THERAPY UPDATE Clostridium difficile infection
THERAPY UPDATE
Clostridium difficile infection: A brief update on emerging therapies Erika J. Goldberg, Sumit Bhalodia, Sherin Jacob, Hatil Patel, Ken V. Trinh, Blessy Varghese, Jungmo Yang, Sean R. Young, and Robert B. Raffa
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he occurrence of Clostridium difficile infection (CDI) is on the rise. Hospitals in particular are breeding grounds for C. difficile: Although only 3% of healthy adults are carriers of C. difficile, up to 20–50% of adults in hospitals and long-term care facilities are carriers.1 CDI can be fatal if it progresses to systemic inflammation that is unresponsive to pharmacotherapy.2 An important predictor of potentially fatal CDI is prior CDI. Deaths attributable to CDI in the United States increased from about 3,000 in 1999–2000 to about 14,000 in 2006–07.3 Patients over 65 years of age are at the highest risk for CDI, especially those in long-term care facilities and hospitals. In the United States, the incidence of nosocomial CDI in adult patients doubled from 31 to 61 per 100,000 between 1996 and 2003; the incidence among those over 65 years of age was 228 per 100,000.3 The higher rate of CDI in the elderly does not appear to be related to antibiotic exposure but is more likely due to age-related changes in fecal flora, changes in the immune system,
Purpose. Established and investigational antibiotic, monoclonal antibody, vaccine, and microbe-based approaches to the prevention and treatment of Clostridium difficile infection (CDI) are reviewed. Summary. CDI is increasingly prevalent in the United States and other countries, particularly among hospitalized patients and the elderly, who are at high risk for potentially fatal CDI-related enterotoxic diarrhea. Established therapies for CDI such as vancomycin and metronidazole (an off-label use) are limited by poor efficacy and high recurrence rates. An investigational antibiotic with potent in vitro activity against all C. difficile strains (including the hypervirulent BI/NAP1/027 strain) has yielded encouraging results in early clinical trials. Another promising approach involves the use of monoclonal antibodies with selective activity against toxins responsible for CDI-associated diarrhea; in a small Phase II clinical trial, a single monoclonal antibody
or comorbid conditions.4 Socioeconomic influences on susceptibility to CDI have not been reported. Oral metronidazole is often the drug of choice in cases of mild-tomoderate CDI, and oral vancomycin
Erika J. Goldberg is a Pharm.D. student; Sumit Bhalodia is a Pharm.D. student; Sherin Jacob is a Pharm.D. student; Hatil Patel is a Pharm.D. student; Ken V. Trinh is a Pharm.D. student; Blessy Varghese is a Pharm.D. student; Jungmo Yang is a Pharm.D. student; Sean R. Young is a Pharm.D. student; and Robert B. Raffa, Ph.D., is Professor, Temple University School of Pharmacy, Philadelphia, PA. Address correspondence to Dr. Raffa (robert.raffa@temple. edu).
infusion in combination with vancomycin or metronidazole therapy was more effective than antibiotic therapy alone in preventing CDI relapse. Other emerging approaches to CDI treatment and prophylaxis include the use of vaccines against C. difficile toxins (several C. difficile–targeted vaccines are under development in Europe and the United States); microbe-based strategies such as fecal microbiota transplants, “microbial ecosystem therapeutics,” and probiotic supplements; and an investigational encapsulated form of β-lactamase designed to prevent C. difficile colonization from progressing to CDI. Conclusion. The current antibiotic therapies for CDI, mainly vancomycin and (off-label) metronidazole and the newer agent fidaxomicin, have limitations with respect to efficacy, recurrence rates, and adverse effects, but a variety of promising approaches are emerging. Am J Health-Syst Pharm. 2015; 72:1007-12
is often the drug of choice for severe infections.5 Unfortunately, the effectiveness of these antibiotic treatments is limited by a lack of response in some patients and high recurrence rates.6 This article reviews emerging
The authors have declared no potential conflicts of interest. Copyright © 2015, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/15/0602-1007. DOI 10.2146/ajhp140645
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CDI treatment approaches, including investigational antibiotic, monoclonal antibody, vaccine, and microbebased therapies. Background C. difficile is an anaerobic, grampositive, spore-forming, toxinreleasing bacillus that is transmitted among humans mainly via contact with fecal matter (the fecal-oral route).7 Until relatively recently, exposure to C. difficile was primarily nosocomial (i.e., hospital/institutionbased), with the most likely route of transmission being transfer via healthcare personnel. However, increasingly the infections originate from noninstitutional environments, and nosocomial transmissions now account for less than half of all CDI cases.8 C. difficile was first described by Hall and O’Toole in 1935 as “the difficult clostridium,”9 partly due to the bacterium’s ability to form spores as a survival mechanism when exposed to hostile conditions.10 Contact with spore-contaminated surfaces is one method by which such pathogens are able to spread from infected individuals to new hosts. Oral ingestion of quiescent-state C. difficile spores transforms them into an active state within the gastrointestinal tract.11 Infections and complications outside the gastrointestinal tract are rare and have only been seen in a small number of cases.12 Colonization by C. difficile stimulates the release of toxins that injure the enteric mucosal lining. The two major toxins, toxin A (encoded by the gene tcdA) and toxin B (encoded by tcdB), are the primary contributors to CDI pathogenesis.13 They are members of the clostridial glucosylating family of toxins.14 The toxins induce inflammation and damage to the intestinal lining by disrupting the tight junctions of the epithelial cells and causing a loss of the epithelial barrier function; the increased permeability of the epithelium allows 1008
the access of neutrophils to the intestinal lumen.14 In addition, the toxins induce apoptosis and necrosis of epithelial cells that contribute to the inflammatory response in CDI. The gastrointestinal tract is host to many resident (autochthonous) organisms, a majority of which are Actinobacteria, Bacteroidetes, Proteobacteria, and Firmicutes (a phylum of which C. difficile is a member).8,15,16 The microbiota can be disrupted (in a process known as dysbiosis) with the introduction of antibiotics16 or the physiologic changes that occur during aging.15 In the older population, there is a reversal of the stability and diversity of the microbiota seen in younger adults. The use of antibiotics increases the risk of infection with C. difficile, even when they are used for short durations.17 Therefore, patients at highest risk for CDI are those who are hospitalized, are older than 65 years of age, and have experienced recent antibiotic use.18 Clinical manifestations of CDI range from diarrhea to fatal pseudomembranous colitis.19 As many as 25% of patients treated for an initial infection experience a recurrent infection within 30 days, and the risk can double after two or more recurrences.20 Patients who mount an antibody response become asymptomatic carriers.21 New hypervirulent strains of C. difficile emerged during the period 2003–09 in North America, many parts of Europe, and other countries. These strains contain a genetic mutation at the gene responsible for toxin inhibition, resulting in an increased production (via disinhibition) of toxins A and B. Higher morbidity and recurrence are seen with these strains.18 The full extent of the problem is difficult to quantify because CDI is not routinely reported and, thus, there is a limited body of surveillance data.5 The available data on CDI in outpatient settings are also limited, but there is evidence of an increase in hospitalizations due
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to C. difficile in the United States,22 with a concomitant increase in U.S. healthcare costs, estimated to be at least $3.2 billion per year.23 Current therapies Current therapy regimens for the treatment of CDI are limited; the two most commonly used drugs worldwide are metronidazole and oral vancomycin. Metronidazole inhibits nucleic acid synthesis in anaerobic bacterial DNA in such a way that further protein synthesis is disabled. Vancomycin disrupts cell wall assembly in gram-positive bacteria by inhibiting the glycopeptide polymerization needed for crosslinking. A third antimicrobial agent, fidaxomicin, was recently approved for the treatment of CDI.18 Fidaxomicin inhibits protein synthesis by inhibition of RNA polymerase, and early evidence suggests that its use against non-NAP1 strains is associated with a lower rate of recurrent infection compared with vancomycin therapy.18 Emerging therapies Antibiotics. CRS3123 (previously REP3123) is an investigational oral agent that is currently in earlystage clinical trials.24 It is a narrowspectrum agent with gram-positive coverage and limited oral bioavailability whose use results in a high concentration of drug in the gastrointestinal tract and low systemic exposure. CRS3123 inhibits protein synthesis, toxin production, and sporulation. CRS3123 was demonstrated to have potent in vitro antibacterial activity against all C. difficile strains tested, including the hypervirulent BI/NAP1/027 variant.25 According to manufacturerprovided information (Crestone, Inc., Boulder, CO), CRS3123 has demonstrated efficacy for selective inhibition of C. difficile growth, as well as inhibition of toxin production and spore formation. If these properties are confirmed in clinical
THERAPY UPDATE Clostridium difficile infection
trials, oral CRS3123 would provide sustained efficacy and (in comparison to vancomycin) less tendency for recurrence. Monoclonal antibodies. Monoclonal antibodies that have selectivity for toxins A and B are being developed.26,27 Monoclonal antibodies were reported to be superior in reducing rates of recurrent CDI in humans when administered in addition to vancomycin or metronidazole— compared with administering the antibiotics alone—in a Phase II randomized, double-blind, placebocontrolled trial involving 200 patients who met the study inclusion criteria (age of ≥18 years and diarrhea associated with a positive stool test for a C. difficile toxin in the two weeks before enrollment).28 The patients were given human monoclonal antibodies active against toxins A and B together in a single i.v. infusion (each agent was given at a dose of 10 mg/kg). The primary endpoint was the recurrence of CDI (defined as a new episode of diarrhea with a positive stool toxin test during the subsequent 84 days). Only 7 (7%) of the patients who received the monoclonal antibodies in combination with antibiotic therapy experienced recurrent CDI, compared with 25 (25%) of the patients who received antibiotics only; similar results were obtained in patients infected with the BI/NAP1/027 strain (recurrence rates with and without monoclonal therapy were 8% and 32%, respectively). Patients who had a history of more than one prior CDI relapsed at a rate of 7% with coadministration of monoclonal antibodies and antibiotics, compared with a relapse rate of 38% among patients given antibiotics alone. These monoclonal antibodies may be useful in preventing recurrent CDI because of their long half-lives (i.e., >20 days).28 There are many positive aspects of monoclonal antibody therapy for CDI; however, there are also some
disadvantages to consider. The delivery of monoclonal antibodies is typically limited to i.v. administration, which is often performed only in inpatient settings, although this mode of delivery may be convenient for hospitalized patients with the most severe infections. These sicker patients with CDI are most likely to have an inadequate response to antibiotics alone and are often too sick to take medications orally. These patients also often have chronic diseases, are elderly, or are taking concomitant antibiotics and are thus at higher risk for recurrence and might benefit the most from monoclonal antibody and antibiotic combination therapy. Although it is inconvenient to administer parenteral medications in outpatient settings, monoclonal antibodies have been administered in a single infusion, enabling patients to get the full benefit of therapy in terms of reduced recurrence risk without requiring further treatment after discharge from the hospital. The general potency of monoclonal antibodies allows for efficient treatment, but the costs of these specialized agents are still relatively high. The top nine monoclonal antibodies in the United States currently cost an average of about $200,000 per year.29 The cost is partly due to the agents’ special manufacturing and storage requirements (necessary to prevent denaturing of the proteins). Since the storage requirements for monoclonal antibodies can be costly for hospitals, many institutions purchase them only on an as-needed basis. It is estimated that the average hospital cost for each patient case of CDI treated with current therapy is almost $4,000.30 Vaccines. Since C. difficile produces toxins A and B, which act synergistically to damage the colonic epithelium, the toxins could be targets for a vaccine. For a vaccine to warrant continued clinical development, it must induce an effective protective immune response against
toxins A and B, and it must be relatively safe. In a prospective cohort study, patients who experienced only one episode of CDI had a notable increase in antibodies to immunoglobulin G (IgG) antitoxin A during the episode, but no such increase occurred in patients who later had recurrent CDI.31 It was found that patients with asymptomatic CDI had high levels of IgG antitoxin A antibody, but there was no association between protection from C. difficile colonization and either serum or secretory IgG antitoxin A levels.32 These observations suggest that recurrent CDI is associated with failure to develop an adequate immune response to the C. difficile toxins. Thus, active or passive immunization could be beneficial for at-risk patients, such as elderly hospitalized patients taking antibiotics and patients who have an anticipated hospital stay (e.g., for elective surgery). According to information on the National Institutes of Health website ClinicalTrials.gov, currently there are several Phase II clinical trials in the United States that are testing vaccines against C. difficile. In one study of a monoclonal antibody vaccine containing GS-CDA1 (a human monoclonal antibody to toxin A) and MDX-1388 (a human monoclonal antibody to toxin B), it was reported that the addition of the monoclonal antibodies to an antibiotic regimen significantly reduced the recurrence of CDI.28 A Phase III clinical trial with an estimated primary completion date of December 2017 33 is evaluating a vaccine that contains toxoids A and B for induction of an immune response against toxins A and B.34 The European Union is funding a three-year initiative to develop an oral (sublingual) vaccine against C. difficile; the intended strategy is to use harmless bacterial spores that carry the antigen and boost immunity by targeting the protein needed for the infection to take hold.35 It has been reported that, overall, the
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candidate C. difficile vaccine has been well tolerated by patients.36 To date, no C. difficile–targeted vaccine has been approved by the Food and Drug Administration, although an agent is currently under clinical development by Pfizer Inc. (PF-06425090). Microbe-based treatment approaches. Fecal microbiota transplantation (FMT) was first used successfully in 1958 to treat four patients with recurrent refractory diarrhea and has gained increasing recognition over the past 60 years as a treatment for CDI.37 The goals of this procedure are to restore the normal balance of the intestinal flora and to provide natural competition for C. difficile, thereby decreasing its overgrowth. While FMT protocols vary, therapy usually begins with the patient receiving a course of antibiotics for a few days before the transplant in order to decrease inflammation and the C. difficile spore burden.37 The antibiotics are stopped prior to the transplant, and a bowel preparation is administered. Stool-donor screening varies but usually includes, at a minimum, exclusion of ova and parasites; Salmonella, Shigella, and Campylobacter strains; and C. difficile toxin using a polymerase chain reaction assay. Other targets of FMTdonor serum screens may include hepatitis A, B, and C; syphilis; and human immunodeficiency virus infection. Many investigators also screen the patient’s blood in order to identify preexisting conditions that might manifest after transplantation. Fresh donor feces are then collected within a few hours before the actual transplantation procedure, and the stool is mixed with water, a preservative-free saline solution, or milk. The stool mixture is administered through a nasogastric tube or via upper endoscopy, colonoscopy, or enema; the total infused volume varies from 50 to 700 mL.37 Doing a colonoscopy allows the bacteria to be delivered directly to the affected site 1010
and also allows the practitioner to examine for comorbid pathology. The oral route of delivery is an available option for patients who are unable to retain a rectal enema or a catheter due to esophageal varices. In a Canadian study, 27 patients who had more than three episodes of recurrent CDI and were unable to tolerate a jejunal catheter or an enema were given 0.47-mL gel capsules that contained fecal microbes.38 The fresh fecal matter (approximately 100 g) was donated on the day of the procedure by relatives who had been screened for pathogens. The fecal matter was suspended in 600–800 mL of prereduced phosphate-buffered saline solution and underwent 2.6 hours of serial centrifugation. The resulting sediment (i.e., microbe pellets) was double-encapsulated to ensure delivery to the intestines and then given to patients, who ingested 24–34 of the custom-assembled capsules over 5–15 minutes on an empty stomach. At the end of the study period, all patients had no recurrence of CDI and complete resolution of all symptoms. Fecal transplants have been shown to be effective in treating resistant cases of CDI, with many physicians reporting success rates as high as 80–95%.39 While the supportive data are largely limited to data from case studies, no other treatment options to date have been reported to yield comparably high success rates. In one of the first randomized controlled studies conducted, patients were assigned to receive one of three regimens: vancomycin 500 mg four times a day for 4 days followed by FMT delivered through a nasoduodenal tube, standard vancomycin therapy (500 mg four times a day for 14 days), and standard vancomycin therapy in combination with bowel lavage on day 4 or 5.40 The primary endpoint was resolution of CDI without relapse after 10 weeks. The study found that the infusion of donor feces was significantly more effective than the use of vancomy-
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cin; the trial was terminated early on ethical grounds. The human gastrointestinal tract is populated not only with bacteria but also with viruses, protozoa, parasites, and fungi. While testing of stool eliminates some of the risk of contracting an illness from the donor, there is concern that current technology might not be sufficient to detect all possible pathogens. In addition, many asymptomatic people carry parasites that cause no problem in their own healthy gut but might cause a reaction in the recipient’s. About one third of the organisms in an individual’s microbiota are common to most people, but the other two thirds are individual specific. In a study of male subjects with metabolic syndrome who underwent bowel lavage followed by either an allogenic (i.e., donor-derived) or autologous (i.e., self-derived) fecal infusion, insulin sensitivity was improved in the group that received allogenic fecal infusion, but there was no notable change in the autologous group.41 That finding raises a question: Can receiving a fecal transfusion from a donor who has metabolic complications lead to an increased risk of diabetes or other undesirable outcomes? Additional testing, guidelines, and restrictions are needed to answer that question definitively. There is also concern over a possible link between the gut’s microbiota and neuropsychiatric disorders. For example, studies of microbe-colonized mice have shown that alterations of gut microbial composition can induce changes in behavior.42 To date, psychiatric illness is not an independent exclusionary factor for fecal donation. Some organizations provide hospitals with screened, filtered, and frozen fecal microbes that are ready for use. While evidence compiled to date indicates no short-term negative effects of FMT, there is insufficient experience to guarantee that there are no long-term adverse effects or risks involved.
THERAPY UPDATE Clostridium difficile infection
A related form of bacteriotherapy, microbial ecosystem therapeutics (MET), involves the use of “synthetic stool” formulations or stool substitutes (similar to those used in the original FMT study). In an early study of MET published in 1989, a consortium of 10 cultured bacterial species, originally isolated from human feces, was used successfully to treat refractory CDI in six patients.43 In that study, the consortium consisted of a mix of facultative and strict anaerobes and was instilled rectally as an enema in a saline carrier solution. All patients became asymptomatic within 24 hours, and subsequent C. difficile toxin testing was negative. Such synthetic stool formulations or stool substitutes might help mitigate many of the current concerns about FMT. Probiotics are live microorganisms that are believed to improve the microbial balance of the host, to counteract disturbances in intestinal flora, and to reduce the risk of colonization by opportunistic pathogenic bacteria.44 They are available without prescription as capsules and food supplements marketed as “functional food” or “good bacteria/yeast.”45 The use of probiotics has been suggested as a means of preventing CDI.46,47 Their low cost and the low associated rate of adverse events48 make probiotics an attractive candidate for CDI treatment. A recent Cochrane review article concluded, “Based on this systematic review and meta-analysis of 23 randomized controlled trials including 4213 patients, moderate quality evidence suggests that probiotics are both safe and effective for preventing Clostridium difficile– associated diarrhea.”49 Prophylaxis. There is currently no prophylactic treatment to prevent the development of infections due to C. difficile. SYN-004, an agent currently in Phase I clinical trials, is intended to be the first. It is β-lactamase in an encapsulated enterically-coated oral form to be
coadministered with i.v. antibiotics.50 The agent is designed to remain within the gastrointestinal tract and degrade i.v. antibiotic that has been excreted into the intestine. A Phase II efficacy study of SYN-004 was initiated in March 2015.51 Conclusion The current antibiotic therapies for CDI, mainly vancomycin and (off-label) metronidazole and the newer agent fidaxomicin, have limitations with respect to efficacy, recurrence rates, and adverse effects, but a variety of promising approaches are emerging. References 1. Clabots CR, Johnson S, Olson MM et al. Acquisition of Clostridium difficile by hospitalized patients: evidence for colonized new admissions as a source of infection. J Infect Dis. 1992; 166:561-7. 2. Dallal RM, Harbrecht BG, Boujoukas AJ et al. Fulminant Clostridium difficile: an underappreciated and increasing cause of death and complications. Ann Surg. 2002; 235:363-72. 3. Hall AC, Curns AT, McDonald LC et al. The roles of norovirus and Clostridium difficile among gastroenteritis deaths in the United States, 1999–2007. Presentation at the 49th Annual Meeting of the Infectious Diseases Society of America. Boston, MA; 2011 Oct 22. 4. Simor AE, Bradley SF, Strausbaugh LJ et al. Clostridium difficile in long-term–care facilities for the elderly. Infect Control Hosp Epidemiol. 2002; 23:696-703. 5. Cohen SH, Gerding DN, Johnson S et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010; 31:431-55. 6. Huang H, Weintraub A, Fang H, Nord CE. Antimicrobial resistance in Clostridium difficile. Intl J Antimicrob Agents. 2009; 34:516-22. 7. Leffler DA, Lamont JT. Treatment of Clostridium difficile-associated disease. Gastroenterology. 2009; 136:1899-912. 8. Hoover DG, Rodriguez-Palacios A. Transmission of Clostridium difficile in foods. Infect Dis Clin North Am. 2013; 27:675-85. 9. Kelly CP, Pothoulakis C, Lamont JT. Clostridium difficile colitis. N Engl J Med. 1994; 330:257-62. 10. Pereira FC, Saujet L, Tomé AR et al. The spore differentiation pathway in the enteric pathogen Clostridium difficile. PLoS Genet. 2013; 9:e1003782.
11. Allen CA, Babakhani F, Sears P et al. Both fidaxomicin and vancomycin inhibit outgrowth of Clostridium difficile spores. Antimicrob Agents Chemother. 2013; 57:664-7. 12. Libby DB, Bearman G. Bacteremia due to Clostridium difficile—review of the literature. Int J Infect Dis. 2009; 13:e3059. 13. Wu D, Joyee AG, Nandagopal S et al. Effects of Clostridium difficile toxin A and B on human T lymphocyte migration. Toxins. 2013; 5:926-38. 14. Sun X, Savidge T, Feng H. The enterotoxicity of Clostridium difficile toxins. Toxins. 2010; 2:1848-80. 15. Khanna S, Tosh PK. A clinician’s primer on the role of the microbiome in human health and disease. Mayo Clin Proc. 2014; 89:107-14. 16. Peniche AG, Savidge TC, Dann SM. Recent insights into Clostridium difficile pathogenesis. Curr Opin Infect Dis. 2013; 26:447-53. 17. Bartlett JG. Antibiotic-associated diarrhea. N Engl J Med. 2002; 346:334-9. 18. Burke KE, Lamont JT. Clostridium difficile infection: a worldwide disease. Gut Liver. 2014; 8:1-6. 19. Korman T. Diagnosis and management of Clostridium difficile infection. Semin Respir Crit Care Med. 2015; 36:31-43. 20. Kelly CP. Can we identify patients at high risk of recurrent Clostridium difficile infection? Clin Microbiol Infect. 2012; 18(suppl 6):21-7. 21. Kyne L, Warny M, Qamar A, Kelly CP. Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. N Engl J Med. 2000; 342:390-7. 22. Zilberberg MD, Shorr AF, Kollef MH. Increase in adult Clostridium difficilerelated hospitalizations and case-fatality rate, United States, 2000–2005. Emerg Infect Dis. 2008; 14:929-31. 23. Surawicz CM, Brandt LJ, Binion DG et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013; 108:478-98. 24. ClinicalTrials.gov. Phase I trial of a single dose of CRS3123. http://clinicaltrials.gov/show/NCT01551004 (accessed 2015 Apr 11). 25. Critchley IA, Green LS, Young CL et al. Spectrum of activity and mode of action of REP3123, a new antibiotic to treat Clostridium difficile infections. J Antimicrob Chemother. 2009; 63:954-63. 26. Davies NL, Compson JE, MacKenzie B et al. A mixture of functionally oligoclonal humanized monoclonal antibodies that neutralize Clostridium difficile TcdA and TcdB with high levels of in vitro potency shows in vivo protection in a hamster infection model. Clin Vaccine Immunol. 2013; 20:377-90. 27. Marozsana AJ, Ma D, Nagashima KA et al. Protection against Clostridium difficile infection with broadly neutralizing
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antitoxin monoclonal antibodies. J Infect Dis. 2012; 206:706-13. Lowy I, Molrine DC, Leav BA et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med. 2010; 362:197-205. Shaughnessy AF. Monoclonal antibodies: magic bullets with a hefty price tag. BMJ. 2012; 345:e8346. Kyne L, Hamel MB, Polavaram R, Kelly CP. Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile. Clin Infect Dis. 2002; 34:346-53. Kyne L, Warny M, Qamar A, Kelly CP. Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea. Lancet. 2001; 357:189-93. Kyne L, Warny M, Qamar A, Kelly CP. Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. N Engl J Med. 2000; 342:390-7. ClinicalTrials.gov. Search results. www. clinicaltrials.gov/show/NCT01887912 (accessed 2015 Apr 11). Sanofi. Tell me more about the Cdiffense s t u d y. w w w. cd i f f e n s e . o r g / n o d e / 9 (accessed 2015 Apr 11). Royal Holloway, University of London. Scientists take a step closer to developing vaccine against C. difficile. www.royal holloway.ac.uk/aboutus/newsandevents/ news/newsarticles/scientiststakeastep closertodevelopingvaccineagainstcdifficile.aspx (accessed 2015 Apr 11). Foglia G, Shah S, Luxemburger C, Pietrobon PJ. Clostridium difficile: development of a novel candidate vaccine. Vaccine. 2012; 30:4307-9.
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37. Austin M, Mellow M, Tierney WM. Fecal microbiota transplantation in the treatment of Clostridium difficile infections. Am J Med. 2014; 127:47983. 38. Louie T, Cannon K, O’Grady H et al. Fecal microbiome transplantation (FMT) via oral fecal microbial capsules for recurrent Clostridium difficile infection (rCDI). https://idsa.confex.com/idsa/2013/ webprogram/Paper41627.html (accessed 2015 Apr 11). 39. McKinney M. FDA slaps regs on fecal transplants. http://web.a.ebscohost. c o m . l i b p r o x y. t e m p l e . e d u / e h o s t / detail?sid=ce87bab3-42ba-45ce-8e3c27707781c8ea%40sessionmgr4001&vid =3&hid=4109&bdata=JnNpdGU9ZWhv c3QtbGl2ZSZzY29wZT1zaXRl#db=aph &AN=87845197 (accessed 2014 Mar 12). 40. Van Nood E, Vrieze A, Nieuwdorp M et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013; 368:407-15. 41. Vrieze A, van Nood E, Holleman F et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012; 143:913-6. 42. Collins SM, Kassam Z, Bercik P. The adoptive transfer of behavioral phenotype via the intestinal microbiota: experimental evidence and clinical implications. Curr Opin Microbiol. 2013; 16:240-5. 43. Tvede M, Rask-Madsen J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients. Lancet. 1989; 333:1156-60.
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44. Sullivan A, Nord C. Probiotics in human infections. J Antimicrob Chemother. 2002; 50:625-7. 45. Drisko J, Bischoff B, Giles C et al. Evaluation of five probiotics products for label claims by DNA extraction and polymerase chain reaction analysis. Dig Dis Sci. 2005; 50:1113-7. 46. D’Souza AL, Rajkumar C, Cooke J, Bulpitt CJ. Probiotics in prevention of antibiotic-associated diarrhoea: metaanalysis. Brit Med J. 2002; 324:1361-7. 47. Dendukuri N, Costa V, McGregor M, Brophy JM. Probiotic therapy for the prevention and treatment of Clostridium difficile-associated diarrhea: a systematic review. Can Med Assoc J. 2005; 173:16770. 48. Hempel S, Newberry SJ, Maher AR et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. J Am Med Assoc. 2012; 307:1959-69. 49. Goldenberg JZ, Ma SS, Saxton JD et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2013; 5:CD006095. 50. Watermark Medical Animations. C. difficile & SYN-004 animation. www.youtube. com/watch?v=97lkgRZyXLc (accessed 2015 Apr 11). 51. Synthetic Biologics initiates phase 2a clinical trial of SYN-004 to protect the microbiome and prevent C. difficile. www. syntheticbiologics.com/2015-03-30Synthetic-Biologics-Initiates-Phase-2aClinical-Trial-of-SYN-004-to-Protectthe-Microbiome-and-Prevent-C-difficile (accessed 2015 Apr 11).
THERAPY UPDATE
Clostridium difficile infection: A brief update on emerging therapies Erika J. Goldberg, Sumit Bhalodia, Sherin Jacob, Hatil Patel, Ken V. Trinh, Blessy Varghese, Jungmo Yang, Sean R. Young, and Robert B. Raffa
T
he occurrence of Clostridium difficile infection (CDI) is on the rise. Hospitals in particular are breeding grounds for C. difficile: Although only 3% of healthy adults are carriers of C. difficile, up to 20–50% of adults in hospitals and long-term care facilities are carriers.1 CDI can be fatal if it progresses to systemic inflammation that is unresponsive to pharmacotherapy.2 An important predictor of potentially fatal CDI is prior CDI. Deaths attributable to CDI in the United States increased from about 3,000 in 1999–2000 to about 14,000 in 2006–07.3 Patients over 65 years of age are at the highest risk for CDI, especially those in long-term care facilities and hospitals. In the United States, the incidence of nosocomial CDI in adult patients doubled from 31 to 61 per 100,000 between 1996 and 2003; the incidence among those over 65 years of age was 228 per 100,000.3 The higher rate of CDI in the elderly does not appear to be related to antibiotic exposure but is more likely due to age-related changes in fecal flora, changes in the immune system,
Purpose. Established and investigational antibiotic, monoclonal antibody, vaccine, and microbe-based approaches to the prevention and treatment of Clostridium difficile infection (CDI) are reviewed. Summary. CDI is increasingly prevalent in the United States and other countries, particularly among hospitalized patients and the elderly, who are at high risk for potentially fatal CDI-related enterotoxic diarrhea. Established therapies for CDI such as vancomycin and metronidazole (an off-label use) are limited by poor efficacy and high recurrence rates. An investigational antibiotic with potent in vitro activity against all C. difficile strains (including the hypervirulent BI/NAP1/027 strain) has yielded encouraging results in early clinical trials. Another promising approach involves the use of monoclonal antibodies with selective activity against toxins responsible for CDI-associated diarrhea; in a small Phase II clinical trial, a single monoclonal antibody
or comorbid conditions.4 Socioeconomic influences on susceptibility to CDI have not been reported. Oral metronidazole is often the drug of choice in cases of mild-tomoderate CDI, and oral vancomycin
Erika J. Goldberg is a Pharm.D. student; Sumit Bhalodia is a Pharm.D. student; Sherin Jacob is a Pharm.D. student; Hatil Patel is a Pharm.D. student; Ken V. Trinh is a Pharm.D. student; Blessy Varghese is a Pharm.D. student; Jungmo Yang is a Pharm.D. student; Sean R. Young is a Pharm.D. student; and Robert B. Raffa, Ph.D., is Professor, Temple University School of Pharmacy, Philadelphia, PA. Address correspondence to Dr. Raffa (robert.raffa@temple. edu).
infusion in combination with vancomycin or metronidazole therapy was more effective than antibiotic therapy alone in preventing CDI relapse. Other emerging approaches to CDI treatment and prophylaxis include the use of vaccines against C. difficile toxins (several C. difficile–targeted vaccines are under development in Europe and the United States); microbe-based strategies such as fecal microbiota transplants, “microbial ecosystem therapeutics,” and probiotic supplements; and an investigational encapsulated form of β-lactamase designed to prevent C. difficile colonization from progressing to CDI. Conclusion. The current antibiotic therapies for CDI, mainly vancomycin and (off-label) metronidazole and the newer agent fidaxomicin, have limitations with respect to efficacy, recurrence rates, and adverse effects, but a variety of promising approaches are emerging. Am J Health-Syst Pharm. 2015; 72:1007-12
is often the drug of choice for severe infections.5 Unfortunately, the effectiveness of these antibiotic treatments is limited by a lack of response in some patients and high recurrence rates.6 This article reviews emerging
The authors have declared no potential conflicts of interest. Copyright © 2015, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/15/0602-1007. DOI 10.2146/ajhp140645
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CDI treatment approaches, including investigational antibiotic, monoclonal antibody, vaccine, and microbebased therapies. Background C. difficile is an anaerobic, grampositive, spore-forming, toxinreleasing bacillus that is transmitted among humans mainly via contact with fecal matter (the fecal-oral route).7 Until relatively recently, exposure to C. difficile was primarily nosocomial (i.e., hospital/institutionbased), with the most likely route of transmission being transfer via healthcare personnel. However, increasingly the infections originate from noninstitutional environments, and nosocomial transmissions now account for less than half of all CDI cases.8 C. difficile was first described by Hall and O’Toole in 1935 as “the difficult clostridium,”9 partly due to the bacterium’s ability to form spores as a survival mechanism when exposed to hostile conditions.10 Contact with spore-contaminated surfaces is one method by which such pathogens are able to spread from infected individuals to new hosts. Oral ingestion of quiescent-state C. difficile spores transforms them into an active state within the gastrointestinal tract.11 Infections and complications outside the gastrointestinal tract are rare and have only been seen in a small number of cases.12 Colonization by C. difficile stimulates the release of toxins that injure the enteric mucosal lining. The two major toxins, toxin A (encoded by the gene tcdA) and toxin B (encoded by tcdB), are the primary contributors to CDI pathogenesis.13 They are members of the clostridial glucosylating family of toxins.14 The toxins induce inflammation and damage to the intestinal lining by disrupting the tight junctions of the epithelial cells and causing a loss of the epithelial barrier function; the increased permeability of the epithelium allows 1008
the access of neutrophils to the intestinal lumen.14 In addition, the toxins induce apoptosis and necrosis of epithelial cells that contribute to the inflammatory response in CDI. The gastrointestinal tract is host to many resident (autochthonous) organisms, a majority of which are Actinobacteria, Bacteroidetes, Proteobacteria, and Firmicutes (a phylum of which C. difficile is a member).8,15,16 The microbiota can be disrupted (in a process known as dysbiosis) with the introduction of antibiotics16 or the physiologic changes that occur during aging.15 In the older population, there is a reversal of the stability and diversity of the microbiota seen in younger adults. The use of antibiotics increases the risk of infection with C. difficile, even when they are used for short durations.17 Therefore, patients at highest risk for CDI are those who are hospitalized, are older than 65 years of age, and have experienced recent antibiotic use.18 Clinical manifestations of CDI range from diarrhea to fatal pseudomembranous colitis.19 As many as 25% of patients treated for an initial infection experience a recurrent infection within 30 days, and the risk can double after two or more recurrences.20 Patients who mount an antibody response become asymptomatic carriers.21 New hypervirulent strains of C. difficile emerged during the period 2003–09 in North America, many parts of Europe, and other countries. These strains contain a genetic mutation at the gene responsible for toxin inhibition, resulting in an increased production (via disinhibition) of toxins A and B. Higher morbidity and recurrence are seen with these strains.18 The full extent of the problem is difficult to quantify because CDI is not routinely reported and, thus, there is a limited body of surveillance data.5 The available data on CDI in outpatient settings are also limited, but there is evidence of an increase in hospitalizations due
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to C. difficile in the United States,22 with a concomitant increase in U.S. healthcare costs, estimated to be at least $3.2 billion per year.23 Current therapies Current therapy regimens for the treatment of CDI are limited; the two most commonly used drugs worldwide are metronidazole and oral vancomycin. Metronidazole inhibits nucleic acid synthesis in anaerobic bacterial DNA in such a way that further protein synthesis is disabled. Vancomycin disrupts cell wall assembly in gram-positive bacteria by inhibiting the glycopeptide polymerization needed for crosslinking. A third antimicrobial agent, fidaxomicin, was recently approved for the treatment of CDI.18 Fidaxomicin inhibits protein synthesis by inhibition of RNA polymerase, and early evidence suggests that its use against non-NAP1 strains is associated with a lower rate of recurrent infection compared with vancomycin therapy.18 Emerging therapies Antibiotics. CRS3123 (previously REP3123) is an investigational oral agent that is currently in earlystage clinical trials.24 It is a narrowspectrum agent with gram-positive coverage and limited oral bioavailability whose use results in a high concentration of drug in the gastrointestinal tract and low systemic exposure. CRS3123 inhibits protein synthesis, toxin production, and sporulation. CRS3123 was demonstrated to have potent in vitro antibacterial activity against all C. difficile strains tested, including the hypervirulent BI/NAP1/027 variant.25 According to manufacturerprovided information (Crestone, Inc., Boulder, CO), CRS3123 has demonstrated efficacy for selective inhibition of C. difficile growth, as well as inhibition of toxin production and spore formation. If these properties are confirmed in clinical
THERAPY UPDATE Clostridium difficile infection
trials, oral CRS3123 would provide sustained efficacy and (in comparison to vancomycin) less tendency for recurrence. Monoclonal antibodies. Monoclonal antibodies that have selectivity for toxins A and B are being developed.26,27 Monoclonal antibodies were reported to be superior in reducing rates of recurrent CDI in humans when administered in addition to vancomycin or metronidazole— compared with administering the antibiotics alone—in a Phase II randomized, double-blind, placebocontrolled trial involving 200 patients who met the study inclusion criteria (age of ≥18 years and diarrhea associated with a positive stool test for a C. difficile toxin in the two weeks before enrollment).28 The patients were given human monoclonal antibodies active against toxins A and B together in a single i.v. infusion (each agent was given at a dose of 10 mg/kg). The primary endpoint was the recurrence of CDI (defined as a new episode of diarrhea with a positive stool toxin test during the subsequent 84 days). Only 7 (7%) of the patients who received the monoclonal antibodies in combination with antibiotic therapy experienced recurrent CDI, compared with 25 (25%) of the patients who received antibiotics only; similar results were obtained in patients infected with the BI/NAP1/027 strain (recurrence rates with and without monoclonal therapy were 8% and 32%, respectively). Patients who had a history of more than one prior CDI relapsed at a rate of 7% with coadministration of monoclonal antibodies and antibiotics, compared with a relapse rate of 38% among patients given antibiotics alone. These monoclonal antibodies may be useful in preventing recurrent CDI because of their long half-lives (i.e., >20 days).28 There are many positive aspects of monoclonal antibody therapy for CDI; however, there are also some
disadvantages to consider. The delivery of monoclonal antibodies is typically limited to i.v. administration, which is often performed only in inpatient settings, although this mode of delivery may be convenient for hospitalized patients with the most severe infections. These sicker patients with CDI are most likely to have an inadequate response to antibiotics alone and are often too sick to take medications orally. These patients also often have chronic diseases, are elderly, or are taking concomitant antibiotics and are thus at higher risk for recurrence and might benefit the most from monoclonal antibody and antibiotic combination therapy. Although it is inconvenient to administer parenteral medications in outpatient settings, monoclonal antibodies have been administered in a single infusion, enabling patients to get the full benefit of therapy in terms of reduced recurrence risk without requiring further treatment after discharge from the hospital. The general potency of monoclonal antibodies allows for efficient treatment, but the costs of these specialized agents are still relatively high. The top nine monoclonal antibodies in the United States currently cost an average of about $200,000 per year.29 The cost is partly due to the agents’ special manufacturing and storage requirements (necessary to prevent denaturing of the proteins). Since the storage requirements for monoclonal antibodies can be costly for hospitals, many institutions purchase them only on an as-needed basis. It is estimated that the average hospital cost for each patient case of CDI treated with current therapy is almost $4,000.30 Vaccines. Since C. difficile produces toxins A and B, which act synergistically to damage the colonic epithelium, the toxins could be targets for a vaccine. For a vaccine to warrant continued clinical development, it must induce an effective protective immune response against
toxins A and B, and it must be relatively safe. In a prospective cohort study, patients who experienced only one episode of CDI had a notable increase in antibodies to immunoglobulin G (IgG) antitoxin A during the episode, but no such increase occurred in patients who later had recurrent CDI.31 It was found that patients with asymptomatic CDI had high levels of IgG antitoxin A antibody, but there was no association between protection from C. difficile colonization and either serum or secretory IgG antitoxin A levels.32 These observations suggest that recurrent CDI is associated with failure to develop an adequate immune response to the C. difficile toxins. Thus, active or passive immunization could be beneficial for at-risk patients, such as elderly hospitalized patients taking antibiotics and patients who have an anticipated hospital stay (e.g., for elective surgery). According to information on the National Institutes of Health website ClinicalTrials.gov, currently there are several Phase II clinical trials in the United States that are testing vaccines against C. difficile. In one study of a monoclonal antibody vaccine containing GS-CDA1 (a human monoclonal antibody to toxin A) and MDX-1388 (a human monoclonal antibody to toxin B), it was reported that the addition of the monoclonal antibodies to an antibiotic regimen significantly reduced the recurrence of CDI.28 A Phase III clinical trial with an estimated primary completion date of December 2017 33 is evaluating a vaccine that contains toxoids A and B for induction of an immune response against toxins A and B.34 The European Union is funding a three-year initiative to develop an oral (sublingual) vaccine against C. difficile; the intended strategy is to use harmless bacterial spores that carry the antigen and boost immunity by targeting the protein needed for the infection to take hold.35 It has been reported that, overall, the
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candidate C. difficile vaccine has been well tolerated by patients.36 To date, no C. difficile–targeted vaccine has been approved by the Food and Drug Administration, although an agent is currently under clinical development by Pfizer Inc. (PF-06425090). Microbe-based treatment approaches. Fecal microbiota transplantation (FMT) was first used successfully in 1958 to treat four patients with recurrent refractory diarrhea and has gained increasing recognition over the past 60 years as a treatment for CDI.37 The goals of this procedure are to restore the normal balance of the intestinal flora and to provide natural competition for C. difficile, thereby decreasing its overgrowth. While FMT protocols vary, therapy usually begins with the patient receiving a course of antibiotics for a few days before the transplant in order to decrease inflammation and the C. difficile spore burden.37 The antibiotics are stopped prior to the transplant, and a bowel preparation is administered. Stool-donor screening varies but usually includes, at a minimum, exclusion of ova and parasites; Salmonella, Shigella, and Campylobacter strains; and C. difficile toxin using a polymerase chain reaction assay. Other targets of FMTdonor serum screens may include hepatitis A, B, and C; syphilis; and human immunodeficiency virus infection. Many investigators also screen the patient’s blood in order to identify preexisting conditions that might manifest after transplantation. Fresh donor feces are then collected within a few hours before the actual transplantation procedure, and the stool is mixed with water, a preservative-free saline solution, or milk. The stool mixture is administered through a nasogastric tube or via upper endoscopy, colonoscopy, or enema; the total infused volume varies from 50 to 700 mL.37 Doing a colonoscopy allows the bacteria to be delivered directly to the affected site 1010
and also allows the practitioner to examine for comorbid pathology. The oral route of delivery is an available option for patients who are unable to retain a rectal enema or a catheter due to esophageal varices. In a Canadian study, 27 patients who had more than three episodes of recurrent CDI and were unable to tolerate a jejunal catheter or an enema were given 0.47-mL gel capsules that contained fecal microbes.38 The fresh fecal matter (approximately 100 g) was donated on the day of the procedure by relatives who had been screened for pathogens. The fecal matter was suspended in 600–800 mL of prereduced phosphate-buffered saline solution and underwent 2.6 hours of serial centrifugation. The resulting sediment (i.e., microbe pellets) was double-encapsulated to ensure delivery to the intestines and then given to patients, who ingested 24–34 of the custom-assembled capsules over 5–15 minutes on an empty stomach. At the end of the study period, all patients had no recurrence of CDI and complete resolution of all symptoms. Fecal transplants have been shown to be effective in treating resistant cases of CDI, with many physicians reporting success rates as high as 80–95%.39 While the supportive data are largely limited to data from case studies, no other treatment options to date have been reported to yield comparably high success rates. In one of the first randomized controlled studies conducted, patients were assigned to receive one of three regimens: vancomycin 500 mg four times a day for 4 days followed by FMT delivered through a nasoduodenal tube, standard vancomycin therapy (500 mg four times a day for 14 days), and standard vancomycin therapy in combination with bowel lavage on day 4 or 5.40 The primary endpoint was resolution of CDI without relapse after 10 weeks. The study found that the infusion of donor feces was significantly more effective than the use of vancomy-
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cin; the trial was terminated early on ethical grounds. The human gastrointestinal tract is populated not only with bacteria but also with viruses, protozoa, parasites, and fungi. While testing of stool eliminates some of the risk of contracting an illness from the donor, there is concern that current technology might not be sufficient to detect all possible pathogens. In addition, many asymptomatic people carry parasites that cause no problem in their own healthy gut but might cause a reaction in the recipient’s. About one third of the organisms in an individual’s microbiota are common to most people, but the other two thirds are individual specific. In a study of male subjects with metabolic syndrome who underwent bowel lavage followed by either an allogenic (i.e., donor-derived) or autologous (i.e., self-derived) fecal infusion, insulin sensitivity was improved in the group that received allogenic fecal infusion, but there was no notable change in the autologous group.41 That finding raises a question: Can receiving a fecal transfusion from a donor who has metabolic complications lead to an increased risk of diabetes or other undesirable outcomes? Additional testing, guidelines, and restrictions are needed to answer that question definitively. There is also concern over a possible link between the gut’s microbiota and neuropsychiatric disorders. For example, studies of microbe-colonized mice have shown that alterations of gut microbial composition can induce changes in behavior.42 To date, psychiatric illness is not an independent exclusionary factor for fecal donation. Some organizations provide hospitals with screened, filtered, and frozen fecal microbes that are ready for use. While evidence compiled to date indicates no short-term negative effects of FMT, there is insufficient experience to guarantee that there are no long-term adverse effects or risks involved.
THERAPY UPDATE Clostridium difficile infection
A related form of bacteriotherapy, microbial ecosystem therapeutics (MET), involves the use of “synthetic stool” formulations or stool substitutes (similar to those used in the original FMT study). In an early study of MET published in 1989, a consortium of 10 cultured bacterial species, originally isolated from human feces, was used successfully to treat refractory CDI in six patients.43 In that study, the consortium consisted of a mix of facultative and strict anaerobes and was instilled rectally as an enema in a saline carrier solution. All patients became asymptomatic within 24 hours, and subsequent C. difficile toxin testing was negative. Such synthetic stool formulations or stool substitutes might help mitigate many of the current concerns about FMT. Probiotics are live microorganisms that are believed to improve the microbial balance of the host, to counteract disturbances in intestinal flora, and to reduce the risk of colonization by opportunistic pathogenic bacteria.44 They are available without prescription as capsules and food supplements marketed as “functional food” or “good bacteria/yeast.”45 The use of probiotics has been suggested as a means of preventing CDI.46,47 Their low cost and the low associated rate of adverse events48 make probiotics an attractive candidate for CDI treatment. A recent Cochrane review article concluded, “Based on this systematic review and meta-analysis of 23 randomized controlled trials including 4213 patients, moderate quality evidence suggests that probiotics are both safe and effective for preventing Clostridium difficile– associated diarrhea.”49 Prophylaxis. There is currently no prophylactic treatment to prevent the development of infections due to C. difficile. SYN-004, an agent currently in Phase I clinical trials, is intended to be the first. It is β-lactamase in an encapsulated enterically-coated oral form to be
coadministered with i.v. antibiotics.50 The agent is designed to remain within the gastrointestinal tract and degrade i.v. antibiotic that has been excreted into the intestine. A Phase II efficacy study of SYN-004 was initiated in March 2015.51 Conclusion The current antibiotic therapies for CDI, mainly vancomycin and (off-label) metronidazole and the newer agent fidaxomicin, have limitations with respect to efficacy, recurrence rates, and adverse effects, but a variety of promising approaches are emerging. References 1. Clabots CR, Johnson S, Olson MM et al. Acquisition of Clostridium difficile by hospitalized patients: evidence for colonized new admissions as a source of infection. J Infect Dis. 1992; 166:561-7. 2. Dallal RM, Harbrecht BG, Boujoukas AJ et al. Fulminant Clostridium difficile: an underappreciated and increasing cause of death and complications. Ann Surg. 2002; 235:363-72. 3. Hall AC, Curns AT, McDonald LC et al. The roles of norovirus and Clostridium difficile among gastroenteritis deaths in the United States, 1999–2007. Presentation at the 49th Annual Meeting of the Infectious Diseases Society of America. Boston, MA; 2011 Oct 22. 4. Simor AE, Bradley SF, Strausbaugh LJ et al. Clostridium difficile in long-term–care facilities for the elderly. Infect Control Hosp Epidemiol. 2002; 23:696-703. 5. Cohen SH, Gerding DN, Johnson S et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010; 31:431-55. 6. Huang H, Weintraub A, Fang H, Nord CE. Antimicrobial resistance in Clostridium difficile. Intl J Antimicrob Agents. 2009; 34:516-22. 7. Leffler DA, Lamont JT. Treatment of Clostridium difficile-associated disease. Gastroenterology. 2009; 136:1899-912. 8. Hoover DG, Rodriguez-Palacios A. Transmission of Clostridium difficile in foods. Infect Dis Clin North Am. 2013; 27:675-85. 9. Kelly CP, Pothoulakis C, Lamont JT. Clostridium difficile colitis. N Engl J Med. 1994; 330:257-62. 10. Pereira FC, Saujet L, Tomé AR et al. The spore differentiation pathway in the enteric pathogen Clostridium difficile. PLoS Genet. 2013; 9:e1003782.
11. Allen CA, Babakhani F, Sears P et al. Both fidaxomicin and vancomycin inhibit outgrowth of Clostridium difficile spores. Antimicrob Agents Chemother. 2013; 57:664-7. 12. Libby DB, Bearman G. Bacteremia due to Clostridium difficile—review of the literature. Int J Infect Dis. 2009; 13:e3059. 13. Wu D, Joyee AG, Nandagopal S et al. Effects of Clostridium difficile toxin A and B on human T lymphocyte migration. Toxins. 2013; 5:926-38. 14. Sun X, Savidge T, Feng H. The enterotoxicity of Clostridium difficile toxins. Toxins. 2010; 2:1848-80. 15. Khanna S, Tosh PK. A clinician’s primer on the role of the microbiome in human health and disease. Mayo Clin Proc. 2014; 89:107-14. 16. Peniche AG, Savidge TC, Dann SM. Recent insights into Clostridium difficile pathogenesis. Curr Opin Infect Dis. 2013; 26:447-53. 17. Bartlett JG. Antibiotic-associated diarrhea. N Engl J Med. 2002; 346:334-9. 18. Burke KE, Lamont JT. Clostridium difficile infection: a worldwide disease. Gut Liver. 2014; 8:1-6. 19. Korman T. Diagnosis and management of Clostridium difficile infection. Semin Respir Crit Care Med. 2015; 36:31-43. 20. Kelly CP. Can we identify patients at high risk of recurrent Clostridium difficile infection? Clin Microbiol Infect. 2012; 18(suppl 6):21-7. 21. Kyne L, Warny M, Qamar A, Kelly CP. Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. N Engl J Med. 2000; 342:390-7. 22. Zilberberg MD, Shorr AF, Kollef MH. Increase in adult Clostridium difficilerelated hospitalizations and case-fatality rate, United States, 2000–2005. Emerg Infect Dis. 2008; 14:929-31. 23. Surawicz CM, Brandt LJ, Binion DG et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013; 108:478-98. 24. ClinicalTrials.gov. Phase I trial of a single dose of CRS3123. http://clinicaltrials.gov/show/NCT01551004 (accessed 2015 Apr 11). 25. Critchley IA, Green LS, Young CL et al. Spectrum of activity and mode of action of REP3123, a new antibiotic to treat Clostridium difficile infections. J Antimicrob Chemother. 2009; 63:954-63. 26. Davies NL, Compson JE, MacKenzie B et al. A mixture of functionally oligoclonal humanized monoclonal antibodies that neutralize Clostridium difficile TcdA and TcdB with high levels of in vitro potency shows in vivo protection in a hamster infection model. Clin Vaccine Immunol. 2013; 20:377-90. 27. Marozsana AJ, Ma D, Nagashima KA et al. Protection against Clostridium difficile infection with broadly neutralizing
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44. Sullivan A, Nord C. Probiotics in human infections. J Antimicrob Chemother. 2002; 50:625-7. 45. Drisko J, Bischoff B, Giles C et al. Evaluation of five probiotics products for label claims by DNA extraction and polymerase chain reaction analysis. Dig Dis Sci. 2005; 50:1113-7. 46. D’Souza AL, Rajkumar C, Cooke J, Bulpitt CJ. Probiotics in prevention of antibiotic-associated diarrhoea: metaanalysis. Brit Med J. 2002; 324:1361-7. 47. Dendukuri N, Costa V, McGregor M, Brophy JM. Probiotic therapy for the prevention and treatment of Clostridium difficile-associated diarrhea: a systematic review. Can Med Assoc J. 2005; 173:16770. 48. Hempel S, Newberry SJ, Maher AR et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. J Am Med Assoc. 2012; 307:1959-69. 49. Goldenberg JZ, Ma SS, Saxton JD et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2013; 5:CD006095. 50. Watermark Medical Animations. C. difficile & SYN-004 animation. www.youtube. com/watch?v=97lkgRZyXLc (accessed 2015 Apr 11). 51. Synthetic Biologics initiates phase 2a clinical trial of SYN-004 to protect the microbiome and prevent C. difficile. www. syntheticbiologics.com/2015-03-30Synthetic-Biologics-Initiates-Phase-2aClinical-Trial-of-SYN-004-to-Protectthe-Microbiome-and-Prevent-C-difficile (accessed 2015 Apr 11).
