Pharmacokinetic and Pharmacodynamic Evaluation of Marbofloxacin and PK/PD Modeling against Escherichia coli in Pigs

Abstract

The aim of this study was to evaluate the activity of marbofloxacin and establish the optimal dose regimens for decreasing the development of fluoroquinolone resistance in pigs against Escherichia coli with ex vivo pharmacokinetic/pharmacodynamic (PK/PD) modeling. The recommended dose (2 mg/kg body weight) of marbofloxacin was orally administered in healthy pigs. The ileum content and plasma were both collected for the determination of marbofloxacin. The main parameters of Cmax, AUC0-24 h, AUC, Ke, t1/2ke, MRT and Clb were 11.28 μg/g, 46.15, 77.81 μg⋅h/g, 0.001 h-1, 69.97 h, 52.45 h, 0.026 kg/h in ileum content, and 0.55 μg/ml, 8.15, 14.67 μg⋅h/ml, 0.023 h-1, 30.67 h, 34.83 h, 0.14 L/h in plasma, respectively In total, 218 E. coli strains were isolated from most cities of China. The antibacterial activity in vitro and ex vivo of marbofloxacin against E. coli was determined following CLSI guidance. The MIC90 of sensitive strains (142) was calculated as 2 μg/ml. The minimum inhibitory concentration (MIC) of HB197 was 2 and 4 μg/ml in broth and ileum fluids, respectively. In vitro mutant prevention concentration, growth and killing-time in vitro and ex vivo of marbofloxacin against selected HB197 were assayed for pharmacodynamic studies. According to the inhibitory sigmoid Emax modeling, the value of AUC0-24 h/MIC produced in ileum content was achieved, and bacteriostatic, bactericidal activity, and elimination were calculated as 16.26, 23.54, and 27.18 h, respectively. Based on Monte Carlo simulations to obtain 90% target attainment rate, the optimal doses to achieve bacteriostatic, bactericidal, and elimination effects were 0.85, 1.22, and 1.41 mg/kg.bw for 50% target, respectively, and 0.92, 1.33, and 1.53 mg/kg.bw for 90% target, respectively, after oral administration. The results in this study provided a more optimized alternative for clinical use and demonstrated that the dosage 2 mg/kg of marbofloxacin by oral administration could have an effect on bactericidal activity against E. coli.

Pharmacokinetic–pharmacodynamic relationship of marbofloxacin for Escherichia coli and Pasturella multocida following repeated intramuscular administration in goats

“…In vitro time‐kill curves demonstrated the concentration‐dependent bactericidal activity of MBF for P. multocida . With exception of P. multocida strain having MIC = 0.40 µg/ml, bacteria were completely eradicated quickly (Figure a,b,c) with 4–8 × MIC as described in previous reports (Lei et al, ; Sidhu et al, , ).…”

Propuesta de una dosis de marbofloxacina para el tratamiento de infecciones asociadas a Escherichia coli en cabras de tres semanas de vida

“…Las dro-gas con bajo porcentaje de unión a proteínas plasmáticas como MFX (<30%), presentan una cinética de unión a proteínas de tipo lineal (Mehvar, 2005) donde ante una disminución de la concentración de la forma libre, el equilibrio entre la forma libre y la forma unida es un proceso que resulta en una constante e instan-tánea concentración de fármaco en forma libre (Li et al 2015). Así las concentraciones totales en plasma de este tipo de drogas pueden considerarse como farma-cológicamente activas y se puede asumir para la f u de MFX un valor de 1 (Lei et al 2017).…”

“…Es efectiva sobre la mayoría de las bacterias gramnegativas, y Mycoplasma (Haritova et al 2006;Vallé et al 2012;Tohamy y El-Gendy, 2013). La farmacocinética de MFX ha sido estudiada en diferentes especies de animales, incluyendo caninos, porcinos, bovinos, bubalinos y caprinos, mostrando que logra elevadas concentraciones plasmáticas y una rápida y extensa distribución tisular, lo que determina que sus concentraciones en tejidos tales como pulmón, hígado y riñón sean mayores a las observadas en plasma, al tiempo que presenta una elevada biodisponibilidad (F) con valores cercanos al 100% (Waxman et al 2001;Schneider et al 2004;Albarellos et al 2005;Ding et al 2010;Sidhu et al 2010;Lei et al 2017). En animales de laboratorio y cerdos su unión a proteínas plasmáticas es débil (<10%), aunque en bovinos su unión es cercana al 30% (EMEA, 1999).…”

PK-PD Analysis of Marbofloxacin against Streptococcus suis in Pigs

“…A third-generation synthetic antibiotic fluoroquinolone, marbofloxacin (MBF), has a wide range of bactericidal effect for Gram-negative, partial Gram-positive pathogens and Mycoplasma ( Haritova et al, 2006b ; Grandemange et al, 2012 ; Vallé et al, 2012 ; Tohamy and El-Gendy, 2013 ; Lei et al, 2017a ). MBF is recommended to orally or parenterally administrated for pigs and bovine diseases in the respiratory and digestive tract ( EMEA, 1996 ; Ding et al, 2010 ).…”

“…It has been studied for the pharmacokinetics (PK) research of MBF in different kinds of animals, including dogs, pigs and so on, showing high concentration, rapid and extensive distribution in the peripheral compartment or tissue and a high bioavailability closed at 100% after extravenous administrations ( Waxman et al, 2001 ; Schneider et al, 2004 ; Albarellos et al, 2005 ; Ding et al, 2010 ; Sidhu et al, 2010 ; Lei et al, 2017a ). These PK profiles make the MBF an attractive option for treating the herd of food-producing animals and effective in treating serious infections (e.g., septicemia and gastroenteritis) caused by Gram-negative or some Gram-positive aerobic bacterium ( Garch et al, 2017 ).…”