolates) carried an ESBL (four isolates with OXA, three with PER and one with GES), a carbapenemase (eight isolates with VIM-2, two with GES and one with IMP) or both (one isolate with VIM-2/OXA and one with VIM-4/SHV-2a).…”

“…A recent study by French investigators characterized a subset of 42 isolates of P. aeruginosa with ceftolozane/tazobactam MICs>4 µg ml −1 and placed each isolate into one of three groups based upon the resistance mechanism identified [14]. The largest group (21 isolates) carried an ESBL (four isolates with OXA, three with PER and one with GES), a carbapenemase (eight isolates with VIM-2, two with GES and one with IMP) or both (one isolate with VIM-2/OXA and one with VIM-4/SHV-2a).…”

The Role of Colistin in the Era of New β-Lactam/β-Lactamase Inhibitor Combinations

“…Fournier et al reported that ceftolozane-tazobactam resistance can be raised from the upregulation of PDC genes due to mutations in the regulator AmpR gene, and changes in the enzymes of the peptidoglycan recycling pathway (AmpD, PBP4 and Mpl). In this study, some previously reported PDC variants with mutations increasing the hydrolytic activity of β-lactamases towards ceftolozane-tazobactam such as F147L, ΔL223-Y226, E247K, N373I were also detected in ceftolozane-tazobactam-resistant P. aeruginosa strains [ 224 ]. Furthermore, modification in MexCD-OprJ efflux pump and mutations in PBP3 can cause ceftolozane-tazobactam resistance in P. aeruginosa strains [ 225 ].…”