Your questions to the PBAC

Readers are invited to write in with their questions about decisions of the Pharmaceutical Benefits Advisory Committee (PBAC). Australian Prescriber publishes selected questions from readers, together with answers from the PBAC. Questions may address issues such as regulatory decisions, pharmaceutical benefits listings and withdrawals.

This exclusive arrangement helps Australian Prescriber readers understand how the contents of the Pharmaceutical Benefits Scheme (PBS, see www.pbs.gov.au) are determined.

Letters and responses are reviewed by the Editorial Executive Committee and may be edited before publication. It may not be possible to reply to all individual questions.

Rifampicin for MRSA

While reviewing an article on bacteria with resistance to multiple antibiotics (Aust Prescr 2010;33:68–71), the Editorial Executive Committee found an anomaly in the availability of rifampicin on the Pharmaceutical Benefits Scheme (PBS). The restrictions for rifampicin do not include the treatment of methicillin-resistant Staphylococcus aureus (MRSA). For infections which can be managed with oral antibiotics, rifampicin is often given with fusidic acid. The PBS restrictions for fusidic acid require it to be used with another antibiotic in the treatment of proven serious staphylococcal infections. The other antibiotic is likely to be rifampicin, but this cannot be prescribed as a pharmaceutical benefit.

The purpose of using two antibiotics is to try to prevent further resistance. The Editorial Executive Committee therefore asked for the advice of the Pharmaceutical Benefits Advisory Committee on how to resolve the apparent anomaly in the PBS restrictions.

PBAC response:

The PBAC has to consider the terms of marketing approval of a product. This approval is granted by the Therapeutic Goods Administration (TGA) and specifies the conditions in which the drug has shown acceptable safety and efficacy. The PBAC is not in a position to recommend that a drug be listed outside the terms of marketing approval specified by the TGA.

Currently, rifampicin is approved by the TGA for the treatment of tuberculosis, leprosy, prophylaxis of meningococcal disease and prophylaxis of household contacts of patients with Haemophilus influenzae type B. Under the National Health Act 1953 there is no provision for the subsidised supply of an item listed as a restricted benefit for use in a condition which lies outside the terms of the restriction specified in the Schedule of Pharmaceutical Benefits. The current PBS listing for rifampicin reflects the TGA registration and so rifampicin cannot be prescribed for MRSA under the PBS.

The PBAC is concerned that rifampicin is not available as a pharmaceutical benefit for treating MRSA and has previously asked the drug\'s sponsor to seek marketing approval for this indication. However, neither the PBAC nor the government can compel a manufacturer to apply for registration of a drug for a particular indication.

Industry response:

The Editorial Executive Committee sought responses from the manufacturers of rifampicin in Australia.

Dr Alex Condoleon, Medical Director Australia & New Zealand, Sanofi-aventis, comments:

The availability of rifampicin as a pharmaceutical benefit in combination with fusidic acid for methicillin-resistant Staphylococcus aureus (MRSA) would require supporting evidence to achieve registration with the TGA and subsequently reimbursement through the PBS. Sanofi-aventis has therefore searched the literature about this combination, to determine the feasability of increasing access to this regimen for patients.

Treatment guidelines

The Therapeutic Guidelines: Antibiotic1 lists the combination of rifampicin and fusidic acid as a treatment option for recurrent staphylococcal skin infections (including MRSA-positive infections), and MRSA osteomyelitis involving the bone or joint prostheses, in both adult and paediatric patients. Similarly, the Australian Medicines Handbook2 lists combination treatment of MRSA infection as an indication under both the monographs for rifampicin and fusidic acid.

Contrary to the Australian guidelines, the combination is not included in DrugDex Evaluations,3 the American Hospital Formulary Service (AHFS) Drug lnformation,4 the Centers for Disease Control and Prevention (CDC),5 the World Health Organization (WHO),6 and the European Centre for Disease Prevention and Control.7

Published clinical studies and reviews

A search of the medical literature retrieved a small number of studies evaluating the combination for the management of MRSA infections and a large number of review articles on the management of MRSA infections. This search is subject to the limitations inherent in these databases and cannot be considered exhaustive.

Studies in adults

Two small (n=<12) Australian trials8,9 studied the combination of rifampicin and fusidic acid for the treatment of MRSA infections in orthopaedic patients and patients with cystic fibrosis respectively. Both studies found this combination to be effective at eradicating MRSA infection.

Studies in children

None of the small number of studies10–13 of MRSA infections evaluated the combination of rifampicin and fusidic acid.

Review articles

Two of four review articles14–17 on the management of MRSA infections specifically listed the combination of rifampicin and fusidic acid as a treatment option for MRSA infections.16,17

None of six paediatric review articles18–23 specifically listed the combination of rifampicin and fusidic acid as a recommended treatment option. However, five of these reviews18–22 listed rifampicin as a treatment option, stating that it must be used in combination with other antibiotics.

Conclusion

Upon current assessment of available data there appear to be inconsistencies in treatment guidelines and only a small number of studies evaluating the combination of rifampicin and fusidic acid for the treatment of MRSA infections. Sanofi-aventis therefore does not believe that the evidence base exists to satisfy regulatory requirements to support this additional indication. However, we are open to reassessing options should further evidence emerge, or be brought to our attention, that could support a formal regulatory submission.

References

  1. Recurrent staphylococcal skin infection [revised 2009 Feb]. In: eTG complete [Internet]. Melbourne: Therapeutic Guidelines Limited; 2010 Mar.
    http://online.tg.org.au/complete/[cited 2010 Sep 20]
  2. Rifampicin Monograph. Australian Medicines Handbook. RACGP/PSA /ASCEPT. Adelaide 2010.
    www.amh.net.au [cited 2010 Sep 20]
  3. DrugDex Evaluations. Micromedex Healthcare Series. DRUGDEX System (electronic version). Thomson Micromedex, Greenwood Village, Colorado, USA.
    www.thomsonhc.com [cited 2010 Sep 20]
  4. McEvoy GK, editor. AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharmacists Inc; 2009.
  5. Centers for Disease Control and Prevention (CDC) [website]. www.cdc.gov/ [cited 2010 Sep 20]
  6. World Health Organization [website].
    www.who.int/en/ [cited 2010 Sep 20]
  7. European Centre for Disease Prevention and Control [website]. www.ecdc.europa.eu/en/ [cited 2010 Sep 20]
  8. Aboltins CA, Page MA, Buising KL, Jenney AW, Daffy JR, Choong PF, et al. Treatment of staphylococcal prosthetic joint infections with debridement, prosthesis retention and oral rifampicin and fusidic acid. Clin Microbiol Infect 2007;13:586-91.
  9. Garske LA, Kidd TJ, Gan R, Bunting JP, Franks CA, Coulter C, et al. Rifampicin and sodium fusidate reduces the frequency of methicillin-resistant Staphylococcus aureus (MRSA) isolation in adults with cystic fibrosis and chronic MRSA infection. J Hosp Infect 2004;56:208-14.
  10. Creech CB, Beekmann SE, Chen Y, Polgreen PM. Variability among pediatric infectious diseases specialists in the treatment and prevention of methicillin-resistant Staphylococcus aureus skin and soft tissue infections. Pediatr Infect Dis J 2008;27:270-2.
  11. Johnigan RH, Pereira KD, Poole MD. Community-acquired methicillin-resistant Staphylococcus aureus in children and adolescents: changing trends. Arch Otolaryngol Head Neck Surg 2003;129:1049-52.
  12. Abdel-Haq N, Al-Tatari H, Chearskul P, Salimnia H, Asmar BI, Fairfax MR, et al. Methicillin-resistant Staphylococcus aureus (MRSA) in hospitalized children: correlation of molecular analysis with clinical presentation and antibiotic susceptibility testing (ABST) results. Eur J Clin Microbiol Infect Dis 2009;28:547-51.
  13. Liu Y, Kong F, Zhang X, Brown M, Ma L, Yang Y. Antimicrobial susceptibility of Staphylococcus aureus isolated from children with impetigo in China from 2003 to 2007 shows community-associated methicillin-resistant Staphylococcus aureus to be uncommon and heterogeneous. Br J Dermatol 2009;161:1347-50.
  14. Deleo FR, Otto M, Kreiswirth BN, Chambers HF. Community-associated meticillin-resistant Staphylococcus aureus. Lancet 2010;375:1557-68.
  15. Bouza E. New therapeutic choices for infections caused by methicillin-resistant Staphylococcus aureus. Clin Microbiol Infect 2009;15(Suppl 7):44-52.
  16. Zervos M. Treatment options for uncomplicated community-acquired skin and soft tissue infections caused by methicillin-resistant Staphylococcus aureus: oral antimicrobial agents. Surg Infect (Larchmt) 2008;9(Suppl 1):S29-34.
  17. Wallin TR, Hern HG, Frazee BW. Community-associated methicillin-resistant Staphylococcus aureus. Emerg Med Clin North Am 2008;26:431-55.
  18. Immergluck LC. Community-associated infections in children – update on community-associated methicillin-resistant Staphylococcus aureus for the practitioner. Ethn Dis 2007;17(2 Suppl):46-9.
  19. Kaplan SL. Treatment of community-associated methicillin-resistant Staphylococcus aureus infections. Pediatr Infect Dis J 2005;24:457-8.
  20. Newland JG, Kearns GL. Treatment strategies for methicillin-resistant Staphylococcus aureus infections in pediatrics. Paediatr Drugs 2008;10:367-78.
  21. Marcinak JF, Frank AL. Epidemiology and treatment of community-associated methicillin-resistant Staphylococcus aureus in children. Expert Rev Anti Infect Ther 2006;4:91-100.
  22. Le J, Lieberman JM. Management of community-associated methicillin-resistant Staphylococcus aureus infections in children. Pharmacotherapy 2006;26:1758-70.
  23. Paintsil E. Pediatric community-acquired methicillin-resistant Staphylococcus aureus infection and colonization: trends and management. Curr Opin Pediatr 2007;19:75-82.

Dr Greg Pearce, Director, Medical Affairs, Alphapharm, comments:

Most parties with an interest in making older medicines more freely available, at an affordable cost, for unapproved indications agree that this is an important issue. Unfortunately, no-one has been able to devise a satisfactory process for registering the indication and listing the product on the PBS. At a minimum, this process needs to balance evidence requirements, commercial considerations and regulatory scrutiny to a point where the documentation expectations are consistent with the commercial objectives of a potential supplier.

This impasse remains, despite meetings between the Royal Australasian College of Physicians, the TGA and industry representatives, a consultancy commissioned by the Department of Health and Ageing on behalf of the Paediatric Medicines Advisory Group, and direct representation by Alphapharm to the TGA.

Alphapharm is sympathetic to addressing this gap in our ability to deliver quality use of medicines but cannot move forward under the current regulatory and reimbursement framework. Recent PBS reforms have shifted the sponsor\'s fulcrum even further away for supporting these requests.

The company would support any further discussions aimed at developing innovative approaches to improve access to treatment. These would need to match the costs and evidence requirements for registration against the needs of a manufacturer to achieve a financial return which at least covers the resource and financial costs associated with applying for approval of a new indication.


First published online: October 2010