Michael H. Woodworth

Challenges in fecal donor selection and screening for fecal microbiota transplantation: A review

ABSTRACT Fecal microbiota transplantation is best understood as an effective and inexpensive therapy for recurrent Clostridium difficile infection but fecal donor selection and screening should be periodically revised. Here, we review current recommendations for selection and screening of fecal donors for fecal microbiota transplantation. We recommend considering diabetes mellitus, prior cardiovascular events, and clinical healthcare exposure as fecal donor exclusion criteria until more is known about the association of these conditions with the human gut microbiome. We review the non-bacterial members of the human gut microbiome, associations of the gut microbiome with colorectal malignancies, the human gut resistome and how these may impact future donor screening recommendations. Collaboration between clinicians, clinical laboratory scientists, industry and regulatory agencies will be critically important for continued improvement in donor selection and screening.

Laboratory Testing of Donors and Stool Samples for Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection

ABSTRACT Fecal microbiota transplantation is an efficacious and inexpensive therapy for recurrent Clostridium difficile infection, yet its safety is thought to depend on appropriate fecal donor screening. FDA guidance for regulation of this procedure is in flux, but screening and manufacture of fecal material from asymptomatic donors present many challenges to clinical laboratories. This minireview summarizes FDA regulatory changes, principles of donor selection, and recommended laboratory screening practices for fecal microbiota transplantation.

Increasing Nocardia Incidence Associated with Bronchiectasis at a Tertiary Care Center

Rationale: Nocardia is a genus of pathogens that most commonly afflict immunocompromised hosts but may be an emerging infection among persons with bronchiectasis. Objectives: To examine the epidemiology and clinical presentation of adult patients with Nocardia and bronchiectasis relative to other patient groups. Methods: We examined a retrospectively assembled cohort of adults at Duke University Hospital in Durham, North Carolina with at least one positive culture from a bodily fluid or tissue specimen for Nocardia between January 1996 and December 2013. Denominator data for key populations (e.g., bronchiectasis, transplant) were obtained using International Classification of Diseases, Ninth Revision codes. In addition, we performed a case‐control analysis to examine the relationship between inhaled corticosteroid use and Nocardia lung infection among otherwise immunocompetent patients with bronchiectasis. Measurements and Main Results: We identified 183 patients with one or more cultures positive for Nocardia: 44 from 1996 to 2001, 64 from 2002 to 2007, and 75 from 2008 to 2013. Immune compromise was common (56%), particularly solid organ or hematopoietic cell transplant (30%). Infection usually was confined to the lungs (62%), followed by skin (10%), other sites (6%), brain (2%), and multiple sites (17%). Non‐cystic fibrosis bronchiectasis was common among both immunocompetent (38%) and immunocompromised (10%) patients. Nocardia incidence in patients with bronchiectasis increased significantly over time, but there was no significant change in Nocardia incidence in hematopoietic cell or solid organ transplant recipients (our largest immunocompromised population). Among patients with bronchiectasis, Nocardia was positively but nonsignificantly associated with use of inhaled corticosteroids (odds ratio, 1.8; 95% confidence interval, 0.7‐4.4). Conclusions: The increasing incidence of Nocardia infections at our medical center appears to be driven by increased incidence in patients with bronchiectasis rather than increases in immunocompromised populations. It is unclear whether increased environmental exposures, microbiologic surveillance, or other factors account for the increased incidence of Nocardia in our patients with bronchiectasis.

Durability and Long-term Clinical Outcomes of Fecal Microbiota Transplant Treatment in Patients With Recurrent Clostridium difficile Infection

Background Fecal microbiota transplant (FMT) appears safe and effective for treatment of recurrent Clostridium difficile infection (RCDI). However, durability, long-term clinical outcomes, and patient satisfaction after FMT are not well described. Methods Eligible patients who received FMT for RCDI at Emory Hospital between 1 July 2012 and 31 December 2016 were contacted via telephone for a follow-up survey. Of 190 eligible patients, 137 (72%) completed the survey. Results Median time from last FMT to follow-up was 22 months. Overall, 82% (113/137) of patients at follow-up had no recurrence of C. difficile infection (CDI) post-FMT (non-RCDI group) and 18% (24/137) of patients had CDI post-FMT (RCDI group). Antibiotic exposure for non-CDI infections after FMT was more common in the RCDI group compared to the non-RCDI group (75% vs 38%, P = .0009). Overall, 11% of patients reported improvement or resolution of diagnoses not related to CDI post-FMT, and 33% reported development of a new medical condition or symptom post-FMT. Ninety-five percent of patients (122/128) indicated that they would undergo FMT again, and 70% of these 122 reported that they would prefer FMT to antibiotics as initial treatment if they were to have a CDI recurrence. Conclusions In this follow-up survey of outcomes after FMT at a median of 22 months follow-up, 82% of patients had durable cure of CDI. Patients with recurrence had more post-FMT antibiotic exposure, underscoring the need for thoughtful antibiotic use and a potential role for prophylactic microbiome enrichment to reduce recurrence.

Tacrolimus concentration to dose ratio in solid organ transplant patients treated with fecal microbiota transplantation for recurrent Clostridium difficile infection

Fecal microbiota transplantation (FMT) is increasingly being performed for Clostridium difficile infection in solid organ transplant (SOT) patients; however, little is known about the potential pharmacokinetic or pharmacomicrobial effects this may have on tacrolimus levels. We reviewed the medical records of 10 SOT patients from September 2012‐December 2016 who were taking tacrolimus at time of FMT for recurrent C. difficile infection. We compared the differences in tacrolimus concentration/dose ratio (C/D ratio) 3 months prior to FMT vs 3 months after FMT. The mean of the differences in C/D ratio calculated as (ng/mL)/(mg/kg/d) was −17.65 (95% CI −1.25 to 0.58) (ng/mL)/(mg/kg/d), P‐value .43 by Wilcoxon signed‐rank test. The mean of the differences in C/D ratio calculated as (ng/mL)/(mg/d) was −0.33 (95% CI −1.25 to 0.58) (ng/mL)/(mg/d), P‐value .28 by Wilcoxon signed‐rank test. Of these patients, 2/10 underwent allograft biopsy for allograft dysfunction in the year after FMT, with no evidence of allograft rejection on pathology. These preliminary data suggest that FMT may not predictably alter tacrolimus levels and support its safety for SOT patients however further study in randomized trials is needed.

Disabling Dactylitis and Tenosynovitis Due to Mycobacterium haemophilum in a Patient With Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome

A 44-year-old man with acquired immune deficiency syndrome (AIDS) and CD4 cell count of 8 cells/mm presented with painful and erythematous swollen hands 1 month after starting antiretroviral therapy (ART) after a 4-year hiatus from care. During his interrupted human immunodeficiency virus (HIV) treatment, he was living in Mexico and incarcerated for a period of time. For the year preceding presentation with hand swelling, he was working as a cook in a Mexican restaurant in San Francisco, California, where he had frequent finger trauma from opening metal cans and preparing shrimp. Thickened flexor tendons and dactylitis were present bilaterally with stiffness and severely limited flexion and extension of his fingers (Figures 1 and 2). He did not have systemic symptoms. Skin biopsies demonstrated granulomatous dermatitis and panniculitis (Figure 3), with negative stains for organisms. Polymerase chain reaction and immunohistochemical stains for mycobacteria were negative. TB treatment along with clarithromycin was initiated empirically. Cultures from a second excisional biopsy of deep palm soft tissue on chocolate agar incubated at 30°C grew Mycobacterium haemophilum, suggesting unmasking immune reconstitution inflammatory syndrome (IRIS) in setting of HIV treatment. Additional biopsies grew M. haemophilium from mycobacterial cultures. Treatment was changed to moxifloxacin, ethambutol, rifabutin, and azithromycin.

Diagnostic and Therapeutic Considerations for Oncology Patients With Clostridium difficile Infection

Diagnosis and Classification Despite the impressive burden ofC difficile infection in the United States, it has become clear that there are many subtle complexities in diagnosis and classification of C difficile infection, which is also the case in oncology patients. Although toxigenic culture for C difficile is the gold-standard diagnostic technique, this method is infrequently performed because of its complex laboratory protocol requiring experienced technologists, delayed turnaround time for results, and limited scalability.Nucleic acid amplification tests are highly sensitive but have correspondingly high rates of falsepositive results. Even a test with 99% sensitivity and 99% specificity (or combination test algorithms with similar performance characteristics) will produce falsepositive results. As Neeman and Freifeld point out, overdiagnosis of C difficile infection in these patients puts them at risk for overtreatment. Overtreatment, in turn, worsens the risk of intestinal dysbiosis, defined as abnormal intestinal microbiota composition or lack of diversity. Oncology patients are already at high risk of developing intestinal dysbiosis through frequent and prolonged health care exposures, and providers should be mindful of other factors that may exacerbate this risk. As examples, in amousemodel, metronidazole was shown to have prolonged detrimental changes in gut microbiota composition, and in an industry-supported study, use of enteric vancomycin was shown to increase risk of colonization with Candida and vancomycin-resistant Enterococcus. Additional work is needed to better understand ideal tests and frequency of C difficile testing in oncology patients. There are multiple scoring systems for severity of C difficile infection, but the importance of classification of infection severity should depend on the implications for clinical care. It is not clear that such classification improves outcomes if therapies such as oral vancomycin or fecal microbiota transplantation are increasingly considered as first-line treatments. The potential to introduce collider bias is another challenge of such scoring systems when they include multiple factors related to C difficile infection that could be either causes or effects (eg, intensive care unit admission or hospitalization) rather than causal factors alone. Collider bias is the creation of an artificial statistical relationship between two factors when conditioning on common effects of a disease rather

The use of microbiome restoration therapeutics to eliminate intestinal colonization with multidrug-resistant organisms

Antibiotic resistance (AR) has been described by the World Health Organization as an increasingly serious threat to global public health. Many mechanisms of AR have become widespread due to global selective pressures such as widespread antibiotic use. The intestinal tract is an important reservoir for many multidrug-resistant organisms (MDROs), and next-generation sequencing has expanded understanding of the resistome, defined as the comprehensive sum of genetic determinants of AR. Intestinal decolonization has been explored as a strategy to eradicate MDROs with selective digestive tract decontamination and probiotics being notable examples with mixed results. This review focuses on fecal microbiota transplantation and the early evidence supporting its efficacy in decolonizing MDROs and potential mechanisms of action to reduce AR genes. Current evidence suggests that fecal microbiota transplantation may have promise in restoring healthy microbial diversity and reducing AR, and clinical trials are underway to better characterize its safety and efficacy.

Fecal microbiota transplantation for the treatment of recurrent and severe Clostridium difficile infection in solid organ transplant recipients: A multicenter experience.

Fecal microbiota transplant (FMT) is recommended for Clostridium difficile infection (CDI) treatment; however, use in solid organ transplantation (SOT) patients has theoretical safety concerns. This multicenter, retrospective study evaluated FMT safety, effectiveness, and risk factors for failure in SOT patients. Primary cure and overall cure were defined as resolution of diarrhea or negative C difficile stool test after a single FMT or after subsequent FMT(s) ± anti‐CDI antibiotics, respectively. Ninety‐four SOT patients underwent FMT, 78% for recurrent CDI and 22% for severe or fulminant CDI. FMT‐related adverse events (AE) occurred in 22.3% of cases, mainly comprising self‐limiting conditions including nausea, abdominal pain, and FMT‐related diarrhea. Severe AEs occurred in 3.2% of cases, with no FMT‐related bacteremia. After FMT, 25% of patients with underlying inflammatory bowel disease had worsening disease activity, while 14% of cytomegalovirus‐seropositive patients had reactivation. At 3 months, primary cure was 58.7%, while overall cure was 91.3%. Predictors of failing a single FMT included inpatient status, severe and fulminant CDI, presence of pseudomembranous colitis, and use of non‐CDI antibiotics at the time of FMT. These data suggest FMT is safe in SOT patients. However, repeated FMT(s) or additional antibiotics may be needed to optimize rates of cure with FMT.

Ethical Considerations in Microbial Therapeutic Clinical Trials.

As understanding of the human microbiome improves, novel therapeutic targets to improve human health with microbial therapeutics will continue to expand. We outline key considerations of balancing risks and benefits, optimising access, returning key results to research participants, and potential conflicts of interest.