In vitro activity of imipenem/relebactam against Pseudomonas aeruginosa isolates recovered from ICU patients in Spain and Portugal (SUPERIOR and STEP studies).

OBJECTIVES To study the in vitro activity of imipenem/relebactam and comparators and the imipenem/relebactam resistance mechanisms in a Pseudomonas aeruginosa collection from Portugal (STEP, 2017-18) and Spain (SUPERIOR, 2016-17) surveillance studies. METHODS P. aeruginosa isolates (n = 474) were prospectively recovered from complicated urinary tract (cUTI), complicated intra-abdominal (cIAI) and lower respiratory tract (LRTI) infections in 11 Portuguese and 8 Spanish ICUs. MICs were determined (ISO broth microdilution). All imipenem/relebactam-resistant P. aeruginosa isolates (n = 30) and a subset of imipenem/relebactam-susceptible strains (n = 32) were characterized by WGS. RESULTS Imipenem/relebactam (93.7% susceptible), ceftazidime/avibactam (93.5% susceptible) and ceftolozane/tazobactam (93.2% susceptible) displayed comparable activity. The imipenem/relebactam resistance rate was 6.3% (Portugal 5.8%; Spain 8.9%). Relebactam restored imipenem susceptibility to 76.9% (103/134) of imipenem-resistant isolates, including MDR (82.1%; 32/39), XDR (68.8%; 53/77) and difficult-to-treat (DTR) isolates (67.2%; 45/67). Among sequenced strains, differences in population structure were detected depending on the country: clonal complex (CC)175 and CC309 in Spain and CC235, CC244, CC348 and CC253 in Portugal. Different carbapenemase gene distributions were also found: VIM-20 (n = 3), VIM-1 (n = 2), VIM-2 (n = 1) and VIM-36 (n = 1) in Spain and GES-13 (n = 13), VIM-2 (n = 3) and KPC-3 (n = 2) in Portugal. GES-13-CC235 (n = 13) and VIM type-CC175 (n = 5) associations were predominant in Portugal and Spain, respectively. Imipenem/relebactam showed activity against KPC-3 strains (2/2), but was inactive against all GES-13 producers and most of the VIM producers (8/10). Mutations in genes affecting porin inactivation, efflux pump overexpression and LPS modification might also be involved in imipenem/relebactam resistance. CONCLUSIONS Microbiological results reinforce imipenem/relebactam as a potential option to treat cUTI, cIAI and LRTI caused by MDR/XDR P. aeruginosa isolates, except for GES-13 and VIM producers.

[1]  J. Klockgether,et al.  Phenotypic and Genomic Comparison of the Two Most Common ExoU-Positive Pseudomonas aeruginosa Clones, PA14 and ST235 , 2020, mSystems.

[2]  J. Lemoine,et al.  Mechanisms of Resistance to Ceftolozane/Tazobactam in Pseudomonas aeruginosa: Results of the GERPA Multicenter Study , 2020, Antimicrobial Agents and Chemotherapy.

[3]  Jason C. Gallagher,et al.  A Clinical Review and Critical Evaluation of Imipenem-Relebactam: Evidence to Date , 2020, Infection and drug resistance.

[4]  A. Oliver,et al.  Distinct epidemiology and resistance mechanisms affecting ceftolozane/tazobactam in Pseudomonas aeruginosa isolates recovered from ICU patients in Spain and Portugal depicted by WGS. , 2020, The Journal of antimicrobial chemotherapy.

[5]  A. Oliver,et al.  Pseudomonas aeruginosa epidemic high-risk clones and their association with horizontally-acquired β-lactamases: 2020 update. , 2020, International journal of antimicrobial agents.

[6]  A. Oliver,et al.  In vitro dynamics and mechanisms of resistance development to imipenem and imipenem/relebactam in Pseudomonas aeruginosa. , 2020, The Journal of antimicrobial chemotherapy.

[7]  J. Campos,et al.  Carbapenemase-producing Pseudomonas aeruginosa in Spain: interregional dissemination of the high risk-clones ST175 and ST244 carrying blaVIM-2, blaVIM-1, blaIMP-8, blaVIM-20 and blaKPC-2. , 2020, International journal of antimicrobial agents.

[8]  S. Beatson,et al.  Antimicrobial Resistance in ESKAPE Pathogens , 2020, Clinical Microbiology Reviews.

[9]  R. Cantón,et al.  In vitro activity of ceftolozane-tazobactam against Enterobacterales and Pseudomonas aeruginosa causing urinary, intra-abdominal and lower respiratory tract infections in intensive care units in Portugal: the STEP multicentre study. , 2020, International journal of antimicrobial agents.

[10]  A. Oliver,et al.  Activity of Imipenem-Relebactam against a Large Collection of Pseudomonas aeruginosa Clinical Isolates and Isogenic β-Lactam-Resistant Mutants , 2019, Antimicrobial Agents and Chemotherapy.

[11]  A. Oliver,et al.  Epidemiology and Treatment of Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas aeruginosa Infections , 2019, Clinical Microbiology Reviews.

[12]  M. Motyl,et al.  Activity of imipenem/relebactam against MDR Pseudomonas aeruginosa in Europe: SMART 2015-17. , 2019, The Journal of antimicrobial chemotherapy.

[13]  G. Bou,et al.  Activity of ceftolozane/tazobactam against Pseudomonas aeruginosa and Enterobacterales isolates recovered from intensive care unit patients in Spain: The SUPERIOR multicentre study. , 2019, International journal of antimicrobial agents.

[14]  L. Peixe,et al.  Antibiotic resistance in Pseudomonas aeruginosa - Mechanisms, epidemiology and evolution. , 2019, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[15]  Sameer S. Kadri,et al.  Difficult-to-Treat Resistance in Gram-negative Bacteremia at 173 US Hospitals: Retrospective Cohort Analysis of Prevalence, Predictors, and Outcome of Resistance to All First-line Agents , 2018, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[16]  L. Peixe,et al.  Two decades of blaVIM-2-producing Pseudomonas aeruginosa dissemination: an interplay between mobile genetic elements and successful clones , 2018, The Journal of antimicrobial chemotherapy.

[17]  M. Ouellette,et al.  Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. , 2017, The Lancet. Infectious diseases.

[18]  V. Kos,et al.  Global emergence of the widespread Pseudomonas aeruginosa ST235 clone. , 2017, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[19]  K. Kazmierczak,et al.  In Vitro Activity of Imipenem-Relebactam against Gram-Negative ESKAPE Pathogens Isolated by Clinical Laboratories in the United States in 2015 (Results from the SMART Global Surveillance Program) , 2017, Antimicrobial Agents and Chemotherapy.

[20]  A. Oliver,et al.  Host and Pathogen Biomarkers for Severe Pseudomonas aeruginosa Infections. , 2017, The Journal of infectious diseases.

[21]  A. Oliver,et al.  Deciphering the Resistome of the Widespread Pseudomonas aeruginosa Sequence Type 175 International High-Risk Clone through Whole-Genome Sequencing , 2016, Antimicrobial Agents and Chemotherapy.

[22]  Carlos Juan,et al.  The increasing threat of Pseudomonas aeruginosa high-risk clones. , 2015, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[23]  D. Landman,et al.  Activity of Imipenem with Relebactam against Gram-Negative Pathogens from New York City , 2015, Antimicrobial Agents and Chemotherapy.

[24]  D. Livermore,et al.  Activity of MK-7655 combined with imipenem against Enterobacteriaceae and Pseudomonas aeruginosa. , 2013, The Journal of antimicrobial chemotherapy.

[25]  Robert E W Hancock,et al.  Pseudomonas aeruginosa: new insights into pathogenesis and host defenses. , 2013, Pathogens and disease.

[26]  M. Falagas,et al.  Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. , 2012, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[27]  R. Hancock,et al.  Pseudomonas aeruginosa: all roads lead to resistance. , 2011, Trends in microbiology.

[28]  A. Oliver,et al.  Wide Dispersion of ST175 Clone despite High Genetic Diversity of Carbapenem-Nonsusceptible Pseudomonas aeruginosa Clinical Strains in 16 Spanish Hospitals , 2011, Journal of Clinical Microbiology.

[29]  OUP accepted manuscript , 2021, Journal of Antimicrobial Chemotherapy.

[30]  J. Karlowsky,et al.  Imipenem–Relebactam and Meropenem–Vaborbactam: Two Novel Carbapenem-β-Lactamase Inhibitor Combinations , 2017, Drugs.

[31]  K. Mertens,et al.  Clinical outcomes of health-care-associated infections and antimicrobial resistance in patients admitted to European intensive-care units: a cohort study. , 2011, The Lancet. Infectious diseases.