Introduction
Clostridioides difficile infection (CDI) is associated with significant morbidity and mortality, as well as burden on the healthcare system. 1,Reference Lurienne, Bandinelli, Galvain, Coursel, Oneto and Feuerstadt2 Various practice guidelines recommend enteral vancomycin 125 mg every 6 hours for 10–14 days as a treatment option for initial CDI. Reference Johnson, Lavergne and Skinner3–Reference van Prehn, Reigadas and Vogelzang6 Recurrence rates are between 10% and 34.7% following successful treatment of an initial occurrence with subsequent recurrence rates up to 65% in patients with multiple occurrences. Reference McFarland, Surawicz and Rubin7–Reference Nelson, Scott and Boules13 Limiting recurrence and successful clinical cure are both primary goals of CDI therapy.
Risk factors for recurrence include previous or severe CDI, age ≥ 65 years, immunosuppression, antibiotic exposure, proton pump inhibitor (PPI) use, chronic kidney disease, diabetes mellitus, inflammatory bowel disease, healthcare-associated CDI, and infection with hypervirulent ribotypes. Reference McFarland, Surawicz and Rubin7,Reference Polivkova, Krutova, Capek, Sykorova and Benes9,Reference Deshpande, Pasupuleti and Thota14,Reference Majors and Ellis15 Treatment with fidaxomicin or bezlotoxumab has been shown to decrease recurrence rates compared to standard vancomycin regimens, but financial or logistic barriers can limit access. Reference Johnson, Lavergne and Skinner3,Reference Kelly, Fischer and Allegretti4,Reference Hensgens, Goorhuis, Dekkers and Kuijper16–Reference Wilcox, Gerding and Poxton18 Fecal microbiota transplant (FMT) demonstrates benefit in patients with multiple CDI recurrences, but use is not routinely recommended for first CDI occurrence. Reference Johnson, Lavergne and Skinner3–Reference van Prehn, Reigadas and Vogelzang6
Tapered or pulsed courses of vancomycin are recommended in recurrent CDI; however, there is limited data in treating initial CDI. Reference Johnson, Lavergne and Skinner3–Reference van Prehn, Reigadas and Vogelzang6 In a case series of 31 patients treated with tapered vancomycin for initial CDI, 9.4% (n = 3) were readmitted for recurrent CDI during an 8 week follow-up period Reference Majors and Ellis15 which is notably lower than the 22%–34.7% recurrence rates observed following standard courses for initial CDI. Reference Fekety, McFarland and Surawicz8,Reference Nelson, Scott and Boules13,Reference Louie, Miller and Mullane19–Reference Sirbu, Soriano, Manzo, Lum, Gerding and Johnson21
Our institutional CDI guideline recommended tapered vancomycin regimens for first occurrence in high-risk patients starting in 2018. Use of tapered vancomycin in first occurrence deviates from society guideline recommendations, but was adopted due to the potential of decreasing recurrent CDI. Reference Johnson, Lavergne and Skinner3–Reference van Prehn, Reigadas and Vogelzang6 The aim of this study is to evaluate the risk of CDI recurrence after first CDI case using tapered vancomycin compared to standard vancomycin.
Materials and methods
Study design and practice environment
This was a retrospective, single community health system, pragmatic, propensity score pair matched cohort study in hospitalized patients ≥ 18 years old treated for a first occurrence of CDI between June 18, 2018 and December 21, 2021. The study site, Norton Healthcare, is located in Louisville, Kentucky, U.S.A. and has four adult hospitals totaling >1500 inpatient beds. The study received exempt status from the University of Louisville Institutional Review Board.
During the study period, there were four infectious diseases pharmacists and one nurse practitioner who dedicated time to a clinical transition of care program called “C. diffiCARE”. Patients were candidates for tapered vancomycin if they were high risk for recurrence defined as ≥ 65 years, immunocompromised, or had severe/fulminant infection. Patients or providers could decline the recommendation to utilize a taper. The C. diffiCARE team assisted in obtaining discharge vancomycin prescriptions and provided outpatient follow-up. Any patient with CDI could utilize the C. diffiCARE program for medication assistance and follow-up, regardless of the vancomycin regimen utilized.
The standard vancomycin cohort included patients prescribed enteral vancomycin regimens for 10–14 days, and the intervention arm included patients prescribed a standardized 12-week taper of enteral vancomycin (Figure 1). Patients could have received partial treatment for CDI with non-vancomycin therapy (e.g., fidaxomicin) prior to switching to enteral vancomycin. Patients were only included once in the study period. CDI diagnosis was defined as a positive C. difficile polymerase chain reaction test (Cepheid Xpert® C. difficile/Epi Assay) with or without a positive toxin enzyme immunoassay (Techlab Quik Chek®) and prescribed enteral vancomycin. Exclusion criteria were previous CDI within the past year, death or transition to hospice during hospitalization, previous colectomy, colectomy during or within 30 days of completing enteral vancomycin, diagnosed prior to admission, and clinical failure defined as a change in CDI therapy prior to the planned stop date of the enteral vancomycin course.
Figure 1. Tapered Vancomycin Regimen.
All eligible patients who received tapered enteral vancomycin were included in the experimental arm. Standard of care controls were identified using exact matching. Controls were identified based on a random number generator and selected if they had an exact propensity match in the experimental arm based on age (< 65 or ≥ 65 years) and receipt of any non-CDI antibiotics during hospitalization or the 6-month post discharge follow up period; patients were not required to receive the same risk category of antibiotics in order to be matched. A matched patient could only be included once. Matched patients were screened for eligibility criteria. If an exclusion criteria was found, another round of matching occurred. 1:1 matching was used based on the anticipated sample size and rigorous criteria of exact matching.
Patient demographics extracted from the electronic medical record included age, sex, race, C. difficile associated risk of death score (CARDS) Reference Kassam, Cribb Fabersunne and Smith22 , dates of hospital admission and discharge, first positive CDI test, start and stop dates of enteral vancomycin including discharge prescriptions, and dates of recurrence and death within 6 months of hospital discharge when relevant. Additional factors collected associated with high risk of recurrence were immunocompromised status and severity of illness per IDSA guidelines. Reference Johnson, Lavergne and Skinner3 Immunocompromised status was defined as receiving chemotherapy, hematopoietic stem cell/solid organ transplant, HIV with CD4 < 200 cells/mm3, B-cell/T-cell depleting therapies, interleukin inhibitor therapy, absolute neutrophil count < 500 cells/mm3 or high-dose corticosteroids (≥20 mg/day of prednisolone equivalents for ≥ 2 weeks). Potential cofounders were collected during hospitalization and within 6 months of discharge including receipt of bezlotoxumab, FMT, rifaximin, metronidazole, fidaxomicin, cholestyramine or colestipol, PPIs, and non-CDI antibiotics. Non-CDI antibiotics were categorized as high, medium or low risk for CDI. Reference Brown, Khanafer, Daneman and Fisman23–Reference Webb, Subramanian and Lopansri26
Outcomes
The primary outcome was CDI recurrence within 6 months post hospital discharge. Recurrences were defined as meeting both of the following criteria: 1. new diarrhea or positive C. difficile microbiologic test; 2. prescription for fidaxomicin, enteral vancomycin every 6 hours or 4 times daily or metronidazole monotherapy. Secondary outcomes were time to CDI recurrence, all-cause mortality within 6 months of discharge, and time to mortality.
Sample size and analysis
Prior to the study, it was estimated that 100 patients received tapered enteral vancomycin. With alpha equal to 0.05 and assuming a 25% CDI recurrence rate in the standard vancomycin arm and a 15% reduction in CDI recurrences in the taper arm, it was estimated there would be 76% power to detect a difference in the primary outcome. The observed rate and number of days to the composite outcomes were summarized between cohorts. If a patient experienced recurrence before mortality, days to recurrence was reported. Multivariate analysis included an inverse probability weight Cox regression for time to recurrence or death stratified by matched pairs. Additionally, a sensitivity analysis was performed on a composite outcome of CDI recurrence or mortality to represent potential cases of recurrence among individuals who died post-hospitalization.
Inverse propensity score weights (IPSWs) were assigned to each observation to further balance covariates between study arms after subject matching. To produce IPSWs, an initial propensity score was calculated from a logistic regression model to estimate the probability of receiving a vancomycin taper given a set of covariates. Covariates in the logistic regression model included sex, race, immunocompromised status, admission to the intensive care unit, acute renal failure, liver disease, cardiopulmonary disease, malignancy, inflammatory bowel disease, diabetes mellitus, and the following confounding treatments during the follow-up period: bezlotoxumab, fidaxomicin, FMT, rifaximin, metronidazole, cholestyramine or colestipol, non-CDI antibiotics, and PPIs. Individual IPSWs were calculated as the inverse probability of being assigned to the vancomycin taper. For subjects who were in the taper arm, IPSWs were calculated as 1/propensity score. For subjects in the control, IPSWs were calculated as 1/(1-propensity score). Reference Chesnaye, Stel and Tripepi27
Comparisons of baseline characteristics included Mann–Whitney U and χ2 tests as appropriate. Balance between study arms was assessed with standardized mean differences (SMDs) for baseline patient information. A cutoff of 0.2 was used to identify characteristics that remained imbalanced after matching. Reference Rubin28 Multivariate analysis included conditional logistic regression models to account for subject matching and IPSWs, and reported as conditional odds ratios (cORs) with 95% confidence interval (CIs). P-values of less than 0.05 were statistically significant. All statistical analyses were performed using R version 4.3.1. 29
Results
Seventy-five patients were included in the taper cohort after applying exclusion criteria (Figure 2). Seventy-five patients were matched into the standard of care cohort. Baseline demographic data and disease severity information can be found in Table 1. The cohorts were well-matched based on age, sex, and disease severity. Immunocompromised status and inflammatory bowel disease were more common in the taper cohort in the unadjusted analysis. However, the SMD for the 18 covariates between the taper and standard vancomycin in the IPSW population indicated balance between study cohorts.
Figure 2. Screening and Exclusion.
Table 1. Patient characteristics, disease severity and confounding factors
AKI: acute kidney injury based on KDIGO Guidelines 36 , CARDS: Clostridium difficile associated risk of death score Reference Kassam, Cribb Fabersunne and Smith22 , IBD: inflammatory bowel disease, ICU: intensive care unit, IQR: interquartile range, NC: not calculated; PPIs: proton pump inhibitors. High risk antibiotics: aztreonam, carbapenems, cephalosporin/beta-lactamase inhibitor; 3rd/4th/5th generation cephalosporins, cephamycins, clindamycin, fluoroquinolones. Medium risk antibiotics: aminoglycosides, 1st/2nd generation cephalosporins, macrolides, penicillin/beta-lactamase inhibitor, sulfonamides. Low risk antibiotics: daptomycin, glycopeptides, nafcillin, nitrofurantoin, penicillins and tetracyclines
Few patients received bezlotoxumab, fidaxomicin or FMT. High-risk antibiotics were used frequently in both cohorts, comprising 75.4% and 70.8% of non-CDI antibiotic use, respectively (Table 1). CDI recurrence with subsequent mortality occurred in four patients; two in each treatment arm.
The primary outcome of 6-month post-discharge CDI recurrence rate in the taper cohort was 5.3% (n = 4/75) compared to 28% (n = 21/75) in the standard vancomycin cohort (p < 0.001). After accounting for matching and the IPSW in the underlying population, patients in the taper cohort were less likely to experience recurrent CDI at 6 months compared to the standard vancomycin counterparts (cOR: 0.269, 95% CI 0.126–0.573, p < 0.001). Median time to CDI recurrence was significantly longer in the taper cohort (Table 2).
Table 2. Primary and secondary outcomes
Recurrence and death times counted in days from hospital discharge.
The 6-month all-cause mortality rate was higher in the taper cohort compared to the standard vancomycin cohort (p = 0.014). After accounting for matching and the IPSW, patients in the taper cohort were still more likely to expire within 6 months (cOR: 2.682, 95% CI 1.313 – 5.478, p = 0.007). Median time to death was not significantly different between the taper and standard cohorts (42 days vs 36.5 days, p = 0.689).
The sensitivity analysis found no difference in the crude rate of CDI recurrence or death between arms, however, the timing of recurrence or mortality occurred later in the taper arm (Table 2).
Discussion
A 12-week enteral vancomycin taper was associated with lower risk of CDI recurrence after initial CDI compared to standard vancomycin regimens. Our 6-month recurrence rate of 5.3% in the tapered cohort was lower than the previously published case series where a recurrence rate of 9.3% was observed in a shorter follow-up period. Reference Majors and Ellis15 Notably, this study reported using a 6 week taper whereas the present study utilized a 12 week taper. Our 12 week duration was selected given reports that CDI recurrence risk is high up to 3 months after receiving systemic antibiotics. Reference Hensgens, Goorhuis, Dekkers and Kuijper16,Reference Guery, Menichetti and Anttila17
Our 6-month recurrence rate of 5.3% was also lower than the 12.7% and 15.5% 1 month recurrence rates reported with fidaxomicin in two randomized controlled trials demonstrating reduced recurrence compared with standard vancomycin. Reference Louie, Miller and Mullane19,Reference Cornely, Crook and Esposito20 It is also noteworthy that the follow up period in the present study was longer, allowing for more time for recurrences to take place. Patients in the fidaxomicin versus vancomycin trials were typically younger and had less frequent antibiotic exposure. Reference Louie, Miller and Mullane19,Reference Cornely, Crook and Esposito20 Including older and more medically complex patients is relevant as both advanced age and antibiotic exposure increase risk for CDI recurrence. Reference McFarland, Surawicz and Rubin7,Reference Polivkova, Krutova, Capek, Sykorova and Benes9,Reference Deshpande, Pasupuleti and Thota14,Reference Majors and Ellis15
In another randomized controlled trial comparing fidaxomicin to standard vancomycin in hospitalized patients, global cure with fidaxomicin (67.3%) was found to be not non-inferior to a 10 day course of oral vancomycin, (65.7%). Reference Mikamo, Tateda and Yanagihara30 Lastly, the 5.3% recurrence rate in this study is similar to the 6% 90-day recurrence rate with extended-pulsed fidaxomicin which demonstrated a benefit over a standard course of vancomycin. Reference Guery, Menichetti and Anttila17 These retrospective data strengthen the hypothesis that tapers of vancomycin in first CDI may be a reasonable alternative to fidaxomicin to reduce risk of recurrence. However, per the composite sensitivity analysis, if it was assumed that all patients who died also had a recurrence, there was no longer a statistically significant difference in rate of CDI recurrence between cohorts. An ongoing phase 3 trial is evaluating clinical outcomes with vancomycin tapers in patients with initial CDI and should provide higher quality data. 31
A large observational study by Nelson et al. found that 34.7% of patients with a first CDI case had a recurrence within 1 year with a mean time to recurrence of 34 days. Reference Nelson, Scott and Boules13 It is likely that our 6-month follow-up period allowed adequate time for recurrences to occur. The median time to recurrence in the taper cohort was 115 days, which supports the hypothesis that a prolonged taper could delay recurrence.
However, higher mortality in the taper arm is concerning, particularly with no baseline difference in median CARDS between cohorts. Additionally, increased mortality has been observed with increased recurrence, which contrasts our findings. Reference Olsen, Yan, Reske, Zilberberg and Dubberke32 However, given the 6-month follow-up and the utilization of all-cause, rather than infection-related mortality, cause of death may not have been related to CDI. One study found 45.9% 1-year all-cause mortality in patients with a first case of CDI, but a CDI-related mortality rate of 2.7%, suggesting that CDI is typically not the cause of death. Reference Feuerstadt, Nelson and Drozd33 There was no observed difference in median time to mortality between cohorts, potentially indicating death may not be linked to group assignment.
As anticipated, patients in the tapered vancomycin cohort were more frequently immunocompromised. A recent retrospective study investigating clinical outcomes in immunocompromised patients with CDI reported a 30-day all-cause mortality rate of 7.1% and that 58.8% of deaths were CDI related. Reference Alsoubani, Chow, Rodday, Kent and Snydman34 The higher observed CDI-related mortality rate in immunocompromised patients relative to the rate in a general patient population reported by Feuerstadt et al should also be considered when interpreting mortality rates in the current study. Reference Feuerstadt, Nelson and Drozd33,Reference Alsoubani, Chow, Rodday, Kent and Snydman34 The propensity analysis included immunocompromised status as a matching component, but could not directly evaluate if those covariates contributed to outcomes nor did we match for the severity of immunocompromise. Finally, it should also be noted that in the taper arm, median time to mortality occurred prior to median time to recurrence. Shorter time to mortality could have contributed to the lower observed recurrence rate in the taper cohort, which is consistent with sensitivity analysis findings.
Not all confounders for recurrence and mortality were included in the multivariate analysis. For instance, our data did not capture adherence with C. difficile therapy, the total number or length of therapy of non-CDI antibiotics, impact on gastrointestinal microbiomes or any data from outside of our health system. There may be other baseline factors in health status that contributed to provider willingness to utilize tapered vancomycin. Individual provider preference was not captured and directly contributed to group assignment.
Clinical pharmacists recommended the vancomycin taper for all patients based on standardized criteria or it could be utilized at prescribers’ discretion. However, Black patients were less represented in the taper arm. Given the retrospective nature of the study, there is limited insight into the difference in Black race, but it may represent a racially-based health inequity, which has been observed in other studies. Reference Feuerstadt, Nelson and Drozd33,Reference Mithani, Cooper and Boyd35 For example, Feuerstadt et al. found that Black patients were more likely to experience CDI-associated mortality. Reference Feuerstadt, Nelson and Drozd33
Other limitations exist, such as the definition of CDI that did not require toxin detection to confirm diagnosis, and may have allowed for inclusion of some patients that were colonized rather than infected. Additionally, CDI recurrence did not require a new positive test, and instead utilized a clinical definition that may have resulted in higher recorded recurrence rates. We also did not capture laxative or enteral feeds, which may cause diarrhea. Reference McDonald, Gerding and Johnson5
In conclusion, larger prospective studies should explore recurrence rates and CDI-related mortality to fully elucidate the clinical utility of vancomycin tapers in the treatment of first occurrence of CDI.
Acknowledgements
Theresa Kluthe, MS.
Author contributions
S Moore, M Song, E Swingler, S Furmanek, M Brenneman and A Wilde contributed to trial design. S Moore, M Song, E Swingler, D Smith and T Chandler contributed to data collection and statistical analysis. All authors contributed to manuscript development.
Financial support
No specific funding was received to support this study.
Competing interests
None to declare.
