Pharmacodynamic Targets

Literature-based PK/PD targets used to optimize antibiotic dosing. Antibiotics are classified into three pharmacodynamic patterns based on the relationship between drug exposure and bacterial killing.

Three PK/PD Killing Patterns
  • Time-dependent (%fT>MIC): Efficacy correlates with the percentage of the dosing interval that free drug concentrations remain above the MIC. Prolonged or continuous infusions maximize this parameter. Applies to beta-lactams.
  • AUC/MIC-dependent: Efficacy correlates with the ratio of the 24-hour area under the concentration–time curve to the MIC. Total daily exposure matters more than peak or duration. Applies to vancomycin, fluoroquinolones, daptomycin, linezolid.
  • Concentration-dependent (Cmax/MIC): Efficacy correlates with the ratio of peak concentration to MIC. Higher peaks drive faster bactericidal activity. Applies to aminoglycosides.

Table 1: Time-Dependent Killing (%fT>MIC)

Beta-lactam antibiotics — penicillins, cephalosporins, carbapenems

Drug Class Bacteriostatic Target Bactericidal Target Critically-Ill Optimal Target Ref
Ampicillin Penicillin 30% 50% 100% fT>4×MIC [1], [16], [17]
Penicillin G Penicillin 30% 50% 100% fT>4×MIC [1], [16], [17]
Piperacillin/Tazobactam Penicillin + BLI 30% 50% 100% fT>4×MIC [1], [16], [17]
Cefazolin Cephalosporin (1st gen) 35–40% 50–60% 100% fT>4×MIC [1], [16], [17]
Ceftazidime Cephalosporin (3rd gen) 40% 60–70% 100% fT>4×MIC [1], [16], [17]
Cefepime Cephalosporin (4th gen) 35–40% 60% 100% fT>4×MIC [1], [6], [16], [17]
Ceftolozane/Tazobactam Cephalosporin + BLI 24–31% 32–42% 100% fT>4×MIC [7], [16]
Cefiderocol Siderophore cephalosporin 58–64% 73–75% 100% fT>4×MIC [8], [16]
Meropenem Carbapenem 20% 40% 100% fT>4×MIC [1], [9], [16], [17]
Note: Targets expressed as %fT>MIC (percentage of dosing interval that free drug concentration exceeds the MIC), calculated as %fT>MIC = (time free concentration ≥ MIC ÷ dosing interval τ) × 100. Carbapenems achieve bactericidal activity at lower %fT>MIC than penicillins or cephalosporins due to a more rapid rate of killing.
Critically-ill optimal target. The classic bacteriostatic/bactericidal thresholds above derive from neutropenic-animal models. In critically ill patients, expert consensus recommends a higher exposure: a minimum of 100% fT>MIC (free drug above the MIC for the entire dosing interval), with an optimal target of free concentrations reaching 4–5× the MIC — the exposure at which beta-lactam bactericidal activity is maximal.1 The French SFPT/SFAR guidelines endorse 100% fT>MIC for critically ill patients.16 Evidence for pushing beyond 4× MIC is limited: Scharf et al. found faster infection resolution with 100% fT>MIC but no additional benefit above 100% fT>4× MIC, recommending 100% fT>MIC and below 4× MIC as the practical optimum.17

Table 2: AUC/MIC-Dependent Killing

Vancomycin, fluoroquinolones, daptomycin, linezolid, fluconazole

Drug PK/PD Target Clinical Goal Ref
Vancomycin AUC24/MIC 400–600 Serious MRSA infections; assumes MIC ≤1 mcg/mL [5]
Daptomycin AUC24/MIC ≥666 1-log bactericidal kill in murine thigh model [10]
Linezolid AUC24/MIC 80–120 Bacteriostatic; keep AUC24 <400 for safety (thrombocytopenia) [11]
Levofloxacin (Gram-negative) AUC24/MIC ≥125 Gram-negative infections [12]
Levofloxacin (Gram-positive) fAUC24/MIC ≥34 S. pneumoniae eradication [13]
Ciprofloxacin AUC24/MIC ≥125 Gram-negative infections [12]
Fluconazole fAUC24/MIC ≥25 Candidemia, invasive/mucosal candidiasis (dose/MIC ≈25) [18]
Note: The 2020 ASHP/IDSA/SIDP vancomycin consensus guidelines recommend AUC-guided dosing (AUC24/MIC 400–600) over trough-based monitoring for serious MRSA infections.5 Fluoroquinolone AUC/MIC targets were derived from critically ill patient outcomes data.
Free vs. total exposure. AUC/MIC targets can be expressed against total or free (protein-unbound) drug. For highly protein-bound agents the distinction is large — daptomycin (≈90–93% bound) targets are conventionally cited as total AUC24/MIC ≥666, whereas fluoroquinolone and fluconazole targets are typically expressed as free exposure (fAUC24/MIC). When comparing a calculated value to a published target, confirm which basis (free or total) the target uses. This tool reports both free and total plasma AUC so either target can be applied.

Table 3: Concentration-Dependent Killing (Cmax/MIC)

Aminoglycosides

Drug PK/PD Target Typical Cmax Goal Ref
Gentamicin Cmax/MIC ≥8–10 8–10 mcg/mL [14], [15]
Tobramycin Cmax/MIC ≥8–10 8–10 mcg/mL [14], [15]
Amikacin Cmax/MIC ≥8–10 25–30 mcg/mL [14], [15]
Note: Aminoglycosides exhibit concentration-dependent killing with a significant post-antibiotic effect (PAE). Extended-interval (once-daily) dosing leverages both properties by maximizing Cmax/MIC while allowing drug-free intervals for reduced nephrotoxicity.

References

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