Multidrug resistant (MDR) bacterial colonization in the gut is frequently induced by excessive use of antibiotics.1 Fecal microbiota transplantation (FMT) has been shown to be quite successful in treating refractory and recurrent Clostridium difficile infection.2 Thus, current research is focusing on how FMT may also help in decolonizing MDR organisms (MDRO) and in preventing recurrent MDR infections.3 Decolonization of MDRO via FMT may be particularly useful in patients with hematologic malignancies, such as those undergoing hematopoietic stem cell transplantation (HSCT),4 as use of chemotherapeutic agents and frequent administration of antibiotics can favor the selection of resistant pathogens.65
In spite of the increasing evidence that the feasibility and safety of FMT in immunocompromised cohorts is comparable to that of immunocompetent patients, administering FMT in the setting of hematologic malignancy remains a cause for concern due to perceived risks of translocation and sepsis.87 Given the growing body of literature associating a dysbiotic microbiome with adverse HSCT outcomes and treatment-related toxicities, including infection, delivering a diverse microbiome via FMT to immunocompromised patients may provide a variety of benefits, such as promoting colonization resistance and reducing the risk of bacterial translocation.9 Thus, attempts to better characterize the safety and efficacy of FMT in these patients are merited.
In this issue of the Journal, Battipaglia et al.10 describe a retrospective case series of 10 patients with hematologic malignancies undergoing FMT for MDRO colonization before or after allogeneic HSCT. In this study, the authors show both the safety and efficacy of using FMT for decolonization of carbapenem-resistant Enterobactericeae (CRE), carbapenem-resistant Pseudomonas (CRP), and vancomycin-resistant Enterococcus (VRE). Notably, the study reports FMT both pre- and post transplant. The majority of patients who received FMT prior to transplant did not have recurrent MDRO even after HSCT, indicating the prophylactic use of FMT. Interestingly, the procedure remained effective for long- term MDRO decolonization in the majority of patients despite the use of broad-spectrum antibiotics in some of the patients after FMT. This implies that FMT can potentially achieve full decolonization of MDRO rather than merely reducing the levels of MDRO below the limit of detection.
While FMT was shown to be successful in decolonizing the MDRO studied, the FMT did not always prevent additional post-transplant infections from other bacteria susceptible to antibiotics. Interestingly, only 50% of patients concomitantly colonized with extended spectrum β-lactamase (ESBL)-producing Enterobacteriaceae obtained decolonization. This is reminiscent of a case report by Stalenhoef et al. where FMT successfully eradicated a Pseudomonas aeruginosa urinary tract infection, while stool cultures remained positive for extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae three months after FMT.11 Thus, the higher frequency of failure of FMT to eradicate the ESBL-producing Enterobacteriaceae in these two studies may suggest potential limitations to this therapy.
Although the specific mechanisms underlying the success of FMT for MDRO colonization remain unclear, Figure 1 depicts an overview of the general concepts regarding the use of FMT for MDRO in patients with hematologic malignancies. Given that this study looked specifically at CRE, CRP, and VRE, it remains unclear if other MDRO may be equally responsive to FMT. Furthermore, given the seemingly discrepant results for CRE, CRP, and VRE compared to ESBL-producing organisms, one might consider that distinct mechanisms of action underlie how FMT mediates response for different MDRO.
Due to the retrospective nature of the study, in contrast to a controlled study, it is unclear how physicians decided to treat each patient with FMT case by case. Moreover, there was a large variation between cases in the time of FMT relative to HSCT and the MDRO colonization/infection in both pre- and post-HSCT groups. Thus, it remains to be determined what the ideal timeframe for FMT is in both scenarios. The use of related donors was preferred as it was perceived that common environmental exposures would reduce additional risk of transferring infectious agents between the donor and recipient. Intriguingly, neither of the two cases using an unrelated donor was successfully decolonized; given so few numbers, we cannot determine if this result is significant. Consequently, the best choice of donor remains to be explored. If it were to be found that related donors are in fact preferable to universal donors, appropriate screening and regulations will be an important consideration in the future.
One critical piece missing from this study is the understanding of the microbiome in this process. Although theoretically FMT decolonization works via restoration of microbial diversity leading to colonization resistance and displacement of the MDRO,1312 experimentally showing what micro-organisms were important for decolonization in each case, which organisms presented robust and durable colonization, as well as if resistance genes were completely displaced after FMT would strengthen these types of studies and vastly improve the understanding of the mechanism by which FMT decolonizes MDRO. This represents an important future opportunity for investigators.
With MDR infections set to be the world’s leading cause of morbidity and mortality by the year 2050, set to surpass even cancer, and with few new antimicrobials in the pipeline, the need for novel and different approaches to treat MDR infections is critical.14 Moreover, we need to improve our clinical understanding of the antibiotic resistome, particularly in immunocompromised patients who experience repeated exposures to antimicrobials. Although no large randomized controlled trials have been performed to study the efficacy and safety of FMT for MDR organisms in the immunocompromised patient, this study and others have provided some promising evidence, and suggest that a non-antibiotic therapy for MDR colonization and infections may become common practice in the future for patients with hematologic malignancies.1715 The use of FMT as a decolonization agent both as a prophylactic and treatment measure may prove effective in preventing MDR outbreaks and transmission, prolonged in-hospital care, recurrent infection, and improve the overall outcomes of HSCT patients. Given the numerous potential benefits, and demonstrated safety and efficacy, the fear and negative perception of FMT in the cancer setting is unjustified.15
Acknowledgments
JGP is supported by the NIH (K01 AI143881). RRJ is supported by the NIH (R01 HL124112) and the Cancer Prevention and Research Institute of Texas (RR160089).
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