Editorial Commentary: The Dawning of Microbiome Remediation for Addressing Antibiotic Resistance.

The Centers for Disease Control and Prevention (CDC) estimates that over 2 million infections in the United States each year are caused by antibiotic-resistant pathogens described as urgent, serious, and concerning threats, leading to 23 000 deaths and billions of dollars in excess medical costs [1]. Nearly half of these 18 antibiotic resistant threats are healthcareassociated pathogens and at least 5 frequently colonize the lower intestinal microbiota of patients. Among the many host and environmental factors that influence the composition of our microbiota, the most significant is the receipt of antibiotics [2–4]. Treatment with antibiotics eliminates not only pathogenic but also beneficial bacteria, resulting in severe disruption of the intestinal microbiota for an extended period of time (>6 months) [2]. This loss of diversity in the intestinal microbial composition places individuals at increased risk for poor outcomes, including colonization by pathogens, such as C. difficile and other multidrugresistant organisms (MDROs), which can give way to their expansion, dominance, and infection and bacteremia [5–8]. Among the almost 500 000 cases of Clostridium difficile infection (CDI) that occur each year, there are an estimated 83 000 recurrences of infection annually [9]. In recent years, the use of fecal microbiota transplantation (FMT) has garnered attention as a method for treating recurrent CDI by restoring the intestinal microbiota to a healthy state, preventing further recurrences [10]. The Food and Drug Administration (FDA) has determined that FMTs are a biological product and a drug, and an investigational new drug (IND) application is required to use FMT for clinical indications, except for recurrent CDI for which an application is encouraged but not required (http:// www.regulations.gov/#!documentDetail; D=FDA-2013-D-0811-0002). This leaves a window open to use FMT for eradication of other MDROs, provided an IND application is submitted. Efforts to treat recurrent CDI have found concomitant eradication of other MDROs [11] and other groups have demonstrated clearance of ongoing colonization or recurrent infection by MDROs through FMT [12, 13]. In this issue of Clinical Infectious Diseases, Millan et al report on a small study (N = 20) of patients who underwent FMT via colonoscopy for recurrent CDI. The investigators demonstrated, using a combination of deep sequencing metagenomics and resistance gene microarray, a reduction in the diversity and number of resistance genes in patients’microbiota (ie, resistome) following FMT. Although this was a small, uncontrolled study, there was additional indirect evidence for a causal role for FMT in shrinking the resistome found in the 9 of 20 patients who failed their initial FMT, requiring a second FMT. This clinical failure correlated with a failure to reduce the resistome, along with a failure to increase bacterial diversity (ie, resistance gene diversity varied inversely with bacterial diversity) and a persistent dominance by Proteobacteria, especially Escherichia coli and Klebsiella pneumoniae. In addition, the investigators demonstrated that the microbiomes of the 3 FMT donors were similar in diversity to a healthy cohort (age 18–40 years) from the Human Microbiome Project. Nonetheless, the study lacks a recurrent CDI control group who did not receive FMT, and therefore one cannot assess how much FMT contributes to shrinkage of the resistome over and above simply avoiding subsequent antibiotic exposure. In addition, current metagenomics methods are unable to link an antibiotic resistance gene to a particular species member of the microbiome and thereby identify potentially pathogenic MDROs present. Finally, the load of antibiotic resistance genes present in these patients and correlation of the load with risk of developing a subsequent MDRO infection or transmitting MDROs or determinants to other patients are unknown. We can anticipate various routes to the future use of microbiome remediation as a means to address antibiotic resistance. Although FMT using screened, healthy donors is currently widely practiced in the treatment of recurrent CDI, one can foresee a possible day when a patient’s own microbiome is electively harvested, frozen or otherwise “banked,” and later used for autologous retransplant following a microbiome-disrupting therapy or Received 11 March 2016; accepted 17 March 2016. Correspondence: L. C. McDonald, 1600 Clifton Rd, MS A31, Atlanta, GA 30333 ([email protected]). Clinical Infectious Diseases Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US. DOI: 10.1093/cid/ciw187