Integrated pharmacokinetic-Pharmacodynamic (PK/PD) model to evaluate the in vivo antimicrobial activity of Marbofloxacin against Pasteurella multocida in piglets

Abstract

Background: Marbofloxacin is a veterinary fluoroquinolone with high activity against Pasteurella multocida. We evaluated it's in vivo activity against P. multocida based on in vivo time-kill data in swine using a tissue-cage model. A series of dosages ranging from 0.15 to 2.5 mg/kg were administered intramuscularly after challenge with P. multocida type B, serotype 2.

Results: The ratio of the 24 h area under the concentration-time curve divided by the minimum inhibitory concentration (AUC₂₄TCF/MIC) was the best PK/PD index correlated with the in vivo antibacterial effectiveness of marbofloxacin (R2 = 0.9279). The AUC₂₄TCF/MIC necessary to achieve a 1-log₁₀ CFU/ml reduction and a 3-log₁₀ CFU/ml (90% of the maximum response) reduction as calculated by an inhibitory sigmoid E_max model were 13.48 h and 57.70 h, respectively.

Conclusions: Marbofloxacin is adequate for the treatment of swine infected with P. multocida. The tissue-cage model played a significant role in achieving these PK/PD results.

Keywords: Marbofloxacin; P. Multocida; PK/PD; Piglets; Tissue-cage model.

Fig. 1

In vivo time killing curve of marbofloxacin against P. multocida in TCF. Kb-1 means the group treated by saline. Mean log₁₀CFU/mL values only (n = 4 experimentations). (Excel, Microsoft Office)

Fig. 2

Pharmacokinetic profiles of marbofloxacin in TCF. The tissue-cages were infected with P. multocida as described above, 24 h later administered with single intramuscularly doses of 0.15, 0.3,0.5,0.8,1.0,1.3,1.6,2.0 and 2.5 mg/kg marbofloxacin as BW. All TCF were sampled by puncture at 1, 3, 6, 9, 12, 24, 30, 36, 48, 72and 96 h after dosing. Marbofloxacin concentrations were determined using a HPLC method with fluorescence detection. But a small number of samples sampled on 96 h were undetected. Each symbol represents the mean ± standard deviation of the levels in the four tissue-cages. (Excel, Microsoft Office)

Fig. 3

Linear regression plots between administered doses and AUC₂₄ values. (Excel, Microsoft Office)

Fig. 4

Relationships between PK/PD parameters (AUC/MIC, Cmax/MIC, T > MIC %) and antibacterial effect (E) after 24 h of therapy. R2 is the correlation coefficient. (Winnonlin software)