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Observational Study
. 2023 Mar;4(3):e159-e170.
doi: 10.1016/S2666-5247(22)00329-9. Epub 2023 Feb 9.

Global epidemiology and clinical outcomes of carbapenem-resistant Pseudomonas aeruginosa and associated carbapenemases (POP): a prospective cohort study

Jinnethe Reyes  1 , Lauren Komarow  2 , Liang Chen  3 , Lizhao Ge  2 , Blake M Hanson  4 , Eric Cober  5 , Erica Herc  6 , Thamer Alenazi  7 , Keith S Kaye  8 , Julia Garcia-Diaz  9 , Lanjuan Li  10 , Souha S Kanj  11 , Zhengyin Liu  12 , Jose M Oñate  13 , Robert A Salata  14 , Kalisvar Marimuthu  15 , Hainv Gao  16 , Zhiyong Zong  17 , Sandra L Valderrama-Beltrán  18 , Yunsong Yu  19 , Paul Tambyah  20 , Gregory Weston  21 , Soraya Salcedo  22 , Lillian M Abbo  23 , Qing Xie  24 , Karen Ordoñez  25 , Minggui Wang  26 , Martin E Stryjewski  27 , Jose M Munita  28 , David L Paterson  29 , Scott Evans  2 , Carol Hill  30 , Keri Baum  30 , Robert A Bonomo  31 , Barry N Kreiswirth  3 , Maria Virginia Villegas  32 , Robin Patel  33 , Cesar A Arias  34 , Henry F Chambers  35 , Vance G Fowler Jr  30 , Yohei Doi  36 , David van Duin  37 , Michael J Satlin  38 ; Antibacterial Resistance Leadership Group and Multi-Drug Resistant Organism Network Investigators
Collaborators, Affiliations
Observational Study

Global epidemiology and clinical outcomes of carbapenem-resistant Pseudomonas aeruginosa and associated carbapenemases (POP): a prospective cohort study

Jinnethe Reyes et al. Lancet Microbe. 2023 Mar.

Abstract

Background: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a global threat, but the distribution and clinical significance of carbapenemases are unclear. The aim of this study was to define characteristics and outcomes of CRPA infections and the global frequency and clinical impact of carbapenemases harboured by CRPA.

Methods: We conducted an observational, prospective cohort study of CRPA isolated from bloodstream, respiratory, urine, or wound cultures of patients at 44 hospitals (10 countries) between Dec 1, 2018, and Nov 30, 2019. Clinical data were abstracted from health records and CRPA isolates were whole-genome sequenced. The primary outcome was 30-day mortality from the day the index culture was collected. We compared outcomes of patients with CRPA infections by infection type and across geographic regions and performed an inverse probability weighted analysis to assess the association between carbapenemase production and 30-day mortality.

Findings: We enrolled 972 patients (USA n=527, China n=171, south and central America n=127, Middle East n=91, Australia and Singapore n=56), of whom 581 (60%) had CRPA infections. 30-day mortality differed by infection type (bloodstream 21 [30%] of 69, respiratory 69 [19%] of 358, wound nine [14%] of 66, urine six [7%] of 88; p=0·0012) and geographical region (Middle East 15 [29%] of 52, south and central America 20 [27%] of 73, USA 60 [19%] of 308, Australia and Singapore three [11%] of 28, China seven [6%] of 120; p=0·0002). Prevalence of carbapenemase genes among CRPA isolates also varied by region (south and central America 88 [69%] of 127, Australia and Singapore 32 [57%] of 56, China 54 [32%] of 171, Middle East 27 [30%] of 91, USA ten [2%] of 527; p<0·0001). KPC-2 (n=103 [49%]) and VIM-2 (n=75 [36%]) were the most common carbapenemases in 211 carbapenemase-producing isolates. After excluding USA patients, because few US isolates had carbapenemases, patients with carbapenemase-producing CRPA infections had higher 30-day mortality than those with non-carbapenemase-producing CRPA infections in both unadjusted (26 [22%] of 120 vs 19 [12%] of 153; difference 9%, 95% CI 3-16) and adjusted (difference 7%, 95% CI 1-14) analyses.

Interpretation: The emergence of different carbapenemases among CRPA isolates in different geographical regions and the increased mortality associated with carbapenemase-producing CRPA infections highlight the therapeutic challenges posed by these organisms.

Funding: National Institutes of Health.

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Conflict of interest statement

Declaration of interests All authors report funding support from the Antibacterial Resistance Leadership Group of the National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID; UM1AI104681) during the conduct of this study. Additionally, during the conduct of this study, and outside of the submitted work, the authors report the following disclosures. KSK reports consulting fees paid directly to him by Merck, Shionogi, Qpex, and Micrux. JG-D reports grants and contracts paid to her institution from NIH, BARDA, Janssen Research & Development LLC, Pfizer, BioNTech SE, GCAR, Hoffman La-Roche, I-Mab Bioppharma, Rebiotix, Target Health, LLC OBO Lilly USA, GlaxoSmithKline, Summit Limited, Cidara Therapeutics, Merck Sharp & Dohme, Seres Therapeutics; and Infectious Diseases Society of America Research Committee participation paid to her directly. SSK reports speaker and advisory board payments from Pfizer, Astellas, Novartis, Merck, and Gilead. JMO reports speaker payments from Pfizer, MSD, and Biotoscana; and board participation on the Chair Ethics Committee. SLV-B reports personal fees from Pfizer, Biotoscana, and MSD; meeting support from MSD and Pfizer; and data safety monitoring board participation with MSD and GlaxoSmithKline. PT reports honoraria payments to his institution from Aj Biologics and bioMérieux. GW reports payment to his institution from Allergan for contracted activities. LMA reports grants and contracts paid to her institution from Rainmakers/CDC multisystem inflammatory syndrome in adults with SARS-CoV-2, and Regeneron study co-investigator; consulting and honoraria paid directly to them from Medscape for CME lectures, and Ferring Pharmaceuticals for advisory board participation; and volunteer work as the director of the IDSA Board of Directors. KO reports payments for educational events and presentations from Pfizer, MSD, AstraZeneca, and Farma de Colombia; meeting support from Pfizer, MSD, and Gilead; and expert testimony support from Pfizer, bioMérieux, and MSD. MES reports speaker fees from Pfizer (Argentina); advisory board participation for Wockhardt; consultancy for Basilea; and data safety monitoring board participation with Fulcrum Therapeutics. JMM reports grants from Pfizer, MSD, and bioMérieux, the National Fund for Scientific and Technological Development; and the Agencia Nacional de Investigation y Desarrollo Millennium Science Initiative/Millennium Initiative for Collaborative Research on Bacterial Resistance, Government of Chile. DLP reports grants and contracts paid to his institution from Merck, Pfizer, and Shionogi; consulting and honoraria payments to him by Merck, Shionogi, QPex, Spero Therapeutics, Sumitomo, Pfizer, and bioMérieux; meeting support from Shionogi; and board and committee participation with Symvivo, and AMR action fund. SE reports grants from the NIAID and the NIH and Degruter (Editor in Chief for Statistical Communications in Infectious Diseases); royalties from Taylor & Francis; consulting fees from Genentech, AstraZeneca, Takeda, Microbiotix, Johnson & Johnson, Endologix, ChemoCentryx, Becton Dickinson, Atricure, Roviant, Neovasc, Nobel Pharma, Horizon, International Drug Development Institute, SVB Leerink; payments from Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks; meeting support from the US Food and Drug Administration, the Deming Conference on Applied Statistics, the Clinical Trial Transformation Initiative, the Council for International Organizations of Medical Sciences, the International Chinese Statistical Association Applied Statistics Symposium, and the Antimicrobial Resistance and Stewardship Conference; and board member participation for the NIH, the Breast International Group, the University of Pennsylvania, Duke University, Roche, Pfizer, Takeda, Akouos, Apellis, Teva, Vir, DayOneBio, Alexion, Tracon, Rakuten, AbbVie, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, Advantagene, the American Statistical Association, the Society for Clinical Trials, and the Frontier Science Foundation. RAB reports grants and contracts, paid to his institution, by VenatoRx, Wockhardt, and Merck; payments made to him by Pfizer to moderate meeting sessions; patents with Case Western Reserve University on the development of boronic acid transition state inhibitors for β-lactamases (WO2022187362A1, US9949995B2, and US20170252326A1); and payment for participation on a data safety monitoring board, safety oversight committee support, and Logistics Associate for DMID-CROMS (contractor) with Technical Resources International. MVV reports contracts, consulting fees, and honoraria payments from Pfizer and MSD; consulting fees from West Quimica Colombia; and honoraria from bioMérieux. RP reports grants from BioFire Diagnostics, ContraFect, and TenNor Therapeutics; is a consultant to Curetis, Specific Technologies, Next Gen Diagnostics, PathoQuest, Selux Diagnostics, 1928 Diagnostics, PhAST, Day Zero Diagnostics, Torus Biosystems, Mammoth Biosciences, and Qvella, for which monies are paid to Mayo Clinic; is a consultant to Netflix and CARB-X; has a patent on Bordetella pertussis and parapertussis PCR issued (US8507201B2), a patent on a device and method for sonication (with royalties paid by Samsung to Mayo Clinic; US7076117B2), and a patent on an anti-biofilm substance issued (US8802414B2); receives an editor's stipend from the Infectious Diseases Society of America; and receives honoraria from the National Board of Medical Examiners, UpToDate, and the Infectious Diseases Board Review Course. CAA reports the grants and contracts paid to his institution from NIH and NIAID, MeMed Diagnostics, Entasis Therapeutics, Merck Pharmaceuticals, and Harris County Public Health; payments to him for UpToDate royalties, reimbursement of meeting attendance, and speaking from Infectious Diseases Society of America, American Society for Microbiology, Society of Hospital Epidemiology of America, European Society for Clinical Microbiology and Infectious Diseases, bioMérieux Foundation, Sociedad Argentina de Infectologia, Sociedad Chilena de Infectologia, Sociedad Colombiana de Infectologia, Panamerican Society for Infectious Diseases, Brazilian Society for Infectious Diseases, reviewer participation as part of the NIH grant Review Study Sections, travel expenses from the Infectious Disease Society of America (IDSA) Board of Directors, and for Editor in Chief for Antimicrobial Agents and Chemotherapy; non-paid participation with WHO Antibacterial Pipeline Advisory Group; and participation on the IDSA Board of Directors. HFC reports participation on a Merck data safety monitoring board for molnupiravir paid directly to him, stock ownership in Moderna and Merck, and a position as expert witness for Lilly and Nexus Pharmaceuticals. VGF reports grants to his institution from the NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, ContraFect, Karius, Genentech, Regeneron, Basilea, and Janssen; royalties from UpToDate; personal fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines, MedImmune, Bayer, Basilea, Affinergy, Janssen, ContraFect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, and Roche; editorial stipend from Infectious Diseases of America; pending patent for a host gene expression signature diagnostic for sepsis (US9850539B2); and stock options with Valanbio and ArcBio. YD reports grants from Entasis, Asahi Kasei Pharma, Shionogi, and Kanto Chemical paid to his institution; consulting fees paid directly to him from Meiji Seika Pharma, Shionogi, Gilead, MSD, Chugai, and bioMérieux; and speaker payments from MSD, Shionogi, AstraZeneca, Teijin Healthcare, Gilead, FujiFilm Toyama Chemical, bioMerieux, HU Frontier, and Eiken Chemical paid to him. DvD reports grants and contracts from the NIH and Merck paid to his institution outside of the published work; and consultancy for Astellas, Merck, Allergan, T2Biosystems, Roche, Achaogen, Neumedicine, Shionogi, Pfizer, Entasis, QPex, Wellspring, and Karius. MJS reports contract payments to his institution from Merck, Allergan, BioFire Diagnostics, Affinity Biosensors, and SNIPRBiome; personal consulting fees from Shionogi; and data and safety monitoring board participation for Spero Therapeutics.

Figures

Figure 1:
Figure 1:. Carbapenemase genes identified in carbapenem-resistant Pseudomonas aeruginosa infection and colonisation isolates
Isolates carried the followed carbapenemase genes: blaVIM-2 (n=5), blaKPC-2 (n=2), blaKPC-3 (n=1), blaNDM-1 (n=1), and blaVIM-1 (n=1) in the USA; blaKPC-2 (n=40), blaVIM-2 (n=6), blaGES-5 (n=2), blaDIM (n=1), blaIMP-14 (n=1), blaIMP-45 (n=1), blaIMP-54 (n=1), blaVIM-24 (n=1), and blaAFM-1 plus blaIMP-45 (n=1) in China; blaKPC-2 (n=41), blaVIM-2 (n=22), blaKPC-2 plus blaVIM-2 (n=20), blaIMP-18 + blaVIM-2 (n=3), blaOXA-23 (n=1), and blaVIM-11 (n=1) in south and central America; blaVIM-2 (n=16), blaGES-5 (n=7), blaIMP-15 (n=2), blaIMP-1 (n=1), and blaIMP-13 (n=1) in the Middle East; and blaIMP-1 (n=12), blaNDM-1 (n=12), blaGES-5 (n=3), blaVIM-2 (n=3), blaVIM-6 (n=1), blaIMP-62 plus blaNDM-1 (n=1) in Australia and Singapore. *blaNDM was identified in one (<1%) of 527 isolates and is thus not shown in the figure.
Figure 2:
Figure 2:
Phylogenetic population structures of carbapenem-resistant Pseudomonas aeruginosa isolates
Figure 3:
Figure 3:
30-day overall survival after carbapenem-resistant Pseudomonas aeruginosa infection (A) 30-day overall survival by region. (B) 30-day overall survival by presence of carbapenemase for infections outside the USA.
See this image and copyright information in PMC

Comment in

References

    1. Livermore DM. Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: our worst nightmare? Clin Infect Dis 2002; 34: 634–40. - PubMed
    1. Thaden JT, Park LP, Maskarinec SA, Ruffin F, Fowler VG Jr, van Duin D. Results from a 13-year prospective cohort study show increased mortality associated with bloodstream infections caused by Pseudomonas aeruginosa compared to other bacteria. Antimicrob Agents Chemother 2017; 61: e02761–16. - PMC - PubMed
    1. Sader HS, Castanheira M, Ryan Arends SJ, Goossens H, Flamm RK. Geographical and temporal variation in the frequency and antimicrobial susceptibility of bacteria isolated from patients hospitalized with bacterial pneumonia: results from 20 years of the SENTRY Antimicrobial Surveillance Program (1997–2016). J Antimicrob Chemother 2019; 74: 1595–606. - PubMed
    1. Cai B, Echols R, Magee G, et al. Prevalence of carbapenem-resistant Gram-negative infections in the United States predominated by Acinetobacter baumannii and Pseudomonas aeruginosa. Open Forum Infect Dis 2017; 4: ofx176. - PMC - PubMed
    1. WHO. Media Center. WHO publishes list of bacteria for which new antibiotics are urgently needed. World Health Organization: Feb 27, 2017. https://www.who.int/news/item/27-02-2017-who-publishes-list-of-bacteria-... (accessed June 30, 2022).

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