Pharmacokinetic and pharmacodynamic testing of marbofloxacin administered as a single injection for the treatment of bovine respiratory disease

Abstract

New approaches in Pharmacokinetic/Pharmacodynamic (PK/PD) integration suggested that marbofloxacin, a fluoroquinolone already licensed for the treatment of bovine respiratory disease at a daily dosage of 2 mg/kg for 3-5 days, would be equally clinically effective at 10 mg/kg once (Forcyl(®)), whilst also reducing the risk of resistance. This marbofloxacin dosage regimen was studied using mutant prevention concentration (MPC), PK simulation, PK/PD integration and an in vitro dynamic system. This system simulated the concentration-time profile of marbofloxacin in bovine plasma established in vivo after a single 10 mg/kg intramuscular dose and killing curves of field isolated Pasteurellaceae strains of high (minimum inhibitory concentration (MIC) MIC ≤ 0.03 μg/mL), average (MIC of 0.12-0.25 μg/mL) and low (MIC of 1 μg/mL) susceptibility to marbofloxacin. The marbofloxacin MPC values were 2- to 4-fold the MIC values for all Mannheimia haemolytica, Pasteurella multocida tested. Marbofloxacin demonstrated a concentration-dependent killing profile with bactericidal activity observed within 1 h for most strains. No resistance development (MIC ≥ 4 μg/mL) was detected in the dynamic tests. Target values for risk of resistance PK/PD surrogates (area under the curve (AUC) AUC(24 h) /MPC and T(>MPC) /T(MSW) ratio) were achieved for all clinically susceptible pathogens. The new proposed dosing regimen was validated in vitro and by PK/PD integration confirming the single-injection short-acting antibiotic concept.

Tissue distribution of marbofloxacin in pigs after a single intramuscular injection

“…In addition to that in pigs, marbofloxacin pharmacokinetics have been investigated in other species. After intramuscular injection, the t 1/2λz was 1.96, 3.15, 3.65, 7.16, 7.72, and 17.50 h in ostriches [4], ducks [8], sheep [15], camels [11], rabbits [13], and calves [17], respectively. These results indicate that the elimination of marbofloxacin from pigs is slower than that in other species.…”

Prediction of marbofloxacin dosage for the pig pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida by pharmacokinetic/pharmacodynamic modelling

“…Ferren et al [34] suggested that even lower doses of marbofloxacin could potentially eradicate low counts (10 5  CFU/mL) in the lung, while having a minimal impact on the microbiota of the large intestine. On the other hand, Vallé et al [35] validated for the bovine pneumonia pathogens, P. multocida and Mannheimia haemolytica , the concept of a single high dose of marbofloxacin compared to a daily dose of 2 mg/kg for 3–5 days. A bactericidal effect against bovine P. multocida was achieved within one hour, when marbofloxacin was administered at five times the recommended daily dose (10 mg/kg).…”

Addressing Antimicrobial Resistance: An Overview of Priority Actions to Prevent Suboptimal Antimicrobial Use in Food-Animal Production

“…Re-evaluation of antimicrobial dosage regimens, considering updated PK/PD requirements, constitutes a first step to limit the impact of antimicrobials on commensal floras. For example, recently in veterinary medicine, the marbofloxacin dosage regimen was re-evaluated for treatment of Gram negative infections and the current labeled dose of 10 mg/kg given in a single injection was added to the first label approved dosage of 2 mg/kg over 3–5 days, leading to a decrease in the time of residence of the drug in the body while maintaining clinical efficacy (Valle et al, 2012). Dosage regimens of existing drugs previously determined according to results of clinical trials can also be evaluated based on standard PK/PD concepts, as performed with tulathromycin in calves (Toutain et al, 2016b).…”