AKAO 2017 Annual Report

7 different types of chemical entities, requiring antibiotics that act in the gram-negative cytoplasm to be specifically designed to permeate both membranes. Antibiotics are classified according to several criteria: • Spectrum: Antibiotics that are effective against a wide variety of bacteria, including both gram-negative and gram-positive organisms, are considered to be broad-spectrum, while those that act upon only a limited number of species are considered to be narrow-spectrum. Narrow-spectrum antibiotics are most often selected if a specific pathogen is suspected or confirmed. • Cidality: Antibiotic action generally falls into two categories: bacteriostatic and bactericidal. Bacteriostatic antibiotics halt the growth of bacteria, relying on the immune system to clear the infection. Bactericidal antibiotics kill the bacterial pathogen directly and are preferred in life-threatening infections and when the patient’s immune system is not functioning optimally. • In vitro microbiological activity: This is the ability of the antibiotic to kill or inhibit growth of bacteria in vitro . In vitro experiments and assays do not take into account the complex interactions that occur in animals or humans, but are relatively easy to perform in the laboratory and usually constitute the extent of routine microbiological testing in hospital laboratories. Potency, which relates drug concentrations to activity, is commonly expressed as the minimum inhibitory concentration (“MIC”) in — g/mL, which is the lowest concentration at which the drug inhibits growth of the bacteria. Antibiotics with lower MICs are considered to be more potent. • Susceptibility/non-susceptibility: The relationship between microbiological activity and the clinical utility of an antibiotic to treat a given infection can be described in terms of susceptibility or non- susceptibility. A susceptible MIC value indicates a high probability that an antibiotic can be used to treat a particular infection. A non-susceptible MIC value from in vitro testing suggests the antibiotic is unlikely to be effective against the causative pathogen and thus should only be used under supervision of an infectious disease specialist. An intermediate MIC value suggests there is a slight chance the antibiotic will be effective against the causative pathogen. The MIC values defining susceptibility are established by FDA on approval of new antibiotics and medical standards organizations including the Clinical Laboratory and Standards Institute (“CLSI”), and the European Committee on Antimicrobial Susceptibility Testing (“EUCAST”). • Antimicrobial resistance: Resistance generally indicates the inability of an antibiotic to effectively treat an infection at usually administered doses. Some bacteria are naturally resistant to certain types of antibiotics. Resistance can also occur due to genetic mutations or acquisition of exogenous genetic material (e.g., plasmids). Mechanisms responsible for resistance to different antibiotics commonly travel together on mobile elements like plasmids which can transfer and spread between different bacteria, leading to multi-drug resistance. New Antibiotics Are Needed for Resistant Gram-negative Infections According to the CDC, at least two million people each year in the United States acquire serious infections with bacteria that are resistant to one or more of the antibiotics designed to treat those infections, and each year, over 23,000 patients in the United States die from these infections. In the EU, the annual burden posed by resistant healthcare associated bacterial infections is approximately 2.5 million hospital days and 25,000 deaths. Similar problems exist throughout the world, and the WHO has declared antibiotic resistance a threat to global health security. The development and spread of resistance is driven by the use of antibiotics. Once they arise, resistant bacteria can be transferred between patients and antibiotic resistance mechanisms can be transferred between bacterial species, thus increasing the problem. Antibiotic-resistant infections not only cause significant morbidity and mortality, but also place a substantial cost burden on the healthcare system. In most cases, antibiotic-resistant infections require prolonged and/or costlier treatments, extend hospital stays, and necessitate additional doctor visits and healthcare expenditures compared with infections that are easily treatable with antibiotics. The CDC estimates that the excess annual cost resulting from these infections in the United States is as high as $20 billion. According to an estimate from a 2012 study of over