Optimisation of antimicrobial therapy using pharmacokinetic and pharmacodynamic parameters.

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.