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A Review of the Current State of Clostridioides difficile in the United States and the Latest Treatment Recommendations

Contagion, October 2020 Supplement,

The gram-positive opportunistic pathogen Clostridioides difficile is an urgent public health threat responsible for almost 223,900 hospitalizations and at least 12,800 US deaths in 2017 alone.1 Examining epidemiology, testing recommendations, risk factors, available treatments, and prevention methods is an important preliminary step to understanding the current state of C difficile infections in the United States.

Epidemiology

C difficile is primarily transmitted through the fecal—oral route2-4 and is associated with health care facilities, such as nursing homes, where clinic furnishings, health care equipment, or medical personnel may harbor C difficile spores, leading to increased rates of infections.5 Infections also can be community-associated and occur in individuals who have not spent recent time in a health care facility.5 Research results suggest that about 41% of C difficile infections may be community-associated.3 The results of a 2020 study examining the national burden of C difficile found a marked decrease in health care—associated infections, whereas community-associated infection rates have remained the same.5 The decrease in health care—related infections could be because of a combination of factors, including widespread decreased use of certain antibiotics, adherence to infection-prevention practices, better public reporting of infections, pay-for-performance programs, and a reduction in unnecessary diagnostic testing.5 Conversely, the steady rate of community-associated infections may be due to an increased testing frequency, fewer diagnostic stewardship efforts in outpatient settings, and a high use of outpatient antibiotics.

The emergence of virulent epidemic strains is largely thought to be responsible for the increased incidence, severity, and mortality of C difficile infections.6,7 These strains can vary by country or region, or even by health care facility.8 C difficile has a diverse population of ribotypes, but only a few strains are dominant. Many of these dominant strains have developed resistance to antibiotics, thereby complicating treatment.8 Among the most common strains found in the United States are ribotype 027, ribotype 106, and ribotype 014-020.7,9-10 Ribotype 027—also known as North American pulsed-field gel electrophoresis type 1, restriction endonuclease analysis type B1, polymerase chain reaction ribotype 027—is highly resistant to fluoroquinolones and produces a previously uncommon binary toxin along with higher levels of common toxins.7 The virulent ribotype has caused outbreaks throughout the United States and other parts of the world over the past 2 decades; it is associated with high mortality and has even been linked to community-associated outbreaks in patients without risk factors.7,9

Ribotype 106 is another of the most common US strains.10 The strain demonstrates resistance to common disinfectants used for cleaning, which may have contributed to its dissemination across the country.11 Ribotype 106 also produces more spores than many other strains and is resistant to a number of commonly used antibiotics.11,12

A wide range of other strains are also found throughout the United States10; however, not all are associated with severe outcomes. For example, ribotype 014-020 is also common, but it is associated with a decreased incidence of both severe infections and severe outcomes, including hospitalization, colectomy, or in-hospital death.9

Collectively, C difficile has a high economic burden in the United States. A meta-analysis of data published between 2005 and 2015 estimated an annual cost of $6.3 billion attributed to C difficile infections.13 Pay-for-performance programs, such as CMS’ Hospital-Acquired Condition Reduction Program, may help reduce this economic burden and encourage preventive practices by rewarding facilities with lower rates of hospital-acquired infections.5,14

Current Testing Recommendations

C difficile is capable of colonizing the gut without causing infection, and asymptomatic carriers may represent up to half of hospitalized patients who test positive for the bacteria.15 Diagnosis should therefore never be based solely on laboratory tests.16 Testing for C difficile infection should be carried out in any patients who have unexplained new-onset diarrhea (that is, at least 3 unformed stools in 24 hours).17 Current local rates of C difficile infections, patient risk factors for infection, and potential underlying factors that could also contribute to diarrhea—including medications, recent surgical interventions, or comorbidities—should also be considered in decisions to test. Testing for C difficile can include detecting either the presence of the microorganism itself or the toxins responsible for infection symptoms; however, many of the most sensitive tests (most proficient at detecting C difficile presence) have a low specificity for differentiating between infection and colonization,16 leading many experts to recommend utilization of a multistep testing process to ensure an accurate diagnosis.17

Two commonly used tests in algorithms are the nucleic acid amplification test (NAAT), which targets common toxin genes or other gene products, and the glutamate dehydrogenase immunoassay test, which detects a metabolic enzyme present at high levels in isolates of the microorganism. Both of these methods are generally thought to be more reliable than toxin enzyme immunoassays, which are less sensitive and have variable performance. When clinical symptoms and patient history alone suggest that C difficile infection is likely, use of NAAT alone or a multistep algorithm may also be sufficient.17

Risk Factors for Infection

The most common risk factor for C difficile infection is use of antibiotics, and nearly every antibiotic has been linked with infection.2,8 Hospitals can also harbor C difficile spores on furnishings, equipment, and even on staff, putting patients with prolonged, multiple, or frequent hospitalizations at greater risk of infection. Residents at long-term care facilities are also at greater risk due frequent antibiotic use in these facilities, communal living conditions, the advanced age of the population, and comorbid conditions.2,8,18 The use of acid suppressants also may put individuals at a greater risk of colonization, highlighting the need for more conservative use of these medications.19 Other common risk factors for C difficile infection include comorbidities such as liver disease and inflammatory bowel disease.8

Between 18% and 35% of patients treated for C difficile infection have at least 1 additional infection within 2 to 8 weeks of initial treatment. These recurrent infections can occur with the initial strain or a new strain of C difficile. Many of the same risk factors for initial infection put patients at higher risk of recurrent infection, including prior antibiotic use, older age, use of proton pump inhibitors, and prolonged hospitalization. Additional factors, such as heart disease, colonization with methicillin-resistant Staphylococcus aureus, venous thromboembolism, and those with community-associated infection, pose a higher risk of recurrent infection.8

Treatment

The latest guideline recommendations from the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) suggest discontinuation of any antibiotics that could have prompted C difficile infection as soon as possible not only to reduce the risk of recurrence, but to increase clinical response. Rather than metronidazole, a 10-day course of vancomycin or fidaxomicin is recommended for initial infection, when possible, due to the superior clinical cure rates these agents offer.17

Progression to fulminant—“severe and complicated”—infection includes the development of hypotension or shock, megacolon, and/or ileus.8,17 Vancomycin has historically been the preferred regimen for fulminant infection and can be combined with intravenously administered metronidazole. Patients who do not respond to these drugs can be considered candidates for intravenous tigecycline or passive immunotherapy with intravenous immunoglobulins.17

The high rates of recurrence remain an ongoing challenge for management of C difficile infection. About a quarter of patients initially treated may have an additional infection, although rates are significantly lower with fidaxomicin compared with vancomycin as the initial treatment. IDSA and SHEA guidelines recommend treating a first recurrence of C difficile infection with oral vancomycin taken as a tapered and pulsed regimen instead of the standard 10-day course. Alternatively, a 10-day course of fidaxomicin can be used instead of a 10-day course of vancomycin. If metronidazole was used for the initial infection, a standard 10-day course of vancomycin could also be used instead of a second course of metronidazole.17

Options for patients who have had more than 1 recurrence include a tapered and pulsed oral vancomycin regimen, or a standard course of oral vancomycin followed by rifaximin or fidaxomicin. Fecal microbiota transplantation also should be considered for patients with multiple recurrences who are not responding to treatments.17

Prevention

Guidelines from IDSA and SHEA also recommend different measures to limit the spread of C difficile, such as a bundled approach of preventive interventions, including the use of gloves and hand hygiene, isolating infected patients, and disinfecting health care facilities to limit environmental spores.17 Antibiotic stewardship can also play an important role in limiting C difficile outbreaks given that the number of antibiotics prescribed, the length of antibiotic exposure, and antibiotic dose all correlate with infection risk. Reducing the frequency and duration of antibiotic use, along with minimizing the number of antibiotics prescribed, could therefore reduce the risk of C difficile infection. Given that different strains can have varying patterns of antibiotic resistance, targeted antibiotics can be based on local epidemiology and strain information. Fluoroquinolones, clindamycin, carbapenems, and cephalosporins should be considered for inclusion in antibiotic stewardship programs because these antibiotics create higher risk for C difficile infection.17

Pediatric Considerations

As many as 40% of neonates can be asymptomatic carriers of C difficile, and this number is even higher for hospitalized neonates. Routine testing of this population is therefore not recommended given the likelihood of false-positive results. Routine testing is similarly not recommended in children aged less than 2 years unless other causes of diarrhea have been excluded, because C difficile colonization rates also remain prevalent for this age group. By age 2 years, colonization rates with C difficile rival those of the healthy adult population, and only 1% to 3% of children aged 2 to 3 years are asymptomatic carriers. Therefore, children who are aged at least 2 years and have prolonged or worsening diarrhea and risk factors for C difficile infection can be more accurately tested.

Research is generally sparse on the most effective treatment for C difficile infections in children.17 Clinical guidelines recommend either metronidazole or vancomycin as the preferred treatment for children with initial or first recurrence of nonsevere C difficile infection.17 Recent studies in children suggest that oral metronidazole may have a higher failure rate20,21; however, these results have limitations and there still remains insignificant evidence to recommend vancomycin over metronidazole for nonsevere infection.17 Similarly, few studies have been completed in pediatric patients with severe C difficile infection. However, studies in adults with severe infection have found better outcomes in patients treated with oral vancomycin compared with metronidazole.22,23 Therefore, the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines recommend oral vancomycin over metronidazole for the treatment of severe C difficile infection and multiple recurrent infections. Although fidaxomicin is not approved for pediatric use or routine treatment in children with severe C difficile infection, the results of a 2014 survey found that 12% of responding pediatric infectious disease physicians used or recommended it.24 Like vancomycin, it may be associated with fewer systemic adverse events given that it is not significantly absorbed when taken orally.17

References

1. Antibiotic resistance threats in the United States 2019. CDC. 2019. Updated December 2019. Accessed September 30, 2020. http://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf

2. Czepiel J, Dróżdż M, Pituch H, et al. Clostridium difficile infection: review. Eur J Clin Microbiol Infect Dis. 2019;38(7):1211-1221. doi:10.1007/s10096-019-03539-6

3. Mada PK, Alam MU. Clostridium difficile. In: Abai B, Abu-Ghosh A, Acharya AB, et al, eds. StatPearls. StatPearls Publishing; 2020.

4. Mounsey A, Lacy Smith K, Reddy VC, Nickolich S. Clostridioides difficile infection: update on management. Am Fam Physician. 2020;101(3):168-175.

5. Guh AY, Mu Y, Winston LG, et al; Emerging Infections Program Clostridioides difficile Infection Working Group. Trends in US burden of Clostridioides difficile infection and outcomes. N Engl J Med. 2020;382(14):1320-1330. doi:10.1056/NEJMoa1910215

6. Culligan EP, Sleator RD. Advances in the microbiome: applications to Clostridium difficile infection. J Clin Med. 2016;5(9):83. doi:10.3390/jcm5090083

7. Guh AY, Kutty PK. Clostridioides difficile infection. Ann Intern Med. 2018;169(7):ITC49-ITC64. doi:10.7326/AITC201810020

8. De Roo AC, Regenbogen SE. Clostridium difficile infection: an epidemiology update. Clin Colon Rectal Surg. 2020;33(2):49-57. doi:10.1055/s-0040-1701229

9. Aitken SL, Alam MJ, Khaleduzzaman M, et al. In the endemic setting, Clostridium difficile ribotype 027 is virulent but not hypervirulent. Infect Control Hosp Epidemiol. 2015;36(11):1318-1323. doi:10.1017/ice.2015.187

10. Tickler IA, Obradovich AE, Goering RV, et al; HAI Consortium. Changes in molecular epidemiology and antimicrobial resistance profiles of Clostridioides (Clostridium) difficile strains in the United States between 2011 and 2017. Anaerobe. 2019;60:102050. doi:10.1016/j.anaerobe.2019.06.003

11. Carlson TJ, Blasingame D, Gonzales-Luna AJ, et al. Clostridioides difficile ribotype 106: a systematic review of the antimicrobial susceptibility, genetics, and clinical outcomes of this common worldwide strain. Anaerobe. 2020;62:102142. doi:10.1016/j.anaerobe.2019.102142

12. Vohra P, Poxton IR. Comparison of toxin and spore production in clinically relevant strains of Clostridium difficile. Microbiology. 2011;157(Pt 5):1343-1353. doi:10.1099/mic.0.046243-0

13. Zhang S, Palazuelos-Munoz S, Balsells EM, et al. Cost of hospital management of Clostridium difficile infection in United States—a meta-analysis and modelling study. BMC Infect Dis. 2016;16(1):447. doi:10.1186/s12879-016-1786-6

14. Hospital-Acquired Condition (HAC) Reduction Program. CMS. Updated July 21, 2020. Accessed September 30, 2020. https://www.cms.gov/Medicare/Quality-Initiatives-Patient-Assessment-Instruments/Value-Based-Programs/HAC/Hospital-Acquired-Conditions.html

15. Madden GR, Poulter MD, Sifri CD. Diagnostic stewardship and the 2017 update of the IDSA-SHEA Clinical Practice Guidelines for Clostridium difficile Infection. Diagnosis (Berl). 2018;5(3):119-125. doi:10.1515/dx-2018-0012

16. Crobach MJT, Vernon JJ, Loo VG, et al. Understanding Clostridium difficile colonization. Clin Microbiol Rev. 2018;31(2):e00021-17. doi:10.1128/CMR.00021-17

17. McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):e1-e48. doi:10.1093/cid/cix1085

18. Jump RLP, Donskey CJ. Clostridium difficile in the long-term care facility: prevention and management. Curr Geriatr Rep. 2015;4(1):60-69. doi:10.1007/s13670-014-0108-3

19. Willems RPJ, van Dijk K, Ket JCF, Vandenbroucke-Grauls CMJE. Evaluation of the association between gastric acid suppression and risk of intestinal colonization with multidrug-resistant microorganisms: a systematic review and meta-analysis. JAMA Intern Med. 2020;180(4):561-571. doi:10.1001/jamainternmed.2020.0009

20. Khanna S, Baddour LM, Huskins WC, et al. The epidemiology of Clostridium difficile infection in children: a population-based study. Clin Infect Dis. 2013;56(10):1401-1406. doi:10.1093/cid/cit075

21. Kim J, Shaklee JF, Smathers S, et al. Risk factors and outcomes associated with severe Clostridium difficile infection in children. Pediatr Infect Dis J. 2012;31(2):134-138. doi:10.1097/INF.0b013e3182352e2c

22. Zar FA, Bakkanagari SR, Moorthi KMLST, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile—associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007;45(3):302-307. doi:10.1086/519265

23. Johnson S, Louie TJ, Gerding DN, et al; Polymer Alternative for CDI Treatment (PACT) Investigators. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis. 2014;59(3):345-354. doi:10.1093/cid/ciu313

24. Shaklee Sammons J, Gerber JS, Tamma PD, et al. Diagnosis and management of Clostridium difficile infection by pediatric infectious diseases physicians. J Pediatric Infect Dis Soc. 2014;3(1):43-48. doi:10.1093/jpids/pit065