Factors Associated with FMT Failure in Clostridioides difficile Infection and Age-Related Considerations: A Review
DOI:
10.29303/jpm.v20i8.10558Published:
2025-12-22Issue:
Vol. 20 No. 8 (2025): Special IssueKeywords:
Aged; Clostridioides difficile Infection; Fecal Microbiota Transplant; Risk FactorsArticles
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Abstract
Clostridioides difficile infection (CDI) is a major cause of nosocomial diarrhea worldwide, and limitations of standard antibiotic therapy have driven the adoption of fecal microbiota transplantation (FMT) as an alternative therapeutic approach. Although FMT achieves clinical success in most patients, treatment failure still occurs in a considerable proportion of cases. Existing literature has examined overall FMT efficacy, yet no review has comprehensively synthesized the multifactorial determinants of FMT failure while incorporating age-related considerations. This narrative review provides an integrative overview of factors contributing to FMT failure in adults with CDI. A literature search of PubMed and Google Scholar identified original research articles published between 2015 and 2025. Evidence indicates that FMT failure is influenced by host-related factors such as comorbidities, immune function, and nutritional status; disease-related characteristics, including CDI severity and recurrence history; technical aspects, such as bowel preparation, donor type, and route of administration; and pharmacological factors, including antibiotic exposure before or after the procedure. These factors collectively affect donor microbiota engraftment and increase the risk of therapeutic failure. Age-related physiological and microbiome changes may additionally modify treatment responses. This review highlights the need for comprehensive patient assessment, standardized procedural protocols, and careful post-FMT monitoring. Addressing current evidence gaps and improving clinical guidance will be essential for optimizing the safety and effectiveness of FMT across different adult age groups.
References
Z. Chen, J. Wu, X. Ye, J. Jin, and W. Zhang, “Global Burden, Trends, and Inequalities of Clostridioides difficile Infections from 1990 to 2021 and Projections to 2040: A Systematic Analysis,” Antibiotics, vol. 14, no. 7, p. 652, Jul. 2025, doi: 10.3390/antibiotics14070652.
Q. Xu et al., “Hospital-acquired Clostridium difficile infection in Mainland China: A seven-year (2009-2016) retrospective study in a large university hospital,” Sci Rep, vol. 7, no. 1, Dec. 2017, doi: 10.1038/s41598-017-09961-0.
D. A. Collins et al., “Prevalence and molecular epidemiology of Clostridium difficile infection in Indonesia,” New Microbes New Infect, vol. 18, pp. 34–37, Jul. 2017, doi: 10.1016/j.nmni.2017.04.006.
S. G. Elgendy, S. A. Aly, R. Fathy, E. A. Deaf, N. H. Abu Faddan, and M. R. Abdel Hameed, “Clinical and microbial characterization of toxigenic Clostridium difficile isolated from antibiotic associated diarrhea in Egypt,” IJM: Iranian Journal of Microbiology, vol. 12, no. 4, pp. 296–304, Aug. 2020, [Online]. Available: http://ijm.tums.ac.ir
L. Alcalá, E. Reigadas, M. Marín, A. Martín, P. Catalán, and E. Bouza, “Impact of clinical awareness and diagnostic tests on the underdiagnosis of Clostridium difficile infection,” European Journal of Clinical Microbiology and Infectious Diseases, vol. 34, no. 8, pp. 1515–1525, Aug. 2015, doi: 10.1007/s10096-015-2380-3.
J. A. Ramirez et al., “Misdiagnosis of Clostridioides difficile Infections by Standard-of-Care Specimen Collection and Testing among Hospitalized Adults, Louisville, Kentucky, USA, 2019–2020,” Emerg Infect Dis, vol. 29, no. 5, pp. 919–928, May 2023, doi: 10.3201/eid2905.221618.
N. H. Zainul et al., “Prevalence of Clostridium difficile infection and colonization in a tertiary hospital and elderly community of North-Eastern Peninsular Malaysia,” Epidemiol Infect, vol. 145, no. 14, pp. 3012–3019, Oct. 2017, doi: 10.1017/S0950268817002011.
T. Odamaki et al., “Age-related changes in gut microbiota composition from newborn to centenarian: A cross-sectional study,” BMC Microbiol, vol. 16, no. 1, May 2016, doi: 10.1186/s12866-016-0708-5.
M. Girotra, S. Garg, R. Anand, Y. Song, and S. K. Dutta, “Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection in the Elderly: Long-Term Outcomes and Microbiota Changes,” Dig Dis Sci, vol. 61, no. 10, pp. 3007–3015, Oct. 2016, doi: 10.1007/s10620-016-4229-8.
M. Kachlíková, P. Sabaka, A. Koščálová, M. Bendžala, Z. Dovalová, and I. Stankovič, “Comorbid status and the faecal microbial transplantation failure in treatment of recurrent Clostridioides difficile infection - Pilot prospective observational cohort study,” BMC Infect Dis, vol. 20, no. 1, Jan. 2020, doi: 10.1186/s12879-020-4773-x.
M. Fischer et al., “Predictors of Early Failure after Fecal Microbiota Transplantation for the Therapy of Clostridium Difficile Infection: A Multicenter Study,” American Journal of Gastroenterology, vol. 111, no. 7, pp. 1024–1031, Jul. 2016, doi: 10.1038/ajg.2016.180.
F. Warraich, S. H. Sohail, A. Knee, J. Smith, H. Schlecht, and D. Skiest, “Factors Associated With Fecal Microbiota Transplant Failure in the Treatment of Recurrent Clostridioides difficile Infection: A Single-Center Retrospective Study,” Cureus, vol. 15, no. 9, p. e45118, Sep. 2023, doi: 10.7759/cureus.45118.
G. Ianiro et al., “Predictors of failure after single faecal microbiota transplantation in patients with recurrent Clostridium difficile infection: results from a 3-year, single-centre cohort study,” Clinical Microbiology and Infection, vol. 23, no. 5, pp. 337.e1-337.e3, May 2017, doi: 10.1016/j.cmi.2016.12.025.
J. R. Allegretti, D. Kao, J. Sitko, M. Fischer, and Z. Kassam, “Early Antibiotic Use after Fecal Microbiota Transplantation Increases Risk of Treatment Failure,” Clinical Infectious Diseases, vol. 66, no. 1, pp. 134–135, Jan. 2018, doi: 10.1093/cid/cix684.
J. D. K. Nguyen et al., “Factors associated with failure of fecal microbiota transplant for recurrent Clostridioides difficile infection,” Therap Adv Gastroenterol, vol. 18, pp. 1–15, Jan. 2025, doi: 10.1177/17562848251334517.
H. J. Shin, A. R. Hays, and C. Warren Alcantara, “Hospitalized Older Patients with Clostridioides difficile Infection Refractory to Conventional Antibiotic Therapy Benefit from Fecal Microbiota Transplant,” Adv Geriatr Med Res, vol. 3, no. 2, 2021, doi: 10.20900/agmr20210012.
C. S. Kraft et al., “Integrated Safety and Efficacy Analyses of Phase 3 Trials of a Microbiome Therapeutic for Recurrent CDI,” Infect Dis Ther, vol. 13, no. 10, pp. 2105–2121, Oct. 2024, doi: 10.1007/s40121-024-01007-z.
P. Feuerstadt et al., “PUNCH CD3-OLS: A Phase 3 Prospective Observational Cohort Study to Evaluate the Safety and Efficacy of Fecal Microbiota, Live-jslm (REBYOTA) in Adults With Recurrent Clostridioides difficile Infection,” Clinical Infectious Diseases, vol. 80, no. 1, pp. 43–51, Jan. 2025, doi: 10.1093/cid/ciae437.
R. Peri et al., “The impact of technical and clinical factors on fecal microbiota transfer outcomes for the treatment of recurrent Clostridioides difficile infections in Germany,” United European Gastroenterol J, vol. 7, no. 5, pp. 716–722, Jun. 2019, doi: 10.1177/2050640619839918.
T. Phenwan, J. Sixsmith, L. McSwiggan, and D. Buchanan, “A narrative review of facilitating and inhibiting factors in advance care planning initiation in people with dementia,” Eur Geriatr Med, vol. 11, no. 3, pp. 353–368, Jun. 2020, doi: 10.1007/s41999-020-00314-1.
A. Meighani, B. R. Hart, C. Mittal, N. Miller, A. John, and M. Ramesh, “Predictors of fecal transplant failure,” Eur J Gastroenterol Hepatol, vol. 28, no. 7, pp. 826–830, Jul. 2016, doi: 10.1097/MEG.0000000000000614.
A. E. Watts, J. A. Sninsky, M. M. Richey, K. Donovan, M. K. Dougherty, and S. K. McGill, “Family Stool Donation Predicts Failure of Fecal Microbiota Transplant for Clostridioides difficile Infection,” Gastro Hep Advances, vol. 1, no. 2, pp. 141–146, Jan. 2022, doi: 10.1016/j.gastha.2021.11.007.
S. H. Park et al., “Factors for Treatment Failure After Fecal Microbiota Transplantation in Clostridioides difficile Infection,” Microorganisms, vol. 12, no. 12, p. 2539, Dec. 2024, doi: 10.3390/microorganisms12122539.
J. R. Allegretti et al., “Risk Factors that Predict the Failure of Multiple Fecal Microbiota Transplantations for Clostridioides difficile Infection,” Dig Dis Sci, vol. 66, no. 1, pp. 213–217, Jan. 2021, doi: 10.1007/s10620-020-06198-2.
A. Parker et al., “Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain,” Microbiome, vol. 10, no. 1, Dec. 2022, doi: 10.1186/s40168-022-01243-w.
Y. Luo, E. N. Tixier, and A. M. Grinspan, “Fecal Microbiota Transplantation for Clostridioides difficile in High-Risk Older Adults Is Associated with Early Recurrence,” Dig Dis Sci, vol. 65, no. 12, pp. 3647–3651, Dec. 2020, doi: 10.1007/s10620-020-06147-z.
V. J. Maffei et al., “Biological Aging and the Human Gut Microbiota,” Journals of Gerontology - Series A Biological Sciences and Medical Sciences, vol. 72, no. 11, pp. 1474–1482, Nov. 2017, doi: 10.1093/gerona/glx042.
R. Anand et al., “Effect of Aging on the Composition of Fecal Microbiota in Donors for FMT and Its Impact on Clinical Outcomes,” Dig Dis Sci, vol. 62, no. 4, pp. 1002–1008, Apr. 2017, doi: 10.1007/s10620-017-4449-6.
A. Darra et al., “Hyperglycemia is associated with duodenal dysbiosis and altered duodenal microenvironment,” Sci Rep, vol. 13, no. 1, Dec. 2023, doi: 10.1038/s41598-023-37720-x.
C. A. Thaiss et al., “Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection,” Science (1979), vol. 359, pp. 1376–1383, Mar. 2018, [Online]. Available: https://www.science.org
E. R. Littmann et al., “Host immunity modulates the efficacy of microbiota transplantation for treatment of Clostridioides difficile infection,” Nat Commun, vol. 12, no. 1, p. 755, Dec. 2021, doi: 10.1038/s41467-020-20793-x.
C. E. Moss et al., “Aging-related defects in macrophage function are driven by MYC and USF1 transcriptional programs,” Cell Rep, vol. 43, no. 4, p. 114073, Apr. 2024, doi: 10.1016/j.celrep.2024.114073.
M. Shete, D. Patil, P. Karade, R. Chopade, N. Gandhi, and U. Alane, “Assessment of age-related changes of salivary immunoglobulin a levels among healthy individuals,” J Pharm Bioallied Sci, vol. 13, no. 5, pp. S461–S464, Jun. 2021, doi: 10.4103/jpbs.JPBS_605_20.
E. L. Moss et al., “Long-term taxonomic and functional divergence from donor bacterial strains following fecal microbiota transplantation in immunocompromised patients,” PLoS One, vol. 12, no. 8, p. e0182585, Aug. 2017, doi: 10.1371/journal.pone.0182585.
Y. P. Hung et al., “Risk factors of Clostridium difficile-associated diarrhea in hospitalized adults: Vary by hospitalized duration,” Journal of Microbiology, Immunology and Infection, vol. 54, no. 2, pp. 276–283, Apr. 2021, doi: 10.1016/j.jmii.2019.07.004.
J. Kirchgesner, M. Lemaitre, F. Carrat, M. Zureik, F. Carbonnel, and R. Dray-Spira, “Risk of Serious and Opportunistic Infections Associated With Treatment of Inflammatory Bowel Diseases,” Gastroenterology, vol. 155, no. 2, pp. 337-346.e10, Aug. 2018, doi: 10.1053/j.gastro.2018.04.012.
W. Hirsch, M. Fischer, A. Khoruts, J. R. Allegretti, C. R. Kelly, and B. Vaughn, “Risk Factors for Antibiotic Exposure Post–Fecal Microbiota Transplantation for Recurrent Clostridioides difficile Infection: A Prospective Multicenter Observational Study,” Open Forum Infect Dis, vol. 12, no. 3, Mar. 2025, doi: 10.1093/ofid/ofaf130.
S. Hendriks et al., “Compromised intestinal integrity in older adults during daily activities: a pilot study,” BMC Geriatr, vol. 21, no. 1, Dec. 2021, doi: 10.1186/s12877-021-02573-4.
G. Corsetti, C. Romano, E. Pasini, C. Testa, and F. S. Dioguardi, “Qualitative nitrogen malnutrition damages gut and alters microbiome in adult mice. A preliminary histopathological study,” Nutrients, vol. 13, no. 4, Apr. 2021, doi: 10.3390/nu13041089.
S. Rho et al., “Protein energy malnutrition alters mucosal IgA responses and reduces mucosal vaccine efficacy in mice,” Immunol Lett, vol. 190, pp. 247–256, Oct. 2017, doi: 10.1016/j.imlet.2017.08.025.
H. Yoon et al., “Factors Related to Outcomes of Fecal Microbiota Transplantation in Patients with Clostridioides difficile Infection,” Gut Liver, vol. 15, no. 1, pp. 61–69, 2021, doi: 10.5009/gnl20135.
D. Knafl et al., “Hypoalbuminemia as predictor of recurrence of Clostridium difficile infection,” Wien Klin Wochenschr, vol. 131, no. 3–4, pp. 68–74, Feb. 2019, doi: 10.1007/s00508-018-1432-y.
R. Z. Kamil, A. Murdiati, M. Juffrie, J. Nakayama, and E. S. Rahayu, “Gut microbiota and short-chain fatty acid profile between normal and moderate malnutrition children in Yogyakarta, Indonesia,” Microorganisms, vol. 9, no. 1, pp. 1–15, Jan. 2021, doi: 10.3390/microorganisms9010127.
S. K. Kirschner, M. P. Engelen, P. Haas, S. C. Bischoff, and N. E. Deutz, “Short-chain fatty acid kinetics and concentrations are higher after inulin supplementation in young and older adults: a randomized trial,” Am J Clin Nutr, vol. 121, no. 6, pp. 1224–1235, Jun. 2025, doi: 10.1016/J.AJCNUT.2025.04.018.
E. C. Tucker, B. Angelica, R. M. Mathias, L. Edwards, R. V. Bryant, and S. P. Costello, “Outcomes of Fecal Microbiota Transplantation for Clostridioides difficile Infection in South Australia,” Open Forum Infect Dis, vol. 12, no. 4, Apr. 2025, doi: 10.1093/ofid/ofaf149.
M. Fischer et al., “Fecal microbiota transplant in severe and severe-complicated Clostridium difficile: A promising treatment approach,” Gut Microbes, vol. 8, no. 3, pp. 289–302, May 2017, doi: 10.1080/19490976.2016.1273998.
E. J. Spartz et al., “Fecal Microbiota Transplantation for Fulminant Clostridioides Difficile Infection: A Combined Medical and Surgical Case Series,” Cureus, vol. 15, no. 2, p. e34998, Feb. 2023, doi: 10.7759/cureus.34998.
D. Popa et al., “Fecal microbiota transplant in severe and non-severe clostridioides difficile infection. Is there a role of fmt in primary severe cdi?,” J Clin Med, vol. 10, no. 24, p. 5822, Dec. 2021, doi: 10.3390/jcm10245822.
T. Zuo et al., “Gut fungal dysbiosis correlates with reduced efficacy of fecal microbiota transplantation in Clostridium difficile infection,” Nat Commun, vol. 9, no. 1, Dec. 2018, doi: 10.1038/s41467-018-06103-6.
J. S. Bajaj et al., “Antibiotic-Associated Disruption of Microbiota Composition and Function in Cirrhosis Is Restored by Fecal Transplant,” Hepatology, vol. 68, no. 4, 2018, doi: 10.1002/hep.30037.
A. R. Weingarden et al., “Delivery of Fecal Material to Terminal Ileum Is Associated with Long-Term Success of Fecal Microbiota Transplantation,” Dig Dis Sci, vol. 68, no. 5, pp. 2006–2014, May 2023, doi: 10.1007/s10620-022-07761-9.
L. Wrzosek et al., “Transplantation of human microbiota into conventional mice durably reshapes the gut microbiota,” Sci Rep, vol. 8, no. 1, Dec. 2018, doi: 10.1038/s41598-018-25300-3.
A. Karmisholt Grosen et al., “Effects of clinical donor characteristics on the success of faecal microbiota transplantation for patients in Denmark with Clostridioides difficile infection: a single-centre, prospective cohort study,” Lancet Microbe, vol. 6, no. 5, p. 101034, May 2025, doi: 10.1016/j.lanmic.2024.101034.
S. Paramsothy et al., “Donor recruitment for fecal microbiota transplantation,” Inflamm Bowel Dis, vol. 21, no. 7, pp. 1600–1606, May 2015, doi: 10.1097/MIB.0000000000000405.
J. Chen, A. Zaman, B. Ramakrishna, and S. W. Olesen, “Stool Banking for Fecal Microbiota Transplantation: Methods and Operations at a Large Stool Bank,” Front Cell Infect Microbiol, vol. 11, Apr. 2021, doi: 10.3389/fcimb.2021.622949.
J. He et al., “A comprehensive approach to stool donor screening for faecal microbiota transplantation in China,” Microb Cell Fact, vol. 20, no. 1, p. 216, Dec. 2021, doi: 10.1186/s12934-021-01705-0.
A. Kazerouni, J. Burgess, L. J. Burns, and L. M. Wein, “Optimal screening and donor management in a public stool bank,” Microbiome, vol. 3, p. 75, Dec. 2015, doi: 10.1186/s40168-015-0140-3.
S. P. Costello, E. C. Tucker, J. La Brooy, M. N. Schoeman, and J. M. Andrews, “Establishing a Fecal Microbiota Transplant Service for the treatment of Clostridium difficile Infection,” Clinical Infectious Diseases, vol. 62, no. 7, pp. 908–914, Nov. 2015, [Online]. Available: http://cid.oxfordjournals.org/
C. Staley et al., “Lower endoscopic delivery of freeze-dried intestinal microbiota results in more rapid and efficient engraftment than oral administration,” Sci Rep, vol. 11, no. 1, p. 4519, Feb. 2021, doi: 10.1038/s41598-021-84152-6.
N. D. Gundacker, A. Tamhane, J. B. Walker, C. D. Morrow, and J. M. Rodriguez, “Comparative effectiveness of faecal microbiota transplant by route of administration,” Journal of Hospital Infection, vol. 96, no. 4, pp. 349–352, Aug. 2017, doi: 10.1016/j.jhin.2017.05.004.
D. Kao et al., “Effect of oral capsule– vs colonoscopy-delivered fecal microbiota transplantation on recurrent Clostridium difficile infection: A randomized clinical trial,” JAMA - Journal of the American Medical Association, vol. 318, no. 20, pp. 1985–1993, Nov. 2017, doi: 10.1001/jama.2017.17077.
L. K. Skjevling et al., “Colonic distribution of FMT by different enema procedures compared to colonoscopy – proof of concept study using contrast fluid,” BMC Gastroenterol, vol. 23, no. 1, Dec. 2023, doi: 10.1186/s12876-023-02979-x.
L. Peto et al., “The impact of different antimicrobial exposures on the gut microbiome in the ARMORD observational study,” Elife, vol. 13, p. RP97751, Jul. 2024, doi: 10.7554/eLife.97751.2.
S. M. D. Baunwall et al., “Donor, patient age and exposure to antibiotics are associated with the outcome of faecal microbiota transplantation for recurrent Clostridioides difficile infection: A prospective cohort study,” Aliment Pharmacol Ther, vol. 58, no. 5, pp. 503–515, Sep. 2023, doi: 10.1111/apt.17642.
Author Biographies
Khaeru Irgi, Department of Pharmacy, Faculty of Health Sciences, University of Singaperbangsa Karawang
Ahsanal Kasasiah, Department of Pharmacy, Faculty of Health Sciences, University of Singaperbangsa Karawang
Agustina Rusmayanti, Department of Pharmacy, Faculty of Health Sciences, University of Singaperbangsa Karawang
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