title: Adaptive resistance of Pseudomonas aeruginosa induced by aminoglycosides and killing kinetics in a rabbit endocarditis model.
abstract: Adaptive resistance following the first exposure to aminoglycosides is a recently described in vitro phenomenon in Pseudomonas aeruginosa and other aerobic gram-negative bacilli. We investigated the in vivo relevance of adaptive resistance in P. aeruginosa following a single dose of amikacin in the experimental rabbit endocarditis model. Rabbits with P. aeruginosa endocarditis received either no therapy (control) or a single intravenous (i.v.) dose of amikacin (80 mg/kg of body weight) at 24 h postinfection, after which they were sacrificed at 5, 8, 12, 16, or 24 h postdose. Excised aortic vegetations were subsequently exposed ex vivo to amikacin at 2.5, 5, 10 or 20 times the MIC for 90 min. In vivo adaptive resistance was identified when amikacin-induced pseudomonal killing within excised aortic vegetations was less in animals receiving single-dose amikacin in vivo than in vegetations from control animals not receiving amikacin in vivo. Maximal adaptive resistance occurred between 8 and 16 h after the in vivo amikacin dose, with complete refractoriness to ex vivo killing by amikacin seen at 12 h postdose. By 24 h postdose, bacteria within excised vegetations had partially recovered their initial amikacin susceptibility. In a parallel treatment study, we demonstrated that amikacin given once daily (but not twice daily) at a total dose of 80 mg/kg i.v. for 1-day treatment significantly reduced pseudomonal densities within aortic vegetations versus those in untreated controls. When therapy was continued for 3 days with the same total daily dose (80 mg/kg/day), amikacin given once or twice daily significantly reduced intravegetation pseudomonal densities versus those in controls. However, amikacin given once daily was still more effective than the twice-daily regimen. These data confirm the induction of aminoglycoside adaptive resistance in vivo and further support the advantages of once-daily aminoglycoside dosing regimens in the treatment of serious pseudomonal infections.
authors.affiliation: Laboratoire d'Antibiologie Clinique et Experimentale, Faculte de Medecine, Centre Hospitalier Universitaire, Nantes, France. XIONG@AFP76.HUMC.EDU
authors.forename: Y Q
authors.initials: YQ
authors.lastname: Xiong
authors.forename: J
authors.initials: J
authors.lastname: Caillon
authors.forename: M F
authors.initials: MF
authors.lastname: Kergueris
authors.forename: H
authors.initials: H
authors.lastname: Drugeon
authors.forename: D
authors.initials: D
authors.lastname: Baron
authors.forename: G
authors.initials: G
authors.lastname: Potel
authors.forename: A S
authors.initials: AS
authors.lastname: Bayer
mesh_terms: D000583:Amikacin / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D019540:Area Under Curve; D004352:Drug Resistance, Microbial; D004697:Endocarditis, Bacterial / Q000188:drug therapy* / Q000382:microbiology*; D005260:Female; D006207:Half-Life; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D011817:Rabbits
chemical_list: D000900:Anti-Bacterial Agents; D000583:Amikacin