Mitigation of Secondary Disease of Allogeneic Mouse Radiation Chimeras by Modification of the Intestinal Microflora

Summary:Invasive fungal infections (IFI) are increasingly diagnosed in patients undergoing allogeneic BMT. We have previously shown that the addition of metronidazole to ciprofloxacin for gastrointestinal bacterial decontamination significantly reduces the incidence of grades II-IV aGVHD by reduction of the anaerobic intestinal bacterial flora. Here, we found that the combined use of ciprofloxacin, metronidazole and fluconazole as antifungal prophylaxis increased intestinal yeast colonization when compared to ciprofloxacin and fluconazole alone (P Ͻ 0.01). Based on the EORTC criteria, a total of 18 out of 134 study patients developed IFI: seven of 68 (10%) patients who received metronidazole compared to 11 of the 66 (17%) patients decontaminated without metronidazole developed IFI (log-rank P = 0.36). Lethal IFI occurred in two of seven patients receiving metronidazole and in four of 11 patients without anaerobic decontamination. In conclusion, bacterial intestinal decontamination using metronidazole as an antibiotic with activity against most anaerobic intestinal bacteria significantly increases the intestinal yeast burden without influencing the incidence of IFI in patients undergoing allogeneic BMT. Bone Marrow Transplantation (2000) 26, 993-997. Keywords: invasive fungal infection; BMT; metronidazole; total gut decontamination; aGVHD Invasive fungal infections (IFI) are increasingly diagnosed in immunocompromised patients after allogeneic stem cell transplantation (SCT). Once a diagnosis of IFI has been made, mortality is high. Prevention of aGVHD is an important factor determining transplant-related morbidity and mortality caused by IFI. 1,2 This is not only due to a decreased administration of immunosuppressive drugs but also to the immunosuppressive effect of aGVHD by itself.Acute GVHD results from an inflammatory process of recipient tissues that is induced by donor T cell clones.

mentioning

confidence: 88%

Fungal colonization and invasive fungal infections following allogeneic BMT using metronidazole, ciprofloxacin and fluconazole or ciprofloxacin and fluconazole as intestinal decontamination

Trenschel

Peceny

Runde

et al. 2000

“…29 GVHD was verified histopathologically in animals that died during the experiment, as well as in animals that were sacrificed at 120 days after BMT. Also, organs from animals of which the SC were used in the proliferation assays (see below) were analysed for GVHD.…”

Section: Diagnosis Of Gvhdmentioning

confidence: 99%

IFN-γ-mediated prevention of graft-versus-host disease: pharmacodynamic studies and influence on proliferative capacity of chimeric spleen cells

Brok

Vossen

Heidt

1998

Summary:Recently we demonstrated that prolonged administration of IFN-␥ prevented the development of GVHD in a MHC-mismatched murine BMT model. Treatment with IFN-␥ allowed the development of mature donorderived allo-tolerant immunocompetent cells in complete chimeric recipients. Here we present data on the pharmacodynamics of this cytokine-mediated protection against GVHD. Treatment with 50 000 U IFN-␥ twice weekly for a period of 5 weeks, starting at the day of BMT, was shown to be the optimal treatment protocol, resulting in complete prevention of GVHD-related mortality. Treatment during 1 week with a three-fold higher weekly dose of IFN-␥ (50 000 U six times) did not result in significantly improved survival. The start of IFN-␥ administration was a critical factor since a delay of 3 days from the time of BMT resulted in substantial GVHD-induced mortality. Furthermore, it was shown that IFN-␥ treatment inhibited the spontaneous and Con-A-induced proliferation of T cells at 7-14 days after BMT, which is the critical period for the initiation of acute GVHD. However, long-term survivors after IFN-␥ treatment showed a recovery of immunity in contrast to long-term survivors of saline-injected animals, as tested by Con-A responsiveness. It seems that injection of high dose IFN-␥ suppresses the response of potentially alloreactive donor T cells during what normally is the initiation phase of the GVH reaction (GVHR), resulting in the abrogation of GVHD.

“…Consequently, strategies of total or selective suppression of the intestinal microbial flora have been pursued routinely in patients undergoing ASCT. 2 Later, 16S-rRNA gene sequencing of stool specimens provided deeper insights into the composition of intestinal microbiomes 3 of ASCTrecipients and, in particular, of those experiencing acute GI GvHD. A marked early loss of intestinal microbiome diversity was observed during the course of ASCT.…”

Section: Introductionmentioning

confidence: 99%

Rifaximin preserves intestinal microbiota balance in patients undergoing allogeneic stem cell transplantation

Weber

Oefner

Dettmer

et al. 2016

Intestinal dysbiosis has been associated with acute gastrointestinal GvHD and poor outcome following allogeneic stem cell transplantation (ASCT). To assess the effect of a switch in 2012 from ciprofloxacin/metronidazole to rifaximin for gut decontamination on intestinal microbiota composition and ASCT outcome, we retrospectively analyzed 394 patients receiving ASCT from September 2008 through June 2015. In 131 and 90 patients, respectively, urinary 3-indoxyl sulfate levels and intestinal enterococcal load were measured before conditioning and weekly within the first 28 days after ASCT. The use of rifaximin correlated with lower enterococcal positivity (6.9 vs 21.9%, P = 0.05) and higher urinary 3-indoxyl sulfate concentrations (10.5 vs 4.6 μmoL/mmoL crea, P o0.001) after ASCT. Patients on rifaximin showed lower 1-year transplant-related mortality (P = 0.04) and higher overall survival (P = 0.008). Treatment of infectious complications with systemic antibiotics did not abrogate the beneficial effects of rifaximin on intestinal microbiota composition in the early course of ASCT and outcome. The data underscore the importance of maintaining a diverse population of symbiotic and mutualistic bacteria in the gut on ASCT outcome.