Antibiotic Pharmacodynamics

Antibiotic pharmacodynamics describes the relationship between drug exposure and antibacterial effect, and is the basis of dose selection. The unit of exposure is the free (unbound) drug concentration at the infection site, related to the MIC of the infecting organism. Three exposure indices predict outcome: the percentage of the dosing interval with free concentration over the MIC (fT>MIC), the peak (Cmax) to MIC ratio, and the 24-hour area under the curve to MIC ratio (AUC24/MIC).

Key terms. MIC is the lowest concentration that prevents visible growth; MBC is the lowest concentration that kills 99.9 percent of the inoculum; a drug is regarded as bactericidal when the MBC to MIC ratio is 4 or less. Breakpoints are MIC values that divide susceptible, susceptible at increased exposure, and resistant categories, set using pharmacokinetic, pharmacodynamic and clinical outcome data. Static concentrations stop growth, whereas killing requires higher exposure.

Mechanism of the pattern. Killing patterns reflect how a drug binds its target: beta-lactams saturate PBP binding at low multiples of the MIC (time-dependent), aminoglycosides and fluoroquinolones increase killing as concentration rises (concentration-dependent), and some drugs depend on total exposure (AUC dependent).

Applying the concept.

• Choose a dose that achieves the target at the organism’s MIC, not just at the breakpoint; infections with MIC near the breakpoint need higher exposure.
• Use extended or continuous infusion for time-dependent drugs in critical illness; once-daily dosing for aminoglycosides.
• Use therapeutic drug monitoring for drugs with a narrow margin or variable clearance (aminoglycosides, vancomycin, teicoplanin, voriconazole, colistin, chloramphenicol).
• Adjust for site: CSF, abscess, vegetation, biofilm and intracellular sites need drugs with penetration and activity there.

Hostile conditions. High inoculum reduces beta-lactam activity (inoculum effect); biofilm and stationary-phase organisms resist growth-dependent drugs; acid pH and anaerobic conditions inactivate aminoglycosides; protein binding limits the free fraction of ceftriaxone, daptomycin, teicoplanin and flucloxacillin.

Pitfalls. Total drug levels overstate exposure for highly protein-bound drugs in hypoalbuminaemia; population targets come from animal models and observational data and are approximate; in vitro MIC methods have a one-dilution error; MIC creep and heteroresistance are not captured by routine testing.

Special populations. Critical illness (increased volume of distribution, augmented clearance, capillary leak), obesity, renal replacement therapy, extracorporeal membrane oxygenation, burns, neonates and pregnancy all alter exposure and need dosing adjustment, preferably with level monitoring.

Monitoring. Peak and trough or AUC-based levels where available; renal function daily in critical illness; clinical and microbiological response to confirm that the target is clinically relevant. Region: many East African hospitals lack drug assay services, so conservative dosing, extended infusion where feasible, and careful clinical review are the practical tools.