The cephalosporin-β-lactamase-inhibitor-combinations, ceftolozane/tazobactam and ceftazidime/avibactam, have revolutionized treatment of carbapenem-resistant Pseudomonas aeruginosa (CR-PA). A contemporary assessment of their in vitro potency against a global CR-PA collection and an assessment of carbapenemase diversity are warranted. Isolates determined as CR-PA by the submitting site were collected from 2019–2021 (17 centers in 12 countries) during the ERACE-PA Global Surveillance Program. Broth microdilution MICs were assessed per CLSI standards for ceftolozane/tazobactam, ceftazidime/avibactam, ceftazidime, and cefepime. Phenotypic carbapenemase testing was conducted (modified carbapenem inactivation method (mCIM)). mCIM positive isolates underwent genotypic carbapenemase testing using the CarbaR, the CarbaR NxG, or whole genome sequencing. The MIC50/90 was reported as well as percent susceptible (CLSI and EUCAST interpretation). Of the 807 isolates, 265 (33%) tested carbapenemase-positive phenotypically. Of these, 228 (86%) were genotypically positive for a carbapenemase with the most common being VIM followed by GES. In the entire cohort of CR-PA, ceftolozane/tazobactam and ceftazidime/avibactam had MIC50/90 values of 2/ > 64 and 4/64 mg/L, respectively. Ceftazidime/avibactam was the most active agent with 72% susceptibility per CLSI compared with 63% for ceftolozane/tazobactam. For comparison, 46% of CR-PA were susceptible to ceftazidime and cefepime. Against carbapenemase-negative isolates, 88 and 91% of isolates were susceptible to ceftolozane/tazobactam and ceftazidime/avibactam, respectively. Ceftolozane/tazobactam and ceftazidime/avibactam remained highly active against carbapenem-resistant P. aeruginosa, particularly in the absence of carbapenemases. The contemporary ERACE-PA Global Program cohort with 33% carbapenemase positivity including diverse enzymology will be useful to assess therapeutic options in these clinically challenging organisms with limited therapies.

Carbapenem-resistant Pseudomonas aeruginosa (CR-PA) is a major healthcare-associated pathogen worldwide. In the United States, 10–30% of P. aeruginosa isolates are carbapenem-resistant, while globally the percentage varies considerably. A subset of carbapenem-resistant P. aeruginosa isolates harbour carbapenemases, although due in part to limited screening for these enzymes in clinical laboratories, the actual percentage is unknown. Carbapenemase-mediated carbapenem resistance in P. aeruginosa is a significant concern as it greatly limits the choice of anti-infective strategies, although detecting carbapenemase-producing P. aeruginosa in the clinical laboratory can be challenging. Such organisms also have been associated with nosocomial spread requiring infection prevention interventions. The carbapenemases present in P. aeruginosa vary widely by region but include the Class A beta-lactamases, KPC and GES; metallo-beta-lactamases IMP, NDM, SPM, and VIM; and the Class D, OXA-48 enzymes. Rapid confirmation and differentiation among the various classes of carbapenemases is key to the initiation of early effective therapy. This may be accomplished using either molecular genotypic methods or phenotypic methods, although both have their limitations. Prompt evidence that rules out carbapenemases guides clinicians to more optimal therapeutic selections based on local phenotypic profiling of non-carbapenemase-producing, carbapenem-resistant P. aeruginosa . This article will review the testing strategies available for optimizing therapy of P. aeruginosa infections.

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The prevalence of carbapenem-resistant Pseudomonas aeruginosa is increasing. Identification of carbapenemase-producing P. aeruginosa will have therapeutic, epidemiological, and infection control implications. This study evaluated the performance of the EDTA-modified carbapenem inactivation method (eCIM) in tandem with the modified carbapenem inactivation method (mCIM) against a large collection of clinical P. aeruginosa isolates (n = 103) to provide clinicians a phenotypic test that not only identifies carbapenemase production but also distinguishes between metallo-β-lactamase and serine-carbapenemase production in P. aeruginosa. The mCIM test was performed according to Clinical and Laboratory Standards Institute guidelines, while the eCIM was conducted as previously described for Enterobacteriaceae. Test performance was compared to the genotypic profile as the reference. mCIM testing successfully categorized 91% (112/123) of P. aeruginosa isolates as carbapenemases or non-carbapenemase producers, with discordant isolates being primarily Guiana extended-spectrum (GES)-type producers. To increase the sensitivity of the mCIM for GES-harboring isolates, a double inoculum, prolonged incubation, or both was evaluated, with each modification improving sensitivity to 100% (12/12). Upon eCIM testing, all Verona integrin-encoded metallo-β-lactamases (VIM; n = 27) and New Delhi metallo-β-lactamases (NDM; n = 13) tested had 100% concordance to their genotypic profiles, whereas all Klebsiella pneumoniae carbapenemase (KPC; n = 8) and GES (n = 12) isolates tested negative, as expected, in the presence of EDTA. The eCIM failed to identify all imipenemase (IMP)-producing (n = 22) and Sao Paulo metallo-β-lactamase (SPM)-producing (n = 14) isolates. KPC-, VIM-, and NDM-producing P. aeruginosa were well defined by the conventional mCIM and eCIM testing methods; additional modifications appear required to differentiate GES-, IMP-, and SPM-producing isolates.

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