A multifunctional probiotic co-delivery platform for the treatment of Clostridium difficile infection.

PurposeThe aim of this work was to develop a clinical practice guideline for the prevention and treatment of Clostridium difficile infection (CDI) in children and adolescents with cancer and pediatric hematopoietic stem-cell transplantation (HSCT) patients.MethodsAn international multidisciplinary panel of experts in pediatric oncology and infectious diseases with patient advocate representation was convened. We performed systematic reviews of randomized controlled trials for the prevention or treatment of CDI in any population and considered the directness of the evidence to children with cancer and pediatric HSCT patients. We used the Grading of Recommendations Assessment, Development, and Evaluation approach to generate recommendations.ResultsThe panel made strong recommendations to administer either oral metronidazole or oral vancomycin for the initial treatment of nonsevere CDI and oral vancomycin for the initial treatment of severe CDI. Fidaxomicin may be considered in the setting of recurrent CDI. The panel suggested that probiotics not be routinely used for the prevention of CDI, and that monoclonal antibodies and probiotics not be routinely used for the treatment of CDI. A strong recommendation to not use fecal microbiota transplantation was made in this population. We identified key knowledge gaps and suggested directions for future research.ConclusionWe present a guideline for the prevention and treatment of CDI in children and adolescents with cancer and pediatric HSCT patients. Future research should include randomized controlled trials that involve children with cancer and pediatric HSCT patients to improve the management of CDI in this population.

Purpose:Clostridium difficile infection (CDI) is a significant problem which is increasing in incidence and severity in hospitalized patients. While reported in vitro resistance to metronidazole (MTZ) and vancomycin (VAN) is relatively nonexistent, clinical outcomes with these drugs have been less than desirable (Clin Infect Dis 2005;40:1586–90, Clin Infect Dis 2006;43:421–7). Furthermore, the concern of possible selection for VAN resistance has created a need for alternative antibiotic therapies for CDI. Nitazoxanide (NTZ) is a first in class thiazolide indicated for the treatment of diarrhea caused by Cryptosporidium parvum and Giardia lamblia. Previous studies have proven NTZ to be a safe and effective agent for the initial treatment of CDI and in patients who failed MTZ therapy (J Antimicrob Chemother 2007;59:705–10, DDW 2008: Presentation W1272). However, data is limited in patients with renal disease, especially in peritoneal dialysis (PD). Methods: This case report details the successful utilization of NTZ for the treatment of recurrent CDI in a PD patient. Results: The patient is a 58 year old female on PD, admitted to our hospital for the first time with orthostatic hypotension, severe nausea and vomiting attributed to MTZ therapy for CDI. This was her 5th hospital admission in the last 3 months. Previous CDI treatment regimens had included MTZ and combinations of MTZ and VAN. During her admission the patient developed pneumonia that was successfully treated with moxifloxacin (MOX). On day 7 of MOX therapy she developed diarrhea and her stool tested positive for CD toxins A or B. MOX was discontinued and the patient was started on an oral regimen of NTZ 500 mg twice daily and probiotics were added to assist in reestablishing the colonic flora. Within 7 days of initiating NTZ therapy the patient's diarrhea completely resolved and her stools were negative for CD toxins A or B. The patient was subsequently discharged and instructed to complete 6 weeks of therapy. Overall, the regimen was well-tolerated and 4 months after the cessation of therapy the patient had no further recurrences of CDI. Conclusion: NTZ was chosen based on our clinical experience and studies demonstrating its effectiveness in CDI. The overall safety of NTZ is well-established and the pharmacologic characteristics of NTZ are well suited for the treatment of CDI. NTZ appears to be a safe and effective therapy for the treatment of recurrent CDI. Additional studies are warranted to further validate the efficacy of NTZ in CDI in patients with various underlying conditions such as renal failure.

Diagnosis and Management of Clostridium difficile Infection

Clostridium difficile infection (CDI) is considered to be the main cause of bacterial infectious diarrhea in nosocomial settings. Since the beginning of the new century a continuous rise in the incidence of severe CDI has been observed worldwide. Even though some CDI cases are not associated with previous antibiotic exposure, this remains as the principal risk factor for the development of CDI. The rate of recurrences represents perhaps one the most challenging aspect on the management of CDI. There are several microbiological tests available, but glutamate dehydrogenase antigen test can be selected as the first screening step in a diagnostic algorithm, with positive samples then confirmed using a toxin(s) test, to distinguish toxinogenic from nontoxinogenic CDI. Although metronidazole and vancomycin are and have been the mainstay treatment options for CDI, there are some unmet medical and therapeutical needs. Usually oral metronidazole is recommended for initial treatment of nonsevere CDI and vancomycin for treatment of severe disease. Fidaxomicin may be considered in patients who cannot tolerate vancomycin, although more data are needed. For treatment of a nonsevere initial recurrence of CDI, oral metronidazole should be used, but for treatment of subsequent recurrences or more severe cases fidaxomicin may be helpful.

To compare the efficacy, recurrence rate, adverse event rate and mortality of fidaxomicin compared with vancomycin in treating different types of Clostridium difficile infection (CDI). A systematic search was conducted on PubMed, Embase, Web of Science, Cochrane Library and clinical trial registration databases for research on fidaxomicin versus vancomycin in the treatment of CDI and the retrieval period extended from the establishment of the database to July 22, 2022. A total of 15 studies were included, including 8 RCTs and 7 retrospective cohort studies. Results showed that there was no significant difference in the overall efficacy of the treatment between fidaxomicin and vancomycin, and results in the subgroups of CDI hypervirulent strains and recurrent CDI were obtained, but vancomycin was more effective than fidaxomicin in the treatment of severe CDI (RR = 0.94, 95% CI: 0.90-0.98, P < .01). Results showed that fidaxomicin is superior to vancomycin in terms of 40-day recurrence rate (RR = 0.52, 95% CI: 0.38-0.70, P < .01), 60-day recurrence rate (RR = 0.38, 95% CI: 0.21-0.69, P < .01) and 90-day recurrence rate (RR = 0.62, 95% CI: 0.50-0.77, P < .01). For the recurrence rate of the treatment in CDI hypervirulent strains, severe CDI and recurrent CDI, there was no significant difference between the 2 groups. In addition, there was no significant difference in the incidence of clinical adverse reactions, and same outcomes appeared in all-cause mortality at 40-day, severe CDI and recurrent CDI, but fidaxomicin was superior to vancomycin in all-cause mortality over 60-day (RR = 0.57, 95% CI: 0.34-0.96, P = .03). There were no significant differences between fidaxomicin and vancomycin in the treatment of CDI in therapeutic effectiveness and adverse reactions, while fidaxomicin was superior to vancomycin in terms of recurrence rate and long-term mortality, and vancomycin is more effective in treating severe CDI.

Clostridioides difficile Infection in Chronic Kidney Disease/End-Stage Renal Disease.

Objectives: Fidaxomicin is a macrocyclic antibiotic drug indicated for the treatment of Clostridium difficile infections (CDI). The purpose of this study was to evaluate from a societal perspective the cost-effectiveness and cost-utility of fidaxomicin in the treatment of severe or recurrent CDI compared to the recommended alternative therapy, vancomycin. Methods: The effectiveness estimates of fidaxomicin and vancomycin, provided by two clinical trials in addition to other studies, were extrapolated to 10 days cycles and a time horizon of 1 year using a Markov model. The costs considered in the study included medication, hospitalization, complications and outpatient visits. Estimates of the indirect costs generated by productivity losses due to absenteeism were not included, for lack of relevant evidence for the Portuguese reality and because the population affected by CDI tends to be no longer active in the labor market. Results: Over a one year horizon and compared to vancomycin treatment, in the base case, fidaxomicin treatment in patients with severe ICD is associated with a gain of 0.010 QALY and a cost increase of 138 €. The treatment of patients with recurrent CDI with fidaxomicin is associated with a gain of 0.019 QALYs and a cost reduction of 626 €. Fidaxomicin treatment has an acceptable incremental cost-utility ratio in patients with severe CDI (ICUR: 13,245 €/ QALY) and dominates in patients with recurrent CDI (ICUR: -33,701 €/ QALY). Fidaxomicin treatment in patients with severe and recurrent CDI is also associated with a reduction in the number of recurrences (ICER: 321 €/ recurrence avoided in patients with severe CDI and ICER: -828 €/ recurrence avoided in patients with recurrent CDI). These results are sensitive to the cost of hospitalization, decreasing with a rising cost of hospitalization. In the probabilistic sensitivity analysis the model predicts that the probability of cost-effectiveness of fidaxomicin is 44,9% in the case of severe CDI and 58% for recurrent CDI for a willingness to pay threshold of 30.000 €. Conclusions: In the Portuguese health system context, fidaxomicin presents good cost-effectiveness and cost-utility results, representing a valuable addition to the therapeutic arsenal for the treatment of CDI.

Previous data have suggested that the nonsystemic antibiotic rifaximin may be effective for the treatment of Clostridium difficile infection (CDI). This single-center retrospective study evaluated the efficacy of rifaximin for the treatment of CDI refractory to standard treatments in patients who had received liver transplants. Among 205 patients who had received liver transplants between July 2001 and December 2007, 3 patients with a confirmed diagnosis of C. difficile experienced recurrent diarrhea even though they received standard therapy. Patient 1, a 56-year-old male, patient 2, a 62-year-old male, and patient 3, a 73-year-old female, developed CDIs 190, 318, and 2310 days after transplantation, respectively. All patients experienced symptom recurrences after oral metronidazole therapy (250 mg 3 times daily for either 14 or 28 days) and after oral vancomycin therapy (125 mg 4 times daily for 14 days). Long-term vancomycin treatment (ie, 28 days) was required for patients 1 and 2. Vancomycin was discontinued in patient 3 because of increased creatinine levels. Oral rifaximin (400 mg 3 times daily) was initiated immediately after discontinuation of vancomycin therapy. Within 36 to 48 hours of the initiation of rifaximin treatment, diarrheal symptoms were resolved in all patients. After completing a 28-day course of rifaximin, patient 1 remained symptom-free during 185 days of follow-up, and patient 2 remained symptom-free during 250 days of follow-up. Patient 3 reported no symptoms within 155 days after the completion of rifaximin treatment. These findings suggest that rifaximin may be effective for the treatment of recurrent CDI and may provide a therapeutic option for CDI in immunocompromised patients.

Clostridioides (Clostridium) difficile infection (CDI) is the leading cause of infectious diarrhoea in hospitalised patients, representing a substantial economic burden driven mainly by increased length of hospital stay (LoS). Currently in Japan, limited evidence on CDI-associated excess LoS is available. We conducted a retrospective, matched-cohort study using a large, Japanese, hospital-based administrative database. CDI was defined as CDI treatment plus either CDI diagnosis or positive enzyme immunoassay result. Propensity score matching at the time of CDI or recurrent CDI (rCDI) onset was applied to adjust baseline confounding and immortal time bias. The analysis included 5 994 054 hospitalisation records during 2008-2017, of which 11 823 were identified as CDI and 1359 as rCDI. The median excess LoS attributable to CDI and rCDI was 3 days and 6.5 days, respectively. The excess mortality attributable to CDI was 6.9%; there was no excess mortality attributable to rCDI (-1.9%). The median difference in costs attributable to CDI and rCDI during the residual stay was JPY 130 296 (USD 1185) and JPY 81 054 (USD 737) per hospitalisation, respectively. By adjusting the biases, the burden of CDI in Japan was evaluated. The findings could support decision making and resource allocation for CDI management in Japanese hospitals.

To evaluate the evidence for the use of tigecycline in the treatment of Clostridium difficile infection (CDI). Searches were performed (2004 to June 2011), using the EMBASE and MEDLINE databases, with the terms tigecycline, Tygacil, Clostridium difficile, C. difficile, Clostridium difficile infection, and CDI. Six case reports that described the use of tigecycline for treatment of CDI were included for review. No clinical trials were identified. In all case reports except 1, tigecycline (alone or in combination with other CDI therapies) was used for the treatment of CDI that was refractory to metronidazole and/or vancomycin. In 6 of the cases, treatment success was reported following initiation of tigecycline therapy; 1 patient died following a complicated hospitalization. The treatment duration with tigecycline was 2-4 weeks. In the cases with successful outcomes, symptoms began to improve within 1 week. None of these patients experienced recurrence during follow-up of various lengths. In vitro studies demonstrated a 90% minimum inhibitory concentration range for tigecycline of 0.016-0.25 mg/L for all C. difficile isolates. Tigecycline exhibited good fecal penetration because of primary biliary excretion of unchanged drug. Up to 59% of the dose is recovered in feces following administration over 4 days in healthy volunteers. Case reports have suggested that tigecycline may be successful for treatment of severe or severe complicated CDI, when prior therapy has failed. Data demonstrating tigecycline use as initial therapy for CDI are limited; therefore, this option should be reserved for patients in whom other therapeutic options, including metronidazole and vancomycin, have failed. A randomized controlled trial is needed to assess the safety and efficacy of tigecycline in this patient population and better define the drug's role in the treatment of CDI.

Introduction Clostridium difficile infection (CDI) is a common cause of nosocomial diarrhea. Metronidazole and vancomycin are the primary treatment options for CDI, but increasing rates of antimicrobial resistance and severe, refractory disease have prompted the need for alternative agents. Tigecycline has previously demonstrated favorable in vitro activity against C. difficile isolates, but clinical data on its use in the treatment of CDI are severely lacking. The objective of this study was to describe our experience using tigecycline in the treatment of severe and severe complicated CDI.MethodsThis was a retrospective case series of hospitalized patients with severe and severe complicated CDI who were treated with tigecycline. Disease severity assessments were determined according to current practice guidelines. Diagnosis of toxigenic CDI was confirmed by polymerase chain reaction and patients were excluded if they received tigecycline for <48 h. Data were collected by review of the electronic medical record. The primary outcome was clinical cure. Secondary outcomes were sustained response, hospital mortality, and 28-day all-cause mortality.ResultsA total of 7 cases of severe and complicated CDI were reviewed. Intravenous tigecycline administered as a 100-mg loading dose followed by 50 mg twice daily resulted in clinical cure in 85.7% (n = 6/7) of cases. The majority of patients (n = 4/5) were treated with the novel triple therapy combination of tigecycline, vancomycin, and metronidazole and resulted in clinical cure in 80% (n = 4/5) cases. Sustained response at 28 days was 100% among evaluable cases (n = 5/5). Hospital mortality did not occur in any patients, and 28-day all-cause mortality was 28.6% (n = 2/7).ConclusionTigecycline appears to be a reasonable addition to the therapeutic regimen in the treatment of severe or complicated CDI, including cases that are refractory to standard therapy. A prospective clinical trial confirming these observational findings is warranted.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-014-0050-x) contains supplementary material, which is available to authorized users.

Two case reports suggest that metronidazole treatment for Clostridium difficile infections (CDI) increases tacrolimus (TAC) trough levels. The primary objective of this study was to determine the clinical significance of this potential interaction in transplant patients receiving CDI treatment. Currently, no robust literature exists to estimate a magnitude of pharmacokinetic interaction between metronidazole and TAC. In this retrospective study, the effects of CDI and metronidazole treatment on TAC levels in 52 adult solid organ transplant patients were investigated. The primary outcome was to determine the difference in dose-normalized TAC levels between baseline and symptom resolution in patients treated with metronidazole or vancomycin. The secondary outcome was to determine the difference in dose-normalized TAC levels at baseline and CDI diagnosis. The average change in log-transformed dose-normalized TAC levels from baseline to symptom resolution was 0.99 for metronidazole (n = 35) and 1.04 for vancomycin (n = 17) treatment. The mean difference between the groups was 0.96 (95% confidence interval: 0.74-1.24). No significant difference was found between dose-normalized TAC levels at CDI diagnosis and baseline (P = 0.37). CDI treatment with metronidazole was not associated with a >30% increase in TAC levels compared with vancomycin. Both treatment groups required TAC dose adjustments to maintain goal TAC levels and those treated with metronidazole did not require a significantly greater dose adjustment.

Clostridium difficile infection (CDI) is a primary cause of antibiotic-associated diarrhoeal illness. Current therapies are insufficient as relapse rates following antibiotic treatment range from 25% for initial treatment to 60% for treatment of recurrence. In this study, we looked at the efficacy of SQ641 in a murine model of CDI. SQ641 is an analogue of capuramycin, a naturally occurring nucleoside-based compound produced by Streptomyces griseus. In a series of experiments, C57BL/6 mice were treated with a cocktail of antibiotics and inoculated with C. difficile strain VPI10463. Animals were treated orally with SQ641 for 5 days at a dose range of 0.1-300 mg/kg/day, 20 mg/kg/day vancomycin or drug vehicle. Animals were monitored for disease severity, clostridial shedding and faecal toxin levels for 14 days post-infection. Five day treatment of CDI with SQ641 resulted in higher 14 day survival rates in mice compared with either vancomycin or vehicle alone. CDI survival rates were 100% (13 of 13) and 94% (32 of 34), respectively, in the 1 and 10 mg/kg/day SQ641 treatment groups, 37% (7 of 19) with vancomycin treatment at 20 mg/kg/day and 32% (14 of 44) in the vehicle-only control group. Secondary measures of efficacy, such as prevention of weight loss, decreased disease severity, decreased C. difficile shedding and decreased toxin in faeces, were observed with SQ641 and vancomycin treatment. SQ641 is effective for CDI treatment with prevention of relapse in the murine model of CDI.

Patients with inflammatory bowel disease (IBD), namely ulcerative colitis (UC) and Crohn's disease (CD), have worse outcomes with Clostridium difficile infection (CDI), including increased readmissions, colectomy, and death. Oral vancomycin is recommended for the treatment of severe CDI, while metronidazole is the standard of care for nonsevere infection. We aimed to assess treatment outcomes of CDI in IBD. We conducted a retrospective observational study of inpatients with CDI and IBD from January 2006 through December 2010. CDI severity was assessed using published criteria. Outcomes included readmission for CDI within 30 days and 12 weeks, length of stay, colectomy, and death. A total of 114 patients met inclusion criteria (UC, 62; CD, 52). Thirty-day readmissions were more common among UC than CD patients (24.2% versus 9.6%; P=0.04). Same-admission colectomy occurred in 27.4% of UC patients and 0% of CD patients (P<0.01). Severe CDI was more common among UC than CD patients (32.2% versus 19.4%; P=0.12) but not statistically significant. Two patients died from CDI-associated complications (UC, 1; CD, 1). Patients with UC and nonsevere CDI had fewer readmissions and shorter lengths of stay when treated with a vancomycin-containing regimen compared to those treated with metronidazole (30-day readmissions, 31.0% versus 0% [P=0.04]; length of stay, 13.62 days versus 6.38 days [P=0.02]). Patients with UC and nonsevere CDI have fewer readmissions and shorter lengths of stay when treated with a vancomycin-containing regimen relative to those treated with metronidazole alone. Patients with ulcerative colitis and CDI should be treated with vancomycin.

Clostridium difficile Infection.