Abstract
The aim of this study was to establish antimicrobial susceptibility breakpoints for tilmicosin against Haemophilus parasuis, which is an important pathogen of respiratory tract infections. The minimum inhibitory concentrations (MICs) of 103 H. parasuis isolates were determined by the agar dilution method. The wild type (WT) distribution and epidemiologic cutoff value (ECV) were evaluated by statistical analysis. The new bronchoaveolar lavage was used to establish intrapulmonary pharmacokinetic (PK) model in swine. The pharmacokinetic (PK) parameters of tilmicosin, both in pulmonary epithelial lining fluid (PELF) and in plasma, were determined using high performance liquid chromatography method and WinNonlin software. The pharmacodynamic cutoff (COPD) was calculated using Monte Carlo simulation. Our results showed that 100% of WT isolates were covered when the ECV was set at 16 μg/mL. The tilmicosin had concentration-dependent activity against H. parasuis. The PK data indicated that tilmicosin concentrations in PELF was rapidly increased to high levels at 4 h and kept stable until 48 h after drug administration, while the tilmicosin concentration in plasma reached maximum levels at 4 h and continued to decrease during 4–72 h. Using Monte Carlo simulation, COPD was defined as 1 μg/mL. Conclusively, the ECV and COPD of tilmicosin against H. parasuis were established for the first time based on the MIC distribution and PK-PD analysis in the target tissue, respectively. These values are of great importance for detection of tilmicosin-resistant H. parasuis and for effective treatment of clinical intrapulmonary infection caused by H. parasuis.
Highlights
Haemophilus parasuis, a Gram-negative bacterium of the Pasteurella group of organisms, is a respiratory pathogens of pigs (Fu et al, 2013; Luan et al, 2013)
The minimum inhibitory concentrations (MICs) for Enterococcus faecalis (ATCC 29212) was 8 μg/mL, which was within the acceptable quality control (QC) range according to Clinical and Laboratory Standards Institute (CLSI) document M31-A3
H. parasuis isolates from Denmark exhibited higher MIC90 to tilmicosin than those isolated from Czech Republic (8 μg/mL vs. 2 μg/mL; Aarestrup et al, 2004; Nedbalcová and Kucerová, 2013)
Summary
Haemophilus parasuis, a Gram-negative bacterium of the Pasteurella group of organisms, is a respiratory pathogens of pigs (Fu et al, 2013; Luan et al, 2013). It is mainly responsible for Glässer’s disease, which is characterized by polyserositis, arthritis, and meningitis (Guo et al, 2011; Mullins et al, 2013; Moleres et al, 2015) and has caused large economic losses in the worldwide pig industry in recent years (Vilalta et al, 2012; Zehr et al, 2012). Tilmicosin has broad clinical application for treatment of respiratory diseases in animals (Frank et al, 2000; Naccari et al, 2001; Fittipaldi et al, 2005)
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