Pharmacokinetics and pharmacodynamics

Pharmacokinetics and pharmacodynamics - Pharmacokinetics of antimicrobial agents determine whether adequate concentrations are obtained at the primary site of infection and likely areas of dissemination. Septic patients often have poor gastrointestinal absorption, so the preferred initial route of therapy is intravenous. Knowledge of anticipated antimicrobial drug concentrations at sites of infection is critical. For example, achieving a ‘therapeutic’ blood level of gentamicin is of little practical use in treating meningitis, as CSF penetration of the drug is severely limited. Knowledge of routes of elimination is also critical in antimicrobial therapy; for instance, a urinary tract infection is more appropriately treated with a drug that is excreted unchanged in the urine than one which is fully eliminated by hepatic metabolism.

Pharmacodynamics vs Pharmacokinetics

Pharmacokinetics and pharmacodynamics parameters

Pharmacodynamics describes the relationship between antimicrobial concentration and microbial killing. For many agents, antimicrobial effect can be categorised as concentration-dependent or time-dependent. The concentration of antimicrobial achieved after a single dose is illustrated in Figure 6.15. The maximum concentration achieved is C max and the measure of overall exposure is the area under the curve (AUC).

The efficacy of antimicrobial agents whose killing is concentration-dependent (e.g. aminoglycosides) increases with the amount by which C max exceeds the minimuminhibitory concentration (C max :MIC ratio). For this reason, it has become customary to administer aminoglycosides (e.g. gentamicin) infrequently at high doses (e.g. 7 mg/kg) rather than frequently at low doses. This has the added advantage of minimising toxicity by reducing the likelihood of drug accumulation. Conversely, the β-lactam antibiotics, macrolides and clindamycin exhibit time-dependent killing, and their efficacy depends on C max exceeding the MIC for a certain time (which is different for each class of agent). This is reflected in the dosing interval of benzylpenicillin, which is usually given every 4 hours in severe infection (e.g. meningococcal meningitis), and may be administered by continuous intravenous infusion. 

For other antimicrobial agents the relationships between MIC, C max and AUC are more complex and often less well understood. With some agents bacterial inhibition persists after antimicrobial exposure (post-antibiotic and post-antibiotic sub-MIC effects).