1. David M. Shlaes Anti-infectives Consulting, LLC Stonington, CT Participation sponsored by: Nabriva, Vienna, AU Novexel, Romainville, FR Consulting relationships with a number of biotechnology companies or investment firms working in the area of antiinfective discovery and development.

2. PERSPECTIVES In the consideration of risk-benefit for antibacterials, the agency could reflect on drugs approved previously (including generics) based on efficacy data which, in retrospect, are questionable. Antibiotics with relatively low risk, but for which the prescription volume is high (esp. generics) may be associated with higher absolute risk. Severe hepatotoxicity is not the only potentially life threatening adverse effect in the antibiotic world.

3. The Dilemma for Physicians and Patients Essentially no antibiotic has been developed based on placebo-controlled trials with bacteriology for ABS – including the 1 st choice Augmentin or Amoxicillin. 2 nd line antibiotics have issues. –Macrolides –resistance which leads to clinical failure. –Tetracyclines – widespread resistance. –SXT – common allergic reactions. –(Fluoroquinolones, others?) Do we no longer need more options?

4. The Numbers – Ketek vs. Drug of 1 st Choice in ABS 10 million prescriptions for Ketek were surveyed in response to reports of serious but rare liver toxicity and death. The FDA has identified 12 cases of acute liver failure among the10 million courses of therapy (including 4 deaths). Based on the rate of fatal anaphylaxis for penicillin, among the 10 million courses of therapy as surveyed for Ketek we could expect 100 to 285 deaths from acute anaphylaxis if the prescriptions had been for a penicillin. –Even if we reduce the anaphylaxis numbers by 10X to account for poor reporting – the event is still more common than fatal hepatoxicity due to Ketek.

5. US Prescription Data 2005 AntibioticUS Prescriptions (MM) Pen-VK10.3 Azi39.2 Ery7.8 Clari6.9 Ketek3.4

6. Logical Conclusions FDA Should Withdraw the Penicillins as therapy for ABS (and AECB). Congress should inquire as to why the FDA did not act more expeditiously against the penicillins. –The problem with argumentum ad absurdum is that sometimes one finds the absurdity valid. If we want efficacious new antibiotics for infections caused by resistant bacteria, we must be realistic (and consistent!) about the risks we are willing to take and the standards we impose.