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Symposium Article SSCI Presidential Symposium: The MicrobiomeSymposium Editor: C. Mel Wilcox, MD| Volume 356, ISSUE 5, P433-440, November 2018

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The Use of Microbiome Restoration Therapeutics to Eliminate Intestinal Colonization With Multidrug-Resistant Organisms

Published:August 29, 2018DOI:https://doi.org/10.1016/j.amjms.2018.08.015

      Abstract

      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.

      Key Indexing Terms

      Bacterial Antimicrobial Resistance

      The World Health Organization describes antimicrobial resistance (AR) as an “increasingly serious threat to global public health.”
      World Health Organization
      Antimicrobial resistance.
      Multidrug-resistant organisms (MDROs) have been growing in prevalence
      • Manges AR
      • Steiner TS
      • Wright AJ
      Fecal microbiota transplantation for the intestinal decolonization of extensively antimicrobial-resistant opportunistic pathogens: a review.
      and global distribution, accompanied by a related rise in costs, disability and mortality.
      • Martens E
      • Demain AL
      The antibiotic resistance crisis, with a focus on the United States.
      • Zhang R
      • Eggleston K
      • Rotimi V
      • et al.
      Antibiotic resistance as a global threat: evidence from China, Kuwait and the United States.
      • Goossens H
      • Ferech M
      • Vander Stichele R
      • et al.
      Outpatient antibiotic use in Europe and association with resistance: a cross-national database study.
      Some AR mechanisms are transmissible through mobile genetic elements that allow their spread beyond specific taxa. However, the Centers for Disease Control and Prevention and other agencies have previously outlined and prioritized the threats posed by specific MDROs such as methicillin-resistant Staphylococcus aureus (MRSA), extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL), carbapenem-resistant Enterobacteriaceae (CRE) and vancomycin-resistant Enterococcus (VRE).

      Center for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. 2013.

      MRSA was one of the first recognized MDROs, identified in the United Kingdom in 1961.
      • Barber M
      Methicillin-resistant staphylococci.
      Since that time, MRSA has been associated with increased inpatient mortality, higher hospital costs, worse quality of life and greater financial costs postdischarge.
      • Pada SK
      • Ding Y
      • Ling ML
      • et al.
      Economic and clinical impact of nosocomial meticillin-resistant Staphylococcus aureus infections in Singapore: a matched case-control study.
      • Cosgrove SE
      • Qi Y
      • Kaye KS
      • et al.
      The impact of methicillin resistance in Staphylococcus aureus bacteremia on patient outcomes: mortality, length of stay, and hospital charges.
      The impact of MRSA extends beyond the hospital setting, with community-acquired MRSA (CA-MRSA) emerging as common pathogen in the United States in the early 2000s.
      • Fridkin SK
      • Hageman JC
      • Morrison M
      • et al.
      Methicillin-resistant Staphylococcus aureus disease in three communities.
      • Moran GJ
      • Krishnadasan A
      • Gorwitz RJ
      • et al.
      Methicillin-resistant S. aureus infections among patients in the emergency department.
      • Stefani S
      • Chung DR
      • Lindsay JA
      • et al.
      Meticillin-resistant Staphylococcus aureus (MRSA): global epidemiology and harmonisation of typing methods.
      Similarly, ESBLs have become a significant source of infection in both nosocomial and community settings, especially with recognition of community-acquired ESBL urinary tract infections (UTIs)
      • Pitout JDD
      • Nordmann P
      • Laupland KB
      • et al.
      Emergence of Enterobacteriaceae producing extended-spectrum β-lactamases (ESBLs) in the community.
      that can be complicated by bacteremia requiring inpatient management.
      • Pitout JD
      • Laupland KB
      Extended-spectrum ??-lactamase-producing Enterobacteriaceae: an emerging public-health concern.
      • Ben-Ami R
      • Schwaber MJ
      • Navon-Venezia S
      • et al.
      Influx of extended-spectrum beta-lactamase-producing enterobacteriaceae into the hospital.
      • Rodríguez-Baño J
      • Navarro MD
      • Romero L
      • et al.
      Bacteremia due to extended-spectrum beta-lactamase-producing Escherichia coli in the CTX-M era: a new clinical challenge.
      Further, according to surveillance by the Centers for Disease Control and Prevention, a rising number of CRE have been identified since 2001,
      Centers for Disease Control and Prevention (CDC)
      Vital signs: carbapenem-resistant Enterobacteriaceae.
      most prominently in southern Europe and Asia.
      • Nordmann P
      • Naas T
      • Poirel L
      Global spread of Carbapenemase-producing Enterobacteriaceae.
      Infections with CRE, including Klebsiella pneumoniae carbapenemase-(KPC) producing organisms have associated mortality of up to 71.9% in solid organ transplant recipients.
      • Borer A
      • Saidel-Odes L
      • Riesenberg K
      • et al.
      Attributable mortality rate for carbapenem-resistant Klebsiella pneumoniae bacteremia.
      • Perez F
      • Van Duin D
      Carbapenem-resistant enterobacteriaceae: a menace to our most vulnerable patients.
      VRE, including Enterococcus faecium and faecalis, are another important group of MDROs. In one meta-analysis, patients with VRE bacteremia were approximately 2.5 times more likely to die than those with Enterococcus bacteremia susceptible to vancomycin.
      • DiazGranados CA
      • Zimmer SM
      • Mitchel K
      • et al.
      Comparison of mortality associated with vancomycin-resistant and vancomycin-susceptible enterococcal bloodstream infections: a meta-analysis.
      VRE bacteremia has also been associated with increased hospital costs
      • Stosor V
      • Peterson LR
      • Postelnick M
      • et al.
      Enterococcus faecium bacteremia: does vancomycin resistance make a difference?.
      • Jung E
      • Byun S
      • Lee H
      • et al.
      Vancomycin-resistant enterococcus colonization in the intensive care unit: clinical outcomes and attributable costs of hospitalization.
      and length of stay.
      • Lucas GM
      • Lechtzin N
      • Puryear DW
      • et al.
      Vancomycin-resistant and vancomycin-susceptible enterococcal bacteremia: comparison of clinical features and outcomes.
      • Lloyd-Smith P
      • Younger J
      • Lloyd-Smith E
      • et al.
      Economic analysis of vancomycin-resistant enterococci at a Canadian hospital: assessing attributable cost and length of stay.
      There are several patient groups at risk for VRE, including the critically ill who require intensive care unit (ICU) care, residents of long-term care facilities and the immunosuppressed.
      • Olivier CN
      • Blake RK
      • Steed LL
      • et al.
      Risk of vancomycin-resistant enterococcus (VRE) bloodstream infection among patients colonized with VRE.
      In one study of adult patients undergoing allogeneic hematopoietic cell transplantation, 10% developed VRE bacteremia with an associated mortality of 88% within 1.1 months.
      • Tavadze M
      • Rybicki L
      • Mossad S
      • et al.
      Risk factors for vancomycin-resistant enterococcus bacteremia and its influence on survival after allogeneic hematopoietic cell transplantation.
      Though phenotypic antimicrobial susceptibility testing remains the gold standard, the increasing availability and decreasing costs of molecular diagnostics to detect genetic determinants of AR are directing increasing attention to integrating these diagnostic tests in research and clinical care.

      The Resistome

      There are numerous mechanisms by which bacteria, such as the aforementioned MDROs, may become resistant to antibiotics. These include variations in antimicrobial targets of activity through changes in gene expression levels or target modification, physical barriers against antibiotics, phenotypic or behavioral changes such as expression or activation of efflux pumps and inactivation of antimicrobial molecules. Determinants of these mechanisms are often coded by genes that reside on chromosomes or plasmids, the latter being more amenable to horizontal transmission.
      • Allen HK
      • Donato J
      • Wang HH
      • et al.
      Call of the wild: antibiotic resistance genes in natural environments.
      Novel mechanisms can develop as a result of spontaneous mutations and lateral gene transfer, resulting in the creation and spread of AR genes,
      • Ochman H
      • Lawrence JG
      • Grolsman EA
      Lateral gene transfer and the nature of bacterial innovation.
      which has been noted in niches as varied as soil
      • Allen HK
      • Donato J
      • Wang HH
      • et al.
      Call of the wild: antibiotic resistance genes in natural environments.
      and the human intestinal tract. The human intestinal microbiota is largely comprised of bacteria, which accounts for its potential for accumulation and transmission of AR genes. Strains of AR bacteria passing through the intestine after ingestion can further introduce additional AR genes
      • Salyers AA
      • Gupta A
      • Wang Y
      Human intestinal bacteria as reservoirs for antibiotic resistance genes.
      • Simonsen GS
      • Haaheim H
      • Dahl KH
      • et al.
      Transmission of VanA-type vancomycin-resistant enterococci and vanA resistance elements between chicken and humans at avoparcin-exposed farms.
      • van den Braak N
      • van Belkum A
      • van Keulen M
      • et al.
      Molecular characterization of vancomycin-resistant enterococci from hospitalized patients and poultry products in the Netherlands.
      with the gut serving as a reservoir for these drug-resistant opportunistic pathogens. The comprehensive sum of AR genes in a microbial community has been dubbed the “resistome.”
      • Forslund K
      • Sunagawa S
      • Kultima JR
      • et al.
      Country-specific antibiotic use practices impact the human gut resistome.
      • van Schaik W
      The human gut resistome.
      Alterations in microbial community composition, including expansion of AR capacity through reductions in protective taxa may contribute to progression from colonization to infectious disease.
      • van Schaik W
      The human gut resistome.
      • Stecher B
      • Maier L
      • Hardt WD
      “Blooming” in the gut: how dysbiosis might contribute to pathogen evolution.
      A healthy intestinal microbiota is thought to be primarily comprised of a variety of anaerobic genera including Lactobacillus, Faecalibacterium and Bacteroides that demonstrate a mutualistic relationship with the body. Pathogenic genera such as Escherichia and Enterococcus can become more relatively abundant when there is reduced intestinal microbiome density and diversity, particularly with reduced presence of the commensal anaerobes.
      • Araos R
      • Tai AK
      • Snyder GM
      • et al.
      Predominance of Lactobacillus spp. among patients who do not acquire multidrug-resistant organisms.
      • Buffie CG
      • Pamer EG
      Microbiota-mediated colonization resistance against intestinal pathogens.
      Antibiotic use is a well-described cause of intestinal dysbiosis. Research using mouse models dating to the 1970s has demonstrated detrimental effects of antibiotics on a normal microbiota.
      • Van Der Waaij D
      • Berghuis-de Vries JM
      • Lekkerkerk-Van Der Wees JEC
      Colonization resistance of the digestive tract in conventional and antibiotic-treated mice.
      • Thijm HA
      • van der Waaij D
      The effect of three frequently applied antibiotics on the colonization resistance of the digestive tract of mice.
      For example, antibiotic treatment increased levels of resistant bacteria which translocated across the intestinal epithelial barrier and caused disseminated infection.
      • Yu LC-H
      • Shih Y-A
      • Wu L-L
      • et al.
      Enteric dysbiosis promotes antibiotic-resistant bacterial infection: systemic dissemination of resistant and commensal bacteria through epithelial transcytosis.
      Ubeda et al showed that antibiotic administration promoted Enterococcus (including VRE), Enterobacteriaceae and Clostridium spp. colonization of the small and large intestines.
      • Ubeda C
      • Taur Y
      • Jenq RR
      • et al.
      Vancomycin-resistant Enterococcus domination of intestinal microbiota is enabled by antibiotic treatment in mice and precedes bloodstream invasion in humans.
      In another murine study, antibiotics that suppress anaerobes such as piperacillin-tazobactam and clindamycin promoted KPC colonization.
      • Perez F
      • Pultz MJ
      • Endimiani A
      • et al.
      Effect of antibiotic treatment on establishment and elimination of intestinal colonization by KPC-producing Klebsiella pneumoniae in mice.
      Caballero et al demonstrated that the intestinal colonization of VRE, did not impede that of KPC, illustrating that colonization with multiple MDROs can occur over time within an individual.
      • Caballero S
      • Carter R
      • Ke X
      • et al.
      Distinct but spatially overlapping intestinal niches for vancomycin-resistant enterococcus faecium and carbapenem-resistant klebsiella pneumoniae.
      In humans, the resistome and AR potential have been shown to vary across countries and have been suspected to be related to historically different antibiotic usage patterns in each place.
      • Forslund K
      • Sunagawa S
      • Kultima JR
      • et al.
      Country-specific antibiotic use practices impact the human gut resistome.
      Furthermore, patients who received anti-anaerobic antibiotic therapy have been found to have significantly more MDRO colonization than those who had received minimal antianaerobic treatment.
      • Donskey CJ
      • Chowdhry TK
      • Hecker MT
      • et al.
      Effect of antibiotic therapy on the density of vancomycin-resistant enterococci in the stool of colonized patients.
      There are additional causes of dysbiosis that increase the risk of MDRO infection in certain patient populations. In patients preparing for hematopoietic stem cell transplantation, chemotherapy was associated with significantly increased concentration of Proteobacteria, Firmicutes and Actinobacteria.
      • Montassier E
      • Gastinne T
      • Vangay P
      • et al.
      Chemotherapy-driven dysbiosis in the intestinal microbiome.
      The hematopoietic stem cell transplantation itself, in combination with antibiotics that may have been started for empiric or prophylactic therapy, reduces microbiome diversity, leading to relative dominance of certain bacterial taxa. This can be extreme, as evidenced by one study where Enterococcus was found to be the most common genus at 40.4% of patients of these patients, 92% had a detected vanA gene consistent with VRE.
      • Taur Y
      • Xavier JB
      • Lipuma L
      • et al.
      Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation.
      A mouse model suggests that burn injury may also lead to dysbiosis, as it was found to decrease aerobic and anaerobic species in a manner similar to antibiotic therapy.
      • Kuethe JW
      • Armocida SM
      • Midura EF
      • et al.
      Fecal microbiota transplant restores mucosal integrity in a murine model of burn injury.

      Decolonization as Treatment

      Given the importance of the intestinal microbiome as a reservoir for AR, decolonization of the intestine has been studied as a treatment option to eradicate MDROs. Studies of the natural history of MDRO colonization suggest that spontaneous clearance of these organisms is hard to predict and frequently incomplete. In 2 studies of VRE colonization in oncology patients, at least 60% of patients had either intermittent or persistent presence of VRE on surveillance after at least 2 weeks.
      • Montecalvc MA
      • Chung M
      • Carraher M
      • et al.
      Natural History of colonization with vancomycin-resistant enterococcus faecium.
      • Roghmann MC
      • Qaiyumi S
      • Schwalbe R
      • et al.
      Natural history of colonization with vancomycin-resistant Enterococcus faecium.
      Similarly, in a study of renal and liver transplant recipients, only 35% of the patients were deemed to have VRE clearance, defined as negative rectal cultures on 3 consecutive occasions at least 1 week apart, with a subsequent 11% relapse rate, which prompted the authors to conclude that VRE colonization often persists for months to years in this population.
      • Patel R
      • Allen SL
      • Manahan JM
      • et al.
      Natural history of vancomycin-resistant enterococcal colonization in liver and kidney transplant recipients.
      In an ICU population, approximately 50% of patients were decolonized after 2 months with a median time for clearance of all MDROs of 4.8 months.
      • Haverkate MR
      • Derde LPG
      • Brun-Buisson C
      • et al.
      Duration of colonization with antimicrobial-resistant bacteria after ICU discharge.
      In patients at a long-term acute care hospital, KPC colonization was lost in only 17% of patients within 4 weeks with more than half of the patients still colonized on readmission over 9 months later.
      • Haverkate MR
      • Weiner S
      • Lolans K
      • et al.
      Duration of colonization with Klebsiella pneumoniae carbapenemase-producing bacteria at long-term acute care hospitals in Chicago, Illinois.
      In another study of patients with history of positive CRE culture, mean time to CRE negativity was calculated to be 387 days with 39% of patients still with positive cultures at 1 year.
      • Zimmerman FS
      • Assous MV
      • Bdolah-Abram T
      • et al.
      Duration of carriage of carbapenem-resistant Enterobacteriaceae following hospital discharge.
      A systematic review calculated via pooled analysis the median clearance time of MRSA to be 88 weeks and that of VRE to be 26 weeks.
      • Shenoy ES
      • Paras ML
      • Noubary F
      • et al.
      Natural history of colonization with methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE): a systematic review.

      Selective Digestive Tract Decontamination

      Proactive MDRO decolonization has also been studied with selective digestive tract decontamination (SDD), which involves prophylactic parenteral and systemic antibiotic therapy in the ICU setting. In 1 randomized control trial (RCT), SDD consisting of intravenous cefotaxime and topical application of tobramycin, colistin and amphotericin B in the oropharynx and stomach reduced the ICU mortality rate by ∼3.5% at day 28.
      • de Smet AMGA
      • Kluytmans JAJW
      • Cooper BS
      • et al.
      Another RCT similarly showed a significantly lower ICU mortality of 15% in the SDD group versus 23% in the control group, as well as a significantly lower hospital mortality of 24% compared to 31% in the control group.
      • de Jonge E
      • Schultz MJ
      • Spanjaard L
      • et al.
      Effects of selective decontamination of digestive tract on mortality and acquisition of resistant bacteria in intensive care: a randomised controlled trial.
      Oostdijk et al demonstrated that SDD led to decolonization in 60-80% of cases, depending on the MDRO.
      • Oostdijk EAN
      • De smet AMGA
      • Kesecioglu J
      • et al.
      Decontamination of cephalosporin-resistant enterobacteriaceae during selective digestive tract decontamination in intensive care units.
      SDD was shown to have a high patient-specific variance on the eradication of aminoglycoside resistance genes with SDD in some patients actually increasing the copy number of resistance genes, as determined by quantitative polymerase chain reaction.
      • Buelow E
      • Gonzalez TB
      • Versluis D
      • et al.
      Effects of selective digestive decontamination (SDD) on the gut resistome.
      In another study from Oostdijk et al, gram-negative bacteria resistance to either ceftazidime, tobramycin or ciprofloxacin increased from 5%, 7% and 7%, respectively, to 15%, 13% and 13% after SDD. There was a brief period during SDD where resistance levels decreased, but ceftazidime resistance in particular significantly increased during SDD itself with all resistance levels peaking months after the intervention, which was described as a rebound effect.
      • Oostdijk EA
      • de Smet AM
      • Blok HE
      • et al.
      Ecological effects of selective decontamination on resistant gram-negative bacterial colonization.
      Similarly, another study revealed significantly increased colistin and tobramycin resistance as well as more frequent bacteremia among patients with ESBL-Klebsiella pneumoniae isolates treated with SDD.
      • Halaby T
      • Naiemi NAl
      • Kluytmans J
      • et al.
      Emergence of colistin resistance in Enterobacteriaceae after the introduction of selective digestive tract decontamination in an intensive care unit.
      Such concerns have raised doubt over SDD and whether it may be counterproductive in the long term.
      • van der Meer JWM
      • Vandenbroucke-Grauls CMJE
      Resistance to selective decontamination: the jury is still out.

      Probiotics

      Probiotics have become a more commonly accepted method of altering the gut microbiome. The principle with probiotics is that the introduction of commensal bacteria, often including Lactobacillus and Bifidobacterium, would promote health
      • Pamer EG
      Resurrecting the intestinal microbiota to combat antibiotic-resistant pathogens.
      through various mechanisms including enhanced immunity
      • Sivan A
      • Corrales L
      • Hubert N
      • et al.
      Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy.
      and infection prevention.
      • Fukuda S
      • Toh H
      • Hase K
      • et al.
      Bifidobacteria can protect from enteropathogenic infection through production of acetate.
      In terms of MDRO decolonization, research regarding the role of probiotics has produced mixed results.
      In vitro and murine studies have demonstrated that Lactobacillus species can be effective in limiting growth of MRSA isolates
      • Sikorska H
      • Smoragiewicz W
      Role of probiotics in the prevention and treatment of meticillin-resistant Staphylococcus aureus infections.
      and decolonizing MDR E coli.
      • Kumar M
      • Dhaka P
      • Vijay D
      • et al.
      Antimicrobial effects of Lactobacillus plantarum and Lactobacillus acidophilus against multidrug-resistant enteroaggregative Escherichia coli.
      Early isolated case reports demonstrated that a lactic acid bacteria preparation removed MRSA from a decubitus ulcer,
      • Kimura S
      • Takeuchi Y
      • Tago H
      • et al.
      Multiple antibiotic-resistant lactic acid bacteria preparation eliminated MRSA from the decubitus of a bed-ridden elderly patient.
      and a treatment regimen involving oral vancomycin and oral administration of Saccharomyces boulardii, a yeast species, contributed to resolution of antibiotic-associated diarrhea from MRSA.
      • Sizemore EN
      • Rivas KM
      • Valdes J
      • et al.
      Enteral vancomycin and probiotic use for methicillin-resistant Staphylococcus aureus antibiotic-associated diarrhoea.
      In another report, Roos et al presented a case series involving 7 patients among whom 5 had resolution of throat and nasal carriage of MRSA with a Lactobacillus probiotic.
      • Roos K
      • Simark-Mattsson C
      • Grahn Håkansson E
      • et al.
      Can probiotic lactobacilli eradicate persistent carriage of meticillin-resistant Staphylococcus aureus?.
      There have since been several clinical trials further exploring the efficacy of probiotics for MDRO decolonization. In an open prospective trial, a probiotic drink containing 2 species of Lactobacillus, Bifidobacterium and Streptococcus thermophilus, reduced the nasal carriage of several organisms, including S aureus, Streptococcus pneumoniae, β-hemolytic streptococci and Haemophilus influenzae, by 19% although these were not necessarily drug-resistant strains.
      • Glück U
      • Gebbers JO
      Ingested probiotics reduce nasal colonization with pathogenic bacteria (Staphylococcus aureus, Streptococcus pneumoniae, and β-hemolytic streptococci).
      Conversely, in a RCT with ICU patients, there was no significant difference in acquisition or loss of MDRO colonization, including ESBL and/or CRE, VRE and Pseudomonas aeruginosa, between patients who received a Lactobacillus rhamnosus probiotic versus standard of care.
      • Kwon JH
      • Bommarito KM
      • Reske KA
      • et al.
      Randomized controlled trial to determine the impact of probiotic administration on colonization with multidrug-resistant organisms in critically ill patients.
      Similarly, upon evaluating a probiotic strain of E coli, Tannock et al concluded that the probiotic did not effectively compete against MDR E coli for gut colonization in a group of patients from a long-term care facility.
      • Tannock GW
      • Tiong IS
      • Priest P
      • et al.
      Testing probiotic strain Escherichia coli Nissle 1917 (Mutaflor) for its ability to reduce carriage of multidrug-resistant E. coli by elderly residents in long-term care facilities.
      Likewise, a RCT in Brazil found that a Lactobacillus probiotic was not effective in decolonizing hospitalized patients with MDR gram-negative bacilli.
      • Salomão MCC
      • Heluany-Filho MA
      • Menegueti MG
      • et al.
      A randomized clinical trial on the effectiveness of a symbiotic product to decolonize patients harboring multidrug-resistant gram-negative bacilli.
      In another study of patients receiving either a L rhamnosus probiotic versus placebo for 4 weeks, gastrointestinal carriage of MRSA decreased by only 3% compared to 12% in the placebo group. However, 3 patients with VRE colonization tested negative after the 4 weeks of probiotics.
      • Warrack S
      • Panjikar P
      • Duster M
      • et al.
      Tolerability of a probiotic in subjects with a history of methicillin-resistant Staphylococcus aureus colonisation.
      In a more recent clinical trial, a L rhamnosus probiotic reduced the odds of methicillin-sensitive S aureus carriage in the gastrointestinal tract by 73%, and all S aureus presence by 83% compared to placebo; however, there were no data regarding efficacy with MRSA decolonization.
      • Eggers S
      • Barker AK
      • Valentine S
      • et al.
      Effect of Lactobacillus rhamnosus HN001 on carriage of Staphylococcus aureus: results of the impact of probiotics for reducing infections in veterans (IMPROVE) study.
      In addition to the mixed data on the efficacy of probiotics, concerns have been raised regarding its potential risks. This includes various gastrointestinal side effects ranging from minor ones such as abdominal cramping and nausea
      • Doron S
      • Snydman DR
      Risk and safety of probiotics.
      to bowel ischemia.
      • Besselink MG
      • van Santvoort HC
      • Buskens E
      • et al.
      Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial.
      More notably, Doron and Snydman found numerous reports of systemic infection; they cited 33 cases of fungemia as well as at least 8 cases of Lactobacillus bacteremia and 9 cases of sepsis. The Food and Drug Administration has highlighted the particular risk in the immunosuppressed population, many of whom may be risk of intestinal dysbiosis due to chemotherapy exposure.
      • Doron S
      • Snydman DR
      Risk and safety of probiotics.
      Thus, despite extensive research into several microbiome restoration techniques, including SDD and probiotics, definitive solutions have yet to be found.

      Fecal Microbiota Transplantation

      Mechanism

      Considering the limitations and risks of the aforementioned modalities, fecal microbiota transplantation (FMT) has begun to emerge as a promising approach to eradicating MDROs from the intestine. The safety and efficacy of FMT has been evaluated extensively, primarily through studies involving its role in treating recurrent Clostridium difficile infection (CDI), and appears to be related to a variety of factors. First, it has been shown to increase prokaryote diversity. After successful FMT, the microbiome composition of a recipient frequently becomes similar to that of the donor with decrease in pathogenic Enterobacteriaceae and increase in Bacteroides and Firmicutes.
      • Weingarden A
      • González A
      • Vázquez-Baeza Y
      • et al.
      Dynamic changes in short- and long-term bacterial composition following fecal microbiota transplantation for recurrent Clostridium difficile infection.
      • Seekatz AM
      • Aas J
      • Gessert CE
      • et al.
      Recovery of the gut microbiome following fecal microbiota transplantation.
      Also observed with gene sequencing techniques after FMT are increases in Streptococcaceae and Enterococcaceae
      • Song Y
      • Garg S
      • Girotra M
      • et al.
      Microbiota dynamics in patients treated with fecal microbiota transplantation for recurrent Clostridium difficile infection.
      as well as an overall increase in phylogenetic diversity.
      • Shahinas D
      • Silverman M
      • Sittler T
      • et al.
      Toward an Understanding of Changes in Diversity Associated with Fecal Microbiome Transplantation Based on 16S rRNA Gene Deep Sequencing.
      While the microbiome may diverge from that of the donor in the long term, it appears to do so in a manner similar to the natural dynamic change seen in healthy patients
      • Weingarden A
      • González A
      • Vázquez-Baeza Y
      • et al.
      Dynamic changes in short- and long-term bacterial composition following fecal microbiota transplantation for recurrent Clostridium difficile infection.
      rather than through a rebound of opportunistic pathogens as described with SDD.
      Genetic studies have also revealed another mechanism by which FMT may be effective—decreasing AR genes. Millan et al demonstrated FMT decreasing the number of AR genes from a mean of 34.5 (±6.7) to 12.2 (±7.0) and decreasing the diversity of genes. This was posited to be clinically significant as the patients whose CDI did not initially respond to FMT also did not have a significant decrease in the number of AR genes; when they underwent a second round of FMT that was successful, a significant decrease in AR genes was noted as well.
      • Millan B
      • Park H
      • Hotte N
      • et al.
      Fecal Microbial Transplants Reduce Antibiotic-resistant Genes in Patients with Recurrent Clostridium difficile Infection.
      In response to this study, Jouhten et al presented similar findings with a reduction in the number and diversity of AR genes in 20 patients post-FMT.
      • Jouhten H
      • Mattila E
      • Arkkila P
      • et al.
      Reduction of antibiotic resistance genes in intestinal microbiota of patients with recurrent clostridium difficile infection after fecal microbiota transplantation.
      Another study showed a 2.4-fold decrease in the abundance of AR genes in a patient post-FMT that persisted after 1 year; the resistome was also noted to have a profile similar to that of the donor.
      • Moss EL
      • Falconer SB
      • Tkachenko E
      • et al.
      Long-term taxonomic and functional divergence from donor bacterial strains following fecal microbiota transplantation in immunocompromised patients.
      Metagenomic sequencing data in a more recent study demonstrated the depletion of 95 AR genes, including loss of quinolone, β-lactamase, ESBL and vancomycin resistance genes in the FMT recipients. There was also acquisition of 37 AR genes from the donors though only a few of these were clinically relevant. The authors noted that this transfer of AR genes from donors was expected given antimicrobial resistance observed in healthy microbiota.
      • Leung V
      • Vincent C
      • Edens TJ
      • et al.
      Antimicrobial resistance gene acquisition and depletion following fecal microbiota transplantation for recurrent clostridium difficile infection.
      Murine models also suggest a beneficial immune response associated with FMT. In 1 study, dysbiosis was established through administration of ceftriaxone, resulting in intestinal membrane compromise and increased expression of inflammatory cytokines. After FMT, the intestinal barrier was noted to recover with cytokine levels returning to normal levels after 3 weeks.
      • Li M
      • Liang P
      • Li Z
      • et al.
      Fecal microbiota transplantation and bacterial consortium transplantation have comparable effects on the re-establishment of mucosal barrier function in mice with intestinal dysbiosis.
      Similarly, in another study, mice were subjected to 8 weeks of broad-spectrum antibiotics. This resulted in a decreased presence of B and T lymphocytes as well as less active dendritic cells, particularly in the intestinal lamina propria. FMT was associated with a reversal of these findings with restoration of the lymphocytes and dendritic cell activity to that seen in mice that were not administered antibiotics.
      • Ekmekciu I
      • von Klitzing E
      • Fiebiger U
      • et al.
      Immune responses to broad-spectrum antibiotic treatment and fecal microbiota transplantation in mice.

      Specific Human Cases of MDRO Elimination With FMT

      As FMT has been performed in increasing numbers of patients for CDI, reports have indicated possible effects of FMT on other comorbid infections. For example, in a study of patients treated with FMT for recurrent CDI, the frequency of recurrent UTIs was found to decrease from a median of 4 episodes per year to 1 episode in the year after FMT. Furthermore, the UTIs that did occur post-FMT rarely involved bacterial isolates with any significant resistance.
      • Tariq R
      • Pardi DS
      • Tosh PK
      • et al.
      Fecal microbiota transplantation for recurrent clostridium difficile infection reduces recurrent urinary tract infection frequency.
      Another patient with recurrent CDI was also found to have intestinal colonization with KPC; FMT not only successfully treated the CDI but also resulted in follow-up stool cultures being negative for KPC up to 100 days post-FMT.
      • Ponte A
      • Pinho R
      • Mota M
      Fecal microbiota transplantation: is there a role in the eradication of carbapenem-resistant Klebsiella pneumoniae intestinal carriage?.
      In another case involving KPC colonization, an elderly patient with recurrent CDI was found to have eradication of VIM-1 producing Klebsiella oxytoca.
      • García-Fernández S
      • Morosini M-I
      • Cobo M
      • et al.
      Gut eradication of VIM-1 producing ST9 Klebsiella oxytoca after fecal microbiota transplantation for diarrhea caused by a Clostridium difficile hypervirulent R027 strain.
      Similarly, in an organ transplant recipient treated with FMT for recurrent CDI who had also had multiple episodes of VRE infections, FMT decreased Enterococcus relative abundance from 84% to 24% after 3 months and 0.2% after 7 months with increased prokaryote diversity.
      • Stripling J
      • Kumar R
      • Baddley JW
      • et al.
      Loss of vancomycin-resistant enterococcus fecal dominance in an organ transplant patient with Clostridium difficile colitis after fecal microbiota transplant.
      In another case report, a patient with quadriplegia resulting from a spinal epidural abscess who had CDI treated with FMT had a marked reduction in colonization of several MDROs, including CRE, MRSA and MDR Acinetobacter baumannii. In total, the MDROs found on cultures decreased from 12 to 4 by 15 weeks after FMT, and while he had recurrent infections and episodes of sepsis prior to FMT, he only had 1 UTI in the post-FMT period from a newly acquired pathogen not previously isolated in the patient and required a 5-day course with a single antibiotic. Furthermore, despite ongoing care in the ICU post-FMT for his other conditions, the number of MDROs remained low, and he did not recolonize with CRE, CR Pseudomonas species or VRE. Over the following 2 years, he only became recolonized with MRSA in the urine and had 1 episode of sepsis secondary to Streptococcus pyogenes bacteremia that was treated with cefazolin.
      • Crum-Cianflone NF
      • Sullivan E
      • Ballon-Landa G
      Fecal microbiota transplantation and successful resolution of multidrug-resistant-organism colonization.
      Mouse models have more directly explored the effect of FMT on MDROs. A study found that reintroducing a diverse intestinal microbiome through FMT to mice densely colonized with VRE resulted in clearance of VRE. They particularly noted a negative correlation between recolonization of Barnesiella, a member of the Bacteroidetes phylum, and VRE colonization.
      • Ubeda C
      • Bucci V
      • Caballero S
      • et al.
      Intestinal microbiota containing Barnesiella species cures vancomycin-resistant Enterococcus faecium colonization.
      In another study, mice were infected with Citrobacter rodentium, which is used as a model for human enteropathogenic and enterohaemorrhagic E coli. FMT resulted in improved innate defense, particularly with increased IL-22 gene expression, and delayed C rodentium recolonization as well as reduced mortality with these effects persisting at least 4 weeks post-FMT.
      • Willing BP
      • Vacharaksa A
      • Croxen M
      • et al.
      Altering host resistance to infections through microbial transplantation.
      Mahieu et al inoculated mice with VRE and a strain of E coli producing a New Delhi metallo-β-lactamase-1 (NDM-1) and then performed FMT. After FMT, the MDRO colonization significantly decreased, particularly with VRE though in this case, the bacteria were not definitively eradicated.
      • Mahieu R
      • Cassisa V
      • Hilliquin D
      • et al.
      Impact of faecal microbiota transplantation on mouse digestive colonization with two extensively resistant bacteria.
      Murine studies have also investigated the role of FMT in treating tuberculosis. FMT reconstituted the intestinal microbiota and reduced Mycobacterium tuberculosis load in the lungs and spleen. Mice treated with FMT also had fewer and smaller granulomas with lesser infiltration of lymphocytes and were thus noted to have less severe cases of tuberculosis.
      • Khan N
      • Vidyarthi A
      • Nadeem S
      • et al.
      Alteration in the gut microbiota provokes susceptibility to tuberculosis.
      Most notably, there are a growing number of cases of FMT being used solely to manage MDROs in humans. In response to Mahieu's murine study, Leung et al described VRE clearance in 7 out of 8 patients 3 months after FMT.
      • Davido B
      • Batista R
      • Fessi H
      • et al.
      Impact of faecal microbiota transplantation to eradicate vancomycin-resistant enterococci (VRE) colonization in humans.
      In a more extensive prospective study, 20 patients with hematologic disorders whose intestines were colonized with various MDROs, including NDM-1+ Klebsiella pneumoniae, carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa, underwent 25 FMTs. Partial MDRO decolonization was achieved in 20 of 25 (80%) of cases at 1 month and 13 of 14 (93%) of cases at 6 months. When accounting for some of the patients who required multiple rounds of FMT, 15 of 20 (75%) of the participants had complete decolonization. In particular, the gene encoding carbapenemase was eradicated in 9 of 17 (53%) of the patients at 1 month and 8 of 9 (89%) of those at 6 months. After 1 month, 6 of 10 (60%) cases of NDM-1+ K. pneumoniae were eradicated while 100% of ESBL (11 patients) and oxacillinase-48 (OXA-48) (1 patient) E coli were eradicated. Also of note in this high-risk population, there were no significant adverse events noted.
      • Bilinski J
      • Grzesiowski P
      • Sorensen N
      • et al.
      Fecal microbiota transplantation in patients with blood disorders inhibits gut colonization with antibiotic-resistant bacteria: results of a prospective, single-center study.
      Another report of FMT eradicating OXA-48 has been documented in an 82-year-old patient with KPC whose stool cultures were negative 7 and 14 days post-FMT.
      • Lagier JC
      • Million M
      • Fournier PE
      • et al.
      Faecal microbiota transplantation for stool decolonization of OXA-48 carbapenemase-producing Klebsiella pneumoniae.
      In another case, here involving an end-stage renal disease patient with recurrent episodes of ESBL E coli induced pyelonephritis, FMT resulted in the eradication of the MDRO at 2-week follow-up that persisted 12 weeks post-FMT. During this period, the patient had no recurrence of infection and was able to be actively listed for renal transplantation.
      • Singh R
      • Nood E
      • Nieuwdorp M
      • et al.
      Donor feces infusion for eradication of extended Spectrum beta‐Lactamase producing Escherichia coli in a patient with end stage renal disease.
      In a 14-year-old patient with a hematologic disorder who had recurrent KPC infections, FMT resulted in documented fecal clearance of MDRO 8 months later with no subsequent infections noted for 1.5 years.
      • Freedman A
      • Eppes S
      Use of stool transplant to clear fecal colonization with carbapenem-resistant enterobacteraciae (CRE): proof of concept.
      FMT has also been used in active infection; one such report found 5 patients with MRSA enteritis that clinically resolved along with eradication of MRSA in the feces using FMT.
      • Wei Y
      • Gong J
      • Zhu W
      • et al.
      Fecal microbiota transplantation restores dysbiosis in patients with methicillin resistant Staphylococcus aureus enterocolitis.
      Thus, there is a growing literature highlighting the potential of FMT and suggesting its long-term role in clinical practice to address MDRO colonization and infection.

      Limitations and Future Considerations

      Despite the cases described above, there are some limitations and concerns raised regarding FMT. There have been some documented reports of MDRO colonization persisting despite FMT or returning shortly after the procedure, both in mouse models
      • Myers-Morales T
      • Bussell KM
      • D'Orazio SE
      Fecal transplantation does not transfer either susceptibility or resistance to food borne listeriosis in C57BL/6 and BALB/c/By mice.
      and patients.
      • Jang MO
      • An JH
      • Jung SI
      • et al.
      Refractory clostridium difficile infection cured with fecal microbiota transplantation in vancomycin-resistant enterococcus colonized patient.
      • Sohn KM
      • Cheon S
      • Kim YS
      Can fecal microbiota transplantation (FMT) eradicate fecal colonization with vancomycin-resistant enterococci (VRE)?.
      One particular report presented a patient with recurrent UTIs from MDR Pseudomonas aeruginosa with both Pseudomonas and ESBL-E coli colonization; FMT resulted in Pseudomonas clearance with no more infections in the next 18 months of follow-up, but the ESBL-E coli persisted.
      • Stalenhoef JE
      • Terveer EM
      • Knetsch CW
      • et al.
      Fecal microbiota transfer for multidrug-resistant gram-negatives: a clinical success combined with microbiological failure.
      In studies of FMT in CDI, adverse effects have been described,
      • Baxter M
      • Colville A
      Adverse events in faecal microbiota transplant: a review of the literature.
      including bacteremia
      • Solari PR
      • Fairchild PG
      • Noa LJ
      • et al.
      Tempered enthusiasm for fecal transplant.
      • Quera R
      • Espinoza R
      • Estay C
      • et al.
      Bacteremia as an adverse event of fecal microbiota transplantation in a patient with Crohn's disease and recurrent Clostridium difficile infection.
      • Baxter M
      • Ahmad T
      • Colville A
      • et al.
      Fatal aspiration pneumonia as a complication of fecal microbiota transplant.
      and fatal aspiration.
      • Baxter M
      • Ahmad T
      • Colville A
      • et al.
      Fatal aspiration pneumonia as a complication of fecal microbiota transplant.
      • Kelly CR
      • Ihunnah C
      • Fischer M
      • et al.
      Fecal microbiota transplant for treatment of clostridium difficile infection in immunocompromised patients.
      These appear to be rare with the more common complications being relatively mild in morbidity, such as abdominal cramping, distention and diarrhea.
      • Baxter M
      • Colville A
      Adverse events in faecal microbiota transplant: a review of the literature.
      Nevertheless, there are a limited long-term outcome data so there may be unintended consequences of FMT that are presently unknown.
      As described above, the literature involving FMT in MDRO colonization and infection has consisted primarily of isolated case reports, small series of cases and small uncontrolled clinical trials. There is a lack of standardization of products used in FMT, lack of standardization of delivery, lack of characterization of the microbiome in the FMT produces, all confounding the comparability of studies. Just as with FMT to treat CDI,
      • van Nood E
      • Vrieze A
      • Nieuwdorp M
      • et al.
      Duodenal infusion of donor feces for recurrent Clostridium difficile.
      structured, randomized, controlled trials are needed to better characterize the safety and efficacy of FMT for MDRO elimination, many of which are currently underway (www.clinicaltrials.gov). Nevertheless, given the limitations of the current antibiotic development pipeline and infection prevention methods, these early signals of FMT support its investigation and potential application as a therapeutic option for MDRO colonization and infection in the future.

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