Abstract
Gamithromycin is approved for the treatment and prevention of bovine respiratory disease (BRD), which is caused mainly by Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma species. In this study, multiple dosage regimens were administered to the neutropenic mouse lung infection model in order to investigate the pharmacokinetic/pharmacodynamic (PK/PD) parameters of gamithromycin treatment of P. multocida and to further define the PK/PD parameter that best correlates with the efficacy of gamithromycin against P. multocida. The PK characteristics of gamithromycin were analyzed after a single subcutaneous (s.c.) injection (1, 3, 6, and 9 mg/kg). The concentration–time profiles of unbound (f) gamithromycin in plasma samples were analyzed by non-compartmental analysis. The main PK parameters of gamithromycin for the area under the concentration–time curve from 0 to 24 h (f AUC0–24) and the peak drug concentration (f C max) values ranged from 0.86 to 8.42 µg·h/ml and from 0.55 to 5.69 µg/ml, respectively. The PD values were calculated based on multiple s.c. injections over 24 h (1, 3, 6, and 9 mg/kg at 6, 8, 12, and 24 h, respectively; total dosage 1–36 mg/ kg). The minimum inhibitory concentration (MIC) of gamithromycin against P. multocida in mice serum was 0.15 μg/ml. Analysis of PK/PD indices using the inhibitory effect E max model indicated a strong correlation (R 2 = 0.9624) between the f AUC0–24/MIC ratio and various antibacterial effects. The area under the unbound concentration–time curve over 24 h to MIC (f AUC0–24/MIC) predicted for bacteriostatic action, 1-log10 reduction, 2-log10 reduction, and 3-log10 reduction were 56.77, 90.18, 143.06, and 239.44 h, respectively. These in vivo data may facilitate gamithromycin dosage optimization against P. multocida in veterinary medicine.
Highlights
Bovine respiratory disease (BRD), which is one of the most common respiratory diseases in calves, occurs with high mortality and morbidity rates, leading to enormous economic losses in the cattle industry
The current study suggested that the f AUC0−24/minimum inhibitory concentration (MIC) ratios required for bacteriostatic action, 1-log10 reduction, and 2-log10 reduction were 56.77, 90.18, and 143.06 h, respectively, which were higher than estimated in a prior study (Zeng et al, 2018)
A neutropenic mouse lung infection model was first used to evaluate the in vivo PK and PD indices of gamithromycin
Summary
Bovine respiratory disease (BRD), which is one of the most common respiratory diseases in calves, occurs with high mortality and morbidity rates, leading to enormous economic losses in the cattle industry. The pathogenesis of BRD is multifactorial, pathogenic bacteria, such as Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma species, are the main contributing factors which contribute to morbidity and mortality (Portis et al, 2012). Gamithromycin, a novel semi-synthetic macrolide, is approved for the treatment and prevention of BRD (Muraro et al, 2012; O’Connor et al, 2016). Like other macrolides, it plays a bacteriostatic and bactericidal role by inhibiting the ribosomal 50S subunit. Pharmacokinetic (PK) data for gamithromycin delivered by subcutaneous (s.c.) injection have been reported in different species, such as foals, sheep, cattle, broiler chickens, and pigs (Watteyn et al, 2013; Kellermann et al, 2014; Wyns et al, 2014; Jones et al, 2015; Berlin et al, 2017)
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