Development of Drugs for Eradication of Nasal Carriage of S. aureus - - PowerPoint PPT Presentation

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Development of Drugs for Eradication of Nasal Carriage of S. aureus - - PowerPoint PPT Presentation

Oct 19, 2022 181 likes •285 views

Development of Drugs for Eradication of Nasal Carriage of S. aureus to Reduce S. aureus Infections in Vulnerable Surgical Patients Richard Bax Transcrip Partners Bax - Eradication of carriage - EMA 25-26 Oct 2012 1 Agenda for this talk

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SLIDE 1

Development of Drugs for Eradication of Nasal Carriage of

  • S. aureus to Reduce S. aureus

Infections in Vulnerable Surgical Patients

Richard Bax Transcrip Partners

Bax - Eradication of carriage - EMA 25-26 Oct 2012 1

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SLIDE 2

Agenda for this talk

– Context

  • Importance of carriage
  • Challenge of clinical trials
  • Possible label wording

– Ways to go forward

  • What is eradication?
  • What is the impact of eradication?
  • Next steps?

Bax - Eradication of carriage - EMA 25-26 Oct 2012 2

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SLIDE 3

Eradication of carriage

  • Nasal/gut colonization with pathogens is common

– S. aureus, N. meningitidis, H. pylori, C. difficile, gut flora (selective decontamination), MDR Pathogens – Logically, you can’t get infected if the pathogen is not present

  • There are precedents for this concept

– nasal mupirocin: S. aureus/MRSA/MSSA – oral ciprofloxacin/rifampicin: N. meningitidis – oral clarithromycin/amoxicillin/metronidazole: H. pylori

  • Regulatory focus going forward on proven clinical benefit
  • ver and above successful eradication (draft guideline 4.2.1.5.4)
  • Focus for this talk: S. aureus decolonization

Bax - Eradication of carriage - EMA 25-26 Oct 2012

3

Context

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SLIDE 4
  • S. aureus nasal eradication
  • Premise: S. aureus nasal carriage is an important risk

factor for infection due to S. aureus1,2 in high risk patients

  • Control of MRSA/MSSA remains a challenge

– Mupirocin resistance is rising

  • New agents are needed:

– How can we achieve this? – Trials based on clinical endpoints are not possible (next slide)…

Bax - Eradication of carriage - EMA 25-26 Oct 2012 4

  • 1. Munoz et al. J Hosp Inf 2008; 68: 25-31
  • 2. Kluytmans et al. Infection 2005; 33: 3-8

Context

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SLIDE 5

10,000 20,000 30,000 40,000 50,000 60,000 70,000 80,000 90,000 100,000

Post-surgery infection rate in placebo group

Total Number of Screening Subjects

60% reduction 50% reduction 40% reduction

60% reduction 4,168 4,800 5,640 6,816 8,584 11,528 17,408 35,064 50% reduction 6,304 7,264 8,544 10,328 13,008 17,472 26,400 53,200 40% reduction 10,320 11,888 13,984 16,920 21,320 28,656 43,320 87,328 8% 7% 6% 5% 4% 3% 2% 1%

  • S. aureus nasal eradication: Sample sizes for a trial

powered on clinical benefit are in the thousands

Bax - Eradication of carriage - EMA 25-26 Oct 2012

Scenario:

  • 25% screened = nasal S.aureus

carriers

  • 2% placebo infection rate post-op
  • objective: 50% reduction of infections
  • 90% power, two-sided type-1 error 5%

→ 26,400 subjects required to show 50% event reduction

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Context

Slide from EFPIA presentation at Feb 2011 EMA guidance workshop

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SLIDE 6

Labelling as a view to the problem

  • But, the point of any such product is to prevent

infection

  • So, how do we go from this…

– Bactroban nasal is indicated for the eradication of nasal colonisation with MRSA in adult patients and health care workers as part of a comprehensive infection control programme to reduce the risk of infection among people in high risk of MRSA infection during institutional outbreaks of infections with this pathogen.

  • To this?

– Product X is indicated for the eradication of nasal colonisation with staphylococci including MRSA to reduce the risk of post operative staphyloccal infections in high risk patients.

Bax - Eradication of carriage - EMA 25-26 Oct 2012 6

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SLIDE 7

What is eradication?

  • The possible tools are well known

– Culture, PCR, etc

  • Can we work together to validate some measure of

microbiological eradication as reliable predictor of clinical benefit?

– Review previous successful papers and micro methodologies and agree microbiological methods – Focus on tools that offer high face validity, long track records, and wide-spread availability – Also think through issues of measurement timing / duration

Bax - Eradication of carriage - EMA 25-26 Oct 2012 7

Ways to go forward

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SLIDE 8
  • Logically, there must be an impact

– If the organism is eradicated, endogenous infection is not possible

  • How do we decide?

– Collective review of available data – Workshop-based discussion and analysis

  • Goals of this work

– Summarize and agree interpretation of available data – Where needed, generate plans for additional research – Also identify possible negative effects of decolonization

  • In so doing, create a road-map for development

Bax - Eradication of carriage - EMA 25-26 Oct 2012 8

What is the impact of eradication?

Ways to go forward

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SLIDE 9

Next Steps

  • New agents for S. aureus decolonization are needed
  • Eradication logically should offer value

– Need to define methods and value.

  • Existing data are probably adequate to show that value
  • We would like to find a way to create a public

conversation on this that enables future work

Bax - Eradication of carriage - EMA 25-26 Oct 2012 9