Trends and Efficacy in Clostridioides difficile Infection Management at a Polish Clinical Hospital

Introduction

Clostridioides difficile is an anaerobic gram-positive bacterium which, under favorable conditions, (eg, when the physiological flora is weakened by antibiotic therapy) can cause colitis with severe diarrhea [1]. C. difficile is the most common cause of antibiotic-associated diarrhea [2]. The course of the disease is variable, from mild forms that do not require hospitalization to severe forms with complications [3,4]. In recent years, the spread of antibiotic resistance in different gram-positive and gram-negative bacteria has become a global challenge [5–8]. With the widespread use of broad-spectrum antibiotics, Clostridioides difficile infection (CDI) is becoming an important clinical problem [9].

In CDI, the antibiotic that caused the disease should be discontinued [10]. The recommended drugs for the treatment of CDI are fidaxomicin and vancomycin, administered orally [11]. Fidaxomicin is used in the primary episode of infection and in recurrence of infection at a dose of 200 mg every 12 hours for 10 days. Vancomycin is used in the primary episode of infection, at a dose of 125 mg 4 times daily for 10 days. In the fulminant form of infection, the drug is used at a dose of 500 mg 4 times daily orally or by nasogastric tube or by rectal infusion (500 mg in 100 ml of saline every 6 hours). Metronidazole intravenously 500 mg every 8 hours should be added to the therapy, and surgical consultation should be considered. In the first recurrence, vancomycin is given at a dose of 125 mg 4 times daily for 10 days if metronidazole was used in the previous episode or if vancomycin was used previously, in decreasing doses according to the following schedule: 125 mg 4 times daily for 10–14 days, then 125 mg 2 times daily for 7 days, then 125 mg once daily for 7 days, and then 125 mg every 2–3 days for 2–8 weeks [12–15].

In the second and subsequent recurrence, decreasing-dose therapy or sequential therapy with rifaximin is used: vancomycin 125 mg 4 times daily for 10 days, followed by rifaximin 400 mg 3 times daily orally for another 20 days. If neither vancomycin nor fidaxomicin is available, metronidazole should be given orally, at a dose of 500 mg 3 times daily for 10 days [16–18].

Bezlotoxumab is also used in the recurrence of CDI. It is a monoclonal antibody that binds toxin B produced by C. difficile. It is administered in a single dose of 10 mg/kg during the first 1–14 days of therapy [16].

In second and subsequent recurrences, treatment with fecal transplantation may be considered. Surgical treatment of CDI includes: subtotal resection of the colon with preservation of the rectum (this method of treatment is considered the criterion standard of surgical management) [19], loop ileostomy with lavage of colon with electrolyte solution and polyethylene glycol, followed by enteral infusions of vancomycin, and total colectomy [20,21].

This study aimed to analyze the method of treatment of CDI among patients hospitalized at the University Clinical Hospital in Wrocław (UCHW) in the years 2016–2018, focusing on examining mortality, length of hospitalization depending on the therapy used, and changes in treatment over the years covered by the study.

Material and Methods

SAMPLE AND SETTINGS:

This retrospective cohort study was conducted by analyzing medical records from the University Clinical Hospital in Wrocław (Poland) during the period 2016–2018. The analysis focused solely on adult patients who were treated in various hospital wards, explicitly excluding those who were treated in the Hospital Emergency Department. This approach ensured that the study accurately reflected the treatment outcomes and practices within the regular inpatient wards of the hospital. CDI was defined according to current Infectious Diseases Society of America (IDSA)/Society for Healthcare Epidemiology of America (SHEA) [16] and European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidance [17].

SELECTION CRITERIA:

The inclusion criteria were: (1) age ≥18 years; (2) admission to any non-emergency department ward at the UCHW for at least 48 hours between January 1, 2016 and December 31, 2018; (3) clinically significant diarrhea, defined as ≥3 unformed stools within a 24-hour period; and (4) laboratory confirmation of CDI by a positive glutamate dehydrogenase immunoassay followed by toxin A/B enzyme immunoassay or PCR for toxin genes. The exclusion criteria were: (1) age <18 years; (2) admission solely to the emergency or pediatric departments; (3) GDH-positive but toxin A/B EIA or PCR-negative stool results (colonization without confirmed toxin production); (4) incomplete clinical or microbiology records preventing determination of CDI treatment or outcome; and (5) insufficient interval to distinguish a new CDI episode from a prior one.

ETHICS CONSIDERATIONS:

This study was approved by the Bioethics Committee of Wrocław Medical University, Poland (approval no. KB-611/2018). The study adhered to the principles of the Helsinki Declaration and Good Clinical Practice. All participants provided written informed consent to participate in the study.

MEDICAL RECORDS:

Based on database analysis, we identified 319 CDI episodes by querying the hospital microbiology database for positive toxin/EIA or PCR results. Of these, 3 records were excluded due to incomplete treatment data, leaving 316 episodes for analysis. We investigated whether there were differences in the treatment between years of hospitalization. Due to the small number of patients treated with fidaxomicin and rifaximin by year, patients receiving these drugs were analyzed together when examining the relationship between the year of hospitalization and the treatment for CDI. Also, due to the small number of cases in different years of hospitalization, patients who did not receive any drug against C. difficile were excluded from this analysis.

If a patient’s hospitalization occurred at the turn of the year, the patient was included in the year in which more days of hospitalization occurred. Moreover, differences in mortality and length of hospitalization according to the therapy used were examined. Information on the number of hospitalized patients and the number of deaths at the UCHW was obtained from the hospital’s database.

STATISTICAL ANALYSIS:

All statistical analyses were conducted using R software (R Foundation for Statistical Computing, Vienna, Austria). To reduce the risk of type I errors due to the small sample size, a stringent P value threshold of 0.01 was used for statistical significance. The chi-square test was used to examine the relationship between qualitative variables such as treatment methods and patient outcomes (death and gender). A post hoc analysis was conducted using standardized residuals to identify specific differences. Fisher’s exact test was used for analyses where some category sizes were small, ensuring accuracy in determining relationships between variables. The Kruskal-Wallis test was applied to assess the relationship between the length of hospitalization (quantitative variable) and the mode of treatment (qualitative variable). This non-parametric method was chosen due to significant deviations from normal distribution. Dunn’s test with Bonferroni correction was used following the Kruskal-Wallis test to pinpoint specific group differences. The Kolmogorov-Smirnov test was used to verify the normality of the distribution of the length of hospitalization, justifying the use of non-parametric tests when normality assumptions were violated. A multivariate logistic regression model was fitted to estimate the independent association between CDI treatment and in-hospital mortality. The analysis excluded the 10 patients who received no CDI-specific antibiotics to avoid complete separation. Treatment groups were coded as metronidazole (reference), vancomycin, metronidazole + vancomycin, and rifaximin/fidaxomicin. We adjusted for age, sex, presence of heart failure, and the total number of non-CDI antibiotics received. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. A P value <0.01 was considered statistically significant.

Results

The study analyzed the treatment of 316 patients out of 319 patients hospitalized with CDI at the UCHW during 2016–2018. In the case of 3 hospitalized patients, treatment methods could not be determined as there were no data in the documentation, and these patients were excluded from the study. Table 1 shows the analysis of antimicrobial therapy used in CDI at the UCHW during 2016–2018.

Most patients (40.51%) were treated with metronidazole and vancomycin. Such treatment was used in of patients, followed by use of metronidazole alone in 26.90% of patients. In the latest guidelines from the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) [16], as well as in the previous ones from 2017 [22], metronidazole was not the first-line drug for CDI and was recommended for use only if other drugs (eg, vancomycin and fidaxomicin) were not available. Vancomycin alone was used in 20.57% of patients. Fidaxomicin was only administered to 5 patients (1.58%), despite its 100% effectiveness (all patients who received it were cured), perhaps due to its high cost in Poland [20,21].

Table 2 presents the results of the analysis of C. difficile treatment by year of hospitalization. In the following years, the percentage of patients treated with metronidazole alone decreased. This could have been related to the updated guidelines for the treatment of CDI announced in 2017 by IDSA/SHEA [9] or the weaker response to treatment observed by physicians. In 2018, the percentage of patients treated with vancomycin increased compared to the 2 previous years. Again, this may have been due to the implementation of new guidelines or to the worse response to metronidazole observed by physicians. In 2017 and 2018, fidaxomicin or rifaximin was used more often than in 2016. Rifaximin was used in 1 patient in 2016, and none of the patients received fidaxomicin in that year. In 2017, rifaximin was used in 12 patients and fidaxomicin in 1. In 2018, fidaxomicin was used in 4 patients and rifaximin in 11. Despite changes in the treatment of CDI in particular years, the mortality rate did not differ significantly by year of hospitalization (P=0.904.

Table 3 presents the results of the analysis of the relationship between the method of treatment and patient survival. Patients who died (p1) were more likely to receive metronidazole plus vancomycin (p1=57.69% vs p0=26.27%) (P=0.009). Patients who survived (p0) were more likely to be treated with metronidazole alone (p1=15.38% vs p0=23.1%) (P=0.009). The percentage of patients receiving vancomycin was similar in the group of patients who died (p1=16.67%) and in the group of patients who survived (p0=16.46%). All patients treated with fidaxomicin survived.

Table 4 shows the mortality rate of patients with CDI by method of therapy. The mortality rate among all patients included in the study was 24.68%. During the same period, 183 729 patients were hospitalized at the UCHW in hospital wards excluding pediatric wards and the Emergency Department, and 2800 patients died. The overall mortality rate was 1.52%, more than 16 times lower than the mortality rate in patients infected with C. difficile. The highest mortality rate was in the group of patients treated with metronidazole and vancomycin, exceeding the overall mortality in all patients by more than 10%, and it was also the most common treatment, used in 40.51% of patients. Fidaxomicin, on the other hand, was used in the most severe cases, usually in patients already receiving other treatments that had no therapeutic effect. Nevertheless, the drug cured all patients who received it. Unfortunately, it was used in only 1.58% of patients. The analysis of patient treatment shows that the use of metronidazole and vancomycin therapy should be reduced in favor of more frequent use of fidaxomicin.

Table 5 presents the results of the analysis of the length of hospitalization by treatment of CDI. Patients who received metronidazole were treated for a shorter time than patients who received combined metronidazole and vancomycin (Z=−5.65, P<0.001).

Table 6 shows the results of treatment of CDI by patient sex, with no statistically significant differences.

Table 7 presents the adjusted odds ratios for in-hospital mortality associated with each CDI treatment and key patient characteristics. Of 306 patients receiving CDI-specific therapy, 78 (25.5%) died in-hospital. After adjustment, there was no statistically significant difference in mortality for vancomycin alone (adjusted OR: 1.17, 95% CI: 0.46–2.99; P=0.75), combination therapy (metronidazole + vancomycin; OR: 1.97, 95% CI: 0.89–4.35; P=0.095), or rifaximin/fidaxomicin (OR: 1.33, 95% CI: 0.40–4.40; P=0.64) compared with metronidazole alone. Older patients had higher mortality (OR: per year 1.02, 95% CI: 1.00–1.05; P=0.052). Sex, heart failure, and antibiotic burden were not significant independent factors (P<0.05). After accounting for key confounders, none of the alternative treatments for CDI had a statistically significant mortality benefit over treatment with metronidazole alone.

Discussion

PRACTICAL IMPLICATIONS:

The 100% cure rate observed with fidaxomicin in our study population underscores its therapeutic promise and suggests that its wider adoption should be considered at multiple levels of healthcare delivery. We recommend that regional and national guideline committees review current CDI treatment algorithms to include fidaxomicin as a first-line option for both primary and recurrent infection, particularly in high-risk populations (eg, the elderly, immunocompromised, or those with severe disease). Cost-effectiveness analyses are needed to model long-term savings from reduced recurrences, shorter hospital stays, and fewer readmissions, thereby informing reimbursement decisions by payers. Additionally, antibiotic stewardship programs across healthcare networks should be encouraged to negotiate volume-based pricing, develop standardized prescribing pathways, and implement outcome monitoring (eg, recurrence rates and length of sta) to ensure that fidaxomicin’s benefits are realized responsibly and sustainably beyond a single institution.

Our results suggest that fidaxomicin deserves consideration as a first-line treatment in regional and national CDI guidelines, especially for high-risk groups. Health authorities and payers may find that up-front investment in fidaxomicin is offset by reductions in recurrence, hospital stay, and overall healthcare utilization. Broad-based antibiotic stewardship initiatives should therefore include fidaxomicin in their protocols, negotiate favorable pricing, and monitor outcomes to ensure clinical benefit and economic sustainability.

STUDY LIMITATIONS:

We acknowledge several limitations in our work. First, because this was a single-center, retrospective study at the University Clinical Hospital in Wrocław, our findings may not capture the full diversity of CDI management practices across Poland. Local drug availability, prescribing habits, and patient populations likely vary among regions. Second, treatment choices were made by clinicians in real time rather than assigned by protocol, so fidaxomicin was often reserved for the sickest or recurrent cases, introducing the possibility of indication bias when comparing outcomes between therapies. We also did not have systematic data on C. difficile strain types or resistance profiles, which might have helped explain differences in treatment response. Third, although 316 patients is an adequate sample size, it limits our ability to draw firm conclusions about less common treatments like rifaximin or fidaxomicin and to perform detailed subgroup analyses.

Conclusions

The mortality rate of patients infected with C. difficile hospitalized at the UCHW in 2016–2018 was high. Changes in the treatment of CDI were observed during the study period, with less use of metronidazole as a stand-alone drug, and more frequent use of other drugs (rifaximin and fidaxomicin). However, these changes did not affect the difference in mortality between specific years of hospitalization. The most commonly used therapy was the combination of metronidazole and vancomycin, but it was not an effective treatment for CDI, and mortality with this therapy exceeded 30%. The most effective drug for CDI was fidaxomicin.