Advancing Regulatory Science Through Development of Innovative Methodologies in the area of Antimicrobial Development (U01)

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PLEASE NOTE: The correct contact information for the project officer is as follows: Nancy Masiello Telephone: 301-796-8498 and FAX: 301-847-8614. FDA is announcing an FOA for research into innovative methodologies in the area of antimicrobial development that can have an impact on the selection of the appropriate dosing and/or combination regimens to prevent emergence of antimicrobial resistance.This FOA is part of the Critical Path Initiative's (CPI's) long-term strategic effort to drive innovation in medical product development. CPI forms a key component of a broader FDA initiative, Advancing Regulatory Science, which focuses on developing new tools, standards, and approaches to assess the safety, efficacy, quality and performance of all FDA-regulated products.There is growing concern over the development of antimicrobial resistance. Even newer antimicrobials such as fluoroquinolones which formerly showed excellent broad spectrum activity are losing their value as the prevalence of resistant organisms continues to increase. Strategies have been explored to curtail the development of resistance. These range from restricting the use of certain antimicrobials, to elaborate infection control measures to prevent the spread of these organisms, to programs for antimicrobial stewardship.Mounting evidence suggests that combinations of antimicrobials and/or high dose and short duration therapy are promising strategies to combat the emergence of resistance. High drug exposure is often necessary to suppress the emergence of resistance and can involve increase in dose, or dosing frequency, or changes in the method of dose administration (e.g., extending infusion time). Combination antimicrobial therapy might prevent emergence of resistance by acting on multiple bacterial targets while simultaneously reducing the effective dose of individual drugs.The use of combination antimicrobials to prevent emergence of resistance and improve patient outcomes is standard practice in the treatment of tuberculosis, H. pylori, HIV, and currently malaria.The development of new antibacterial agents typically focuses on primary efficacy and the generation of resistance has not been a major consideration. This approach carries a legacy of failure with widespread resistance to almost all available agents.The purpose of this FOA is to investigate the potential value of novel PK/PD-based dosing and combination therapy approaches in preventing the development of antimicrobial resistance.[4] New modeling systems, such as in vitro hollow fiber systems, may be helpful in clarifying the potential value of these approaches. Areas of primary concern are Gram-negative pathogens that are frequent in health care settings as well as in the community, and are commonly treated with single agents, e.g. pathogens responsible for uncomplicated urinary tract infections. Many of these organisms, including E. coli, K. pneumoniae, Serratia, Acinetobacter, Proteus, P. aeruginosa, and Enterobacter spp., exhibit growing resistance to multiple antimicrobial agents.

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