Gram-Negative Infections due to Multidrug-Resistant Enterobacteriaceae | Decision Base | US/EU | 2014

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The increasing prevalence and severity of infections caused by multidrug-resistant (MDR) gram-negative pathogens, particularly MDR Enterobacteriaceae, and the meager pipeline of novel antibiotic therapies in development to treat gram-negative infections (GNIs) have resulted in limited treatment options for an increasing number of patients. Government efforts are under way to promote the development of novel antibiotics to treat these infections, including the Infectious Diseases Society of America’s proposed Limited Population Antibacterial Drug (LPAD) approval pathway. This regulatory pathway was submitted as part of the Antibiotic Development Plan to Advance Patient Treatment Act of 2013 (ADAPT), which was introduced into the House of Representatives in December 2013. The LPAD approval pathway and ADAPT legislation are designed to promote the prompt approval of drugs intended for diseases for which there is high unmet need. Although the regulatory environment for developing new antibiotic therapies has been challenging, the late-stage clinical pipeline for antibiotics against MDR gram-negative pathogens includes two promising cephalosporin/beta-lactamase inhibitor combinations: Cubist’s CXA-201 (ceftolozane/tazobactam) and AstraZeneca/Forest Laboratories’ CAZ-AVI (ceftazidime/avibactam). Other promising therapies in development include Tetraphase’s IV and oral tetracycline eravacycline; Achaogen’s next-generation aminoglycoside plazomicin; and Merck’s Primaxin plus MK-7655 (imipenem/cilastatin + MK-7655), a combination carbapenem/beta-lactamase inhibitor therapy. Despite these developments, opportunities remain for more therapies that can improve clinical cure rates and reduce all-cause mortality in patients with GNIs due to MDR Enterobacteriaceae. Recent changes to FDA and EMA guidelines for antibiotic drug development now provide pathways moving forward for manufacturers developing new antibiotics to treat serious GNIs for which treatment options are limited.