Do We Want New Antibiotics for Mild Infections Is Bacterial Bronchitis in the Setting of Chronic Lung Disease a Mild Infection

The FDA and Europe could make an enormous difference immediately. First, for mild, acute infections like otitis, sinusitis and bronchitis, they need to reconsider their entire approach. For example, for otitis, where most authorities agree that expectant therapy is a reasonable approach, placebo-controlled trials remain difficult to accomplish, especially in the US. Guidelines from the American Society of Pediatrics suggest that patients with severe symptoms, those age 2 or less and those where the diagnosis is certain that it is otitis media, be treated with antibiotics immediately. This leaves older children, those with milder disease and those where the diagnosis is less certain (the majority of patients) available for expectant therapy. Nevertheless, recent surveys have shown that only 15% of children in the US are treated expectantly. The most common reason is parental concern (85% of parents) about not using antibiotics. One solution is based on a recent study reviewing many placebo-controlled trials in otitis. The data indicate that between days 2 and 4, 25% fewer children on antibiotics will have continued symptoms compared to patients on placebo. If this were true, one could design a comparative trial where symptoms on day 4 were the endpoint. Comparing two antibiotics with a margin of 10% (at worst, the new antibiotic could be no more that 10% worse than the comparator treatment) should be acceptable. The FDA may argue that since the data does not come from a single large placebo controlled trial it is invalid. Of course that single large placebo controlled trial may not be feasible. If we ever want to have new antibiotics for ear infections, the regulatory agencies must find another way forward.

A similar approach could probably be taken with sinusitis. In one study, only 11% of 44 illnesses in placebo recipients had completely resolved by day 10 compared with a complete resolution rate of 38.5% (32 of 83) among patients treated with antibiotics. By day 10, a total of 25 patients (57%) in the placebo group had complete resolution or were much better, compared with 71 (85.5%) of those receiving antibiotics. These data would suggest a treatment effect of about 30% (that is 30% more antibiotic treated patients were symptom free than placebo treated patients) for an endpoint of complete resolution by days 5-10. Again, a comparison of two antibiotics for this endpoint with a margin of 10% should be very acceptable. The FDA and EMEA could again make the same counter argument here as I noted above for otitis. My response is also the same. They have to find a way forward other than placebo-controlled trials if we ever want to have new antibiotics for sinusitis.

For severe exacerbations of chronic bronchitis, the regulatory agencies simply have to look at the Cochrane report and clinical practice guidelines, and then back off their current requirement for placebo-controlled trials. Administration of a placebo to these patients would probably not be ethical, clearly contradicts current practice guidelines, and may put patients' lives at risk. According to the Cochrane database, antibiotic treatment of COPD exacerbations with increased cough and sputum purulence reduces the risk of short-term mortality (as in DEATH!) by 77%, decreases the risk of treatment failure by 53% and the risk of sputum purulence by 44%. Given these impressive numbers, we could easily justify a return to our previous method of carrying out comparative trials of antibiotics with a statistical margin of 10% and be more than satisfied.

To be fair, the proposed changes to the European guidelines (not yet approved) indicate more flexibility in their approach to these so-called mild bacterial infections. But this approach leaves everything uncertain. Maybe if Europe took a courageous stand here the FDA would follow.

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