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One hundred <i>Actinobacillus pleuropneumoniae</i> (App) and sixty <i>Pasteurella multocida</i> subsp. <i>multocida</i> serogroup A (PmA) isolates were recovered from porcine pneumonic lungs collected from eight central or southern states of Brazil between 2014 and 2018 (App) or between 2017 and 2021 (PmA). <i>A. pleuropneumoniae</i> clinical isolates were typed by multiplex PCR and the most prevalent serovars were 8, 7 and 5 (43, 25% and 18%, respectively). In addition, three virulence genes were assessed in <i>P. multocida</i> isolates, all being positive to <i>capA</i> (PmA) and <i>kmt1</i> genes, all negative to <i>capD</i> and <i>toxA</i>, and most of them (85%) negative to <i>pfhA</i> gene. The susceptibility of both pathogens to tildipirosin was investigated using a broth microdilution assay. The percentage of isolates susceptible to tildipirosin was 95% for App and 73.3% for PmA. The MIC₅₀ values were 0.25 and 1 μg/mL and the MIC₉₀ values were 4 and >64 μg/mL for App and PmA, respectively. Finally, a multiple-dose protocol of tildipirosin was tested in suckling piglets on a farm endemic for both pathogens. Tildipirosin was able to prevent the natural colonization of the tonsils by App and PmA and significantly (<i>p</i> < 0.0001) reduced the burden of <i>Glaesserella parasuis</i> in this tissue. In summary, our results demonstrate that: (i) tildipirosin can be included in the list of antibiotics to control outbreaks of lung disease caused by App regardless of the capsular type, and (ii) in the case of clinical strains of App and PmA that are sensitive to tildipirosin based on susceptibility testing, the use of this antibiotic in eradication programs for <i>A. pleuropneumoniae</i> and <i>P. multocida</i> can be strongly recommended.