PK/PD Analysis by Nonlinear Mixed-Effects Modeling of a Marbofloxacin Dose Regimen for Treatment of Goat Mastitis Produced by Coagulase-Negative Staphylococci

SIMPLE SUMMARY: Coagulase-negative staphylococci are main pathogens that produce goat mastitis. Marbofloxacin is a third-generation fluoroquinolone approved to treat mastitis in animals. Since the efficacy of an antimicrobial is related with its concentration in the site of infection, and the latter depends of dose and biological processes that determine the distribution of the antimicrobial in different tissues and secretions, the objectives of this study were to evaluate the efficacy of a dose regimen of marbofloxacin (10 mg/kg/24 h) administered intramuscularly for five days in goats with mastitis induced by coagulase-negative staphylococci, by an evaluation of the concentrations of marbofloxacin achieved in blood and milk over time (called pharmacokinetics), and characterizing the concentration–effect relationship of marbofloxacin against coagulase-negative staphylococci in Mueller Hinton broth and goat milk, by time kill assays, in order to determine the concentrations of marbofloxacin related with an adequate bacterial count reduction (measured by efficacy index AUC/MIC). The proposed dose regimen was adequate for the treatment of goat mastitis produced by coagulase-negative staphylococci, resulting in a microbiological and clinical cure of all animals. The animal model used in this study provided important pharmacokinetic information about the effect of the infection on the pharmacokinetics of marbofloxacin. Pharmacodynamic modeling showed that marbofloxacin concentrations needed for antimicrobial efficacy were higher in goat milk compared with Mueller Hinton broth. Bacterial resistance to antimicrobials is a serious problem, since marbofloxacin is considered a critically important antimicrobial, and its rational and prudent use could extend its utility over time. ABSTRACT: Coagulase-negative staphylococci are main pathogens that produce goat mastitis. Marbofloxacin is a third-generation fluoroquinolone approved for treat mastitis in animals. The objectives of this study were: (i) to determine the pharmacokinetics of marbofloxacin (10 mg/kg/24 h) in serum and milk administered intramuscularly for five days in goats with mastitis induced by coagulase-negative staphylococci; (ii) to characterize the concentration–effect relationship of marbofloxacin against coagulase-negative staphylococci in Mueller Hinton broth and goat milk; (iii) to determine AUC/MIC cutoff values of marbofloxacin, and (iv) to perform a PK/PD analysis to evaluate the efficacy of the dose regimen for the treatment of goat mastitis produced by coagulase-negative staphylococci. Marbofloxacin presented context-sensitive pharmacokinetics, influenced by the evolution of the disease, which decreased marbofloxacin disposition in serum and milk. Marbofloxacin showed a median (95% CI) fAUC/MIC values for MIC of 0.4 and 0.8 µg/mL of 26.66 (22.26–36.64) and 32.28 (26.57–48.35) related with −2 log(10)CFU/mL reduction; and 32.26 (24.81–81.50) and 41.39 (29.38–128.01) for −3 log(10)CFU/mL reduction in Mueller Hinton broth. For milk, −2 log(10)CFU/mL reduction was achieved with 41.48 (35.29–58.73) and 51.91 (39.09–131.63), and −3 log(10)CFU/mL reduction with 51.04 (41.6–82.1) and 65.65 (46.68–210.16). The proposed dose regimen was adequate for the treatment of goat mastitis produced by coagulase-negative staphylococci, resulting in microbiological and clinical cure of all animals. The animal model used in this study provided important pharmacokinetic information about the effect of the infection on the pharmacokinetics of marbofloxacin. Pharmacodynamic modeling showed that fAUC/MIC cutoff values were higher in goat milk compared with Mueller Hinton broth.