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Mortality, Health Care Use, and Costs of Clostridioides difficile Infections in Older Adults

Open AccessPublished:March 11, 2022DOI:https://doi.org/10.1016/j.jamda.2022.01.075

      Abstract

      Objectives

      Estimate mortality, cost, and health care resource utilization for Medicare beneficiaries aged ≥65 years who suffered a primary Clostridioides difficile infection (CDI) episode only or any recurrent CDI, and understand how outcomes covary with death.

      Design

      Retrospective observational claims analysis.

      Setting and Participants

      Patients aged ≥65 years who had an inpatient or outpatient CDI diagnosis claim to Medicare and continuous enrollment in Medicare parts A, B, and D during the 12-month pre- and post-index periods.

      Methods

      Using 100% Medicare Fee-for-Service claims data for 2009–2017, primary (pCDI, n = 345,893) and recurrent (rCDI: n = 151,596) CDI episodes were identified. Demographic and clinical characteristics, mortality, health care resource utilization, and costs (per patient per month) were summarized for 12 months before and up to 12 months after episode start. Regression models were estimated for hospitalization risk, hospital length of stay (LOS), and cost to adjust for comorbidities.

      Results

      CDI-associated deaths were almost 10 times higher after recurrent CDI (25.4%) than primary CDI (2.7%). Compared with survivors, decedents were older, had higher Charlson Comorbidity Index scores, and were more likely Black. Adjusting for comorbidities, during follow-up, decedents had higher hospitalization rates [pCDI: odds ratio (OR) = 1.83, P < .001; rCDI: OR = 2.58, P < .001], and recurrent CDI decedents had more intensive care unit use (OR = 2.34, P < .001) compared with survivors. Decedents also had a longer length of stay (pCDI: +3.2 days, P < .001; rCDI: +2.6 days, P < .001), and higher total cost (pCDI: +303%, P < .001; rCDI: +297%, P < .001).

      Conclusions and Implications

      CDI is an important contributing diagnosis to all-cause mortality, particularly for recurrences. Prior to death, older Medicare beneficiaries who experienced CDI received longer, more intensive, and more costly care compared with survivors. Clinicians should be particularly attentive to prevention, identification, and appropriate treatment of CDI in older adults. Better treatments to reduce primary C difficile infection and recurrences in this vulnerable population can lower both mortality and economic burden.

      Keywords

      Clostridioides difficile infection (CDI) is recognized as the most common health care–associated infection in the United States, especially in older patients, for whom it is associated with high mortality, cost, and clinical burden.
      • Ma G.K.
      • Brensinger C.M.
      • Wu Q.
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      Changes in prevalence of health care-associated infections in U.S. hospitals.
      In 2017, there were approximately 462,000 cases of CDI in the United States.
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      Trends in U.S. burden of Clostridioides difficile infection and outcomes.
      Although rates of CDI have fallen in the past decade, recently CDI rates have plateaued.
      • Magill S.S.
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      • Janelle S.J.
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      Changes in prevalence of health care-associated infections in U.S. hospitals.
      • Guh A.Y.
      • Mu Y.
      • Winston L.G.
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      Trends in U.S. burden of Clostridioides difficile infection and outcomes.
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      • Lewis C.
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      Clostridioides difficile infection in US hospitals: a national inpatient sample study.
      Approximately 35% of patients who experience a first CDI episode will go on to develop a recurrence (rCDI),
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      Healthcare resource utilization and costs of recurrent Clostridioides difficile infection in the elderly: a real-world claims analysis.
      and 65% of patients who experience at least 1 recurrence will suffer a subsequent recurrence.
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      Can we identify patients at high risk of recurrent Clostridium difficile infection?.
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      • Smits W.K.
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      Clostridium difficile infection.
      Recurrent CDI can amplify health care resource utilization (HRU) and associated medical costs, relative to those who experience only a primary CDI (pCDI) episode, for at-risk patients.
      • Zhang D.
      • Prabhu V.S.
      • Marcella S.W.
      Attributable healthcare resource utilization and costs for patients with primary and recurrent Clostridium difficile infection in the United States.
      Direct medical costs related to recurrent CDI in the United States are estimated at $2.8 billion annually, with higher per-patient costs associated with CDI-related surgery or hospitalization during the year after recurrence, as well as a higher likelihood of death, compared to patients who do not experience a recurrence.
      • Rodrigues R.
      • Barber G.E.
      • Ananthakrishnan A.N.
      A comprehensive study of costs associated with recurrent Clostridium difficile infection.
      When CDI is present as a secondary infection during hospitalization, readmission and mortality risks increase.
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      • Baser O.
      • Yu H.
      Mortality and costs in Clostridium difficile infection among the elderly in the United States.
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      • Drozd E.M.
      • Inocencio T.J.
      • Braithwaite S.
      • et al.
      Mortality, hospital costs, payments, and readmissions associated with Clostridium difficile infection among Medicare beneficiaries.
      CDI also increases mortality risk regardless of treatment setting.
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      • Caffrey A.R.
      • Beganovic M.
      • Avramovic S.
      • LaPlante K.L.
      Predictors of mortality among a national cohort of Veterans with recurrent Clostridium difficile infection.
      The burden of recurrent CDI, based on population incidence, has not improved despite a nationally decreasing trend of all CDI rates between 2011 and 2017.
      • Guh A.Y.
      • Mu Y.
      • Winston L.G.
      • et al.
      Trends in U.S. burden of Clostridioides difficile infection and outcomes.
      Furthermore, in a single tertiary-care hospital, recurrent CDI increased 6-month mortality by 33% after adjusting for risk factors.
      • Olsen M.A.
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      • Reske K.A.
      • Zilberberg M.D.
      • Dubberke E.R.
      Recurrent Clostridium difficile infection is associated with increased mortality.
      This persistence of refractory disease and the increased mortality risk underscores the importance of reducing recurrent CDI.
      Older adults experience CDI at a much higher rate than younger persons (500 vs 90 cases per 100,000 persons among US adults).
      • Pechal A.
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      • Allen S.
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      National age group trends in Clostridium difficile infection incidence and health outcomes in United States community hospitals.
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      Global burden of Clostridium difficile infections: a systematic review and meta-analysis.
      Older people are at increased risk for initial infection and recurrence and are twice as likely to develop complicated CDI compared with younger people.
      • Nour Abou Chakra C.
      • Pepin J.
      Risk factors for recurrence, complications and mortality in Clostridium difficile infection: a systematic review.
      Much of the data on CDI in general, and in older adults specifically, is somewhat limited in its scope: being derived from smaller sample groups (eg, single medical center, 5% Medicare sample data, only patients hospitalized for CDI) or covering a modest time frame of 30-90 days following a primary CDI episode.
      • Shorr A.F.
      • Zilberberg M.D.
      • Wang L.
      • Baser O.
      • Yu H.
      Mortality and costs in Clostridium difficile infection among the elderly in the United States.
      ,
      • Appaneal H.J.
      • Caffrey A.R.
      • Beganovic M.
      • Avramovic S.
      • LaPlante K.L.
      Predictors of mortality among a national cohort of Veterans with recurrent Clostridium difficile infection.
      ,
      • Enoch D.A.
      • Murray-Thomas T.
      • Adomakoh N.
      • et al.
      Risk of complications and mortality following recurrent and non-recurrent Clostridioides difficile infection: a retrospective observational database study in England.
      • Kelly C.R.
      • Fischer M.
      • Allegretti J.R.
      • et al.
      ACG clinical guidelines: prevention, diagnosis, and treatment of Clostridioides difficile Infections.
      • McDonald L.C.
      • Gerding D.N.
      • 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).
      Additionally, there is a dearth of data on the relative characteristics and outcomes of patients who died vs those who survived after suffering CDI.
      This study provides direct estimates of the mortality, cost, and HRU for Medicare beneficiaries aged ≥65 years who suffered either a primary CDI episode only or any recurrent CDI, stratified by those who survived and died, to understand how outcomes covary with death. The analyses were adjusted to account for patient risk factors.

      Methods

      Study Design

      We conducted a retrospective cohort study to assess HRU and cost outcomes for older adults enrolled in traditional fee-for-service (FFS) Medicare with primary CDI and recurrent CDI from 2009 through 2017. The study utilized 100% of Medicare FFS final action claims and enrollment data via a research-focused Data Use Agreement with the Centers for Medicare & Medicaid Services (CMS). This includes 100% of Medicare Part A and Part B (medical) claims and 100% of Part D (pharmacy) prescription drug events (Supplementary Material 1).
      The study included Medicare beneficiaries not enrolled in a private Medicare Advantage plan between 2009 and 2017 who had simultaneous, continuous enrollment in Parts A, B, and D during the same period (see specific enrollment criteria below). The use of these data abided by Health Insurance Portability and Accountability Act (HIPAA) requirements for the privacy and security of protected health information as well as additional CMS requirements.

      Patient Identification

      We analyzed claims for Medicare beneficiaries aged 65 years and older with a first CDI diagnosis (index date) and continuous enrollment in Medicare Parts A, B, and D during the 12 months prior to (baseline) and up to 12 months following the index event date (follow-up), except in cases of disenrollment or death. Allowable dates for the index CDI episode were January 1, 2010, through December 31, 2016. By study design, there were no CDI-related claims during pre-index baseline. We identified an episode of CDI based on either an inpatient stay attributed to a CDI diagnosis code (primary or secondary diagnosis) or an outpatient medical claim with CDI diagnosis plus evidence of use of a CDI treatment. Inpatient settings included acute hospitals, long-term care hospitals [also known as long-term acute care hospitals (LTCHs)], and inpatient rehabilitation facilities (IRFs). Acceptable CDI treatments included vancomycin, fidaxomicin, metronidazole, rifaximin, bezlotoxumab, or fecal microbiota transplant (FMT) (Supplementary Table 1).
      CDI episodes began on the date of the first CDI medical claim and included all subsequent claims with a CDI diagnosis with no more than a 14-day gap between claims (a longer gap between CDI claims ended the episode). A minimum 14-day CDI-claim-free period separated one episode from a subsequent episode (Supplementary Figure 1). A recurrent episode was one with an index date no later than 8 weeks following the end of a previous episode.
      Centers for Disease Control and Prevention
      Clostridioides difficile Infection (CDI) Tracking. Accessed March 26, 2021.
      Patients who experienced only a primary CDI episode during the study period comprised the pCDI cohort, and patients with a primary episode plus 1 or more recurrent CDI episodes comprised the rCDI cohort. We defined deaths as CDI associated if the most proximal health care visit to the date of death had CDI as the primary or secondary diagnosis.

      Baseline Characteristics

      We extracted demographic characteristics at the date of index CDI episode: age; gender; race/ethnicity; geographic region; dual eligible status; and original reason for entitlement to Medicare. We identified clinical characteristics during the baseline period: Charlson Comorbidity Index (CCI); individual CCI conditions; select other comorbid conditions; frailty indicators; medication exposure (any use of gastric acid–suppressing agents, antimicrobials, or immunosuppressant agents) reported by National Drug Codes; and baseline medical procedures and treatments (transplants, gastrointestinal surgery, enteral feeding, chemotherapy). HRU included mean number of stays, days, visits, and average length of stay by setting. Total cost included the sum of Medicare program cost plus patient responsibility (eg, private pay, coinsurance), stratified by spending category. Utilization and total cost are reported for the 6 months immediately prior to index CDI episode (to identify potential precipitating events of CDI), and the 7-12 months preceding the index CDI episode.

      Outcomes

      Outcomes analyzed included mortality (overall and CDI-associated), HRU [hospital admissions and hospital length of stay; intensive care unit (ICU) stays; emergency department (ED) visits; non-ED outpatient visits; post-acute care (PAC) stays]; and total cost on a per-patient per-month (PPPM) basis for the follow-up period. Post-acute care settings are composed of skilled nursing facilities (SNFs), home health agencies (HHAs), inpatient rehabilitation facilities, long-term care hospitals, and hospices. We stratified outcomes by whether the patient suffered primary CDI only (pCDI) or recurrent CDI (rCDI), whether the patient survived or died during the study period, and whether the death was CDI associated or not.

      Data Analysis

      The analyses described the demographic and clinical characteristics, utilization, and total cost, as well as differences in hospitalization rates, ICU use rates, hospital length of stay, and total cost, adjusted for demographic and baseline risk factors (diagnoses, treatments, and frailty characteristics). We calculated counts and percentages of categorical factors (eg, age between 65 and 74 years, dual eligible status, and comorbid conditions), and means and SDs of continuous factors (eg, age, CCI, and total cost). Survival analysis by study cohort was performed with the Kaplan-Meier method. We adjusted costs to 2018 values using the medical care component of the Consumer Price Index.
      US Bureau of Labor Statistics
      Measuring price change in the CPI: Medical care.
      We adjusted outcomes using logit models for hospitalization and ICU use rates and log-link gamma-distributed generalized linear models for length of stay and total cost. We reported odds ratios for rates and percentage increases for length of stay and total cost, and reported adjusted means for survivors and decedents, calculated for a balanced population.
      SAS Institute Inc
      Shared concepts and topics: LSMEANS statement.
      Covariates associated with utilization and cost outcomes were examined for differences between decedents and survivors during baseline and follow-up periods. The final set of adjustors were age; gender; race; census region; Medicare-Medicaid dual eligibility; original reason for entitlement; CCI score; presence of each CCI condition in the 12 months prior to index date; presence of other chronic conditions (Crohn disease, ulcerative colitis) and frailty conditions (abnormality of gait, abnormal weight loss, failure to thrive, debility, difficulty walking, risk of falls, muscle weakness, pressure ulcer); and selected treatments and procedures that occurred during the 12-month baseline period (transplants, gastrointestinal surgery, enteral feeding, chemotherapy). All analyses were conducted with Base SAS software, version 9.4M4, and SAS/STAT software, version 14.2, of the SAS System for Linux x64.

      Results

      Summary of CDI Patient Mortality

      Of 497,489 Medicare beneficiaries ≥65 years with CDI who were included in the study, 30.5% experienced recurrent CDI. In total, 186,996 patients with primary CDI survived (37.6% of total sample), 158,897 patients with primary CDI died (31.9% of sample), 97,738 patients with recurrent CDI survived (19.6% of sample), and 53,858 patients with recurrent CDI died during the 12-month follow-up (10.8% of sample; Table 1 and Supplementary Figure 2). Of the patients who died during the follow-up period, the CDI-associated mortality rate was 2.7% for patients who suffered primary CDI only and 25.4% for patients who suffered recurrent CDI, nearly 10 times higher than for those with primary CDI (Table 2). The survival analysis showed that most deaths occurred early during the follow-up year. By 16 weeks after the index CDI, half or more of decedents in each cohort had died (Figure 1). Non-CDI-associated deaths after primary CDI, potentially owing to an inciting illness that precipitated the index CDI, occurred the soonest. The other cohorts of decedents (CDI-associated deaths in primary CDI, CDI-associated deaths in recurrent CDI, and non–CDI-associated deaths in recurrent CDI) had similar patterns of early mortality during the follow-up year, though less pronounced.
      Table 1Selected Baseline Characteristics for Patients With Primary or Recurrent
      Any recurrent CDI during follow-up period of 12 months.
      CDI
      Supplementary Table 5 provides an analogous table for pCDI-only and rCDI patient decedents, stratifying by whether death can be associated with CDI. Supplementary Tables 6–10 provide details on additional baseline characteristics.
      by Survival Outcome
      Baseline CharacteristicPrimary CDI (n = 345,893)Recurrent CDI (n = 151,596)
      SurvivorsDecedentsSurvivorsDecedents
      Number of patients in analysis sample186,996158,89797,73853,858
      Percentage of analysis sample, %37.631.919.610.8
      Mean age, y78.481.578.080.4
      Age group, %
       65-74 y36.524.238.428.1
       75-84 y38.436.138.337.4
       ≥85 y25.139.723.334.5
      Sex, %
       Female68.961.768.360.8
       Male31.138.331.739.2
      Race, %
       White86.782.988.382.7
       Black8.911.77.812.2
       Other
      “Other” races (not White or Black) included Asian, Hispanic, North American Native, and Other.
      4.45.33.95.0
      Medicare-Medicaid dual eligibility status, %
       Nondual64.659.467.155.5
       Dual35.440.632.944.5
      Mean CCI5.07.25.27.2
      Top 5 comorbid medical conditions
      Top 5 conditions are the 5 individual CCI conditions most prevalent among all CDI patients.
      , %
       Congestive heart failure43.465.844.465.4
       Chronic obstructive pulmonary disease49.562.350.262.8
       Diabetes without complications45.552.645.054.9
       Peripheral vascular disease43.055.744.056.5
       Renal disease37.955.641.357.1
      Antibiotic use, 0-12 mo baseline, %82.880.387.083.6
      0-6-mo baseline HRU, %
       Acute hospitalization53.872.860.675.8
       Emergency department40.041.042.743.4
       Outpatient (excluding ED)98.198.098.998.5
       Long-term care hospital4.79.14.18.3
       Inpatient rehabilitation facility6.15.96.16.9
       Skilled nursing facility27.149.032.149.6
       Home health agency30.339.132.941.3
       Hospice0.72.30.51.5
      0-6-mo baseline PPPM cost
      0-6-month baseline per-patient per-month (PPPM) cost computed as the cost (Medicare program payments plus beneficiary responsibility) for each service setting for the 6-month period immediately prior to the index CDI event, divided by 6 months.
      , $
       Total670210,502820411,717
       Acute hospitalization2171359926903979
       ED173156180165
       Outpatient (excluding ED)555744691890
       Long-term care hospital377846331775
       Inpatient rehabilitation facility222207214248
       Skilled nursing facility75014509921638
       Home health agency190258191263
       Hospice14361025
       Physician services and tests1607249118602669
       DME176225523533
       Pharmacy468490523533
      DME, durable medical equipment; ED, emergency department.
      Any recurrent CDI during follow-up period of 12 months.
      Supplementary Table 5 provides an analogous table for pCDI-only and rCDI patient decedents, stratifying by whether death can be associated with CDI. Supplementary Table 10, Supplementary Table 6, Supplementary Table 7, Supplementary Table 8, Supplementary Table 9 provide details on additional baseline characteristics.
      “Other” races (not White or Black) included Asian, Hispanic, North American Native, and Other.
      § Top 5 conditions are the 5 individual CCI conditions most prevalent among all CDI patients.
      0-6-month baseline per-patient per-month (PPPM) cost computed as the cost (Medicare program payments plus beneficiary responsibility) for each service setting for the 6-month period immediately prior to the index CDI event, divided by 6 months.
      Table 2Mortality Rate for Patients With Primary or Recurrent CDI
      Episode TypeRecurrence NumberNumber of SurvivorsNumber of DecedentsAll-Cause Mortality Rate During Follow-up
      Ratio of the number of decedents to sum of survivors plus decedents in each row.
      , %
      CDI-Related Mortality Rate During Follow-up
      For in-hospital deaths, based on the primary and secondary diagnosis fields documented on the hospital discharge claim. For other deaths, based on the primary and secondary diagnoses from the most proximal visit to the date of death.
      , %
      Percentage of All Decedents
      Ratio of the number of decedents in the row to the sum of the number of primary and all recurrent CDI decedents.
      , %
      Primary Only (n = 345,893)186,996158,89745.92.774.7
      Recurrent (n = 151,596)All97,73853,85835.525.425.3
      First40,27727,80640.816.413.1
      Second24,03312,71334.630.96.0
      All subsequent33,42813,33928.539.06.3
      Ratio of the number of decedents to sum of survivors plus decedents in each row.
      For in-hospital deaths, based on the primary and secondary diagnosis fields documented on the hospital discharge claim. For other deaths, based on the primary and secondary diagnoses from the most proximal visit to the date of death.
      Ratio of the number of decedents in the row to the sum of the number of primary and all recurrent CDI decedents.
      Figure thumbnail gr1
      Fig. 1Survival analysis during 12-month follow-up, by study cohort. By week 16, half or more of the decedents in each cohort had died. CDI cohorts: primary CDI only (pCDI); recurrent CDI (rCDI): patients with ≥1 recurrence during a follow-up period of up to 12 months. Kaplan-Meier survival curves estimated with SAS/STAT version 14.2 PROC LIFETEST.
      Of those who suffered rCDI and died during follow-up, CDI-associated mortality rates increased with number of recurrences: 16.4% CDI-associated mortality for those with 1 rCDI episode, 30.9% for those with 2 rCDI episodes, and 39.0% for those with 3+ rCDI episodes. Sepsis and acute respiratory failure were the 2 most frequent non-CDI causes of death for patients with either primary or recurrent CDI (Supplementary Tables 2 and 3). The average follow-up time from index episode to death was 63 days for patients with primary CDI and 77 days for those with recurrent CDI (Supplementary Table 4).

      Baseline Patient Characteristics

      Certain baseline characteristics were different between decedents and survivors regardless of whether they were in the primary or recurrent CDI cohort (Table 1 and Supplementary Tables 5 and 6). Decedents were more likely to be aged ≥85 years (P < .001) relative to survivors. Survivors were an average of 78 years, with decedents 3.1 years older on average in the primary CDI cohort and 2.4 years older on average in the recurrent cohort (P < .001). Decedents were more often dual eligible than survivors (40.6%-44.5% vs 32.9%-35.4%; P < .001).
      Decedents, on average, had a higher burden of comorbid conditions than survivors at baseline. Decedents' CCI scores were higher than survivors' scores, and decedents were more likely to have the 5 most common CCI conditions: congestive heart failure, chronic obstructive pulmonary disease, diabetes without complications, peripheral vascular disease, and renal disease (all P < .001 relative to survivors).
      Decedents had greater utilization of acute hospitalizations and post-acute care stays vs survivors during the baseline period 0-6 months before the index CDI episode (P < .001) (Supplementary Table 7). Decedents' acute hospital length of stay in 0-6 months baseline was also longer by about 1 day (8.1 vs 7.0-7.1, P < .001). Decedents had higher total medical costs than survivors during 0-6 months baseline ($63,014-$70,304 vs $40,210-$49,223, P < .001), including higher costs for acute hospitalizations, nonemergency hospital outpatient, long-term care hospitals, skilled nursing facilities, and physician services (all P < .001; Supplementary Table 8). Baseline utilization and costs for the 7-12-month preindex period are provided in Supplementary Tables 9 and 10, respectively.

      Unadjusted Outcomes

      In contrast to baseline HRU and costs, there were few quantitative differences in unadjusted outcomes between primary CDI and recurrent CDI cohorts when examining decedent and survivor data. For both primary and recurrent CDI cohorts, total costs were about 4.5 times higher among decedents compared with survivors (P < .001). We separated acute hospital costs into those associated with the index hospital stay vs those associated with 30-day readmissions (Figure 2, Supplementary Figure 3, and Supplementary Table 11). Decedents had much higher inpatient costs (pCDI: 23 times higher; rCDI: 8 times higher; P < .001) and 30-day readmission costs (pCDI and rCDI: nearly 5.5 times higher; P < .001) than survivors. In addition, decedents had 2-3 times higher total costs for nonemergency outpatient care, and 2.6-4.5 times higher post-acute care costs than survivors. Decedents' greater post-acute care costs were driven by skilled nursing facility and long-term care hospital stays (all P < .001). Emergency department, home health agency, and physician office visit costs were similar among decedents and survivors.
      Figure thumbnail gr2
      Fig. 2Follow-up per-patient per-month cost of care for patients with primary or recurrent∗ CDI by survival outcome and relatedness of mortality. Top: For both primary and recurrent CDI cohorts, decedents had higher follow-up costs than survivors, with inpatient costs and post-acute care constituting the largest portions of costs. Bottom: For those who died during the follow-up period, overall costs for deaths not associated with Clostridioides difficile infection (CDI) were higher than those for CDI-associated deaths. For reference, the average annual Medicare cost per beneficiary in 2020 was $15,673, which corresponds to a monthly cost of $1306.
      2021 annual report of the boards of trustees of the federal hospital insurance and federal supplementary medical insurance trust funds. Accessed August 31, 2021.
      CDI cohorts: primary CDI only (pCDI); recurrent CDI (rCDI): patients with ≥1 recurrence during a follow-up period of up to 12 months. Total per-patient per-month (PPPM) costs across all settings noted at the top of each column. Settings with PPPM cost >$2000 are shown in each individual stacked bar. Acute 30-day readmissions are to an acute hospital within 30 days of the prior hospitalization. provides details on additional follow-up costs. DME, durable medical equipment.
      Decedents' health care utilization exceeded survivors' during the 12-month follow-up period, with at least double the odds for ≥1 acute hospital or long-term care hospital stay, and higher odds of ICU use or having a 30-day readmission (all P < .001). However, decedents were half as likely to have an ED visit or home health agency visit, and much less likely to use nonemergency outpatient services (all P < .001). Unsurprisingly, decedents' use of hospice was greater than survivors' (P < .001) (Supplementary Table 12).
      The length of stay at a skilled nursing facility was 40% shorter for decedents than survivors in both primary and recurrent CDI cohorts (P < .001). However, decedents' acute hospital stays tended to be longer than survivors by 3.0-3.7 days for primary and recurrent CDI cohorts (P < .001). This is consistent with decedents dying more often in a post-acute care setting (long-term care hospital or skilled nursing facility), or even before admission to these settings.

      Adjusted Outcome Differences Between Survivors and Decedents

      Adjusted outcomes were calculated for hospitalization rates, ICU rates, acute hospital length of stay, and total cost (covariates are listed in the Methods section) (Table 3). During the 12-month follow-up period, decedents' adjusted difference in hospitalizations was 4.3% greater for primary CDI patients and 3.6% greater for recurrent CDI patients than survivors (both P < .001). The adjusted ICU rate difference was 20.6% higher for recurrent CDI patients who died (P < .001). Decedents' acute inpatient length of stay was longer than survivors for both primary CDI (38.3%) and recurrent CDI (32.6%; both P < .001), and total cost was 3 times higher for primary CDI and recurrent CDI (both P < .001).
      Table 3Adjusted
      Outcomes for decedents vs survivors were adjusted for age; sex; race; census region; Medicare-Medicaid dual eligibility; original reason for Medicare entitlement; CCI; presence of each CCI condition in the 12 months prior to index date; presence of other conditions (Crohn disease, ulcerative colitis) and frailty (abnormality of gait, abnormal weight loss, failure to thrive, debility, difficulty walking, risk of falls, muscle weakness, pressure ulcer); and selected conditions in prior 12 months (transplants, gastrointestinal surgery, enteral feeding, chemotherapy). Inpatient hospitalizations and ICU stay were adjusted with logit model; ALOS and total cost were adjusted with gamma-distributed generalized linear model with log link. Outcome adjustments were made using SAS/STAT LSMEANS. Supplementary Tables 6–10 provide details on additional baseline characteristics.
      and Unadjusted HRU and Costs
      CDI Cohort
      CDI cohorts: pCDI: patients with primary CDI only; rCDI: patients with recurrent CDI during a follow-up period of up to 12 months.
      OutcomeUnadjusted
      Supplementary Table 12 provides details on additional follow-up unadjusted outcomes.
      Mean, Survivors
      Unadjusted Mean, DecedentsAdjusted OR or % Change, Died vs SurvivedOR or % Change 95% CI
      All adjusted odds ratios and percentage changes are significantly different from 1 (odds ratios) or 0 (percent changes, with P < .001).
      Adjusted Mean, Survivors
      Adjusted mean calculated at mean of covariates other than whether survivor or decedent.
      Adjusted Mean, Decedents
      pCDIAcute hospitalization, %86.193.61.831.78, 1.8889.994.2
      pCDIICU stay, %21.322.50.940.92, 0.9623.122.0
      pCDIALOS, d7.611.3+38.3%+37.6%, +39.1%8.211.4
      pCDITotal cost
      Total cost (sum of Medicare program payments plus patient responsibility) inflation-adjusted to 2018.
      , $ PPPM
      634829,150+303%+300%, +305%752030,279
      rCDIAcute hospitalization, %88.696.62.582.45, 2.7294.097.6
      rCDIICU stay, %29.853.22.342.29, 2.4034.154.7
      rCDIALOS, d7.610.6+32.6%+31.7%, +33.5%7.910.5
      rCDITotal cost, $ PPPM795935,767+297%+294%, +301%925636,766
      ALOS, average length of stay; CCI, Charlson Comorbidity Index; ICU, intensive care unit; OR, odds ratio; PPPM, per patient per month.
      Outcomes for decedents vs survivors were adjusted for age; sex; race; census region; Medicare-Medicaid dual eligibility; original reason for Medicare entitlement; CCI; presence of each CCI condition in the 12 months prior to index date; presence of other conditions (Crohn disease, ulcerative colitis) and frailty (abnormality of gait, abnormal weight loss, failure to thrive, debility, difficulty walking, risk of falls, muscle weakness, pressure ulcer); and selected conditions in prior 12 months (transplants, gastrointestinal surgery, enteral feeding, chemotherapy). Inpatient hospitalizations and ICU stay were adjusted with logit model; ALOS and total cost were adjusted with gamma-distributed generalized linear model with log link. Outcome adjustments were made using SAS/STAT LSMEANS. Supplementary Table 10, Supplementary Table 6, Supplementary Table 7, Supplementary Table 8, Supplementary Table 9 provide details on additional baseline characteristics.
      CDI cohorts: pCDI: patients with primary CDI only; rCDI: patients with recurrent CDI during a follow-up period of up to 12 months.
      Supplementary Table 12 provides details on additional follow-up unadjusted outcomes.
      § All adjusted odds ratios and percentage changes are significantly different from 1 (odds ratios) or 0 (percent changes, with P < .001).
      Adjusted mean calculated at mean of covariates other than whether survivor or decedent.
      ∗∗ Total cost (sum of Medicare program payments plus patient responsibility) inflation-adjusted to 2018.

      Discussion

      CDI is associated with relatively high mortality among Medicare beneficiaries aged ≥65 years, between 35% and 45% within 1 year of a first CDI episode.
      Centers for Disease Control and PreventionNational Center for Health Statistics
      Underlying cause of death 1999-2019 on CDC WONDER Online Database, released in 2020. Data are from the multiple cause of death files, 1999-2019, as compiled from data provided by the 57 vital statistics jurisdictions through the Vital Statistics Cooperative Program. Accessed August 31, 2021.
      With the probability of any recurrence after initial infection of approximately 35%,
      • Cubanski J.
      • Neuman T.
      • Griffin S.
      • Damico A.
      Medicare Spending at the End of Life: A Snapshot of Beneficiaries Who Died in 2014 and the Cost of Their Care.
      and our study showing that each recurrence brings additional CDI-attributable mortality risk, we now have a better understanding of the concerning associated risks of recurrent disease in older adults. Here, the CDI-associated mortality rate increased substantially from 2.7% for patients who had only a primary CDI episode, to 25% for patients who had 1 or more recurrences, providing yet another reason to be particularly attentive to prevention, identification, and appropriate (rather than overly conservative) treatment, to break the vicious cycle of recurrent CDI and its burden on the health care system and patients' lives. Our study interestingly also shows that, of those who died following CDI, most of the deaths occurred after primary CDI within a few weeks of CDI diagnosis, with few deaths in the primary CDI cohort that were associated with CDI itself (eg, 2.7%). This implies that those decedents with only a primary CDI episode were likely severely ill with another disease and CDI was a complication of that; their deaths may have been due to factors that increased the risk of both death and CDI. Therefore, clinicians should consider CDI as a potential indicator of short-term mortality risk and consider care goals appropriately. The background mortality rates of this older population may have partially obscured the mortality trends over the follow-up period. Future research with more precise cause of death data could elicit further insights.
      CDI is also costly in older adults, especially if it occurs during the last year of life. On average, Medicare spends about $1300 per month, per beneficiary across the entire Medicare population.
      2021 annual report of the boards of trustees of the federal hospital insurance and federal supplementary medical insurance trust funds. Accessed August 31, 2021.
      In the last 3 months of life, the average per-patient per-month cost of care in the national Medicare population increases to approximately $10,400 per Medicare beneficiary, based on 2016 costs.
      • Duncan I.
      • Ahmed T.
      • Dove H.
      • Maxwell T.L.
      Medicare cost at end of life.
      Here, we documented average per-patient per-month costs of $29,000 to almost $36,000 for patients who experienced primary CDI only or recurrent CDI, respectively, who had an average of 2.5 months of follow-up after the first CDI event.
      This study was designed to estimate the real-world differences in HRU and total cost outcomes in older Medicare beneficiaries, between decedents and survivors of primary and recurrent CDI. This approach has not been a previous focus of the literature. Our study extends existing research by measuring how mortality may modulate these outcomes following a CDI episode, vs analyzing mortality separately from other outcomes, as is more common in the literature.
      • Guh A.Y.
      • Mu Y.
      • Winston L.G.
      • et al.
      Trends in U.S. burden of Clostridioides difficile infection and outcomes.
      ,
      • Ramai D.
      • Dang-Ho K.P.
      • Lewis C.
      • et al.
      Clostridioides difficile infection in US hospitals: a national inpatient sample study.
      ,
      • Nelson W.W.
      • Scott T.A.
      • Boules M.
      • et al.
      Healthcare resource utilization and costs of recurrent Clostridioides difficile infection in the elderly: a real-world claims analysis.
      ,
      • Rodrigues R.
      • Barber G.E.
      • Ananthakrishnan A.N.
      A comprehensive study of costs associated with recurrent Clostridium difficile infection.
      ,
      • Drozd E.M.
      • Inocencio T.J.
      • Braithwaite S.
      • et al.
      Mortality, hospital costs, payments, and readmissions associated with Clostridium difficile infection among Medicare beneficiaries.
      • Appaneal H.J.
      • Caffrey A.R.
      • Beganovic M.
      • Avramovic S.
      • LaPlante K.L.
      Predictors of mortality among a national cohort of Veterans with recurrent Clostridium difficile infection.
      • Olsen M.A.
      • Yan Y.
      • Reske K.A.
      • Zilberberg M.D.
      • Dubberke E.R.
      Recurrent Clostridium difficile infection is associated with increased mortality.
      • Pechal A.
      • Lin K.
      • Allen S.
      • Reveles K.
      National age group trends in Clostridium difficile infection incidence and health outcomes in United States community hospitals.
      • Balsells E.
      • Shi T.
      • Leese C.
      • et al.
      Global burden of Clostridium difficile infections: a systematic review and meta-analysis.
      ,
      • Zilberberg M.D.
      • Shorr A.F.
      • Wang L.
      • Baser O.
      • Yu H.
      Development and validation of a risk score for Clostridium difficile infection in Medicare beneficiaries: a population-based cohort study.
      It also includes patients with community-acquired CDI, which has been less studied in the literature that often solely focuses on hospital-acquired infections.
      • Cho J.M.
      • Pardi D.S.
      • Khanna S.
      Update on treatment of Clostridioides difficile infection.
      In general, older patients are more at risk for CDI; therefore, the 100% Medicare sample is a particularly useful population in which to understand the broader impact of CDI in older adults.
      The demographics and baseline characteristics of our CDI cohorts are broadly similar to those found in other studies of patients who suffer CDI,
      • Guh A.Y.
      • Mu Y.
      • Winston L.G.
      • et al.
      Trends in U.S. burden of Clostridioides difficile infection and outcomes.
      ,
      • Ramai D.
      • Dang-Ho K.P.
      • Lewis C.
      • et al.
      Clostridioides difficile infection in US hospitals: a national inpatient sample study.
      ,
      • Shorr A.F.
      • Zilberberg M.D.
      • Wang L.
      • Baser O.
      • Yu H.
      Mortality and costs in Clostridium difficile infection among the elderly in the United States.
      • Drozd E.M.
      • Inocencio T.J.
      • Braithwaite S.
      • et al.
      Mortality, hospital costs, payments, and readmissions associated with Clostridium difficile infection among Medicare beneficiaries.
      • Appaneal H.J.
      • Caffrey A.R.
      • Beganovic M.
      • Avramovic S.
      • LaPlante K.L.
      Predictors of mortality among a national cohort of Veterans with recurrent Clostridium difficile infection.
      ,
      • Pechal A.
      • Lin K.
      • Allen S.
      • Reveles K.
      National age group trends in Clostridium difficile infection incidence and health outcomes in United States community hospitals.
      ,
      • Nour Abou Chakra C.
      • Pepin J.
      Risk factors for recurrence, complications and mortality in Clostridium difficile infection: a systematic review.
      ,
      • Cubanski J.
      • Neuman T.
      • Griffin S.
      • Damico A.
      Medicare Spending at the End of Life: A Snapshot of Beneficiaries Who Died in 2014 and the Cost of Their Care.
      including being more likely to be female, and more likely to be dual eligible for Medicaid (indicating low income) compared to all older Medicare FFS beneficiaries. Compared with other studies that often look at the general adult population (≥18 years) who suffer CDI and to the national Medicare population, our Medicare population had more chronic conditions, including congestive heart failure, chronic obstructive pulmonary disease, diabetes, peripheral vascular disease, and renal disease.
      • Nelson W.W.
      • Scott T.A.
      • Boules M.
      • et al.
      Healthcare resource utilization and costs of recurrent Clostridioides difficile infection in the elderly: a real-world claims analysis.
      ,
      • Appaneal H.J.
      • Caffrey A.R.
      • Beganovic M.
      • Avramovic S.
      • LaPlante K.L.
      Predictors of mortality among a national cohort of Veterans with recurrent Clostridium difficile infection.
      ,
      • Cubanski J.
      • Neuman T.
      • Griffin S.
      • Damico A.
      Medicare Spending at the End of Life: A Snapshot of Beneficiaries Who Died in 2014 and the Cost of Their Care.
      The risk factors we identified that were associated with a greater risk of mortality from CDI (eg, age, comorbid conditions, and recent post-acute care) were consistent with other studies,
      • Appaneal H.J.
      • Caffrey A.R.
      • Beganovic M.
      • Avramovic S.
      • LaPlante K.L.
      Predictors of mortality among a national cohort of Veterans with recurrent Clostridium difficile infection.
      and those factors were similar for both primary and recurrent CDI cohorts. These risk factors, importantly, have also been shown to increase the risk of primary and recurrent CDI.
      • Nelson W.W.
      • Scott T.A.
      • Boules M.
      • et al.
      Healthcare resource utilization and costs of recurrent Clostridioides difficile infection in the elderly: a real-world claims analysis.
      ,
      Centers for Disease Control and Prevention
      Clostridioides difficile Infection (CDI) Tracking. Accessed March 26, 2021.
      ,
      • Zilberberg M.D.
      • Shorr A.F.
      • Wang L.
      • Baser O.
      • Yu H.
      Development and validation of a risk score for Clostridium difficile infection in Medicare beneficiaries: a population-based cohort study.
      ,
      • Donskey C.J.
      Clostridium difficile in older adults.
      ,
      • Davies K.
      • Lawrence J.
      • Berry C.
      • et al.
      Risk factors for primary Clostridium difficile infection; results from the observational study of risk factors for Clostridium difficile infection in hospitalized patients with infective diarrhea (ORCHID).
      Therefore, the cycle of recurrence, potentially ending in death, feeds on itself with the same risk factors. It is essential for clinicians to understand these risk factors, modify those they can, and aggressively try to break the cycle of recurrence with therapeutics available to them, including emerging therapies such as bezlotoxumab and fecal microbiota transplantation.
      All decedents (primary and recurrent cohorts) had greater rates of hospitalization after the index CDI episode than survivors, likely indicating that they suffered from more severe CDI. ICU use and readmissions were also more common among recurrent CDI decedents than survivors; however, this was not the case for patients with primary CDI, for which the utilization of decedents and survivors were similar. Although this may be due in part to the shorter follow-up period (because of higher all-cause mortality) for primary vs recurrent CDI, the higher readmission rate among decedents vs survivors with recurrent CDI suggests that recurrence increases the risk of having a severe or fulminant case, further increasing mortality and HRU.
      • Cho J.M.
      • Pardi D.S.
      • Khanna S.
      Update on treatment of Clostridioides difficile infection.
      Survivors' greater use of outpatient facilities, EDs, and home health is likely due to decedents having shorter follow-up time to use these services. A similar reason may underlie why decedents with recurrent CDI had increased use of skilled nursing facilities compared to decedents with primary CDI only. Using a skilled nursing facility may indicate worse health status or may confer an increased risk of health care–acquired infection, and the relatively short follow-up for decedents with primary CDI only makes them less likely to survive to the point of being admitted to a skilled nursing facility (eg, if they expire in an acute setting). Coinciding with greater HRU, the costs for acute hospital and post-acute care stays were substantially higher for decedents than survivors. These were largely driven by differences in acute hospital costs, but among patients with recurrent CDI, costs for post-acute care and outpatient services also contributed to the difference. These data continue to support the idea that those who died did not have the opportunity to utilize certain services during follow-up, but they were acutely sicker and required acute expensive interventions in the efforts to keep them alive.
      The strengths of this study include the large sample (all Medicare FFS beneficiaries aged ≥65 years with CDI during the study period) as well as the longitudinal nature of these claims data that capture utilization and costs across a variety of health care settings. However, features of the Medicare claims data may limit the generalizability of results. Because the study focuses on older Medicare FFS beneficiaries, excluding those in private Medicare health plans, younger patients, or those covered by other insurance such as commercial, Medicaid only, or Veterans Affairs, the results may not be representative of those populations. However, these results are consistent with studies of CDI mortality in Veterans Affairs facilities.
      • Shorr A.F.
      • Zilberberg M.D.
      • Wang L.
      • Baser O.
      • Yu H.
      Mortality and costs in Clostridium difficile infection among the elderly in the United States.
      Medicare claims indicate costs that are the patient's responsibility but not who ultimately pays those charges, which could be paid by the patient out of pocket or covered by Medicare supplemental insurance. Furthermore, long-term care in a skilled nursing facility is not covered by Medicare; we lose insight into costs beyond 100 days, the length covered by Medicare. This study can only identify associations in cost and utilization differences between survivors and decedents, not specific causal relationships; however, the adjusted outcomes do account for many clinical and social confounders. Future studies could be conducted to explore longitudinal patterns of CDI episodes and long-term health outcomes in the Medicare population.

      Conclusions and Implications

      This study found that CDI-related mortality rates among older Medicare beneficiaries were almost 10 times higher for patients who experienced recurrent CDI relative to patients who experienced primary CDI only. Each recurrence brought additional risk for death attributable to CDI. Along with high mortality, CDI is associated with high cost and health care utilization near the end of life. We believe that advances in therapeutic options to reduce recurrent CDI can potentially ease the economic, physical, and mortality burden among the frail older population.

      Supplementary Data

      Supplementary Table 1Clinical Codes to Identify CDI-related Claims
      Medical Diagnoses, Procedures, and TreatmentsICD-9-CM CodeICD-9-CM Procedure CodeICD-10 CM CodeICD-10-PCS CodeCPT CodeHCPCS Code
      Clostridioides difficile infection008.45A04.7, A04.71, A04.72
      Fecal microbiota transplantation44705, 44799G0455
      Chronic pulmonary disease490.xx-496.99; 500.xx-505.99; 506.4xJ40, J41, J42, J43, J44, J45, J46, J47, J60, J61, J62, J63, J64, J65, J66, J67, I278, I279, J684, J701, J703
      Cerebrovascular disease430.xx-438.99G45, G46, I60, I61, I62, I63, I64, I65, I66, I67, I68, I69, H340
      Diabetes250.0x-250.39, 250.7x, 250.4x-250.69E100, E101, E106, E108, E109, E110, E111, E116, E118, E119, E120, E121, E126, E128, E129, E130, E131, E136, E138, E139, E140, E141, E146, E148, E149, E102, E103, E104, E105, E107, E112, E113, E114, E115, E117, E122, E123, E124, E125, E127, E132, E133, E134, E135, E137, E142, E143, E144, E145, E147
      Congestive heart failure428.xxI43, I50, I099, I110, I130, I132, I255, I420, I425, I426, I427, I428, I429, P290
      Peripheral vascular disease441.xx; 443.9x; 785.4x; v43.4xI70, I71, I731, I738, I739, I771, I790, I792, K551, K558, K559, Z958, Z959
      Renal disease582.xx; 583.0x-583.79; 585.xx-586.99; 588.xxN18, N19, N052, N053, N054, N055, N056, N057, N250, I120, I131, N032, N033, N034, N035, N036, N037, Z490, Z491, Z492, Z940, Z992
      Gastrointestinal surgery43.xx-54.xx0D1∗-0DY∗43500-46999
      Chemotherapy963.1, V58.0x, V58.1x, V58.65, V58.6999.25, 99.28, 00.10, 00.15, 17.70Z51.11, Z51.12, T45.1X1A3E00X05, 3E00X0M, 3E01305, 3E0130M, 3E02305, 3E0230M, 3E03002, 3E03003, 3E03005, 3E0300M, 3E0300P, 3E03302, 3E03303, 3E03305, 3E0330M, 3E0330P, 3E04002, 3E04002, 3E04003, 3E04003, 3E04005, 3E04005, 3E0400M, 3E0400M, 3E0400P, 3E0400P, 3E04302, 3E04303, 3E04303, 3E04305, 3E04305, 3E0430M, 3E0430M, 3E0430P, 3E0430P, 3E05002, 3E05002, 3E05003, 3E05003, 3E05005, 3E05005, 3E0500M, 3E0500M, 3E0500P, 3E0500P, 3E05302, 3E05303, 3E05303, 3E05305, 3E05305, 3E0530M, 3E0530M, 3E0530P, 3E0530P, 3E06002, 3E06003, 3E06005, 3E0600M, 3E0600P, 3E06303, 3E06305, 3E0630M, 3E0630P, 3E0930M, 3E09705, 3E0970M, 3E09X05, 3E09X0M, 3E0A305, 3E0A30M, 3E0B305, 3E0B30M, 3E0B705, 3E0B70M, 3E0BX05, 3E0BX0M, 3E0C305, 3E0C30M, 3E0C705, 3E0C70M, 3E0CX05, 3E0CX0M, 3E0D305, 3E0D30M, 3E0D705, 3E0D70M, 3E0DX05, 3E0DX0M, 3E0E305, 3E0E30M, 3E0E705, 3E0E70M, 3E0E805, 3E0E80M, 3E0F305, 3E0F30M, 3E0F705, 3E0F70M, 3E0F805, 3E0F80M, 3E0G305, 3E0G30M, 3E0G705, 3E0G70M, 3E0G805, 3E0G80M, 3E0H305, 3E0H30M, 3E0H705, 3E0H70M, 3E0H805, 3E0H80M, 3E0J305, 3E0J30M, 3E0J705, 3E0J70M, 3E0J805, 3E0J80M, 3E0K305, 3E0K30M, 3E0K705, 3E0K70M, 3E0K805, 3E0K80M, 3E0L305, 3E0L30M, 3E0L705, 3E0L70M, 3E0M305, 3E0M30M, 3E0M705, 3E0M70M, 3E0N305, 3E0N30M, 3E0N705, 3E0N70M, 3E0N805, 3E0N80M, 3E0P305, 3E0P30M, 3E0P705, 3E0P70M, 3E0P805, 3E0P80M, 3E0Q005, 3E0Q00M, 3E0Q305, 3E0Q30M, 3E0Q705, 3E0Q70M, 3E0R302, 3E0R303, 3E0R305, 3E0R30M, 3E0S303, 3E0S305, 3E0S30M, 3E0U305, 3E0U30M, 3E0V305, 3E0V30M, 3E0W305, 3E0W30M, 3E0Y305, 3E0Y30M, 3E0Y705, 3E0Y70M, 3E04302, 3E05302, 3E06302, 3E06305, 3E09305, 3E0S302, XW03351, XW033B3, XW033C3, XW04351, XW043B3, XW043C396400-96549Q0083- Q0085
      TransplantV42.xx, 996.8x11.6x, 33.5∗, 33.6, 37.51, 41.0∗, 46.97, 50.5∗, 52.8∗, 55.6∗Z94∗ Z48.2xx, T86.∗02YA, 02YA0, 02YA0Z, 02YA0Z0, 02YA0Z1, 02YA0Z2, 07YM, 07YM0, 07YM0Z, 07YM0Z0, 07YM0Z1, 07YM0Z2, 07YP, 07YP0, 07YP0Z, 07YP0Z0, 07YP0Z1, 07YP0Z2, 0BYC, 0BYC0, 0BYC0Z, 0BYC0Z0, 0BYC0Z1, 0BYC0Z2, 0BYD, 0BYD0, 0BYD0Z, 0BYD0Z0, 0BYD0Z1, 0BYD0Z2, 0BYF, 0BYF0, 0BYF0Z, 0BYF0Z0, 0BYF0Z1, 0BYF0Z2, 0BYG, 0BYG0, 0BYG0Z, 0BYG0Z0, 0BYG0Z1, 0BYG0Z2, 0BYH, 0BYH0, 0BYH0Z, 0BYH0Z0, 0BYH0Z1, 0BYH0Z2, 0BYJ, 0BYJ0, 0BYJ0Z, 0BYJ0Z0, 0BYJ0Z1, 0BYJ0Z2, 0BYK, 0BYK0, 0BYK0Z, 0BYK0Z0, 0BYK0Z1, 0BYK0Z2, 0BYL, 0BYL0, 0BYL0Z, 0BYL0Z0, 0BYL0Z1, 0BYL0Z2, 0BYM, 0BYM0, 0BYM0Z, 0BYM0Z0, 0BYM0Z1, 0BYM0Z2, 0DY5, 0DY50, 0DY50Z, 0DY50Z0, 0DY50Z1, 0DY50Z2, 0DY6, 0DY60, 0DY60Z, 0DY60Z0, 0DY60Z1, 0DY60Z2, 0DY8, 0DY80, 0DY80Z, 0DY80Z0, 0DY80Z1, 0DY80Z2, 0DYE, 0DYE0, 0DYE0Z, 0DYE0Z0, 0DYE0Z1, 0DYE0Z2, 0FY0, 0FY00, 0FY00Z, 0FY00Z0, 0FY00Z1, 0FY00Z2, 0FYG, 0FYG0, 0FYG0Z, 0FYG0Z0, 0FYG0Z1, 0FYG0Z2, 0TY0, 0TY00, 0TY00Z, 0TY00Z0, 0TY00Z1, 0TY00Z2, 0TY1, 0TY10, 0TY10Z, 0TY10Z0, 0TY10Z1, 0TY10Z2, 0UY0, 0UY00, 0UY00Z, 0UY00Z0, 0UY00Z1, 0UY00Z2, 0UY1, 0UY10, 0UY10Z, 0UY10Z0, 0UY10Z1, 0UY10Z2, 0UY9, 0UY90, 0UY90Z, 0UY90Z0, 0UY90Z1, 0UY90Z2, 0WY2, 0WY20, 0WY20Z, 0WY20Z0, 0WY20Z1, 0XYJ, 0XYJ0, 0XYJ0Z, 0XYJ0Z0, 0XYJ0Z1, 0XYK, 0XYK0, 0XYK0Z, 0XYK0Z0, 0XYK0Z1, 30230A, 30230AZ, 30230G, 30230G0, 30230G2, 30230G3, 30230G4, 30230X, 30230X0, 30230X2, 30230X3, 30230X4, 30230Y, 30230Y0, 30230Y2, 30230Y3, 30230Y4, 30233A, 30233AZ, 30233G, 30233G0, 30233G2, 30233G3, 30233G4, 30233X, 30233X0, 30233X2, 30233X3, 30233X4, 30233Y, 30233Y0, 30233Y2, 30233Y3, 30233Y4, 30240A, 30240AZ, 30240G, 30240G0, 30240G2, 30240G3, 30240G4, 30240X, 30240X0, 30240X2, 30240X3, 30240X4, 30240Y, 30240Y0, 30240Y2, 30240Y3, 30240Y4, 30243A, 30243AZ, 30243G, 30243G0, 30243G2, 30243G3, 30243G4, 30243X, 30243X0, 30243X2, 30243X3, 30243X4, 30243Y, 30243Y0, 30243Y2, 30243Y3, 30243Y4, 30250G, 30250G0, 30250G1, 30250X, 30250X0, 30250X1, 30250Y, 30250Y0, 30250Y1, 30253G, 30253G0, 30253G1, 30253X, 30253X0, 30253X1, 30253Y, 30253Y0, 30253Y1, 30260G, 30260G0, 30260G1, 30260X, 30260X0, 30260X1, 30260Y, 30260Y0, 30260Y1, 30263G, 30263G0, 30263G1, 30263X, 30263X0, 30263X1, 30263Y, 30263Y0, 30263Y1, 3E03305, 3E04305, 3E0530532851, 32852, 32853, 32854, 33935, 33945, 38240, 38241, 38242, 38243, 44135, 44136, 47135, 47136, 48160, 48554, 50360, 50365, 50380, 65710, 65730, 65750, 65755, 65756S2053, S2054, S2060, G0341, G0342, G0343, S2102, S2103, S2142, S2150
      CDI, Clostridioides difficile infection; CPT, Common Procedural Terminology; HCPCS, Healthcare Common Procedure Coding System; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modifications; ICD-10-CM, International Classification of Diseases, Tenth Revision, Clinical Modifications.
      Supplementary Table 2Top 20 ICD-10-CM Diagnosis Codes on Claim Proximal to Decedents' Dates of Death
      For in-hospital deaths, based on the primary and secondary diagnosis fields documented on the hospital discharge claim. For other deaths, based on the primary and secondary diagnoses from the most proximal visit to the date of death.
      (excluding CDI-Related Diagnoses), Primary CDI
      Diagnosis RankICD-10-CMDescriptionNumber of EpisodesPercentage of Episodes
      Total154,580100
       1A419Sepsis, unspecified organism31,22920.2
       2J9600Acute respiratory failure, unspecified whether with hypoxia or hypercapnia16,68110.8
       3J189Pneumonia, unspecified organism10,9427.1
       4I509Heart failure, unspecified95956.2
       5I469Cardiac arrest, cause unspecified95666.2
       6R6521Severe sepsis with septic shock81135.2
       7N186End-stage renal disease77325.0
       8J449Chronic obstructive pulmonary disease, unspecified62244.0
       9J690Pneumonitis due to inhalation of food and vomit61364.0
       10N179Acute kidney failure, unspecified57783.7
       11R5381Other malaise41862.7
       12Z5189Encounter for other specified aftercare41662.7
       13J9620Acute and chronic respiratory failure, unspecified whether with hypoxia or hypercapnia41442.7
       14I10Essential (primary) hypertension37502.4
       15G309Alzheimer's disease, unspecified36242.3
       16F0390Unspecified dementia without behavioral disturbance33612.2
       17N390Urinary tract infection, site not specified32922.1
       18C3490Malignant neoplasm of unspecified part of unspecified bronchus or lung31122.0
       19R627Adult failure to thrive30472.0
       20I4891Unspecified atrial fibrillation27381.8
      CDI, Clostridioides difficile infection; ICD-10-CM, International Classification of Diseases, Tenth Revision, Clinical Modifications.
      For in-hospital deaths, based on the primary and secondary diagnosis fields documented on the hospital discharge claim. For other deaths, based on the primary and secondary diagnoses from the most proximal visit to the date of death.
      Supplementary Table 3Top 20 ICD-10-CM Diagnosis Codes on Claim Proximal to Decedents' Dates of Death
      For in-hospital deaths, based on the primary and secondary diagnosis fields documented on the hospital discharge claim. For other deaths, based on the primary and secondary diagnoses from the most proximal visit to the date of death.
      (excluding CDI-Related Diagnoses), Recurrent CDI
      Diagnosis RankICD-10-CMDescriptionNumber of EpisodesPercentage of Episodes
      Total40,169100
       1A419Sepsis, unspecified organism740218.4
       2J9600Acute respiratory failure, unspecified whether with hypoxia or hypercapnia414910.3
       3N186End-stage renal disease32588.1
       4I469Cardiac arrest, cause unspecified30147.5
       5I509Heart failure, unspecified27266.8
       6J189Pneumonia, unspecified organism25256.3
       7R6521Severe sepsis with septic shock19975.0
       8J449Chronic obstructive pulmonary disease, unspecified17584.4
       9J690Pneumonitis due to inhalation of food and vomit15123.8
       10J9620Acute and chronic respiratory failure, unspecified whether with hypoxia or hypercapnia13433.3
       11R5381Other malaise12203.0
       12N179Acute kidney failure, unspecified10532.6
       13I10Essential (primary) hypertension9712.4
       14G309Alzheimer's disease, unspecified9532.4
       15Z5189Encounter for other specified aftercare9482.4
       16N390Urinary tract infection, site not specified8812.2
       17F0390Unspecified dementia without behavioral disturbance8722.2
       18I4891Unspecified atrial fibrillation8182.0
       19R627Adult failure to thrive8112.0
       20I2510Atherosclerotic heart disease of native coronary artery without angina pectoris7201.8
      CDI, Clostridioides difficile infection; ICD-10-CM, International Classification of Diseases, Tenth Revision, Clinical Modifications.
      For in-hospital deaths, based on the primary and secondary diagnosis fields documented on the hospital discharge claim. For other deaths, based on the primary and secondary diagnoses from the most proximal visit to the date of death.
      Supplementary Table 4Average Follow-up (Days), by Type of CDI Episode
      CDI TypeSurvivorsDecedentsRatio, Survivors vs Decedents% Difference, Survivors vs Decedents
      All352.977.24.6+357
      Primary351.963.25.6+457
      Recurrent354.8118.43.0+200
      CDI, Clostridioides difficile infection.
      Supplementary Table 5Selected Baseline Characteristics Among Decedents With Primary or Recurrent CDI
      Any recurrent CDI during a follow-up period of 12 months.
      , by Relatedness of Mortality
      Deaths are considered CDI-associated if the most proximal health care visit to date of death was with CDI as the primary or secondary diagnosis.
      ,
      Supplemental Tables 6–10 provide details on additional baseline characteristics.
      Baseline CharacteristicPrimary CDIRecurrent CDI
      CDI-AssociatedNot AssociatedCDI-AssociatedNot Associated
      Mean age, y81.781.581.480.1
      Age group, %
       65-74 y22.224.323.729.6
       75-84 y37.336.137.737.2
       ≥85 y40.539.738.633.1
      Sex, %
       Female64.061.664.359.6
       Male36.038.435.740.4
      Race, %
       White87.282.886.981.3
       Black8.311.88.913.4
       Other4.55.34.25.3
      Medicare-Medicaid dual eligibility status, %
       Nondual63.259.361.853.4
       Dual36.840.738.246.6
      Mean CCI6.77.26.77.3
      Top-5 comorbid medical conditions
      Top 5 conditions are the 5 individual CCI conditions most prevalent among all CDI patients.
      , %
       Congestive heart failure59.366.061.566.7
       Chronic obstructive pulmonary disease58.862.461.763.2
       Diabetes without complications49.252.749.556.8
       Peripheral vascular disease52.855.852.957.8
       Renal disease51.755.752.558.7
      0-6-mo baseline HRU, %
       Acute hospitalization71.872.877.075.3
       Emergency department46.640.846.642.3
       Outpatient98.598.098.798.5
       Long term care hospital4.49.24.39.7
       Inpatient rehabilitation facility7.75.87.46.8
       Skilled nursing facility42.549.147.650.3
       Home health agency43.339.045.639.9
       Hospice1.32.31.11.7
      0-6-mo baseline PPPM cost
      0-6-month baseline per-patient per-month (PPPM) cost computed as the cost (Medicare program payments plus beneficiary responsibility) for each service setting for the 6-month period immediately prior to the index CDI event, divided by 6 months.
      ($)
       Total888910,547954812,110
       Acute hospitalization2937361832934212
       Emergency department183155178160
       Outpatient791743817915
       Long-term care hospital336861306935
       Inpatient rehabilitation facility259205261243
       Skilled nursing facility1191145714131714
       Home health agency285257284256
       Hospice21361728
       Physician services and tests2097250222222822
       DME242225242285
       Pharmacy548489515539
      CCI, Charlson Comorbidity Index; CDI, Clostridioides difficile infection; DME, durable medical equipment; HRU, health care resource utilization.
      Any recurrent CDI during a follow-up period of 12 months.
      Deaths are considered CDI-associated if the most proximal health care visit to date of death was with CDI as the primary or secondary diagnosis.
      § Top 5 conditions are the 5 individual CCI conditions most prevalent among all CDI patients.
      0-6-month baseline per-patient per-month (PPPM) cost computed as the cost (Medicare program payments plus beneficiary responsibility) for each service setting for the 6-month period immediately prior to the index CDI event, divided by 6 months.
      Supplementary Table 6Baseline Patient Characteristics
      Patient Characteristics (12-mo Baseline)Primary CDIRecurrent CDI
      Survivors (n = 186,996)Decedents (n = 158,897)% Change, or OR
      Values are ORs (decedents vs survivors) unless otherwise indicated as a difference (Δ).
      Survivors (n = 97,738)Decedents (n = 53,858)% Change, or OR
      Values are ORs (decedents vs survivors) unless otherwise indicated as a difference (Δ).
      Age at index date, y
       Mean78.481.5Δ = +3.178.080.4Δ = +2.4
       SD8.028.497.948.38
       Age group: 65-74 y36.524.20.5638.428.10.63
       Age group: 75-84 y38.436.10.9138.337.40.96
       Age group: ≥85 y25.139.71.9623.334.51.73
      Gender
       Female68.961.70.7368.360.80.72
       Male31.138.31.3831.739.21.39
      Race
       White86.782.90.7488.382.70.63
       Black8.911.71.377.812.21.65
       Hispanic or Latino2.22.61.182.02.61.30
       Asian1.62.21.351.31.91.46
       Native American0.60.50.920.60.50.95
       Unknown1.31.41.041.31.41.08
      Census region
       Northeast21.122.91.1122.022.71.04
       Midwest25.223.70.9227.425.10.89
       South38.138.41.0135.337.51.10
       West15.615.10.9615.414.80.95
       Unknown0.40.10.140.10.00.25
      Census division
       East North Central17.617.50.9918.918.60.98
       East South Central7.16.90.976.26.41.04
       Middle Atlantic15.017.21.1814.816.61.14
       Mountain5.04.00.805.24.10.79
       New England6.05.60.947.16.10.85
       Pacific10.611.01.0510.110.61.05
       South Atlantic20.520.81.0219.620.11.03
       West North Central7.56.10.808.46.50.76
       West South Central10.410.71.039.410.91.18
       Unknown0.40.10.140.10.00.25
      Dual eligible (Medicaid) status
       Nondual64.659.40.8067.155.50.61
       Dual35.440.61.2532.944.51.63
       Unknown0.30.00.000.10.00.00
      OREC
       Age80.882.31.1080.280.10.99
       Disability and/or ESRD19.217.70.9119.819.91.01
      CCI
       Mean5.037.16Δ = +2.15.207.19Δ = +2.0
       SD3.393.613.453.58
       Score: 06.10.60.095.80.80.13
       Score: 18.72.50.278.22.40.27
       Score: 211.15.00.4210.54.90.44
       Score: 312.07.60.6011.67.50.62
       Score: 411.79.50.7911.39.10.78
       Score: 510.810.81.0010.710.40.97
       Score: 69.311.01.219.410.81.18
       Score: ≥730.553.02.5832.654.12.44
      CCI conditions
       Myocardial infarction18.227.11.6618.926.61.56
       Congestive heart failure43.465.82.5144.465.42.36
       Peripheral vascular disease43.055.71.6744.056.51.65
       Cerebrovascular disease38.350.31.6338.750.21.60
       Dementia18.832.92.1217.530.92.11
       Chronic obstructive pulmonary disease49.562.31.6950.262.81.68
       Rheumatologic disease9.99.60.9610.310.31.00
       Peptic ulcer disease7.18.91.267.09.01.32
       Mild liver disease13.317.11.3414.817.41.22
       Moderate/severe liver disease1.63.32.142.13.51.69
       Diabetes without complications45.552.61.3345.054.91.49
       Diabetes with complications22.526.91.2723.330.51.45
       Hemiplegia or paraplegia6.79.41.457.09.91.46
       Renal disease37.955.62.0541.357.11.89
       Malignancy22.631.41.5723.530.81.45
       Metastatic solid tumor5.012.42.685.210.92.24
       HIV/AIDS0.30.31.190.30.31.15
      Autoimmune conditions
       Ulcerative colitis5.14.80.956.35.20.81
       Crohn disease2.21.60.702.41.70.73
       Celiac disease0.10.00.600.10.00.37
       Type 1 diabetes12.315.91.3412.918.51.52
      Other comorbid conditions
       Psoriasis/psoriatic arthritis1.81.50.832.01.70.84
       Multiple sclerosis0.90.80.911.00.90.84
       Lupus1.00.90.861.11.10.99
       Addison disease0.20.20.940.20.21.02
       Graves' disease0.60.60.970.60.61.10
       Sjogren syndrome0.70.50.680.80.50.65
       Hashimoto thyroiditis0.10.10.420.10.10.44
       Myasthenia gravis0.10.10.820.10.00.60
       Vasculitis0.60.71.140.70.81.20
       Pernicious anemia2.73.21.192.73.31.27
       Renal insufficiency33.337.61.2135.438.41.14
       Smoking/history of smoking7.15.30.737.44.90.64
      Indicators of frailty
       Abnormality of gait29.638.31.4830.939.11.43
       Abnormal weight loss15.832.62.5817.631.22.12
       Adult failure to thrive5.213.22.765.511.52.23
       Cachexia0.30.72.040.30.51.34
       Debility17.728.71.8718.928.91.74
       Difficulty in walking24.534.81.6426.235.51.55
       Fall15.421.31.4915.921.01.41
       Muscular wasting and atrophy2.53.21.292.83.41.21
       Muscle weakness34.951.82.0137.152.11.84
       Pressure ulcer12.026.22.6113.026.42.39
       Senility without psychosis1.72.81.671.62.41.52
       Durable medical equipment12.014.01.2013.415.41.17
      Medical procedures
       Transplants1.42.41.696.25.20.84
       Gastrointestinal surgery29.932.81.1531.034.31.16
       Enteral feeding3.98.42.274.39.22.23
       Chemotherapy43.751.41.3646.954.21.34
      CCI, Charlson Comorbidity Index; CDI, Clostridioides difficile infection; ESRD, end-stage renal disease; OR, odds ratio; OREC, original reason for entitlement code.
      Unless otherwise noted, values are percentages.
      Values are ORs (decedents vs survivors) unless otherwise indicated as a difference (Δ).
      Supplementary Table 7Baseline Health Resource Utilization: 0-6 Months Baseline
      MeasurePrimary CDIRecurrent CDI
      Survivors (n = 186,996)Decedents (n = 158,897)% Change, or OR
      Values are ORs (decedents vs survivors) unless otherwise indicated as a difference (Δ).
      Survivors (n = 97,738)Decedents (n = 53,858)% Change, or OR
      Values are ORs (decedents vs survivors) unless otherwise indicated as a difference (Δ).
      Acute hospital
       Utilization, %53.872.8OR = 2.3060.675.8OR = 2.04
       Stays
      Mean1.61.9+161.72.0+15
      SD1.01.11.01.2
      Median1.02.01.02.0
       Days
      Mean11.415.0+3212.215.6+28
      SD12.614.212.915.7
      Median8.011.08.011.0
       ALOS, d
      Mean7.08.1+167.18.1+14
      SD7.57.87.29.2
      Median5.06.05.06.0
      ICU
       Days
      Mean12.615.3+2113.616.3+20
      SD12.915.714.318.4
      Median9.011.09.011.0
      Emergency department
       Utilization, %40.041.0OR = 1.0442.743.4OR = 1.03
       Visits
      Mean2.02.0+12.02.0+2
      SD1.71.61.71.6
      Median1.01.01.02.0
      Hospital outpatient
       Utilization, %98.198.0OR = 0.9698.998.5OR = 0.78
       Visits
      Mean10.612.1+13.611.913.0+10
      SD7.99.18.79.8
      Median9.010.010.011.0
      Skilled nursing facility
       Utilization, %27.149.0OR = 2.5832.149.6OR = 2.08
       Stays
      Mean1.41.6+101.51.6+11
      SD0.70.90.80.9
      Median1.01.01.01.0
       Days
      Mean40.742.8+542.846.5+9
      SD38.637.837.938.6
      Median28.031.030.035.0
       ALOS, d
      Mean30.629.8−331.231.3+0
      SD31.929.830.529.4
      Median21.021.022.022.0
      Home health agency
       Utilization, %30.339.1OR = 1.4732.941.3OR = 1.43
       Episodes
      Mean1.71.8+21.71.8+6
      SD1.01.01.01.0
      Median1.01.01.01.0
       Days
      Mean63.165.5+457.764.2+11
      SD51.650.048.949.3
      Median48.055.043.053.0
       Average length of episode, d
      Mean33.034.2+431.633.9+7
      SD16.216.516.416.3
      Median34.036.032.035.0
      Hospice
       Utilization, %0.72.3OR = 3.440.51.5OR = 2.82
       No. of days
      Mean74.759.1−2167.260.1−11
      SD58.555.858.056.7
      Median62.038.050.038.0
      Inpatient rehabilitation facility
       Utilization, %6.15.9OR = 0.966.16.9OR = 1.16
       Stays
      Mean1.11.2+21.11.2+2
      SD0.40.40.40.4
      Median1.01.01.01.0
       Days
      Mean15.815.1−415.115.2+1
      SD9.28.68.98.9
      Median14.014.014.014.0
       ALOS, d
      Mean14.013.2−613.313.2−1
      SD7.36.86.96.8
      Median13.013.013.013.0
      Long-term care hospital
       Utilization, %4.79.1OR = 2.034.18.3OR = 2.14
       No. of stays
      Mean1.11.1+41.11.2+5
      SD0.30.40.40.4
      Median1.01.01.01.0
       Hospital days
      Mean33.636.6+934.038.0+12
      SD20.425.922.626.8
      Median28.030.028.030.0
       ALOS, d
      Mean30.532.2+630.532.7+7
      SD17.222.219.322.4
      Median27.027.026.028.0
      ALOS, average length of stay; CDI, Clostridioides difficile infection; ICU, intensive care unit; OR, odds ratio.
      Values are ORs (decedents vs survivors) unless otherwise indicated as a difference (Δ).
      Supplementary Table 8Baseline Total 6-Month Cost: 0-6 Months Baseline
      MeasurePrimary CDIRecurrent CDI
      Survivors (n = 186,996)Decedents (n = 158,897)% ChangeSurvivors (n = 97,738)Decedents (n = 53,858)% Change
      Total health care cost
       Mean40,21063,014+5749,22370,304+43
       SD91,343117,781100,173123,811
       Median14,49525,77219,33429,547
      Total medical cost
       Mean37,40360,072+6146,08767,108+46
       SD85,493111,69793,529117,556
       Median13,06424,31917,79827,965
      Acute hospital
       Mean13,02521,596+6616,13823,872+48
       SD24,43032,35829,54337,041
       Median520212,125720513,225
      Emergency department
       Mean1037935−101080988−8
       SD1607145516601565
       Median330424353482
      Hospital outpatient
       Mean33304463+3441475342+29
       SD6842861679149605
       Median1204149315051796
      Skilled nursing facility
       Mean44988701+9359519827+65
       SD10,80414,02112,80715,423
       Median0000
      Home health agency
       Mean11401547+3611451577+38
       SD2433272523492729
       Median0000
      Hospice
       Mean82216+16462151+143
       SD1261199511251676
       Median0000
      Inpatient rehabilitation facility
       Mean13311240−712841488+16
       SD6366612162406767
       Median0000
      Long-term care hospital
       Mean22625079+12419864649+134
       SD13,17321,74312,86020,804
       Median0000
      Physician services and tests
       Mean964214,945+5511,15816,017+44
       SD10,93214,62412,38615,693
       Median632910,256720010,881
      Durable medical equipment
       Mean10551352+2831353196+2
       SD7646804066446254
       Median02115361582
      Pharmacy
       Mean28072942+531353196+2
       SD5850608466446254
       Median1431145415361582
      CDI, Clostridioides difficile infection.
      Unless otherwise stated, values are in US dollars.
      Supplementary Table 9Baseline Health Resource Utilization: 7-12 Months Baseline
      MeasurePrimary CDIRecurrent CDI
      Survivors (n = 186,996)Decedents (n = 158,897)% Change, or OR
      Values are ORs (decedents vs survivors) unless otherwise indicated as a difference (Δ).
      Survivors (n = 97,738)Decedents (n = 53,858)% Change, or OR
      Values are ORs (decedents vs survivors) unless otherwise indicated as a difference (Δ).
      Acute hospital
       Utilization, %28.036.1OR = 1.4528.439.0OR = 1.60
       Stays
      Mean1.51.7+91.61.7+9
      SD0.91.11.01.2
      Median1.01.01.01.0
       Days
      Mean9.010.8+199.711.5+19
      SD10.515.312.313.2
      Median6.07.06.07.0
       ALOS, d
      Mean5.66.2+115.86.3+10
      SD6.111.38.06.8
      Median4.05.04.05.0
      ICU
       Days
      Mean9.811.3+1510.612.3+16
      SD11.213.413.215.6
      Median6.07.07.08.0
      Emergency department
       Utilization, %27.328.8OR = 1.0827.830.5OR = 1.14
       Visits
      Mean1.91.9−11.91.90
      SD1.71.61.81.5
      Median1.01.01.01.0
      Hospital outpatient
       Utilization, %96.495.9OR = 0.8896.896.6OR = 0.92
       Visits
      Mean9.29.9+89.710.4+7
      SD7.38.17.78.4
      Median7.08.08.08.0
      Skilled nursing facility
       Utilization, %12.618.7OR = 1.6012.019.3OR = 1.75
       Stays
      Mean1.41.4+51.41.5+6
      SD0.70.80.80.8
      Median1.01.01.01.0
       Days
      Mean51.055.3+849.353.8+9
      SD48.450.247.148.4
      Median34.038.033.038.0
       ALOS, d
      Mean40.542.9+638.440.4+5
      SD43.445.341.642.4
      Median26.027.024.027.0
      Home health agency
       Utilization, %21.228.3OR = 1.4720.628.9OR = 1.57
       Episodes
      Mean1.92.0+41.92.0+5
      SD1.11.21.11.1
      Median1.02.01.02.0
       Days
      Mean73.076.6+570.575.5+7
      SD57.557.756.457.0
      Median55.058.054.058.0
       Average length of episode, d
      Mean34.535.4+234.235.1+3
      SD15.315.115.515.2
      Median37.038.036.037.0
      Hospice
       Utilization, %0.51.1OR = 2.270.40.9OR = 1.96
       Days
      Mean94.491.5−386.885.7−1
      SD62.063.261.262.4
      Median89.083.579.075.0
      Inpatient rehabilitation facility
       Utilization, %1.82.2OR = 1.182.02.5OR = 1.27
       Stays
      Mean1.11.1+11.11.1+1
      SD0.40.40.40.4
      Median1.01.01.01.0
       Days
      Mean13.914.2+214.714.7−0
      SD8.17.68.58.2
      Median13.014.014.014.0
       ALOS, d
      Mean12.612.8+213.012.9−1
      SD6.26.06.66.4
      Median12.013.012.013.0
      Long-term care hospital
       Utilization, %0.81.4OR = 1.751.02.0OR = 1.95
       Stays
      Mean1.11.1+21.21.2−1
      SD0.40.40.40.4
      Median1.01.01.01.0
       Days
      Mean29.132.2+1132.532.5−0.0
      SD20.827.825.827.3
      Median25.025.026.026.0
       ALOS, d
      Mean25.728.2+1027.627.9+1
      SD17.424.721.022.9
      Median23.023.024.023.0
      ALOS, average length of stay; CDI, Clostridioides difficile infection; ICU, intensive care unit; OR, odds ratio.
      Values are ORs (decedents vs survivors) unless otherwise indicated as a difference (Δ).
      Supplementary Table 10Baseline Total 6-Month Cost: 7-12 Months Baseline
      MeasurePrimary CDIRecurrent CDI
      Survivors (n = 186,996)Decedents (n = 158,897)% ChangeSurvivors (n = 97,738)Decedents (n = 53,858)% Change
      Total health care cost
       Mean21,60829,123+3524,23833,745+39
       SD63,46678,22570,50788,728
       Median4873572953946602
      Total medical cost
       Mean18,84126,114+3921,24230,530+44
       SD57,78772,30064,07382,182
       Median3438414139024924
      Acute hospital
       Mean50267402+4758078989+55
       SD13,91318,13617,14922,046
       Median0000
      Emergency department
       Mean880456−48922499−46
       SD1533107516251118
       Median0000
      Hospital outpatient
       Mean28103777+3433924544+34
       SD5963782067619371
       Median947110111281321
      Skilled nursing facility
       Mean21743384+5620763558+71
       SD80349984789610,196
       Median0000
      Home health agency
       Mean9261285+398761303+49
       SD2407279523312821
       Median0000
      Hospice
       Mean73158+11659111+87
       SD1251182011151495
       Median0000
      Inpatient rehabilitation facility
       Mean351431+23401516+29
       SD3053346134833894
       Median0000
      Long-term care hospital
       Mean325618+90455884+94
       SD4839706861158516
       Median0000
      Physician services and tests
       Mean52867336+3961158614+41
       SD869512,008983313,710
       Median2491304027743602
      Durable medical equipment
       Mean9891267+2811391513+33
       SD8098813477649016
       Median0000
      Pharmacy cost
       Mean27673009+929963215+7
       SD5679592564356546
       Median1435158814921679
      CDI, Clostridioides difficile infection.
      Values are in US dollars.
      Supplementary Table 11Follow-up Total Costs, per Patient per Month
      MeasurePrimary CDIRecurrent CDI
      Survivors (n = 186,996)Decedents (n = 158,897)% ChangeSurvivors (n = 97,738)Decedents (n = 53,858)% Change ∗
      Length of follow-up, d
       Mean351.963.2−82354.8118.4
       SD55.591.447.092.0
       Median365.017.0365.086.0
      Total health care cost
       Mean634829,150+359795935,767+349
       SD711733,256821833,746
       Median445919,510572827,167
      Total medical cost
       Mean582128,886+396726435,131+384
       SD699933,293808133,881
       Median392719,248501226,492
      Total inpatient hospital
       Mean263021,956+735338320,809+515
       SD474431,818500526,160
       Median140313,456200213,355
      30-d readmission (to acute hospital)
       Mean215911,317+424239613,308+455
       SD322113,031329314,908
       Median1192774813778972
      Emergency department
       Mean93149+61114282+147
       SD176364187424
       Median34055159
      Hospital outpatient
       Mean8801694+9312073728+209
       SD1379230617693279
       Median4418916402776
      Skilled nursing facility
       Mean12772730+14412084095+239
       SD2165500220205151
       Median0001977
      Home health agency
       Mean230121−47259246−5
       SD470432495578
       Median0000
      Hospice
       Mean1361047+671120804+567
       SD73422356571598
       Median0000
      Inpatient rehabilitation facility
       Mean112139+24232576+148
       SD63413669813003
       Median0000
      Long-term care hospital
       Mean153905+4933994313+982
       SD13025394192412,813
       Median0000
      Physician services and tests
       Mean22488−61233163−30
       SD609526590698
       Median99010817
      Durable medical equipment
       Mean8958−34108116+7
       SD339334370448
       Median80110
      Pharmacy
       Mean527264−50695636−8
       SD100781211601217
       Median3070412274
      CDI, Clostridioides difficile infection.
      Unless otherwise stated, values are in US dollars.
      Supplementary Table 12Follow-up Unadjusted Health Resource Utilization
      MeasurePrimary CDIRecurrent CDI
      Survivors (n = 186,996)Decedents (n = 158,897)% Change, or OR
      Values are ORs (decedents vs survivors) unless otherwise indicated as a difference (Δ).
      Survivors (n = 97,738)Survivors (n = 53,858)% Change, or OR
      Values are ORs (decedents vs survivors) unless otherwise indicated as a difference (Δ).
      Follow-up period
       Length of follow-up, d
      Mean351.963.2−82354.8118.4−67
      SD55.591.447.092.0
      Median365.017.0365.086.0
      Acute hospital
       Utilization, %86.193.6OR = 2.3488.696.6OR = 3.61
       Stays
      Mean0.20.9+3790.21.0+307
      SD0.20.50.20.6
      Median0.21.00.20.9
       Days
      Mean1.510.5+6131.810.1+459
      SD2.312.32.19.8
      Median0.97.01.27.3
       ALOS, d
      Mean0.88.6+10020.75.0+612
      SD1.711.71.06.8
      Median0.55.00.52.9
       ALOS, d (not PPPM)
      Mean7.611.3+497.610.6+40
      SD7.512.26.710.3
      Median6.08.06.08.3
      ICU
       Utilization, %21.322.5OR = 1.0829.853.2OR = 2.68
       Stays
      Mean0.10.6+3420.10.6+339
      SD0.10.50.10.5
      Median0.10.50.10.5
      30-d readmissions (to acute hospital)
       Utilization, %20.222.2OR = 1.1245.163.0OR = 2.07
       Stays
      Mean0.20.6+3240.20.7+315
      SD0.10.40.10.5
      Median0.10.60.10.6
       ALOS, d (per readmission), mean0.63.4+4580.74.1+531
      60-d readmissions (to acute hospital)
       Utilization, %26.526.5OR = 1.0056.975.6OR = 2.35
       Stays
      Mean0.20.6+2740.20.7+273
      SD0.20.20.4
      Median0.10.60.20.7
       ALOS, d (per readmission), mean0.63.3+4490.63.9+521
      Emergency department
       Utilization, %49.821.7OR = 0.2855.739.2OR = 0.51
       Visits
      Mean0.20.6+1850.20.6+139
      SD0.20.60.30.5
      Median0.20.50.20.4
      Hospital outpatient
       Utilization, %99.460.6OR = 0.0199.996.0OR = 0.03
       Visits
      Mean2.73.4+253.14.1+32
      SD1.72.51.82.6
      Median2.42.92.73.6
      Skilled nursing facility
       Utilization, %45.139.7OR = 0.8046.062.4OR = 1.95
       Stays
      Mean0.20.7+3550.20.6+279
      SD0.10.40.10.5
      Median0.10.70.20.5
       Days
      Mean6.412.5+956.112.0+98
      SD6.88.66.57.7
      Median4.311.04.011.0
       ALOS, d
      Mean4.410.0+1283.58.0+126
      SD5.48.24.66.6
      Median2.77.32.26.0
       ALOS, d (not PPPM)
      Mean49.027.3−4440.224.7−38
      SD60.930.053.524.9
      Median31.519.026.019.0
      Home health agency
       Utilization, %36.514.2OR = 0.2939.925.3OR = 0.51
       Episodes
      Mean0.20.5+1310.20.5+95
      SD0.20.40.20.3
      Median0.20.50.20.4
       Days
      Mean4.56.9+554.56.6+45
      SD7.07.16.66.6
      Median2.55.02.64.8
       Average length of episode, d
      Mean1.65.2+2301.54.5+190
      SD1.56.01.34.9
      Median1.33.11.33.0
       Average length of episode, d (not PPPM)
      Mean17.314.2−1817.314.8−15
      SD11.211.111.011.0
      Median15.312.015.512.7
      Hospice
       Utilization, %5.438.6OR = 11.05.242.8OR = 13.6
       Days
      Mean11.88.1−3110.96.7−38
      SD9.88.69.27.7
      Median9.14.68.53.4
      Inpatient rehabilitation facility
       Utilization, %7.02.8OR = 0.399.77.3OR = 0.73
       Stays
      Mean0.10.5+3790.10.4+287
      SD0.10.40.10.3
      Median0.10.40.10.3
       Days
      Mean1.34.2+2131.65.5+242
      SD1.13.81.24.7
      Median1.12.81.44.0
       ALOS, d
      Mean1.13.8+2411.34.8+268
      SD0.93.71.04.4
      Median1.02.41.23.2
       ALOS, d (not PPPM)
      Mean12.511.2−1014.714.1−4
      SD6.26.46.96.8
      Median12.011.014.014.0
      Long-term care hospital
       Utilization, %5.29.6OR = 1.938.619.5OR = 2.56
       Stays
      Mean0.10.7+5000.10.5+352
      SD0.10.40.10.3
      Median0.11.00.10.4
       Days
      Mean3.89.9+1643.413.3+288
      SD4.37.93.48.6
      Median2.47.72.411.7
       ALOS, d
      Mean2.98.8+2052.712.0+344
      SD3.77.72.58.8
      Median1.96.12.19.2
       ALOS, d (not PPPM)
      Mean29.825.3−1529.328.9−1
      SD32.927.321.919.0
      Median22.618.025.025.5
      ALOS, average length of stay; CDI, Clostridioides difficile infection; ICU, intensive care unit; OR, odds ratio; PPPM, per patient per month.
      Values are ORs (decedents vs survivors) unless otherwise indicated as a difference (Δ).
      Figure thumbnail fx1
      Supplementary Fig. 1Definition of index CDI episode, the 14-day CDI-claim-free period after last CDI claim, and 8-week period to identify rCDI.
      Figure thumbnail fx2
      Supplementary Fig. 2Study patient cohort counts.
      Figure thumbnail fx3
      Supplementary Fig. 3Follow-up PPPM cost of care for patients with primary or recurrent CDI by survival outcome and relatedness of mortality, with detailed post-acute care setting costs. CDI cohorts: pCDI: patients with primary CDI only; rCDI: patients with recurrent CDI during a follow-up period of up to 12 months. Total per-patient per-month (PPPM) costs across all settings are noted at the top of each column. Settings with PPPM cost >$2000 are shown in each individual stacked bar. Acute 30-day readmissions are to an acute hospital within 30 days of the prior hospitalization. provides details on additional follow-up costs. DME, durable medical equipment.

      Supplementary Material 1

      Description of Data Use Agreement With the Centers for Medicare & Medicaid Services (CMS)

      Avalere accessed 100% of Medicare fee-for-service (FFS) final action claims via a research-focused Data Use Agreement with CMS. This includes 100% of Medicare Part A and Part B Medicare FFS claims data and 100% of Part D event data for all Part D plans (including Medicare Advantage Part D plans). Specifically, these data were extracted from the Chronic Condition Warehouse Standard Analytic Files, Medicare Beneficiary Summary File Base, and PDE File data administered by the Centers for Medicare & Medicaid Services (CMS) and its contractors. The medical claims data files for each year are created 6 months after the end of the respective calendar year and are final action claims (adjustment claims are rolled up into a single claim, and payment information is final as of the creation date). The Part D event file contains final action events that include posttransaction adjustments that occur between plans and pharmacy, between plan (for misenrollees), and between plans and CMS.
      Claims data contain medical service and final payment information from bills submitted to and reimbursed by Medicare from institutional and professional providers for services covered by Medicare Parts A and B. PDE data include prescription and final payment information from Part D transactions. Enrollment data contain demographic and enrollment information, including age, sex, dual-eligible status for Medicaid, original reason for Medicare entitlement (age or disability/end-stage renal disease), and race or ethnicity for all Medicare FFS beneficiaries.
      The use of these data abided by the Health Insurance Portability and Accountability Act (HIPAA) requirements for the privacy and security of protected health information as well as additional CMS requirements.
      Avalere Health accessed these data through their parent company, Inovalon, which has been designated by CMS as an organization approved through the Qualified Entity Certification Program (QECP). Research with this data source is allowed under a HIPAA-compliant, research-focused data use agreement. Information about the QECP and the Medicare RIF data can be found at https://resdac.org/research-identifiable-files-rif-requests.

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