The Impact of the Use and Type of Antibiotics on Acute-Versus-Host Disease

The intestinal microbiota plays an important role in the pathogenesis of acute graft-versus-host disease (aGVHD). During the course of hematopoietic stem cell transplantation (HSCT), the intestinal microbiota is influenced by the use of broad-spectrum antibiotics. However, the impact of the use and type of antibiotics on the microbiota composition and, subsequently, the onset of aGVHD are still poorly understood. We hypothesized that the use and type of antibiotics had the impact on the occurrence of aGVHD, and planed this retrospective analysis.We assessed 275 patients who underwent their 1^st allogeneic HSCT from January 2005 to June 2015 at Kyoto University Hospital. We monitored the six most frequently administered antibiotics (4^th cephalosporin, glycopeptide, piperacillin-tazobactam, carbapenem, aminoglycoside, quinolone) given between day-14 and +14 relative to allo-HSCT, and it's duration. The primary endpoint was cumulative incidence of grade II to IV acute GVHD that occurred after day14 from HSCT. We applied Fine and Gray's test for proportional hazards model for the sub-distribution of a competing risk.The cumulative incidence of grade II to IV aGVHD in study population was 37.8% (95% CI, 31.6 - 44.2%). The administration of 4^th cephalosporin had a significant impact on the occurrence of grade II to IV aGVHD (HR 1.98, 95% CI, 1.19-3.29, P=0.0087) and grade III to IV aGVHD (HR 8.03, 95% CI, 1.07-60.51, P=0.043). On the other hand, there was no significant association between administration of other antibiotics and acute GVHD. The administration of 4^th cephalosporin consistently had the impact on the occurrence of aGVHD regardless of its start date and duration. The administration of 4^th cephalosporin was marginally associated with the risk of NRM (HR 1.94, 95% CI, 0.93-4.03, P=0.076).In conclusion, we demonstrated that the administration of 4^th cephalosporin had a strong impact on the development of aGVHD. When we use 4^th cephalosporin around HSCT, we need to consider these impact on aGVHD.