fidaxomicin and Enterocolitis--Pseudomembranous

There is a lack of real-world evidence of the comparative effectiveness of fidaxomicin versus vancomycin or metronidazole for treating patients with Clostridium difficile (CDI) infection. No systematic evidence comparing these treatment regimens using real-world observational studies was published up to date. The goal of this study is to compare the fidaxomicin and vancomycin/metronidazole regimens in terms of treatment outcomes in CDI patients.. Systematic and comprehensive search was carried out in the following databases and search engines: EMBASE, Cochrane, MEDLINE, ScienceDirect, and Google Scholar from 1954 until January 2022. Newcastle-Ottawa (NO) scale was used to assess the risk of bias. Meta-analysis was carried out using random effects model, and pooled odds ratios (OR) with 95% confidence interval (CI) were reported.. A total of 10 studies satisfied the inclusion criteria, most of them were with poorer quality. The pooled OR was 0.40 (95% CI: 0.09-1.68; I. Fidaxomicin and vancomycin/metronidazole regimens did not have significant difference in terms of treatment outcomes, such as clinical cure, sustained cure, recurrence, and all-cause mortality. However, there was significantly higher risk of treatment failure in CDI patients taking fidaxomicin.

Topics: Aminoglycosides; Anti-Bacterial Agents; Clostridium Infections; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Metronidazole; Vancomycin

Clostridium difficile infection remains a common nosocomial illness with a significant impact on health care delivery. As molecular phenotyping of this organism has changed our understanding of its transmission and virulence, so too have diagnostic methods and treatment strategies evolved in recent years. The burden of this infection falls predominantly on elderly patients with comorbidities who have recently received antibiotics. Oral or enteral vancomycin is now preferred for first-line antimicrobial treatment across the disease spectrum, including mild-moderate initial cases. Fidaxomicin (a novel macrolide antibiotic), bezlotoxumab (a monoclonal antibody against toxin TcdB), and fecal microbiota transplantation expand the therapeutic armamentarium, particularly for recurrent infection. Operative treatment should be reserved for patients with fulminant infection, and early identification of patients who would benefit from an operation remains a challenge. Less invasive surgical options-such as laparoscopic diverting ileostomy with colonic irrigation-may improve survival and other outcomes relative to total abdominal colectomy and represent an attractive alternative particularly for frail patients.

Topics: Anti-Bacterial Agents; Antibodies, Monoclonal; Bacterial Toxins; Broadly Neutralizing Antibodies; Clostridioides difficile; Colectomy; Enterocolitis, Pseudomembranous; Fecal Microbiota Transplantation; Fidaxomicin; Humans; Ileostomy; Risk Factors; Therapeutic Irrigation; Vancomycin

Clostridioides difficile infection (CDI) is a major health-care burden and increasingly seen in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Increased antibiotic use, alteration in host defenses, and gastric acid suppression are some of the etiologies for increased risk of CDI in these populations. Patients with CKD/ESRD have a higher risk of initial episode, recurrence, and development of severe CDI than those without CKD or ESRD. Diagnosis and management of CDI in patients with CKD/ESRD are similar to that in the general population. The mortality, length of stay, and health-care costs are higher in patients with CDI and CKD/ESRD. Antimicrobial stewardship with reduction in antibiotic use along with infection-control measures such as contact isolation and hand hygiene with soap and water is essential in the control and prevention of CDI in patients with CKD/ESRD.

Topics: Anti-Bacterial Agents; Antibodies, Monoclonal; Antimicrobial Stewardship; Broadly Neutralizing Antibodies; Clostridium Infections; Enterocolitis, Pseudomembranous; Fecal Microbiota Transplantation; Fidaxomicin; Hand Hygiene; Health Care Costs; Humans; Infection Control; Kidney Failure, Chronic; Length of Stay; Metronidazole; Patient Isolation; Renal Insufficiency, Chronic; Secondary Prevention; Vancomycin

Antibiotic-associated diarrhoea is among the most common adverse events related to antibiotic use. Most cases are mild, but

Topics: Anti-Bacterial Agents; Clostridioides difficile; Clostridium Infections; Diarrhea; Enterocolitis, Pseudomembranous; Fecal Microbiota Transplantation; Fidaxomicin; Humans; Metronidazole; Probiotics; Vancomycin

Clostridium difficile (C. difficile) is recognized as a frequent cause of antibiotic-associated diarrhoea and colitis. This review is an update of a previously published Cochrane review.. The aim of this review is to investigate the efficacy and safety of antibiotic therapy for C. difficile-associated diarrhoea (CDAD), or C. difficile infection (CDI), being synonymous terms.. We searched MEDLINE, EMBASE, CENTRAL and the Cochrane IBD Group Specialized Trials Register from inception to 26 January 2017. We also searched clinicaltrials.gov and clinicaltrialsregister.eu for ongoing trials.. Only randomised controlled trials assessing antibiotic treatment for CDI were included in the review.. Three authors independently assessed abstracts and full text articles for inclusion and extracted data. The risk of bias was independently rated by two authors. For dichotomous outcomes, we calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI). We pooled data using a fixed-effect model, except where significant heterogeneity was detected, at which time a random-effects model was used. The following outcomes were sought: sustained symptomatic cure (defined as initial symptomatic response and no recurrence of CDI), sustained bacteriologic cure, adverse reactions to the intervention, death and cost.. Twenty-two studies (3215 participants) were included. The majority of studies enrolled patients with mild to moderate CDI who could tolerate oral antibiotics. Sixteen of the included studies excluded patients with severe CDI and few patients with severe CDI were included in the other six studies. Twelve different antibiotics were investigated: vancomycin, metronidazole, fusidic acid, nitazoxanide, teicoplanin, rifampin, rifaximin, bacitracin, cadazolid, LFF517, surotomycin and fidaxomicin. Most of the studies were active comparator studies comparing vancomycin with other antibiotics. One small study compared vancomycin to placebo. There were no other studies that compared antibiotic treatment to a placebo or a 'no treatment' control group. The risk of bias was rated as high for 17 of 22 included studies. Vancomycin was found to be more effective than metronidazole for achieving symptomatic cure. Seventy-two per cent (318/444) of metronidazole patients achieved symptomatic cure compared to 79% (339/428) of vancomycin patients (RR 0.90, 95% CI 0.84 to 0.97; moderate quality evidence). Fidaxomicin was found to be more effective than vancomycin for achieving symptomatic cure. Seventy-one per cent (407/572) of fidaxomicin patients achieved symptomatic cure compared to 61% (361/592) of vancomycin patients (RR 1.17, 95% CI 1.04 to 1.31; moderate quality evidence). Teicoplanin may be more effective than vancomycin for achieving a symptomatic cure. Eightly-seven per cent (48/55) of teicoplanin patients achieved symptomatic cure compared to 73% (40/55) of vancomycin patients (RR 1.21, 95% CI 1.00 to 1.46; very low quality evidence). For other comparisons including the one placebo-controlled study the quality of evidence was low or very low due to imprecision and in many cases high risk of bias because of attrition and lack of blinding. One hundred and forty deaths were reported in the studies, all of which were attributed by study authors to the co-morbidities of the participants that lead to acquiring CDI. Although many other adverse events were reported during therapy, these were attributed to the participants' co-morbidities. The only adverse events directly attributed to study medication were rare nausea and transient elevation of liver enzymes. Recent cost data (July 2016) for a 10 day course of treatment shows that metronidazole 500 mg is the least expensive antibiotic with a cost of USD 13 (Health Warehouse). Vancomycin 125 mg costs USD 1779 (Walgreens for 5. No firm conclusions can be drawn regarding the efficacy of antibiotic treatment in severe CDI as most studies excluded patients with severe disease. The lack of any 'no treatment' control studies does not allow for any conclusions regarding the need for antibiotic treatment in patients with mild CDI beyond withdrawal of the initiating antibiotic. Nonetheless, moderate quality evidence suggests that vancomycin is superior to metronidazole and fidaxomicin is superior to vancomycin. The differences in effectiveness between these antibiotics were not too large and the advantage of metronidazole is its far lower cost compared to the other two antibiotics. The quality of evidence for teicoplanin is very low. Adequately powered studies are needed to determine if teicoplanin performs as well as the other antibiotics. A trial comparing the two cheapest antibiotics, metronidazole and teicoplanin, would be of interest.

Topics: Adult; Aminoglycosides; Anti-Bacterial Agents; Bacitracin; Clostridioides difficile; Diarrhea; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Metronidazole; Randomized Controlled Trials as Topic; Teicoplanin; Treatment Outcome; Vancomycin

Clostridium difficile infection (CDI) has steadily increased in incidence since the 1990s, with an associated increase in recurrence and severity, which has in turn lead to more intensive care unit (ICU) admissions. The development of recurrent CDI, in particular, has been associated with increasing patient morbidity and mortality as well as an immense financial burden on the health care system. Recently, fecal microbiota transplantation (FMT) has received much publicity as an effective means of treatment for recurrent CDI. The goal of this review is to provide evidence-based recommendations for the diagnosis and management of CDI, with a particular focus on FMT and its utilization in the ICU.

Topics: Aminoglycosides; Anti-Infective Agents; Clostridioides difficile; Enterocolitis, Pseudomembranous; Fecal Microbiota Transplantation; Fidaxomicin; Humans; Intensive Care Units; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Recurrence; Rifamycins; Rifaximin; Treatment Outcome

Diarrhoea is one of the most commonly occurring diseases. This article presents a review of the current state of the treatment of acute infectious diarrhoea, as well as of the most important pathogens. The general principles of the therapy of diarrhoea are exemplified, followed by a description of the targeted antimicrobial therapy of the most important bacterial gastrointestinal infections, including salmonellosis, shigellosis and Campylobacter infections, as well as infections with pathogenic Escherichia coli strains, yersiniosis and cholera. Diarrhoea caused by toxigenic Clostridium difficile strains has increased in incidence and in severity. These infections will therefore be described in detail, including important new aspects of treatment. Symptomatic therapy is still the most important component of the treatment of infectious diarrhoea. However, empirical antibiotic therapy should be considered for severely ill patients with a high frequency of stools, fever, bloody diarrhoea, underlying immune deficiency, advanced age or significant comorbidities. Increasing resistance, in particular against fluoroquinolones, must be taken into consideration. Therapy with motility inhibitors is not recommended for Shiga toxin-producing Escherichia coli (STEC) infections, Clostridium difficile infections (CDI), and severe colitis. The macrocyclic antibiotic fidaxomicin can reduce the rate of recurrent disease in CDI. Furthermore, evidence for the benefits of faecal microbiota transplantation as a treatment option for multiple recurrences of CDI is increasing. In conclusion, the treatment of acute diarrhoea is still primarily supportive. General empirical antibiotic therapy for acute diarrhoea is not evidence-based.

Topics: Acute Disease; Aminoglycosides; Anti-Bacterial Agents; Azithromycin; Bacterial Infections; Campylobacter Infections; Cholera; Ciprofloxacin; Diarrhea; Dysbiosis; Dysentery, Bacillary; Enterocolitis, Pseudomembranous; Escherichia coli Infections; Fidaxomicin; Gastroenteritis; Humans; Rifamycins; Rifaximin; Salmonella Infections; Shiga-Toxigenic Escherichia coli; Yersinia Infections

Clostridium difficile infection (CDI) is a significant cause of healthcare-associated diarrhoea, and the emergence of endemic strains resulting in poorer outcomes is recognised worldwide. Patients with cancer are a specific high-risk group for development of infection. Areas covered: In this review, modifiable and non-modifiable risk factors for CDI in adult patients with haematological malignancy or solid tumours are evaluated. In particular, the contribution of antimicrobial exposure, hospitalisation and gastric acid suppression to risk of CDI are discussed. Recent advances in CDI treatment are outlined, namely faecal microbiota transplantation and fidaxomicin therapy for severe/refractory infection in cancer populations. Outcomes of CDI, including mortality are presented, together with the need for valid severity rating tools customised for cancer populations. Expert commentary: Future areas for research include the prognostic value of C. difficile colonisation in cancer patients and the potential impact of dedicated antimicrobial stewardship programs in reducing the burden of CDI in cancer units.

Topics: Adult; Aminoglycosides; Anti-Bacterial Agents; Bacteriological Techniques; Clostridioides difficile; Drug Utilization; Enterocolitis, Pseudomembranous; Fecal Microbiota Transplantation; Fidaxomicin; Humans; Neoplasms; Risk Factors

Clostridium difficile infection (CDI) is a serious complication of hospitalization and antibiotic use with a high mortality and very high costs. Despite appropriate treatment, a subset of patients develop chronic recurrent CDI. Some other patients develop severe and life-threatening colitis. The risk factors, pathogenesis, and treatment of recurrent CDI and severe CDI are discussed in this review. In particular, fecal microbiota transplantation (FMT) as a treatment strategy is outlined and a treatment algorithm incorporating FMT is described.

Topics: Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Enterocolitis, Pseudomembranous; Feces; Fidaxomicin; Humans; Metronidazole; Microbiota; Recurrence; Severity of Illness Index; Transplantation; Vancomycin

Clostridium difficile infection is a major public health problem. However, in recent years the epidemiology, risk factors, diagnosis, and treatment of C. difficile infection have undergone a significant change. The incidence of C. difficile has increased, not only in the healthcare sector but also in the community. Hospital-acquired infection and community-acquired disease have different risk factors, with the latter occurring in children and younger individuals without a history of antibiotic use or previous infections. From a clinician's perspective, a quick efficient diagnosis is required for patient treatment; however, the old method of using enzyme immunoassays is insensitive and not very specific. Recent literature around diagnostic testing for C. difficile infection suggests using PCR or a two-step algorithm to improve sensitivity and specificity. More failures and recurrence with metronidazole have led to treatment algorithms suggesting its use for mild infections and switching to vancomycin if there is no clinical improvement. Alternatively, if signs and symptoms suggest severe infection, then oral vancomycin is recommended as a first-line agent. The addition of a new but costly agent, fidaxomicin, has seen some disparity between the European and North American guidelines with regard to when it should be used. Lastly, rapid developments and good results with fecal microbial transplantation have also left clinicians wondering about its place in therapy. This article reviews the literature around some of the recent controversies in the field of C. difficile infection.

Topics: Aminoglycosides; Anti-Bacterial Agents; Enterocolitis, Pseudomembranous; Fecal Microbiota Transplantation; Fidaxomicin; Humans; Incidence; Metronidazole; Molecular Diagnostic Techniques; Polymerase Chain Reaction; Probiotics; Recurrence; Risk Factors; Vancomycin

Topics: Aminoglycosides; Anti-Bacterial Agents; Bacterial Vaccines; Clostridioides difficile; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Probiotics; Randomized Controlled Trials as Topic; Treatment Outcome; Vancomycin

To evaluate the efficacy of fidaxomicin treatment, which has a limited effect on the normal gut flora, compared with vancomycin and metronidazole treatment in Clostridium difficile infections (CDIs).. A systematic literature review was conducted in July to August 2011 and updated in July 2013. For fidaxomicin versus vancomycin, efficacy was evaluated using meta-analysis of data from two Phase III direct comparative studies (n = 1164). As there were no studies comparing fidaxomicin and metronidazole, an indirect comparison was made using data from three vancomycin versus metronidazole studies (n = 345), using the methodology of Bucher et al. (J Clin Epidemiol 1997; 50: 683-91). This provides an OR for the indirect comparison of fidaxomicin versus metronidazole when direct evidence of fidaxomicin versus vancomycin and vancomycin versus metronidazole is available.. Clinical cure rates were similar for fidaxomicin and vancomycin; the OR (95% CI) was 1.17 (0.82, 1.66). Recurrence [0.47 (0.34, 0.65)] was significantly lower and sustained cure rates [1.75 (1.35, 2.27)] significantly higher for fidaxomicin than vancomycin. Similar results were obtained in patient subgroups with severe CDI and with non-severe CDI. From the indirect comparison, the likelihood of recurrence [0.42 (0.18, 0.96)] and sustained cure [2.55 (1.44, 4.51)] were significantly improved for fidaxomicin versus metronidazole. Again, similar results were obtained in those with severe and non-severe CDI.. Fidaxomicin provides improved sustained cure rates in patients with CDI compared with vancomycin. An indirect comparison indicates that the same is also true for fidaxomicin versus metronidazole. In view of these data, fidaxomicin may be considered as first-line therapy for CDI.

Topics: Aminoglycosides; Anti-Bacterial Agents; Clinical Trials, Phase III as Topic; Clostridioides difficile; Clostridium Infections; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Metronidazole; Treatment Outcome; Vancomycin

To review the chemistry, pharmacology, microbiology, pharmacodynamics, pharmacokinetics, clinical efficacy, tolerability, drug interactions, dosing, and administration of fidaxomicin (FDX).. A search of PubMed using the terms "fidaxomicin," "OPT-80," "PAR-101," "OP-1118," "difimicin," "tiacumicin," and "lipiarmycin" was performed. All English-language articles from 1983 to November 2013 were reviewed for relevance. Bibliographies of all articles were reviewed as well as the manufacturer's Web site to further identify relevant information.. All English-language articles from 1983 to November 2013 appearing in these searches were reviewed for relevance to this paper. In addition, their bibliographies were reviewed to identify any articles not identified in the searches.. FDX is the first macrolide antibiotic with a narrow spectrum of activity targeted against Clostridium difficile. It is administered orally without regard to food. The primary route of elimination is fecal excretion. Advanced age, hepatic dysfunction, or renal impairment do not alter its disposition. Phase III clinical trials have demonstrated that FDX 200 mg twice daily for 10 days is noninferior to vancomycin 125 mg four times daily for 10 days in the treatment of adults with C. difficile infection and is associated with lower recurrence rates. FDX has a favorable side effect profile and a low potential for drug interactions.. FDX has been shown to be safe and effective in the treatment of adults with C. difficile infection. Further research and pharmacoeconomic studies are needed to clarify and refine its role in the treatment of patients at high risk for recurrence.

Topics: Administration, Oral; Adult; Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Drug Interactions; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Intestinal Elimination; Macrolides; Nucleic Acid Synthesis Inhibitors; Recurrence; Tissue Distribution

Clostridium difficile infection, also known as C. difficile-associated diarrhea (CDAD), is the most common cause of nosocomial diarrhea, typically initiated by the use of broad-spectrum antibiotics that disrupt gut flora, thereby allowing C. difficile to proliferate. It is an increasing cause of morbidity and mortality, especially in hospitals and long-term care facilities. A particularly challenging aspect to treating CDAD has been maintenance of clinical response: following initial treatment success, recurrence occurs in approximately 15-30% of patients after the first episode and up to 50-60% subsequently. Fidaxomicin, marketed as DIFICID® in the United States, is approved in multiple countries and is the first new drug to be approved for this indication in over 25 years. It is a novel, narrow spectrum antibiotic with potent bactericidal activity against C. difficile and low activity against the normal gut microbiota. In clinical trials, fidaxomicin has been shown to be noninferior in initial clinical response to CDAD compared to vancomycin, and superior in limiting recurrence and providing sustained clinical response. In this review, the development and characteristics of fidaxomicin are described.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Clostridioides difficile; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Treatment Outcome

Clostridium difficile is the leading cause of antibiotic associated infectious nosocomial diarrhoea. Limited number of new pharmaceutical products have been developed and registered in the past decades for the treatment of Clostridium difficile infection. The available scientific evidence is limited and hardly comparable.. To analyse the clinical efficacy and safety of metronidazole, vancomycin and fidaxomicin in the therapy of Clostridium difficile infection.. Systematic review and meta-analysis of the literature data.. Meta-analysis of literature data showed no significant difference between these antibiotics in clinical cure endpoint (odss ratios: fidaxomicin vs. vancomycin 1.19; vancomycin vs. metronidazol 1.69 and fidaxomicin vs. metronidazol 2.00). However, fidaxomicin therapy was significantly more effective than vancomicin and metronidazol in endpoints of recurrence and global cure (odds ratios: fidaxomicin vs. vancomycin 0.47; vancomycin vs. metronidazol 0.91 és fidaxomicin vs. metronidazol 0.43). There was no significant difference between fidaxomicin, vancomycin and metronidazole in safety endpoints.. Each antibiotic similarly improved clinical cure. Fidaxomicin was the most effective therapeutic alternative in lowering the rate of recurrent Clostridium difficile infections.. Bevezetés: A Clostridium difficile az antibiotikum asszociálta hasmenések leggyakoribb kórokozója, aminek kezelésére az elmúlt évtizedekben kevés új szer került kifejlesztésre, és a tudományos bizonyítékok korlátozott mértékben és nehezen összehasonlítható módon állnak rendelkezésre. Célkitűzés: A Clostridium difficile okozta fertőzés terápiájának hatásossági és biztonságossági végpontjainak elemzése a metronidazol, vancomycin és a fidaxomicin alkalmazása esetén. Módszer: A szakirodalom áttekintése és az eredmények metaanalízise. Eredmények: A metaanalízis szerint a klinikai gyógyulás végpontban nincs szignifikáns különbség a három terápia között (esélyarányok: fidaxomicin vs. vancomycin 1,19, vancomycin vs. metronidazol 1,69 és fidaxomicin vs. metronidazol 2,00). A rekurrencia és a globális gyógyulás végpontokban a fidaxomicin szignifikánsan hatásosabbnak bizonyult, mint a vancomycin és a metronidazol (esélyarányok: fidaxomicin vs. vancomycin 0,47, vancomycin vs. metronidazol 0,91 és fidaxomicin vs. metronidazol 0,43). A biztonságossági végpontokat tekintve nem volt szignifikáns különbség az antibiotikumok között. Következtetések: A klinikai gyógyulás esetében a vizsgált antibiotikumok hatásossága hasonló. A rekurrens fertőzések megakadályozásában jelenleg a fidaxomicin a leghatásosabb terápiás alternatíva. Orv. Hetil., 2013, 154, 890–899.

Topics: Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Cross Infection; Diarrhea; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Metronidazole; Treatment Outcome; Vancomycin

Oral fidaxomicin (Dificid(®); Dificlir(®)) is a first-in-class macrocyclic antibacterial that is approved in several countries for the treatment of adult patients with Clostridium difficile-associated diarrhoea. Fidaxomicin 200 mg twice daily for 10 days was an effective and generally well tolerated treatment in adult patients with a first episode or first recurrence of C. difficile infection. In two multinational phase III trials, fidaxomicin treatment was noninferior to vancomycin treatment with regard to clinical cure rates and was associated with statistically significantly lower C. difficile infection recurrence rates and statistically significantly higher global cure rates than vancomycin. The drug has a favourable pharmacological profile, including having a narrow spectrum of activity that targets relevant pathogens, minimal impact on normal faecal microflora, a convenient treatment regimen and attainment of very high faecal concentrations. Albeit further clinical experience is required to fully define the position of fidaxomicin, it is a valuable emerging option for the treatment of first episode and recurrent episodes of C. difficile-associated diarrhoea.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Clinical Trials, Phase III as Topic; Clostridioides difficile; Drug Resistance, Multiple, Bacterial; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Microbial Sensitivity Tests; Treatment Outcome

Currently available broad spectrum antibiotics are not sufficiently effective against recurrent Clostridium difficile infections (CDI). Donor faecal microbiota transplantation is a very effective treatment for second and recurrent infection but is time-consuming and requires careful screening of donors. The new narrow spectrum antibiotic fidaxomicin is a good alternative in a first CDI or a first recurrence, but treatment is expensive and there are no data on its effectiveness in a second or later recurrence. Fidaxomicin is less effective against infections caused by the Ribotype 027 strain, a virulent strain that is regularly encountered in the Netherlands. The effectiveness of various other promising narrow spectrum antibiotics is currently being investigated. Medications that support the gut flora or the immune system seem to offer new perspectives. Expectations for the currently available probiotic preparations and toxin binders are not high.

Topics: Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Clostridium Infections; Enterocolitis, Pseudomembranous; Feces; Fidaxomicin; Humans; Netherlands; Probiotics; Recurrence; Treatment Outcome

Clostridium difficile remains an important cause of infectious colitis, particularly in healthcare facilities. This review summarizes recent advances in the epidemiology, diagnosis, and treatment of this endemic pathogen.. C. difficile infection (CDI) hospitalizations and mortality rates have increased over the last decade. The BI/NAP1/027 strain has been responsible for epidemics with increased severity and mortality and is now endemic in many settings, particularly North America. Concurrent antibiotics have now been shown to decrease the cure rates for anti-C. difficile therapy and increase the risk of recurrence. Although studies implicate proton pump inhibitors as a risk for CDI, the magnitude of and the biological basis for that risk remain unclear. Molecular diagnostic techniques are rapid and sensitive but highlight the importance of using appropriate clinical testing criteria. Fidaxomicin is a promising new therapy associated with decreased recurrence; infections due to BI strains, however, are associated with inferior outcomes regardless of the treatment agent. Fecal transplantation continues to have impressive success rates for patients with recurrent CDI, and a new colon-sparing surgical procedure presents an intriguing suggested alternative to total colectomy in severe, complicated cases.. Elucidating CDI risk factors, identifying rapid, accurate diagnostic tools, and validating new treatment approaches remains an urgent priority.

Topics: Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Enterocolitis, Pseudomembranous; Feces; Fidaxomicin; Humans; Polymerase Chain Reaction; Recurrence; Risk Factors

Clostridium difficile is a main cause of health care-associated infections. The incidence and severity have been increasing. Elderly persons are at an increased risk of morbidity and mortality from C. difficile infection (CDI). Relatively few advances have been made in the treatment of CDI since it was first identified as a cause of antibiotic-associated diarrhea more than 30 years ago.. This article reviews CDI and provides an update on its treatment, including recently published clinical practice guidelines and the recently approved drug, fidaxomicin.. English-language literature was identified through a search of PubMed (1966-October 2011), Iowa Drug Information Service (1966-October 2011), and International Pharmaceutical Abstracts (1970-October 2011). Key search terms included Clostridium difficile, Clostridium infections, pseudomembranous colitis, antibiotic-associated diarrhea, Clostridium difficile-associated diarrhea, elderly, geriatric, epidemiology, microbiology, diagnosis, risk factors, treatment, drug therapy, vancomycin, metronidazole, and fidaxomicin.. Metronidazole and vancomycin remain the mainstays of CDI treatment. Current guidelines recommend oral metronidazole for initial mild to moderate episodes or first recurrence. Oral vancomycin is recommended for initial severe episodes, or first or second recurrence. Fidaxomicin was approved in 2011 for treatment of CDI, but its place in therapy has yet to be determined. Other antibiotics have been used with variable success. Saccharomyces boulardii is the only probiotic that has shown efficacy in CDI. Fecal transplants have been used successfully in some patients, but randomized studies are needed. Immune therapy with a vaccine and monoclonal antibodies is being studied in clinical trials.. Treatment of CDI is challenging due to the limited number of drugs that have proven to be effective, concerns about antibiotic resistance, and recurring disease. The recent approval of fidaxomicin provides a new alternative. Immune therapy will likely play a greater role in the future.

Topics: Aged; Aminoglycosides; Anti-Bacterial Agents; Anti-Infective Agents; Clostridioides difficile; Clostridium Infections; Diarrhea; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Infection Control; Metronidazole; Risk Factors; Vancomycin

Fidaxomicin, a macrolide antibiotic, was the first medication for the management of Clostridium difficile infections (CDI) to be approved by the US Food and Drug Administration in more than 20 years.. This article reviews published literature on fidaxomicin for management of CDI, including its chemistry, spectrum of activity, pharmacokinetic properties, pharmacodynamics, therapeutic efficacy, adverse events, dosing, administration, and pharmacoeconomic considerations.. Pertinent English-language literature was reviewed through searches of MEDLINE, EMBASE, and BIOSIS from 1975 through September 2011. Reference lists of identified publications and published abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy meetings were also reviewed. Search terms included, but were not limited to, fidaxomicin, difimicin, lipiarmycin, tiacumicin B, OPT-80, Clostridium spp, and diarrhea.. A total of 79 publications were identified and 10 were excluded; 6 review articles and 4 abstracts that were later published as articles. Fidaxomicin's in vitro profile is favorable compared with oral metronidazole and vancomycin, with minimum inhibitory concentrations against C difficile that are 2 dilutions lower. From the 2 published Phase III trials, fidaxomicin was deemed to be noninferior in the treatment of mild to moderate CDI compared with oral vancomycin. Recurrence rates for all strains of CDI were lower with fidaxomicin than vancomycin. Adverse events associated with fidaxomicin were similar to placebo, with nausea and vomiting being the most common. Although no pharmacoeconomic studies have compared fidaxomicin with metronidazole or vancomycin, the current price exceeds $2500 (US) per treatment course.. Reports suggest that fidaxomicin is noninferior to oral vancomycin in the treatment of mild or moderate CDI, although no published comparisons with metronidazole exist to date. Additionally, fidaxomicin improved outcomes compared with oral vancomycin in terms of rates of relapse and recurrent CDI, and in patients who might require concomitant antibiotics. Prospective, randomized studies comparing fidaxomicin with metronidazole in the treatment of mild or moderate CDI, as well as against vancomycin for severe CDI, should be undertaken to clarify the exact role of fidaxomicin in clinical practice.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Clostridioides difficile; Drug Costs; Drug Resistance, Bacterial; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Recurrence; Treatment Outcome

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.

Topics: Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Metronidazole; Risk Factors; Secondary Prevention; Severity of Illness Index; Treatment Outcome; Vancomycin

Clostridium difficile infection (CDI) publications have advanced in 2010 at a pace paralleling the increased frequency and severity of clinical infection. Both toxins A and B are essential virulence factors, pcr diagnostic testing is rapid, sensitive and specific, and recurrent CDI can be prevented using monoclonal antibodies to toxins A and B.

Topics: Aminoglycosides; Antibodies, Monoclonal; Bacterial Proteins; Bacterial Toxins; Clostridioides difficile; DNA, Bacterial; Enterocolitis, Pseudomembranous; Enterotoxins; Fidaxomicin; Humans; Reverse Transcriptase Polymerase Chain Reaction

Infection with Clostridium difficile is currently the leading cause of infectious diarrhea in hospitalized patients, and recent surveillance data indicate that C. difficile has surpassed methicillin-resistant Staphylococcus aureus as the number one cause of hospital-acquired infections in some areas of the USA. In addition, concern over C. difficile has increased over the past decade due to the appearance of new hypervirulent strains. Metronidazole and vancomycin have remained the treatments of choice for initial therapy of primary infection with C. difficile for the past 25 years, but the persistence of spores leads to a recurrence of infection in an estimated 20-25% of patients. Patients who have one recurrent episode have up to a 65% chance of having additional recurrence. While the judicious use of antimicrobials in accordance with antibiotic stewardship guidelines remains the most effective method for the control of C. difficile, the high recurrence rate, increasing incidence, and changing epidemiology of C. difficile has led to an increased interest in the study of alternative strategies for the prevention and treatment of C. difficile disease. These alternative strategies attempt to eliminate C. difficile spores, replenish the normal gut flora, reduce the C. difficile toxin load in the bowel, or bolster the patient's own immune response to the C. difficile toxins. To evaluate the available evidence on these alternative strategies, we conducted a literature search of MEDLINE (1966-March 2011) and International Pharmaceutical Abstracts (1970-March 2011). Available citations from these articles were also utilized. The aim of this review is to summarize the available evidence for alternative treatment strategies for C. difficile disease and to make recommendations for their place in therapy.

Topics: Aminoglycosides; Anti-Infective Agents; Clostridioides difficile; Clostridium Infections; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Immunotherapy; Nitro Compounds; Polymers; Probiotics; Thiazoles

Clostridium difficile infection is now a major concern throughout the developed world and its occurrence is a consequence of broad-spectrum antibiotic therapy primarily in the elderly in-patient population and high spore loads in hospitals in these regions. With the emergence of a hypervirulent, endemic strain, more severe disease is being recognized and is occurring in previously considered unusual patient groups. Vancomycin and metronidazole are the current mainstays for therapy of severe and nonsevere disease, respectively. Relapse is a major concern, with treatment options for these cases often difficult. Any new drug must be better than vancomycin for severe disease with fewer relapses. Fidaxomicin, a macrocyclic RNA polymerase inhibitor, has a narrow spectrum of activity, which is almost C. difficile specific. This drug appears to have a higher clinical cure rate than vancomycin, and fewer patients relapse following initial treatment. From the results of a recent Phase III trial, fidaxomicin appears to be an extremely promising drug for treating C. difficile infection and preventing relapses.

Topics: Aged; Aminoglycosides; Anti-Bacterial Agents; Bacterial Proteins; Clinical Trials as Topic; Clostridioides difficile; Cross Infection; DNA-Directed RNA Polymerases; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Secondary Prevention; Treatment Outcome; Vancomycin

Clostridium difficile infection (CDI) is associated with consumption of antibiotics which disrupt the normal microbial flora of the gut, allowing C. difficile to establish itself and produce disease. Currently, only vancomycin or metronidazole are recommended for treatment and many patients suffer from relapse on infection. Hence, there is a need for new treatment options.. This review evaluates five agents in development where the focus is on treatment of CDI.. This review gives up-to-date information on fidaxomicin, REP3123, oritavancin, NVB302 and nitazoxanide and their likelihood of being licensed for the treatment of CDI.. One agent, fidaxomicin, has undergone Phase III clinical trials which show it to be a promising new agent for the treatment of CDI with a low rate of relapse. Nitazoxanide is licensed for the treatment of parasitic intestinal infections but is not licensed for CDI. However, in small scale clinical trials it has been shown to have activity comparable to that of vancomycin and metronidazole. The other agents are all at early stages of development and clinical trials to evaluate their therapeutic potential for CDI have not yet been undertaken.

Topics: Aminoglycosides; Anti-Bacterial Agents; Benzopyrans; Clostridioides difficile; Enterocolitis, Pseudomembranous; Fidaxomicin; Glycopeptides; Humans; Lipoglycopeptides; Nitro Compounds; Thiazoles; Thiophenes

Treatment of Clostridium difficile infection (CDI) has relied on 2 antimicrobial agents, metronidazole and vancomycin, since the recognition of this disease entity. While effective, these "inside the box" approaches to CDI management have the disadvantage of further microbial disruption of the host indigenous microflora. "Outside the box" therapies use non-antimicrobial approaches to management and are theoretically less prone to causing recurrent CDI episodes. Recent advances in understanding of "inside the box" approaches include appreciation of the decreased efficacy of metronidazole overall and the superior efficacy of vancomycin for treatment of severe CDI, as well as a new agent under development, fidaxomicin, which appears to be equal in efficacy to vancomycin but with less risk of subsequent CDI recurrences. Several "outside the box" approaches have also entered clinical development, including use of monoclonal antibodies, active vaccination, luminal toxin binders, and nontoxigenic C. difficile. These reports provide optimism that more-effective management of CDI is forthcoming.

Topics: Aminoglycosides; Anti-Bacterial Agents; Antibodies, Bacterial; Antibodies, Monoclonal; Antitoxins; Clostridioides difficile; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Metronidazole; Vaccination; Vancomycin

Clostridium difficile-associated diarrhea (CDAD) is common during hematopoietic stem-cell transplantation (HSCT) and is associated with increased morbidity and mortality. We evaluated fidaxomicin for prevention of CDAD in HSCT patients.. In this double-blind study, subjects undergoing HSCT with fluoroquinolone prophylaxis stratified by transplant type (autologous/allogeneic) were randomized to once-daily oral fidaxomicin (200 mg) or a matching placebo. Dosing began within 2 days of starting conditioning or fluoroquinolone prophylaxis and continued until 7 days after neutrophil engraftment or completion of fluoroquinolone prophylaxis/clinically-indicated antimicrobials for up to 40 days. The primary endpoint was CDAD incidence through 30 days after study medication. The primary endpoint analysis counted confirmed CDAD, receipt of CDAD-effective medications (for any indication), and missing CDAD assessment (for any reason, including death) as failures; this composite analysis is referred to as "prophylaxis failure" to distinguish from the pre-specified sensitivity analysis, which counted only confirmed CDAD (by toxin immunoassay or nucleic acid amplification test) as failure.. Of 611 subjects enrolled, 600 were treated and analyzed. Prophylaxis failure was similar in fidaxomicin and placebo recipients (28.6% vs 30.8%; difference 2.2% [-5.1, 9.5], P = .278). However, most failures were due to non-CDAD events. Confirmed CDAD was lower in fidaxomicin vs placebo recipients (4.3% vs 10.7%; difference 6.4% [2.2, 10.6], P = .0014). Drug-related adverse events occurred in 15.0% of fidaxomicin recipients and 20.0% of placebo recipients.. While no difference was demonstrated between arms in the primary analysis, results of the sensitivity analysis demonstrated that fidaxomicin significantly reduced the incidence of CDAD in HSCT recipients.. NCT01691248.

Topics: Adult; Aged; Anti-Bacterial Agents; Clostridioides difficile; Double-Blind Method; Enterocolitis, Pseudomembranous; Female; Fidaxomicin; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged

Clostridium difficile infection causes severe complications and frequently recurs. An extended-pulsed fidaxomicin regimen might facilitate sustained clinical cure by prolonging C difficile suppression and supporting gut microbiota recovery. We aimed to compare clinical outcomes of extended-pulsed fidaxomicin with standard vancomycin.. In this randomised, controlled, open-label, superiority study, we recruited hospitalised adults aged 60 years and older with confirmed C difficile infection at 86 European hospitals. Patients were randomly assigned (1:1) using an interactive web response system to receive extended-pulsed fidaxomicin (200 mg oral tablets, twice daily on days 1-5, then once daily on alternate days on days 7-25) or vancomycin (125 mg oral capsules, four times daily on days 1-10), stratified by baseline C difficile infection severity, cancer presence, age (≥75 years vs <75 years), and number of previous C difficile infection occurrences. The primary endpoint was sustained clinical cure 30 days after end of treatment (day 55 for extended-pulsed fidaxomicin and day 40 for vancomycin), assessed in all randomised patients who met the inclusion criteria and received at least one dose of study medication (modified full analysis set). Adverse events were assessed in all patients who received at least one dose of study drug. The study is registered with ClinicalTrials.gov, number NCT02254967.. Between Nov 6, 2014, and May 5, 2016, 364 patients were enrolled and randomly assigned to receive extended-pulsed fidaxomicin or vancomycin. 362 patients received at least one dose of study medication (181 in each group). 124 (70%) of 177 patients in the modified full analysis set receiving extended-pulsed fidaxomicin achieved sustained clinical cure 30 days after end of treatment, compared with 106 (59%) of 179 patients receiving vancomycin (difference 11% [95% CI 1·0-20·7], p=0·030; odds ratio 1·62 [95% CI 1·04-2·54]). Incidence of treatment-emergent adverse events did not differ between extended-pulsed fidaxomicin (121 [67%] of 181) and vancomycin (128 [71%] of 181) treatment arms. One death in the vancomycin arm was considered by the investigator to be related to study drug.. Extended-pulsed fidaxomicin was superior to standard-dose vancomycin for sustained cure of C difficile infection, and, to our knowledge, extended-pulsed fidaxomicin recurrence rates in this study are the lowest observed in a randomised clinical trial of antibiotic treatment for C difficile infection.. Astellas Pharma, Inc.

Topics: Aged; Aged, 80 and over; Clostridioides difficile; Enterocolitis, Pseudomembranous; Female; Fidaxomicin; Humans; Male; Middle Aged; Vancomycin

In patients with first episode Clostridium difficile infection treated with vancomycin or fidaxomicin, more patients receiving fidaxomicin achieved at least 2 log10 colony-forming units/g reduction in spores at the follow-up visit (P=.02). Similar to published literature, a higher proportion of patients receiving fidaxomicin demonstrated sustained clinical response.

Topics: Adult; Aged; Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Colony Count, Microbial; Connecticut; Enterocolitis, Pseudomembranous; Feces; Female; Fidaxomicin; Humans; Male; Middle Aged; Polymerase Chain Reaction; Vancomycin

Patients with cancer are at increased risk for Clostridium difficile-associated diarrhea (CDAD). Little is known about treatment response.. Two double-blind trials randomly allocated 1,105 patients with CDAD to fidaxomicin or vancomycin treatment (modified intent-to-treat [mITT]), and 183 of these had cancer. Univariate and multivariate post hoc analyses compared effects of treatment and patient characteristics on cure, recurrence, and sustained response after 4 weeks. Time to resolution of diarrhea (TTROD) was also evaluated.. Patients with cancer had a lower cure rate and longer TTROD than patients without cancer. Recurrence rates were similar. Cure was more likely with fidaxomicin than vancomycin (odds ratio [OR] 2.0; P = .065), recurrence was less likely (OR = 0.37; P = .018), and sustained response more frequent (OR = 2.56; P = .003). Under vancomycin, median TTROD was longer in patients with cancer than in those without (123 v 58 hours; log-rank P < .001). With fidaxomicin, median TTROD was not significantly affected by presence of cancer (74 v 54 hours; log-rank P = .145). In the full mITT population, age, hypoalbuminemia, and cancer were inversely associated with clinical cure by multivariate analysis. Study treatment with vancomycin was a significant predictor of recurrence (P < .001). Within the cancer population, low albumin was negatively and fidaxomicin was positively associated with improved cure.. For patients with cancer, fidaxomicin treatment was superior to vancomycin, resulting in higher cure and sustained response rates, shorter TTROD, and fewer recurrences.

Topics: Adult; Aged; Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Diarrhea; Double-Blind Method; Enterocolitis, Pseudomembranous; Female; Fidaxomicin; Humans; Kaplan-Meier Estimate; Logistic Models; Male; Middle Aged; Multivariate Analysis; Secondary Prevention; Treatment Outcome; Vancomycin

Clostridium difficile infections remain a problem especially for patients in the intensive care unit. The fact that C. difficile infections are strongly associated with antibiotic therapy calls for more caution in the use of antibiotics, especially in patients with a high risk of developing C. difficle infections. Severe infections and recurrent episodes are usually difficult to manage and therapeutic options are often limited. The method of stool transplantation, though not new, has received more attention in recent years, with studies showing stool transplantation to be a promising and easy method which has high clinical cure rates even for recurrent C. difficile infections. However, more randomised and controlled trials are needed to further study the efficacy of stool transplantation in patients with C. difficile infection.

Topics: Aminoglycosides; Biodiversity; Cause of Death; Colonoscopy; Cross Infection; Disinfection; Enterocolitis, Pseudomembranous; Feces; Fidaxomicin; Hospital Mortality; Humans; Metronidazole; Patient Readmission; Prognosis; Recurrence; Tomography, X-Ray Computed; Transplantation; Vancomycin

Infection with Clostridium difficile is the primary infective cause of antibiotic-associated diarrhoea. We aimed to compare efficacy and safety of fidaxomicin and vancomycin to treat patients with C difficile infection in Europe, Canada, and the USA.. In this multicentre, double-blind, randomised, non-inferiority trial, we enrolled patients from 45 sites in Europe and 41 sites in the USA and Canada between April 19, 2007, and Dec 11, 2009. Eligible patients were aged 16 years or older with acute, toxin-positive C difficile infection. Patients were randomly allocated (1:1) to receive oral fidaxomicin (200 mg every 12 h) or oral vancomycin (125 mg every 6 h) for 10 days. The primary endpoint was clinical cure, defined as resolution of diarrhoea and no further need for treatment. An interactive voice-response system and computer-generated randomisation schedule gave a randomisation number and medication kit number for each patient. Participants and investigators were masked to treatment allocation. Non-inferiority was prespecified with a margin of 10%. Modified intention-to-treat and per-protocol populations were analysed. This study is registered with ClinicalTrials.gov, number NCT00468728.. Of 535 patients enrolled, 270 were assigned fidaxomicin and 265 vancomycin. After 26 patients were excluded, 509 were included in the modified intention-to-treat (mITT) population. 198 (91·7%) of 216 patients in the per-protocol population given fidaxomicin achieved clinical cure, compared with 213 (90·6%) of 235 given vancomycin, meeting the criterion for non-inferiority (one-sided 97·5% CI -4·3%). Non-inferiority was also shown for clinical cure in the mITT population, with 221 (87·7%) of 252 patients given fidaxomicin and 223 (86·8%) of 257 given vancomycin cured (one-sided 97·5% CI -4·9%). In most subgroup analyses of the primary endpoint in the mITT population, outcomes in the two treatment groups did not differ significantly; although patients receiving concomitant antibiotics for other infections had a higher cure rate with fidaxomicin (46 [90·2%] of 51) than with vancomycin (33 [73·3%] of 45; p=0·031). Occurrence of treatment-emergent adverse events did not differ between groups. 20 (7·6%) of 264 patients given at least one dose of fidaxomicin and 17 (6·5%) of 260 given vancomycin died.. Fidaxomicin could be an alternative treatment for infection with C difficile, with similar efficacy and safety to vancomycin.. Optimer Pharmaceuticals.

Topics: Aged; Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Diarrhea; Double-Blind Method; Enterocolitis, Pseudomembranous; Feces; Female; Fidaxomicin; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Prospective Studies; Vancomycin

Clostridium difficile infection is a serious diarrheal illness associated with substantial morbidity and mortality. Patients generally have a response to oral vancomycin or metronidazole; however, the rate of recurrence is high. This phase 3 clinical trial compared the efficacy and safety of fidaxomicin with those of vancomycin in treating C. difficile infection.. Adults with acute symptoms of C. difficile infection and a positive result on a stool toxin test were eligible for study entry. We randomly assigned patients to receive fidaxomicin (200 mg twice daily) or vancomycin (125 mg four times daily) orally for 10 days. The primary end point was clinical cure (resolution of symptoms and no need for further therapy for C. difficile infection as of the second day after the end of the course of therapy). The secondary end points were recurrence of C. difficile infection (diarrhea and a positive result on a stool toxin test within 4 weeks after treatment) and global cure (i.e., cure with no recurrence).. A total of 629 patients were enrolled, of whom 548 (87.1%) could be evaluated for the per-protocol analysis. The rates of clinical cure with fidaxomicin were noninferior to those with vancomycin in both the modified intention-to-treat analysis (88.2% with fidaxomicin and 85.8% with vancomycin) and the per-protocol analysis (92.1% and 89.8%, respectively). Significantly fewer patients in the fidaxomicin group than in the vancomycin group had a recurrence of the infection, in both the modified intention-to-treat analysis (15.4% vs. 25.3%, P=0.005) and the per-protocol analysis (13.3% vs. 24.0%, P=0.004). The lower rate of recurrence was seen in patients with non–North American Pulsed Field type 1 strains. The adverse-event profile was similar for the two therapies.. The rates of clinical cure after treatment with fidaxomicin were noninferior to those after treatment with vancomycin. Fidaxomicin was associated with a significantly lower rate of recurrence of C. difficile infection associated with non–North American Pulsed Field type 1 strains. (Funded by Optimer Pharmaceuticals; ClinicalTrials.gov number, NCT00314951.)

Topics: Adult; Aged; Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Clostridium Infections; Double-Blind Method; Enterocolitis, Pseudomembranous; Feces; Female; Fidaxomicin; Humans; Intention to Treat Analysis; Male; Microbial Sensitivity Tests; Middle Aged; Prospective Studies; Secondary Prevention; Treatment Outcome; Vancomycin

A 10-day course of oral fidaxomicin (200 mg twice a day [b.i.d.]), a potent new macrocyclic drug, was compared to vancomycin (125 mg four times a day [q.i.d.]) in 1,164 adults (1,105 in the modified intent-to-treat [mITT] population) with Clostridium difficile infection in two phase III randomized, double-blind trials at sites in North America and 7 European countries. Of 1,105 mITT patients, 792 (71.7%), including 719/999 (72.0%) in the per-protocol (PP) population, provided a C. difficile strain at baseline, of whom 356 received fidaxomicin with 330 cures (92.7%) and 363 received vancomycin with 329 cures (90.6%). The susceptibilities (MIC(90)) of baseline isolates did not predict clinical cure, failure, or recurrence for fidaxomicin (MIC(90), 0.25 μg/ml for both; range, ≤ 0.007 to 1 μg/ml), but there was a one-dilution difference in the MIC(90) (but not the MIC(50)) for vancomycin (MIC(90), 2 μg/ml [range, 0.25 to 8 μg/ml] for cure and 4.0 μg/ml [range, 0.5 to 4 μg/ml] for failures). A total of 65 (7.9%) "rifaximin-resistant" (MIC > 256 μg/ml) strains were isolated in both treatment groups on enrollment, which increased to 25% for failures at the end of therapy. No resistance to either fidaxomicin or vancomycin developed during treatment in either of the phase III studies, although a single strain isolated from a cured patient had an elevated fidaxomicin MIC of 16 μg/ml at the time of recurrence. All isolates were susceptible to ≤ 4 μg/ml of metronidazole. When analyzed by restriction endonuclease analysis (REA) type, 247/719 (34.4%) isolates were BI group isolates, and the MICs were generally higher for all four drugs tested (MIC(90)s: fidaxomicin, 0.5; vancomycin, 2.0; metronidazole, 2.0; and rifaximin, >256 μg/ml) than for the other REA types. There was no correlation between the MIC of a baseline clinical isolate and clinical outcome. MIC(90)s were generally low for fidaxomicin and vancomycin, but BI isolates had higher MICs than other REA group isolates.

Topics: Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Enterocolitis, Pseudomembranous; Female; Fidaxomicin; Humans; Male; Prohibitins; Vancomycin

Clostridium difficile infections have a high recurrence rate, which can complicate the prognosis of affected patients. It is therefore important to establish an early detection and an appropriate therapeutic strategy. The objective of this manuscript was to gather the opinion of an expert group about the predictive factors of poor progression, as well as when to use fidaxomicin in different groups of high-risk patients.. A scientific committee of three experts in infectious diseases reviewed the most recent literature on the management of C. difficile infections, and the use of fidaxomicin. They developed a questionnaire of 23 items for consensus by 15 specialists in this type of infection using a modified Delphi method.. The consensus reached by the panelists was 91.3% in terms of agreement. The most important agreements were: recurrence is a risk criterion per se; fidaxomicin is effective and safe for the treatment of infections caused by C. difficile in critical patients, immunosuppressed patients, or patients with chronic renal failure; fidaxomicin is recommended from the first episode of infection to ensure maximum efficacy in patients with well-contrasted recurrence risk factors.. The experts consulted showed a high degree of agreement on topics related to the selection of patients with poorer prognosis, as well as on the use of fidaxomicin in groups of high-risk patients, either in the first line or in situations of recurrence.

Topics: Anti-Bacterial Agents; Clostridioides difficile; Clostridium Infections; Consensus; Delphi Technique; Disease Progression; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Patient Selection; Prognosis; Recurrence; Surveys and Questionnaires

Topics: Clostridium Infections; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans

Antibiotic drug development remains a major challenge with few candidates in clinical development. Ramizol, a first-in-class styrylbenzene antibiotic, is under development for the treatment of Clostridium difficile associated disease. Here, we investigate the in vitro antibacterial activity of Ramizol in comparison to fidaxomicin, vancomycin and metronidazole against 100 clinical isolates of C. difficile by the broth microdilution method. We show there is no apparent impact of ribotype, toxin-production, or resistance to fidaxomicin, vancomycin or metronidazole on the activity of Ramizol. Moreover, we show Ramizol has a narrower MIC range translating to potentially better control over the therapeutic dose. Together, these results support the further development of Ramizol for the treatment of C. difficile associated disease.

Topics: Anti-Bacterial Agents; Benzoates; Clostridioides difficile; Drug Resistance, Bacterial; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Inhibitory Concentration 50; Metronidazole; Microbial Sensitivity Tests; Stilbenes; Vancomycin

The aim of this work was to describe the use of a combination of fidaxomicin and fecal microbiota therapy (FMT) in Clostridium difficile infection (CDI).. A 78-year-old female, who was admitted for surgery due to acute diverticulitis caused by postoperative complications and broad antibiotic therapy, developed CDI-induced colitis. Despite the introduction of metronidazole and vancomycin therapy, her clinical condition continued to deteriorate. She was transferred to the intensive care unit where FMT followed by fidaxomicin were performed because her C-reactive protein and leucocyte levels remained elevated. Further clinical improvement and the resolution of colitis was observed.. In this case, severe CDI colitis was successfully treated with the combination of FMT and fidaxomicin.

Topics: Aged; Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Clostridium Infections; Enterocolitis, Pseudomembranous; Fecal Microbiota Transplantation; Female; Fidaxomicin; Humans

To report the successful use of crushed fidaxomicin via a nasogastric tube for treatment of a severe Clostridium difficile infection in a critically ill patient.. Clinical observation of a patient, images of abdominal computed tomography, antimicrobial therapy and course of infection parameters.. Relevant information contained in the medical observation of the patient and selection of image and laboratory parameters performed in the patient.. We report a case of a 79-year old patient who developed septic shock with an increasing need for norepinephrine and acute renal failure due to a severe Clostridium difficile infection. Antimicrobial therapy with vancomycin via a nasogastric tube and metronidazole i.v. did not lead to improvement, infection parameters further increased, and the clinical condition became increasingly impaired. After 10 days, antimicrobial therapy was changed to fidaxomicin, crushed and administered via nasogastric tube. Within 24hours, infection parameters decreased. Further diarrhoea ceased and stool samples were negative for Clostridium difficile antigen.. Our case confirms that administration of fidaxomicin via a nasogastric tube was safe and effective in this patient. Further studies are needed to evaluate the efficacy of this strategy in critically ill patients systematically.

Topics: Aged; Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Critical Illness; Diarrhea; Enterocolitis, Pseudomembranous; Female; Fidaxomicin; Humans; Intubation, Gastrointestinal; Shock, Septic; Treatment Outcome

Clostridium difficile infection (CDI) is characterized by high rates of recurrence, resulting in substantial health care costs. The aim of this study was to analyze the cost-effectiveness of treatments for the management of second recurrence of community-onset CDI in France.. We developed a decision-analytic simulation model to compare 5 treatments for the management of second recurrence of community-onset CDI: pulsed-tapered vancomycin, fidaxomicin, fecal microbiota transplantation (FMT) via colonoscopy, FMT via duodenal infusion, and FMT via enema. The model outcome was the incremental cost-effectiveness ratio (ICER), expressed as cost per quality-adjusted life year (QALY) among the 5 treatments. ICERs were interpreted using a willingness-to-pay threshold of €32,000/QALY. Uncertainty was evaluated through deterministic and probabilistic sensitivity analyses.. Three strategies were on the efficiency frontier: pulsed-tapered vancomycin, FMT via enema, and FMT via colonoscopy, in order of increasing effectiveness. FMT via duodenal infusion and fidaxomicin were dominated (i.e. less effective and costlier) by FMT via colonoscopy and FMT via enema. FMT via enema compared with pulsed-tapered vancomycin had an ICER of €18,092/QALY. The ICER for FMT via colonoscopy versus FMT via enema was €73,653/QALY. Probabilistic sensitivity analysis with 10,000 Monte Carlo simulations showed that FMT via enema was the most cost-effective strategy in 58% of simulations and FMT via colonoscopy was favored in 19% at a willingness-to-pay threshold of €32,000/QALY.. FMT via enema is the most cost-effective initial strategy for the management of second recurrence of community-onset CDI at a willingness-to-pay threshold of €32,000/QALY.

Topics: Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Community-Acquired Infections; Computer Simulation; Cost-Benefit Analysis; Decision Trees; Enterocolitis, Pseudomembranous; Fecal Microbiota Transplantation; Fidaxomicin; France; Health Care Costs; Humans; Models, Economic; Quality-Adjusted Life Years; Recurrence; Vancomycin

The promotion of colonization with vancomycin-resistant enterococci (VRE) is one potential side effect during treatment of Clostridium difficile-associated diarrhea (CDAD), resulting from disturbances in gut microbiota. Cadazolid (CDZ) is an investigational antibiotic with potent in vitro activity against C. difficile and against VRE and is currently in clinical development for the treatment of CDAD. We report that CDZ treatment did not lead to intestinal VRE overgrowth in mice.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Clostridioides difficile; Colony Count, Microbial; Diarrhea; Enterocolitis, Pseudomembranous; Fidaxomicin; Intestines; Metronidazole; Mice; Microbial Sensitivity Tests; Oxazolidinones; Streptococcal Infections; Treatment Outcome; Vancomycin; Vancomycin Resistance; Vancomycin-Resistant Enterococci

Clostridium difficile infection (CDI) represents a significant economic healthcare burden, especially the cost of recurrent disease. Fidaxomicin produced significantly lower recurrence rates and higher sustained cure rates in clinical trials. We evaluated the cost-effectiveness and budget impact of fidaxomicin compared with vancomycin in Germany in the first-line treatment of patient subgroups with CDI at increased risk of recurrence.. A semi-Markov model was used to compare the cost-effectiveness and budget impact of fidaxomicin vs. vancomycin from a payer perspective in Germany. The model cycle length was 10 days. The time horizon was 1 year. Model inputs were probability of clinical cure, 30-day probability of recurrence, and 30-day attributable mortality based on evidence from two randomized controlled trials comparing fidaxomicin and vancomycin in patients with CDI. Cost-effectiveness outcomes were cost per quality-adjusted life year gained, cost per bed-day saved, and cost per recurrence avoided.. Despite higher drug acquisition costs, fidaxomicin was dominant in the cancer subgroup (less costly and more effective) and cost-effective in the other subgroups, with incremental cost-effectiveness ratios vs. vancomycin ranging from €26,900 to €44,500. Hospitalization costs of the first-line treatment of CDI with fidaxomicin vs. vancomycin were lower in every patient subgroup, resulting in budget impacts ranging from -€1325 (in patients ≥65 years) to -€2438 (in cancer patients). Reductions in the cost of treating recurrence with fidaxomicin ranged from -€574.32 per patient in those receiving concomitant antibiotics to -€1500.68 per patient in renally impaired patients.. In patient subgroups with CDI at increased recurrence risk, fidaxomicin was cost-effective vs. vancomycin, and less costly and more effective in patients with cancer.

Topics: Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Cost-Benefit Analysis; Enterocolitis, Pseudomembranous; Fidaxomicin; Germany; Humans; Markov Chains; Recurrence

The advantages and disadvantages of various antibiotics used in the treatment of Clostridium difficile infection (CDI) are compared with respect to their pharmacokinetic and pharmacodynamic properties. Recommendations are made for their optimal use in clinical practice. Metronidazole is suitable for the treatment of mild forms of CDI which are essentially self-limiting. Vancomycin kills clostridia reliably but the treatment is encumbered with considerable risk of recurrence. This can be decreased by shortening the treatment to seven days and then switching to a (pulse, taper, chaser) regimen to prevent recurrence or by active restoration of the intestinal ecosystem (fecal transplant). Fidaxomicin works faster than vancomycin and is associated with a lower risk of recurrence. Thus, it can be profitably used in patients with impending ileus and also in those whose medical condition does not allow prolonged treatment. The duration of fidaxomicin treatment could be reduced to as few as five days. Rifaximin does not have a clear place in the treatment of CDI because no compelling data are available on its efficacy in this disease. The risk of resistance is also important. Tigecycline is a promising antibiotic for parenteral use. According to the available data, it should be more effective than intravenous metronidazole which has been considered the drug of choice.Clostridial colitis is associated with intestinal dysmicrobia which is the major cause of recurrence. Severe dysmicrobia cannot be treated by antibiotics but only by gut flora restoration; stool transplant from a healthy donor is the only proven therapy for this condition.

Topics: Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Drug Resistance, Bacterial; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Metronidazole; Recurrence; Vancomycin

Clostridium difficile (C. difficile) is an anaerobic, Gram-positive, spore-forming, toxin-secreting bacillus. It is transmitted via a fecal-oral route and can be found in 1-3 % of the healthy population. Symptoms caused by C. difficile range from uncomplicated diarrhea to a toxic megacolon. The incidence, frequency of recurrence, and mortality rate of C. difficile infections (CDIs) have increased significantly over the past few decades. The most important risk factor is antibiotic treatment in elderly patients and patients with severe comorbidities. There is a screening test available to detect C. difficile-specific glutamate dehydrogenase (GDH), which is produced by both toxigenic and non-toxigenic strains. To confirm CDIs, it is necessary to test for toxins in a fresh, liquid stool sample via polymerase chain reaction or an enzyme-coupled immune adsorption test. If CDIs are diagnosed, then ongoing antibiotic treatment should be ended. Metronidazole is used to treat mild cases, and vancomycin is recommended for severe cases. Vancomycin or fidaxomicin should be used to treat recurrences (10-25 % of patients). In cases with several recurrences, a treatment option is fecal microbiome transfer (FMT). The cure rate following FMT is approximately 80 %. The treatment of severe and complicated CDI with a threatening toxic megacolon remains problematic. The degree of evidence of medicated treatment in this situation is low; the significance of metronidazole i. v. as an additional therapeutic measure is controversial. Tigecycline i. v. is an alternative option. Surgical treatment must be considered in patients with a toxic megacolon or an acute abdomen.

Topics: Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Diarrhea; Enterocolitis, Pseudomembranous; Evidence-Based Medicine; Fidaxomicin; Humans; Megacolon, Toxic; Metronidazole; Treatment Outcome; Vancomycin

For surgeons the early identification of patients with clostridium difficile infections (CDI) is important, because the incidence and virulence of this potentially life-threatening disease are increasing.. The aim of this study was to describe the frequency of CDI among surgical patients, to analyze which treatment was successful and to define which factors were associated with mortality.. A retrospective analysis of patients with CDI was performed.. From January 2004 to June 2012 the overall incidence of CDI among all departments at the St. Josef Hospital, Ruhr University Bochum was 0.6 % (1669 out of 301,919 patients). In 2004 the number of surgical patients with CDI was 1 which increased to 41 in 2011. Before the diagnosis of CDI was made 84 % (151 out of 179) of patients had received an antibiotic treatment. Conservative management of CDI was performed with metronidazole in 75 % (134 out of 179), 60 % (107 out of 179) received vancomycin, while 44 % (79 out of 179) received a combination of metronidazole and vancomycin, tygecycline or fidaxomidin. The overall mortality was 7 % (12 out of 179). There was a significant association with mortality for patients with sepsis, readmission to the intensive care unit (ICU), requirement for vasopressor therapy and intubation with mechanical ventilation. In 4 % of patients (7 out of 179) colectomy was carried out. Despite maximum intensive care management, 86 % (6 out of 7) of patients who underwent colectomy ultimately died.. Although conservative management is successful for most patients with CDI, the mortality is high for patients who require intensive care management secondary to CDI. Mortality after colectomy for CDI is almost 100 %, mostly because the operation is usually only performed as a last resort in patients with sepsis. The most important risk factor for CDI is a prior antibiotic therapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Cohort Studies; Cross Infection; Cross-Sectional Studies; Drug Therapy, Combination; Enterocolitis, Pseudomembranous; Female; Fidaxomicin; Germany; Hospital Mortality; Humans; Incidence; Intensive Care Units; Male; Metronidazole; Middle Aged; Minocycline; Patient Readmission; Retrospective Studies; Survival Rate; Tigecycline; Vancomycin; Young Adult

Topics: Abdominal Pain; Aged; Aged, 80 and over; Aminoglycosides; Anti-Bacterial Agents; Biological Therapy; Capsules; Clostridioides difficile; Colonoscopy; Diarrhea; Drug Administration Schedule; Enterocolitis, Pseudomembranous; Feces; Female; Fidaxomicin; Freezing; Humans; Irritable Bowel Syndrome; Male; Metronidazole; Microbiota; Recurrence; Transplantation, Homologous; Treatment Outcome; Vancomycin

In 2011 a surveillance study for the susceptibility to fidaxomicin and epidemiology of Clostridium difficile isolates in the United States was undertaken in seven geographically dispersed medical centers. This report encompasses baseline surveillance in 2011 and 2012 on 925 isolates. A convenience sample of C. difficile isolates or toxin positive stools from patients were referred to a central laboratory. Antimicrobial susceptibility was determined by agar dilution (CLSI M11-A8). Clinical and Laboratory Standards Institute (CLSI), Food and Drug Administration, or European Union of Clinical Antimicrobial Susceptibility Testing (EUCAST) breakpoints were applied where applicable. Toxin gene profiles were characterized by multiplex PCR on each isolate. A random sample of 322 strains, stratified by institution, underwent restriction endonuclease analysis (REA). The fidaxomicin MIC90 was 0.5 μg/ml for all isolates regardless of REA type or toxin gene profile, and all isolates were inhibited at ≤1.0 μg/ml. By REA typing, BI strains represented 25.5% of the isolates. The toxin gene profile of tcdA, tcdB, and cdtA/B positive with a tcdC 18-bp deletion correlated with BI REA group. Moxifloxacin and clindamycin resistance was increased among either BI or binary toxin-positive isolates. Metronidazole and vancomycin showed reduced susceptibility (EUCAST criteria) in these isolates. Geographic variations in susceptibility, REA group and binary toxin gene presence were observed. Fidaxomicin activity against C. difficile isolated in a national surveillance study did not change more than 1 year after licensure. This analysis provides baseline results for future comparisons.

Topics: Aminoglycosides; Anti-Bacterial Agents; Bacterial Toxins; Clindamycin; Clostridioides difficile; Diarrhea; Drug Resistance, Bacterial; Enterocolitis, Pseudomembranous; Fidaxomicin; Fluoroquinolones; Genes, Bacterial; Humans; Metronidazole; Microbial Sensitivity Tests; Moxifloxacin; Multiplex Polymerase Chain Reaction; Prohibitins; Sentinel Surveillance; United States; Vancomycin

Topics: Adult; Aminoglycosides; Child; Clostridioides difficile; Enterocolitis, Pseudomembranous; Feces; Fidaxomicin; Humans; Male; Pouchitis; Rifamycins; Rifaximin; Vancomycin

Toxigenic strains of Clostridium (C.) difficile are the most prevalent pathogens of antibiotic associated intestinal disease and nosocomial diarrhoea. During the last 10 years, incidences of C. difficile infection (CDI) have increased worldwide.. With clinical and microbiological original data for 2002-2012 from the University Hospitals Leipzig and Halle (Saale), Germany, the authors illustrate the current situation regarding CDI in the states of Saxony and Saxony-Anhalt and exemplify the latest developments in terms of incidence, prevalence of resistance, diagnosis and treatment strategies regarding CDI with an emphasis on surgical options.. Following the general trend, at the University Hospitals of Leipzig and Halle (Saale) there was also an increase in incidence of CDI, especially of severe clinical courses. In primary and secondary care facilities, prevention of CDI is based on hygiene management and restricted usage of antibiotics, preferably as "Antibiotic Stewardship" programmes. In 2012, the new macrocyclic antibiotic Fidaxomicin was approved in the European Union for the treatment of CDI. The therapeutic armamentarium, previously based on metronidazole or vancomycin, has now been enriched by a substance that presumably will reduce the rate of recurrence of CDI. Moreover, early data from case series and controlled trials suggest that the re-establishment of eubiosis in the colon of patients with recurrent CDI by stool transplantation from healthy donors is an alternative to antibiotics. Standard surgical intervention for refractory CDI is subtotal colectomy with terminal ileostomy. In patients with adequate life expectancy and without organ dysfunction, a colon-saving surgical technique should be considered.. Taking antibiotics for most remains the main risk factor for suffering from symptomatic CDI. With the introduction of Fidaxomicin there is hope for an improvement in the conservative treatment of CDI. Stool transplants from healthy donors are now considered to be better than giving antibiotics for severe CDI, but this treatment has not found broad acceptance yet. In cases with a lack of early treatment success, the surgeon must be consulted. Here, the evidence for preferably colon-saving surgical procedures is so far unfortunately low.

Topics: Aminoglycosides; Clostridioides difficile; Colectomy; Colostomy; Cross-Sectional Studies; Drug Resistance, Multiple, Bacterial; Enterocolitis, Pseudomembranous; Feces; Fidaxomicin; Germany; Humans; Incidence; Metronidazole; Recurrence; Transplantation; Vancomycin

Clostridium difficile infection (CDI) is a common, debilitating infection with high morbidity and mortality. C. difficile causes diarrhea and intestinal inflammation by releasing two toxins, toxin A and toxin B. The macrolide antibiotic fidaxomicin was recently shown to be effective in treating CDI, and its beneficial effect was associated with fewer recurrent infections in CDI patients. Since other macrolides possess anti-inflammatory properties, we examined the possibility that fidaxomicin alters C. difficile toxin A-induced ileal inflammation in mice. The ileal loops of anesthetized mice were injected with fidaxomicin (5, 10, or 20 μM), and after 30 min, the loops were injected with purified C. difficile toxin A or phosphate-buffered saline alone. Four hours after toxin A administration, ileal tissues were processed for histological evaluation (epithelial cell damage, neutrophil infiltration, congestion, and edema) and cytokine measurements. C. difficile toxin A caused histologic damage, evidenced by increased mean histologic score and ileal interleukin-1β (IL-1β) protein and mRNA expression. Treatment with fidaxomicin (20 μM) or its primary metabolite, OP-1118 (120 μM), significantly inhibited toxin A-mediated histologic damage and reduced the mean histology score and ileal IL-1β protein and mRNA expression. Both fidaxomicin and OP-1118 reduced toxin A-induced cell rounding in human colonic CCD-18Co fibroblasts. Treatment of ileal loops with vancomycin (20 μM) and metronidazole (20 μM) did not alter toxin A-induced histologic damage and IL-1β protein expression. In addition to its well known antibacterial effects against C. difficile, fidaxomicin may possess anti-inflammatory activity directed against the intestinal effects of C. difficile toxins.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Bacterial Toxins; Clostridioides difficile; Edema; Enterocolitis, Pseudomembranous; Enterotoxins; Epithelial Cells; Fibroblasts; Fidaxomicin; Gene Expression; Ileum; Injections, Intralesional; Interleukin-1beta; Intestinal Mucosa; Male; Metronidazole; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; RNA, Messenger; Vancomycin

To report our experience with the use of fidaxomicin (FDX), an oral macrocyclic antibiotic, in cancer patients with Clostridium difficile infection (CDI).. A single-center retrospective case series was conducted at The University of Texas MD Anderson Cancer Center. Patients with CDI treated with FDX from May 2011 to January 2013 were identified via the pharmacy database. Clinical response and recurrence after FDX initiation were evaluated.. Twenty-two patients were included, most of whom were male (55%) with a mean age of 58 years (range: 20-83 yrs). The most common underlying malignancies were nine patients with lymphoma (41%), seven with leukemia (32%), and six with solid tumors (27%). Indications for FDX included recurrent CDI in 16 patients (72%) and failure of both metronidazole and oral vancomycin in 6 patients (28%). Nineteen patients (86%) were on concomitant antimicrobials during CDI treatment. Clinical response to FDX was 91%, and overall sustained clinical response was 82%. FDX was well tolerated with no major adverse events that were FDX related or discontinuations due to drug-related adverse events.. In cancer patients, FDX is effective treatment for the first episode of CDI after failure of standard therapies and treatment of recurrent CDI. This was interesting given the large number of high-risk patients who continued to receive concomitant antimicrobial therapy, which is common in this immunocompromised patient population.

Topics: Adult; Aged; Aged, 80 and over; Aminoglycosides; Anti-Bacterial Agents; Cancer Care Facilities; Clostridioides difficile; Drug Prescriptions; Drug Resistance, Multiple, Bacterial; Electronic Health Records; Enterocolitis, Pseudomembranous; Female; Fidaxomicin; Formularies, Hospital as Topic; Humans; Immunocompromised Host; Male; Middle Aged; Neoplasms; Recurrence; Retrospective Studies; Texas; Young Adult

Clostridium difficile infection (CDI) is an increasingly problem in everyday clinical practice. The most important risk factor of this infection is antibiotics use. The incidence of Clostridium difficile associated diarrhea (CDAD) in patients after renal transplantation is estimated to be about 6% in the early postoperative period. Due to the applied immunosuppression and frequent infections requiring intensive, broad spectral antibiotics, the later prevalence of CDAD may remain at a similar level. Massive diarrhea caused by Clostridium difficile may lead to fluctuations in immunosuppressive drugs concentration, in renal transplant patients. The authors present a case study of a 23-year old patient after kidney transplantation from deceased donor, with diagnosed polymorphic PTLD (Post-Transplant Lymphoproliferative Disorder). During biological treatment with rituximab in this patient 4 recurrences of CDI were observed. In this article the clinical manifestation of recurrent CDAD are presented. The authors discuss therapeutic procedure with fidaxomicin use, its results and influence on immunosuppressive drugs concentration.

Topics: Aminoglycosides; Antibodies, Monoclonal, Murine-Derived; Clostridioides difficile; Diarrhea; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Immunosuppression Therapy; Kidney Transplantation; Lymphoproliferative Disorders; Male; Recurrence; Rituximab; Young Adult

In November 2008, a study was performed with support from the European Centre for Disease Prevention and Control (ECDC) to obtain an overview of Clostridium difficile infections (CDIs) in European hospitals. A collection of 398 C. difficile isolates obtained from this hospital-based survey was utilized to identify antimicrobial susceptibility patterns of common C. difficile PCR ribotypes across Europe.. The MICs of three approved therapeutic agents (vancomycin, metronidazole and fidaxomicin) and LFF571 (a novel semi-synthetic thiopeptide antibiotic) were determined by the agar dilution method.. MICs of fidaxomicin and LFF571 were in general 2-4-fold lower than those of vancomycin and metronidazole. Isolates belonging to clade 2, including the hypervirulent ribotype 027, had one-dilution higher MIC50 and MIC90 values for fidaxomicin and metronidazole, whereas similar MIC values were observed for vancomycin and LFF571. Isolates belonging to C. difficile PCR ribotype 001 were more susceptible to fidaxomicin than other frequently found PCR ribotypes 014/020 and 078. Six isolates from three different countries had a metronidazole MIC of 2 mg/L. Four of the six isolates were characterized as PCR ribotype 001.. There was no evidence of in vitro resistance of C. difficile to any of the four agents tested. However, the results suggest type-specific differences in susceptibility for the treatment agents we investigated. Continuous surveillance of C. difficile isolates in Europe is needed to determine the possible clinical implications of ribotype-specific changes in susceptibility to therapeutic agents.

Topics: Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Clostridium Infections; Cross Infection; Enterocolitis, Pseudomembranous; Europe; Fidaxomicin; Humans; Metronidazole; Microbial Sensitivity Tests; Multilocus Sequence Typing; Polymerase Chain Reaction; Ribotyping; Thiazoles; Treatment Outcome; Vancomycin

Topics: Aminoglycosides; Anti-Bacterial Agents; Child; Clostridioides difficile; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Male; Recurrence; Treatment Outcome

Topics: Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Colectomy; Combined Modality Therapy; Cross Infection; Disease Notification; Enterocolitis, Pseudomembranous; Fidaxomicin; Metronidazole; Probiotics; Vancomycin; Virulence

Patients with chronic kidney disease (CKD) have increased risk for Clostridium difficile infection (CDI) and for subsequent mortality. We determined the effect of CKD on response to treatment for CDI.. This is a post hoc analysis of two randomized controlled phase 3 trials that enrolled patients with CDI. Patients received either fidaxomicin 200 mg b.i.d. or vancomycin 125 mg q.i.d. for 10 days. Univariate and multivariate analyses compared end points by treatment received and CKD stage.. At baseline, 27, 21, and 9% of the patients had stage 2 (60-89 ml/min/1.73 m(2)), stage 3 (30-59), and stage 4 or higher (<30) CKD. Cure rates were similar for normal (91%) and stage 2 CKD (92%), but declined to 80% for stage 3 and to 75% for stage 4 CKD (p < 0.001 for trend). Time to resolution of diarrhea (TTROD) increased with stage 3 and stage 4 CKD. CDI recurrence rates 4 weeks after treatment were 16, 20, 27, and 24% for normal, stage 2, stage 3, and stage 4 or higher CKD, respectively. Mortality increased with CKD stage. In multivariate analyses, stage 3 or higher CKD correlated with lower odds of cure, greater chance of recurrence, and lower odds of sustained response 28 days after treatment. Initial cure rates were similar in the vancomycin or fidaxomicin groups; however, the rate of recurrence was higher following vancomycin treatment independent of renal function. The presence of immunosuppression did not alter this effect.. Progressive CKD is associated with increased TTROD, lower cure rates, and higher recurrence rates with treatment of CDI.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aminoglycosides; Anti-Bacterial Agents; Clinical Trials, Phase III as Topic; Clostridioides difficile; Enterocolitis, Pseudomembranous; Female; Fidaxomicin; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Multivariate Analysis; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Severity of Illness Index; Treatment Outcome; Vancomycin; Young Adult

The feasibility of fidaxomicin versus vancomycin and metronidazole (conventional therapy) was assessed in 59 transplant recipients with 61 episodes of Clostridium difficile-associated diarrhea (CDAD). Overall clinical cure was achieved in 86% of episodes, and in 7% of episodes, infection recurred. Fidaxomicin was well tolerated. Clinical cures were not significantly different compared with conventional therapy (67% versus 89%, respectively; P = 0.06). Univariate analysis of predictors for lack of clinical cure included continued use of broad-spectrum systemic antibiotics (P = 0.026) and prior diagnosis of CDAD (95% confidence interval, 1.113 to 19.569; odds ratio, 4.667; P = 0.041). New-onset vancomycin-resistant Enterococcus (VRE) colonization was not noted after fidaxomicin therapy alone. However, this occurred in 10 of 28 patients (36%) following conventional therapy, and 2 of 3 patients with subsequent bacteremia died.

Topics: Adult; Aged; Aminoglycosides; Analysis of Variance; Anti-Bacterial Agents; Clinical Trials as Topic; Clostridioides difficile; Diarrhea; Enterocolitis, Pseudomembranous; Female; Fidaxomicin; Hematopoietic Stem Cell Transplantation; Humans; Male; Metronidazole; Middle Aged; Organ Transplantation; Survival Analysis; Treatment Outcome; Vancomycin; Vancomycin Resistance

Topics: Aged; Aminoglycosides; Anti-Bacterial Agents; Carcinoma, Squamous Cell; Clostridioides difficile; Critical Care; Cross Infection; Enterocolitis, Pseudomembranous; Female; Fidaxomicin; Humans; Intubation, Gastrointestinal; Mandibular Neoplasms; Mouth Neoplasms; Necrosis; Shock, Septic

Topics: Adult; Aged; Aged, 80 and over; Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Drug Administration Schedule; Enterocolitis, Pseudomembranous; Female; Fidaxomicin; Humans; Male; Recurrence; Treatment Outcome; Vancomycin

Antibiotic treatment, including vancomycin, for Clostridium difficile infection (CDI) has been associated with recurrence of disease in up to 25% of infected persons. This study investigated the effects of vancomycin on the clinical outcomes, intestinal histopathology, and anaerobic community during and after treatment in a murine model of CDI. C57BL/6 mice were challenged with C. difficile strain VPI 10463 after pretreatment with an antibiotic cocktail. Twenty-four hours after infection, mice were treated daily with vancomycin, nitazoxanide, fidaxomicin, or metronidazaole for 5 days. Mice were monitored for either 6 or 12 days postinfection. Clinical, diarrhea, and histopathology scores were measured. Cecal contents or stool samples were assayed for clostridial or Bacteroides DNA and C. difficile toxins A and B. Vancomycin treatment of infected mice was associated with improved clinical, diarrhea, and histopathology scores and survival during treatment. However, after discontinuation of the drug, clinical scores and histopathology were worse in treated mice than in untreated infected controls. At the end of the study, 62% of the vancomycin-treated mice succumbed to recurrence, with an overall mortality rate equivalent to that of the untreated infected control group. Fidaxomicin-treated mice had outcomes similar to those of vancomycin-treated mice. C. difficile predominated over Bacteroides in cecal contents of vancomycin-treated mice, similar to findings for untreated infected mice. Decreasing the duration of vancomycin treatment from 5 days to 1 day decreased recurrence and deaths. In conclusion, vancomycin improved clinical scores and histopathology acutely but was associated with poor outcome posttreatment in C. difficile-infected mice. Decreasing vancomycin exposure may decrease relapse and improve survival in CDI.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Bacteroides; Cecum; Clostridioides difficile; Clostridium Infections; DNA, Bacterial; Enterocolitis, Pseudomembranous; Feces; Fidaxomicin; Intestines; Male; Metronidazole; Mice; Mice, Inbred C57BL; Nitro Compounds; Recurrence; Thiazoles; Treatment Outcome; Vancomycin

The in vitro activities of LFF571, a novel analog of GE2270A that inhibits bacterial growth by binding with high affinity for protein synthesis elongation factor Tu, fidaxomicin, and 10 other antimicrobial agents were determined against 50 strains of Clostridium difficile and 630 other anaerobic and aerobic organisms of intestinal origin. LFF571 possesses potent activity against C. difficile and most other Gram-positive anaerobes (MIC(90), ≤ 0.25 μg/ml), with the exception of bifidobacteria and lactobacilli. The MIC(90)s for aerobes, including enterococci, Staphylococcus aureus (as well as methicillin-resistant S. aureus [MRSA] isolates), Streptococcus pyogenes, and other streptococci were 0.06, 0.125, 2, and 8 μg/ml, respectively. Comparatively, fidaxomicin showed variable activity against Gram-positive organisms: MIC(90)s against C. difficile, Clostridium perfringens, and Bifidobacterium spp. were 0.5, ≤ 0.015, and 0.125 μg/ml, respectively, but >32 μg/ml against Clostridium ramosum and Clostridium innocuum. MIC(90) for S. pyogenes and other streptococci was 16 and >32 μg/ml, respectively. LFF571 and fidaxomicin were generally less active against Gram-negative anaerobes.

Topics: Aminoglycosides; Anti-Bacterial Agents; Bacteria, Aerobic; Bacteria, Anaerobic; Clostridioides difficile; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Intestines; Microbial Sensitivity Tests; Microbial Viability; Peptide Elongation Factor Tu; Protein Biosynthesis; Species Specificity; Thiazoles

Topics: Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Diarrhea; Enterocolitis, Pseudomembranous; Female; Fidaxomicin; Humans; Male; Vancomycin

Topics: Aminoglycosides; Anti-Bacterial Agents; Clinical Trials, Phase III as Topic; Clostridioides difficile; Diarrhea; Endpoint Determination; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Metronidazole; Polymers; Sulfonic Acids; Treatment Outcome; Vancomycin

Topics: Aminoglycosides; Anti-Bacterial Agents; Bacterial Infections; Ceftaroline; Cephalosporins; Clostridioides difficile; Drug Resistance, Multiple, Bacterial; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections; Streptococcal Infections; Streptococcus pneumoniae; Streptococcus pyogenes

Topics: Aminoglycosides; Anti-Bacterial Agents; Bacterial Infections; Clostridioides difficile; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Metronidazole; Secondary Prevention; Streptococcal Infections; United States; United States Food and Drug Administration; Vancomycin

Luminal inflammation of the intestine is a trigger of numerous gastrointestinal and non-gastrointestinal diseases. Several mechanisms have an impact on luminal inflammation, such as antibiotic or immunosuppressive therapies. In this paper recent data and new therapeutic approaches are reported concerning gastrointestinal and non-gastrointestinal diseases, for example eosinophilic esophagitis, irritable bowel syndrome, Crohn's disease and hepatic encephalopathy. In addition, recommendations are provided for the concurrent medication with proton pump inhibitors (PPIs) with respect to cardiovascular and gastrointestinal complications in patients in whom dual antiplatelet therapy including clopidrogel is indicated. Finally, an outlook is given on new and interesting therapeutic concepts in clostridium difficile colitis.

Topics: Aminoglycosides; Anti-Bacterial Agents; Anti-Inflammatory Agents; Clostridioides difficile; Crohn Disease; Enterocolitis, Pseudomembranous; Eosinophilic Esophagitis; Fidaxomicin; Gastrointestinal Agents; Gastrointestinal Diseases; Hepatic Encephalopathy; Humans; Irritable Bowel Syndrome; Platelet Aggregation Inhibitors; Proton Pump Inhibitors

Topics: Aminoglycosides; Clinical Trials as Topic; Clostridioides difficile; Diarrhea; Drug Approval; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans

Topics: Aminoglycosides; Anti-Bacterial Agents; Cross Infection; Drug Approval; Drug Industry; Enterocolitis, Pseudomembranous; Fidaxomicin; United States; United States Food and Drug Administration

Treatment guidelines recommend stopping all implicated antibiotics at the onset of Clostridium difficile infection (CDI), but many individuals have persistent or new infections necessitating the use of concomitant antibiotics (CAs). We used data from 2 phase 3 trials to study effects of CAs on response to fidaxomicin or vancomycin.. Subjects with CDI were treated for 10 days with fidaxomicin 200 mg every 12 hours or vancomycin 125 mg every 6 hours, assessed for resolution of symptoms, and followed up for an additional 4 weeks for evidence of recurrence. Rates of cure, recurrence, and global cure (cure without recurrence) were determined for subgroups of subjects defined by CA use and treatment group.. CAs were prescribed for 27.5% of subjects during study participation. The use of CAs concurrent with CDI treatment was associated with a lower cure rate (84.4% vs 92.6%; P < .001) and an extended time to resolution of diarrhea (97 vs 54 hours; P < .001). CA use during the follow-up was associated with more recurrences (24.8% vs 17.7%; not significant), and CA administration at any time was associated with a lower global cure rate (65.8% vs 74.7%; P = .005). When subjects received CAs concurrent with CDI treatment, the cure rate was 90.0% for fidaxomicin and 79.4% for vancomycin (P = .04). In subjects receiving CAs during treatment and/or follow-up, treatment with fidaxomicin compared with vancomycin was associated with 12.3% fewer recurrences (16.9% vs 29.2%; P = .048).. Treatment with CAs compromised initial response to CDI therapy and durability of response. Fidaxomicin was significantly more effective than vancomycin in achieving clinical cure in the presence of CA therapy and in preventing recurrence regardless of CA use.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Drug Therapy, Combination; Enterocolitis, Pseudomembranous; Female; Fidaxomicin; Humans; Male; Middle Aged; Vancomycin; Young Adult

Topics: Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Drug Approval; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Randomized Controlled Trials as Topic; Risk Factors; United States; United States Food and Drug Administration

Fidaxomicin is a first-in-class macrocyclic antibacterial that primarily demonstrates activity against species of clostridia, predominantly Clostridium difficile, while having limited or no activity against normal faecal microflora. Fidaxomicin is minimally absorbed following oral administration and is excreted almost solely in the faeces. Fidaxomicin displayed a high level of antibacterial activity against C. difficile in vitro, with a minimum inhibitory concentration required to inhibit 90% of C. difficile strains of 0.125-0.5 μg/mL, and was ≈2- to 8-fold more active than vancomycin or metronidazole. Fidaxomicin demonstrated a prolonged postantibiotic effect against C. difficile relative to vancomycin and metronidazole. In two randomized, double-blind, phase III trials, oral fidaxomicin 200 mg every 12 hours for 10 days was no less effective than oral vancomycin 125 mg every 6 hours for 10 days in the treatment of C. difficile infection, based on noninferiority analyses of clinical cure rates (primary endpoint). Fidaxomicin therapy was associated with a significantly lower rate of recurrence, as well as a significantly higher rate of global cure (i.e. sustained clinical response; resolution of diarrhoea without recurrence) compared with vancomycin therapy in the two clinical trials. Fidaxomicin was generally well tolerated in patients with C. difficile infection, with a tolerability profile generally similar to that of vancomycin.

Topics: Administration, Oral; Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Microbial Sensitivity Tests; Randomized Controlled Trials as Topic; Treatment Outcome

The effects of the inoculum, pH, cation concentrations, and different lots of commercial media on the in vitro susceptibility of Clostridium difficile to fidaxomicin were examined. Of the factors evaluated, only pH alterations influenced the activity of fidaxomicin against C. difficile, noticeably reducing its activity at higher pH (> or =7.9).

Topics: Agar; Aminoglycosides; Anti-Bacterial Agents; Cations; Clostridioides difficile; Colony Count, Microbial; Culture Media; Enterocolitis, Pseudomembranous; Fidaxomicin; Glycosides; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Microbial Sensitivity Tests

Agar dilution antimicrobial susceptibility testing (CLSI, M11-A7, 2007) performed for 208 toxin-producing clinical isolates of Clostridium difficile resulted in OPT-80 MICs ranging from 0.06 to 1 microg/ml, with 90% of the isolates inhibited by a concentration of 0.5 microg/ml. The in vitro activity of OPT-80 was independent of the susceptibilities of isolates to nine other antimicrobial agents.

Topics: Anti-Bacterial Agents; Bacterial Toxins; Clostridioides difficile; Cross Infection; Enterocolitis, Pseudomembranous; Glycosides; Humans; In Vitro Techniques; Microbial Sensitivity Tests

The incidence and severity of Clostridium difficile-associated disease (CDAD) is increasing, and standard treatment is not always effective. Therefore, more-effective antimicrobial agents and treatment strategies are needed. We used the agar dilution method to determine the in vitro susceptibility of the following antimicrobials against 110 toxigenic clinical isolates of C. difficile from 1983 to 2004, primarily from the United States: doripenem, meropenem, gatifloxacin, levofloxacin, moxifloxacin, OPT-80, ramoplanin, rifalazil, rifaximin, nitazoxanide, tizoxanide, tigecycline, vancomycin, tinidazole, and metronidazole. Included among the isolates tested were six strains of the toxinotype III, NAP1/BI/027 group implicated in recent U.S., Canadian, and European outbreaks. The most active agents in vitro were rifaximin, rifalazil, tizoxanide, nitazoxanide, and OPT-80 with MICs at which 50% of the isolates are inhibited (MIC(50)) and MIC(90) values of 0.0075 and 0.015 microg/ml, 0.0075 and 0.03 microg/ml, 0.06 and 0.125 microg/ml, 0.06 and 0.125 microg/ml, 0.125 and 0.125 microg/ml, respectively. However, for three isolates the rifalazil and rifaximin MICs were very high (MIC of >256 microg/ml). Ramoplanin, vancomycin, doripenem, and meropenem were also very active in vitro with narrow MIC(50) and MIC(90) ranges. None of the isolates were resistant to metronidazole, the only agent for which there are breakpoints, with tinidazole showing nearly identical results. These in vitro susceptibility results are encouraging and support continued evaluation of selected antimicrobials in clinical trials of treatment for CDAD.

Topics: Anti-Bacterial Agents; Bacterial Toxins; Clostridioides difficile; Drug Resistance, Bacterial; Enterocolitis, Pseudomembranous; Humans; Microbial Sensitivity Tests; United States

Tiacumicins B and C are members of a novel group of 18-membered macrolide antibiotics with in vitro activity against Clostridium difficile. The MICs against 15 strains of C. difficile were 0.12 to 0.25 microgram/ml for tiacumicin B, 0.25 to 1 microgram/ml for tiacumicin C, and 0.5 to 1 microgram/ml for vancomycin. The resistance frequency for both compounds against C. difficile was less than 2.8 x 10(-8) at four and eight times the MIC. The in vivo activities of the tiacumicins against two strains of C. difficile were compared with that of vancomycin in a hamster model of antibiotic-associated colitis. Oral therapy with 0.2, 1, or 5 mg of tiacumicin B or C per kg of body weight protected 100% of clindamycin-treated hamsters exposed to C. difficile ATCC 9689. Oral treatment with identical doses of vancomycin produced a prolonged, dose-dependent survival of hamsters, but it did not prevent the development of fatal colitis at doses of up to 5 mg/kg. When clindamycin-treated animals were exposed to another strain of C. difficile, both tiacumicin B and vancomycin were protective at 5 mg/kg, but not at lower doses. Tiacumicin C was not tested in vivo against the second strain of C. difficile. No tiacumicin B or C was detected in the sera of hamsters treated with single oral doses of 25 mg/kg, while antibiotic levels in the ceca of these hamsters reached 248 micrograms/ml and 285 mg/ml for tiacumicins B and C, respectively. The tiacumicins demonstrated in vitro and in vivo potencies against C. difficile and achieved high concentrations in the cecum, but not the serum, of hamsters after oral administration.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Biological Availability; Cecum; Clostridioides difficile; Cricetinae; Drug Resistance, Microbial; Enterocolitis, Pseudomembranous; Fidaxomicin; Hydrogen-Ion Concentration; Macrolides; Male; Mesocricetus; Mice; Microbial Sensitivity Tests