AUTHOR=Lee Eon-Bee , Abbas Muhammad Aleem , Park Jonghyun , Tassew Dereje D. , Park Seung-Chun 

TITLE=Optimizing tylosin dosage for co-infection of Actinobacillus pleuropneumoniae and Pasteurella multocida in pigs using pharmacokinetic/pharmacodynamic modeling

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1258403

DOI=10.3389/fphar.2023.1258403

ISSN=1663-9812

ABSTRACT=<p>Formulating a therapeutic strategy that can effectively combat concurrent infections of <italic>Actinobacillus pleuropneumoniae</italic> (<italic>A. pleuropneumoniae</italic>) and <italic>Pasteurella multocida</italic> (<italic>P. multocida</italic>) can be challenging. This study aimed to 1) establish minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), time kill curve, and post-antibiotic effect (PAE) of tylosin against <italic>A. pleuropneumoniae</italic> and <italic>P. multocida</italic> pig isolates and employ the MIC data for the development of epidemiological cutoff (ECOFF) values; 2) estimate the pharmacokinetics (PKs) of tylosin following its intramuscular (IM) administration (20 mg/kg) in healthy and infected pigs; and 3) establish a PK–pharmacodynamic (PD) integrated model and predict optimal dosing regimens and PK/PD cutoff values for tylosin in healthy and infected pigs. The MIC of tylosin against both 89 and 363 isolates of <italic>A. pleuropneumoniae</italic> and <italic>P. multocida</italic> strains spread widely, ranging from 1 to 256 μg/mL and from 0.5 to 128 μg/mL, respectively. According to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) ECOFFinder analysis ECOFF value (≤64 µg/mL), 97.75% (87 strains) of the <italic>A. pleuropnumoniae</italic> isolates were wild-type, whereas with the same ECOFF value (≤64 µg/mL), 99.72% (363 strains) of the <italic>P. multicoda</italic> isolates were considered wild-type to tylosin. Area under the concentration time curve (AUC), T<sub>1/2</sub>, and C<sub>max</sub> values were significantly greater in healthy pigs than those in infected pigs (13.33 h × μg/mL, 1.99 h, and 5.79 μg/mL vs. 10.46 h × μg/mL, 1.83 h, and 3.59 μg/mL, respectively) (<italic>p</italic> &lt; 0.05). In healthy pigs, AUC<sub>24 h</sub>/MIC values for the bacteriostatic activity were 0.98 and 1.10 h; for the bactericidal activity, AUC<sub>24 h</sub>/MIC values were 1.97 and 1.99 h for <italic>A. pleuropneumoniae</italic> and <italic>P. multocida</italic>, respectively. In infected pigs, AUC<sub>24 h</sub>/MIC values for the bacteriostatic activity were 1.03 and 1.12 h; for bactericidal activity, AUC<sub>24 h</sub>/MIC values were 2.54 and 2.36 h for <italic>A. pleuropneumoniae</italic> and <italic>P. multocida</italic>, respectively. Monte Carlo simulation lead to a 2 μg/mL calculated PK/PD cutoff. Managing co-infections can present challenges, as it often demands the administration of multiple antibiotics to address diverse pathogens. However, using tylosin, which effectively targets both <italic>A. pleuropneumoniae</italic> and <italic>P. multocida</italic> in pigs, may enhance the control of bacterial burden. By employing an optimized dosage of 11.94–15.37 mg/kg and 25.17–27.79 mg/kg of tylosin can result in achieving bacteriostatic and bactericidal effects in 90% of co-infected pigs.</p>