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FMT in carriers of MDRB undergoing allo-HSCT
their profound immune depression.3 In cases of bloodstream infections from MDRB, outcomes are even poorer, leading to increased mortality.4 For example, an Italian study showed that carbapenemase producing (CP-) bacteria, including Pseudomonas aeruginosa, were inde- pendent predictors of death in patients diagnosed with acute leukemia, while this was not observed in cases of extended-spectrum β-lactamase (ESBL) Enterobacteriaceae.5
In order to prevent bacteria spreading to other patients, preventive measures are required, including isolating patients, limitating transfer to other healthcare centers, and management by dedicated staff. These measures result in an increase in healthcare costs, which cannot always be met.6 According to French recommendations, patients colonized with MDRB may be denied access to healthcare facilities if dedicated staff are not available.7
New classes of antibiotics are under study to treat infec- tions related to MDRB, and research is ongoing to find effective decolonization strategies.8 The use of oral gen- tamicin was initially proposed in some MDR-gram nega- tive strains but failure is common, and management of gentamicin-resistant strains may also be an issue.9,10
Fecal microbiota transplantation (FMT) is a procedure that has been proved to be effective and safe in the treat- ment of recurrent Clostridium difficile infection (CDI), and it is now a recommended therapy in this setting.11 Use of FMT in patients carrying MDRB is still at an investigation- al stage, but there are reports and case series showing its efficacy in this setting.12,13 Many concerns were initially raised about the feasibility of FMT in immunocompro- mised patients, such as those affected by hematologic malignancies, because of the theoretical potential for local and bloodstream infections. However, recent case reports revealed the efficacy and safety in this particular popula- tion.14-16 Recently, Bilinski et al. reported the results of a prospective study evaluating FMT in 20 patients with MDRB gut colonization and contemporarily affected by hematologic malignancies. Overall 25 FMT were per- formed and 15 of 20 patients experienced complete MDRB decolonization,17 including some of them with graft-versus-host disease (GvHD) after allo-HSCT.
In this retrospective study, we report our experience with FMT in patients diagnosed with hematologic malig- nancies and undergoing FMT either before or after allo- HSCT.
Methods
In this single-center study, we retrospectively analyzed data on all consecutive adult patients diagnosed with hematologic malig- nancies who underwent FMT before or after allo-HSCT due to MDRB colonization. In our center, microbiological screening is performed weekly in all inpatients, with consequent preventive measures in positive patients in order to limit MDRB spread, according to national guidelines.7 (See Online Supplementary Appendix for details).
This study was approved by the institutional ethics commit- tees. The treatment plan was discussed in advance by a multidis- ciplinary team (hematologist, gastroenterologist, pharmacist) who approved the procedure. The decision was made on a patient-to- patient basis. All patients signed informed consent explaining the theoretical risks of the procedure because of the current investiga- tional use of FMT in the field of MDRB and in patients with hema- tologic malignancies.
Eligibility criteria included: asymptomatic carriers or systemic infections from vancomycin-resistant enterococci (VRE), car- bapenemase-producing Enterobacteriaceae (CPE) or CP-Pseudomonas aeruginosa. The rationale for FMT and MDRB decolonization were mainly to limit infectious complications related to these bacteria and to facilitate patient transfer to other departments, such as intensive care units or rehabilitation centers.
Contemporary colonization from ESBL-producing bacteria was also registered in patients undergoing FMT. We, therefore, subse- quently evaluated whether FMT also allowed decolonization from these MDRB.
For the purpose of this retrospective analysis, we also classified MDRB as multi-drug (MDR), extensive-drug (XDR) and pan-drug- resistant (PDR), according to the definition proposed by Magiorakos et al.;18 MDR was defined as the presence of acquired non-susceptibility to at least one agent in three or more antimicro- bial categories, XDR as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one or two categories), and PDR as non-susceptibility to all agents in all antimicrobial categories. Details on donor selection, microbiological testing, fecal material preparation and delivery are available in the Online Supplementary Appendix.
Decolonization from VRE, CPE or CP-Pseudomonas aeruginosa after negative results on a minimum of three consecutive microbi- ological cultures (performed weekly) was defined as “major decol- onization”, while “persistent decolonization” was defined as the persistence of negative rectal swab until last follow up after a first or second FMT, whenever this was feasible. In patients concomi- tantly colonized by ESBL-producing Enterobacteriaceae, “concomi- tant decolonization” was defined as negative results on at least three consecutive rectal swabs after FMT. The safety of the proce- dure was also registered. For all patients, data on significant infec- tions (defined as bacteriemia or sepsis occurring during the first 90 days after FMT) were also collected. Although febrile neutropenia or fever of unknown origin was not considered a significant infec- tious episode, such events were also recorded. A second attempt could be proposed in those patients presenting either a relapse of MDRB colonization or experiencing FMT failure.
Results
During the period between 2014 and 2017, ten patients underwent FMT: seven due to gut colonization without systemic infection by either CPE (Escherichia coli, n=1; Citrobacter freundii, n=2; Klebsiella pneumoniae, n=1), or CP- Pseudomonas aeruginosa (n=1) or VRE (n=2), and three after having experienced systemic infections from CP- Pseudomonas aeruginosa. Median age at FMT was 48 (range, 16-64) years. Four patients underwent FMT as a decolo- nization strategy before allo-HSCT, with a median inter- val from FMT to transplant of 28 (range, 9-46) days. Of note, one patient was contemporarily colonized by three different CPE. Two patients started conditioning regimen three days after FMT and the other two after a month. Six patients underwent FMT after allo-HSCT, with a median time from allo-HSCT to FMT of 163 (range, 98-344) days. Of note, all patients undergoing FMT after allo-HSCT were still on immunosuppressive therapy at the time of FMT, with only one of six presenting active grade IV steroid-dependent gut GvHD. Overall, six patients were also colonized by ESBL-producing Enterobacteriaceae. All ESBL-producing bacteria were classified as MDR.
A frozen product was used in eight of ten patients and
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