Abstract
BackgroundBacterial pneumonia in pigs occurs widely and requires antimicrobial therapy. It is commonly caused by the pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida. Marbofloxacin is an antimicrobial drug of the fluoroquinolone class, licensed for use against these organisms in the pig. In recent years there have been major developments in dosage schedule design, based on integration and modelling of pharmacokinetic (PK) and pharmacodynamic (PD) data, with the objective of optimising efficacy and minimising the emergence of resistance. From in vitro time-kill curves in pig serum, PK/PD breakpoint Area under the curve (AUC) 24h /minimum inhibitory concentration (MIC) values were determined and used in conjunction with published PK, serum protein binding data and MIC distributions to predict dosages based on Monte Carlo simulation (MCS).ResultsFor three levels of inhibition of growth, bacteriostasis and 3 and 4log10 reductions in bacterial count, mean AUC24h/MIC values were 20.9, 45.2 and 71.7 h, respectively, for P. multocida and 32.4, 48.7 and 55.5 h for A. pleuropneumoniae. Based on these breakpoint values, doses for each pathogen were predicted for several clinical scenarios: (1) bacteriostatic and bactericidal levels of kill; (2) 50 and 90% target attainment rates (TAR); and (3) single dosing and daily dosing at steady state. MCS for 90% TAR predicted single doses to achieve bacteriostatic and bactericidal actions over 48 h of 0.44 and 0.95 mg/kg (P. multocida) and 0.28 and 0.66 mg/kg (A. pleuropneumoniae). For daily doses at steady state, and 90% TAR bacteriostatic and bactericidal actions, dosages of 0.28 and 0.59 mg/kg (P. multocida) and 0.22 and 0.39 mg/kg (A. pleuropneumoniae) were required for pigs aged 12 weeks. Doses were also predicted for pigs aged 16 and 27 weeks.ConclusionsPK/PD modelling with MCS approaches to dose determination demonstrates the possibility of tailoring clinical dose rates to a range of bacterial kill end-points.
Highlights
Bacterial pneumonia in pigs occurs widely and requires antimicrobial therapy
Minimum inhibitory concentration Twenty isolates each of A. pleuropneumoniae and P. multocida were obtained from EU cases of pig pneumonia
PK/PD breakpoint values For each isolate of each organism, growth inhibition curves were generated in the time-kill studies in broth and pig serum
Summary
Bacterial pneumonia in pigs occurs widely and requires antimicrobial therapy. Marbofloxacin is an antimicrobial drug of the fluoroquinolone class, licensed for use against these organisms in the pig. It has high bioavailability when administered to pigs by intramuscular injection [1] It accumulates in the cytosol of macrophages, leucocytes, neutrophils, epithelial lining fluid and plasma [2, 3]. Concentrations in the biophase, the pulmonary epithelial lining fluid in pigs with pneumonia, at steady state will be determined by free drug concentration in plasma. This has been shown to be 50.6% of total concentration in pigs [4]
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