Structure and Function of Antimicrobial Stewardship Programs (ASPs)

One standard approach to limit the spread of MDROs is to reduce the unnecessary use of antibiotics, especially antibiotics that are the last line of defense against MDRO infections. Appropriate antibiotic prescribing involves giving an antibiotic that kills the microbe causing the infection, administered by the correct route (e.g. oral, intravenous), at the proper dose, for the correct length of time, considering any unique patient characteristics such as allergy.^{Reference Dellit, Owens, McGowan, Gerding, Weinstein, Burke, Huskins, Peterson, Fish-man, Carpenter, Brennan, Billeter and Hooton7} Improved antibiotic utilization in hospitals has been accomplished in part via the formation of ASPs.

Since 2014, the CDC has recommended ASPs for all U.S. hospitals and identified seven core elements for an effective ASP.⁸ (Table 1) Guidelines for the formation and function of ASPs are also available from the Infectious Disease Society of America/Society for Hospital Epidemiologists.⁹ ASPs are led by a multidisciplinary team that includes a minimum of an infectious disease physician, infection preventionist, pharmacist, information technologist, and a clinical microbiologist.¹⁰ The ASP is charged with ensuring that antibiotic use in the hospital is for approved clinical indications with the correct dosing and duration of therapy. The overarching goal of these programs is appropriate antibiotic prescribing that results in optimal clinical outcomes, decreased antibiotic toxicity, and reduced numbers of MDROs.^{Reference Leuthner and Doern11}

Table 1

Selected elements of antimicrobial stewardship programs and how they relate to FMT

This goal is accomplished via several different mechanisms. Examples include careful selection of antibiotics on the pharmacy formulary, monitoring and restricting antibiotic prescribing, and developing guidelines for correct antibiotic use for common clinical infections (e.g. community acquired pneumonia).¹² ASPs track antibiotic resistant rates for different bacteria to aid in clinical decision making and educate health care providers and patients regarding best practices to reduce the emergence of MDROs.¹³ This is often done through the creation of clinical pathways built into the electronic medical record that provide decision support to assist in antibiotic prescribing.

Legal Framework for ASPs

The Centers for Medicare & Medicaid Services (CMS) proposed adding an ASP requirement to the Conditions of Participation for hospitals in 2016.¹⁴ CMS issued a final rule for LTC facilities on October 4, 2016,¹⁵ that became effective in November 2017. CMS identified infection prevention and control as a critical issue for LTC facility residents because of an estimated 1.6-3.8 million HAIs in LTC facilities annually.¹⁶ By their estimate, these infections result in an estimated 150,000 hospitalizations; 388,000 deaths; and healthcare costs between $673 million and $2 billion.¹⁷ LTC residents may be more susceptible than individuals in other healthcare facilities because of their increased opportunities for exposure to infectious agents and likelihood of malnutrition, dehydration, comorbidities, and functional impairments as well as medications that diminish immunity or mobility.¹⁸

Effective January 1, 2017, the Joint Commission revised Medicaid Management Standard MM.09.01.01 for Critical Access Hospital, Hospital, and Nursing Care Center accreditation programs to require ASPs.¹⁹ While the Joint Commission is not a governmental entity with official regulatory power, accreditation by the Joint Commission is recognized by federal and state agencies^{Reference Wei20} as an indication that a facility meets or exceeds the standards²¹ required to participate in the federal and state Medicare and Medicaid programs. Of the more than 6,000 hospitals in the United States, approximately 4,000 are accredited by the Joint Commission.^{Reference Hyun22} For health care entities that choose to pursue Joint Commission accreditation, failure to meet a Joint Commission standard risks the entities' ability to continue to care for, and receive government reimbursement for, patients insured through Medicare and Medicaid. As a result, despite the technically “voluntary” nature of the Joint Commission's standards, they are understood by health care facilities as law. By January 1, 2017, Joint Commission-accredited hospitals and critical access hospitals were required to have ASPs in place “based on current scientific literature,”²³ which included the development and implementation of infection prevention plans, in part through organization-approved multidisciplinary protocols (for example, clinical pathways).

More recently, CMS extended its timeline for publishing a final rule for hospitals until June 16, 2020 because it needed more time to fully consider and address the over 200 comments it received in response to its 2016 proposed rule.²⁴ Once finalized, this rule will apply to all hospitals in the United States that receive payment from either the Medicare or Medicaid programs.

Adverse Events from FMT

While generally considered a safe therapy, there are inherent risks in FMT therapy regardless of the clinical indication.^{Reference Wang, Xu, Wang, Cao, Piao, Khan, Yan, Cao, Wang, Baxter and Colville40} In addition to common adverse effects such as fever, abdominal pain, diarrhea, and bloating there are other considerations when discussing expanding FMT. The first is that stool is not a uniform product and clinical outcomes may depend on the donor.^{Reference Ma, Liu, Rhodes, Nie, Zhang, Rhodes, Sacks and Woodworth41} While healthy stool contains fewer ARGs than patients who have received multiple courses of antibiotics, the number is not zero and a recent study documents transmission of ARGs from the donor to the FMT recipient.^{Reference Leung, Vincent, Edens, Miller and Manges42} While it is currently difficult to identify all MDROs in donor stool, guidelines do recommend screening for ESBL and CRE to reduce this risk to the FMT recipient.⁴³ In fact, a recent FDA safety alert reported invasive disease in two adults, including one death, as a result of an MDRO infection after FMT from the same donor.⁴⁴ Importantly, the stool was not screened for MDROs prior to the transplant. There is also the risk of transmitting any other infectious agent to the recipient not screened for in the stool. Finally, the long-term effects of FMT are not understood and the microbes of the gut may influence diverse aspects of human health such as mood, weight, and allergy.⁴⁵ These risk factors must be weighed with the potential benefits both for the patient and for the public (i.e. cure of infection, reducing antibiotic use and the transmission of MDROs).

A. Clinical Ethics

“Clinical ethics” refers to a body of literature that looks at the ethical implications of clinician-patient encounters and is focused on the ethical treatment of the patient. Clinical ethics are currently most frequently discussed in terms of “principles” of beneficence, nonmaleficence, respect for patient autonomy and justice^{Reference Childress and Beauchamp46} and a deliberate and thoughtful consideration of a patient's medical indications, preferences, quality of life and contextual features.^{Reference Jonsen, Siegler and Winslade47} A clinician's decision to use FMT for clinical purposes, i.e., to cure or comfort a patient, requires a consideration of (1) whether the clinical benefit of the FMT outweighs the likely burden of the treatment, and (2) is consistent with the patient's preferences and values, taking into consideration the social, legal, spiritual, and financial implications for the patient.

Weighing the clinical benefit of FMT against the potential burdens can be difficult, especially in cases with limited evidence.^{Reference Ma, Liu, Rhodes, Nie and Zhang48} The scenario in Case 1 represents a novel therapeutic indication for FMT. Currently, there is no widely accepted therapy to eliminate MDRO colonization of the gut.^{Reference Tacconelli49} The clinical benefit of FMT for this 14-year-old with leukemia is theoretical, preventing an infection that may or may not occur. Importantly, previous colonization with an MDRO increases the risk for serious infection from the same bacteria.⁵⁰ A common adverse effect of chemotherapy is to kill the healthy white blood cells required to fight bacteria, leaving oncology patients susceptible to severe infections. Patients who come into the hospital with fever and low white blood cells are given specific antibiotics, often guided by the ASP, for possible infection. If a patient is known to harbor a MDRO, they will instead get the extended-spectrum antibiotics. Breaking this cycle of extended-spectrum antibiotics to treat MDRO infections that then select for additional MDROs can best be accomplished by maintaining healthy, “normal” microbes in the gut.⁵¹

There are multiple examples of small-scale studies in the literature that describe mixed success with FMT to eliminate MDRO in the stool. For example, a recent French pilot study demonstrated eradication of CRE in only 25% (2/8) and elimination of VRE colonization in (38%) 3/8 of patients after FMT.^{Reference Davido, Batista, Michelon, Lepainteur, Bouchand, Lepeule, Salomon, Vittecoq, Duran, Escaut, Sobhani, Paul, Lawrence, Perronne, Chast and Dinh52} One patient with persistent VRE that remained colonized after FMT died from VRE in the bloodstream, demonstrating why strategies to eliminate these bacteria from the stool are urgently needed and also highlighting the potential limitations of FMT as a therapeutic intervention.⁵³ Another study of 20 patients with blood disorders had a higher success rate, with 75% achieving MDRO decolonization without any serious adverse events.^{Reference Bilinski54} In both studies, some patients required multiple FMTs to clear the MDRO.⁵⁵ There is currently not enough cumulative evidence to make a recommendation regarding the clinical utility of FMT for MDRO gut decolonization. Whether MDRO gut eradication is sustainable over a long period remains to be determined. For patients with frequent exposure to antibiotics and the healthcare system, the risk of re-colonization with an MDRO may make any intervention successful only in the short term. Whether a temporary eradication, such as while a patient is getting high risk chemotherapy, is worth the risk of FMT is likely to be patient specific. There are several clinical trials evaluating FMT for the decolonization of high-risk patients to prevent MDRO infection, including one enrolling renal transplant patients.⁵⁶ (Table 2).

While the existing evidence suggests a relatively low risk profile for FMT when donors and samples are screened for MDRO colonization,⁵⁷ for patients like the 14-year-old child with leukemia, FMT presents additional risk. Patients receiving chemotherapy can have a damaged gut lining such that bacteria can move more easily into the blood stream.^{Reference Rolston58} If the bacteria reach the blood stream the weak immune system cannot control the infection, with the potential for life-threatening illness. A review of existing scientific literature using FMT in immunocompromised patients, including those who have received stem cell transplants, finds it to be effective with a safety profile similar to immunocompetent patients.^{Reference Webb, Brunner, Ford, Gazdik, Petersen and Hoda59} For example, one study of eighty immunosuppressed patients reported no infections attributable to the FMT.^{Reference Kelly60} Another review of solid organ transplant recipients found the most common adverse effects were worsening of pre-existing inflammatory bowel disease (25%) and re-activation of existing cytomegalovirus infection (14%).^{Reference Cheng61} Again, no blood stream infections from the FMT were reported.⁶² However, the patients in the previously noted FDA safety alert were immunocompromised adults.

In Case 2, using FMT as therapy for primary severe C. difficile, the potential clinical benefit of FMT is not merely theoretical. This is the narrowest expansion of FMT because it is similar to the current clinical indication. The failure rate of antibiotics for C. difficile ranges from 40-60%. Patients who suffer recurrences must deal with debilitating symptoms and multiple courses of antibiotics. As with other populations, the scientific literature supports FMT as a safe therapy for elderly patients with C. difficile infection.^{Reference Friedman-Korn63} However, adverse effects for the patient in Case 2 would include exposure to an uncomfortable procedure or high pill burden potentially without his full understanding of why he was being subjected to these hardships. Unlike the patient in Case 1, the unknown long-term risks are less of a concern because of the decreased time that this patient will have for these risks to manifest. In Case 2, FMT is given as a single administration and does not require prolonged antibiotic therapy where adherence can be an issue.^{Reference El-Saifi, Moyle and Jones64} In other words, use of FMT may very well reduce the treatment burden on the patient (and his non-professional caregiver) when compared with 10 days of oral vancomycin given four times daily or an even longer slow taper of the drug.

A treatment failure described in the literature involves a patient discharged from the hospital on oral vancomycin.^{Reference Bunnell, Danziger and Johnson65} She returned to the hospital three days later with worsening diarrhea after she had difficulty filling the prescription. The high cost of the prescription (> $1000) required an insurance approval which took >48 hrs. during which time the patient was off antibiotics and the diarrhea returned.⁶⁶ An economic analysis of FMT as primary treatment for C. difficile infection found FMT to be cheaper than vancomycin by about $200 dollars and also more effective^{Reference Varier, Biltaji, Smith, Roberts, Jensen, LaFleur and Nelson67} The study concludes that FMT is the most cost-effective option for primary C.difficile infection, an added benefit to consider for both the patients and the health-care system.⁶⁸

While non-professional home-based caregivers are frequently relied upon for providing medication to patients with dementia, the extra care requirements for effectively managing the spread of infection (both in terms of equipment and personal hygiene/care) may also require additional support that is not typically covered by health insurance.^{Reference Denton, Topping and Humphreys69} The challenges of filling the prescription soon after discharge and then administering it successfully over a prolonged period demonstrate why patients (and their caregivers) may prefer a single round of FMT treatment in the hospital.

There is limited published data regarding FMT as first line therapy for primary, severe C. difficile infection, replacing oral vancomycin. One small study compared 11 patients treated with antibiotics with nine patients receiving FMT for primary C. difficile infection.^{Reference Juul70} Antibiotics cured 45% of patients compared with 78% of patients receiving FMT.⁷¹ As of April 1, 2019, there were three clinical trials comparing FMT with antibiotics for primary C. difficile infection, although none were yet actively recruiting (Table 2).⁷²

Once clinicians have evaluated the available treatment options (including FMT) for their likely clinical benefits and burdens, the shared decision-making model requires a conversation between the clinician and patient where the burden and risks of treatment are discussed to identify the therapy most likely to benefit the patient consistent with the best evidence and the patient's values.^{Reference Brody73} Early research on patients' acceptance of FMT as a treatment option suggests that many perceive FMT as “natural” and “organic,”^{Reference Kahn, Gorawara-Bhat, Rubin, Kahn, Vachon, Rodriquez, Goeppiger, Surma, Marks and Rubin74} but a meaningful minority of patients may have significant concern about the potential for disease transmission, means of administration, and perception of the treatment as “dirty” or otherwise contrary to their preferences.^{Reference Park, Mone, Price, Tzimas, Hirsh, Poles, Malter and Chen75} For patients with these concerns, the benefits and burdens of the current standards of care may be more acceptable than FMT, especially considering the limited data on the long-term and mental health effects of FMT.⁷⁶

In Cases 1 and 2, this shared decision-making process is complicated by each of these patients' limited or lack of decision-making capacity. In Case 1, despite being a minor (and generally lacking the legal right to consent to or refuse treatment), the 14-year-old patient is presumed to have ethical decision-making capacity for most of her health care decisions.^{Reference Unguru and Diekema77} Her prior lived experience with cancer treatment means that she has a greater appreciation than many, if not most, people of the trade-off between clinical burden and benefit. So long as she is both able and willing, she should be given the opportunity to participate in the discussion of whether FMT should be used to potentially prevent additional infection.^{Reference Kahn, Nicholson and Gulati78} While there is early clinical data to suggest that FMT may prevent the Case 1 patient from a future MDRO infection, given the limited knowledge of long-term effects of FMT and the experimental nature of the use in Case 1, without both the patient's informed assent (if possible) and her parents' informed permission (i.e., legal consent), FMT use to prevent infection would be unethical.

Similarly, in Case 2, the 73-year-old patient should be given the opportunity to participate in the conversation regarding his care, if not to discuss the specifics of the treatment then to clarify his values and priorities. A diagnosis of dementia and designation of a health care proxy does not inherently mean that a patient lacks ethical decision-making capacity or is no longer able to contribute to the shared decision-making process.⁷⁹ Additionally, as explained above, the potential clinical benefit of a single-day treatment administered in a hospital as opposed to a minimum of a 10-day course of an expensive prescription drug to be administered by non-professional home-based caregivers also implicates the patient's ability and willingness to swallow pills, any support (or lack thereof) provided for the patient's spouse in caring for the patient, and the financial resources of the couple. If the patient's priority is to return home, but the patient's spouse is concerned about whether they will be able to afford the vancomycin, successfully administer the full course of antibiotics, or otherwise handle the increased care burden that accompanies an infectious disease that presents with diarrhea in a patient with some level of cognitive impairment, then any increased clinical risk of FMT over the current standard of care may be outweighed by the reduced financial and emotional burden.

B. Organizational Ethics

“Organizational ethics” frame the nature and function of a health care organization or system,^{Reference Bean80} balancing “the ethical complexities of [] quality patient care with other important goals such as financial sustainability, staff well-being, and public accountability.”^{Reference Silva, Gibson, Sibbald, Connolly, Singer, Gibson, Sibbald, Connolly, Singer, Singer and Viens81} At present, ASPs are built into the expectations and requirements for health care organizations (hospitals and LTC facilities).^{Reference Jump, Gaur, Katz, Crnich, Dumyati, Ashraf, Frentzel, Schweon, Sloane and Nace82} As a result, the use of FMT as part of an ASP will implicate organizational ethics in addition to clinical and research ethics.

ASPs and other organizational or system policies to standardize or improve value-based care consider respect for the individual patient as only one factor in the ethical framework. In addition to providing quality patient care, health care organizations and systems are also responsible for improving the health of populations and reducing the per capita cost of health care.⁸³ Bringing FMT under an ASP's authority is consistent with a health care organization's or system's responsibility for improving the health of populations provided that it is likely to reduce the incidence and prevalence of MDROs, extend the effective lifecycle of critical antibiotics, or better inform our understanding of the clinical safety and efficacy of FMT for future treatment decisions.^{Reference Tosh and McDonald84}

Early antibiotic exposure increases the risk for atopic diseases later in life. In further alignment with the Triple Aim goal to improve population health, an ASP that reduces antibiotic exposure for the very young may reduce the risk for asthma, eczema, and allergy for these children.^{Reference O'Doherty, Virani and Wilcox85} Similarly, a health care organization or system may reduce the per capita cost of health care if FMT is likely to reduce a patient's length of hospital stay, likelihood of readmission, risk of contracting a HAI, or need to purchase an expensive antibiotic.^{Reference Waye, Atkins, Kao, Varier, Biltaji, Smith, Roberts, Jensen, LaFleur, Nelson, Varier, Biltaji, Smith, Roberts, Kyle Jensen, LaFleur and Nelson86} In fact, one study found a per patient savings of close to $30,000 with earlier FMT for C.difficile infection compared with FMT later in the course of hospitalization.^{Reference Waye, Atkins and Kao87} To the extent that the reduction in per capita cost of health care is likely to inure to the benefit of the hospital or system rather than the individual patient, there is a potential conflict of interest in the early adoption of FMT as part of an ASP, especially given the relatively coercive and paternalistic nature of clinical pathways to limit individual patient choice and autonomy. This might happen where orally administered FMT is less expensive for the hospital than a multiple-day course of oral vancomycin because the payment system for inpatient care tends to reflect the “average” costs of inpatient care. If there were evidence that adopting FMT as a recommended or required first-line treatment option as part of an ASP significantly increases the risk and burden to individual patients and confers the primary financial benefit to the system or organization, the decision could only be ethically justified by sound evidence that there will also be a significant public health benefit.

One way that an early adopter ASP could increase the likelihood of public benefit is to incorporate FMT as a formulary product subject to the same oversight and control by the ASP when used for prevention or treatment of infectious disease.⁸⁸ Inherent in an ASP's work is systemic review of antimicrobial agent utilization and revision of clinical pathways for internal quality improvement purposes.

C. Research Ethics

ASPs are actively engaged in the collection, review, and analysis of patient-specific data for purposes beyond the immediate clinical care of those patients. In other words, ASPs conduct “systematic investigation,”⁹⁰ of “identifiable private information” belonging to “living individual[s],”⁹¹ all aspects of human subjects research that are subject to regulation by the federal government. Despite meeting many of the elements of what it means to be human subjects research governed by the federal Common Rule,⁹² an ASP's system evaluation and quality improvement is not traditionally considered to be human subjects research because it is not “designed to develop or contribute to generalizable knowledge,” but rather solely for localized ASP operations.⁹³

Additionally, ASPs are not typically understood as conducting human subjects research because they are driving the standard of care within an organization, informed by evidence-based decisions pertaining to standardized FDA-approved products. Because of the continuing variability between stool samples and the lack of any FDA-approved product, the FDA expects that FMT in the United States will be performed under the regulatory framework of an Investigational New Drug (IND) application,⁹⁴ including compliance with regulatory requirements for clinical investigations⁹⁵ like informed consent⁹⁶ and review by an institutional review board.⁹⁷

The antimicrobial agents typically controlled by an ASP have all been FDA-approved for at least one indication but have not always used exclusively for FDA-approved or otherwise evidence-based indications (thus, the need for ASPs). Similarly, it is foreseeable that some physicians may use FMT for additional clinical indications not yet accepted as standard of care. An example might be an ill patient with inflammatory bowel disease who has not responded to multiple, FDA-approved standard therapies where there is some evidence FMT may be beneficial. These individual cases may not be published to contribute to the general knowledge.^{Reference Khoruts, Hoffmann and Palumbo98} Until such evidence exists to expand FMT as standard of care, any new use case should be considered experimental and treated as research,⁹⁹ ideally part of a larger study. As a result, it should comply with the ethical (and federal regulatory) framework for clinical studies and INDs.¹⁰⁰ Any ASP quality improvement or system evaluation efforts related to FMT utilization as a method to prevent or treat infectious diseases should be more widely disseminated than an ASP's typical scope may support. Any potential public health benefit of FMT use to reduce transmission of and infection by MDROs requires widespread dissemination of this information. This is likely to limit, perhaps appropriately, an ASPs willingness to implement routine use of FMT at the institutional level unless there is a clear distinction between standard of care (e.g. treatment for recurrent C.difficile infection) and research indications.

Because research requires (as much as possible) standardized interventions and methods, ASPs adopting FMT should rely primarily on a single source of product. Similarly, because ethical research requires the minimization of known risks, this single source should be one vetted for rigorous screening of donors using criteria currently established in the field.^{Reference Woodworth, Neish, Miller, Dhere, Burd, Carpentieri, Sitchenko and Kraft101} The recent FDA safety alert regarding the risk of transmitting MDROs during FMT from unscreened stool emphasizes the need for such careful screening of donor material as well as the value of continued research and the dissemination of new information about the risks and benefits of FMT as it becomes available. Additionally, because of the potential divergence between the researcher's and individual patient's interests, research ethics (and the current federal Common Rule)¹⁰² require external consideration/review of research protocols for equipoise (i.e., a state of genuine uncertainty regarding the comparative therapeutic merits of each arm in a trial), minimization of risk for subjects, written disclosure of foreseeable risks (including both physical and privacy risks), equitable and uncoerced recruitment of subjects, and research-specific informed consent (with the option of withdrawing at any time).^{Reference Freedman, Hey, Weijer, Taljaard and Kesselheim103} If there is substantial “off-label” use of FMT at an institution not being performed as part of clinical trials, an ASP could potentially step in via its formulary oversight to ensure FMT is dispensed only for approved indications.

In order for an ASP to ethically support the use of FMT in Case 1 or Case 2, or any other indication that is not currently standard of care, any ASP-approved indication or clinical pathway would also need to incorporate the research-specific informed consent components and institutional review board approval. Both children and adults with dementia are considered vulnerable populations that are often underrep-resented in biomedical research given their relative need for care and new therapies.^{Reference Jongsma, Bos and van de Vathorst104} “Their dependence and limited decision-making capacities increase their vulnerability, necessitating extra precautions when including them in clinical trials.”¹⁰⁵ Research with incompetent research subjects is considered ethical only if the population is necessary for the research and cannot be conducted with competent subjects.¹⁰⁶ Research that involves more than minimal risk to children, as Case 1 presents, may be justified by the prospect of direct benefit to the individual subjects (i.e., the potential prevention of MDRO infection). For this research, the Common Rule additionally requires that: (1) the relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches (i.e., the anticipated benefits and risks of FMT are at least as favorable as the current standard of care to prevent infection), and (2) “adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians.”¹⁰⁷ Although there are many studies of FMT in other pediatric populations (e.g., with C.difficile infection or inflammatory bowel disease), the research to support the use of FMT in children to reduce MDRO colonization comes primarily from competent adults and may not fully inform the risk and benefits of FMT in Case 1. Additionally, the patient's lack of legal right to consent in this situation (the source of her incompetence) does not necessarily reflect an ethical lack of capacity. She may be able, and should be encouraged, to evaluate whether she will assent to the research.

For Case 2, the Common Rule allows a subject's legally authorized representative, e.g., a health care proxy, to consent to participation in research, provided that the legally authorized representative is provided meaningful information about the research in language understandable to the representative and given sufficient opportunity to discuss and consider whether or not to consent to patient participation. The consent process must also minimize the possibility of coercion or undue influence.¹⁰⁸ Here, the use of FMT for initial C. difficile may be researched in competent subjects; it is unlikely that a patient's diagnosis of dementia would uniquely affect his clinical response to FMT insofar as treating his C. difficile infection. To the extent, though, that a patient's likelihood of treatment failure on an extended course of vancomycin is increased by a concurrent diagnosis of dementia because of the reliance on non-professional home-based caregivers and possible difficulties with swallowing pills associated with dementia, the inclusion of patients like the 73-year-old in Case 2 may be ethically justified.

For the patients in both Case 1 and Case 2, the current Common Rule is silent on their ability to withdraw from the study. “Competent research subjects always have the possibility of withdrawing their consent at any time, for whatever reason.”¹⁰⁹ Because the Case 1 and Case 2 patients both lack the legally recognized ability to consent, they should not be assumed to share the competent patient's agency. Instead, they must depend in large part on others for protecting their well-being during the trial.¹¹⁰ To the extent that incompetent research subjects can express their dissent, i.e., their wish to discontinue participation in the research, this wish should be respected.¹¹¹ Additionally, inclusion of incompetent research subjects should explicitly require heightened monitoring for these subjects and they should be withdrawn if they appear unduly distressed.¹¹²

An important variable to consider in expanding the indications for FMT is which patient populations will be eligible for the transplant. Previous trials have included both immunocompetent and immunocom-promised patients as well as children suggesting these would be candidate populations for additional clinical indications for FMT. An ASP will have an important role in defining which patients within the hospital are eligible for FMT to reduce MDRO colonization. This decision making can be guided in part by the results of previously published papers and on-going clinical trials (Table 2) with careful attention to both the efficacy of and the adverse events from FMT.