Minggui Wang1, Michelle Earley2, Liang Chen3, Blake M Hanson4, Yunsong Yu5, Zhengyin Liu6, Soraya Salcedo7, Eric Cober8, Lanjuan Li9, Souha S Kanj10, Hainv Gao11, Jose M Munita12, Karen Ordoñez13, Greg Weston14, Michael J Satlin15, Sandra L Valderrama-Beltrán16, Kalisvar Marimuthu17, Martin E Stryjewski18, Lauren Komarow2, Courtney Luterbach19, Steve H Marshall20, Susan D Rudin20, Claudia Manca21, David L Paterson22, Jinnethe Reyes23, Maria V Villegas23, Scott Evans2, Carol Hill24, Rebekka Arias24, Keri Baum24, Bettina C Fries25, Yohei Doi26, Robin Patel27, Barry N Kreiswirth21, Robert A Bonomo28, Henry F Chambers29, Vance G Fowler24, Cesar A Arias30, David van Duin31. 1. Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China. 2. The Biostatistics Center, The George Washington University, Rockville, MD, USA. 3. Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA; Department of Medical Sciences, Hackensack Meridian School of Medicine, Nutley, NJ, USA. 4. Division of Infectious Diseases and Center for Antimicrobial Resistance and Microbial Genomics, UTHealth, McGovern School of Medicine at Houston, Houston, TX, USA; Center for Infectious Diseases, UTHealth School of Public Health, Houston, TX, USA. 5. Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. 6. Infectious Disease Section, Department of Internal Medicine, Peking Union Medical College Hospital, Beijing, China. 7. Servicio de Infectología, Organizacion Clinica General del Norte, Barranquilla, Colombia; Facultad de Ciencias de la Salud, Universidad Simón Bolívar, Barranquilla, Colombia. 8. Department of Infectious Diseases, Cleveland Clinic, Cleveland, OH, USA. 9. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of Medical School of Zhejiang University, Hangzhou, China. 10. Division of Infectious Disease, American University of Beirut Medical Center, Beirut, Lebanon. 11. Department of Infectious Diseases, Shulan Hangzhou Hospital, Hangzhou, China. 12. Division of Infectious Diseases and Center for Antimicrobial Resistance and Microbial Genomics, UTHealth, McGovern School of Medicine at Houston, Houston, TX, USA; Millennium Initiative for Collaborative Research On Bacterial Resistance, Santiago, Chile; Instituto de Ciencias e Innovación en Medicina, Clínica Alemana, Universidad del Desarrollo, Santiago, Chile. 13. Department of Infectious Diseases, E.S.E Hospital Universitario, San Jorge de Pereira, Pereira, Colombia. 14. Division of Infectious Diseases, Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, New York, NY, USA. 15. Division of Infectious Diseases, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, NY, USA. 16. Infectious Diseases Research Group, School of Medicine, Hospital Universitario San Ignacio, Pontificia Universidad Javeriana, Bogotá, Colombia. 17. Department of Infectious Diseases, Tan Tock Seng Hospital, Singapore; National Centre for Infectious Diseases, Singapore. 18. Department of Medicine and Division of Infectious Diseases, Centro de Educación Médica e Investigaciones Clínicas, Buenos Aires, Argentina. 19. Division of Infectious Diseases, University of North Carolina, Chapel Hill, NC, USA. 20. Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH, USA. 21. Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA. 22. Department of Infectious Diseases, University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia. 23. Grupo de Resistencia Antimicrobiana y Epidemiología Hospitalaria, Universidad El Bosque. Bogotá, Colombia; Molecular Genetics and Antimicrobial Resistance Unit, International Center for Microbial Genomics, Universidad El Bosque. Bogotá, Colombia. 24. Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA. 25. Department of Medicine, Division of Infectious Diseases, Stony Brook University, Stony Brook, NY, USA. 26. Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Microbiology and Infectious Diseases, Fujita Health University School of Medicine, Fujita Health University, Aichi, Japan. 27. Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Division of Infectious Diseases, Department of Medicine, Mayo Clinic, Rochester, MN, USA. 28. Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH, USA; Department of Medicine, Case Western Reserve University School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Departments of Pharmacology, Molecular Biology and Microbiology, Biochemistry, and Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Case Western Reserve University, Cleveland, OH, USA; CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology, Cleveland, OH, USA. 29. Department of Medicine, University of California San Francisco, San Francisco, CA, USA. 30. Division of Infectious Diseases and Center for Antimicrobial Resistance and Microbial Genomics, UTHealth, McGovern School of Medicine at Houston, Houston, TX, USA; Center for Infectious Diseases, UTHealth School of Public Health, Houston, TX, USA; Molecular Genetics and Antimicrobial Resistance Unit, International Center for Microbial Genomics, Universidad El Bosque. Bogotá, Colombia. 31. Division of Infectious Diseases, University of North Carolina, Chapel Hill, NC, USA. Electronic address: david_vanduin@med.unc.edu.
Abstract
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.
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.
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