The 53rd ICAAC Sep.10-13, 2013 - Denver
 
Thursday, Sep 12, 2013, 11:00 AM - 1:00 PM  

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F1-1201_FSI-1671, a Novel Anti-Acinetobacter Carbapenem; In Vivo Efficacy against Carbapenem-Resistance Gram-Negative Bacterial Infection    
H.Y. Joo, D.I. Kim, E. Kowalik, Y. Li, S. Mao, S. Liu, M. W. Hager, W.B. Choi
 
Abstract: Background: FSI-1671 is a novel anti-Acinetobacter carbapenem with excellent in vitro activity against A.baumannii. This study was to determine the pharmacokinetic parameters in rat model and the ED50 in mouse septicemia model caused by Carbapenem-Resistance (CR) Gram-negative bacteria. Methods: The Stability of FSI-1671 against renal Dehydropeptidase-I (DHP-I) was determined with purified hog renal DHP-I. The stability to DHP-I was measured spectrophotometrically. The relative rate of hydrolysis was expressed as a ratio against the rate for Meropenem, which was assigned a value of 1.0. The Sprague-Dawley(SD) rats(200-220g) were used for pharmacokinetic study. Four rats per group were dosed by a single IV bolus at 20 mg/kg. Septicemia induced intraperitonially in mice (4-5 weeks old, male, 18-21g) by a single inoculation of bacteria (prepared in 5% mucin). FSI-1671, Meropenem, Doripenem, Colistin and Tigecycline were administered subcutaneously 5minute & 2 hour after bacterial challenge. Control and treatment groups at each dose were composed of 5 mice. The 50% protective dose (ED50, mg/kg) was calculated by Probit analysis method from the survival rates on the 5th day after the infection. Results: The FSI-1671 has low protein binding rates in animal serums and the rates are compatible to those of other carbapenems. FSI-1671 has excellent pharmacokinetics profiles in rat model. The half life of FSI-1671 was 3 times longer than Meropenem and comparable to Doripenem. FSI-1671 has excellent potency against CR-A.baumannii, K.pneumoniae and P.aeruginosa in mouse septicemia model. FSI-1671(ED50=0.71mg/kg) has 8 times better efficiency than Meropenem (ED50=5.87mg/kg) against CR-A.baumannii. FSI-1671 (6.1 mg/kg) has 7.4 times better potency than Meropenem (45.1mg/kg) in CR-P.aeruginosa septicemia model. Efficacy of FSI-1671(ED50=15.7mg/kg) has 2 times better potency than Meropenem (ED50=31.5mg/kg) in CR-Klebsiella pneumoniae septicemia model. Conclusion: FIS-1671 showed highly effective efficacies in mouse septicemia model against CR gram-negative bacterial infections. The FSI-1671 is a potent carbapenem which is used for treatment of bacterial infections with multi-drug resistant gramnegative pathogens.


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F1-1202_FSI-1671, a Novel Anti-Acinetobacter Carbapenem; In Vitro Activity of FSI-1671 and FSI-1671_Sulbactam against MDR-A.baumannii
 
H.Y. Joo, D.I. Kim, E. Kowalik, Y. Li, S. Mao, S. Liu, M. W. Hager, W.B. Choi

Abstract: Background: FSI-1671 is a new class of Carbapenem antibiotic which possesses excellent antibacterial activity against A.baumannii. The FSI-1671/Sulbactam combination showed excellent synergy against Multi-Drug Resistance-A.baumannii. In this study we compared the activity of FSI-1671 and FSI-1671/Sulbactam with Meropenem, Imipenem, Doripenem, Colistin and Tigecycline. Methods: MICs (Minimum Inhibitory Concentration) were determined by the agar dilution method which is recommended by CLSI (M7-A8) against A.baumannii(85), K.pneumoniae(80), E.coli(54), P.aeruginosa(125), Respiratory tract infection species(37) and other Enterobacteriaceae(175). Results: FSI-1671/Sulbactam, a fixed concentration of Sulbactam at 6ug/ml has excellent potency (MIC90=1ug/ml) against MDR-Acinetobacter baumannii. It has 32 times more active than Imipenem (MIC90=32ug/ml) and Doripenem (MIC90=32ug/ml). It has 4 times better activity than Colistin and Tigecycline. Conclusion: The FSI-1671 is a new class of Carbapenem with potent activity against MDR-A.baumannii. The FSI-1671/Sulbactam combination has excellent synergy against MDR-A.baumannii. The FSI-1671/Sulbactam is a potential Carbapenem which is used for treatment of bacterial infections with multi-drug resistant A.baumannii.