In vitro and in vivo pharmacodynamics of tulathromycin against Actinobacillus pleuropneumoniae

PhD student - Astrid Katarina Larberg

BACKGROUND for the project 

Actinobacillus pleuropneumoniae is an important lung pathogen in pig production which is commonly treated and prevented with antimicrobials.

Tulathromycin is a long-acting macrolide antimicrobial, frequently used in the treatment and prevention of A. pleuropneumoniae. One single injection of tulathromycin creates a sufficient antimicrobial exposure for effect, which is beneficial for the user.

In order to combat the emergence of antimicrobial resistance, strategies to preserve the efficacy of existing antimicrobials must be used. Important strategies are to reduce the overuse of antimicrobials and using them optimally when needed. The base of optimal use lays in the understanding of the pharmacokinetics and pharmacodynamics of an antimicrobial.

The pharmacodynamics of antimicrobials are roughly categorized as time-dependent or concentration-dependent depending on how optimal antimicrobial activity is gained. It is considered an advantage to have a long in vivo half-life if a drug is time-dependent, since less frequent dosing is needed to reach effect. For concentration-dependent drugs, an optimal effect is instead dependent on high maximum concentrations, and the persistent effects after exposure are often prolonged.

Macrolides constitute an antimicrobial class which historically has been considered to have a time-dependent antimicrobial activity. In the two last decades, several macrolides with extremely long plasma half-life (> 70 h) have been approved for use in food producing animals. These new compounds have shown different pharmacodynamic properties with tendencies of a concentration-dependent rather than time-dependent activity. A long half-life is not considered necessary for concentration-dependent antimicrobials and may have the unwanted side effect of selecting for antimicrobial resistance due to prolonged drug exposure.


The overall aim of this PhD project was to increase the pharmacodynamics knowledge of the long-acting macrolide tulathromycin against the important swine respiratory pathogen A. pleuropneumoniae, to contribute to more evidence-based use of this drug in pig production. The project was based on the hypothesis that the long in vivo half-life of tulathromycin might be unnecessary from a pharmacodynamics point of view.

Two main studies were performed:

Study 1: Evaluate if the antibacterial activity of tulathromycin against A. pleuropneumoniae is dependent on maximum concentration or half-life in an in vitro kinetic model.

Study 2: Compare the early pharmacodynamic effects of two different doses of tulathromycin in an experimentally induced acute A. pleuropneumoniae lung infection in pig.


The conclusions from the in vitro study (study 1) are that the antibacterial effect of tulathromycin against A. pleuropneumoniae appears to be mostly concentration–dependent, thus supporting the hypothesis. However, a time-dependent effect cannot be entirely excluded due to limitations of the in vitro model.

Because of the in vitro results, our hypothesis for the in vivo study (study 2) was that tulathromycin would have a fast and almost complete clinical effect, and that the bacterial load would be largely reduced 48 h after treatment. This would have indicated that the prolonged half-life was not necessary for effect.

This study, although small, instead indicated that the in vivo clinical and microbiological effect of tulathromycin at the recommended dose (2.5 mg/kg) is limited against acute to peracute A. pleuropneumoniae infection and that doubling the dose only increased the effect slightly.  Also, Our results did not indicate that the in vivo pharmacodynamics of tulathromycin was comparable to that of the concentration-dependent treatment control enrofloxacin.

Since our results was not in line with what we expected, the necessity of the long half-life of tulathromycin cannot be ruled out.


Since Macrolides are regarded critically important antimicrobials for human medicine by the WHO, it is recommended that use should be limited and responsible in animals.

Future studies should continue to evaluate the risk-benefit relationship of the long half-life of tulathromycin and similar long-acting macrolides.