The clinical presentation of CDI can range from asymptomatic to fulminant pseudomembranous colitis, septic shock, and death [
So far, the known risk factors for CDI include antibiotic use [
Chronic kidney disease (CKD) is a worldwide epidemiology burden, estimated at an alarming 8–16% prevalence [
A recent meta-analysis concluded that CKD and end-stage renal disease (ESRD) patients have a 1.95-fold and a 2.63-fold higher risk of CDI than the general population, respectively [
The main culprit for the frequency and severity of CDI among CKD patients seems to be the immune system impairment of these patients with an inadequate response to C. difficile toxins [
According to recent guidelines from the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA), the recommended treatment of an initial CDI episode to ensure the complete resolution of the symptoms is either vancomycin or fidaxomycin over metronidazole [
Since the intestinal microbiota is of utmost importance in the resolution and prevention of CDI, faecal microbiota transplantation (FMT) is an emerging therapy, recommended especially for patients with recurrent and even refractory CDIs. The procedure consists of transplanting faecal bacteria from a healthy donor in order to restore their normal colonic flora by replacing the pathogenic organisms with harmless bacteria [
Considering the epidemiological importance of C. difficile infection in CKD patients, the aim of this review is to explore the possibilities of prevention and treatment of CDI in patients with chronic kidney disease. To fulfil our aim, we conducted a meta-analysis on clinical studies analysing CDI treatment and prevention issues in CKD patients.
We used MEDLINE, PUBMED, and SCOPUS databases to search for English language articles that reported up to April 2021.
During our search, we used keywords for the population of interest and intervention of interest which are shown in Table
Searched keywords.
(1) Clostridium | OR 1-6 | |
(7) Chronic kidney disease | OR 7-11 | |
(12) Treatment | OR 12-15 |
Articles that were considered suitable by title and a thorough abstract reading were included for full-text evaluation. Referenced articles in the selected studies were also read thoroughly for any significance.
Initially, we included all randomized controlled trials and cohort studies that reported an intervention to prevent or to treat Clostridium difficile infection in CKD patients. We searched for prophylactic antibiotherapy, triple therapy, and faecal microbial transplant.
We established a timeline from 2000 to 2021, so any article prior to this date was excluded. We considered that any manuscript older than 20 years discussed a practice that is outdated and does not have any significance in current practice. The exposure to antibiotics and risk factors for this infection has changed in this period.
The primary outcome of interest of this systematic review was the prevention or treatment of prevalent CDI in patients with chronic kidney disease. The assessment of treatment was based upon the time to resolution of diarrhea (TTROD) and the response at end of therapy (EOT) in the treated groups. Additionally, the efficacy of the treatments was compared to each other by looking at the recurrence rates in various groups depending on the severity of their CKD.
The study quality of our randomized controlled trial was done based on Cochrane Risk of Bias tool [
The Newcastle-Ottawa Scale [
Data extraction and analysis including all relevant information from the text, figures, tables, and charts were evaluated by the reviewers, and studies that presented duplicate information were included only once. The extracted data included baseline characteristics, population, and the study period. The total number of CKD patients with CDI was extracted. The methods of intervention, duration of diarrhea, severity of infection, recurrence rate, time until recurrence, and outcome measures were also included. The recurrence CDI episodes were defined as the return of >3 unformed bowel movements per 24 hours and a positive stool toxin test.
Our initial search generated 1064 articles and after title and abstract review, 950 articles were excluded leaving 114 articles for full-length review—Figure
Results flow chart.
After thorough evaluation and full-text screening, only four studies were included in our analysis for prevention and treatment. Table
Study characteristics.
Author | Year | Origin | Population | Study type | Study period | Total patients | N=CKD | Intervention | Cured patients | Recurrence | Outcome measures |
---|---|---|---|---|---|---|---|---|---|---|---|
Mullane | 2013 | Department of Medicine, University of Chicago, Chicago | Renal impairment and CDI | Randomized controlled trials | 2012 | 1054 | 321 | Fidaxomycin 158 | 252 | 66 | (i) Clinical cure |
Lachowicz | 2014 | Department of Medical Microbiology, Medical University of Warsaw | Dialysis patients | Retrospective non-RCT (observational study) | November 2012–December 2012 | 9 | 9 | Environmental decontamination (chlorine bleach, indomethacin, octenisept, and hydrogen peroxide vapour) | 4 | 3 | (i) Spread of infection |
Kujawa | 2015 | Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia in Katowice | Kidney transplant and immunosuppressive therapy | Retrospective non-RCT (observational study) | October 2012–October 2013 and December 2013–December 2014 | 23 | 17 | Lactobacillus | N/A | N/A | (i) C. difficile infection incidence |
Cammarota [ | 2015 | Department of Internal Medicine, a.Gemelli University Hospital Roma, Italy | Recurrent C. difficile patients | Randomized controlled trial | July 2013-June 2014 | 39 | 20 | Faecal microbiota transplantation by colonoscopy | 18 | 2 | (i) Recurrence rate of C. difficile infection with FMT and vancomycin |
Out of the 4 included studies, two studies were randomized controlled trials that focused primarily on the treatment of CDI associated with CKD, while two studies were nonrandomized controlled trials focusing on prevention.
Three studies (two RCTs and one of the observational non RCT) focused mainly on mortality and recurrence. One of the non-RCT focused on the severity of recurrent CDI by monitoring the duration of diarrhea, number of stools per day, and average CRP. Generally, the recurrence of CDI was mentioned in the majority of studies as a parameter to monitor the efficacy of the treatment or prevention they used. Recurrent CDI was defined as the onset of infection 28 days after the symptoms of the previous episode were completely resolved. Outcome measures are summarized in Table
Outcome measures.
Outcome | Study | Participants | Results | ||
---|---|---|---|---|---|
Baseline | Posttesting | % change | |||
Cure rate (no. of patients) | Mullane et al. 2013 [ | Fidaxomycin stage 3 CKD | 112 | 89 | 79.5 |
Fidaxomycin stage 4 CKD | 46 | 34 | 73.9 | ||
Vancomycin stage 3 CKD | 113 | 91 | 80.5 | ||
Vancomycin stage 4 CKD | 50 | 38 | 76.0 | ||
Cammarota et al. 2015 [ | FMT | 20 | 18 | 90.0 | |
Vancomycin | 19 | 12 | 63.2 | ||
Lackowicz et al. 2014 [ | Nephrology ward patients | 9 | 4 | 44.4 | |
Kujawa et al. 2015 [ | LP299v | 21 | 19 | 90.4 | |
Recurrence (no. of patients) | Mullane et al. 2013 [ | Fidaxomycin stage 3 CKD | 89 | 19 | 21.4 |
Fidaxomycin stage 4 CKD | 34 | 5 | 14.7 | ||
Vancomycin stage 3 CKD | 91 | 30 | 33.0 | ||
Vancomycin stage 4 CKD | 38 | 12 | 31.6 | ||
Lackowicz et al. 2014 [ | Nephrology ward patients | 4 | 3 | 75.0 | |
Cammarota et al. 2015 [ | FMT | 18 | 2 | 11.1 | |
Vancomycin | 17 | 12 | 70.5 | ||
Kujawa et al. 2015 [ | LP299v | 21 | 2 | 9.0 | |
Mortality (no. of patients) | Mullane et al. 2013 [ | Stage 3 CKD | — | — | — |
Stage 4 CKD | — | — | — | ||
Lackowicz et al. 2014 [ | Nephrology ward patients | 9 | 2 | 22 | |
Cammarota et al. 2015 [ | FMT | 20 | 2 | 10 | |
Vancomycin | 19 | 6 | 31.5 | ||
Duration of diarrhea (days) | Kujawa et al. 2015 [ | LP299v in the patients with recurrence ( | 28 | 9.5 | 33.9 |
Number of stools per day | Kujawa et al. 2015 [ | LP299v in the patients with recurrence ( | 8 | 7 | — |
Average CRP serum concentration (mg/l) | Kujawa et al. 2015 [ | LP299v in the patients with recurrence ( | 96.5 | 43.8 |
The two studies included under the heading of prevention were by Kujawa et al. and Lachowicz et al. [
The two RCTs included under the heading of treatment compared the use of fidaxomycin, vancomycin, and faecal microbiota transplantation in stages 3-4 CKD.
In the RCT carried out by Mullane et al., the cure rate in stage 3 CKD was 80.5% with vancomycin and 79.5% with fidaxomycin. In stage 4, similar results were reported with a cure rate of 76% with vancomycin compared to 73.9% with fidaxomycin.
However, the treatment with faecal microbiota transplantation (FMT) cure rate exceeded the antibiotics. Cammarota et al. reported a significant 90% cure rate with faecal microbiota transplantation in comparison to 63.2% with vancomycin. In addition to the cure rate, FMT proved to be the better option with a low recurrence rate of 11.1% compared to the high recurrence rate of 70.5% with vancomycin. Furthermore, the use of FMT also resulted in a low mortality rate of 10% in comparison to 31.5% with the use of vancomycin as treatment.
Quality scores of the included studies ranged from 4 to 6, with a mean quality score of 5. This corresponds to a medium-to-high quality of the included studies. The detailed scores are provided in Tables
Quality assessment scores randomized trials.
Randomized controlled trials | Sequence generation | Allocation concealment | Blinding | Incomplete outcome data | Selective reporting | Intention to treat | Other |
---|---|---|---|---|---|---|---|
Mullane et al. (2013) [ | — | — | — | — | — | ? | NA |
Cammarota et al. (2015) [ | — | — | — | — | — | ? | NA |
Quality assessment scores nonrandomized trials.
Nonrandomized controlled trials | Selection | Comparability | Outcome | ||||||
---|---|---|---|---|---|---|---|---|---|
Representative cohort | Selection of nonexposed cohort | Ascertainment of exposure | Not present at start | Control for most important factor | Control for additional factors | Assessment of outcome | Follow-up long enough | Adequacy of follow-up | |
Kujawa et al. (2015) | |||||||||
Lachowicz et al. (2014) | |||||||||
To the best of our knowledge, this is the first systematic review that discusses the role of treatment and prevention of CDI in a CKD population. Another recent meta-analysis and review [
Using a nationwide hospital-based database (NHDS), Keddis et al. reported a significant hospital-associated morbidity and mortality of CKD patients with associated CDI [
General guidelines for treatment in adults with CDI recommend treatment with vancomycin 125 mg 4 times daily for 10 days or fidaxomycin 200 mg twice daily for 10 days for the initial nonsevere episodes. Oral metronidazole, 500 mg three times daily, is recommended only if vancomycin or fidaxomycin are not available, while intravenous metronidazole is recommended in fulminant CDI with ileus [
The Mullane study, an RCT, compared the treatment recommended by the general adult population guidelines—oral fidaxomycin vs. oral vancomycin—in a CKD population. The cure ratio and sustained response rate to vancomycin and fidaxomycin declined in the later stages of CKD (stages 3 and 4), which can hint on the possible role of normal kidney function in the efficacy of this treatment. However, both drugs are poorly absorbed and remain in the faeces; hence, the bioavailability should not be affected by the abnormal kidney function. Therefore, there must be another reason for the reduced treatment efficacy in the advanced stages of CKD, one hypothesis may be the proven gut microbiota dysbiosis in CKD patients [
Overall, fidaxomycin proved to be a more efficient treatment in CKD patients because it demonstrated increased odds of sustained response by 1.89-fold relative to vancomycin, with a significant
Regarding prevention, treatment with fidaxomycin demonstrated 54% lower odds of recurrence relative to vancomycin.
The role of fidaxomycin was also supported by Rubio Teres et al. in their study that reported a low (3.8%) recurrence of CDI in comparison to a 5% recurrence risk, with vancomycin.
Looking at the faecal microbiota transplantation (FMT), Cammarota et al. conducted a randomized clinical trial in 39 patients to compare FMT and vancomycin for the treatment of recurrent CDI. The study population consisted of 20 CKD patients, stages 3 and 4, treated with FMT. 18 of them presented a complete resolution of CDI, while recurrence was reported in 2 patients (10%). Furthermore, 13 of the 18 subjects were cured after the first infusion of FMT.
According to the guidelines, FMT is recommended in the treatment of second or subsequent recurrence of CDI and can also be considered for refractory CDI. Taking into account the promising results of Cammarota et al. and the gut microbiota dysbiosis present in CKD patients, we do think that with more studies and larger clinical trials, FMT may become a step forward in efficient treatment for CDI in CKD patients.
Lachowicz et al. highlighted the importance of CDI patients’ isolation by providing a segregated area for them to separate toilets and shower facilities until discharge, regardless of their symptoms.
Furthermore, another preventive measure was mentioned based upon previous studies [
Moreover, Fawley et al. compared the effect of different disinfectants on epidemic and nonepidemic
To further elaborate on the preventive measures, we found another study that explored the use of the strain 299 v of Lactobacillus plantarum (LP299v) in CKD patients with CDI.
LP299v is a gram-positive lactic acid bacterium that was isolated from the mucosa of human intestines and is also commonly found in food products [
Kujawa et al. are the first ones to report the use of LP299v in transplanted patients. The study was divided into two twelve-month intervals, before and after the initiation of LP299v agent as a prophylactic agent. The results show a significant decrease in the incidence of recurrence of CDI after the initiation of prophylaxis (
According to the data we extracted in Table
Looking at other patients with a similar immunological profile to CKD patients, we analysed the issue of C. difficile infection in cancer patients. Cancer patients also have a 2-fold higher risk of CDI, due to risk factors such as frequent hospitalization, increased use of antibiotics, immune deficiency, and disturbed microbiota [
Even for cancer patients, studies show a higher cure rate and fewer recurrences with fidaxomycin compared to vancomycin [
Considered for many years as a hospital-acquired infection, CDI epidemiology research revealed interesting data: the proportion of community-associated CDI (CA-CDI) is higher than expected, with 20 to 27% of the total CDI cases being community-associated, both in Europe and in North America [
Diabetic patients are a population which, in terms of impaired immune response, antibiotic use, healthcare exposure, and disturbed gut microbiota are very similar to the CKD population. A review of C. difficile infection in diabetes mellitus patients [
A high rate of asymptomatic colonization with toxigenic C difficile (16%) was demonstrated in geriatric patients at admission in the geriatric ward. The risk factors for colonization were previous CDI, antibiotic use, and postsurgery status. The great majority (87.5%) of the asymptomatic carriers further developed C. difficile diarrhea, leading to the conclusion that screening for C. difficile colonization prior to admission could be a very useful tool in CDI prevention in a geriatric ward [
This systematic review does have some limitations that need to be pointed out. The total number of CKD patients is rather low. The trials are mainly observational, with only two RCTs looking at treatment and prevention. Treatment regimen and prevention methods are heterogenic in the analysed studies, and the number of patients enrolled in each trial is rather low.
Our review provides an insight on the very serious problem of C. difficile infection in CKD patients, from the prevention and treatment point of view. The most important aspect of prevention is isolation and disinfection with chlorine-based solution and hydrogen peroxide vapour in order to stop the spread of bacteria. Treatment with oral fidaxomycin is more effective than with oral vancomycin for the initial episode of CDI in CKD patients. FMT has a better cure rate and a lower recurrence rate than vancomycin when used for recurrence episodes and qualifies for a safe and efficient emerging treatment that needs to be further investigated in bigger trials. Prevention of recurrence episodes can be safely addressed with LP299v, a probiotic that lowers the rate of CDI in renal transplant patients.
More large-sample RCTs are necessary to conclude on the best treatment and prevention strategy of CDI in CKD patients.
The authors declare that there is no conflict of interest regarding the publication of this paper.