AKAO 2017 Annual Report

11 • Potent in vitro activity and in vivo efficacy in nonclinical studies against MDR Enterobacteriaceae, including ESBL-producers and CRE. Plazomicin retains activity in nonclinical studies against clinical Enterobacteriaceae isolates possessing -lactamases including most varieties of carbapenemases, as well as most types of resistance to other key antibiotics, including commercially available aminoglycosides, colistin, and tigecycline. We believe that plazomicin has the potential to become a new standard of care for the treatment of CRE, based on the attributes outlined above. Carbapenem-Resistant Enterobacteriaceae Pose an Urgent Threat to Patients The need for new antibiotics to treat CRE is particularly acute, as CRE are one of the top global threats in infectious disease. In 2013, the CDC labeled CRE as a “nightmare bacteria” and indicated that CRE pose a public health threat requiring “urgent and aggressive action.” These bacteria are commonly MDR, exhibiting resistance not only to carbapenems, but also to most antibiotics commonly used to treat gram-negative infections, including cephalosporins, -lactam/ -lactamase inhibitor combinations, fluoroquinolones, and currently-marketed aminoglycosides. Resistance to carbapenems has been highlighted because these drugs are one of the last lines of defense against resistant gram-negative infections. Most CRE express enzymes called carbapenemases which break down the carbapenem antibiotic molecule before it can kill the bacteria. Due to the lack of effective therapies, CRE infections are associated with significant mortality, with up to 50% mortality observed in patients with BSI and greater than 70% in patients with cancer or receiving a liver transplant. With limited treatment options available for CRE infections, physicians have resorted to drugs such as colistin and tigecycline, or more recently approved agents such as ceftazidime-avibactam or meropenem-vaborbactam with limited clinical data in CRE. However, there is evidence that these antibiotics are failing patients. For example, in BSI due to carbapenemase-producing K. pneumoniae , all-cause mortality for treatment with colistin, tigecycline, or combinations of antibiotics that do not include a carbapenem active in vitro against the infecting isolate were reported to be 46%, 47%, and 37%, respectively. Recently, resistance to even these last-resort treatments has begun to be reported, further increasing the urgency for new therapeutic options. The CRE problem is global and the incidence has increased significantly over the last decade. We estimate that there were approximately 180,000 cases of CRE infections in the United States and the EU5 in 2016, of which 70,000 to 80,000 were in the United States. We believe that CRE incidence will continue to increase in the future. A key driver of resistance growth, the use of carbapenems, is increasing. Once restricted in use to limit the emergence of resistance, hospitals are changing their policies due to the pressing need for carbapenems to treat the growing number of MDR infections. For example, ESBL-producing bacteria now account for over 18% of E. coli cultured from urine in the United States. This has led to carbapenems being used in 350,000 cases of UTI infection in 2014 up from 72,000 a decade ago. Two-thirds of U.S. hospital pharmacy directors reported that carbapenems are now unrestricted on their hospital formularies, likely a reflection of the increasing incidence of difficult-to-treat gram- negative infections. Additionally, the spread of CRE among patients, between healthcare facilities, and across geographic regions is exacerbated by the ability of Enterobacteriaceae to readily transfer their resistance genes from one bacterium to another. Especially concerning is the potential of CRE to spread in the outpatient setting, which could lead to an epidemic of community-based CRE infections. Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae Pose a Serious Threat to Patients The need for new antibiotics to treat ESBL-producing Enterobacteriaceae is high, as these bacteria have become widespread globally in both healthcare-associated and community-onset infections and the use of carbapenems to treat infections caused by these organisms is felt to be contributing to the rise in CRE. In 2013, the CDC indicated that ESBL-producing Enterobacteriaceae pose a serious concern to public health threat requiring “prompt and sustained action.” Similar to CRE, these bacteria are commonly MDR, exhibiting resistance not only to extended spectrum cephalosporins but also to fluoroquinolones, and currently-marketed aminoglycosides. In many cases the remaining treatment option is a carbapenem and use of carbapenems to treat these infections is thought to be contributing to increased carbapenem resistance. We estimate that there were greater than 600,000 cases of hospital treated infections caused by ESBL-producing Enterobacteriaceae in the United States in 2016. Infections caused by these organisms are associated with significant mortality; patients with BSI caused by ESBL-producing