Murine Thigh Microdialysis to Evaluate the Pharmacokinetic/Pharmacodynamic Integration of Cefquinome Against Actinobacillus pleuropneumoniae

To understand the relationship between drug dose and efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics need to be integrated. Patterns of antimicrobial activity fall into one of two major patterns: time-dependent killing and concentration-dependent killing. Time-dependent killing is characteristic of many antibiotic classes, such as beta-lactams and macrolides, and seeks to optimise the duration of exposure of a pathogen to an antimicrobial. The major PK/PD parameter correlating with efficacy of time-dependent antimicrobials is the serum concentration present for 40-50% of the dosing interval, and this concentration is the susceptibility limit or breakpoint for the dosing regimen used. The second pattern, concentration-dependent killing, seeks to maximise antimicrobial concentration and is seen with aminoglycosides, quinolones and azalides. The major PK/PD parameter correlating with efficacy of these agents is the 24-h area under the curve to MIC ratio, which should be > or =25 for less severe infections or in immunocompetent hosts, and > or =100 in more severe infections or in immunocompromised hosts. PK/PD breakpoints for concentration-dependent agents can therefore be calculated from the formula AUC divided by 25. This enables development of PK/PD breakpoints based on the above parameters for time- and concentration-dependent agents for defined dosing regimens. For an antimicrobial to be useful empirically, the MIC90s of the agent against the common pathogens responsible for the disease being treated should be below the PK/PD breakpoint. This is particularly important for oral dosing regimens for treating emerging resistant respiratory tract pathogens, where efficacy against the predominant pathogens, Streptococcus pneumoniae and Haemophilus influenzae, is required.

In veterinary drug development procedures, pharmacokinetic (PK) and pharmacodynamic (PD) data have generally been established in separate, parallel studies to assist in the design of dosage schedules for subsequent evaluation in clinical trials. This review introduces the concept of PK/PD modelling, an approach in which PK and PD data are generated in the same study, and used to derive numerical values for PD parameters based on drug plasma concentrations. The PD parameters define the efficacy, potency and slope (sensitivity) of the concentration-effect relationship. It is proposed that the parameters derived from PK/PD modelling may be used as an alternative and preferred approach to dose titration studies for selecting rational dosage regimens (both dose and dosing interval) for further evaluation in clinical trials. In PK/PD modelling, the explicative variable for effect is the plasma concentration profile. The PK/PD approach provides several advantages over dose-titration studies, including determination of a projected dosage regimen by investigation of a single dose, in contrast to dose-ranging studies which by definition require testing of multiple dosage. Implementation of PK/PD modelling in the veterinary drug development process is currently constrained by the limited number of veterinary studies performed to date, and the consequently limited understanding of PK/PD concepts and their absence from regulatory authority guidelines. Nevertheless, PK/PD modelling has major potential for rational dosage regimen determination, as it considers and quantifies the two main sources of interspecies variability (PK and PD). It is therefore applicable to interspecies extrapolation and to multiple species drug development. As well as the currently limited appreciation of PK/PD principles in the veterinary scientific community, a further constraint in implementing PK/PD modelling is the need to validate PK/PD approaches and thereby gain confidence in its value by pharmaceutical companies and regulatory authorities.