Fidaxomicin: first-in-class macrocyclic antibiotic

The incidence of Clostridium difficile has doubled over the past 15 years, and rising mortality rates associated with this infection have followed in its wake. C. difficile infection (CDI) has supplanted methicillin-resistant Staphylococcus aureus as the major cause of nosocomial infection. An insufficient response rate to currently available CDI therapies has prompted the search for new and alternative treatment modalities for this disease. The investigational pipeline includes evaluation of new antimicrobial agents that exhibit good activity against C. difficile without altering normal gut flora, C. difficile toxin-absorbing compounds, and preformed antibodies and vaccines against C. difficile toxin. In two robust clinical trials comparing fidaxomicin to vancomycin in the treatment of CDI, treatment with fidaxomicin demonstrated a superior global cure (cure without recurrence) rate compared with the current gold standard, vancomycin. Fidaxomicin, the first of a new class of macrocyclic antimicrobial agents, represents an advance in the management of CDI.     

Clinical and Economic Benefits of Fidaxomicin Compared to Vancomycin for Clostridium difficile Infection

We studied the clinical and economic impact of a protocol encouraging the use of fidaxomicin as a first-line drug for treatment of Clostridium difficile infection (CDI) in patients hospitalized during a 2-year period. This study evaluated patients who received oral vancomycin or fidaxomicin for the treatment of CDI during a 2-year period. All included patients were eligible for administration of fidaxomicin via a protocol that encouraged its use for selected patients. The primary clinical endpoint was 90-day readmission with a diagnosis of CDI. Hospital charges and insurance reimbursements for readmissions were calculated along with the cost of CDI therapy to estimate the financial impact of the choice of therapy. Recurrences were seen in 10/49 (20.4%) fidaxomicin patients and 19/46 (41.3%) vancomycin patients (P = 0.027). In a multivariate analysis that included determinations of severity of CDI, serum creatinine increases, and concomitant antibiotic use, only fidaxomicin was significantly associated with decreased recurrence (adjusted odds ratio [aOR], 0.33; 95% confidence interval [CI], 0.12 to 0.93). The total lengths of stay of readmitted patients were 183 days for vancomycin and 87 days for fidaxomicin, with costs of $454,800 and $196,200, respectively. Readmissions for CDI were reimbursed on the basis of the severity of CDI, totaling $151,136 for vancomycin and $107,176 for fidaxomicin. Fidaxomicin drug costs totaled $62,112, and vancomycin drug costs were $6,646. We calculated that the hospital lost an average of $3,286 per fidaxomicin-treated patient and $6,333 per vancomycin-treated patient, thus saving $3,047 per patient with fidaxomicin. Fidaxomicin use for CDI treatment prevented readmission and decreased hospital costs compared to use of oral vancomycin.     

My Treatment Approach to Clostridioides difficile Infection

Clostridioides difficile infection is the most common cause of infectious diarrhea in hospitals with an increasing incidence in the community. Clinical presentation of C difficile infection ranges from diarrhea manageable in the outpatient setting to fulminant infection requiring intensive care admission. There have been significant advances in the management of primary and recurrent C difficile infection including diagnostics, newer antibiotics, antibody treatments, and microbiome restoration therapies. Because of the risk of clinical false-positive results with the polymerase chain reaction test, a two-step assay combining an enzyme immune assay for glutamate dehydrogenase and the C difficile toxin is being used. Cost permitting, I treat a first episode of C difficile infection preferably with fidaxomicin over vancomycin but not metronidazole. The most common complication after C difficile infection is recurrence. I manage a first recurrence with a vancomycin taper and pulse or fidaxomicin and recommend a single dose of intravenous bezlotoxumab (a monoclonal antibody against the toxin B) to reduce recurrence rates for those patients at high risk. Patients with multiply recurrent C difficile infection are managed with a course of antibiotics such as vancomycin or fidaxomicin followed by microbiota restoration. The success of fecal microbiota transplantation is greater than 85%, compared with the 40% to 50% success rate of antibiotics in this situation. Fecal microbiota transplantation is heterogeneous and has rare but serious risks such as transmission of infections. Standardized microbiota restoration therapies are in clinical development and have completed phase III clinical trials. This review answers common clinical questions in the management of C difficile infection.     

Cost-effectiveness analysis of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in Japan

BackgroundThe cost of treating Clostridioides difficile infection (CDI), particularly recurrent disease, is high. In clinical trials, fidaxomicin has been associated with significantly lower recurrence rates and higher sustained cure rates versus vancomycin. The high acquisition cost of fidaxomicin has limited its acceptance into clinical practice.ObjectiveTo evaluate the cost-effectiveness of fidaxomicin versus vancomycin in patients with CDI after failure of metronidazole in the Japanese healthcare setting.MethodsClinical results from three phase III trials and inputs based on assumptions validated by clinical experts in Japan were used in a semi-Markov model with 1-year time horizon. Incremental cost-effectiveness ratios (ICERs) for fidaxomicin versus vancomycin were expressed as cost per quality-adjusted life year (QALY) and interpreted using willingness-to-pay thresholds of JPY 5,000,000 (primary) and JPY 7,500,000 (secondary) per QALY gained in Japan. Probabilistic sensitivity analyses and scenario analyses were performed.ResultsHigher drug acquisition costs for fidaxomicin were partially offset by lower hospitalization costs driven by fewer recurrences, lower costs of complications, and fewer general practitioner visits versus vancomycin. The ICER for fidaxomicin versus vancomycin was estimated at JPY 5,715,183 per QALY gained. Sensitivity analyses showed a 46% probability of fidaxomicin being cost-effective versus vancomycin at a willingness-to-pay threshold of JPY 5,000,000 per QALY gained. At a threshold of JPY 7,500,000, there was a 54% probability of fidaxomicin being cost-effective.ConclusionsFidaxomicin treatment in patients with CDI following failure of metronidazole improves health outcomes with partial offset of higher drug acquisition costs versus vancomycin.     

Subinhibitory Concentrations of LFF571 Reduce Toxin Production by Clostridium difficile

LFF571 is a novel semisynthetic thiopeptide antibacterial that is undergoing investigation for safety and efficacy in patients with moderate Clostridium difficile infections. LFF571 inhibits bacterial protein synthesis by interacting with elongation factor Tu (EF-Tu) and interrupting complex formation between EF-Tu and aminoacyl-tRNA. Given this mechanism of action, we hypothesized that concentrations of LFF571 below those necessary to inhibit bacterial growth would reduce steady-state toxin levels in C. difficile cultures. We investigated C. difficile growth and toxin A and B levels in the presence of LFF571, fidaxomicin, vancomycin, and metronidazole. LFF571 led to strain-dependent effects on toxin production, including decreased toxin levels after treatment with subinhibitory concentrations, and more rapid declines in toxin production than in inhibition of colony formation. Fidaxomicin, which is an RNA synthesis inhibitor, conferred a similar pattern to LFF571 with respect to toxin levels versus viable cell counts. The incubation of two toxigenic C. difficile strains with subinhibitory concentrations of vancomycin, a cell wall synthesis inhibitor, increased toxin levels in the supernatant over those of untreated cultures. A similar phenomenon was observed with one metronidazole-treated strain of C. difficile. These studies indicate that LFF571 and fidaxomicin generally result in decreased C. difficile toxin levels in culture supernatants, whereas treatment of some strains with vancomycin or metronidazole had the potential to increase toxin levels. Although the relevance of these findings remains to be studied in patients, reducing toxin levels with sub-growth-inhibitory concentrations of an antibiotic is hypothesized to be beneficial in alleviating symptoms.     

Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized,double-blind,comparative Phase III study in Japan

We assessed the efficacy and safety of fidaxomicin, a narrow-spectrum macrocyclic antibiotic, for treating inpatients with Clostridioides (Clostridium) difficile infection (CDI) in Japan. The objective was to demonstrate the non-inferior efficacy of fidaxomicin versus vancomycin.This Phase III, vancomycin-controlled, double-blind, parallel-group study enrolled adults with CDI. Patients were randomly assigned to receive fidaxomicin (200 mg twice daily, orally) or vancomycin (125 mg four-times daily, orally) for 10 days. The primary endpoint was global cure rate of CDI (proportion of patients cured at end of treatment with no recurrence during 28-day follow-up). Non-inferiority margin of 10% was pre-specified.Two-hundred and twelve patients were randomized and received treatment at 82 hospitals. Global cure rate was 67.3% (70/104) with fidaxomicin and 65.7% (71/108) with vancomycin: difference 1.2% [95% confidence interval (CI) ?11.3–13.7]. Non-inferiority was not demonstrated. Post-hoc analysis in full analysis set patients who received at least 3 days' treatment revealed a higher global cure rate for fidaxomicin [70/97 (72.2%)] than vancomycin [71/106 (67.0%)]: difference 4.6% (95% CI ?7.9–17.1). Recurrence rate in the full analysis set for recurrence was lower in fidaxomicin- [17/87 (19.5%)] than vancomycin-treated [24/95 (25.3%)] patients. Adverse event incidences and profiles were similar for both treatments.Though non-inferiority was not demonstrated for fidaxomicin versus vancomycin, global cure rate was numerically higher and recurrence rate lower for fidaxomicin than vancomycin. Fidaxomicin could be an option for the treatment of CDI in an era of reduced antibiotic susceptibility, and to reduce the incidence of recurrence in Japanese patients.

Comment traiter une infection digestive à Clostridium difficile en 2014 ?

During the last decade, Clostridium difficile emerged as a major enteropathogen, mainly because the infections became more frequent, more severe, and more refractory to standard treatments. In order to take into account recent therapeutic advances in the clinical management of patients with C. difficile infections (CDI), the European guidelines have been updated in 2013. Oral metronidazole (500 mg × 3/d, 10 d) is still the drug of choice for the initial episode ofmild tomoderate CDI. Vancomycin (125mg × 4/d, 10 d) is proposed in case of severe CDI, but fidaxomicin (200 mg × 2/d, 10 d) can be used as an alternative. Colectomy should be early considered in case of severely ill patients (megacolon or septic shock). Treatment of the first recurrence or patients at high risk of recurrence is based on the use of vancomycin (125 mg × 4/d, 10 d) or fidaxomicin (200 mg × 2/d, 10 d). Fecal transplantation has become the best treatment of multiple recurrences (A-I) but the use of fidaxomicin or tapered and pulse dose of vancomycin are two other possible options (B-II).     

Susceptibility of Clostridium difficile Isolates of Varying Antimicrobial Resistance Phenotypes to SMT19969 and 11 Comparators

We determined the in vitro activity of SMT19969 and 11 comparators, including metronidazole, vancomycin, and fidaxomicin, against 107 C. difficile isolates of different antimicrobial resistance phenotypes. Fidaxomicin and SMT19969 were the most active. The fidaxomicin and SMT19969 geometric mean MICs were highest in ribotypes known to show multiple resistance. Coresistance to linezolid and moxifloxacin was evident in ribotypes 001, 017, 027, and 356. The high-level ceftriaxone resistance in ribotypes 356 and 018 was location linked.     

Clostridium difficile infection in older adults: a review and update on its management

BackgroundClostridium 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.ObjectiveThis article reviews CDI and provides an update on its treatment, including recently published clinical practice guidelines and the recently approved drug, fidaxomicin.MethodsEnglish-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.ResultsMetronidazole 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.ConclusionsTreatment 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.     

Susceptibility of Clostridium species isolated in Japan to fidaxomicin and its major metabolite OP-1118

The narrow-spectrum macrocyclic antibiotic fidaxomicin is approved for treatment of Clostridium difficile infection in many countries and is currently under evaluation in Japan for this indication. This study was conducted to evaluate the effects of fidaxomicin and its major metabolite, OP-1118, on Clostridium spp. isolated in Nagasaki University Hospital, Japan. Isolates were cultured and antimicrobial susceptibility analyses performed according to the Clinical Laboratory Standards Institute methods.Ninety-eight isolates were obtained between 2012 and 2015, 50 of C. difficile and 48 of eight other Clostridium spp. Fidaxomicin had the lowest minimum inhibitory concentration (MIC) of the antimicrobials tested against C. difficile, with MIC₉₀ (MIC range) 0.12 μg/mL (0.015–0.25), versus vancomycin MIC₉₀ 0.5 μg/mL (0.5), metronidazole MIC₉₀ 0.5 μg/mL (0.12–0.5), and OP-1118 MIC₉₀ 4.0 μg/mL (0.5–4.0). Fidaxomicin and OP-1118 each had a similar spectrum of activity against the other Clostridium spp. C. butyricum and the 29 fidaxomicin- and OP-1118-susceptible C. perfringens isolates had the lowest MIC values, and C. bolteae and C. hathewayi higher. All the C. ramosum isolates (n = 6) and one of 30 C. perfringens isolates had low susceptibility to fidaxomicin and OP-1118 (i.e., MIC >64 μg/mL).In summary, this study showed that fidaxomicin was active against a number of Clostridium spp., including C. difficile. Fidaxomicin was generally more effective than its major metabolite OP-1118, but both showed a similar spectrum of activity, suggesting that OP-1118 contributes to the antimicrobial activity of fidaxomicin. These findings were broadly in accordance with those of similar studies conducted in other settings.     

The gut microbiome diversity of Clostridioides difficile-inoculated mice treated with vancomycin and fidaxomicin

ObjectiveTo investigate the effect of vancomycin and fidaxomicin on the diversity of intestinal microbiota in a mouse model of Clostridioides difficile infection.MethodsMice were divided into 11 models (4 mice per model): 6 uninoculated models and 5 models inoculated with C. difficile BI/NAP1/027. Inoculated models were prepared using intraperitoneal clindamycin followed by inoculation with C. difficile BI/NAP1/027. Uninoculated and C. difficile-inoculated mice received 2 or 7 days’ vancomycin or fidaxomicin. Clostridium butyricum MIYAIRI 588 probiotic and lactoferrin prebiotic were administered for 10 days to uninoculated mice. Intestinal microbiome composition was investigated by sequence analyses of bacterial 16S rRNA genes from faeces, and microbiota diversity estimated.ResultsIn uninoculated, untreated (‘normal’) mice, Clostridia (57.8%) and Bacteroidia (32.4%) accounted for the largest proportions of gut microbiota. The proportion of Clostridia was numerically reduced in C. difficile-inoculated versus normal mice. Administration of vancomycin to C. difficile-inoculated mice reduced the proportions of Bacteroidia and Clostridia, and increased that of Proteobacteria. Administration of fidaxomicin to C. difficile-inoculated mice reduced the proportion of Clostridia to a lesser extent, but increased that of Bacteroidia. Microbiota diversity was lower in C. difficile-inoculated versus normal mice (164.5 versus 349.1 operational taxonomic units (OTUs), respectively); treatment of C. difficile-inoculated mice with 7 days' vancomycin reduced diversity to a greater extent than did 7 days' fidaxomicin treatment (26.2 versus 134.2 OTUs, respectively).ConclusionsBoth C. difficile inoculation and treatment with vancomycin or fidaxomicin reduced microbiota diversity; however, dysbiosis associated with fidaxomicin was milder than with vancomycin.     

Epidemiology,diagnosis and treatment of Clostridium difficile infection

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

Treatment of Clostridioides (Clostridium) difficile infection

Abstract

Clostridioides (formerly: Clostridium) difficile infection (CDI) is a major cause of diarrhoea for inpatients as well as outpatients. Usually, CDI is healthcare-associated but the number of community-acquired infections is increasing. CDI is generally associated with changes in the normal intestinal microbiota caused by administration of antibiotics. Elderly and immunocompromised patients are at greater risk for CDI and CDI recurrence. Recently, the treatment options of CDI have undergone major changes: current recommendations speak against using metronidazole for primary CDI, fidaxomicin and bezlotoxumab have been added to the treatment armamentarium and microbial replacement therapies have emerged. Several other therapies are undergoing clinical trials. In this article, we review current treatment guidelines, present the most recent data on the options to treat CDI and glance towards future developments.

• KEY MESSAGES

• The cornerstones for the treatment of CDI are vancomycin and fidaxomicin. Metronidazole should be used only in mild-to-moderate disease in younger patients who have no or only few risk factors for recurrence.

• In recurrent CDI, bezlotoxumab infusion (a monoclonal antibody against C. difficile toxin B) may be considered as an adjunctive therapeutic strategy in addition to the standard care provided to patients with several risk factors for recurrence.

• Faecal microbiota transplantation (FMT) should be offered to patients with frequently recurring CDI.

     

Clostridium difficile Infection: New Insights Into Management

Clostridium difficile was first described as a cause of diarrhea in 1978 and is now among the leading 3 hospital-acquired infections in the United States, along with methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. In the past 2 decades, there has been an increase in the incidence, severity, and recurrence rates of C difficile infection, all of which are associated with poor outcomes. In addition, several novel risk factors and newer treatment methods are emerging, including fidaxomicin therapy, treatment using monoclonal antibodies, and fecal microbiota transplantation, that have shown promise for the treatment of C difficile infection. This review focuses on the changing epidemiology, risk factors, and newer methods for treatment of C difficile infection.     

Fidaxomicin versus Conventional Antimicrobial Therapy in 59 Recipients of Solid Organ and Hematopoietic Stem Cell Transplantation with Clostridium difficile-Associated Diarrhea

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.     

Fidaxomicin Therapy in Critically Ill Patients with Clostridium difficile Infection

Fidaxomicin use to treat proven Clostridium difficile infection (CDI) was compared between 20 patients receiving care in critical care units (CCUs) and 30 patients treated on general medical floors. At baseline, the CCU patients had more initial CDI episodes, more severe and complicated disease, and more concurrent broad-spectrum antibiotic coverage. On multivariate analysis, the response to fidaxomicin therapy among the critically ill patients was comparable to that among patients in the general medical wards.     

Both Fidaxomicin and Vancomycin Inhibit Outgrowth of Clostridium difficile Spores

Fidaxomicin (FDX) is approved to treat Clostridium difficile-associated diarrhea and is superior to vancomycin in providing a sustained clinical response (cure without recurrence in the subsequent 25 days). The mechanism(s) behind the low recurrence rate of FDX-treated patients could be multifactorial. Here, we tested effects of FDX, its metabolite OP-1118, and vancomycin on spore germination and determined that none affected the initiation of spore germination but all inhibited outgrowth of vegetative cells from germinated spores.     

Fidaxomicin: first-in-class macrocyclic antibiotic

The incidence of Clostridium difficile has doubled over the past 15 years, and rising mortality rates associated with this infection have followed in its wake. C. difficile infection (CDI) has supplanted methicillin-resistant Staphylococcus aureus as the major cause of nosocomial infection. An insufficient response rate to currently available CDI therapies has prompted the search for new and alternative treatment modalities for this disease. The investigational pipeline includes evaluation of new antimicrobial agents that exhibit good activity against C. difficile without altering normal gut flora, C. difficile toxin-absorbing compounds, and preformed antibodies and vaccines against C. difficile toxin. In two robust clinical trials comparing fidaxomicin to vancomycin in the treatment of CDI, treatment with fidaxomicin demonstrated a superior global cure (cure without recurrence) rate compared with the current gold standard, vancomycin. Fidaxomicin, the first of a new class of macrocyclic antimicrobial agents, represents an advance in the management of CDI.     

U.S.-Based National Sentinel Surveillance Study for the Epidemiology of Clostridium difficile-Associated Diarrheal Isolates and Their Susceptibility to Fidaxomicin

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.