Analysis of Antibiotic Exposure and Development of Acute Graft-vs-Host Disease Following Allogeneic Hematopoietic Cell Transplantation

Abstract

ImportanceCertain antibiotic exposures have been associated with increased rates of acute graft-vs-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (allo-HCT). Since antibiotic exposure can both affect and be affected by infections, analyzing time-dependent exposure in the presence of multiple potential confounders, including prior antibiotic exposures, poses specific analytical challenges, necessitating both a large sample size and unique approaches.ObjectiveTo identify antibiotics and antibiotic exposure timeframes associated with subsequent aGVHD.Design, Setting, and ParticipantsThis cohort study assessed allo-HCT at a single center from 2010 to 2021. Participants included all patients aged at least 18 years who underwent their first T-replete allo-HCT, with at least 6 months of follow-up. Data were analyzed from August 1 to December 15, 2022.ExposuresAntibiotics between 7 days before and 30 days after transplant.Main Outcomes and MeasuresThe primary outcome was grade II to IV aGVHD. The secondary outcome was grade III to IV aGVHD. Data were analyzed using 3 orthogonal methods: conventional Cox proportional hazard regression, marginal structural models, and machine learning.ResultsA total of 2023 patients (median [range] age, 55 [18-78] years; 1153 [57%] male) were eligible. Weeks 1 and 2 after HCT were the highest-risk intervals, with multiple antibiotic exposures associated with higher rates of subsequent aGVHD. In particular, exposure to carbapenems during weeks 1 and 2 after allo-HCT was consistently associated with increased risk of aGVHD (minimum hazard ratio [HR] among models, 2.75; 95% CI, 1.77-4.28), as was week 1 after allo-HCT exposure to combinations of penicillins with a β-lactamase inhibitor (minimum HR among models, 6.55; 95% CI, 2.35-18.20).Conclusions and RelevanceIn this cohort study of allo-HCT recipients, antibiotic choices and schedules in the early course of transplantation were associated with aGVHD rates. These findings should be considered in antibiotic stewardship programs.

Bring it on again: antimicrobial stewardship in transplant infectious diseases: updates and new challenges

“… 5 , 6 Rashidi et al modeled the association using data from a cohort of 2023 allogeneic SCT patients. 7 The risk of aGVHD following exposure to carbapenems <2 weeks post-allogeneic SCT was high (hazard ratio [HR] 2.75; 95% CI, 1.77–4.28), as was exposure to beta-lactamase inhibitor-penicillin combinations <1 week after transplant (HR, 6.55; 95%CI, 2.35–18.20), suggesting limiting unnecessary antibiotic exposure may prevent aGVHD. Recent surveys described variation in practice regarding de-escalating or discontinuing antibiotics in febrile neutropenia indicating the need for further research.…”

Determining the Optimal Use of Antibiotics in Hematopoietic Stem Cell Transplant Recipients

“…The results from the study by Rashidi et al improve our understanding of the deleterious association of gut microbiota disruption with the development of aGVHD and contribute to risk vs benefit assessments in antibiotic prescribing. These findings pave the way for designing and evaluating future antimicrobial stewardship interventions aimed at tailoring antibiotic regimens to minimize potential harms and maximize likelihood of benefits in patients undergoing allo-HCT. Prescribers and antimicrobial stewardship clinicians share a common goal in allo-HCT: to ensure the patient undergoes successful transplantation with minimal risk of infections or aGVHD.…”

“…Of note, carbapenems exposure weeks 1 and 2 after allo-HCT was associated with a minimum hazard ratio (HR) of 2.75 (95% CI, 1.77-4.28), whereas week 1 after allo-HCT exposure to penicillins with β-lactamase inhibitors was associated with a minimum HR of 6.55 (95% CI, 2.35-18.20). Across all 3 methods, the data from the study by Rashidi et al also suggest that pre–allo-HCT exposure to penicillins with β-lactamase inhibitors was associated with a lower risk of aGVHD.…”

“…This study by Rashidi and colleagues sought to characterize the association of antibiotic exposure and timing of the exposure relative to allogeneic hematopoietic stem cell transplantation (allo-HCT) with the hazard of developing acute graft-vs-host disease (aGVHD), which is one of the most common complications of allo-HCT. Rashidi et al applied 3 orthogonal methods (conventional Cox proportional-hazards regression, marginal structural models, and machine learning) to analyze data collected from 2023 patients who underwent their first T-replete allo-HCT at a single center between 2010 and 2021. Each of the included analytical methods has its own strengths and weaknesses, but together they provided a comprehensive perspective.…”

“…Each of the included analytical methods has its own strengths and weaknesses, but together they provided a comprehensive perspective. Rashidi et al reported that weeks 1 and 2 after allo-HCT were the highest-risk intervals, with several antibiotic exposures associated with higher risk of subsequent aGVHD. Of note, carbapenems exposure weeks 1 and 2 after allo-HCT was associated with a minimum hazard ratio (HR) of 2.75 (95% CI, 1.77-4.28), whereas week 1 after allo-HCT exposure to penicillins with β-lactamase inhibitors was associated with a minimum HR of 6.55 (95% CI, 2.35-18.20).…”