Broad-Spectrum Antibiotics and Risk of Graft-versus-Host Disease in Pediatric Patients Undergoing Transplantation for Acute Leukemia: Association of Carbapenem Use with the Risk of Acute Graft-versus-Host Disease

Caitlin W. Elgarten, Yimei Li, Kelly D. Getz, Michael Hemmer, Yuan Shung V. Huang, Matthew Hall, Tao Wang, Carrie L. Kitko, Madan H. Jagasia, Taiga Nishihori, Hemant S. Murthy, Hasan Hashem, Mitchell S. Cairo, Akshay Sharma, Shahrukh K. Hashmi, Medhat Askar, Amer Beitinjaneh, Matthew S. Kelly, Jeffery J. Auletta, Sherif M. BadawyMelissa Mavers, Richard Aplenc, Margaret L. MacMillan, Stephen R. Spellman, Mukta Arora, Brian T. Fisher

Research output: Contribution to journalArticlepeer-review

Abstract

Variation in the gastrointestinal (GI) microbiota after hematopoietic cell transplantation (HCT) has been associated with acute graft-versus-host disease (aGVHD). Because antibiotics induce dysbiosis, we examined the association of broad-spectrum antibiotics with subsequent aGVHD risk in pediatric patients undergoing HCT for acute leukemia. We performed a retrospective analysis in a dataset merged from 2 sources: (1) the Center for International Blood and Marrow Transplant Research, an observational transplantation registry, and (2) the Pediatric Health Information Services, an administrative database from freestanding children's hospitals. We captured exposure to 3 classes of antibiotics used for empiric treatment of febrile neutropenia: (1) broad-spectrum cephalosporins, (2) antipseudomonal penicillins, and (3) carbapenems. The primary outcome was grade II-IV aGVHD; secondary outcomes were grade III-IV aGVHD and lower GI GVHD. The adjusted logistic regression model (full cohort) and time-to-event analysis (subcohort) included transplantation characteristics, GVHD risk factors, and adjunctive antibiotic exposures as covariates. The full cohort included 2550 patients at 36 centers; the subcohort included 1174 patients. In adjusted models, carbapenems were associated with an increased risk of grade II-IV aGVHD in the full cohort (adjusted odds ratio [aOR], 1.24; 95% confidence interval [CI], 1.02 to 1.51) and subcohort (sub hazard ratio [HR], 1.31; 95% CI, 0.99 to 1.72), as well as with an increased risk of grade III-IV aGVHD (subHR, 1.77; 95% CI, 1.25 to 2.52). Early carbapenem exposure (before day 0) especially impacted aGVHD risk. For antipseudomonal penicillins, the associations with aGVHD were in the direction of increased risk but were not statistically significant. There was no identified association between broad-spectrum cephalosporins and aGVHD. Carbapenems, more than other broad-spectrum antibiotics, should be used judiciously in pediatric HCT recipients to minimize aGVHD risk. Further research is needed to clarify the mechanism underlying this association.

Original languageEnglish (US)
Pages (from-to)177.e1-177.e8
JournalTransplantation and Cellular Therapy
Volume27
Issue number2
DOIs
StatePublished - Feb 2021

Bibliographical note

Funding Information:
Financial disclosure: The CIBMTR is supported primarily by Public Health Service U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID); U24HL138660 from the NHLBI and NCI; OT3HL147741, R21HL140314, and U01HL128568 from the NHLBI; HHSH250201700006C, SC1MC31881-01-00, and HHSH250201700007C from the Health Resources and Services Administration (HRSA); and N00014-18-1-2850, N00014-18-1-2888, and N00014-20-1-2705 from the Office of Naval Research. Additional federal support is provided by P01CA111412, R01CA152108, R01CA215134, R01CA218285, R01CA231141, R01AI128775, R01HL129472, R01HL130388, R01HL131731, U01AI069197, U01AI126612, and BARDA. Support is also provided by Be the Match Foundation, Boston Children's Hospital, Dana Farber, Japan Hematopoietic Cell Transplantation Data Center, St. Baldrick's Foundation, the National Marrow Donor Program, the Medical College of Wisconsin and from the following commercial entities: AbbVie, Actinium Pharmaceuticals, Adaptive Biotechnologies; Adienne, Allovir, Amgen, Angiocrine Bioscience; Anthem, Astellas Pharma US, AstraZeneca, Atara Biotherapeutics, bluebird bio, Bristol Myers Squibb, Celgene Corp.; CSL Behring, CytoSen Therapeutics, Daiichi Sankyo, Gamida-Cell, Genzyme, HistoGenetics, Incyte, Janssen Biotech, Janssen/Johnson & Johnson; Jazz Pharmaceuticals, Kiadis Pharma; Kite Pharma, Kyowa Kirin, Legend Biotech, Magenta Therapeutics, Mallinckrodt, Medac, Merck & Company, Merck Sharp & Dohme, Millennium, the Takeda Oncology Co, Miltenyi Biotec, Novartis Oncology; Novartis Pharmaceuticals, Omeros, Oncoimmune, OptumHealth, Orca Biosystems, Pfizer, Pharmacyclics, REGiMMUNE, Sanofi Genzyme, Shire, Sobi, Takeda Pharma, Terumo BCT, Viracor Eurofins, and Xenikos. The views expressed in this article do not reflect the official policy or position of the NIH, Department of the Navy, Department of Defense, HRSA, or any other agency of the US Government. This research was supported by a training grant from the NIH (Clinical Pharmacoepidemiology Training Grant T32-GM075766, to C.W.E.) and Alex's Lemonade Stand Foundation (C.W.E.). The CIBMTR supports accessibility of research in accord with the NIH's Data Sharing Policy and the NCI's Cancer Moonshot Public Access and Data Sharing Policy. The CIBMTR only releases deidentified datasets that comply with all relevant global regulations regarding privacy and confidentiality. Conflict of interest statement: B.T.F. reports grants from Pfizer and Merck and other remuneration from Astellas, outside the submitted work. M. Askar reports other remuneration from CareDx and Immucor, outside the submitted work. M. Arora reports grants from Syndax, grants from Pharmacyclics, grants from Kadmon, and personal fees from Fate Therapeutics, outside the submitted work. K.D.G. reports a grant from NIH/NHLBI (5K01HL143153) during the conduct of the study. T.N. reports other from Novartis, other from Karyopharm, outside the submitted work. A.S. reports salary support from Vertex Pharmaceuticals/CRISPR Therapeutics paid to the institution, nonfinancial support from Novartis, nonfinancial support from Magenta Therapeutics, outside the submitted work. He is the principal investigator of a clinical trial for gene therapy of sickle cell disease sponsored by Vertex Pharmaceuticals/CRISPR Therapeutics. The sponsor provides funding for the clinical trial which includes salary support paid to his institution. This is not related in any way to this work product. He also has research collaboration with Novartis, Magenta Therapeutics and Bluebird Bio for which he is not financially compensated in any way. T.W. reports grants from NIH/NCI (5U24 CA76518-22) during the conduct of the study. Financial disclosure: See Acknowledgments on page 177.e7.

Funding Information:
Financial disclosure: The CIBMTR is supported primarily by Public Health Service U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID); U24HL138660 from the NHLBI and NCI; OT3HL147741, R21HL140314, and U01HL128568 from the NHLBI; HHSH250201700006C, SC1MC31881-01-00, and HHSH250201700007C from the Health Resources and Services Administration (HRSA); and N00014-18-1-2850, N00014-18-1-2888, and N00014-20-1-2705 from the Office of Naval Research. Additional federal support is provided by P01CA111412, R01CA152108, R01CA215134, R01CA218285, R01CA231141, R01AI128775, R01HL129472, R01HL130388, R01HL131731, U01AI069197, U01AI126612, and BARDA. Support is also provided by Be the Match Foundation, Boston Children's Hospital, Dana Farber, Japan Hematopoietic Cell Transplantation Data Center, St. Baldrick's Foundation, the National Marrow Donor Program, the Medical College of Wisconsin and from the following commercial entities: AbbVie, Actinium Pharmaceuticals, Adaptive Biotechnologies; Adienne, Allovir, Amgen, Angiocrine Bioscience; Anthem, Astellas Pharma US, AstraZeneca, Atara Biotherapeutics, bluebird bio, Bristol Myers Squibb, Celgene Corp.; CSL Behring, CytoSen Therapeutics, Daiichi Sankyo, Gamida-Cell, Genzyme, HistoGenetics, Incyte, Janssen Biotech, Janssen/Johnson & Johnson; Jazz Pharmaceuticals, Kiadis Pharma; Kite Pharma, Kyowa Kirin, Legend Biotech, Magenta Therapeutics, Mallinckrodt, Medac, Merck & Company, Merck Sharp & Dohme, Millennium, the Takeda Oncology Co, Miltenyi Biotec, Novartis Oncology; Novartis Pharmaceuticals, Omeros, Oncoimmune, OptumHealth, Orca Biosystems, Pfizer, Pharmacyclics, REGiMMUNE, Sanofi Genzyme, Shire, Sobi, Takeda Pharma, Terumo BCT, Viracor Eurofins, and Xenikos. The views expressed in this article do not reflect the official policy or position of the NIH, Department of the Navy, Department of Defense, HRSA, or any other agency of the US Government. This research was supported by a training grant from the NIH (Clinical Pharmacoepidemiology Training Grant T32-GM075766, to C.W.E.) and Alex's Lemonade Stand Foundation (C.W.E.). The CIBMTR supports accessibility of research in accord with the NIH's Data Sharing Policy and the NCI's Cancer Moonshot Public Access and Data Sharing Policy. The CIBMTR only releases deidentified datasets that comply with all relevant global regulations regarding privacy and confidentiality.

Publisher Copyright:
© 2020 The American Society for Transplantation and Cellular Therapy

Keywords

  • Acute graft-versus-host disease
  • Antibiotics
  • Carbapenems
  • Pediatrics

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