title: Therapeutic effect of meropenem on an experimental guinea pig model of meningitis with type b β-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae.
abstract: The purpose of this study was to investigate the relationship between efficacy and percentage of time above the MIC (%T>MIC) in the cerebrospinal fluid (CSF) for different dosing regimens of meropenem against an experimental lethal meningitis model in guinea pigs with type b β-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae (Hib BLNAR). Guinea pigs were intrathecally inoculated with 10(8) CFU/head of Hib BLNAR 8 h before the start of therapy. A single dose of 20, 40, or 80 mg/kg meropenem or multiple doses of 40 mg/kg meropenem were subcutaneously administered. Numbers of bacteria in CSF were counted 8 h after the start of therapy. Meropenem concentration in serum and CSF were determined in infected guinea pigs receiving a single dose of 40 mg/kg. In the single-dose regimen, 40 and 80 mg/kg meropenem significantly reduced the number of bacteria in CSF compared with the control, but 20 mg/kg meropenem did not. The %T>MIC for an 8-h period of 20, 40, and 80 mg/kg meropenem were 41, 52, and 62, respectively. Two and four doses of 40 mg/kg meropenem, for both of which %T>MIC was calculated as 100, had similar efficacy and were significantly superior to a single-dose of 40 mg/kg. In conclusion, meropenem had high efficacy when %T>MIC in the CSF was increased because of the high dose level and shortening of the dosing interval in a guinea pig meningitis model caused by Hib BLNAR, suggesting that high and frequent doses of meropenem are useful for treatment of meningitis with Hib BLNAR.
authors.affiliation: Oncology and Immunology Group I, Discovery Pharmacology II, Pharmacology Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 3-1-98, Kasugade-naka, Konohana-ku, Osaka, 554-0022, Japan. koichi-fujimoto@ds-pharma.co.jp
authors.forename: Koichi
authors.initials: K
authors.lastname: Fujimoto
authors.forename: Katsunori
authors.initials: K
authors.lastname: Kanazawa
authors.forename: Koji
authors.initials: K
authors.lastname: Takemoto
authors.forename: Kokichi
authors.initials: K
authors.lastname: Urasaki
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Ueda
authors.forename: Kimiko
authors.initials: K
authors.lastname: Ubukata
authors.forename: Keisuke
authors.initials: K
authors.lastname: Sunakawa
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002443:Ceftriaxone / Q000493:pharmacokinetics / Q000494:pharmacology; D004195:Disease Models, Animal; D006168:Guinea Pigs; D019741:Haemophilus influenzae type b / Q000187:drug effects*; D008297:Male; D008583:Meningitis, Haemophilus / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D013845:Thienamycins / Q000493:pharmacokinetics / Q000494:pharmacology*; D018440:beta-Lactam Resistance
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D002443:Ceftriaxone; D000077731:Meropenem