Pharmacokinetic/pharmacodynamic evaluation of marbofloxacin as a single injection for Pasteurellaceae respiratory infections in cattle using population pharmacokinetics and Monte Carlo simulations

Abstract

Population pharmacokinetic of marbofloxacin was investigated with 52 plasma concentration-time profiles obtained after intramuscular administration of Forcyl® in cattle. Animal's status, pre-ruminant, ruminant, or dairy cow, was retained as a relevant covariate for clearance. Monte Carlo simulations were performed using a stratification by status, and 1000 virtual disposition curves were generated in each bovine subpopulation for the recommended dosage regimen of 10 mg/kg as a single injection.The probability of target attainment (PTA) of pharmacokinetic/pharmacodynamic (PK/PD) ratios associated with clinical efficacy and prevention of resistance was determined in each simulated subpopulation. The cumulative fraction of response (CFR) of animals achieving a PK/PD ratio predictive of positive clinical outcome was then calculated for the simulated dosage regimen, taking into account the minimum inhibitory concentration (MIC) distribution of Pasteurella multocida, Mannheimia haemolytica, and Histophilus somni. When considering a ratio of AUC 0-24 hr /MIC (area under the curve/minimum inhibitory concentration) greater than 125 hr, CFRs ranging from 85% to 100% against the three Pasteurellaceae in each bovine subpopulation were achieved.The PTA of the PK/PD threshold reflecting the prevention of resistances was greater than 90% up to MPC (mutant prevention concentration) values of 1 μg/ml in preruminants and ruminants and 0.5 μg/ml in dairy cows. | INTRODUCTIONFluoroquinolones are broad-spectrum antimicrobial drugs with high therapeutic value in both human and veterinary practice. Drug exposure, measured by the area under the concentration-time curve (AUC), is used to compute the ratio between the AUC and the minimum inhibitory concentration (MIC), a surrogate pharmacokinetic/pharmacodynamic (PK/PD) efficacy index for fluoroquinolones. Interindividual variability (IIV) of drug exposure can lead to variations in the probability of clinical success. Subpopulations with specific pharmacokinetic parameters could need dosage regimen adjustments to ensure efficacy and/or minimize the risk of emergence of antimicrobial resistance.Population pharmacokinetics associated with Monte Carlo simulations (MCSs) can contribute to optimization of antimicrobial drugs dosage regimen taking into account both the variability of the PK and the PD parameters. This approach is widely used in human medicine (DeRyke, Kuti, & Nicolau, 2007;Frei, Wiederhold, & Burgess, 2008;Roberts, Kirkpatrick, & Lipman, 2011;Tanigawara, Nozawa, & Tsuda, 2012;Turnidge & Paterson, 2007;Zelenitsky, Ariano, Harding, & Forrest, 2005). A growing interest in population pharmacokinetics and MCS applied to the assessment of anti-infectives dosage regimens was recently shown in veterinary medicine (Black, Landersdorfer, Bulitta, Griffith, & Govendir, 2014;Rey et al., 2014;Vilalta, Giboin, Schneider, El Garch, & Fraile, 2014;Yuan et al., 2015). This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which per...

Population pharmacokinetics/pharmacodynamics modelling of enrofloxacin for the three major trout pathogens Aeromonas salmonicida, Flavobacterium psychrophilum and Yersinia ruckeri

“…In addition, higher enrofloxacin MICs values were observed at 4°C compared to 15°C for A. salmonicida (Martinsen et al, 1992). Further in vitro studies involving time-kill curves with these fish bacteria under specific condition are needed to better define the target values of the PKPD indexes for different level of efficacy (bacteriostase, bactericidal, virtual eradication) in trout,as already published for other bacteria and food-animal species (Dorey et al, 2017;Paulin et al, 2018;Pelligand et al, 2019;Toutain et al, 2019).…”

Effect of supportive therapy on the pharmacokinetics of intravenous marbofloxacin in endotoxemic sheep

“…Marbofloxacin is recommended to the use at 2 mg/kg dose by EMA (1999) in livestock animals. However, the results of simulation and therapeutic studies proposed use at 10 mg/kg dose to achieve an adequate antimicrobial efficacy (Kacar, Batmaz, Yilmaz, & Mecitoglu, 2018; Lorenzutti et al, 2018; Paulin, Schneider, Dron, & Woehrle, 2018; Valle, Schneider, Galland, Giboin, & Woehrle, 2012). In this study, sheep received marbofloxacin at 10 mg/kg dose.…”

“…Because fluoroquinolones are substrates of efflux pumps (Schrickx & Fink‐Gremmels, 2007), the transporter saturation in the administration of marbofloxacin at five times (10 mg/kg dose) the recommended dose can be expected. However, marbofloxacin has shown dose‐proportional PKs at 2–10 mg/kg dose in sheep (Altan et al, 2019) and at 5–20 mg/kg dose in ruminant calves (Paulin et al, 2018).…”

Therapeutic efficacy of marbofloxacin and ceftiofur in feedlot steers with bovine respiratory disease complex

“…However, erroneous antibiotic treatment protocols, mainly regarding dose and frequency of application, have increased bacterial resistance to antibiotics such as oxytetracycline and penicillin, and until recent antibiotics as tulathromycin. There is still no reported resistance to florfenicol, enrofloxacin, ceftiofur and marbofloxacin (PAULIN et al, 2017;TIMSIT et al, 2017).…”