Reply to Woodworth, et al.

To the Editor—We thank Woodworth and colleagues for their letter [1] about our manuscript [2], and are happy to provide clarification.

Our study described outcomes after fecal microbiota transplantation (FMT) in patients with intestinal colonization with multi-drug resistant organisms (MDROs), who were either at risk of invasive MDRO disease (principally patients with hematological malignancy) or those with prior recurrent invasive MDRO disease (including patients with recurrent urinary tract infections (UTIs)). As described in the study, 41% of patients (n = 7/17) underwent intestinal decolonization (as assessed by culture of rectal swabs/ stool samples) over the course of study follow-up, a figure comparable to a reported spontaneous decolonization rate of 48% [3]. As the correspondents have themselves noted [4], prior FMT studies for attempted decolonization of intestinal MDROs have assessed decolonization endpoints in a relatively consistent fashion, with culture and PCR being the predominant laboratory tools used, and a binary “present/ not present” being the typical reporting outcome. Current best clinical practice in this area employs a similar approach. In this study, we did not assess titers of specific MDROs or quantify levels of antibiotic resistance genes (ARGs) within stool. Interestingly, in the context of FMT for recurrent Clostridioides difficile infection (rCDI), a post-FMT reduction in ARGs was more common in patients whose diarrhea resolved with FMT compared to nonresponders [5]; evidently, similar assessment of this in the context of FMT for MDRO is of importance. It is also feasible, but unknown, as to whether, for instance, an FMT-related log-fold reduction in intestinal MDRO titer may reduce the possibly of translocation and bacteremia, even without true undetectability on a PCR assay.

We agree that many uncertainties remain in relation to optimal FMT administration in non-CDI settings [6]. In our study, all patients received a single FMT only, apart from one patient who received a second FMT. This was a patient with recurrent UTIs; following the initial FMT, the frequency of their UTIs reduced, although they still did develop at least one symptomatic infection (albeit with an organism sensitive to oral antibiotics). As such, the patient underwent a second FMT at 6 months after the initial one; this was successful, with no further UTIs occurring over the course of study follow-up.

Despite the modest decolonization rate that we observed, our major novel finding was of clinical benefits in FMT recipients, including reduced antibiotic duration, bacteremia, and length of inpatient stay compared to a matched group not receiving FMT [2]. Our data built upon those in the FMT/ rCDI literature, whereby reduction in bacteremia and length of stay—together with improved survival—was observed in FMT-treated patients compared to those administered antibiotics alone [7]. We agree that a priority for future studies is evaluation of mechanisms by which FMT exerts these effects, with restoration of altered gut barrier integrity and modulation of systemic immunity being two areas of key interest [8–10].

Notes

Financial support. The Department of Metabolism, Digestion and Reproduction at Imperial College London receives funding from the National Institute of Health Research (NIHR) Biomedical Research Centre (BRC) based at Imperial College London and Imperial College Healthcare NHS Trust. B. H. M. is the recipient of an NIHR Academic Clinical Lectureship. J. A. K. M. is the recipient of a Wellcome Trust Institutional Strategic Support Fund (ISSF) fellowship. F. D. receives funding from the Medical Research Council (MRC) Clinical Academic Research Partnership Scheme.

Potential conflicts of interest. B. H. M. reports personal consultancy fees from Finch Therapeutics Group, outside the submitted work. J. R. M. reports personal fees from EnteroBiotix Ltd, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

References

Author notes