Pharmacokinetic/pharmacodynamic relationships of antimicrobial drugs used in veterinary medicine

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Abstract
The rise in incidence of antimicrobial resistance, consumer demands and improved understanding of antimicrobial action has encouraged international agencies to review the use of antimicrobial drugs. More detailed understanding of relationships between the pharmacokinetics (PK) of antimicrobial drugs in target animal species and their action on target pathogens [pharmacodynamics (PD)] has led to greater sophistication in design of dosage schedules which improve the activity and reduce the selection pressure for resistance in antimicrobial therapy. This, in turn, may be informative in the pharmaceutical development of antimicrobial drugs and in their selection and clinical utility. PK/PD relationships between area under the concentration time curve from zero to 24 h (AUC0‐‐24) and minimum inhibitory concentration (MIC), maximum plasma concentration (Cmax) andMICand time during which plasma concentrations exceed theMIChave been particularly useful in optimizing efficacy and minimizing resistance. Antimicrobial drugs have been classified as concentration‐dependent where increasing concentrations at the locus of infection improve bacterial kill, or time‐dependent where exceeding theMICfor a prolonged percentage of the inter‐dosing interval correlates with improved efficacy. For the latter group increasing the absolute concentration obtained above a threshold does not improve efficacy. The PK/PD relationship for each group of antimicrobial drugs is ‘bug and drug’ specific, although ratios of 125 forAUC0‐‐24:MICand 10 forCmax:MIChave been recommended to achieve high efficacy for concentration‐dependent antimicrobial drugs, and exceedingMICby 1–5 multiples for between 40 and 100% of the inter‐dosing interval is appropriate for most time‐dependent agents. Fluoroquinolones, aminoglycosides and metronidazole are concentration‐dependent and beta‐lactams, macrolides, lincosamides and glycopeptides are time‐dependent. For drugs of other classes there is limited and conflicting information on their classification. Resistance selection may be reduced for concentration‐dependent antimicrobials by achieving anAUC0‐‐24:MICratio of greater than 100 or aCmax:MICratio of greater than 8. The relationships between time greater thanMICand resistance selection for time‐dependent antimicrobials have not been well characterized.