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 Table of Contents  
REVIEW ARTICLE
Year : 2014  |  Volume : 5  |  Issue : 2  |  Page : 152-154

Fidaxomicin: A new fight against clostridium difficile-associated diarrhea


Department of Pharmacology, Armed Forces Medical College, Pune, Maharashtra, India

Date of Web Publication1-Jul-2014

Correspondence Address:
Dick B. S. Brashier
Department of Pharmacology, Armed Forces Medical College, Pune - 411 013, Maharashtra
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0975-9727.135753

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  Abstract 

Clostridium difficile-associated diarrhea (CDAD) occurs commonly as a side effect of broad-spectrum antibiotics. Drugs approved for CDAD are only two of them, metronidazole and vancomycin. Most promising drug for treatment of CDAD is vancomycin, but due to emergence of hypervirulent strains, outcomes have become poor. Fidaxomicin has being approved lately for treatment of CDAD, which has shown good results as compared to vancomycin. Fidaxomicin inhibits protein synthesis by inhibiting transcription carried out by sigma subunit of RNA polymerase. Fidaxomicin has been seen to be a well tolerated, with minimal adverse effects. Clinical trials has showed that fidaxomicin has similar results to vancomycin in showing clinical response, whereas it was superior to vancomycin in having sustained clinical effect, in CDAD.

Keywords: Clostridium deficits associated diarrhoea, Fidaxomicin, metronidazole, vancomycin


How to cite this article:
Brashier DB, Khanapure A, Sharma A K. Fidaxomicin: A new fight against clostridium difficile-associated diarrhea. Muller J Med Sci Res 2014;5:152-4

How to cite this URL:
Brashier DB, Khanapure A, Sharma A K. Fidaxomicin: A new fight against clostridium difficile-associated diarrhea. Muller J Med Sci Res [serial online] 2014 [cited 2019 Oct 16];5:152-4. Available from: http://www.mjmsr.net/text.asp?2014/5/2/152/135753


  Introduction Top


Clostridium difficile-associated diarrhea (CDAD) occurs commonly as a side effect of broad-spectrum antibiotics. [1] Most of them resolve by itself on stopping the antibiotic, on the other hand, some patients require specific treatment. [1] Drugs approved for CDAD are only two of them, metronidazole and vancomycin. [2] Problems with metronidazole are that it is absorbed from intestine, so less amount of drug reaches the site of action and has also shown to be associated with high failure rates. [2] Most promising drug for treatment of CDAD is vancomycin, but due to emergence of hypervirulent strains of clostridium lime North American pulsed field type-I (NAP-I), there has being increase in severity of illness, deaths and increased rates of recurrence of infection, needing retreatment. [3] Fidaxomicin has being approved lately for treatment of CDAD, which has shown good results as compared to vancomycin. [4],[5] Fidaxomicin is obtained by fermentation of dactylosporangicin aurantiacum, an actinomyetes from soil. It is also called tiacumicin B, OPT - 80, PAR - 101, lipramycin or difimicin. [5]


  Pharmacokinetics Top


Fidoxomicin is given orally and is minimally absorbed, hence its absorption is not affected with presence of food. [6] Therefore, it has been approved to be given with or without food. [7] It has half life of 9 hrs. It is hydrolysed locally in gastrointestinal tract to a main metabolite, an ester OP-1118. This active metabolite is equally active as fidaxomicin against Clostridia. [7] It is mainly excreted through faeces. [7]


  Mechanism of Action and Resistance Top


Fidaxomicin is a narrow-spectrum macrolide. [8] It is hydrolysed by intestinal enzyme into a microbiologically active metabolite OP1118, having selective activity for Clostridium difficile. [8] In vitro studies showed MIC values of less than 0.25 μg/ml for Clostridia. [8] It inhibits protein synthesis by inhibiting transcription carried out by sigma subunit of RNA polymerase. [8]

Resistance shown by Clostridia toward fidaxomicin is mainly due to mutations. [9] As such Clostridia has shown low frequency of spontaneous mutations of genes for subunits of RNA Polymerase (rpo A, rpo B and rpo C). [9] It has post antibiotic effect of 6 to 10 hours. [10]

Adverse Effects

Fidaxomicin has been seen to be a well tolerated. [11] It has adverse effects similar to vancomycin. A phase 3 trial comparing it with vancomycin showed both having nausea (11%), vomiting (7%), abdominal pain (6%), gastrointestinal haemorrhages (4%), anaemia (2%), and neutropenia (2%). [11]

Clinical Trials

A phase 2 study was carried out to find safe and efficacious dose. [12] It was a randomized, open label study having three treatment arms, enrolling adult subjects having CDAD. [12] First arm received 50 mg, second arm 100 mg, and third arm 200 mg of fidaxomicin. [12] Result of this trial showed that the dose of 200 mg was most suitable for treating CDAD. [12]

Present approval was based on the outcome of one phase 3 studies. It was randomized double-blinded non-inferiority study. [11] The study was carried out in various centres and had two treating arms enrolling CDAD-positive patients. [11] The first arm was given fidaxomicin 200 mg orally twice a day for 10 days and second arm was given vancomycin 125 mg orally four times a day for 10 days. [11]

Primary end point was clinical response rate at end of 10 days and sustained clinical response at 25 days. [11] In this trial clinical response rate with fidaxomicin was 88%, whereas with vancomycin was 86% and sustained clinical response for fidaxomicin was 70%, which was much higher than that of vancomycin having 57%. [11]

In the second trial outcome was similar to the first one. Clinical response rate for fidaxomicin was 88% and for vancomycin was 87%, but sustained clinical response for fidaxomicin was 72%, which was much more then vancomycin having 57%. [13]

These trials showed that fidaxomicin had similar response to vancomycin in showing clinical response to CDAD, whereas it was superior to vancomycin in having sustained clinical effect, which decreased chances of recurrence in fidaxomicin-treated subjects. [11],[13]

Present Status

Fidaxomicin is approved for treatment of CDAD, in adults (age more than 18 years), and this approval was given by Food and Drug Administration (FDA) on 27 May 2011. [8] Fidaxomicin is available as 200 mg enteric-coated tablets, and is given twice a day for 10 days. [8] Fidaxomicin can be given safely in renal and hepatically compromised patients. Its safety in paediatric age group has not being yet studied. [8] It falls in category B for pregnant women (is given only if clearly indicated). [8] It is not known whether fidaxomicin is secreted in milk, therefore its indication in lactating women is doubtful. [8] Fidaxomicin is also being tried for treatment of vancomycin-resistant Enterococci (VRE) and methicillin-resistant Staphylococci aureus (MRSA). [14]


  Conclusion Top


Fidaxomicin is a new hope for treatment of CDAD. As there are only two drugs before fidaxomicin been approved for CDAD. It has come as a new welcome molecule to fight with issues as bioavailability and resistance. CDAD being relatively less important as compared to diabetes mellitus, hypertension, and cancer for research and development, therefore not much research is carried out for this disease. Hence, a new molecule has opened new avenues in treating CDAD. Fighting bacterial resistance is a long and never ending journey, and more molecules having antibiotic properties are needed to be developed. Whatever said and done, fidaxomicin seems to be a promising molecule for CDAD.

 
  References Top

1.Hensgens MP, Goorhuis A, Dekkers OM, Kuijper EJ. Time interval of increased risk for Clostridium difficile infection after exposure to antibiotics. J Antimicrob Chemother 2012;67:742-8.  Back to cited text no. 1
    
2.Nelson RL, Kelsey P, Leeman H, Meardon N, Patel H, Paul K, et al. Antibiotic treatment for Clostridium difficile-associated diarrhea in adults. Cochrane Database Syst Rev 2011:CD004610.  Back to cited text no. 2
    
3.Vaishnavi C. Clostridium difficile infection: Clinical spectrum and approach to management. Indian J Gastroenterol 2011;30: 245-54.  Back to cited text no. 3
    
4.Miftode E, Leca D, Dorneanu O. Clostridium difficile infections: What is new?. Rev Med Chir Soc Med Nat Iasi 2011;115: 656-61.  Back to cited text no. 4
    
5.Duggan ST. Fidaxomicin: In Clostridium difficile Infection. Drugs 2011;71:2445-56.  Back to cited text no. 5
    
6.Hausmann J, Zeuzem S, Schröder O. Fidaxomicin-the next step? A new narrow-spectrum macrocyclic antibiotic for the management of clostridium difficile infection. Gastroenterology 2011;141:1116-8.  Back to cited text no. 6
    
7.Hardesty JS, Juang P. Fidaxomicin: A macrocyclic antibiotic for the treatment of Clostridium difficile infection. Pharmacotherapy 2011;31:877-86.  Back to cited text no. 7
    
8.Venugopal AA, Johnson S. Fidaxomicin: A novel macrocyclic antibiotic approved for treatment of clostridium difficile infection. Clin Infect Dis 2012;54:568-74.  Back to cited text no. 8
    
9.Srivastava A, Talaue M, Liu S, Degen D, Ebright RY, Sineva E, et al. New target for inhibition of bacterial RNA polymerase: ′switch region′. Curr Opin Microbiol 2011;14:532-43.  Back to cited text no. 9
    
10.Babakhani F, Gomez A, Robert N, Sears P. Postantibiotic effect of fidaxomicin and its major metabolite, OP-1118, against Clostridium difficile. Antimicrob Agents Chemother 2011;55:4427-9.  Back to cited text no. 10
    
11.Goldstein EJ, Citron DM, Sears P, Babakhani F, Sambol SP, Gerding DN, et al. Comparative susceptibilities to fidaxomicin (OPT-80) of isolates collected at baseline, recurrence, and failure from patients in two phase III trials of fidaxomicin against Clostridium difficile infection. Antimicrob Agents Chemother 2011;55:5194-9.  Back to cited text no. 11
    
12.Citron DM, Babakhani F, Goldstein EJ, Nagaro K, Sambol S, Sears P, et al. Typing and susceptibility of bacterial isolates from the fidaxomicin (OPT-80) phase II study for C. difficile infection. Anaerobe 2009;15:234-6.  Back to cited text no. 12
    
13.Louie TJ, Miller MA, Mullane KM, Weiss K, Lentnek A, Golan Y, et al. OPT-80-003 Clinical Study Group. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011;364:422-31.  Back to cited text no. 13
    
14.Gualtieri M, Tupin A, Brodolin K, Leonetti JP. Frequency and characterisation of spontaneous lipiarmycin-resistant Enterococcus faecalis mutants selected in vitro. Int J Antimicrob Agents 2009;34:605-6.  Back to cited text no. 14
    




 

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Abstract
Introduction
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