What are the key considerations for a pharmacokinetic (PK)/pharmacodynamic (PD) dependent antibiotic policy?

PK/PD-Dependent Antibiotic Policy: Key Considerations

Implement antibiotic dosing based on PK/PD optimization rather than manufacturer's prescribing information, using specific PK/PD targets for each antibiotic class to maximize efficacy and minimize resistance development. 1

Fundamental PK/PD Classification

Antibiotics must be categorized by their killing pattern to guide dosing strategies:

Time-Dependent Antibiotics (β-lactams)

• Efficacy depends on the percentage of time drug concentrations remain above the MIC (%fT > MIC) 1
• For bacteriostatic effect: maintain free drug concentrations above MIC for 35-40% of the dosing interval 1
• For bactericidal effect: maintain free drug concentrations above MIC for 60-70% of the dosing interval 1
• Optimal target: maintain concentrations at 4-8 times the MIC for 100% of the dosing interval in critically ill patients 2
• Penicillins require 30-40% time above MIC 2
• Cephalosporins require 40-50% time above MIC 2
• Carbapenems require only 15-25% time above MIC due to rapid bacterial killing 2

Concentration-Dependent Antibiotics

Aminoglycosides and Fluoroquinolones:

• Target Cmax/MIC ratio >10 for optimal efficacy 1
• Alternative target: AUC24/MIC >125 for fluoroquinolones (specifically ciprofloxacin against Pseudomonas aeruginosa) 1
• For fluoroquinolones against S. pneumoniae: AUC/MIC ≥33.7 correlates with bacterial eradication 1

Glycopeptides (Vancomycin, Teicoplanin) and Lipopeptides (Daptomycin):

• Primary target: AUC24/MIC ratio 1
• For daptomycin: AUC24/MIC ≥250 achieves 80% kill efficacy against S. aureus 1
• Consider daptomycin doses of 8-10 mg/kg/day for complicated MRSA bacteremia and endocarditis 1

Dosing Strategy Implementation

For β-Lactams in Critically Ill Patients

Use continuous or prolonged infusions rather than intermittent bolus dosing 1, 2

• Loading dose followed by continuous infusion achieves greatest %fT ≥ MIC 2
• Continuous administration improves clinical cure rates (70% vs 43%, p=0.037) 2
• Particularly beneficial for lower respiratory tract infections and non-fermenting Gram-negative bacilli 2
• Reduces hospital mortality in patients with APACHE II ≥17 2

For Concentration-Dependent Antibiotics

Administer as single daily high doses to maximize Cmax/MIC ratio 1

• Aminoglycosides should never be used as monotherapy for HAP/VAP 1
• Once-daily dosing optimizes concentration-dependent killing and reduces toxicity 1

PK/PD Breakpoint Determination

Use PK/PD breakpoints rather than traditional NCCLS breakpoints for resistance definition 1

• PK/PD breakpoints remain consistent across all pathogens for the same drug 1
• Traditional breakpoints vary by pathogen and may not reflect achievable PK/PD targets 1
• Resistance is defined when the PK/PD goal cannot be achieved with standard dosing 1
• For time-dependent drugs: determine the MIC at which drug remains above that concentration for the required percentage of dosing interval 1
• For concentration-dependent drugs: divide the AUC (unbound fraction) by 25-30 to determine breakpoint 1

Special Considerations

Site of Infection

• PK/PD goals generally do not change based on infection site 1
• Exception: macrolides accumulate in epithelial lining fluid, potentially affecting PK/PD targets 1
• For endocarditis: cardiac vegetations create mechanical barriers requiring prolonged therapy despite optimal PK/PD targets 1

Resistance Prevention

Achieving optimal PK/PD targets suppresses resistance development 3, 4

• Suboptimal dosing creates selective pressure for resistant subpopulations 3, 4
• Target attainment increases likelihood of clinical success and microbiological eradication 3, 4

Monitoring Requirements

Use therapeutic drug monitoring (TDM) for PK/PD optimization 1

• Measure antibiotic blood concentrations to adjust dosing 1
• Apply weight-based dosing for certain antibiotics 1
• When MIC unavailable, use epidemiological cut-off value (ECOFF) as reference 2

Common Pitfalls to Avoid

• Do not use standard manufacturer dosing in critically ill patients—altered pharmacokinetics require individualized PK/PD-optimized regimens 1
• Avoid excessive β-lactam concentrations (>8 times MIC) due to neurotoxicity risk, especially with renal impairment 2
• Never assume host defenses are adequate—PK/PD targets from animal models may underestimate requirements in immunocompromised patients 1
• Do not mix β-lactams with aminoglycosides in the same solution—chemical incompatibility occurs 5
• Avoid using lactated Ringer's solution with piperacillin-tazobactam—not compatible 5