Fecal Microbiota Transplant Mitigates Adverse Outcomes Seen in Patients Colonized With Multidrug-Resistant Organisms Undergoing Allogeneic Hematopoietic Cell Transplantation

Andrew J Innes, Benjamin H Mullish, Rohma Ghani, Richard M Szydlo, Jane F Apperley, Eduardo Olavarria, Renuka Palanicawandar, Edward J Kanfer, Dragana Milojkovic, Julie A K McDonald, Eimear T Brannigan, Mark R Thursz, Horace R T Williams, Frances J Davies, Julian R Marchesi, Jiří Pavlů, Andrew J Innes, Benjamin H Mullish, Rohma Ghani, Richard M Szydlo, Jane F Apperley, Eduardo Olavarria, Renuka Palanicawandar, Edward J Kanfer, Dragana Milojkovic, Julie A K McDonald, Eimear T Brannigan, Mark R Thursz, Horace R T Williams, Frances J Davies, Julian R Marchesi, Jiří Pavlů

Abstract

The gut microbiome can be adversely affected by chemotherapy and antibiotics prior to hematopoietic cell transplantation (HCT). This affects graft success and increases susceptibility to multidrug-resistant organism (MDRO) colonization and infection. We performed an initial retrospective analysis of our use of fecal microbiota transplantation (FMT) from healthy donors as therapy for MDRO-colonized patients with hematological malignancy. FMT was performed on eight MDRO-colonized patients pre-HCT (FMT-MDRO group), and outcomes compared with 11 MDRO colonized HCT patients from the same period. At 12 months, survival was significantly higher in the FMT-MDRO group (70% versus 36% p = 0.044). Post-HCT, fewer FMT-MDRO patients required intensive care (0% versus 46%, P = 0.045) or experienced fever (0.29 versus 0.11 days, P = 0.027). Intestinal MDRO decolonization occurred in 25% of FMT-MDRO patients versus 11% non-FMT MDRO patients. Despite the significant differences and statistically comparable patient/transplant characteristics, as the sample size was small, a matched-pair analysis between both groups to non-MDRO colonized control cohorts (2:1 matching) was performed. At 12 months, the MDRO group who did not have an FMT had significantly lower survival (36.4% versus 61.9% respectively, p=0.012), and higher non relapse mortality (NRM; 60.2% versus 16.7% respectively, p=0.009) than their paired non-MDRO-colonized cohort. Conversely, there was no difference in survival (70% versus 43.4%, p=0.14) or NRM (12.5% versus 31.2% respectively, p=0.24) between the FMT-MDRO group and their paired non-MDRO cohort. Collectively, these data suggest that negative clinical outcomes, including mortality associated with MDRO colonization, may be ameliorated by pre-HCT FMT, even in the absence of intestinal MDRO decolonization. Further work is needed to explore this observed benefit.

Keywords: antimicrobial resistance; fecal microbiota transplant; gut microbiota; hematological malignances; hematopoietic (Stem) cell transplantation (HCT); multidrug resistant bacteria.

Conflict of interest statement

BM reports consultancy fees from Finch Therapeutics Group, outside the submitted work. JRM reports consultancy fees from Enterobiotix Ltd., outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Innes, Mullish, Ghani, Szydlo, Apperley, Olavarria, Palanicawandar, Kanfer, Milojkovic, McDonald, Brannigan, Thursz, Williams, Davies, Marchesi and Pavlů.

Figures

Figure 1
Figure 1
CONSORT diagram.
Figure 2
Figure 2
Impact of FMT on clinical outcomes for MDRO-colonized patients receiving HCT. (A) Kaplan-Meier curve of overall survival in MDRO-colonized HCT patients who underwent FMT (‘FMT’, solid line; n = 8) and those who did not (No FMT, n = 11); (B) Comparison of days of fever (normalized for days of admission, i.e. number of days with fever divided by total number of admission days) in MDRO colonized HCT patients who underwent FMT (‘FMT’) vs those who did not (‘No FMT’).
Figure 3
Figure 3
Impact of MDRO colonization on clinical outcomes for patients receiving HCT – matched MDRO vs non-MDRO groups. (A) Kaplan-Meier curve of overall survival in patients colonized with multidrug-resistant organisms who did not receive FMT (‘no FMT MDRO’, dotted line; n = 11) in comparison to controls who were not colonized and were matched for disease type, disease stage, transplant intensity, donor type (matched sibling, matched unrelated, and haploidentical), and age (‘no FMT no MDRO control 1’, dashed line; n = 21); (B) Kaplan-Meier curve of overall survival in patients colonized with multidrug-resistant organisms who underwent fecal microbiota transplantation (‘FMT MDRO, solid line; n = 8) comparison to controls who were not colonized and were matched for disease type, disease stage, transplant intensity, donor type (matched sibling, matched unrelated, and haploidentical), and age (‘no FMT no MDRO control 2’, dash-dotted line n = 16).

References

    1. Allegretti J. R., Mullish B. H., Kelly C., Fischer M. (2019). The Evolution of the Use of Faecal Microbiota Transplantation and Emerging Therapeutic Indications. Lancet 394, 420–431. 10.1016/s0140-6736(19)31266-8
    1. Andermann T. M., Peled J. U., Ho C., Reddy P., Riches M., Storb R., et al. . (2018). The Microbiome and Hematopoietic Cell Transplantation: Past, Present, and Future. Biol. Blood Marrow Transpl. 24, 1322–1340. 10.1016/j.bbmt.2018.02.009
    1. Artz A. S., Wickrema A., Dinner S., Godley L. A., Kocherginsky M., Odenike O., et al. . (2008). Pretreatment C-Reactive Protein is a Predictor for Outcomes After Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation. Biol. Blood Marrow Transpl. J. Am. Soc Blood Marrow Transpl. 14, 1209–1216. 10.1016/j.bbmt.2008.08.004
    1. Bar-Yoseph H., Carasso S., Shklar S., Korytny A., Even Dar R., Daoud H., et al. . (2021). Oral Capsulized Fecal Microbiota Transplantation for Eradication of Carbapenemase-Producing Enterobacteriaceae Colonization With a Metagenomic Perspective. Clin. Infect. Dis. 73, e166–e175. 10.1093/cid/ciaa737
    1. Battipaglia G., Malard F., Rubio M. T., Ruggeri A., Mamez A. C., Brissot E., et al. . (2019). Fecal Microbiota Transplantation Before or After Allogeneic Hematopoietic Transplantation in Patients With Hematologic Malignancies Carrying Multidrug-Resistance Bacteria. Haematologica 104, 1682–1688. 10.3324/haematol.2018.198549
    1. Belkaid Y., Hand T. W. (2014). Role of the Microbiota in Immunity and Inflammation. Cell 157, 121–141. 10.1016/j.cell.2014.03.011
    1. Bilinski J., Grzesiowski P., Sorensen N., Madry K., Muszynski J., Robak K., et al. . (2017). Fecal Microbiota Transplantation in Patients With Blood Disorders Inhibits Gut Colonization With Antibiotic-Resistant Bacteria: Results of a Prospective, Single-Center Study. Clin. Infect. Dis. 65, 364–370. 10.1093/cid/cix252
    1. Bilinski J., Robak K., Peric Z., Marchel H., Karakulska-Prystupiuk E., Halaburda K., et al. . (2016). Impact of Gut Colonization by Antibiotic-Resistant Bacteria on the Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective, Single-Center Study. Biol. Blood Marrow Transplant. 22, 1087–1093. 10.1016/j.bbmt.2016.02.009
    1. Cammarota G., Ianiro G., Kelly C. R., Mullish B. H., Allegretti J. R., Kassam Z., et al. . (2019). International Consensus Conference on Stool Banking for Faecal Microbiota Transplantation in Clinical Practice. Gut 68, gutjnl–2019-319548. 10.1136/gutjnl-2019-319548
    1. Cattaneo C., Di Blasi R., Skert C., Candoni A., Martino B., Di Renzo N., et al. . (2018). Bloodstream Infections in Haematological Cancer Patients Colonized by Multidrug-Resistant Bacteria. Ann. Hematol. 97, 1717–1726. 10.1007/s00277-018-3341-6
    1. Cheng Y.-W., Phelps E., Ganapini V., Khan N., Ouyang F., Xu H., et al. . (2019). Fecal Microbiota Transplantation for the Treatment of Recurrent and Severe Clostridium Difficile Infection in Solid Organ Transplant Recipients: A Multicenter Experience. Am. J. Transpl. 19, 501–511. 10.1111/ajt.15058
    1. Craven L. J., McIlroy J. R., Mullish B. H., Marchesi J. R. (2020). Letter: Intestinal Microbiota Transfer—Updating the Nomenclature to Increase Acceptability. Aliment. Pharmacol. Ther. 52, 1622–1623. 10.1111/apt.16109
    1. Davido B., Moussiegt A., Dinh A., Bouchand F., Matt M., Senard O., et al. . (2018). Germs of Thrones - Spontaneous Decolonization of Carbapenem-Resistant Enterobacteriaceae (CRE) and Vancomycin-Resistant Enterococci (VRE) in Western Europe: Is This Myth or Reality? Antimicrob. Resist. Infect. Control 7, 100. 10.1186/s13756-018-0390-5
    1. DeFilipp Z., Bloom P. P., Soto M. T., Mansour M. K., Sater M. R. A., Huntley M. H., et al. . (2019). Drug-Resistant E. Coli Bacteremia Transmitted by Fecal Microbiota Transplant. N. Engl. J. Med. 381, 2043–2050. 10.1056/NEJMoa1910437
    1. Ghani R., Mullish B. H., McDonald J. A. K., Ghazy A., Williams H. R. T., Brannigan E. T., et al. . (2020). Disease Prevention Not Decolonization: A Model for Fecal Microbiota Transplantation in Patients Colonized With Multidrug-Resistant Organisms. Clin. Infect. Dis. 72, 1444–1447. 10.1093/cid/ciaa948
    1. Huus K. E., Frankowski M., Pučić-Baković M., Vučković F., Lauc G., Mullish B. H., et al. . (2021). Changes in IgA-Targeted Microbiota Following Fecal Transplantation for Recurrent Clostridioides Difficile Infection. Gut Microbes 13, 1–12. 10.1080/19490976.2020.1862027
    1. Ianiro G., Murri R., Sciumè G. D., Impagnatiello M., Masucci L., Ford A. C., et al. . (2019). Incidence of Bloodstream Infections, Length of Hospital Stay, and Survival in Patients With Recurrent Clostridioides Difficile Infection Treated With Fecal Microbiota Transplantation or Antibiotics a Prospective Cohort Study. Ann. Intern. Med. 171, 695–702. 10.7326/M18-3635
    1. Kamada N., Chen G. Y., Inohara N., Núñez G. (2013). Control of Pathogens and Pathobionts by the Gut Microbiota. Nat. Immunol. 14, 685–690. 10.1038/ni.2608
    1. Kim S. M., DeFazio J. R., Hyoju S. K., Sangani K., Keskey R., Krezalek M. A., et al. . (2020). Fecal Microbiota Transplant Rescues Mice From Human Pathogen Mediated Sepsis by Restoring Systemic Immunity. Nat. Commun. 11, 2354. 10.1038/s41467-020-15545-w
    1. Malard F., Gasc C., Plantamura E., Doré J. (2018). High Gastrointestinal Microbial Diversity and Clinical Outcome in Graft-Versus-Host Disease Patients. Bone Marrow Transpl. 53, 1493–1497. 10.1038/s41409-018-0254-x
    1. Martinez-Gili L., McDonald J. A. K., Liu Z., Kao D., Allegretti J. R., Monaghan T. M., et al. . (2020). Understanding the Mechanisms of Efficacy of Fecal Microbiota Transplant in Treating Recurrent Clostridioides Difficile Infection and Beyond: The Contribution of Gut Microbial-Derived Metabolites. Gut Microbes 12, 1810531. 10.1080/19490976.2020.1810531
    1. McDonald J. A. K., Mullish B. H., Pechlivanis A., Liu Z., Brignardello J., Kao D., et al. . (2018). Inhibiting Growth of Clostridioides Difficile by Restoring Valerate, Produced by the Intestinal Microbiota. Gastroenterology 155, 1495–1507.e15. 10.1053/j.gastro.2018.07.014
    1. Monaghan T., Mullish B. H., Patterson J., Wong G. K. S. K., Marchesi J. R., Xu H., et al. . (2019). Effective Fecal Microbiota Transplantation for Recurrent Clostridioides Difficile Infection in Humans is Associated With Increased Signalling in the Bile Acid-Farnesoid X Receptor-Fibroblast Growth Factor Pathway. Gut Microbes 10, 1–7. 10.1080/19490976.2018.1506667
    1. Montassier E., Gastinne T., Vangay P., Al-Ghalith G. A., Bruley des Varannes S., Massart S., et al. . (2015). Chemotherapy-Driven Dysbiosis in the Intestinal Microbiome. Aliment. Pharmacol. Ther. 42, 515–528. 10.1111/apt.13302
    1. Mullish B. H., Ghani R., McDonald J. A. K., Davies F., Marchesi J. R. (2020). Clin. Infect. Dis. 72, e924–e925. 10.1093/cid/ciaa1526 Reply to Woodworth.
    1. Mullish B. H., Marchesi J. R., Thursz M. R., Williams H. R. T. (2015). Microbiome Manipulation With Faecal Microbiome Transplantation as a Therapeutic Strategy in Clostridium Difficile Infection. QJM 108, 355–359. 10.1093/qjmed/hcu182
    1. Mullish B. H. B. H., McDonald J. A. K. J. A. K. K., Pechlivanis A., Allegretti J. R. J. R., Kao D., Barker G. F. G. F., et al. . (2019). Microbial Bile Salt Hydrolases Mediate the Efficacy of Faecal Microbiota Transplant in the Treatment of Recurrent Clostridioides Difficile Infection. Gut 68, 1791–1800. 10.1136/gutjnl-2018-317842
    1. Mullish B. H., Quraishi M. N., Segal J. P., McCune V. L., Baxter M., Marsden G. L., et al. . (2018). The Use of Faecal Microbiota Transplant as Treatment for Recurrent or Refractory Clostridium Difficile Infection and Other Potential Indications: Joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) Guidelines. Gut 67, 1920–1941. 10.1136/gutjnl-2018-316818
    1. Otter J. A., Mookerjee S., Davies F., Bolt F., Dyakova E., Shersing Y., et al. . (2020). Detecting Carbapenemase-Producing Enterobacterales (CPE): An Evaluation of an Enhanced CPE Infection Control and Screening Programme in Acute Care. J. Antimicrob. Chemother. 75, 2670–2676. 10.1093/jac/dkaa192
    1. Patel A., Szydlo R. M., Auner H. W., Kanfer E. J., MacDonald D. H., Milojkovic D., et al. . (2018). C-Reactive Protein Prior to Myeloablative Allogeneic Haematopoietic Cell Transplantation Identifies Patients at Risk of Early- and Long-Term Mortality. Br. J. Haematol. 180, 889–892. 10.1111/bjh.14454
    1. Pavlů J., Kew A. K., Taylor-Roberts B., Auner H. W., Marin D., Olavarria E., et al. . (2010). Optimizing Patient Selection for Myeloablative Allogeneic Hematopoietic Cell Transplantation in Chronic Myeloid Leukemia in Chronic Phase. Blood 115, 4018–4020. 10.1182/blood-2010-01-263624
    1. Peled J. U., Devlin S. M., Staffas A., Lumish M., Khanin R., Littmann E. R., et al. . (2017). Intestinal Microbiota and Relapse After Hematopoietic-Cell Transplantation. J. Clin. Oncol. Off. J. Am. Soc Clin. Oncol. 35, 1650–1659. 10.1200/JCO.2016.70.3348
    1. Peled J. U., Gomes A. L. C., Devlin S. M., Littmann E. R., Taur Y., Sung A. D., et al. . (2020). Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation. N. Engl. J. Med. 382, 822–834. 10.1056/NEJMoa1900623
    1. Relman D. A., Lipsitch M. (2018). Microbiome as a Tool and a Target in the Effort to Address Antimicrobial Resistance. Proc. Natl. Acad. Sci. 115, 12902 LP – 12910. 10.1073/pnas.1717163115
    1. Saha S., Tariq R., Tosh P. K., Pardi D. S., Khanna S. (2019). Faecal Microbiota Transplantation for Eradicating Carriage of Multidrug-Resistant Organisms: A Systematic Review. Clin. Microbiol. Infect. 25, 958–963. 10.1016/j.cmi.2019.04.006
    1. Samet A., Śledzińska A., Krawczyk B., Hellmann A., Nowicki S., Kur J., et al. . (2013). Leukemia and Risk of Recurrent Escherichia Coli Bacteremia: Genotyping Implicates E. Coli Translocation From the Colon to the Bloodstream. Eur. J. Clin. Microbiol. Infect. Dis. 32, 1393–1400. 10.1007/s10096-013-1886-9
    1. Satlin M. J., Cohen N., Ma K. C., Gedrimaite Z., Soave R., Askin G., et al. . (2016). Bacteremia Due to Carbapenem-Resistant Enterobacteriaceae in Neutropenic Patients With Hematologic Malignancies. J. Infect. 73, 336–345. 10.1016/j.jinf.2016.07.002
    1. Schluter J., Peled J. U., Taylor B. P., Markey K. A., Smith M., Taur Y., et al. . (2020). The Gut Microbiota is Associated With Immune Cell Dynamics in Humans. Nature 588, 303–307. 10.1038/s41586-020-2971-8
    1. Segal J. P., Mullish B. H., Quraishi M. N., Iqbal T., Marchesi J. R., Sokol H. (2020). Mechanisms Underpinning the Efficacy of Faecal Microbiota Transplantation in Treating Gastrointestinal Disease. Therap. Adv. Gastroenterol. 13, 175628482094690. 10.1177/1756284820946904
    1. Shogbesan O., Poudel D. R., Victor S., Jehangir A., Fadahunsi O., Shogbesan G., et al. . (2018). A Systematic Review of the Efficacy and Safety of Fecal Microbiota Transplant for Clostridium Difficile Infection in Immunocompromised Patients. Can. J. Gastroenterol. Hepatol. 2018, 1–10. 10.1155/2018/1394379
    1. Taur Y., Coyte K., Schluter J., Robilotti E., Figueroa C., Gjonbalaj M., et al. . (2018). Reconstitution of the Gut Microbiota of Antibiotic-Treated Patients by Autologous Fecal Microbiota Transplant. Sci. Transl. Med. 10, eaap9489. 10.1126/scitranslmed.aap9489
    1. van Lier Y. F., Davids M., Haverkate N. J. E., de Groot P. F., Donker M. L., Meijer E., et al. . (2020). Donor Fecal Microbiota Transplantation Ameliorates Intestinal Graft-Versus-Host Disease in Allogeneic Hematopoietic Cell Transplant Recipients. Sci. Transl. Med. 12, eaaz8926. 10.1126/SCITRANSLMED.AAZ8926
    1. van Nood E., Vrieze A., Nieuwdorp M., Fuentes S., Zoetendal E. G., de Vos W. M., et al. . (2013). Duodenal Infusion of Donor Feces for Recurrent Clostridium Difficile. N. Engl. J. Med. 368, 407–415. 10.1056/NEJMoa1205037
    1. Wong W. F., Santiago M. (2017). Microbial Approaches for Targeting Antibiotic-Resistant Bacteria. Microb. Biotechnol. 10, 1047–1053. 10.1111/1751-7915.12783
    1. Woodworth M. H., Hayden M. K., Young V. B., Kwon J. H. (2019). The Role of Fecal Microbiota Transplantation in Reducing Intestinal Colonization With Antibiotic-Resistant Organisms: The Current Landscape and Future Directions. Open Forum Infect. Dis. 6, 1–9. 10.1093/ofid/ofz288

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi