Unrecognized Costs Associated With Clostridium Difficile Infection: What HCPs Often Miss

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From an economic perspective, C. difficile has a staggering financial impact on the US health care system, as well on the patients infected.

Since the early 2000s, Clostridium difficile infection (CDI) has become one of the most common hospital-acquired infections (HAI) in the United States, affecting nearly 500,000 people annually.1,2 Hospitalizations due to CDI alone increased by 339% over the period of 2000-2014 in the United States, and impose a significant burden on the health care system.3

Hospitalized patients developing CDI have a longer length of hospital stay (LOS),3 and in acute care facilities, approximately $6.3 billion is spent on CDI annually.4 Risk factors for CDI include previous antibiotic exposure, patient age greater than 65 years, and hospitalization or stay in long-term care facilities.5-8

Other risk factors include having pre-existing, inflammatory bowel disease, undergoing gastrointestinal surgeries, having undergone solid organ transplantation, pre-existing chronic kidney diseases, and concomitant immunosuppressant drug therapy.8,9

Although CDI has been associated with health care exposure, there has been a stark rise in the number of CDI cases in the community. A population-based surveillance study performed through the CDC’s Emerging Infections Program (EIP) was done to measure the burden of CDI in the population, characterize C. difficile strains associated with disease, and to monitor trends in disease over time.10

EIP data revealed that from 2011-2017, the number of cases of CDI overall remained stable number while there was a 14.4% increase in the community-setting CDI cohort. Although the estimated burden of CDI among health care-associated infections (HAI) declined a similar pattern over the same 7-year period, this decline was not observed among community-acquired infections, which contributed to nearly 50% of the burden of CDI in 2017.2

The added risk of recurrent CDI infections (rCDI) increases the overall burden of disease. Data from the Healthcare Cost and Utilization Project in the United States over a 15-year period showed a steady increase in the number of hospitalizations associated with CDI, reaching nearly 350,000 hospitalizations in 2008.11 The proportion of patients diagnosed with complicated CDI over a 15-year period (i.e. having active disease with the concomitant development of megacolon, intestinal perforation, need for colectomy, or vasopressor support) increased from 7.1% to 18.2%, while 30-day mortality, specifically, rose from 4.7% to a staggering 13.8% during this same period.11

In the ICU setting, mortality rates increase more than 3 times—with the mortality rate directly from CDI being 5%, mortality secondary to CDI complications ranges between 15% and 25%, and the overall mortality in ICU setting is approximately 34%.12-14

CDI also carries a higher risk of hospital readmission, with as many as 30% of patients within 30 days of initial discharge.4 Disease recurrence with rCDI is especially problematic and is increasing disproportionately relative to initial episodes.

Between 2001 and 2012, rCDI increased by 189%, independent of known CDI risk factors.15 Of these first recurrences, a subset of >30% will recur a second time, and of these second recurrences, a further 40%-60% will subsequently recur with CDI again. rCDI is associated with worse health outcomes and longer hospitalization LOS, resulting in a demonstrable, financial burden in which the gap between hospital costs and drug reimbursements are most pronounced with rCDI.16-19

Seen and Unseen Financial Cost and Economic Burden of CDI

From an economic perspective, CDI has a staggering financial impact on the US health care system, as well on the patients infected. Some of the known, contributory factors to the extraordinary burden, are those direct costs associated with hospitalization and the treatment of secondary complications as they arise (which include surgical costs, prolonged LOS, and requiring intensive care).

Development of rCDI only worsens this burden. Lesser-considered, indirect, patient costs of CDI include productivity loss because of absenteeism (missed days of work) and secondary, economic costs incurred through burden placed on caregivers. From 2002-2016, the annual cost of CDI in the United States increased from $1.3 billion23 to $6.3 billion.4 Several studies have determined both the total and attributable cost of CDI per case (Table 1).4,25,26,30-39 

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Additionally, it has been found that the burden of CDI adds up to 20 hospital days/patient, with additional expenditures exceeding $1 billion per year.21-25 A meta-analysis of 45 studies, performed in the United States over a 16-year period reported the attributable, CDI costs to range from $8911 to $30,049 in hospitalized patients.26

A systematic review of studies in patients between 1986 and 2013 found that not only was CDI among the top 5 most-expensive health care-associated infections (HAIs) in the United States, but it also accounted for 15.4% of all HAIs.27 However, these studies were limited in that the focus was on hospitalization and drug costs, while excluding indirect expenses.

What needs to be considered include the cost of treatment of serious complications due to CDI cases requiring surgery and postoperative care, follow-up, outpatient care, as well as the need for decontamination, isolation, and rigorous hygiene within the hospitals. The median cost of an individual case of CDI increases by 1.4–1.5 times when societal costs are considered in addition to direct hospital costs, further illustrating the overall economic burden of CDI.28

The standard of care for CDI has shifted from metronidazole and vancomycin towards fidaxomicin, fecal microbiota transplantation, and when appropriate, the use of bezlotoxumab.29 While being more expensive from a drug cost perspective, these emerging therapies have shown to be more efficacious in preventing recurrences, thereby proving to be more beneficial forms of therapy from a pharmacoeconomic perspective. The cost efficacy of various treatment regimens in the management of either the initial or recurrent CDI has been examined (Table 2).40-59

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It is important to note that some studies have examined individual treatments, whereas others not only evaluated treatment strategies, but also the appropriate use of novel therapeutic options. It is imperative to be mindful that the cost efficacy is incumbent upon not only the direct costs of the treatment used, but also the relative efficacy in reducing recurrent disease-related morbidity and mortality.

Unrecognized Administrative Cost Implications of CDI

As stated earlier, CDI is one of the most common HAIs and comes within the US government’s Hospital Acquired Condition (HAC) reduction program. This program encourages hospitals to improve patient safety and reduce the number of conditions patients experience from their time in hospital. This program applies to most general acute care hospitals. There are some exemptions, such as critical access hospitals and rehabilitation units, among others. The HAC Reduction Program covers many types of events, including HAI, such as CDI.60

The impact of a hospital’s Medicare reimbursement from CMS is directly attributed to their HAC score. The overall Medicare program can reduce the total payment by 1% if a hospital has a total HAC score greater than 75th percentile of all total HAC scores. Although the calculation process is multi-factorial, the impact occurs with each DRG claimed. The payments apply to all fee-for-service discharges.61

One of the components included in the calculation of HAC Reduction Program is the Standardized Infection Ratio (SIR), which is calculated by formula published by the National Healthcare Safety Network (NHSN). SIR is a summary measure used to track HAI at a national, state, or local level over time. The SIR adjusts for various facility and/or patient-level factors that contribute to HAI risk within each facility. The SIR is currently calculated in NHSN for a variety of HAI types, including CDI.

Using this system, it is possible to compare a hospital with itself over time to determine whether infection reduction is occurring and to what degree.61 Finally, another measure used in the determination of the impact of CDI is the in-patient rehabilitation facility quality reporting program which is enforced by the IMPACT Act of 2014. The identification of hospital-onset CDI is included in these data submissions.62

Other programs relating to 30-day readmissions can also play a part in the overall assessment of health care performance. Thus, it is evident that CDI has an impact on reimbursement of Medicare fees. If a hospital does not achieve certain standards such as reduction in the incidence of CDI, calculated by various formulae, the implications can be financially important. It is therefore important to employ management approaches which can help reduce the recurrence of CDI.

In summary, CDI is a significant condition in terms of morbidity, mortality, and health care economics. The various cost analyses usually do not include the likely negative impact of CDI on the total hospital reimbursement to a hospital. One percent of an annual fee payment can mount up, CDI and its recurrences are financially significant, and appropriate management can contribute to the overall financial status of an institution.

References

  1. Magill SS, O'Leary E, Janelle SJ, Thompson DL, Dumyati G, Nadle J, et al. Changes in Prevalence of Health Care-Associated Infections in U.S. Hospitals. N Engl J Med. 2018;379:1732-44.
  2. Guh AY, Mu Y, Winston LG, Johnston H, Olson D, Farley MM, et al. Trends in U.S. Burden of Clostridioides difficile Infection and Outcomes. New England Journal of Medicine. 2020;382:1320-30.
  3. Zhang D, Prabhu VS, Marcella SW. Attributable Healthcare Resource Utilization and Costs for Patients With Primary and Recurrent Clostridium difficile Infection in the United States. Clin Infect Dis. 2018;66:1326-32.
  4. Zhang S, Palazuelos-Munoz S, Balsells EM, Nair H, Chit A, Kyaw MH. Cost of hospital management of Clostridium difficile infection in United States-a meta-analysis and modelling study. BMC Infect Dis. 2016;16:447.
  5. Kuijper EJ, Coignard B, Tüll P, et al. Emergence of Clostridium difficile-associated disease in North America and Europe. Clin Microbiol Infect. 2006;12:2–18.
  6. Vehreschild MJGT, Weitershagen D, Biehl LM, et al. Clostridium difficile infection in patients with acute myelogenous leukemia and in patients undergoing allogeneic stem cell transplantation: epidemiology and risk factor analysis. Biol Blood Marrow Transplant. 2014;20:823–8.
  7. Slimings C and Riley TV. Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis. J Antimicrob Chemother. 2014;69:881–91.
  8. Leffler DA and Lamont JT. Clostridium difficile infection. N Engl J Med. 2015; 372: 1539–48.
  9. Chitnis AS, Holzbauer SM, Belflower RM, et al. Epidemiology of community-associated Clostridium difficile infection, 2009 through 2011. JAMA Intern Med. 2013;173:1359–1367.
  10. CDC. Clostridioides difficile infection (CDI) tracking, https://www.cdc.gov/hai/eip/cdifftracking.html (accessed 1 July 2021).
  11. Ananthakrishnan AN. Clostridium difficile infection: epidemiology, risk factors and management. Nat Rev Gastroenterol Hepatol. 2011;8:17–26.
  12. Czepiel J, Kędzierska J, Biesiada G, et al. Epidemiology of Clostridium difficile infection: results of a hospital-based study in Krakow, Poland. Epidemiol Infect. 2015; 143:3235–3243.
  13. Vincent JL, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302:2323–2329.
  14. Sidler JA, Battegay M, Tschudin-Sutter S, et al. Enterococci, Clostridium difficile and ESBL-producing bacteria: epidemiology, clinical impact and prevention in ICU patients. Swiss Med Wkly. 2015;144:w14009.
  15. Ma GK, Brensinger CM, Wu Q, Lewis JD. Increasing Incidence of Multiply Recurrent Clostridium difficile Infection in the United States: A Cohort Study. Ann Intern Med. 2017;167:152-8.
  16. Olsen MA, Yan Y, Reske KA, Zilberberg M, Dubberke ER. Impact of Clostridium difficile recurrence on hospital readmissions. Am J Infect Control. 2015;43:318-22.
  17. Olsen MA, Yan Y, Reske KA, Zilberberg MD, Dubberke ER. Recurrent Clostridium difficile infection is associated with increased mortality. Clin Microbiol Infect. 2015;21:164-70.
  18. Dubberke ER, Carling P, Carrico R, Donskey CJ, Loo VG, McDonald LC, et al. Strategies to prevent Clostridium difficile infections in acute care hospitals: 2014 Update. Infect Control Hosp Epidemiol. 2014;35:628-45.
  19. Zilberberg MD, Nathanson BH, Marcella S, Hawkshead JJ, 3rd, Shorr AF. Hospital readmission with Clostridium difficile infection as a secondary diagnosis is associated with worsened outcomes and greater revenue loss relative to principal diagnosis: A retrospective cohort study. Medicine (Baltimore). 2018;97:e12212.
  20. Gupta A and Ananthakrishnan AN. Economic burden and cost-effectiveness of therapies for Clostridiodes difficile infection: a narrative review. Ther Adv Gastroenterol. 2021;14:1–13.
  21. Pépin J, Valiquette L and Cossette B. Mortality attributable to nosocomial Clostridium difficile-associated disease during an epidemic caused by a hypervirulent strain in Quebec. CMAJ. 2005;173:1037–41.
  22. Song X, Bartlett JG, Speck K, et al. Rising economic impact of Clostridium difficile-associated disease in adult hospitalized patient population. Infect Control Hosp Epidemiol. 2008;29:823–8.
  23. Kyne L, Hamel MB, Polavaram R, et al. Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile. Clin Infect Dis. 2002;34:346–53.
  24. Vonberg RP, Reichardt C, Behnke M, et al. Costs of nosocomial Clostridium difficile-associated diarrhoea. J Hosp Infect. 2008;70:15–20.
  25. Wilcox MH, Cunniffe JG, Trundle C, et al. Financial burden of hospital-acquired Clostridium difficile infection. J Hosp Infect. 1996;34:23–30.
  26. Nanwa N, Kendzerska T, Krahn M, et al. The economic impact of Clostridium difficile infection: a systematic review. Am J Gastroenterol. 2015;110:511–9.
  27. Zimlichman E, Henderson D, Tamir O, et al. Health care-associated infections: a meta-analysis of costs and financial impact on the US healthcare system. JAMA Intern Med. 2013;173:2039–46.
  28. McGlone SM, Bailey RR, Zimmer SM, et al. The economic burden of Clostridium difficile. Clin Microbiol Infect 2012;18:282–9.
  29. Johnson S, Lavergne V, Skinner AM, et al.Clinical Practice Guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 Focused Update Guidelines on Management of Clostridioides difficile Infection in Adults. Clin Infect Dis. 2021. DOI: 10.1093/cid/ciab549.
  30. Nanwa N, Kwong JC, Krahn M, et al. The economic burden of hospital-acquired Clostridium difficile infection: a population-based matched cohort study. Infect Control Hosp Epidemiol. 2016;37:1068–78.
  31. Le Monnier A, Duburcq A, Zahar JR, et al. Hospital cost of Clostridium difficile infection including the contribution of recurrences in French acute-care hospitals. J Hosp Infect. 2015;91:117–22.
  32. Wiegand PN, Nathwani D, Wilcox MH, et al. Clinical and economic burden of Clostridium difficile infection in Europe: a systematic review of healthcare-facility-acquired infection. J Hosp Infect 2012; 81: 1–14.
  33. Grube RF, Heinlein W, Scheffer H, et al. Economic burden of Clostridium difficile enterocolitis in German hospitals based on routine DRG data. Z Gastroenterol. 2015;53:391–7.
  34. Magalini S, Pepe G, Panunzi S, et al. An economic evaluation of Clostridium difficile infection management in an Italian hospital environment. Eur Rev Med Pharmacol Sci. 2012;16:2136–41.
  35. Asensio A, Di Bella S, Lo Vecchio A, et al. The impact of Clostridium difficile infection on resource use and costs in hospitals in Spain and Italy: a matched cohort study. Int J Infect Dis. 2015;36:e31–8.
  36. Al-Eidan FA, McElnay JC, Scott MG, et al. Clostridium difficile-associated diarrhoea in hospitalised patients. J Clin Pharm Ther 2000;25:101–9.
  37. Yasunaga H, Horiguchi H, Hashimoto H, et al. The burden of Clostridium difficile-associated disease following digestive tract surgery in Japan. J Hosp Infect. 2012;82:175–80.
  38. Choi H-Y, Park S-Y, Kim Y-A, et al. The epidemiology and economic burden of Clostridium difficile infection in Korea. Biomed Res Int. 2015;2015:510386.
  39. Jackson T, Nghiem HS, Rowell D, et al. Marginal costs of hospital-acquired conditions: information for priority-setting for patient safety programmes and research. J Health Serv Res Policy. 2011;16:141–146.
  40. Stranges PM, Hutton DW and Collins CD. Cost-effectiveness analysis evaluating fidaxomicin versus oral vancomycin for the treatment of Clostridium difficile infection in the United States. Value Health. 2013;16:297–304.
  41. Varier RU, Biltaji E, Smith KJ, et al. Cost-effectiveness analysis of treatment strategies for initial Clostridium difficile infection. Clin Microbiol Infect. 2014;20:1343–51.
  42. Wagner M, Lavoie L, and Goetghebeur M. Clinical and economic consequences of vancomycin and fidaxomicin for the treatment of Clostridium difficile infection in Canada. Can J Infect Dis Med Microbiol. 2014;25:87–94.
  43. Nathwani D, Cornely OA, van Engen AK, et al. Cost-effectiveness analysis of fidaxomicin versus vancomycin in Clostridium difficile infection. J Antimicrobial Chemother 2014; 69:2901–12.
  44. Marković V, Kostić M, Iličković I, et al. Cost-effectiveness comparison of fidaxomicin and vancomycin for treatment of Clostridium difficile infection: a Markov model based on data from a South West Balkan country in socioeconomic transition. Value Health Reg Issues. 2014;4:87–94.
  45. Rubio-Terrés C, Cobo Reinoso J, Grau Cerrato S, et al. Economic assessment of fidaxomicin for the treatment of Clostridium difficile infection (CDI) in special populations (patients with cancer, concomitant antibiotic treatment or renal impairment) in Spain. Eur J Clin Microbiol Infect Dis. 2015;34:2213–23.
  46. Watt M, McCrea C, Johal S, et al. A cost-effectiveness and budget impact analysis of first-line fidaxomicin for patients with Clostridium difficile infection (CDI) in Germany. Infection. 2016;44:599–606.
  47. 84. Watt M, Dinh A, Le Monnier A, et al. Cost-effectiveness analysis on the use of fidaxomicin and vancomycin to treat Clostridium difficile infection in France. J Med Econ. 2017;20:678–86.
  48. Konijeti GG, Sauk J, Shrime MG, et al. Cost-effectiveness of competing strategies for management of recurrent Clostridium difficile infection: a decision analysis. Clin Infect Dis 2014;58:1507–14.
  49. Rajasingham R, Enns EA, Khoruts A, et al. Cost-effectiveness of treatment regimens for Clostridioides difficile infection: an evaluation of the 2018 Infectious Diseases Society of America guidelines. Clin Infect Dis. 2020;70:754–62.
  50. Zowall H, Brewer C and Deutsch A. Cost-effectiveness of fecal microbiota transplant in treating Clostridium difficile infection in Canada. Value Health. 2014;17:A676.
  51. Varier RU, Biltaji E, Smith KJ, et al. Cost-effectiveness analysis of fecal microbiota transplantation for recurrent Clostridium difficile infection. Infect Control Hosp Epidemiol. 2015;36:438–44.
  52. Lapointe-Shaw L, Tran KL, Coyte PC, et al. Cost-effectiveness analysis of six strategies to treat recurrent Clostridium difficile infection. PLoS One. 2016;11:e0149521.
  53. Merlo G, Graves N, Brain D, et al. Economic evaluation of fecal microbiota transplantation for the treatment of recurrent Clostridium difficile infection in Australia. J Gastroenterol Hepatol. 2016;31:1927–32.
  54. Waye A, Atkins K and Kao D. Cost averted with timely fecal microbiota transplantation in the management of recurrent Clostridium difficile infection in Alberta, Canada. J Clin Gastroenterol. 2016;50:747–53.
  55. Baro E, Galperine T, Denies F, et al. Cost-effectiveness analysis of five competing strategies for the management of multiple recurrent community-onset Clostridium difficile infection in France. PLoS One. 2017;12:e0170258.
  56. Prabhu VS, Dubberke ER, Dorr MB, et al. Cost-effectiveness of bezlotoxumab compared with placebo for the prevention of recurrent Clostridium difficile infection. Clin Infect Dis. 2018;66:355–62.
  57. Jiang M, Leung N-H, Ip M, et al. Cost-effectiveness analysis of ribotype-guided fecal microbiota transplantation in Chinese patients with severe Clostridium difficile infection. PLoS One. 2018;13:e0201539.
  58. Abdali ZI, Roberts TE, Barton P, et al. Economic evaluation of faecal microbiota transplantation compared to antibiotics for the treatment of recurrent Clostridioides difficile infection. EClinicalMedicine 2020; 24: 100420.
  59. You JHS, Jiang X, Lee WH, et al. Cost-effectiveness analysis of fecal microbiota transplantation for recurrent Clostridium difficile infection in patients with inflammatory bowel disease. J Gastroenterol Hepatol. 2020;35:1515–23.
  60. Centers for Medicare & Medicaid Services.https://www.cms.gov/Medicare/Quality-Initiatives-Patient-Assessment-Instruments/Value-Based-Programs/HAC/Hospital-Acquired-Conditions. (Accessed 23 August 2021).
  61. CDC.The NHSN Standardized Infection Ratio (SIR) – A Guide to the SIR. https://www.cdc.gov/nhsn/pdfs/ps-analysis-resources/nhsn-sir-guide.pdf. (Accessed 23 August 2021).
  62. Centers for Medicare and Medicaid Services.https://www.cms.gov/Medicare/Quality-Initiatives-Patient-Assessment-Instruments/IRF-Quality-Reporting/IRF-Quality-Reporting-Program-Measures-Information-.(Accessed on 23 August 2021).