Condition

Clostridium difficile infection (CDI) rates in the United States and the world have increased in the last decade, along with associated morbidity and mortality. Clostridium difficile is a gram-positive, anaerobic bacterium generally associated through ingestion. Various strains of the bacteria may produce disease generating toxins, TcdA and TcdB, as well as the lesser understood binary toxin. Our use of the term CDI indicates this review's focus is the presence of clinical disease rather than asymptomatic carriage of C. difficile. CDI symptoms can range from mild diarrhea to severe cases including pseudomembranous colitis and toxic megacolon and death.

Estimated U.S. health-care-associated CDI incidence in 2011 was 95.3 per 100,000, or about 293,000 cases nationally. Incidence is higher among females, whites, and persons 65 years of age or older.¹ About one-third to one-half of health-care onset CDI cases begin in long-term care, thus residents in these facilities are at high risk.^1,2 Incidence rates may increase by four- or five-fold during outbreaks.³

Community-associated CDI, where CDI occurs outside the institutional setting, is also on the rise, though still generally lower than institution-associated rates and may be in part due to increased surveillance. Estimated community-associated CDI was 51.9 per 100,000, or 159,700 cases in 2011.¹. Community-associated CDI complicates measuring the effectiveness of prevention within an institutional setting.³ Additionally, the pathogenesis of CDI is complex and not completely understood, and onset may occur as late as several months after hospitalization or antibiotic use.

The estimated mortality rate for health-care-associated CDI ranged from 2.4 to 8.9 deaths per 100,000 population in 2011.¹ For individuals ≥65 years of age, the mortality rate was 55.1 deaths per 100,000;¹ CDI was the 17^th leading cause of death in this age group.⁴

Hypervirulent C. difficile strains have emerged since 2000. These affect a wider population that includes children, pregnant women, and other healthy adults, many of whom lack standard risk profiles such as previous hospitalization or antibiotic use.⁵ The hypervirulent strains account for 51 percent of CDI, compared to only 17 percent of historical isolates.^6,7 Time from symptom development to septic shock may be reduced in the hypervirulent strains, making quick diagnosis and proactive treatment regimens critical for positive outcomes.

Diagnosis

Effective containment and treatment of CDI depends on accurate and swift diagnosis. An increasing number of diagnostic tests are designed to detect either the presence of the organism or toxins A and/or B with a variety of sensitivities, specificities, predictive values, biotechnologies used, training required, costs, and time-to-results. The testing strategies used in health systems are rapidly evolving. A study from 2008 showed that more than 90 percent of labs in the United States use enzyme immunoassay because it is fast, inexpensive, and easy to perform.⁸ Just 3 years later, however, data showed that 43 percent of laboratories in the United States used nucleic acid amplification tests (NAAT) (e.g., polymerase chain reaction [PCR]).⁹

Clinically, CDI is diagnosed using tests such as: (1) immunoassays (including enzyme immunoassays, enzyme-linked immunosorbent assays, and immunochromatography assay), (2) tests for C. difficile toxins, and (3) amplification of C. difficile DNA, through means such as PCR and loop mediated isothermal amplification (LAMP). Some diagnostic testing strategies rely on two-step procedures, the first being a sensitive, inexpensive, fast screen for the presence of the organism and, if that is positive, a second test for toxins. Toxigenic culture and cell cytotoxicity neutralization assay are no longer standard practice and are not universally available. However, given the rapid evolution of testing strategies, studies of diagnostic test performance often use toxigenic culture or cell cytotoxicity neutralization assay as the reference standard. Clinicians are not always well informed on the best diagnostic test to use, the operating characteristics of the tests used in their practice setting, or the relatively low likelihood of a false negative result (e.g., evidence suggests retesting with the same test is common practice, yet not recommended).

Treatment Strategies

Although there is not yet consensus on the definitions of mild, moderate, or severe CDI, treatment strategies do differ based on disease severity. Treatment for mild to moderate CDI is generally metronidazole, in part because of concerns that overuse of vancomycin may contribute to increasing pathogen resistance. Vancomycin is recommended for severe initial incident CDI.¹⁰ However, both vancomycin and metronidazole have been implicated in leading to increased frequency of vancomycin-resistant enterococci.¹¹ In 2011, the FDA approved a new agent, fidaxomicin, for the treatment of CDI. A previous review found that while fidaxomicin was not superior for the initial cure of CDI, recurrence was less frequent with fidaxomicin than with vancomycin.¹² Measuring cure, however, can be challenging; no specific consensus exists regarding symptom resolution, clearance of the organism, or recurrence of CDI.

Treatment for relapsed or recurrent CDI is even more problematic. CDI recurs in 15 – 35 percent of patients with one previous episode and 33 – 65 percent of patients with more than two episodes.¹³ Currently, clinicians choose from a number of antibiotics, dosing protocols, and adjunctive treatments (such as the use of antimicrobials, probiotics, toxin-binding agents, and immune-system enhancing agents).^14-16 The goal of most adjunctive treatments is to reduce patient susceptibility to relapse or reinfection. Fecal microbiota transplantation (FMT) in particular has garnered significant clinical interest. FMT transfers fecal microbiota from a healthy individual to a CDI patient to restore a healthy gut microbiota.

Prevention

Not all people who acquire C. difficile develop CDI; thus prevention measures can target reducing both the spread of the bacteria or spores and patient susceptibility to infection. One study statistically modeled CDI within the hospital setting and suggested that reducing patient susceptibility to infection is more effective in reducing CDI cases than lowering transmission rates.¹⁷ The likelihood of developing CDI depends on a number of factors that allow colonization and toxin production, including failure of the immune defenses, use of antibiotics, particularly broad-spectrum or multiple antibiotics, and changes to the intestinal microbiota. Known risk factors for CDI include older age, comorbidities, and use of gastric acid suppressant medications.¹³ Mortality is associated with age, white blood cell count, serum albumin, and serum creatinine.¹⁸ Risk profiles for recurrent CDI are similar.¹⁹ Recent prevention efforts have included antimicrobial stewardship and using environmental and infection control strategies, as well as seeking to improve the patient's immune defenses through healthy digestive function and gut flora and improved nutrition.²⁰

Preventing transmission of C. difficile within institutional settings depends on staff compliance with national guidelines and standards²⁰ and locally determined hygiene protocols. Unfortunately, protocols for some targeted hospital-associated infections may not be effective against C. difficile. For example, the availability of alcohol hand rubs improved physician compliance and reduced Methicillin-resistant staphylococcus aureus (MRSA) infections,²¹ yet C. difficile produces spores that can withstand hostile environments and are resistant to alcohol hand rubs and other routine antiseptics. Spores may be best removed by handwashing. Other institutional prevention strategies may be required as C. difficile transmission knowledge develops. For example, one study isolated C. difficile spores and cultured the bacterium from air samples in a United Kingdom hospital 4 to 7 weeks after the last confirmed CDI case in the ward.²²

Scope and Key Questions

PICOTS

Table 1 provides the PICOTS (population, intervention, comparisons, outcomes, timing, and settings) for the KQs. The analytic frameworks can be found in Appendix A.

Table 1

Review PICOTS.

Organization of the Report

This report presents the systematic review update in a summary fashion to focus the readers' attention on the main messages. The Methods section provides a brief overview of methods used. As is noted in that section, greater detail on methods can be found in the review protocol. The Results section provides a summary overview with key messages for each KQ. Detailed analyses for results are provided in the Appendixes. A table of contents for the Appendixes is provided at the beginning of the Appendix document. The report concludes with the Discussion section that summarizes how findings have changed from the original systematic review, on-going issues, research needs, and limitations of the review.