Fecal microbial transplantation as a therapeutic option in patients colonized with antibiotic resistant organisms

ABSTRACT

Despite increasing interest in fecal microbiota transplantation (FMT), its full therapeutic potential has yet to be determined. Since its increase in popularity, FMT has been shown to be highly effective in the treatment of both Clostridium difficile infection (CDI) and its recurrent form. Interest in FMT now expands well beyond the treatment of CDI to other processes with known associations to the microbiota such as antibiotic resistant infections, inflammatory bowel disease (IBD), hepatic encephalopathy, neuropsychiatric disorders, and metabolic disease. The rampant use and misuse of antibiotics in both medicine and agriculture has resulted in an increase in antibiotic resistant organisms which pose a significant risk to human health. The purpose of this commentary is to address the general issue of antibiotic resistance in the human microbiota and the restorative potential of FMT in this area.

Introduction

Selective pressures created by the clinical and agricultural use and misuse of antibiotics have resulted in the development of multidrug resistant (MDR) bacteria. The development of antimicrobial resistance has become a major threat to human health due to a lack of effective treatments of MDR bacterial infections. Patients infected with MDR bacteria stay in hospital longer and experience higher rates of morbidity and mortality.^1,2 Both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) infections have been shown to be associated with worse clinical outcomes.^2,3 Indeed, infections with MDR bacteria are associated with an increased risk of septic shock, acute kidney injury, and death. MDR bacteria are believed to colonize the gastrointestinal tract, contributing to the reservoir of antibiotic resistant (ABR) genes within the gut, and subsequently infecting their host.⁴ Patients that become colonized with MDR bacteria often require prolonged hospitalization, which increases the risk of acquiring further MDR bacteria. Unfortunately, persistent reservoirs of MDR can occur in hospital settings, leading to a spread of MDR throughout the patient population. The Centers for Disease Control and Prevention recommend contact precautions (i.e. patient isolation procedures) to prevent this spread; however, despite these precautions, these reservoirs lead to an increased incidence of adverse events, increased symptoms of depression and anxiety, and decreased patient satisfaction with care.^5,6 Previous strategies aimed at intestinal decolonization through disinfectant, bowel preparations, and antibiotic treatment have been met with limited success.^7-10

Antibiotic resistance is not a modern phenomenon and predates the use of antibiotics. The genes responsible for ABR can be acquired by bacteria through conjugation, transformation, transduction and mutation. However, the inappropriate over prescription of antibiotics was identified in North America as early as the 1970s.¹¹ In addition, the indiscriminant use of antibiotics in agriculture to promote growth and act as prophylactic agents was also recognized as a concerning threat to human health.¹² The concept of the ‘resistome’ was first introduced in 2006 by Wright and colleagues to describe the ABR gene profile of the microbiota, taking into account both genes contained in relevant human pathogens and non-pathogenic bacteria.¹³ Our improved understanding of the antibiotic resistome and the clinical reality of increasing ABR infections suggest the need for new and different approaches to their treatment.

Use of FMT to promote colonization resistance

Colonization resistance refers to the ability of a healthy gut microbiota to prevent pathogen colonization.¹⁴ Mechanisms underlying colonization resistance include competition for nutrients, the production of antimicrobial factors, alterations in pH, and prevention of access to adherence sites or niches associated with the mucosa, and production of microbial metabolites that directly antagonize other species. Using fecal microbial transplantation as a method to replenish a healthy gut microbial environment and restore colonization resistance has showed astonishing effectiveness in the treatment of recurring infection with Clostridium difficile with cure rates ranging from 80–95% following a single infusion.^15-17 In our single center study of 20 patients who underwent FMT for recurrent CDI, we showed using a combination of metagenomics and DNA microarray that the number of antibiotic-resistant genes in the resistome of patients was significantly reduced following the procedure.¹⁸ These results were further corroborated by Jouhten et al. in 8 patients undergoing FMT for recurrent CDI using a quantitative PCR array containing 85 ABR genes.¹⁹ In both studies, FMT proved to be a safe and effective therapeutic option for recurrent CDI. FMT was also effective in reducing the number of ABR genes in the patients’ resistome. Manges and colleagues recently published a review summarizing 8 different case reports on the success of FMT in the eradication of MDR organisms,²⁰ further supporting the concept of using FMT for this purpose. In these studies, the MDR organisms included extended spectrum β-lactamase producing Escherichia coli, carbapenemase-producing Klebsielle pneumoniae, methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, highly drug-resistant A. baumannii, carbapenemase-producing P. aruginosa, and vancomycin-resistant Enterococcus faecalis. There were no reports of adverse events in any of the case reports. Although no larger randomized controlled trials have been performed to study the efficacy and safety of FMTs for MDR organisms, preliminary evidence is promising and suggests that a non-antibiotic therapy for ABR infections may be in the future of health care.

The future of FMT in the health care system

Since their discovery, antibiotics have drastically changed the clinical approach to the treatment of bacterial infections. However, the emergence of MDR organisms as a result of widespread antibiotic usage has left the world on the cusp of a ‘post-antibiotic’ era.²¹ An approach to address these MDR organisms is required in the healthcare setting to prevent the resurgence of previously preventable infection-related adverse outcomes. A role for FMT as a decolonization therapy may be fast approaching. The principle behind decolonization therapy is to identify, isolate, and treat carriers, with the goal of eradicating the pathogen from health care facilities.²² In the case of MRSA, targeted decolonization of carriers may reduce the spread of the resistant organism.²³ FMT may prove useful in the decolonization of intestinal MDR organisms. Currently, those colonized by MDR organisms are managed with contact isolation precautions, without any established protocols for decolonization. The use of FMT as a decolonization agent may prove effective in preventing disease outbreaks, and in minimizing the length of time colonized patients spend under costly and dangerous contact isolation precautions. At this point, FMT has only demonstrated efficacy in reducing MDR organisms within the bowel, and may need to be used in combination with other decolonization strategies to ensure MDR-eradication of all contaminated sites.

Decolonization of enteric MDR organisms may prove especially useful in the subset of immunocompromised patients who are susceptible to infection from endogenous bacteria through the gastrointestinal tract, such as those undergoing haematopoietic stem cell transplantation.²⁴ MDR infections are rampant in this patient population, and are associated with significant mortality.²⁵ FMT, which is safe in immunocompromised patients,²⁶ may not prevent bacterial translocation and subsequent bacteremia in these patients, but it may select for infections that are more easily treated.

FMT offers substantial benefits over antibiotics as a decolonization therapy. The side effect profile of FMT is modest, with no direct serious adverse effects noted.²⁷ Most importantly, selective decontamination antibiotic treatment is associated with an increase in the overall incidence of ABR genes in intestinal microbes.²⁸ As such, there is a reluctance to institute widespread selective decontamination antibiotic treatment despite its apparent beneficial effect on adverse outcomes.^29,30 FMT may act as an alternative therapy to decontamination, without perpetuating the problem of MDR organisms.

Conclusion

A joint statement released by the World Health Organization, World Organization for Animal Health, and the United Nations in September 2016 identified AMR as “a fundamental threat to human health, development, and security.”³¹ The ability of FMT to dramatically reduce the number of ABR genes in a patient's resistome offers a potentially important therapeutic option. Further study regarding the efficacy of FMT in specific clinical situations is warranted.

Abbreviations

ABR

Antibiotic Resistance

CDI

Clostridium difficile infection

FMT

Fecal Microbiota Transplantation

IBD

Inflammatory Bowel Disease

MDR

Multi-drug Resistance

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Funding

This work was supported by Alberta Health Services, Alberta Innovates, and CIHR.