C. difficile: trials, treatments and new guidelines CONTENTS REVIEW: Vulnerability of long-term care facility residents to Clostridium difficile infection due to microbiome disruptions FUTURE MICROBIOLOGY Vol. 13, No. 13 INTERVIEW: The gut microbiome and the potentials of probiotics: an interview with Simon Gaisford FUTURE MICROBIOLOGY Vol. 14, No. 4 REVIEW: Clostridioides (Clostridium) difficile infection: current and alternative therapeutic strategies FUTURE MICROBIOLOGY Vol. 13, No. 4 EDITORIAL: Microbiome therapeutics – the pipeline for C. difficile infection INTERVIEW: Updates on C. difficile: from clinical trials and guidelines – an interview with Yoav Golan NEWS ARTICLE: Could common painkillers promote C. difficile infection? Review For reprint orders, please contact: [email protected] Vulnerability of long-term care facility residents to Clostridium difficile infection due to microbiome disruptions Beth Burgwyn Fuchs*,1, Nagendran Tharmalingam1 & Eleftherios Mylonakis**,1 1Rhode Island Hospital, Alpert Medical School & Brown University, Providence, Rhode Island 02903 *Author for correspondence: Tel.: +401 444 7309; Fax: +401 606 5624; Helen [email protected]; **Author for correspondence: Tel.: +401 444 7845; Fax: +401 444 8179; [email protected] Aging presents a significant risk factor for Clostridium difficile infection (CDI). A disproportionate number of CDIs affect individuals in long-term care facilities compared with the general population, likely due to the vulnerable nature of the residents and shared environment. Review of the literature cites a number of underlying medical conditions such as the use of antibiotics, proton pump inhibitors, chemotherapy, renal disease and feeding tubes as risk factors. These conditions alter the intestinal environment through direct bacterial killing, changes to pH that influence bacterial stabilities or growth, or influence nutrient availability that direct population profiles. In this review, we examine some of the contributing risk factors for elderly associated CDI and the toll they take on the microbiome. First draft submitted: 18 May 2018; Accepted for publication: 8 August 2018; Published online: 12 October 2018 Keywords: Clostridium difficile • elderly • long-term care facilities • microbiome • vulnerable population Background The intestinal environment is constantly bombarded with microbiome-altering conditions through diet, probiotic- supplemented foods, antibiotics or gastric acid altering medications to name a few [1]. At times, the flux of the microbiome can become favorable to pathogenic bacterial residents, leading to disease. As we learn more about the intestinal microbiome, we find that medical interventions associated with aging particularly contribute to intestinal bacteria imbalances. Harbored within the ranks of the intestinal milieu can be the Gram-positive, spore forming bacterium Clostridium difficile. About 5% of healthy adults have toxigenic C. difficile in their feces and are deemed carriers of the bacteria [2]. The bacteria can benignly reside or colonize the gut without generating symptoms. Conversely, patients can also newly acquire the bacteria, most typically in a healthcare setting. Once acquired, conditions can arise that ignite an active infection. In one such case, necessary therapeutic treatments for primary diseases can result in the reduction of gut flora that normally ensures a low population of C. difficile. This gut dysbiosis can lead to an active Clostridium difficile infection (CDI). Long-term care facility (LTCF) residents often experience or fall within multiple risk factor categories leaving them prone to CDI [3]. Vulnerability and incidence within the elderly population C. difficile was estimated to cause 500,000 infections in the USA in 2011; among the infected, approximately 29,000 died within 30 days of diagnosis [4]. In CDC reports provided by the Emerging Infections Program between 2012 and 2015, each year exhibit increase incidences compared with the previous year in the most advanced aged group within the study; the ≥65 years of age group was determined to have an incidence of 559.15 per 1000 persons in a 2015 annual report [5]. Within this group, there was a higher incidence of healthcare-associated CDI than community-associated CDI [4,6]. Transfer from acute care facilities to LTCF C. difficile acquisition is typically spread by healthcare workers, contact with contaminated surfaces, or by an individual shedding spores as a result of a recent infection. Among elderly patients with CDI during their hospital- 10.2217/fmb-2018-0157 C 2018 Future Medicine Ltd Future Microbiol. (2018) 13(13), 1537–1547 ISSN 1746-0913 1537 Review Fuchs, Tharmalingam & Mylonakis ization, 28% were discharged to LTCFs [7], facilitating the spread of C. difficile from the acute care setting to the LTCF community. A study of LTCF residents predicted a patient colonization rate upon admission of 8.9% [8]. Primary acquisitions at LTCFs Among LTCF residents, approximately 1 in 50 individuals ≥65 years of age was diagnosed with CDI during their stay (median resident stay was 33 days, ranging from 19 to 90 days) [9] and, for individuals housed in nursing homes with CDI, it was estimated that 8% died within 30 days of onset [10]. Between 2006 and 2012, a study that included 120 LTCFs managed by the United States Veterans Health Administration reviewed 35,754 cases of CDI, 20% were diagnosed at a LTCF [11]. Although the study of a veteran’s facility included a higher population of men compared with women, it does generate a portrait of the problem that C. difficile constitutes within a shared living environment. The question then arises whether LTCF CDI onset is the result of recent hospitalization or a new acquisition. In an investigation that included 33 LTCF conducted in Monroe County, New York, researchers found 425 onset cases of CDI within LTCF with an incidence of 2.3 cases per 10,000 resident-days in 2010. Within this study, they found that 50% of these CDI cases were more than 4 weeks after hospital discharge [3]. Infections occurring more than 4 weeks after hospitalization could possibly be attribute to a new infection. To examine this point, Ponnada and colleagues followed patients for 6 weeks after transfer to LTCFs. Among a group of 110 individuals that were followed in the study, 12 (11%) were tested positive for C. difficile atthetimeof admission (as tested by screening perirectal swabs using an enzymatic immunoassay test followed by confirmatory PCR), 4 of which developed CDI within 1 month. Among a group of 82 patients that entered the LTCF as negative for C. difficile carriership, 22 (27%) acquired the bacteria while in residence [12]. Thus, transient carriership or colonization in the LTCF is an issue. CDI burden Once colonized, patients can suffer not only from an initial onset infection, but potentially numerous reoccurrence events. A 2014 cost estimate of CDI was placed at US$5.4 billion with 68.6% of infections attributed to individuals >64 year of age within the care settings of hospitals, LTCF or long-term acute care facilities. Of the estimated 606,058 cases in the study, 25% were LTCF residents [13]. The problem is exacerbated when one considers that C. difficile can be acquired in conjunction to a primary infection and may contribute to patient morbidity and mortality. Archbald-Pannone and colleagues report that according to medical billing data, in 2008 10% (45 of 457) of all inpatient elderly deaths had a diagnosis of CDI concurrent to another disease among the Virginia hospitals included in the study [7]. To explore the risk factors associated with C. difficile acquisition in the elderly and the role played in microbiome dysbiosis, we searched PubMed from 2002 up to June, 2018 using the term: C. difficile infection, risk factors and elderly. We screened articles by title and abstract. Only manuscripts in English were reviewed. Studies were considered within the USA were preferential, but when data were lacking, we also included studies conducted outside the USA. Conference abstracts were not considered for inclusion. Additional references were obtained if further information was needed. Microbiome The human gut is a major complex ecosystem and within this ecological niche homeostasis plays a major role in preventing CDI [14,15]. Up to 30% of intestinal spore-forming bacteria represent bacterial families from Lach- nospiraceae, Ruminococcaceae, Clostridiaceae and Peptostreptococcaceae. The further populous is made up of normal intestinal microbiota such as Enterobacteriaceae, Rikenellaceae, Porphyromonadaceae, Bacteroidaceae, Coriobacteriaceae, Bifidobacteriaceae, Erysipelotrichaceae, Enterococcaceae, Bacillaceae, Lactobacillaceae and Veil- lonellaceae colonizing the gut from birth [14]. Although most of the microbiome remain consistent throughout life, structural changes can occur in the bacterial populations as individuals advance in age. Although these changes may not be reflected in altered species varieties, there can be fluctuations detectable in the viable bacteria cell counts [16]. Outside of naturally influenced fluctuations, numerous medical interventions encountered with advanced age result in dysbiosis of normal adult flora and can subsequently lead to bouts with CDI. 16S rRNA pyrosequencing analysis found a reduction in microbiota in elderly CDI patients [17]. A study by Hopkins et al. aimed to interrogate the fecal microbiota to species level in healthy young adults (aged 21–34), adults ≥67 and adults ≥67 with C.