title: Pharmacokinetics and Pharmacodynamics of Minocycline against Acinetobacter baumannii in a Neutropenic Murine Pneumonia Model.
abstract: Multidrug-resistant (MDR)Acinetobacter baumanniiis increasingly more prevalent in nosocomial infections. Althoughin vitrosusceptibility ofA. baumanniito minocycline is promising, thein vivoefficacy of minocycline has not been well established. In this study, thein vivoactivity of minocycline was evaluated in a neutropenic murine pneumonia model. Specifically, we investigated the relationship between minocycline exposure and bactericidal activity using fiveA. baumanniiisolates with a broad range of susceptibility (MIC ranged from 0.25 mg/liter to 16 mg/liter). The pharmacokinetics of minocycline (single dose of 25 mg/kg of body weight, 50 mg/kg, 100 mg/kg, and a humanized regimen, given intraperitoneally) in serum and epithelial lining fluid (ELF) were characterized. Dose linearity was observed for doses up to 50 mg/kg and pulmonary penetration ratios (area under the concentration-time curve in ELF from 0 to 24 h [AUCELF,0-24]/area under the concentration time curve in serum from 0 to 24 h [AUCserum,0-24]) ranged from 2.5 to 2.8. Pharmacokinetic-pharmacodynamics (PK-PD) index values in ELF for various dose regimens against differentA. baumanniiisolates were calculated. The maximum efficacy at 24 h was approximately 1.5-log-unit reduction of pulmonary bacterial burdens from baseline. The AUC/MIC ratio was the PK-PD index most closely correlating to the bacterial burden (r2= 0.81). The required AUCELF,0-24/MIC for maintaining stasis and achieving 1-log-unit reduction were 140 and 410, respectively. These findings could guide the treatment of infections caused byA. baumanniiusing minocycline in the future. Additional studies to examine resistance development during therapy are warranted.
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, Texas, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas, USA.
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Ledesma
authors.affiliation: Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas, USA.
authors.forename: Kai-Tai
authors.initials: KT
authors.lastname: Chang
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, Texas, USA.
authors.forename: Henrietta
authors.initials: H
authors.lastname: Abodakpi
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, Texas, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, Texas, USA vtam@uh.edu.|Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas, USA.
authors.forename: Vincent H
authors.initials: VH
authors.lastname: Tam
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy* / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000302:isolation & purification; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D003428:Cross Infection / Q000188:drug therapy / Q000382:microbiology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008168:Lung / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D009503:Neutropenia / Q000139:chemically induced / Q000276:immunology*; D011014:Pneumonia / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D008911:Minocycline
keywords: Gram-negative bacteria; tetracyclines