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

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/

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

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

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.

Visual Representation of RNA Polymerase Mechanism of Action

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.

Round Table Figure Discussion

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.

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.

http://www.studyblue.com/notes/note/n/15-transcription-of-rna/deck/10793388

Without Fidaxomicin

DNA

With Fidaxomicin

DNA

DNA enters active site and initiation and transcription

occurs

DNA cannot enter active site due to closed clamp configuration and initiation cannot be achieved

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

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?