PharmacologyTier 1Medical Sciences concept

Pharmacodynamic indices of antibiotic efficacy (concentration- vs time-dependent killing)

Core concept

Index	Killing pattern	Classes
Cmax/MIC (peak)	Concentration-dependent	Aminoglycosides, daptomycin, metronidazole, colistin
fT>MIC (time above MIC)	Time-dependent, no PAE	Beta-lactams - penicillins, cephalosporins, carbapenems
AUC24/MIC	Time-dependent with persistent effect	Vancomycin, fluoroquinolones, macrolides, linezolid, clindamycin, tetracyclines

Post-antibiotic effect (PAE) - continued suppression after concentration falls below MIC
- Present with aminoglycosides and quinolones; absent for beta-lactams against Gram-negatives
The index determines the dosing strategy, not the total daily dose
- Concentration-dependent + long PAE -> large infrequent doses
- Time-dependent, no PAE -> frequent or continuous dosing

Aminoglycosides - target Cmax/MIC >= 8-10
- Extended-interval (once-daily) dosing maximises peak, allows a trough near zero
- Uptake into renal tubular and cochlear cells is saturable -> a low trough limits toxicity
- Monitor with an AUC or post-dose level against a nomogram, not a trough alone
Beta-lactams - target fT>MIC of 40-70% of the dosing interval (carbapenems lowest, penicillins highest)
- Achieved by shortening the interval, extended (3-4 h) infusion, or continuous infusion
- Raising the individual dose adds little - the curve is above MIC either way
- Extended infusion piperacillin-tazobactam or meropenem in critical illness with high-MIC organisms
Vancomycin - target AUC24/MIC >= 400 (assuming MIC 1)
- AUC-guided dosing has replaced trough-only targeting; troughs of 15-20 overshoot and drive AKI
Fluoroquinolones - AUC/MIC >= 100-125 for Gram-negatives, >= 30-40 for pneumococcus
MIC is not an absolute - it is organism- and method-specific; a "sensitive" report means the achievable exposure exceeds the MIC at standard dosing
Mutant prevention concentration and the mutant selection window explain resistance emergence at sub-target exposure

Septic shock and augmented renal clearance (young, burns, trauma) -> subtherapeutic beta-lactam exposure; give a loading dose and extend the infusion
Obesity, third-spacing and hypoalbuminaemia expand Vd -> load on actual weight, maintain on renal function
Once-daily gentamicin in Australia: empirical dosing by weight and renal function, with a level to guide the interval, and duration limited to 48-72 h wherever possible
Vancomycin AUC targeting reduces nephrotoxicity compared with trough-based dosing at 15-20 mg/L
Sanctuary sites (CNS, bone, vegetations, abscess) need higher exposure than serum MIC alone implies - source control is part of the pharmacodynamics
An antibiotic that is bactericidal in vitro is not necessarily better clinically - it must reach the site at the right index

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