1. JOURNAL CLUB
PRESENTATION
Fidaxomicin: A Novel Macrocyclic Antibiotic
Approved for Treatment of Clostridium difficile
Infection
Authors: Anilrudh A. Venugopal and Stuart Johnson
Clin Infect Dis. (2012) 54 (4): 568-574.
Clinical Infectious Diseases
2. Background
• Clostridium difficile Gram-positive, spore-forming bacteria and
is the causative agent of Clostridium difficile Infection (CDI)
and 20%-30% of the cases of antibiotic-associated diarrhea.
• Why is this important?
• In recent decades we have seen reports of increasing
morbidity and mortality, suggesting that C. diff. is becoming
more dangerous.
• There have also been reports of the emergence of a group of
strains associated with global outbreaks and higher rates of
complications and death.
http://vaccinenewsdaily.com/news/211310-study-of-vaccine-against-clostridium-
difficile-expands-into-the-u-s/
3. Complications of C. diff. Infections
• Disruption of the normal gut flora
• Extreme intestinal discomfort
• Uncontrollable bowel movements
• Clear, watery diarrhea
• Pseudomembranous colitis
• Toxic megacolon
• Bacterial sepsis
• Death
http://www.studentozdoc.com.au/blogs/18/48/clostridium-difficile-associated
4. How Do We Treat C. diff. Infection?
• Fecal transplantation – tube in the nose, transplant goes through the stomach
• ANTIBIOTICS!
• Patients are given specific antibiotics based on the severity of the illness
• The three main antibiotics used are vancomycin, metronidazole, and
fidaxomicin
http://www.rxlist.com/vancomycin-injection-drug.htm,
http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=9463,
http://www.rxlist.com/dificid-drug.htm
5. How is Fidaxomicin Relevant to this Course?
• Fidaxomicin is a bacterial RNA polymerase inhibitor!
• First, how does a bacterial RNA polymerase work?
• The core RNA polymerase molecule is composed of
an α-dimer, β, β’, and ω (omega) subunits. This core
molecule combines with promoter specificity factor
σ (sigma) to locate and bind the promoter region of
DNA.
• DNA double-strand is melted, an open-promoter
complex (RPo) is formed, and using new
ribonucleoside triphosphates, the new RNA molecule
is synthesized.
6. Visual Representation of RNA
Polymerase Mechanism ofAction
Artsimovitch, I., Seddon, J., & Sears, P. (2012). Fidaxomicin Is an Inhibitor of the Initiation of
Bacterial RNA Synthesis. Clinical Infectious Diseases, 55, S127-S131. (2012, August 1). Retrieved September 22, 2014, from PubMed.
8. Summary
Venugopal and Johnson found that fidaxomicin was effective in treating C. diff.
infections, while minimizing damage to the other gut flora
The Minimal Inhibitory Concentration needed to eliminate 90% of tested
isolates was drastically lower than for vancomycin and metronidazole.
Unfortunately, it was also seen that sensitivity to fidaxomicin, vancomycin, and
metronidazole decreased over time, suggesting that C. diff. has mechanisms of
resistance to the antibiotic.
9. Clinical Infectious Diseases Volume 55 August 1, 2012
Fidaxomicin Is an Inhibitor of the Initiation of
Bacterial RNA Synthesis
Artsimovitch, I., Seddon, J., & Sears
• Proposed the mechanism by which fidaxomicin inhibits
transcription by RNA polymerase
• Fidaxomicin binds to and drastically alters the switch-2 element of the β’
subunit of RNA polymerase
• This conformational change is thought to affect the action of the “pincers”
of the RNA polymerase claw-like clamp, preventing clamp opening to
allow for loading of the DNA molecule to be transcribed.
• It is also thought that fidaxomicin affects the ability of the switch-2
element to interact with the template DNA strand and determine its
poistion.
11. Clinical Infectious Diseases December, 2013 Volume 57 Issue 4
Is Fidaxomicin Worth the Cost?
Bartsch, S., Umscheid, C., Fishman, N., & Lee, B.
• Found that fidaxomicin is currently not cost-effective when
compared to vancomycin and metronidazole.
• Fidaxomicin - $336/day
• Vancomycin - $103.16/day
• Metronidazole - $5.85/day
• Fidaxomicin would need to be ≤ $150/day to be used for
treatment in all cases, and $160-$400 for use in treatment along
with strain typing
• Fidaxomicin still has the lowest rate of recurrent infections
12. Future Work
• Make fidaxomicin more cost-effective
• Improve chemistry? Manufacturing process?
• Further research on mechanism of action
• Current mechanism of action is based of known mechanism of action of
structurally similar antibiotic
• Determine effectiveness on different strains to develop better
guidelines on when to use fidaxomicin
• Determine mechanisms of resistance in C. difficile and other
enteric organisms
Any other ideas?
