Introduction

Clostridium difficile infection (CDI) is a serious healthcare-associated infection and a growing health care problem. C. difficile is a Gram-positive, spore-forming, anaerobic bacterium that, when ingested, can cause CDI if it is a toxigenic strain. CDI symptoms include varying levels of diarrhea severity, as well as pseudomembranous colitis and toxic megacolon. CDI incidence is estimated at 6.5 cases per 10,000 patient days in hospital.¹ About 250,000 hospitalizations were associated with CDI in 2005.² Direct attributable mortality from CDI has been reported to be as high as 6.9 percent of cases.³ Elderly people in hospitals account for the vast majority of severe morbidity and mortality.^4-6 Residents of long-term care facilities are also at higher risk.^7,8 Incidence rates may increase by fourfold or fivefold during outbreaks.⁹ In addition to institutional care environments, C. difficile is also common in the community, being easily isolated from soil and water samples.¹⁰ Community-associated CDI rates are generally much lower, accounting for 27 percent of all CDI cases in a recent prevalence study,⁹ but are also on the rise.¹¹ However, the source of the C. difficile organisms responsible for cases of CDI in the community is not well understood.

In order for CDI to develop, a person must be infected with a strain of C. difficile capable of making toxin in the person's colon. Toxigenic strains are those that make toxin B (a cytotoxin), with or without toxin A (an enterotoxin). Approximately 1–2 percent of healthy individuals are colonized with C. difficile.¹² If these people have usual, healthy colonic flora, the risk of CDI is very low. There is a small risk of CDI if the colon flora becomes disturbed, commonly through antibiotic use, while the person is colonized with a toxigenic strain. Antibiotics that disturb colon flora enough to allow CDI to develop must get into the colon, and they are associated with alterations in relative amounts of colon bacterial constituents.^13,14 The immune status of the patient also contributes to the risk of developing CDI and the experienced severity.¹⁵ Other risk factors include increasing age, female gender, comorbidities, gastrointestinal procedures, and use of gastric acid suppression medications.^16-25 Risk profiles for recurrent CDI are similar.²¹ One study, which statistically modeled CDI within the hospital setting, suggested that reducing patient susceptibility to infection is more effective in reducing CDI cases than lowering transmission rates.²⁶

New, more virulent strains have emerged since 2000. Characteristics associated with hypervirulent strains can include increased toxin production (due to a deletion in a toxin regulatory gene), an additional binary toxin, whose role in disease etiology is not well understood, hypersporulation, and high-level resistance to fluoroquinolone antibiotics.²⁷ These new strains affect a wider population, often people with a lack of established risk factors for CDI based on older strains, such as previous hospitalization or antibiotic use, and include children, pregnant women, and other healthy adults.²⁸ With hypervirulent strains, the time from symptom development to septic shock may be reduced, making quick diagnosis and proactive treatment regimens critical for positive outcomes.

The highly virulent strain associated with the epidemic of CDI described in the early 2000s may be decreasing in prevalence in limited locations.²⁹ Recent analysis of an archived collection of C. difficile isolates revealed that predominant strains shifted from year to year among a population served at a single institution,³⁰ suggesting that this strain shift may occur on a larger scale. However, this phenomenon potentially cuts both ways as strains drift toward lesser or higher virulence, and the possible future risks and costs of CDI remain significant.

Scope and Key Questions

The purpose of this systematic review was to provide an overarching assessment of the evidence for comparing the accuracy of diagnostic tests and the effectiveness of prevention and treatment interventions on initial and recurrent CDI-related patient outcomes in adult patients. This purpose was developed during the project's topic refinement stage. There was consensus among key informants that this systematic review's single greatest contribution to the field could be to provide a comprehensive review by an independent organization that covered the major concerns of the field. CDI is an active topic in the literature as well as a vital clinical concern. The consensus opinion included the idea that clinicians and researchers both would be well served by a reaffirmation of what is and is not supported by evidence in the literature, and at what level of evidence, to balance against this activity level.

The major impetus of this review is the presence of clinical disease, not asymptomatic carriage of the C. difficile organism. While we were interested in how treatment of CDI varies by organism strain, molecular epidemiology studies whose main purpose was to identify the strains of C. difficile present in the population are also outside the scope of this review. The review focuses on adult patients because adults, and particularly elderly adults, carry the large majority of the morbidity and mortality burden.

The following Key Questions (KQs) form the basis for this review:

KQ 1.

How do different methods for detection of toxigenic C. difficile to assist with diagnosis of CDI compare in their sensitivity and specificity?

• Do the differences in performance measures vary with sample characteristics?

KQ 2.

What are effective prevention strategies?

• What is the effectiveness of current prevention strategies?
• What are the harms associated with prevention strategies?
• How sustainable are prevention practices in health care (outpatient, hospital inpatient, extended care) and community settings?

KQ 3.

What are the comparative effectiveness and harms of different antibiotic treatments?

• Does effectiveness vary by disease severity or strain?
• Does effectiveness vary by patient characteristics: age, gender, comorbidity, hospital- versus community-acquired setting?
• How do prevention and treatment of CDI affect resistance of other pathogens?

KQ 4.

What are the effectiveness and harms of nonstandard adjunctive interventions?

• In patients with relapse/recurrent CDI?

Methods

We used the key word “difficile” to identify all articles related to C. difficile. Articles were limited to English language and humans. No date limits were applied. We searched MEDLINE, AMED, the Cochrane Library, and ClinicalTrials.gov. For systematic reviews, we searched MEDLINE, the Cochrane Database of Systematic Reviews, and the Web sites of the National Institute for Clinical Excellence, Guidelines.gov, and the National Health Service Health Technology Assessment Programme. We also manually searched reference lists of review articles and articles that were read for the review. Searches were conducted in February 2010 and updated in March and June 2010. An updated search was performed specifically for KQ 3 (standard treatment) in Auguest 2011, because of a new study that led to FDA approval of fidaxomicin in May 2011.

For KQ 1, we included studies that used clinical stool specimens from patients suspected to have CDI. We included studies that concurrently compared at least two diagnostic tests in the same laboratory using the same stool samples and using the same reference standard to reduce heterogeneity in the estimates. Studies must have used toxigenic culture, cell cytotoxicity assay, or combinations of tests as the reference test for toxigenic CDI. Direct comparisons of diagnostic tests without a reference test were not included. We sought studies that included patient outcomes or outcomes related to changes in therapy. We present study results in positive terms, that is, true positives (sensitivity) and false positives (1 minus specificity).

For KQ 2, we included studies that examined the effects of prevention strategies aimed at breaking routes of transmission within institutional settings or reducing susceptibility to CDI through antibiotic prescribing practices. We included only studies with CDI incidence, or other measures of CDI, as an outcome. We excluded studies that used only intermediate outcomes, such as reduced spore count in environmental samples. Accepted study designs included randomized controlled trials (RCTs), prospective cohort, retrospective cohort, time series, and before/after trials. We also identified good quality studies that identified specific risk factors for development of CDI in general hospital inpatients to facilitate infectious disease control efforts to target likely effective preventive strategies.

For KQ 3, we included RCTs that compared two active antimicrobial treatments, including vancomycin, metronidazole, bacitracin, nitazoxanide, rifaximin, fidaxomicin, and rifampin, on adult patients. We also included placebo-controlled trials for vancomycin or metronidazole, the agents of most interest. We included initial cure, recurrence (variably defined by symptoms with or without a positive test for C. difficile), and mortality, which are outcomes of interest to clinicians and are reported in most studies. We also included time to resolution of diarrhea.

For KQ 4, we included all studies that examined any nonstandard intervention, such as toxin binding agents, probiotics, vaccinations, or other treatments aimed at enhancing a patient's resilience. Outcomes included resolution of symptoms and recurrence.

Diagnostics (KQ1) Results

We found 13 references that provided comparative data about diagnostic tests of interest.^31-43 The number and type of paired (within study) comparisons available for each diagnostic test varied considerably, and not all possible comparisons were available.

Sixteen paired comparisons of seven commonly used immunoassays for toxins A and B provided low-strength evidence that the test sensitivities do not differ. There was moderate-strength evidence for no differences in test specificities for two comparisons and for a difference of 2 percent in one comparison. Otherwise, there was only low-strength evidence for or against differences in test specificities. There was insufficient evidence of differences between all tests that were not directly compared.

Nine comparisons of two toxin gene detection tests that focus on toxin B to toxin immunoassays provided only low-strength evidence that the gene-based tests are substantially more sensitive. There was moderate evidence that the test specificities in one comparison did not differ. Otherwise, there was only low-strength evidence for differences in either direction between test specificities. There was insufficient evidence of differences between all tests that were not directly compared.

There was no evidence to determine whether any differences in sensitivity or specificity between diagnostic tests depend on patient or specimen characteristics or the clinical scenarios that lead to testing for toxigenic CDI.

Prevention (KQ2) Results

We found 1 Cochrane review, ⁴⁴ 4 studies on antibiotic prescribing restrictions,^45-48 11 on single preventive practices aimed at transmission interruption,^49-58 and 10 studies that bundled multiple practices into a prevention strategy.^59-68 We updated a previous systematic review and found 11 studies examining risk factors that met the inclusion criteria.²⁰

Overall, the evidence available to link prevention strategies to clinically important outcomes, such as CDI incidence, is of low quality and is not extensive.

Four observational studies^45-48 and one Cochrane review⁴⁴ found that prescribing practice interventions decreasing the use of high-risk antimicrobials are associated with decreased CDI incidence. Prescribing practices were also used in multicomponent interventions credited with reducing CDI incidence; however, it is difficult to isolate the specific effects of the prescribing practices.

One controlled trial found glove use significantly reduced CDI incidence in the hospital setting.⁴⁹ Likewise, three observational studies, including two controlled, found that disposable thermometer use is likely to reduce CDI incidence.^50-52

No study examined the effect of handwashing on CDI incidence. Four studies found use of alcohol gels as interventions for other infectious diseases, presumably in the presence of common protocols requiring handwashing in the presence of CDI or visible soiling, did not increase CDI incidence.^53-55,69

Four single-component intervention studies provide low evidence that disinfection with a chemical compound that kills C. difficile spores in the hospital environment prevents CDI, at least in epidemic or hyperendemic settings.^56-58,70 Seven studies included disinfection in multicomponent interventions.^{60,62,63,66,71} Disinfection agents examined included hypochlorite solution, hydrogen peroxide, aldehydes, and detergent.

Ten time series/before–after studies have examined bundled multiple interventions using before–after study designs.^59-68,71 All of the studies described the use of the measures to bring epidemic CDI, or endemic CDI which was felt to be excessive, under control. The number of interventions, and the specific nature of any particular intervention, varied widely. Studies employed between two and nine different types of interventions. Study design and intervention complexity, along with the fact that many outbreaks naturally diminish, made it difficult to conclude whether the reduced CDI prevalence was due to one or more intervention components, or entirely independent.

Risk factors for developing CDI include antibiotic use, substantial chronic illness, hospitalization in an ICU, acid suppression, and age.

No data on patient harms or harms to hospital staff due to preventive interventions were reported. Likewise, no studies assessed the sustainability of a prevention program beyond an intervention period.

Standard Treatment (KQ3) Results

Eleven randomized clinical trials were identified that evaluated different antimicrobials (or different doses of a single drug) available for treatment of CDI in the United States.^72-82 These 11 studies enrolled 1,463 patients and reported efficacy analysis on 1,239 patients.

Overall, study quality is low. Vancomycin and metronidazole, the most frequently clinically used antimicrobials, were also the most frequently compared antimicrobials. Three RCT comparisons of vancomycin to metronidazole, with a total of 335 pooled subjects, found no significant differences in any examined outcome.^73,76,79 One RCT comparing vancomycin to metronidazole, using a prespecified subgroup analysis of 69 patients, found a small but significant increase in the proportion of subjects with severe CDI who achieved initial clinical cure with vancomycin, using a treatment-received analysis.⁷³ The significance of this difference did not persist when a strict intention-to-treat analysis was performed.

Moderate-strength evidence from one large, high-quality study demonstrated that vancomycin and fidaxomicin performed equally well for initial cure, but that recurrence was significantly decreased with fidaxomicin versus vancomycin.⁸² No other head-to-head trial demonstrated superiority of any single antimicrobial for initial clinical cure, clinical recurrence, or mean days to resolution of diarrhea. Combination therapy with rifampin and metronidazole resulted in significantly higher mortality when compared to treatment with metronidazole only.⁷⁴ Pooled data of 104 subjects comparing vancomycin to bacitracin showed significantly higher rates of organism or toxin clearance for vancomycin.^77,80

Harms were not reported with sufficient detail to compare the risks of any particular antimicrobial with another antimicrobial. When harms were reported, they were generally not serious (e.g. nausea, emesis) and transient.

A single study assessed initial cure and recurrence by strain, categorized as North American pulsed-field gel electrophoresis type 1 (NAP1) versus non-NAP1.⁸² Strain data was available for 324 of 629 (51.5%) participants. For initial cure, no significant difference was observed, regardless of strain. However, among patients with non-NAP1 strains, those treated with fidaxomicin recurred less frequently than those treated with vancomycin (10% vs. 28%; P < 0.001), whereas among patients with the NAP1 strain, recurrence was similarly frequent regardless of treatment.⁸²

Nonstandard Treatment (KQ4) Results

Five RCTs on nonstandard adjunctive treatments of CDI and 13 studies that addressed prevention of CDI formed the basis of this analysis. Four of the studies on treatment of CDI compared a nonstandard intervention with an active control, that is, a standard antibiotic treatment for CDI, oral vancomycin or metronidazole.^83-86 One study compared a nonstandard intervention with placebo.⁸⁷ All of the 13 prevention studies compared the nonstandard intervention with placebo rather than with another intervention, reflecting the current state of the science in this area. Five of the 13 prevention studies analyzed antibiotic-acquired diarrhea as a primary outcome and CDI as a secondary outcome.^83-86 Numerous published case reports, as well as nonexperimental studies, describe additional nonstandard approaches for treatment of CDI and their possible harms. As found with the other Key Questions, overall, study quality was low. Definitions of CDI with regard to diarrhea, that is, number and consistency of stools, were inconsistent across studies.

For treatment of CDI, C. difficile immune whey that binds C. difficile toxin A is similar to metronidazole in a small study of 38 patients with recurrent CDI.⁸⁵ Colestipol, an absorptive resin, is not more effective in treating CDI than placebo.⁸⁷ Probiotics administered as an adjunct to antibiotic treatment were not more effective than treatment with antibiotics alone.^83,84,86

There is low-strength limited evidence that the probiotic^88-93 interventions in this review are not more effective than placebo for primary prevention of CDI. There is low-strength limited evidence from one subgroup analysis that a prebiotic may reduce diarrhea recurrence in patients treated for CDI more so than placebo with standard antibiotics.^94,95 Fungemia is a serious potential harm associated with administration of probiotics for CDI in critically ill patients.^96,97 In one review, 46 percent of 60 critically ill patients who developed fungemia had been administered a probiotic containing Saccharomyces boulardii and 5 more patients were in the vicinity of an administered probiotic. Seventeen patients subsequently died.⁹⁶

There is limited moderate-strength evidence from one study that monoclonal antibodies are effective in preventing recurrence of CDI.⁹⁸

There is limited low-strength evidence from two case series that fecal flora reconstitution is effective in treating recurrent CDI for up to 1 year.^99,100

Discussion

There is very limited high-strength evidence to support the diagnostic, preventive, and treatment practices for CDI carried out by providers in hospital, long-term care, and outpatient settings. Table A provides a summary of the evidence and results presented in this review. Inconsistency in definitions of diarrhea, severity, resolution of symptoms, recurrence, or cure contributes to the difficulty in drawing conclusions from the evidence.

Table A

Summary of evidence.

In general, there is little evidence that the sensitivities of commonly used immunoassays for toxins A and B differ, and any differences in their percent of false positives (1 minus specificity) most likely are small (3 percent or less). However, the strength of the evidence is low due to the number of studies that have directly compared various immunoassays in the literature. Future research possibly could impact the findings. The available comparative data does not rule out the possibility of larger differences in test sensitivities between some of the immunoassays that have or have not been directly compared in adequate numbers. While the precision of the findings is such that we cannot rule out the possibility of differences in sensitivity on the order of 3 to 5 percent, it is unclear whether such differences would affect clinical decisionmaking.

Gene detection tests that focus on toxin B tended to have better sensitivity than immunoassays for toxins A and B. Results, however, should be viewed with caution, given rather imprecise confidence intervals on the estimated differences. Further study of the differences in false positives, if any, is needed, too. Few studies contributed to the findings, and many direct comparisons were not found. Furthermore, variation in the stability of the toxins in stool specimens as they were collected, stored, and processed may have contributed to the observed variation between studies in the estimates of the sensitivities of the immunoassays, whereas detection of amplified toxin gene fragments could be less susceptible to specimen degradation and more susceptible to contamination of specimens. Differences in the sensitivities of the reference tests could affect the estimated sensitivity for immunoassays to greater degrees than gene detection tests as well.

The immunoassays and gene detection tests require varying skills, equipment, and time to carry out, and heterogeneity is a significant factor in reviewing the literature. Previous reviews by Planche et al.¹⁰¹ and Crobach et al.¹⁰² encountered difficulty comparing the sensitivities and specificities of immunoassays in large part because there was too much variation between studies in the estimates of the sensitivity and specificity of a particular test. We attempted to control for the heterogeneity between studies by examining the differences in sensitivity and specificity in stool samples tested within the same lab using the sample patient stool specimens and reference test, and we did not find strong evidence of differences between tests within several immunoassays for toxins type A and B. The extent of any publication bias for these comparisons is unknown.

A clinically important question is whether the potential differences in the accuracy of the diagnostic tests being employed in practice would translate into differences in clinical behaviors or patient outcomes. Indeed, how well clinicians actually know the sensitivity and specificity of the test(s) for toxigenic C. difficile employed by their laboratories and incorporate this information into their patient care decisions is not clear. If test results are combined with pretest probabilities that patients have toxigenic C. difficile using Bayes' formula, then the differences in post-test probabilities might not lead to different clinical decisions even if there are substantial differences in the sensitivities and specificities of tests for toxigenic C. difficile.

Very little evidence connects prevention strategies and techniques directly to patient-related outcomes, such as CDI incidence. Available evidence is generally from before–after study designs or limited time series. Hospital settings with outbreaks or hyperendemic episodes further limit applicability of the findings and leave open the question of the relative contribution of regression to the mean (i.e., that CDI rates returned to baseline rates even in the absence of effective interventions). The studies also varied in the degree to which they described CDI surveillance, diagnostic accuracy, or laboratory performance. In most, surveillance was passive and depended on a positive toxin test on a stool specimen sent by clinicians caring for a patient with diarrhea. Unknown numbers of cases might have been missed or misdiagnosed. Additionally, attention has not been given to describing a prevention strategy's potential harm (e.g., increase in other pathogens, reduction in direct patient care contact due to isolation or restrictive contact requirements, increased costs) or the long-term sustainability of a practice.

There is low-strength evidence that antibiotic prescribing practices appear to reduce CDI incidence, a finding consistent with the Cochrane review.⁴⁴ None of the studies explicitly addressed the potential harms of changes in antibiotic use policy, but there are several theoretical harms. They include the possibility that preferred drugs will be less effective than drugs that physicians are discouraged from using, or drugs that are made unavailable for treating infections other than CDI. Preferred antimicrobials might have greater costs or greater toxicities unrelated to CDI. C. difficile strains might evolve to develop resistance to the preferred antibiotics, which might increase the likelihood that the recommended antibiotics might induce CDI.

While several studies found increased risk with specific antibiotics or antibiotic classes, the antibiotics that confer greater risk for CDI have changed over time and vary by location because of differences in prevalent toxigenic strains and especially the susceptibility patterns of those strains.¹⁰³ Clindamycin resistance was identified soon after the role of C. difficile in pathogenesis was discovered.^49,104,105 More recently, quinolones have assumed greater importance because strains have become more resistant over time.¹⁰⁶

Fewer studies are available to support prevention practices aimed at breaking transmission. There was limited low-strength evidence that gloves, disposable thermometers, handwashing, and intensive disinfection solutions help to reduce CDI incidence. In addition, the presence and use of alcohol gel to prevent other hospital-acquired infections, such as MRSA, did not increase the rate of CDI incidence as might be expected if alcohol gel use replaced handwashing.

Similar to the antibiotic prescribing practice research, none of the studies aimed at breaking transmission addressed potential harms for other prevention practices. Costs of disinfection, time to perform disinfection, and the possible harm to surfaces and equipment should be anticipated. Failures with vapor disinfection systems would be possible and might lead to toxic exposures of personnel or patients. Nor is there evidence to inform infection control professionals whether such practices are sustainable after an intervention period. That is, we cannot answer whether environmental cleaning staff will have developed professional habits that will continue when the intense monitoring related to an intervention period discontinues.

The potential for prevention research is often compromised by the swift uptake of newly described prevention strategies with the belief that these will improve institutional practices and health care quality and will reduce CDI morbidity and mortality. Current prevention strategies often rely on studies using intermediate outcomes such as process. Newly acquired strategies are then added to current practice, bundling them into multiple component interventions. When introduced in outbreak or hyperendemic situations, these “bundled” multipronged prevention efforts in natural settings have been associated with reduction in CDI incidence. The bundles appear to be beneficial, but from a research standpoint, it is challenging to design research that would tease out the relative contributions of single components to the overall bundle of prevention strategies to determine which ones are essential or what might be added.

The available evidence is insufficient to say whether any antimicrobial treatment is better than another, including the two most commonly used treatments, metronidazole and vancomycin. The total number of subjects from comparative studies on metronidazole and vancomycin is just 335 patients. This raises the possibility that, although a significant difference in effectiveness has not been detected, a true difference may exist. There is moderate strength of evidence that recurrence is less frequent with fidaxomicin than with vancomycin, and that these two agents are not significantly different from one another for initial cure. Otherwise, there is no evidence for a difference in effectiveness for other agents, but again the possibility remains that such a difference exists. However, at this time, any claims that one agent is superior to another for all cases of CDI are not supported by available evidence. The findings apply to general adult inpatients. Bias due to selectively reporting outcomes is possible if cut-points are changed for CDI definitions, for example, number or consistency of stools. The clinical differences of changes in cut-points are also unknown, however, so the clinical significance could remain.

We found insufficient evidence that vancomycin was superior to metronidazole for subjects classified as having severe disease. One subgroup analysis of a single trial used a prespecified analysis, and the severity classification appears to have been made before treatment allocation. However, the superiority of vancomycin over metronidazole does not persist when a strict intention-to-treat analysis is used.

We sought to document the range of treatments under investigation for treatment and prevention of CDI, particularly recurrent CDI. The evidence for effectiveness of nonstandard interventions for treating CDI shows that probiotics, prebiotics, C. difficile immune whey, and colestipol are not more effective in treating CDI than standard antibiotic treatment with oral vancomycin or metronidazole or compared with placebo. The evidence supporting this conclusion is limited and of low strength.

Prevention of CDI, both initial and recurrent cases, through interventions intended to improve gut flora and host immunity is also a very active topic in the literature. There is limited, low-strength evidence that the nonstandard prevention interventions are not more effective than placebo for primary prevention of CDI. There is limited evidence of low strength that administering the prebiotic oligofructose or a monoclonal antibody to C. difficile toxins A and B along with standard antibiotics for CDI are better than placebo and active control in preventing recurrence of CDI in patients treated for CDI. Although the studies for both treatment and prevention of CDI using a nonstandard intervention included components of experimental designs, few had adequate rigor to yield high-quality findings or power to detect a significant difference between the interventions (or placebo) compared. In some studies, a low rate of CDI precluded statistical testing.

Caution is recommended regarding new, nonstandard treatments and not extrapolating study findings beyond the data. For example, one cannot assume that if a probiotic treatment is effective for antibiotic-associated diarrhea, it will be effective for CDI. Likewise, attention should be paid to which patients were included and excluded in probiotic treatment studies. Such studies generally exclude high-risk patients. Thus, there is no evidence for the use of probiotics in high-risk patients.

Future Research

A number of important questions need to be addressed regarding diagnostic testing, prevention, and treatment of CDI. Table B summarizes the research recommendations.

Table B

Future research recommendations.

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