Veterinärmedizinische Wissenschaft und Technologie

Optimization of Dosage Regimen of Gentamicin against Pasteurella multocida in Bovines: Old Drug, New Approach

Abstract

Pritam Kaur Sidhu, Gurpreet Kaur, Ganesh Kumbhar, Balaje RM, Mohinder Partap Gupta

Background: Gentamicin is commonly used to treat Haemorrhagic Septicemia (HS) and other respiratory tract infections in bovines. But no data on its doses and schedules optimized for therapeutic success against P. multocida using pharmacokinetics (PK) - pharmacodynamic (PD) integration and modeling is available in farm animals. We investigated PD of gentamicin against P. multocida isolates and optimized the dosage schedules in buffalo species using novel approach of PK-PD modeling.

Results: The minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of gentamicin against P. multocida in Mueller Hinton Broth (MHB) and serum were similar. The MBC:MIC ratios were 1.23 and 1.27, respectively, for MHB and calf serum.. The mutant prevention concentration (MPC) =6 μg/mL of gentamicin was higher than MIC (0.75 μg/mL) and MBC (0.95 μg/mL). In vitro growth inhibition curves of gentamicin in MHB and serum were characteristic of bactericidal activity against P. multocida. Time kill kinetics demonstrated that killing activity of gentamicin is concentration andtime dependent.. The values of PK-PD indicators, Cmax/MIC and AUC24h /MIC were 21 and 61 h, respectively. Based on MPC, PK-PD indices, Cmax/MPC and AUC24h /MPC were 2.60 and 7.62 h, respectively. Using PK-PD modelling, the predicted gentamicin values of AUC24h/MIC for bacteriostatic bactericidal action and bacterial eradication were 32.13, 47.15 and 60.96 h, respectively.

Conclusions: The PK-PD indicespredicted therapeutic success of the gentamicin against P. multocida. Based on PK-PD modeling, optimum daily dosage of gentamicin was 2-2.5 mg/kg for treating infections caused by P. multocida (MIC90 ≤1.0 μg/mL) in buffalo calves. However, in difficult clinical infections associated with pathogens of MIC90≤4.0 μg/mL, a higher dosage of 7.5 mg/kg is recommended. Low MPC of gentamicin against P. multocida suggested low selection pressure for emergence and amplification of resistant subpopulation during treatment.