P245 ME1100: In Vivo Efficacy of a New Inhaled Formulation of Arbekacin, semi-synthetic aminoglycoside antibiotic Nobuyoshi Baba, Masashi Tanaka, Yoshihiro Takayama, Masahiro Nomoto, Shohei Ouchi, Takashi Ida, Kenichiro Kondo Meiji Seika Pharma Co., Ltd., Tokyo, Japan

Introduction Methods cont. Results Conclusions The treatment of nosocomial pneumonia caused by Viable cell counts in lungs at 18 hours after • The murine lung infection model for inhaled methicillin-resistant Staphylococcus aureus (MRSA) administration were measured by the agar plate ABK evaluation was shown to produce a high a) MRSA MSC03154 and /or Gram-negative bacteria is becoming method. ELF ABK exposure (Cmax and AUC) which is increasingly difficult, due to reduced susceptibility approximately 100 fold greater than that in to available antibacterial agents and their limited  Murine pneumonia model plasma. bioavailability in the lung via IV administration. • Inhaled ABK was the most efficacious therapy Arbekacin (ABK) is a unique aminoglycoside in reducing bacterial loads in the murine lung antibiotic with a useful anti-staphylococcus activity infections due to MRSA, P. aeruginosa or A. coupled with a potent bactericidal activity against baumannii, and showed a dose-dependent Gram-negative pathogens. An ABK formulation MRSA infection model efficacy, reflecting better antibacterial activities optimized for oral inhalation (ME1100) is currently Mice: CBA/JN, ♂, 7 - 8 weeks CY (cyclophosphamide): 200 mg/kg (-4 d), over comparator aminoglycosides. under clinical development for mechanically intraperitoneal injection ventilated patients with bacterial pneumonia, aiming • Inhaled ABK therapy could be an important for a rapid delivery into the lung of the broad PA or AB infection model b) P. aeruginosa MSC17707 addition to the already limited armamentarium spectrum bactericidal agent into the lung in very Mice: ICR, ♂, 3.5 - 4 weeks of the antibacterial agents for pneumonia in high concentrations. CY: 150 (-4 d) and 100 (-1 d) mg/kg, hospital settings, with very high intra-pulmonary We evaluated inhaled arbekacin in experimental intraperitoneal injection ABK exposure levels expected (ELF Cmax: 3272 murine lung infections caused by MRSA, amikacin (SD, 1544) µg/ml at an inhaled 450mg ABK (AMK) and tobramycin (TOB)-resistant dose in healthy human subjectsRef1 ) and better Pseudomonas aeruginosa or Acinetobacter antibacterial activity shown over existing baumannii. aminoglycosides Ref 2&3.

References Ref 1: ICAAC2014 Poster F-1614 S.Ouchi, et al. c) A. baumannii MSC19410 Safety, Tolerability, Systemic and Pulmonary Pharmacokinetics of Arbekacin following ME1100 Nebulizer Arbekacin (INN) Inhalation in Healthy Volunteers (eFlow; PARI Pharma GmbH) Ref 2: ICAAC2014 Poster F-1611, HS. Sader, et al. Figure 1 Murine PK Profiles of ABK with Contemporary Arbekacin Activity When Tested Methods Nebulization of ABK 30 mg/mL for 5 min against Clinical Bacteria Isolated from Patients Pulmonary infections were induced in immuno- Hospitalized with Pneumonia in United States suppressed mice by intranasal inoculation of MRSA, Table 1 MICs of Test Aminoglycosides (AGs) (USA) Hospitals P. aeruginosa or A. baumannii at a final inoculum of Ref 3: ICAAC2014 Poster F-1615, HS Sader, et al.

6.06, 5.09 or 6.32 Log10 CFU/lung, respectively. Organism/ MIC (μg/mL) Arbekacin Tested against Well Characterized The individual animal was confined in a plastic Strain No. ABK AMK TOB Multidrug Resistant (MDR) Gram-negative Bacilli chamber and exposed to aerosolized drug (ABK, and Methicillin-Resistant Staphylococcus aureus MRSA MSC03154 AMK or TOB in saline), once for 5 minutes 1 16 64 (MRSA) after 2 hours following the inoculation. P. aeruginosa 8 64 64 The test drug solutions were aerosolized and MSC17707 Figure 2 Efficacy of Inhaled AGs in Murine Acknowledgement nebulized into the chamber at a rate of A. baumannii Lung Infections We appreciate the support from PARI Pharma approximately 0.5 mL/min. using a PARI Pharma 32 128 128 MSC19410 GmbH for supplying the eFlow nebulizer. eFlow nebulizer. NB, MT, YT, MN, SO, TI and KK are all full-time employees of Meiji Seika Pharma Co., Ltd. Presented at the 25th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID); Apr 25-28, 2015; Copenhagen, Denmark Copyright © 2015 Meiji Seika Pharma Co., Ltd. All Rights Reserved.