title: First-exposure adaptive resistance to aminoglycoside antibiotics in vivo with meaning for optimal clinical use.
abstract: The first exposure of gram-negative bacilli to an aminoglycoside antibiotic in vitro induces a biphasic bactericidal response and adaptive drug resistance (G. L. Daikos, G. G. Jackson, V. T. Lolans, and D. M. Livermore, J. Infect. Dis. 162:414-420, 1990; G. G. Jackson, G. L. Daikos, and V. T. Lolans, J. Infect. Dis. 162:408-413, 1990). The therapeutic implications were examined in netilmicin treatment of a Pseudomonas aeruginosa infection of normal and neutropenic mice. For 2 h after the first dose, the bactericidal rates were rapid, 0.75, 1.0, and 1.5 log10 CFU/h with doses of 10, 30, and 60 mg/kg, respectively. Each twofold increase in dosage reduced the number of surviving bacteria fivefold. Between 2 and 6 h, the second-phase bactericidal rate was slow, less than or equal to 0.3 log10 CFU/h, regardless of the dose. In a multiple-dose regimen, the same amount of netilmicin given in one dose was 70 and 90% more effective than two or three doses, respectively. Doses calculated to keep the drug level in plasma above the MIC were less effective than regimens giving first exposure to a high drug concentration. Adaptive resistance occurred when doses were given more than 2 h after the start of treatment. Temporary survival of bacteremic neutropenic mice was 60 to 70% greater with a second dose at 2 h than after a longer interval. In a thigh infection of neutropenic mice treated every 2 h, doses 4, 6, and 8 h after the first one showed no bactericidal effect. A drug-free interval of 8 h (20 times the drug half-life) renewed bacterial susceptibility to drug action. The results in vivo confirm the biphasic bactericidal action and induction of adaptive resistance that characterized first exposure of gram-negative bacilli to aminoglycoside antibiotics. The phenomena have meaning for the optimum clinical use of aminoglycosides.
authors.affiliation: Department of Medicine, University of Miami, Florida 33124.
authors.forename: G L
authors.initials: GL
authors.lastname: Daikos
authors.forename: V T
authors.initials: VT
authors.lastname: Lolans
authors.forename: G G
authors.initials: GG
authors.lastname: Jackson
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004352:Drug Resistance, Microbial / Q000502:physiology*; D005260:Female; D051379:Mice; D008813:Mice, Inbred ICR; D009428:Netilmicin / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D011552:Pseudomonas Infections / Q000188:drug therapy; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D009428:Netilmicin