Tag Archives: fidaxomicin

U.S. Food and Drug Administration (FDA) Has Accepted 2 New Drug Applications (NDA) for DIFICID (fidaxomicin) In Children Aged Six Months Or Older



Known as MSD outside the United States and Canada

announced the U.S. Food and Drug Administration (FDA) has accepted for review a New Drug Application (NDA) for DIFICID ® (fidaxomicin) for oral suspension, and a supplemental NDA (sNDA) for a new indication for use of DIFICID tablets and oral suspension for the treatment of Clostridium (also known as Clostridioides ) difficile infections (CDI) in children aged six months or older. Both applications have received a priority review classification by the FDA. The Prescription Drug User Fee Act (PDUFA), or target action date for both applications, is set for Jan. 24, 2020. The investigational pediatric indication for DIFICID was granted Orphan Drug Designation (ODD) in 2010.

“Evidence indicates the increasing incidence of C. difficile -associated diarrhea among hospitalized children 1,” said Dr. Nicholas Kartsonis, senior vice president, Clinical Research, infectious diseases and vaccines, Merck Research Laboratories. “The filings for the pediatric indication for the new investigational oral suspension formulation of DIFICID, as well as for DIFICID tablets, underscore Merck’s focus and dedication to developing infectious disease treatments for those with unmet needs.”

The sNDA is based primarily on results of the Phase 3 SUNSHINE study 2, which were presented as part of the Late Breaker Oral Abstracts on Emerging Infections at IDWeek 2018 in San Francisco, California.

About DIFICID (fidaxomicin)

DIFICID is a macrolide antibacterial medicine indicated in adults (18 years of age or older) for treatment of Clostridium difficile -associated diarrhea (CDAD). To reduce the development of drug-resistant bacteria and maintain the effectiveness of DIFICID and other antibacterial drugs, DIFICID should be used only to treat infections that are proven or strongly suspected to be caused by Clostridiumdifficile. DIFICID is contraindicated in patients who have known hypersensitivity to fidaxomicin or any other ingredient in DIFICID. DIFICID should only be used for the treatment of C. difficile-associated diarrhea. DIFICID is not effective for the treatment of other types of infections due to minimal systemic absorption of fidaxomicin.

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Study Investigators Find Combination of Vancomycin and FMT Superior In Treating Recurrent C.difficile Infection (rCDI)

The combination of vancomycin and fecal microbiota transplantation was found to be superior to fidaxomicin or vancomycin in the treatment of patients with recurrent Clostridium difficile infection (rCDI), according to a study published in Gastroenterology.

This randomized, single-center trial was designed to compare the efficacy of fecal microbiota transplantation with that of fidaxomicin and vancomycin.

Sixty-four adults with recurrent CDI seen at a gastroenterology clinic in Denmark between April 5, 2016 and June 10, 2018 were randomly assigned to a group receiving fecal microbiota transplantation applied by colonoscopy or nasojejunal tube after 4 to 10 days of 125 mg vancomycin 4 times daily (n=24), or 10 days of 200 mg fidaxomicin 2 times daily (n=24), or 10 days of 125 mg vancomycin 4 times daily (n=16).

Patients experiencing a CDI recurrence after this course of treatment, and those who could not be randomly assigned were provided rescue fecal microbiota transplantation. The primary study outcome was combined clinical resolution and negative polymerase chain reaction test for C difficile toxin at 8 weeks post-treatment, and secondary end points included week 8 clinical resolution.

The combination of negative C difficile test results and clinical resolution was observed in 71% of the 24 participants who received fecal microbiota transplantation (95% CI, 49-87%; n=17), 33% of the 24 participants who received fidaxomicin (95% CI, 16-55%; n=8), and 19% of the 16 participants (95% CI, 5-46%; n=3) who received vancomycin (fecal microbiota transplantation vs fidaxomicinP=.009; fecal microbiota transplantation vs vancomycin, P=.001; fidaxomicin vs vancomycin, P=.31). Clinical resolution was observed in 92% of participants who received fecal microbiota transplantation (n=22; P=.0002), 42% of participants who were treated with fidaxomicin (n=10; <.0001), and 19% of participants who were treated with vancomycin (n=3; P=.13). No significant differences in results were seen between patients receiving initial fecal microbiota transplantation therapy and those who received rescue treatment with such a transplant.

Of note, adverse events (transient abdominal pain, constipation, bloating and diarrhea) were observed in 10 of the participants who received a fecal microbiota transplant, 1 of which was classified as severe.

Researchers noted limitation of a lack of patients with C difficile ribotype 027, such that results may not be generalizable to settings with a high ribotype 027 frequency. Study interventions were also unblinded, introducing the possibility of observer bias, although the C difficile toxin test was applied to all patients at all time points in an effort to obtain objective outcome measures.

Study investigators concluded, “[fecal microbiota transplantation] was superior to both fidaxomicin and vancomycin monotherapies for [recurrent] CDI, with regard to both combined clinical and microbiological resolution and clinical resolution alone.”



Hvas CL, Jørgensen SMD, Jørgensen SP, et al. Fecal microbiota transplantation is superior to fidaxomicin for treatment of recurrent Clostridium difficile infection [published online January 2, 2019]. Gastroenterology. doi: 10.1053/j.gastro.2018.12.019

Rutgers University and International Scientists Have Determined the Molecular Target and Mechanism of the Antibacterial Drug fidaxomicin (Trade Name Dificid)

Fidaxomicin was approved in 2011 for treatment of the CDC “urgent threat” bacterial pathogen Clostridium difficile (C. diff) and currently is one of two front-line drugs for treatment of C. diff.

A team of Rutgers University and international scientists has determined the molecular target and mechanism of the antibacterial drug fidaxomicin (trade name Dificid).

Resource:  https://www.sciencedaily.com/releases/2018/03/180329141050.htm

Fidaxomicin also exhibits potent antibacterial activity against other CDC “serious threat” bacterial pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus (VRSA), and the tuberculosis bacterium, Mycobacterium tuberculosis. However, the low solubility and low systemic bioavailability of fidaxomicin have precluded use of fidaxomicin for treatment of MRSA, VRSA, and tuberculosis.

To design next-generation fidaxomicin derivatives with improved clinical activity against C. diff and useful clinical activity against MRSA, VRSA, and tuberculosis, it is essential to know how the drug binds to and inhibits its molecular target, bacterial RNA polymerase, the enzyme responsible for bacterial RNA synthesis.

In a paper published in Molecular Cell today, the researchers report results of cryo-electron microscopy (cryo-EM) and single molecule spectroscopy analyses showing how fidaxomicin binds to and inhibits bacterial RNA polymerase.

The researchers report a cryo-EM structure of fidaxomicin bound to Mycobacterium tuberculosis RNA polymerase at 3.5 Å resolution. The structure shows that fidaxomicin binds at the base of the RNA polymerase “clamp,” a part of RNA polymerase that must swing open to allow RNA polymerase to bind to DNA and must swing closed to allow RNA polymerase to hold onto DNA. The structure further shows that fidaxomicin traps the RNA polymerase “clamp” in the open conformation.

The researchers also report results of single-molecule fluorescence spectroscopy experiments that confirm that fidaxomicin traps the RNA polymerase “clamp” in the open conformation and that define effects of fidaxomicin on the dynamics of clamp opening and closing.

The researchers show that fidaxomicin inhibits bacterial RNA polymerase through a binding site and mechanism that differ from those of rifamycins, another class of antibacterial drugs that target bacterial RNA polymerase. The finding that fidaxomicin inhibits bacterial RNA polymerase functions through a different, non-overlapping binding site and mechanism explains why fidaxomicin is able to kill bacterial pathogens resistant to rifamycins and why fidaxomicin is able to function additively when combined with rifamycins.

The new results enable rational, structure-based design of new, improved fidaxomicin derivatives with higher antibacterial potency, higher solubility, and higher systemic bioavailability. Based on the structure of fidaxomicin bound to its target, the researchers identified atoms of fidaxomicin that are not important for binding to the target and thus that can be modified without compromising the ability to bind to the target. The researchers then developed chemical procedures that allow selective attachment of new chemical groups at those atoms, including new chemical groups that can improve potency, solubility, or systemic bioavailability.

“The results set the stage for development of improved fidaxomicin derivatives, particularly improved fidaxomicin derivatives having the solubility and systemic bioavailability needed for treatment of systemic infections, such as MRSA and tuberculosis,” said Ebright, Board of Governors Professor of Chemistry and Chemical Biology and Laboratory Director at the Waksman Institute of Microbiology at Rutgers, who led the research.

In addition to Richard H. Ebright, the research team included Wei Lin, David Degen, Abhishek Mazumder, Dongye Wang, Yon W. Ebright, Richard Y. Ebright, Elena Sineva, Matthew Gigliotti, Aashish Srivastava, Sukhendu Mandal, Yi Jiang, Ruiheng Yin, and Dennis Thomas from Rutgers University; Kalyan Das from KU Leuven; Zhening Zhang and Edward Eng from the National Resource for Automated Molecular Microscopy and the Simons Electron Microscopy Center; Stefano Donadio from NAICONS Srl.; Haibo Zhang and Changsheng Zhang from the Chinese Academy of Sciences Guangzhou.

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Extended-pulsed fidaxomicin Found Superior to Standard-dose vancomycin To Treat C.difficile Infection In Older Adults

In a randomized, controlled, open label phase 3b/4 trial (ClinicalTrials.gov identifier: NCT02254967), hospitalized patients age 60 years and older with confirmed C difficile infection were recruited from 86 European hospitals. Patients were randomly assigned 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, 4 times daily on days 1-10).

Of the 177 patients receiving fidaxomicin, 124 (70%) achieved the primary end point of sustained clinical cure 30 days posttreatment, compared with 106 (59%) of 179 who received vancomycin (odds ratio 1.62; 95% CI 1.04-2.54, P =.03).

Multivariate analysis, which included treatment arm and baseline stratification factors (infection severity, cancer presence, age, and number of previous C difficile infection occurrences) as covariates, also indicated fidaxomicin to be superior (P =.035). A subanalysis of microbiota diversity concluded that microbiota recovery was greater in the fidaxomicin group, and a Cox proportional hazards model suggested that the hazard of infection recurrence in the vancomycin group was 3.8 times greater.

This study demonstrates the superiority of extended-pulsed fidaxomicin treatment over standard treatment with vancomycin. The researchers note the absence of blinding and racial diversity in the study group as limitations and recommend that future investigations should study this treatment course in patients age 60 years and younger and should compare this treatment course with standard fidaxomicin treatment protocols.


The study was funded by Astellas Pharma Inc, who were involved in all stages of the study, including manuscript preparation.


Guery B, Menichetti F, Anttila V-J, et al.; for the EXTEND Clinical Study Group. Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients 60 years and older (EXTEND): a randomised, controlled, open-label, phase 3b/4 trial. [published online December 19, 2017]. Lancet Infect Dis. doi: 10.1016/S1473-3099(17)30751-X


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Clostridium difficile Treatment Strategies


Authors: Teena Chopra, Ellie J.C. Goldstein, Sherwood L. Gorbach

  • First published: 20 December 2016 Full publication history
  • DOI: 10.1002/phar.1863View/save citation
  • Funding: This work was supported by Merck & Co., Inc., Kenilworth, New Jersey.
  • Disclosures: T.C. served as a speaker for Pfizer Inc., Merck & Co., Inc., Cubist Pharmaceuticals, Inc., and Actavis, plc. E.J.C.G. has participated in advisory boards sponsored by Merck & Co., Inc., Cubist Pharmaceuticals, Inc., Optimer Pharmaceuticals, Inc., Bayer AG, Bio-K Plus International, Inc., Summit Therapeutics, plc, Kindred Healthcare, Inc., Novartis Pharmaceuticals Corporation, Daiichi Sankyo Company, Ltd., and Rempex Pharmaceuticals, Inc. He has served as a speaker for Bayer AG, Merck & Co., Inc., Forest Laboratories, Inc., Optimer Pharmaceuticals, Inc., and Cubist Pharmaceuticals, Inc.; he has received research grants from Merck and Co., Inc., Schering-Plough Pharmaceuticals, LLC, Optimer Pharmaceuticals, Inc., Theravance Biopharma, Cubist Pharmaceuticals, Inc., Pfizer, Inc., Astellas Pharma US, Inc., Cerexa, Inc., Forest Laboratories, Inc., Impax Laboratories, Inc., Novartis Pharmaceuticals Corporation, Clinical Microbiology Institute, Genzyme Corporation, a Sanofi company, Nano Pacific Holdings, Inc., Romark Laboratories, LC, ViroXis Corp., Warner Chilcott, plc, AvidBiotics Corp., GLSynthesis, Inc., Immunome, Inc., Salix Pharmaceuticals, Inc., Summit Therapeutics, plc, GlaxoSmithKline plc, Rempex Pharmaceuticals, Inc., Symbiomix Therapeutics, Gynuity Health Projects, Durata Therapeutics, Inc., and Toltec Pharmaceuticals, LLC. S.L.G. has served as a consultant for Seres Therapeutics, Inc., Medimmune, LLC, and Cempra Pharmaceuticals. He was also a consultant for Cubist Pharmaceuticals, now Merck & Co, Inc., at the time that the manuscript was written.


In recent years, Clostridium difficile infection (CDI) has become a global public health threat associated with increased morbidity, mortality, and economic burden, all of which are exacerbated with disease recurrence. Current guidelines informing treatment decisions are largely based on definitions of disease severity at diagnosis, with subjective components not well delineated across treatment algorithms and clinical trials. Furthermore, there is little evidence linking severity at onset to outcome. However, reducing the risk of recurrence may offer both a better outcome for the individual and decreased downstream economic impact.

The authors present data supporting the opinion that patients deemed at low risk for recurrence should receive vancomycin (or metronidazole when cost is an issue), while those at higher risk of recurrence would benefit from fidaxomicin treatment.

Although further prospective studies are needed, choosing treatment with the goal of preventing recurrent CDI may offer a better guide than disease severity.

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