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

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.