title: Trospectomycin, a novel spectinomycin analogue: antibacterial activity and preliminary human pharmacokinetics.
abstract: Trospectomycin (TSP; U-63366F) is a novel spectinomycin (SP) analogue with broad-spectrum antibacterial activity. The in vitro activity of the analogue was compared to that of SP against approximately 400 bacterial isolates. The in vivo activity of the compound was assessed using experimental infection models for both Gram-positive and Gram-negative facultative bacteria. The preliminary human pharmacokinetics of TSP were evaluated following single-dose i.v. or i.m. administration. TSP was more active in vitro than SP (2 to 32-fold) against strains of numerous bacterial species, including staphylococci, streptococci, Haemophilus influenzae, Branhamella catarrhalis, Neisseria gonorrhoeae, Proteus spp., Bacteroides spp., Gardnerella vaginalis and Chlamydia trachomatis. The activity of TSP for most species of the family Enterobacteriaceae was comparable to that of SP. TSP was more active than SP (2 to 32-fold) in curing experimental infections due to streptococci, Salmonella typhi, Serratia marcescens, Klebsiella pneumoniae and Haemophilus influenzae. TSP was well-absorbed following both i.v. and i.m. administration. Pharmacokinetic analysis of microbiological assay data for the 1000 mg dose yielded the following mean values for the i.v. and i.m. routes, respectively: Cmax = 81.2, 28.7 micrograms/ml; serum half-life = 2.2, 2.2 h; Tmax = 25, 75 min; and AUC = 156.6, 116.2 h micrograms/ml. Pharmacokinetic analysis of assay data derived using the more sensitive HPLC assay revealed the biphasic nature of trospectomycin elimination, highlighted by a short apparent serum half-life (2.2 h) and a prolonged tissue half-life (approximately 36 h). TSP inhibits a variety of clinically important organisms, including agents of sexually transmitted diseases and pelvic inflammatory disease, and demonstrates favourable pharmacokinetic properties.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Infectious Diseases Research, Upjohn Company, Kalamazoo, MI 49001.
authors.forename: G E
authors.initials: GE
authors.lastname: Zurenko
authors.forename: C W
authors.initials: CW
authors.lastname: Ford
authors.forename: E
authors.initials: E
authors.lastname: Novak
mesh_terms: D002851:Chromatography, High Pressure Liquid; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D000198:Spectinomycin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: C043267:trospectomycin; D000198:Spectinomycin