Abstract
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.
Highlights
Gentamicin is commonly used to treat Haemorrhagic Septicemia (HS) and other respiratory tract infections in bovines
The viable count decreased by 3-log colony forming units/mL after 2 h of incubation at 4×minimum inhibitory concentrations (MICs) for isolates of P. multocida and reduction of 4-log cfu/ml occurred at 5 h of incubation at 2,4 and 8×MIC
It is concluded that the mutant prevention concentration (MPC) measurements along with MIC values of gentamicin allowed us to define the Mutant Selection Window (MSW) for P. multocida in buffalo calves
Summary
Gentamicin is commonly used to treat Haemorrhagic Septicemia (HS) and other respiratory tract infections in bovines. 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. Designing optimal dosage schedules of antimicrobials is critical to achieve therapeutic success and prevention of emergence of resistance. For this a comprehensive study on pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in target species is recommended [4,5]. Pharmacokinetic models describe the relationship between the dose of a drug and resulting concentrations at different sites of the body. Pharmacodynamic models describe the relationship between drug concentrations in plasma/serum or tissues and resulting therapeutic effect. PK-PD modeling provides a quantitative description of the time course of drug disposition and drug effects and dose optimization of antimicrobial agents by this method had been suggested by various workers [5,6,7]
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