The impact of antibiotics on acute graft-versus-host disease development

The intestinal microbiota plays a major role in inflammation and augmenting cytokine response in acute graft-versus-host disease (aGvHD) development after allogenic hematopoietic stem cell transplantation (allo-HSCT). Katsuyuki Nishi and colleagues from Kyoto University, Kyoto, Japan, investigated certain types of antibiotics whether these drugs can influence the incidence of aGvHD. The results were published ahead of print in the Biology of Blood and Marrow Transplantation on 3 July 2018.

In this retrospective study, 275 patients were included who underwent allo-HSCT between January 2005 and June 2015 at Kyoto University Hospital. The study group investigated the most frequently used antibiotics administered between Days -14 and +14 before or after HSCT. The primary endpoint was cumulative incidence of grades II to IV aGvHD.

Antibiotics:

• Fourth-generation cephalosporins: 160 patients (66%)
• Piperacillin-tazobactam: 115 patients (47%)
• Quinolone: 42 patients (17%)

Key findings:

• The cumulative incidence (CI) of grade II to IV: 37.8% (95% CI, 31.6–44.2 %)
  • The CI of grade II to IV aGvHD in patients receiving fourth-generation cephalosporins: 44.3%
  • The CI of grade II to IV aGvHD in patients not receiving fourth-generation cephalosporins: 26.0%
  • The CI of grade II to IV aGvHD in patients receiving piperacillin-tazobactam: 41.4%
  • The CI of grade II to IV aGvHD in patients not receiving piperacillin-tazobactam: 34.9%
• The CI of grade III to IV aGvHD: 7.6% (95% CI, 4.6–11.5%)
  • The CI of grade III to IV aGvHD in patients receiving fourth-generation cephalosporins: 10.5%
  • The CI of grade III to IV aGvHD in patients not receiving fourth-generation cephalosporins: 1.4%
• Fourth-generation cephalosporins showed significant impact on the occurrence of grades II to IV aGvHD: HR = 1.98 (95% CI, 1.19–3.29), P = 0.0087
• Piperacillin-tazobactam and carbapenems did not influence the incidence of grade II to IV aGvHD: HR = 0.77 (95% CI, 0.51–1.18), P = 0.23; HR = 1.36 (95% CI, 0.89–2.06), P = 0.15
• Fourth-generation cephalosporins showed significant impact on grade III to IV aGvHD occurrence: HR = 8.03 (95% CI, 1.07–60.51), P = 0.043
• No other significant association was observed between the administration of other antibiotics and aGvHD

Prof Nishi and colleagues concluded by stating that “fourth-generation cephalosporins had a strong impact on the development of acute graft-versus-host disease regardless of the treatment start date. The influence of antibiotics on aGvHD may vary within a study population.”

Limitations of the study included the contradiction of the impact of fourth-generation cephalosporins on aGvHD whether it was mediated through the gut microbiome, furthermore, levofloxacin prophylaxis in patients undergoing allo-HSCT had not been routinely prescribed for this group of patients, and lastly, the small sample size and the heterogeneous patient population with varying transplant background. The authors further added that “these findings should be tested in a prospective study in the future.”