Clinical outcomes and bacterial characteristics of carbapenem-resistant Klebsiella pneumoniae complex among patients from different global regions (CRACKLE-2): a prospective, multicentre, cohort study.

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a global threat. We therefore analysed the bacterial characteristics of CRKP infections and the clinical outcomes of patients with CRKP infections across different countries.
Methods: In this prospective, multicentre, cohort study (CRACKLE-2), hospitalised patients with cultures positive for CRKP were recruited from 71 hospitals in Argentina, Australia, Chile, China, Colombia, Lebanon, Singapore, and the USA. The first culture positive for CRKP was included for each unique patient. Clinical data on post-hospitalisation death and readmission were collected from health records, and whole genome sequencing was done on all isolates. The primary outcome was a desirability of outcome ranking at 30 days after the index culture, and, along with bacterial characteristics and 30-day all-cause mortality (a key secondary outcome), was compared between patients from China, South America, and the USA. The desirability of outcome ranking was adjusted for location before admission, Charlson comorbidity index, age at culture, Pitt bacteremia score, and anatomical culture source through inverse probability weighting; mortality was adjusted for the same confounders, plus region where relevant, through multivariable logistic regression. This study is registered at ClinicalTrials.gov, NCT03646227, and is complete.
Findings: Between June 13, 2017, and Nov 30, 2018, 991 patients were enrolled, of whom 502 (51%) met the criteria for CRKP infection and 489 (49%) had positive cultures that were considered colonisation. We observed little intra-country genetic variation in CRKP. Infected patients from the USA were more acutely ill than were patients from China or South America (median Pitt bacteremia score 3 [IQR 2-6] vs 2 [0-4] vs 2 [0-4]) and had more comorbidities (median Charlson comorbidity index 3 [IQR 2-5] vs 1 [0-3] vs 1 [0-2]). Adjusted desirability of outcome ranking outcomes were similar in infected patients from China (n=246), South America (n=109), and the USA (n=130); the estimates were 53% (95% CI 42-65) for China versus South America, 50% (41-61) for the USA versus China, and 53% (41-66) for the USA versus South America. In patients with CRKP infections, unadjusted 30-day mortality was lower in China (12%, 95% CI 8-16; 29 of 246) than in the USA (23%, 16-30; 30 of 130) and South America (28%, 20-37; 31 of 109). Adjusted 30-day all-cause mortality was higher in South America than in China (adjusted odds ratio [aOR] 4·82, 95% CI 2·22-10·50) and the USA (aOR 3·34, 1·50-7·47), with the mortality difference between the USA and China no longer being significant (aOR 1·44, 0·70-2·96).
Interpretation: Global CRKP epidemics have important regional differences in patients' baseline characteristics and clinical outcomes, and in bacterial characteristics. Research findings from one region might not be generalisable to other regions.
Funding: The National Institutes of Health.
Competing Interests: Declaration of interests MW, ME, LC, YY, ZL, SS, EC, LL, SSK, HG, KM, LK, SDR, SHM, CM, JR, MVV, CH, RA, KB, BCF, BNK, and RAB report funding support from the ARLG of the National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID; UM1AI104681) during the conduct of this study. BMH reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681), during the conduct of this study, and a grants from the NIH and the NIAID (K01AI148593–01), outside the submitted work. JMM reports funding support from the ALRG of the NIH and the NIAID (UM1AI104681) during the conduct of this study and grants from Pfizer, MSD, and bioMerieux, outside the submitted work. KO reports funding support from the ALRG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; payments for educational events and presentations from Pfizer, MSD, AstraZeneca, and Farma de Colombia; and meeting support from Pfizer, MSD, and Gilead, outside the submitted work. GW reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681), and from Allergan. MJS reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; contracts payments, to his institution, from Merck, Allergan, BioFire Diagnostics, and Affinity Biosensors; personal consulting fees from Achaogen and Shionogi; and board participation for Spero Therapeutics, outside the submitted work. SLV-B reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study and personal fees from MSD and Biotoscana, outside the submitted work. MES reports grants from the NIH during the conduct of the study; speaker fees from Pfizer (Argentina); advisory board participation for Wockhardt; and consultancy for Basilea, outside the submitted work. CL reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study and salary support from the National Institute of General Medical Sciences of the NIH (award number T32GM086330) outside the submitted work. DLP reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; grants and contracts with MERCK, Pfizer, and Shionogi; consulting fees from Merck, Shionogi, and Qpex; payments and financial support from Sumitomo, Merck, Pfizer, bioMerieux, and Shionogi; and board participation for Symvivo, outside the submitted work. 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, Cardinal Health, Microbiotix, Stryker, Atricure, Roivant, Neovasc, Nobel Pharma, Horizon, the International Drug Development Institute, and SVB Leerink; payments from Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, Osaka University, and the National Cerebral and Cardiovascular Center of Japan; 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, 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, Novartis, Amgen, Teva, Vir, Shire, Alexion, Gilead, 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, outside the submitted work. YD reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; grants from Janssen, Pfizer, MSD, Shionogi, Astellas, and Kanto Chemical, outside the submitted work; and personal fees from Janssen, MSD, Entasis, VenatoRx, AstraZeneca, Gilead, FUJIFILM Toyama Chemical, bioMerieux, and Meiji Seika Pharma, outside the submitted work. RP reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; reports grants from Merck, ContraFect, TenNor Therapeutics, and Shionogi; is a consultant to Curetis, Specific Technologies, Next Gen Diagnostics, PathoQuest, Selux Diagnostics, 1928 Diagnostics, PhAST, and Qvella, for which monies are paid to Mayo Clinic; is a consultant to Netflix; has a patent on Bordetella pertussis (parapertussis) PCR issued, a patent on a device and method for sonication (with royalties paid by Samsung to Mayo Clinic), and a patent on an anti-biofilm substance issued; 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, outside the submitted work. HFC reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; personal fees from Merck; and stock ownership from Moderna, outside the submitted work. VGF reports personal Fees from Novartis, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines, Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Basilea, Affinergy, Janssen, xBiotech, Contrafect, Regeneron, Basilea, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, and Aridis; 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; educational fees from Green Cross, Cubist, Cerexa, Durata, Theravance, and Debiopharm; royalties from UpToDate; and stock options in Valanbio. CAA is employed at the University of Texas Health Science Center in Houston, TX, USA; declares money paid to the University of Texas as part of a grant from Merck, MeMed Diagnostics, Entasis Therapeutics, and the ARLG of the NIH and the NIAID (UM1AI104681); reports royalties paid as personal fees from UptoDate (Harrison Principles of Internal Medicine and Mandell Principles and Practice of Infectious Diseases); reports personal fees from the NIH and the NIAID for being a study section member and grant reviewer; reports an editor-in-chief stipend from the American Society for Microbiology for Antimicrobial Agents and Chemotherapy; reports reimbursement for travel to Infectious Disease Week and Infectious Disease programme committee meetings as Infectious Disease chair from the Infectious Disease Society of America; and reports reimbursement for traveling to the American Society for Microbiology Microbe conference from the American Society for Microbiology. DvD reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; is a consultant for Actavis, Tetraphase, Sanofi Pasteur, MedImmune, Astellas, Merck, Allergan, T2Biosystems, Roche, Achaogen, Neumedicine, Shionogi, Pfizer, Entasis, QPex, Wellspring, Karius, and Utility; receives an editor's stipend from the British Society for Antimicrobial Chemotherapy; and reports grants from the NIH, outside the submitted work.
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