After seven decades of traditional antibiotic research, we are fighting a losing battle with antimicrobial resistance. Why is this the case and how can we turn this around? Experience suggests antibacterial drug development suffers a much lower success rate than other therapeutic areas, greatly limiting the number of potential new antibiotics that could be introduced into the market. Especially important, it has limited our access to novel mechanism agents that have no pre-existing resistance.<br/>Comparing antibacterial development to other therapeutic areas, the dose of antibacterials have remained much higher, typically multiple grams per day. Key reasons for this high dose include physicians treating patients empirically. Since there are no rapid diagnostics we must assume the causative pathogen is the hardest to treat, and the patient treated has the lowest exposure, two opposing forces that drive up the dose. Also, antibacterial therapy is highly acute. The infecting bacterial biomass is able to double every 20 min, requiring more drug to account for the increased number of targets. In addition, the bacterial membrane is very good at keeping out antibiotics and in some cases there can be a million-fold concentration gradient of the antibiotic from the outside to the inside of bacteria<br/>High doses create multiple challenges, the most important of which is the need for an exquisite safety profile. Higher exposures lead to a greater chance of off-target activity, thus reducing the safety margin. A positive therapeutic index must be maintained for clinical success.<br/>To ensure a strong pipeline, we need a transformational approach where future antibiotics are dosed a levels that are in-line with other therapeutic areas, and alternative approaches are pioneered. This presentation will analyze historic data, review the challenges and propose options to regain our advantage over bacterial resistance.

What have we learned from traditional antibiotic research and what are our alternatives?

251st National Meeting (2016)

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