Pharmacokinetics and Pharmacodynamics of Minocycline against Acinetobacter baumannii in a Neutropenic Murine Pneumonia Model

Abstract

Multidrug-resistant (MDR) Acinetobacter baumannii is increasingly more prevalent in nosocomial infections. Although in vitro susceptibility of A. baumannii to minocycline is promising, the in vivo efficacy of minocycline has not been well established. In this study, the in vivo activity of minocycline was evaluated in a neutropenic murine pneumonia model. Specifically, we investigated the relationship between minocycline exposure and bactericidal activity using five A. baumannii isolates 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 [AUC_ELF,0-24]/area under the concentration time curve in serum from 0 to 24 h [AUC_serum,0-24]) ranged from 2.5 to 2.8. Pharmacokinetic-pharmacodynamics (PK-PD) index values in ELF for various dose regimens against different A. baumannii isolates 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 AUC_ELF,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 by A. baumannii using minocycline in the future. Additional studies to examine resistance development during therapy are warranted.

Keywords: Gram-negative bacteria; tetracyclines.

FIG 1

Serum and ELF minocycline concentration-time profiles. The observed data are shown as means ± standard deviations (SDs) (error bars). Red closed circles are observed serum data; blue closed circles are observed ELF data; red solid lines depict best-fit serum profiles; blue solid lines depict best-fit ELF profiles; black dashed line represents the target serum profile in humans.

FIG 2

Correlation between observed and best-fit PK data. (A) 25 mg/kg, 50 mg/kg, and humanized regimen. (B) 100 mg/kg. The dashed line is the line of identity (i.e., y = x).

FIG 3

Correlation of PK-PD indices in ELF and tissue burden at 24 h. Each data point represents an observation from a single animal. In view of the logarithmic scale used, AUC/MIC values were input as 1 and C_max/MIC values were input as 0.1 for placebo controls. Black solid lines depict the best-fit profiles.