Pharmacokinetics and pharmacokinetic/pharmacodynamic integration of marbofloxacin in calf serum, exudate and transudate

Abstract

Marbofloxacin is a fluoroquinolone antimicrobial drug used in cattle for the treatment of respiratory infections. In this investigation the pharmacokinetics (PK) of marbofloxacin were determined after intravenous and intramuscular dosing at a dosage of 2 mg/kg. In addition the ex vivo pharmacodynamics (PD) of the drug were determined in serum and three types of tissue cage fluid (transudate, inflammatory exudate generated by carrageenan and exudate generated by lipopolysaccharide). Marbofloxacin PK was characterized by a high volume of distribution after dosing by both routes (1.28 L/kg intravenous and 1.25 L/kg intramuscular). Corresponding area under the concentration-time curve (AUC) and elimination half-life (t(1/2)el) values were 9.99 and 10.11 microg h/mL and 4.23 and 4.33 h, respectively. Values of AUC for carrageenan-induced exudate, lipopolysaccharide-induced exudate and transudate were, respectively, 8.28, 7.83 and 7.75 microg h/mL after intravenous and 8.84, 8.53 and 8.52 microg h/mL after intramuscular dosing. Maximum concentration (Cmax) values were similar for the three tissue cage fluids after intravenous and intramuscular dosing. For in vivo PK data values of AUC: minimum inhibitory concentration (MIC) (AUIC) ratio for serum were 250 and 253, respectively, after intravenous and intramuscular dosing of marbofloxacin against a pathogenic strain of Mannheimia haemolytica (MIC=0.04 microg/mL). For all tissue cage fluids AUIC values were >194 and >213 after intravenous and intramuscular dosing, and Cmax/MIC ratios were 9 or greater, indicating a likely high level of effectiveness in clinical infections caused by M. haemolytica of MIC 0.04 microg/mL or less. This was confirmed by both in vitro (serum) and ex vivo (serum, exudate and transudate) measurements, which demonstrated a concentration-dependent killing profile for marbofloxacin against M. haemolytica. Ex vivo, after 24-h incubation, virtually all bacteria were killed (<10 cfu/mL) in all samples collected up to 9 h (serum), 24 h (carrageenan-induced exudate and transudate) and 36 h (lipopolysaccharide-induced exudate). Application of the sigmoid Emax equation to the ex vivo antibacterial data provided, for serum, AUIC24 h values of 37.1 for bacteriostasis, 46.3 for bactericidal activity and 119.6 for elimination of bacteria. These data may be used as a rational basis for setting dosing schedules which optimize clinical efficacy and minimize the opportunities for emergence of resistant organisms.

Integration of Pharmacokinetic and Pharmacodynamic Indices of Marbofloxacin in Turkeys

“…It has a broad spectrum of activity (58), and bactericidal concentration-dependent killing is observed against many gram-negative bacteria (12,49,51,52). The pharmacokinetic (PK) properties of marbofloxacin have been studied in several mammalian species, and some advantages over other fluoroquinolones, such as a longer elimination half-life, have been described (2,43,47,48). In practice, this would enable a single treatment per 24 h, with serum concentrations remaining above the MIC for more than 12 h. Comparable kinetic data for turkeys are lacking, however, as yet.…”

“…Increasing evidence suggests that the main PK-PD surrogate markers for fluoroquinolones correlating with clinical cure and bacterial eradication are the area under the serum concentration-time curve (AUC)/MIC ratio and the maximum concentration of the drug in serum (C max )/MIC ratio (9,46). Hence, this approach determines ex vivo PK-PD indices, which subsequently allow a more targeted design in confirmatory in vivo studies (1,2,3). PK-PD experiments with marbofloxacin were previously conducted with calves, cows, goats, and dogs (2,43,48,55).…”

Determination of Marbofloxacin residues in Rabbit Tissues by HPLC

“…Marbofloxacin is a third generation of fluoroquinolone with broad spectrum antimicrobial activity against some grampositive, most gram-negative organisms and Mycoplasma [2][3][4] with a relatively low concentration [5,6]. It prevents the bacterial DNA replication and synthesis via inhibition of the A subunit of the bacterial DNA gyrase.…”

“…It has bactericidal action by a concentration -dependent mechanism [5]. It inhibits bacterial DNA gyrase enzyme which is responsible for supercoiling of DNA within the cells [6].…”

Bioavailability pharmacokinetics and residues of marbofloxacin in normal and E.coli infected broiler chicken

“…It acts by hindrance of bacterial DNA-gyrase and has high antimicrobial movement in vitro against an extensive variety of gram-negative and some gram-positive microscopic organisms (Staphylococcus aureus, Staphylococcus intermedius, Escherichia coli, Klebsiella sp., Pasteurella multocida, Pasteurella haemolytica, and Haemophilus somnus) and Mycoplasma (Spreng et al, 1995). Similar to other fluoroquinolones, marbofloxacin has low plasma protein binding (Ismail and El-Kattan, 2007), large volume of distribution with good concentrations in tissues and body fluids (Aliabadi and Lees, 2002;Anadon et al, 2002) and activity at extremely low concentrations (Ding et al, 2013). The disposition kinetic of marbofloxacin has been evaluated in some avian species like broiler chickens (Anadon et .…”