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 , as well as confirming the importance of toxin A , 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; 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.
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▪▪].
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.
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 . 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 . Prediction of treatment failure and complications remains imprecise and better prediction models are urgently needed.
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., 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.
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.
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. 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▪].
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 , 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.
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 , monoclonal antibodies , more effective probiotics  and biotherapeutics , 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.
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.
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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