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Important clinical advances in the understanding of Clostridium difficile infection

Pacheco, Susan M.a,b; Johnson, Stuartb,c

Current Opinion in Gastroenterology: January 2013 - Volume 29 - Issue 1 - p 42–48
doi: 10.1097/MOG.0b013e32835a68d4
LARGE INTESTINE: Edited by Ciarán P. Kelly
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Purpose of review Clostridium difficile remains an important cause of infectious colitis, particularly in healthcare facilities. This review summarizes recent advances in the epidemiology, diagnosis, and treatment of this endemic pathogen.

Recent findings C. difficile infection (CDI) hospitalizations and mortality rates have increased over the last decade. The BI/NAP1/027 strain has been responsible for epidemics with increased severity and mortality and is now endemic in many settings, particularly North America. Concurrent antibiotics have now been shown to decrease the cure rates for anti-C. difficile therapy and increase the risk of recurrence. Although studies implicate proton pump inhibitors as a risk for CDI, the magnitude of and the biological basis for that risk remain unclear. Molecular diagnostic techniques are rapid and sensitive but highlight the importance of using appropriate clinical testing criteria. Fidaxomicin is a promising new therapy associated with decreased recurrence; infections due to BI strains, however, are associated with inferior outcomes regardless of the treatment agent. Fecal transplantation continues to have impressive success rates for patients with recurrent CDI, and a new colon-sparing surgical procedure presents an intriguing suggested alternative to total colectomy in severe, complicated cases.

Summary Elucidating CDI risk factors, identifying rapid, accurate diagnostic tools, and validating new treatment approaches remains an urgent priority.

aDepartment of Medicine, Hines VA Hospital, Hines

bDepartment of Medicine, Loyola University Medical Center, Maywood

cDepartment of Research, Hines VA Hospital, Hines, Illinois, USA

Correspondence to Susan M. Pacheco, MD, Division of Infectious Diseases, Department of Medicine, Loyola University Medical Center, 2160 S. First Avenue, Fahey Bldg, Rm 114B, Maywood, IL 60153, USA. Tel: +1 708 216 3232; e-mail: spacheco@lumc.edu

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INTRODUCTION

Clostridium difficile is the most important cause of infectious colitis among patients in healthcare settings and is frequently seen in patients outside of the hospital as well. Many important advances in understanding the epidemiology, diagnosis, and treatment of C. difficile infection (CDI) have occurred in the last year. In addition, recent advances in the genetic manipulation of C. difficile have provided insight into the molecular pathogenesis of CDI, including support for an independent role of toxin B [1], as well as confirming the importance of toxin A [2], the two main virulence determinants of this pathogen. The epidemic BI/NAP1/027 strain has become endemic in many North American healthcare settings [3▪,4▪,5▪▪] and over the past decade has had enormous impact on the epidemiology and management of CDI. This strain, often referred to as ‘hypervirulent’ has an additional toxin, C. difficile transferase (CDT), the role of which has remained unclear. New data, however, suggest that CDT may act by inducing microtubule-based protrusions on the surface of epithelial cells, which facilitate adherence of C. difficile[6]; a possible receptor for this toxin has also recently been identified [7▪]. We anticipate a surge of data over the next several years highlighting new insights into the pathogenesis of CDI using these new molecular techniques to manipulate clinically relevant strains. Here we describe several recent advances highlighting the epidemiology, diagnosis, and treatment of CDI.

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EPIDEMIOLOGY

Although significant progress has been made in reducing healthcare-associated infections attributable to other organisms, CDI remains largely unaffected. In 2009, CDI was associated with 336 600 US hospitalizations, which comprised almost 1% of total admissions that year and was more than double the number of hospitalizations a decade earlier [8▪]. Reporting of CDI has now been mandated in parts of several countries including the UK, Ontario, Canada, and several US states [9,10,11▪▪].

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CLOSTRIDIUM DIFFICILE INFECTION COMPLICATIONS

Well described complications of CDI include the need for intensive care unit stay, colectomy, and death. Although rates of colectomy remain low [12▪], mortality has steadily increased over time [13▪]. Hall et al.[13▪] examined the trends in gastroenteritis mortality between 1999 and 2007 and found that all-cause mortality rates increased from 25 to 57 per million person-years over the period, the majority of which were due to increases in CDI-coded deaths (from 10 to 48 per million person-years). In addition to traditionally recognized complications, the potential risk of graft-versus-host disease (GVHD) after CDI was recently evaluated in a cohort of 999 hematopoietic stem cell transplant patients [14▪]; in the course of 1 year, CDI was found to occur in 9.2% overall, generally early in the course of disease, and when present was an independent risk factor for gastrointestinal GVHD after allogeneic transplant.

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RISK FACTORS FOR CLOSTRIDIUM DIFFICILE INFECTION AND OUTCOMES

Given the significant complications and mortality associated with this infection, there has been marked effort to identify risk factors for acquisition of C. difficile, development of disease including its complications, development of recurrence, and mortality. One of the most significant risk factors for C. difficile acquisition is recent hospitalization and data from CDC's Emerging Infections Program in 2010 determined that 94% of cases overall were healthcare-associated, despite 75% of them having onset outside of the hospital setting [11▪▪]. Studies have similarly shown that the majority of cases occurring in the long-term care setting involve patients who were recently hospitalized [11▪▪,15,16]. Antibiotic use has been well documented to alter the colonic microflora and, along with increased age, is a well established risk factor for CDI [3▪]. It has also been suspected that continuing antibiotic use during and after CDI treatment is detrimental. In two phase III trials of fidaxomicin versus vancomycin, patients who took non-CDI antimicrobials during CDI therapy had a decreased cure rate and increased time to resolution of diarrhea [17▪▪]. Receipt of antibiotics during follow-up after CDI treatment had a nonsignificant trend toward increased CDI recurrence in this study population [17▪▪]; as further evidence, in a separate study, Drekonja et al.[18▪] showed that posttreatment non-CDI antimicrobials significantly increased CDI recurrence.

The role of acid suppression therapy, especially proton pump inhibitors (PPIs), in the risk of developing CDI, complications of CDI, and recurrent disease continues to be debated as recent studies continue to reach differing conclusions [3▪,14▪,19–21,22▪]. Two recently published meta-analyses both found an overall increased risk of CDI with PPI use; however, significant study heterogeneity and the observational nature of many of the studies limit the ability to make definitive conclusions [23▪,24▪]. Despite the lack of conclusive evidence, the US Food and Drug Administration issued a drug safety communication in February of 2012 warning of the perceived risk of PPI use and the development of CDI [25]. The relative importance of this risk factor, if real, is clearly much less than that of antibiotic use. In addition, the biological basis for PPI risk has not been demonstrated, so for now, it seems the role of acid suppression in CDI remains unanswered.

Epidemic BI (aka, NAP1/027) strains have been associated with increased severity of disease and mortality. A recent study also showed that BI strains were associated with decreased cure rates and increased rates of recurrence compared with other strain types regardless of initial therapy [5▪▪].

There has been much interest in the development of clinical prediction rules to try to identify patients who are at risk for complications of CDI in order that they might receive more aggressive intervention or more effective treatment earlier. Most of these studies were of suboptimal study design and did not perform particularly well as highlighted by a recent meta-analysis [26]. Prediction of treatment failure and complications remains imprecise and better prediction models are urgently needed.

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MOLECULAR DIAGNOSTICS

Diagnosis of CDI has been limited by the lack of a sensitive and specific test that is predictive of disease and simple and rapid to perform. Toxigenic culture, although relatively sensitive and specific, can take several days to obtain final results, which does not allow for expeditious implementation of therapy and infection control precautions. The cytotoxicity assay is more sensitive than toxin enzyme immunoassays (EIAs), but less so than culture, and is labor-intensive, which precludes its widespread use in many clinical laboratories. EIA for C. difficile toxins A and B had become the predominant methodology because it has a short turnaround time and is easy to perform, but this methodology has been limited by its relatively lower sensitivity. In a multisite study by Tenover et al.[27], which compared a commercially available PCR assay to enrichment toxigenic culture, direct cytotoxicity testing, and toxin EIA among other algorithms, 2292 stool samples were tested with each of the various assays. PCR had significantly improved sensitivity over EIA overall. In the subset of 275 samples, which were ribotyped, PCR was significantly more sensitive than EIA in detecting ribotypes 002, 027, and 106. Given the emergence of increasing numbers of infections with ribotype 027 (aka, BI/NAP1) over the last decade, this may explain the seemingly worsening performance of the EIA test in more recent studies.

Molecular nucleic acid amplification tests (NAATs) such as PCR and loop-mediated isothermal amplification (LAMP) have emerged as rapid and highly sensitive and specific assays for C. difficile detection with PCR targeting, as a minimum, the tcdB gene and LAMP targeting a conserved region of the tcdA gene. There are currently several commercially available NAAT assays that are approved by FDA for diagnosis of CDI in the USA. Recent evaluations of PCR assays including two meta-analyses have consistently shown sensitivities and specificities generally exceeding 90% compared with toxigenic culture or cytotoxicity assays and superior performance in comparison with EIA toxin testing [28▪,29▪]. LAMP has also been shown to be highly sensitive [30▪,31▪]. Positive predictive values (PPVs) for PCR are dependent on the prevalence of CDI in the sample studied; PPV has been reported to be 93% in high-prevalence populations (CDI >20%) compared with only 71% in populations in which prevalence of CDI was less than 10% [28▪]. The negative predictive value of PCR, however, is generally more than 95%, indicating a negative test is excellent for ruling out CDI [28▪]. Along these lines, Khanna et al. [32▪] performed a retrospective review of their experience with repeat PCR testing and found that although it happened infrequently (12.7% within 14 days of the first sample), it was also rarely positive, so that routine repeat testing for the same diarrheal episode was discouraged.

With the increased sensitivity of NAAT testing, however, comes an increased potential for false positive results including identification of patients who are asymptomatically colonized highlighting the importance of clinical correlation of the results to avoid unnecessary anti-C. difficile therapy, cessation of antibiotics for other indications, and contact isolation. Dubberke et al. [33▪] prospectively examined the performance characteristics of commonly utilized assays when clinical symptoms were incorporated as part of the definition of the gold standard for diagnosing CDI. When the standard was toxigenic C. difficile culture and clinically significant diarrhea, sensitivity was unchanged but specificity was significantly decreased for both PCR and LAMP assays, as well as EIA testing, underscoring the importance of selecting the appropriate patient population for testing to avoid intervening on patients who do not have symptomatic CDI.

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ANTIBIOTIC THERAPY FOR CLOSTRIDIUM DIFFICILE INFECTION

One of the promising discoveries in recent years is fidaxomicin, a macrocyclic antibiotic with minimal systemic absorption, excellent anti-C. difficile activity, but relatively little effect on other normal gut flora. Two phase III studies comparing fidaxomicin to oral vancomycin have demonstrated noninferiority of fidaxomicin to vancomycin with respect to initial cure of CDI [34▪▪,35▪▪]. Additionally, in one study, treatment with fidaxomicin resulted in higher initial cure rates in patients who were receiving additional non-CDI antibiotics [35▪▪]. Importantly, fidaxomicin was also shown to have overall decreased rates of recurrence [34▪▪,35▪▪], resulting in a higher sustained response than vancomycin [36▪]. Subgroup analysis showed the reduced rate of recurrence for fidaxomicin was only for non-NAP1 strains [34▪▪]. Analyzing the data from both of these phase III studies using cases in which C. difficile isolates were recovered and typed, it was shown that initial cure was lower with both fidaxomicin and vancomycin for BI strains (aka, NAP1/027) and that recurrence was also increased with BI (27.4 versus 16.6%) [5▪▪]; in multivariate analysis, the BI strain was an independent risk factor for reduced cure and increased recurrence. So, although fidaxomicin seems to have improved efficacy preventing recurrence overall, treatment of BI-associated cases remains more challenging. Given that no agent has been shown to be superior in this instance, treatment decisions should be based on clinical assessments and not strain typing results.

Rifaximin has anti-C. difficile activity and has been used at the end of primary therapy courses including vancomycin tapers in an attempt to decrease recurrences. Garey et al.[37▪] undertook a randomized, double-blind, placebo-controlled pilot study of rifaximin used as a ‘chaser’ after a course of metronidazole or vancomycin. Patients taking rifaximin developed fewer recurrences of diarrhea from all causes after treatment, although the difference for those due to recurrent CDI was not significant between the two groups, as the study was likely underpowered. Further studies will be required to determine whether a role exists for rifaximin in the treatment of CDI.

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FECAL MICROBIOTA TRANSPLANTATION

It is well established that the human colon microflora is one of the most important natural barriers to C. difficile colonization and infection. As such, fecal microbiota transplantation (FMT) has been increasingly utilized in patients with recurrent CDI. In an elegant case study, Khoruts et al.[38] were able to characterize the bacterial composition of the stool of a patient with recurrent C. difficile prior to and after FMT and show that, posttransplant, the patient's stool became remarkably similar in composition to the donor's. FMT has been accomplished by a variety of different delivery methods including colonoscopy, upper endoscopy, nasogastric tube, and retention enema and there is no current agreement on the best delivery, although one systematic review reported possible decreased efficacy with delivery into the upper gastrointestinal tract [39▪]. Reports of success from case series and systematic reviews remain impressive with more than 90% of patients achieving cure and many of those who relapse being successfully treated with an additional FMT or a course of anti-C. difficile antimicrobials [39▪–43▪]. As this procedure is increasingly used, several groups have proposed both guidelines for selection and testing of stool donors and protocols for performance of the procedure [41▪,43▪]. And perhaps somewhat surprisingly, the procedure seems to be well accepted by patients; in a recent study examining long-term follow-up of patients who underwent FMT, 53% said if they had further recurrences of CDI, they would prefer FMT over an additional course of antibiotics as the first-line therapy [40▪].

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SURGICAL MANAGEMENT

Colectomy has long been considered the surgical procedure of choice for patients with severe CDI unresponsive to antimicrobial and other therapies. However, outcomes after colectomy have been dismal with mortality in some series still greater than 50% even after surgery [44], likely in part due to the multiple comorbidities of some of these patients, the multiorgan dysfunction often present with severe disease, and the delay in performing this procedure due to the morbidity of the operation. An intriguing case series of a new, less invasive, colon-sparing approach was reported describing a procedure that involves the creation of a diverting loop-ileostomy through which the colon is lavaged intraoperatively followed by postoperative antegrade vancomycin enemas and intravenous metronidazole for 10 days in patients with severe complicated CDI [45▪▪]. Eighty-three percent of these procedures were performed laparoscopically, and the colon was spared in 93% of the patients; 79% were eventually able to undergo ileostomy reversal. Mortality in this case series was markedly improved over the institution's historical baseline when performing total abdominal colectomies (19 versus 50% with colectomy). Given the decreased morbidity and mortality of this procedure, it may ideally encourage earlier surgical consultation and intervention as well as improved outcomes for patients with severe CDI. Further studies will be helpful in evaluating this new and innovative method.

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CONCLUSION

Rates of C. difficile attributable to our healthcare facilities remain unacceptably high. Antibiotic use continues to play an important role in susceptibility to both incident and recurrent CDI, but the role of acid-suppression therapy remains less clear. Our ability to accurately predict severe complicated disease and mortality remains inadequate. NAAT testing is improving diagnostic sensitivity, including for epidemic strains, but requires consideration of the clinical context for interpretation. Fidaxomicin shows promise in decreasing overall CDI recurrence, whereas fecal transplantation continues to show encouraging results for those with recurrent or refractory CDI. We anticipate more data in the near future on new treatment and prevention strategies, including additional narrow spectrum antibiotics [46], monoclonal antibodies [47], more effective probiotics [48] and biotherapeutics [49], and vaccines. One C. difficile toxoid vaccine (using inactivated whole toxins) was shown to be well tolerated and immunogenic in a phase I dose-finding trial [50▪] and other vaccines are in preclinical development phases [51▪]. Hopefully, with these and other advances, we can start to significantly impact the rates of this persistent pathogen.

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Acknowledgements

None.

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Conflicts of interest

S.M.P. has no conflicts of interest to declare. S.J. has served as a consultant for Optimer, Pfizer, and Bio-K+.

S.M.P. receives support from the Hines VA Hospital. S.J. is supported by the US Department of Veterans Affairs Research Service (Merit Review grant I01 BX000121) and has grants from Merck, Actelion, and Cubist.

None declared.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 99–100).

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REFERENCES

1. Lyras D, O’Connor JR, Howarth PM, et al. Toxin B is essential for virulence of Clostridium difficile. Nature 2009; 458:1176–1181.
2. Kuehne SA, Cartman ST, Heap JT, et al. The role of toxin A and toxin B in Clostridium difficile infection. Nature 2010; 467:711–713.
3▪. Loo VG, Bourgault A-M, Poirier L, et al. Host and pathogen factors for Clostridium difficile infection and colonization. N Engl J Med 2011; 365:1693–1703.

Risk factors for healthcare-associated CDI and healthcare-associated C. difficile colonization were evaluated and strain typing by pulsed field gel electrophoresis was performed in a 15-month prospective study of 4143 patients in six Canadian hospitals. Rates of infection and colonization were similar, but the prevalence of NAP1 (aka, BI/027) among those infected (62.7%) was twice that of those that were colonized (36.1%), supporting increased virulence for this strain.

4▪. Black SR, Weaver KN, Jones RC, et al. Clostridium difficile outbreak strain BI is highly endemic in Chicago area hospitals. Infect Control Hosp Epidemiol 2011; 32:897–902.

The authors prospectively evaluated CDI cases in 25 hospitals in Chicago in February 2009 and described rates of incident CDI, rates of related complications, and results of genotyping showing endemicity of the BI strain.

5▪▪. Petrella LA, Sambol SP, Cheknis A, et al. Decreased cure and increased recurrence rates for Clostridium difficile infection caused by the epidemic C. difficile BI strain. Clin Infect Dis 2012; 55:351–357.

C. difficile isolates from phase III clinical trials evaluating fidaxomicin were typed using restriction endonuclease analysis; multivariate analysis demonstrated the BI strain to be a risk factor for decreased clinical cure and increased recurrence including patients treated with fidaxomicin.

6. Schwan C, Stecher B, Tzivelekidis T, et al. Clostridium difficile toxin CDT induces formation of microtubule-based protrusions and increases adherence of bacteria. PLoS Pathog 2009; 5:e1000626.
7▪. Papatheodorou P, Carette JE, Bell GW, et al. Lipolysis-stimulated lipoprotein receptor (LSR) is the host receptor for the binary toxin Clostridium difficile transferase (CDT). Proc Natl Acad Sci U S A 2011; 108:16422–16427.

The lipolysis-stimulated lipoprotein receptor has been identified as a likely receptor for the binary actin-ADP-ribosylating toxin of C. difficile. This finding helps elucidate the mechanism of action of the binary toxin produced in some strains of C. difficile, including the epidemic BI/NAP1/027 strain.

8▪. Lucado J, Gould C, Elixhauser A. Clostridium difficile infections (CDI) in hospital stays, 2009. HCUP Statistical Brief #124. January 2012. Rockville, MD: Agency for Healthcare Research and Quality. http://www.hcup-us.ahrq.gov/reports/statbriefs/sb124.pdf.

This update from the Agency for Healthcare Research and Quality reports data from the Healthcare Cost and Utilization Project on rates of C. difficile hospitalization, associated conditions, and mortality through 2009.

9. United Kingdom. Department of Health. The health and social care act 2008: code of practice on the prevention and control of infections and related guidance. December 2010. http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/documents/digitalasset/dh_123923.pdf. [Accessed 1 August 2012]
10. Ontario, Canada. Ministry of Health and Long-term Care. Public Hospitals Act. Hospital Management, RRO 1990, Reg 965. July 2012. http://canlii.ca/t/51v7k. [Accessed 1 August 2012]
11▪▪. McDonald LC, Lessa F, Sievert D, et al. Vital signs: preventing Clostridium difficile infections. MMWR Morb Mortal Wkly Rep 2012; 61:1–6.

The Centers for Disease Control and Prevention report epidemiological data for US CDIs obtained from Emerging Infections Program active surveillance in eight areas, National Healthcare Safety Network reporting, and three state-led healthcare-associated infection reduction programs. The majority of infections from this population-based study were noted to be related to healthcare exposure.

12▪. Kasper AM, Nyazee HA, Yokoe DS, et al. A multicenter study of Clostridium difficile infection-related colectomy, 2000–2006. Infect Control Hosp Epidemiol 2012; 33:470–476.

Colectomy rates for C. difficile at five academic US medical centers did not increase over the period; community onset of disease was identified as an independent risk factor for colectomy.

13▪. Hall AJ, Curns AT, McDonald LC, et al. The roles of Clostridium difficile and Norovirus among gastroenteritis-associated deaths in the United States, 1999–2007. Clin Infect Dis 2012; 55:216–223.

Gastroenteritis mortality was reviewed between 1999 and 2007 and estimates of the proportion related to C. difficile and Norovirus discussed; C. difficile was the predominant infectious contributor to increasing mortality.

14▪. Alonso CD, Treadway SB, Hanna DB, et al. Epidemiology and outcomes of Clostridium difficile infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2012; 54:1053–1063.

The 1-year incidence of CDIs was described for a cohort of 999 hematopoietic stem cell transplant patients and risk factors for disease in allogeneic transplants were evaluated; an association with gastrointestinal GVHD was noted.

15. Hun Kim J, Toy D, Muder RR. Clostridium difficile infection in a long-term care facility: hospital-associated illness compared with long-term care-associated illness. Infect Control Hosp Epidemiol 2011; 32:656–660.
16. Guerrero DM, Nerandzic MM, Jury LA, et al. Clostridium difficile infection in a Department of Veterans Affairs long-term care facility. Infect Control Hosp Epidemiol 2011; 32:513–515.
17▪▪. Mullane KM, Miller MA, Weiss K, et al. Efficacy of fidaxomicin versus vancomycin as therapy for Clostridium difficile infection in individuals taking concomitant antibiotics for other concurrent infections. Clin Infect Dis 2011; 53:440–447.

Outcomes of cure rate and recurrence in patients with CDI with and without concurrent antibiotic use were evaluated in two phase III trials comparing fidaxomicin and vancomycin. Patients who took concurrent antibiotics had inferior outcomes for both cure and recurrence (the latter did not reach statistical significance) compared with those who did not receive additional non-C. difficile antibiotics.

18▪. Drekonja DM, Amundson WH, DeCarolis DD, et al. Antimicrobial use and risk for recurrent Clostridium difficile infection. Am J Med 2011; 124:1081.e1–1081.e7.

Patients with CDI were assessed for risk of infection recurrence based on whether they were given non-C. difficile antimicrobials after completion of therapy for CDI; antimicrobials given after infection were associated with a three-fold increased risk.

19. Morrison RH, Hall NS, Said M, et al. Risk factors associated with complications and mortality in patients with Clostridium difficile infection. Clin Infect Dis 2011; 53:1173–1178.
20. Gil Kim Y, Graham DY, Ik Jang B. Proton pump inhibitor use and recurrent Clostridium difficile-associated disease. A case–control analysis matched by propensity score. J Clin Gastroenterol 2012; 46:397–400.
21. Stevens V, Dumyati G, Brown J, van Wijngaarden E. Differential risk of Clostridium difficile infection with proton pump inhibitor use by level of antibiotic exposure. Pharmacoepidemiol Drug Saf 2011; 20:1035–1042.
22▪. Naggie S, Miller BA, Zuzak KB, et al. A case-control study of community-associated Clostridium difficile infection: no role for proton pump inhibitors. Am J Med 2011; 124:276.e1–276.e7.

The authors performed a case–control study in multiple centers examining risk factors for community-associated CDI including acid suppression therapy and antimicrobial use and showed that a large proportion of these patients do not have identifiable antimicrobial exposure.

23▪. Shing Kwok C, Kobina Arthur A, Ifeanyichukwu Anibueze C, et al. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. Am J Gastroenterol 2012; 107:1011–1019.

The authors undertook a systematic review of studies evaluating the risk of CDI with acid-suppressing drugs; although the trend seems to be an increased risk with acid suppression (possibly decreased with H2 blockers versus PPIs), studies were of poor quality limiting the ability to draw definitive conclusions.

24▪. Janarthanan S, Ditah I, Adler DG, Ehrinpreis MN. Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis. Am J Gastroenterol 2012; 107:1001–1010.

A meta-analysis of CDI and PPI use revealed an increased incidence of infection with PPI use, but there was significant study heterogeneity.

25. United States. Department of Health and Human Services. Food and Drug Administration. Proton Pump Inhibitors (PPIs) – Drug Safety Communication: Clostridium difficile-associated diarrhea (CDAD) can be associated with stomach acid drugs. February 2012. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm290838.htm. [Accessed 30 July 2012]
26. Abou Chakra CN, Pepin J, Valiquette L. Prediction tools for unfavourable outcomes in Clostridium difficile infection: a systematic review. PLoS One 2012; 7:e30258.
27. Tenover FC, Novak-Weekley S, Woods CW, et al. Impact of strain type on detection of toxigenic Clostridium difficile: comparison of molecular diagnostic and enzyme immunoassay approaches. J Clin Microbiol 2010; 48:3719–3724.
28▪. Deshpande A, Pasupuleti V, Rolston DDK, et al. Diagnostic accuracy of real-time polymerase chain reaction in detection of Clostridium difficile in the stool samples of patients with suspected Clostridium difficile infection: a meta-analysis. Clin Infect Dis 2011; 53:e81–e90.

This meta-analysis included published studies comparing C. difficile PCR to cell culture cytotoxicity neutralization assay or toxigenic culture and evaluated sensitivity, specificity, and positive and negative predictive values. Although sensitivity and specificity are excellent, the overall diagnostic accuracy depends on the prevalence of CDI and must be considered when interpreting test results.

29▪. O’Horo JC, Jones A, Sternke M, et al. Molecular techniques for diagnosis of Clostridium difficile infection: systematic review and meta-analysis. Mayo Clin Proc 2012; 87:643–651.

A meta-analysis evaluating 25 studies comparing PCR for C. difficile to toxigenic culture or cytotoxicity assay was performed and demonstrated PCR to be a fairly sensitive and specific test. Loop-mediated isothermal amplification studies could not be examined by meta-analysis.

30▪. Lalande V, Barrault L, Wadel S, et al. Evaluation of a loop-mediated isothermal amplification assay for diagnosis of Clostridium difficile infections. J Clin Microbiol 2011; 49:2714–2716.

A commercially available LAMP assay for C. difficile is evaluated compared with toxigenic culture. This assay may be easier to perform than PCR for some laboratories, as it does not require more expensive thermocycling equipment.

31▪. Boyanton BL Jr, Sural P, Loomis CR, et al. Loop-mediated isothermal amplification compared to real-time PCR and enzyme immunoassay for toxigenic Clostridium difficile detection. J Clin Microbiol 2012; 50:640–645.

A LAMP assay for C. difficile was compared with PCR and two toxin EIAs and was found to be overall comparable to PCR and superior to EIA testing.

32▪. Khanna S, Pardi DS, Rosenblatt JE, et al. An evaluation of repeat stool testing for Clostridium difficile infection by polymerase chain reaction. J Clin Gastroenterol 2012. [Epub ahead of print]

Khanna et al. quantified the incidence of repeat stool testing with C. difficile PCR and evaluated the clinical utility of this practice. Repeat testing did not appear to increase sensitivity, supporting the previous SHEA/IDSA guideline recommendation (based on EIA data) to avoid multiple C. difficile tests for the same diarrhea episode.

33▪. Dubberke ER, Han Z, Bobo L, et al. Impact of clinical symptoms on interpretation of diagnostic assays for Clostridium difficile infections. J Clin Microbiol 2011; 49:2887–2893.

The authors studied nine diagnostic assays for C. difficile and assessed the effect on sensitivity and specificity when clinical symptoms were included as part of the gold standard comparison. This study highlighted the importance of correct selection of the test population for C. difficile.

34▪▪. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011; 364:422–431.

This is the first published phase III clinical trial of fidaxomicin versus vancomycin for CDI. Fidaxomicin was noninferior to vancomycin for clinical cure and had a lower recurrence rate at 4 weeks after treatment for non-NAP1 strains. This study established fidaxomicin as a beneficial new therapy, but demonstrates that treatment of BI (aka, NAP1/027) associated infections are more challenging and outcomes were not better for either agent in the treatment of these infections.

35▪▪. Cornely OA, Crook DW, Esposito R, et al. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, noninferiority, randomized controlled trial. Lancet Infect Dis 2012; 12:281–289.

A double-blind randomized controlled phase III trial in three countries comparing fidaxomicin with oral vancomycin in the treatment of CDI found fidaxomicin to be noninferior for clinical cure (superior in the subset taking concomitant antibiotics) and superior in terms of disease relapse in patients not on additional antibiotic therapy. This study validated the noninferiority findings in the initial published phase III study and confirmed fidaxomicin as a promising new therapy for C. difficile.

36▪. Johnson S, Gerding DN, Louie TJ, et al. Sustained clinical response as an endpoint in treatment trials of Clostridium difficile-associated diarrhea. Antimicrob Agents Chemother 2012; 56:4043–4045.

An endpoint of sustained clinical response that combines the traditionally studied endpoints of clinical cure and recurrence is proposed as a useful metric to evaluate new therapies for CDI and is demonstrated in the context of two previously reported clinical trials.

37▪. Garey KW, Ghantoji SS, Shah DN, et al. A randomized, double-blind, placebo-controlled pilot study to assess the ability of rifaximin to prevent recurrent diarrhoea in patients with Clostridium difficile infection. J Antimicrob Chemother 2011; 66:2850–2855.

This is a pilot study comparing a course of rifaximin versus placebo both for 20 days after standard therapy for CDI. These data support the concept of postprimary therapy treatment with rifaximin (aka, the ‘chaser’ strategy) for interrupting recurrent CDI episodes, but the study was underpowered and included primary as well as recurrent CDI cases.

38. Khoruts A, Dicksved J, Jansson JK, Sadowsky MJ. Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea. J Clin Gastroenterol 2010; 44:354–360.
39▪. Gough E, Shaikh H, Manges AR. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis 2011; 53:994–1002.

A systematic review of case series and case reports evaluating fecal microbiota transplantation for CDI and pseudomembranous colitis was performed and describes outcomes in 317 patients.

40▪. Brandt LJ, Aroniadis OC, Mellow M, et al. Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol 2012; 107:1079–1087.

This is a long-term follow-up study of patients from five US medical centers who had undergone fecal microbiota transplantation to describe outcomes, donor characteristics, and acceptability of the procedure.

41▪. Kelly CR, de Leon L, Jasutkar N. Fecal microbiota transplantation for relapsing Clostridium difficile infection in 26 patients. Methodology and results. J Clin Gastroenterol 2012; 46:145–149.

Kelly et al. evaluated outcomes in 26 patients undergoing fecal microbiota transplantation for C. difficile via colonoscopy and detailed a protocol for transplantation.

42▪. Kassam Z, Hundal R, Marshall JK, Lee CH. Fecal transplant via retention enema for refractory or recurrent Clostridium difficile infection. Arch Intern Med 2012; 172:191–193.

The authors describe outcomes in 27 patients undergoing fecal microbiota transplantation for CDI through a retention enema protocol.

43▪. Bakken JS, Borody T, Brandt LJ, et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol 2011; 9:1044–1049.

This article is a good review of fecal microbiota transplantation for CDI and provides protocol recommendations for donor screening and testing as well as for the transplantation procedure.

44. Dallal RM, Harbrecht BG, Boujoukas AJ, et al. Fulminant Clostridium difficile: an underappreciated and increasing cause of death and complications. Ann Surg 2002; 235:363–372.
45▪▪. Neal MD, Alverdy JC, Hall DE, et al. Diverting loop ileostomy and colonic lavage. An alternative to total abdominal colectomy for the treatment of severe, complicated Clostridium difficile-associated disease. Ann Surg 2011; 254:423–429.

A colon-sparing surgical procedure as an alternative to total abdominal colectomy for severe CDI is described in 42 patients. The colon was preserved in the majority of cases, and the authors noted significant improvement in mortality. Neal et al. suggest that this less morbid procedure may result in earlier consideration for surgical intervention with improved outcomes.

46. Patino H, Stevens C, Louie T, et al. Efficacy and safety of the lipopeptide CB-183,315 for the treatment of Clostridium difficile infection. In: Proceedings of the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy; 17–20 September 2011; Chicago, IL; abstract# K-205a.
47. Lowy I, Molrine DC, Leav BA, et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med 2010; 362:197–205.
48. Johnson S, Maziade P-J, McFarland LV, et al. Is primary prevention of Clostridium difficile infection possible with specific probiotics? Int J Infect Dis 2012. [Epub ahead of print]
49. Villano SA, Seiberling M, Tatarowicz W, et al. Evaluation of an oral suspension of spores of VP20621, nontoxigenic Clostridium difficile (NTCD) strain M3, in healthy subjects. Antimicrob Agents Chemother 2012; 56:5224–5229.
50▪. Greenberg RN, Marbury TC, Foglia G, Warny M. Phase I dose finding studies of an adjuvanted Clostridium difficile toxoid vaccine. Vaccine 2012; 30:2245–2249.

This is a phase I clinical trial of adults showing that a C. difficile toxoid vaccine is immunogenic and well tolerated. These favorable results prepare the way for phase II clinical efficacy studies assessing primary and secondary prevention.

51▪. Tian J-H, Fuhrmann SR, Kluepfel-Stahl S, et al. A novel fusion protein containing the receptor binding domains of C. difficile toxin A and toxin B elicits protective immunity against lethal toxin and spore challenge in preclinical efficacy models. Vaccine 2012; 30:4249–4258.
Keywords:

acid suppression therapy; Clostridium difficile; fecal microbiota transplantation; fidaxomicin; molecular diagnostics

© 2013 Lippincott Williams & Wilkins, Inc.