AUTHOR=Zhang Huilin , Mao Chunxiao , Li Jinju , Huang Zilong , Gu Xiaoyan , Shen Xiangguang , Ding Huanzhong 

TITLE=Pharmacokinetic/Pharmacodynamic Integration of Doxycycline Against Mycoplasma hyopneumoniae in an In Vitro Model

JOURNAL=Frontiers in Pharmacology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.01088

DOI=10.3389/fphar.2019.01088

ISSN=1663-9812

ABSTRACT=<p>Doxycycline is a broad-spectrum antibacterial drug. It is used widely to treat diseases caused by <italic>Mycoplasma</italic> species. We investigated the antibacterial activity of doxycycline against the <italic>Mycoplasma hyopneumoniae</italic> strain ATCC25934. The minimum inhibitory concentration (MIC) of doxycycline against <italic>M. hyopneumoniae</italic> determined by a microdilution method was 0.125 μg/ml. Static time–kill curves with constant drug concentrations (0–64 MIC) showed that a bacteriostatic effect occurred if the doxycycline concentration reached 4 MIC. Doxycycline produced a maximum antimycoplasmal effect (reduction of 2.76 log<sub>10</sub>CFU/ml) at 64 MIC within 48 h. The effect of doxycycline against <italic>M. hyopneumoniae</italic> was analyzed by a sigmoid <italic>E</italic><sub>max</sub> model, and there was high correlation between the kill rate and doxycycline concentration (<italic>R</italic><sup>2</sup> = 0.986). A one-compartment open model with first-order absorption was adopted and was used to simulate doxycycline pharmacokinetics in porcine plasma. The dynamic time–concentration curve showed that the area under the curve at 24 h (AUC<sub>24 h</sub>) and <italic>C</italic><sub>max</sub> (peak concentration) after each drug administration was 1.78–48.4 μg h/ml and 0.16–3.41 μg/ml, respectively. The reduction of <italic>M. hyopneumoniae</italic> (log<sub>10</sub>CFU/ml) for 1, 2.5, 5, 7.5, 10, 15, 20, and 30 mg/kg body weight was 0.16, 1.29, 1.75, 2.94, 3.35, 3.91, 4.35, and 5.77, respectively, during the entire experiment, respectively. When the dose was &gt;10 mg/kg body weight, continuous administration for 3 days could achieve a bactericidal effect. The correlation coefficient of AUC<sub>24 h</sub>/MIC, <italic>C</italic><sub>max</sub>/MIC, and %T &gt; MIC (the cumulative percentage of time over a 24-h period that the drug concentration exceeds the MIC) with antibacterial effect was 0.917, 0.923, and 0.823, respectively. Doxycycline showed concentration-dependent activity, and the value of AUC<sub>24 h</sub>/MIC and <italic>C</italic><sub>max</sub>/MIC required to produce a drop of 1 log<sub>10</sub>CFU/ml was 164 h and 9.89, respectively.</p>