GERBER J, SMIRNOV A, YAMINI P, RAGHEB J, WETTICH K, KALISCH S, NAU R; Interscience Conference on Antimicrobial Agents and Chemotherapy.

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 1999 Sep 26-29; 39: 44 (abstract no. 1775).

Dept. of Neurology, Univ. of Gottingen, Gottingen, GERMANY

OBJECTIVE: To study the activity of LY333328 against S. pneumoniae in an in vivo model of S. pneumoniae meningitis.METHODS: NZW Rabbits were infected intracisternally with 10[6] CFU of a penicillin-sensitive S. pneumoniae type 3 strain (MIC for LY333328 = 0.015 mg/l, MBC = 0.03 mg/l). At 12 h after infection, they were treated with a single dose of LY333328 [1mg/kg (n = 5), 2.5 mg/kg (n = 5), 10mg/kg (n = 10), 40mg/kg (n = 2)] infused over 30 min. Controls received a bolus of ceftriaxone (20mg/kg) followed by a continuous infusion of 10 mg/ kg/h (n = 12). CSF was drawn at 12, 14, 17, 20, and 24 h for the determination of bacterial titers, leukocyte densities, lipoteichoic/teichoic acid, lactate and protein concentrations. The concentration of the neuron-specific enolase in CSF was measured at 24 h. Bactericidal activity in CSF was estimated by log-linear regression of bacterial titers versus time. Additionally, in vitro time-kill curves were performed with 10mg/1 LY333328.RESULTS: In vitro, 10mg/1 of LY333328 killed S. pneumoniae within 1 h, whereas cultures treated with 10mg/1 ceftriaxone were sterile after 12 h. A single dose of 10mg/kg of LY333328 reduced the CSF bacterial titers as rapidly as ceftriaxone 10mg/kg/h (Delta log CFU/ml/h+/- SD: -0.29+/- 0.21 vs. -0.34+/- 0.15). Protein, lactate and lipoteichoic/teichoic acid concentrations in CSF showed no significant differences. The bactericidal activity of 2.5mg/kg LY333328 was slightly lower (Delta log CFU/ml/h +/- SD: -0.26 +/- 0.22). A dose of 40mg/ kg LY333328 reduced the bacterial titers by -0.52 +/- 0.02 Delta log CFU/ml/ h. A dose of 1mg/kg was bacteriostatic (Delta log CFU/ml/h +/- SD: 0.01 +/- 0.11). The half-maximal dose (K[D]) and the maximum bactericidal rate (E[max]) of LY333328 as estimated by Lineweaver-Burk plot were 5.3 mg/kg and -0.88 Delta log CFU/ml/h, respectively. The mean concentration of the neuron-specific enolase in CSF at 24 h as a parameter of neuronal damage was slightly lower in LY333328 treated animals (10mg/kg) than in rabbits receiving ceftriaxone (92.3 +/- 68.7 vs. 152.5 +/- 97; p = 0.14).CONCLUSION: The in vivo activity suggests that LY333328 may qualify for the treatment of S. pneumoniae meningitis. The inflammatory reaction during treatment with LY333328 was comparable to that during ceftriaxone therapy.

Publication Types:

• Meeting Abstracts

Keywords:

• Animals
• Anti-Bacterial Agents
• Ceftriaxone
• In Vitro
• Inflammation
• Meningitis, Pneumococcal
• Microbial Sensitivity Tests
• Penicillins
• Rabbits
• Teichoic Acids
• immunology

Other ID:

• GWAIDS0007106

UI: 102244602

From Meeting Abstracts