Pharmacokinetics and antibacterial efficacy of cefpirome (HR 810) in experimental Escherichia coli and Haemophilus influenzae type b meningitis

Abstract

Cefpirome (HR 810) is a new cephalosporin related to cefotaxime that has potent bactericidal activity against a broad spectrum of gram-negative and gram-positive organisms. The pharmacokinetics and bacteriological efficacy of cefpirome administered as a single intravenous dose were assessed in rabbits with experimental Haemophilus influenzae type b and Escherichia coli Kl meningitis. The mean penetrations into the cerebrospinal fluid (CSF) in relation to the amount of drug in serum of animals infected with H. influenzae and E. coli were 25 and 54%, respectively. The median CSF bactericidal titers were 1:128 against both organisms at 1 h after the dose and 1:32 and 1:16 against H. influenzae and E. coli, respectively, at 8 h after the dose. In CSF of uninfected animals, the mean penetration was 4.5%. There was a significant reduction in the concentrations of bacteria in CSFs of both groups of animals treated with cefpirome compared with that in untreated groups. Mortality was also significantly lower in treated animals than it was in untreated animals. Intravenous administration of dexamethasone before the cefpirome dose did not compromise penetration, bactericidal titers, or antibacterial activity of cefpirome in CSF.Cefpirome (HR 810) is a new cephalosporin related to cefotaxime that has potent bactericidal activity against a broad range of gram-negative and gram-positive organisms including Pseudomonas aeruginosa and methicillin-susceptible Staphylococcus spp. It is also highly active against Haemophilus influenzae type b and many members of the family Enterobacteriaceae (1, 2, 13). Escherichia coli Kl and H. influenzae type b are the two most important gramnegative pathogens involved in bacterial meningitis affecting infants and children.The objectives of the present study were (i) to determine the concentrations of cefpirome, after a single intravenous (i.v.) dose, in the sera and cerebrospinal fluid (CSF) of rabbits with experimental E. coli Kl and H. influenzae type b meningitis; (ii) to evaluate the penetration and bacteriologic efficacy of this investigational cephalosporin in CSF of infected and uninfected animals; and (iii) to assess the effects of dexamethasone, administered i.v. before the antibiotic dose, on penetration, bacteriostatic and bactericidal titers, and antibacterial activity of cefpirome in CSF of infected animals. MATERIALS AND METHODSSix rabbits in each of the following groups of animals were used to study cefpirome pharmacokinetics: (i) E. coli meningitis, (ii) H. influenzae meningitis, (iii) uninfected controls, and (iv) H. influenzae meningitis with dexamethasone therapy. Because of the higher mortality in untreated animals, up to 18 animals had to be used in all groups in order to compare the antibacterial activities between the treated and untreated groups.Experimental meningitis model. New Zealand White male rabbits (weight, 2 to 3 kg) were prepared as described * Corresponding author. previously (3). Briefly, a dental acrylic helmet was attached to the skull of each rabbit, and ...

Evaluation of CP-99,219, a new fluoroquinolone, for treatment of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis

“…Experimental meningitis model. We used our well-characterized meningitis model (9,10,12,18), modified from the original description of Dacey and Sande (2). CSF samples (100 to 200 l) were withdrawn before and at 5, 10, and 24 h after the antibiotic was given.…”

Effect of dexamethasone on therapy of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis

“…The well-characterized rabbit meningitis model (17,21,24,32), modified from the original description of Dacey and Sande (9), was used. Briefly, New Zealand White male rabbits weighing 2 to 2.5 kg were intramuscularly anesthetized with ketamine (40 mg/kg of body weight) and acepromazine (3 mg/kg) before each procedure.…”

Cefpirome (HR 810), a New Cephalosporin

“…Cefpirome is a semisynthetic cephalosporin; its in vitro and in vivo activities in animal models, and pharmacokinetic properties, have been evaluated (Ansorg et al 1990;Arai & Hayashi 1990;Bakhtiar & Selwyn 1989;Bertram et al 1984;Clarke et al 1985;Eng et al 1989;Jafari et al 1991;Jones et al 1991;Kavi et al 1989;King et al 1990;KIesel et al 1990;Pucci et al 1991;Sapico et al 1991;Saxby et al 1990;Valdes et al 1 990a). These studies have shown that cefpirome is stable against the action of many fj-lactamases and that it has an improved pharmacokinetic profile compared with most of the existing cephalosporins, excellent in vitro activity against commonly isolated bacterial pathogens, and is effective in eradicating serious infections in experimental animals.…”