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New HPA Guidance Includes DIFICLIR™ (fidaxomicin) To Curb Clostridium Difficile infection


New antibiotic treatment recommended for all recurrent cases of potentially fatal hospital-acquired infection

The Department of Health (DH) and Health Protection Agency (HPA) (Public Health England) have issued new best practice guidance recommending fidaxomicin, a first-in-class antibiotic for Clostridium difficile infection (CDI) for the treatment of CDI in adults with CDI recurrence and/or with severe cases of the infection who are considered at high risk for recurrence (elderly patients with multiple comorbidities who are receiving concomitant antibiotics).1

In clinical trials, fidaxomicin demonstrated a similar efficacy and safety profile to the current mainstay of therapy, vancomycin (primary endpoint), but more than halved the rate of recurrence in patients with CDI compared to vancomycin (planned secondary endpoint, 12.7% versus 26.9%, p=0.0002).2 Recurrence of CDI occurs in up to 25% of patients within 30 days of initial treatment with current treatment2,3 and has been identified as the most important problem in CDI treatment.4 Having launched in the UK in June 2012, fidaxomicin has been nationally welcomed as an effective treatment for CDI with proven advantages over existing treatments, however, there are inconsistencies from the various national bodies around recommended patient types in which to use fidaxomicin. For example, in England, evidence summary documentation produced by the National Institute of Clinical Excellence (NICE) and separately by the London New Drugs Group recommends treatment with fidaxomicin for CDI recurrence and in patients at high risk of recurrence.5 However, the Scottish Medicines Consortium (SMC) recommends fidaxomicin for the treatment of patients with a first recurrence.6 More recently, the All Wales Medicines Strategy Group (AWMSG) recommends fidaxomicin treatment for severe cases of CDI and CDI recurrence.7

Dr Simon Goldenberg, consultant microbiologist & infection control doctor, commented on the news, saying, “As CDI continues to be a persistent problem in both our communities and hospitals, I am very pleased to have access to fidaxomicin for my patients. I believe it should be used first line for all patients presenting with CDI. Up to a quarter of patients have more than 1 episode of infection, so I feel it is crucial to provide an effective treatment that reduces that risk as much as possible.”

Reducing CDI is a high priority for the NHS in England this year; with new 2013/2014 targets set at a 30% reduction in cases for the average acute Trust and a 21% reduction for the average CCG,8,9 with significant financial penalties as a potential possibility for those not achieving these objectives. The updated HPA and DH guidance, which supersedes existing guidance from 2009, has been prompted by new evidence and management approaches to delivering good infection control and environmental hygiene.

CDI, which results from infection of the internal lining of the colon by C. Difficile bacteria, is one of the most common healthcare-acquired infections in the UK. CDI is a significant problem in hospitals, nursing homes and other long-term care facilities.10 CDI is a potentially fatal, hospital-acquired infection that affects nearly 27,00011,12,13,14 people every year in the UK and is associated with around 3,00015,16,17 deaths per annum.

About the HPA guidance

Treatment recommendations:

For severe CDI - oral vancomycin 125 mg qds for 10-14 days. Fidaxomicin should be considered for patients with severe CDI who are considered at high risk for recurrence; these include elderly patients with multiple comorbidities who are receiving concomitant antibiotics. In severe CDI cases not responding to oral vancomycin 125 mg qds, oral fidaxomicin 200 mg bd is an alternative; or high-dosage oral vancomycin (up to 500 mg qds, if necessary administered via a nasogastric tube), +/- iv metronidazole 500 mg tds is recommended. The addition of oral rifampicin (300 mg bd) or iv immunoglobulin (400 mg/kg) may also be considered.

For recurrent CDI – oral fidaxomicin 200 mg bd is recommended; oral vancomycin 125 mg qds is an alternative.

This guidance has been prepared by Professor Mark H. Wilcox of Public Health England, an executive agency of the Department of Health formed in 2013 from a number of expert organisations in public health.

About Clostridium difficile Infection (CDI)

CDI is a serious illness resulting from infection of the internal lining of the colon by C. Difficile bacteria. The bacteria produce toxins that cause inflammation of the colon, diarrhoea and, in some cases, death. Patients typically develop CDI after the use of broad-spectrum antibiotics that disrupt normal bowel flora, allowing C. difficile bacteria to flourish. The risk of CDI and disease recurrence is particularly high in patients aged 65 years and older18 but also affects younger patients. CDI results in substantial costs to healthcare systems, in particular because of extended hospitalisation.19 Hospitalised patients with CDI have a longer hospital stay of 3.6 days and 54% higher adjusted hospital costs compared with those without CDI.

About clinical trials for DIFICLIR:

Lancet Infectious Diseases

In the multi-centre, double-blind, randomised, non-inferiority Phase III trial (known as Study OPT-80-004), 509 adults with CDI in North America and seven European countries, including the UK, received fidaxomicin 200mg BD oral tablets (every 12 hours) or vancomycin 125mg oral tablets (every 6 hours) for 10 days. The proportion of subjects in whom clinical cure* was achieved were similar for the two treatments (87.7% vs. 86.8% respectively) meaning that fidaxomicin met the primary endpoint of non-inferiority to vancomycin. Also, fidaxomicin recipients were more likely than those treated with vancomycin to experience a sustained antibiotic response (clinical cure* without recurrence) within 30 days of completing treatment (76.6% vs. 63.4% respectively, p=0.001).2

*Please note: clinical cure was defined as the resolution of diarrhoea for the duration of treatment and no need for further CDI therapy 2 days after completion of study medication, as determined by the investigator.

New England Journal of Medicine

In the prospective, multicentre, double-blind, randomised, parallel-group Phase III trial (known as OPT-80-003), 629 patients aged 16 years or older were randomised to treatment with fidaxomicin 200mg BD oral tablets (every 12 hours) or vancomycin 125mg oral tablets (every 6 hours) for 10 days, of whom 596 (287 with fidaxomicin; 309 with vancomycin) could be evaluated for the modified intention-to-treat analysis. Results showed that significantly fewer patients in the fidaxomicin group than in the vancomycin group had a recurrence (15.4% vs. 25.3%, p=0.005).21

Clinical Infectious Diseases

Data from 2 Phase III clinical trials were pooled and analysed to study the effect of concomitant antibiotics on the response to fidaxomicin or vancomycin. The results demonstrated that the clinical cure* rate for patients who received fidaxomicin was 90.0% versus 79.4% for vancomycin (P=0.04). In patients receiving concomitant antibiotics during treatment and/or follow up, treatment with fidaxomicin compared with vancomycin was associated with 12.3% fewer recurrences (16.9% vs 29.2%; p=0.048).22

*Please note: clinical cure was defined as the resolution of diarrhoea for the duration of treatment and no need for further CDI therapy 2 days after completion of study medication, as determined by the investigator.

About the NICE evidence summary23

Evidence summaries: new medicines provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within the summary, but the summary is not NICE guidance.

Source

1 HPA Guidance

2 Cornely et al. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada and the USA: a double-blind, non-inferiority. Randomised controlled trial. Lancet Infectious Diseases 2012; 12:4:281-9

3 Bouza et al. Results of a phase III trial comparing tolevamer, vancomycin and metronidazole in patients with Clostridium difficile-associated diarrhoea. 18th European Congress of Clinical Microbiology and Infectious Diseases 2008. N Engl J Med 2010; 362: 197-205

4 Bauer MP, et al. European Society of Clinical Microbiology and Infectious Disease (ESCMID):treatment guidance document for Clostridium difficile-infection (CDI). Clin Microbiol Infect.2009;15:1067-79.

5 London New Drugs Group APC/DTC Briefing Document, Fidaxomicin (Dificlir) June 2012

6 Scottish Medicines Consortium. fidaxomicin 200mg film-coated tablets (Dificlir®). 8th June 2012.

7 All Wales Medicines Strategy Group Final Appraisal Recommendation – 3712: Fidaxomicin (Dificlir®) 200 mg tablets November 2012

8 NHS outcomes framework – technical guidance 2013/2014

9 Clinical commissioning group and Provider Objectives for Reduction in Clostridium difficile: 2013/14

10 Simor AE, et al. Clostridium difficile in long-term-care facilities for the elderly. Infect Control Hosp Epidemiol. 2002;23:696-703

11 Health Protection Agency. Summary points on Clostridium difficile infection (CDI) July 2011 [Last accessed January 2013]

12 Health Protection Scotland. Quarterly reports on the Surveillance of Clostridium difficile infection (CDI) in Scotland. 2010/2011. [Last accessed May 2012]

13 HSCNI Public Health Agency Summary Tables for Clostridium difficile and MRSA (MeticillinResistant Staphylococcus aureus) cases 2006/07 to 2011/12. April 2012. [Last accessed May 2012]

14 Public Health Wales. All Wales commentaries: Clostridium difficile reports. February 2012 [last accessed May 2012]

15 Office for National Statistics. Deaths involving Clostridium difficile: England and Wales, 2006 to 2010. [Last accessed May 2012]

16 General Register Office for Scotland. Clostridium difficile (C.diff) deaths. November 2011. [Last accessed May 2012]

17 Northern Ireland Statistics & Research Agency. Healthcare-Associated Infection. [Last accessed May 2012]

18 Health Protection Agency. Clostridium difficile.

19 Ghantoji SS, et al. Economic healthcare costs of Clostridium difficile infection: a systematic review.Hosp Infect. 2010;74:309-18.

20 Kyne L, et al. Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile. Clin Infect Dis. 2002;1;34(3):346-53.

21 Louie et al. Fidaxomicin versus Vancomycin for Clostridium difficile infection. N Engl J Med 2011;364:422-31

22 Mullane KM, Miller MA, Weiss K et al. Efficacy of fidaxomicin versus vancomycin as therapy for Clostridium difficile Infection in individuals taking concomitant antibiotics for other concurrent infections. Clinical Infectious Diseases 2011; 53(5):440-447

23 NICE Evidence summary: new medicine_ Clostridium difficile infection: fidaxomicin Published 13 July 2012

Source: Astellas Pharma Ltd.