What are examples of time-dependent killing antibiotics?

Time-Dependent Killing Antibiotics

Time-dependent antibiotics include β-lactams (penicillins, cephalosporins, carbapenems, monobactams) and macrolides (erythromycin, clarithromycin, azithromycin), with efficacy determined by the duration that drug concentrations remain above the pathogen's MIC rather than peak concentration. 1

Primary Time-Dependent Antibiotic Classes

β-Lactam Antibiotics

β-lactams are the prototypical time-dependent killing antibiotics, requiring drug concentrations to remain above the MIC for 40-50% of the dosing interval for optimal bacterial eradication. 1

• Penicillins: Require free drug concentrations above MIC for 30-40% of the dosing interval 1, 2, 3
• Cephalosporins: Require free drug concentrations above MIC for 40-50% of the dosing interval 1, 2
• Carbapenems (imipenem, meropenem): Require only 15-25% time above MIC due to more rapid bacterial killing effect 1, 2
• Monobactams (aztreonam): Exhibit time-dependent killing similar to other β-lactams 4

Macrolides/Azalides

Macrolides exhibit time-dependent killing with moderate to prolonged persistent effects (post-antibiotic effect), making their pharmacodynamics slightly different from β-lactams. 1

• Erythromycin: Time-dependent with prolonged post-antibiotic effect 1
• Clarithromycin: Time-dependent with prolonged post-antibiotic effect 1
• Azithromycin: Time-dependent with prolonged post-antibiotic effect 1

Key Pharmacodynamic Principles

Mechanism of Action

• β-lactams do not kill more efficiently when concentrations greatly exceed the MIC; increasing drug concentration beyond 2-4 times the MIC does not improve bacterial killing rate or extent. 1, 5
• The critical parameter is maintaining adequate concentrations for sufficient duration, not achieving high peak levels. 1

Optimal Dosing Targets

• For critically ill patients, maintain free plasma β-lactam concentrations at 4-8 times the MIC for 100% of the dosing interval for maximum bacteriological and clinical response. 2, 5
• Standard targets of 40-50% time above MIC may be insufficient in ICU patients; 100% time above MIC improves clinical outcomes (OR 1.56,95% CI 1.15-2.13, p<0.03). 5

Post-Antibiotic Effect Considerations

• β-lactams have minimal or no post-antibiotic effect against gram-negative bacilli (except carbapenems which show modest PAE against Pseudomonas aeruginosa), requiring frequent dosing or continuous infusion. 1, 6, 7
• Macrolides have prolonged post-antibiotic effects against gram-positive cocci and H. influenzae, allowing for less frequent dosing despite time-dependent killing. 1, 6

Clinical Dosing Strategies

Administration Methods

• For critically ill patients or infections with less susceptible organisms, extended or continuous infusions are superior to intermittent bolus dosing for achieving optimal time above MIC. 2, 5, 4
• A loading dose followed by continuous infusion achieves the greatest percentage of time above MIC compared to intermittent administration. 2, 5
• Continuous administration improves clinical cure rates (70% vs 43%, p=0.037) and decreases hospital mortality in patients with high severity scores (APACHE II ≥17). 2

Frequency Requirements

• β-lactams require multiple daily doses or continuous infusion to maintain concentrations above MIC throughout the dosing interval due to lack of post-antibiotic effect. 1, 6, 7
• Macrolides can be dosed less frequently despite time-dependent killing due to their prolonged post-antibiotic effect. 1, 6

Important Clinical Caveats

Concentration Limits

• Avoid exceeding 8 times the MIC with β-lactams, as excessive concentrations increase neurotoxicity risk, particularly in patients with renal failure. 2, 5

Protein Binding

• Only free (unbound) drug is microbiologically active; hypoalbuminemia significantly alters β-lactam pharmacokinetics and necessitates dose adjustments. 1, 5

Resistance Selection

• Azithromycin's long half-life (68 hours) creates prolonged subinhibitory concentrations lasting 14-20 days, potentially selecting for resistant strains (carriage rates of resistant S. pneumoniae increased from 2% to 55% at 2-3 weeks post-treatment). 1

Critical Illness Considerations

• ICU patients often have increased volume of distribution and variable clearance (augmented renal clearance or acute kidney injury), requiring higher doses and extended/continuous infusions when treating less-susceptible pathogens, especially Pseudomonas aeruginosa. 4