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FMT in carriers of MDRB undergoing allo-HSCT
Moreover, it is worth underlining the significant benefit of major decolonization in the patient who had experi- enced multiple infectious episodes due to a CP-Pseudomonas aeruginosa, limiting breakthrough infec- tions.
Our results also highlight that, despite the fact that administration of large spectrum antibiotics may hypo- thetically represent a risk for decolonization failure, the procedure remained effective in the majority of patients, without recurrence of MDRB in the majority of them despite use of broad spectrum antibiotics early after FMT. Interestingly, in one patient, VRE was detectable again at the time of disease relapse, despite no large-spectrum antibiotics having been used just before. One can specu- late that disease relapse may probably have been associ- ated to dysbiosis favoring selection of VRE, but conclu- sions cannot be drawn on just one case.
Despite the initial aforementioned concerns in immuno- compromised patients, results of FMT in this setting are promising in terms of both efficacy and safety.4,15,16 A recent prospective study showed that FMT allowed total eradication of MDRB in 60% of cases, without any signif- icant adverse event after the procedure.17 This is the only prospective study published to date using FMT in 20 patients with blood disorders and colonized with MDRB. Differently from our series, in this study, all types of MDRB were included and only a few patients underwent allo-HSCT.
In our Center, we only chose patients colonized with highly resistant bacteria, and in particular those classified as eXDR according to French guidelines or those known to cause a significant higher risk of systemic infection with very poor prognosis (i.e. CP-Pseudomonas aeruginosa).
So far, no specific guidelines have been defined as to the ideal timing, the best preparation of stools for FMT, and the best method of administration. In our experience, FMT was successfully undertaken either before or after allo-HSCT and, interestingly, it was also successful in two patients starting conditioning regimen for allo-HSCT three days after FMT.
As for stool preparation, frozen material was preferred in our center for logistical reasons, although in two cases fresh stools were used; this did not modify the results of FMT. It has recently been reported in a meta-analysis of patients receiving FMT for CDI, that the success rate of FMT was similar when using frozen or fresh stools.26 In contrast to most of the reported series of FMT for MDRB decolonization, we preferred enema as a method of administration as this is associated with lower risk of inhalation as compared to nasogastric administration.
The mechanisms underlying the efficacy of FMT for MDRB decolonization are still not clear. Recent studies showed that recipient stool assumed donor-like taxonom- ic and functional composition immediately following FMT.27 Therefore, we hypothesize that FMT for MDRB decolonization works through the restoration of a more physiological microbiome, thus increasing the ecological pressure on MDRB. However, given the absence of trans- lational studies on antibiotic resistance genes and micro- biota composition on the patient’s stool after FMT, we cannot exclude the possibility that FMT works through lowering MDRB below the threshold of detection rather than through true elimination.
In our series, after FMT, almost all patients had no major
infectious complications during the first three months after FMT. Interestingly, in those patients subsequently undergoing allo-HSCT, no severe infectious bacterial com- plications occurred during the early transplant phase.
Regarding the impact of FMT on GvHD, only one of our patients had a grade IV acute gut GvHD concomitant to a carbapenemase-producing Pseudomonas aeruginosa at the time of FMT. In this specific case, the procedure was not efficacious either for MDRB or for GvHD. However, it is worth underlining that FMT was performed at a very late stage for compassionate use, and this may also explain the failure of the procedure. Importantly, among the nine remaining patients, only one experienced grade III acute gut GvHD after FMT (with a possible differential diagno- sis with CMV colitis). A role for FMT in causing GvHD in this patient cannot formally be excluded and this point may be addressed in a prospective clinical trial.
Early studies in mice and humans suggested a link between gut microbiota and propensity to GvHD, with mice treated with gut-decontaminating antibiotics devel- oping GvHD less often.28,29 Recent results of a pilot study also highlight the possible advantage of microbiota mod- ulation with FMT in patients affected by steroid-refracto- ry or steroid-dependent GvHD.30
With regards to donor choice, when available, people living in the same household of the patient were preferred as they widely share the same pathogens and environ- mental exposure, thus reducing the risk of transferring additional infectious agents from the donor to the recipi- ent.
In line with previous reports, we consider that targeting gut microbiota in patients with impaired immune recon- stitution in an attempt to reinstate a more equilibrated flora may favor stable eradication of the carrier status and prevent subsequent life-threatening infections.
This study has some limitations, including its retrospec- tive nature, low number of patients, heterogeneous inclu- sion criteria, and differences in FMT procedure, making it difficult for any definitive conclusions to be drawn. However, we consider that our results support the use of FMT as a promising strategy to manage the considerable potential risks associated with the MDRB carrier status in immunocompromised patients with intestinal dysbiosis and in those patients having experienced single or multi- ple systemic infections. The majority of patients experi- enced no breakthrough infections after decolonization or MDRB recurrence despite the use of broad spectrum antibiotics. Furthermore, our results provide fresh evi- dence of the safety of the procedure in this population, despite previous concerns in immunocompromised patients. These preliminary results underline the need for further prospective studies on the safety and efficacy of FMT.
Acknowledgments
The authors thank Prof. Junia V. Melo (University of Adelaide, Australia, and Imperial College, London) for medical editing of this manuscript.
Funding
This study was supported by educational grants from the “Association for Training, Education and Research in Hematology, Immunology and Transplantation” (ATERHIT, Nantes, France).
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