Time Dependent Antibiotic Killing

Time-dependent killing means that bacterial killing depends on how long the free drug concentration stays over the MIC, not on how high the peak is. Once concentrations reach about 4 to 5 times the MIC, killing rate is maximal, so extra peak adds nothing. The beta-lactams (penicillins, cephalosporins, carbapenems, aztreonam) are the main examples, together with erythromycin, clindamycin and flucytosine. Several drugs that combine this with AUC dependence (linezolid, vancomycin, tetracyclines) show a mixed pattern.

Mechanism. Beta-lactams kill only growing cells during cell wall synthesis and show saturable target binding at PBPs, so sustained occupancy matters. They have little or no post-antibiotic effect against Gram-negatives, so bacteria resume growth as soon as concentrations drop under the MIC.

Targets. The free drug concentration should exceed the MIC for about 40 percent of the interval for carbapenems, 50 percent for penicillins and 60 to 70 percent for cephalosporins. In critically ill patients and in infections with high bacterial burden or poor penetration, aiming for 100 percent over the MIC, or for a concentration of 4 times the MIC throughout, is associated with better clinical response.

• Short half-life drugs (benzylpenicillin, ampicillin, piperacillin, ceftazidime, cefepime, meropenem, imipenem): the most sensitive to dosing schedule; benefit most from extended or continuous infusion.
• Long half-life drugs (ceftriaxone, ertapenem): reach the target with once-daily dosing in most patients, although free fraction falls in hypoalbuminaemia.
• Stability limits: meropenem degrades within a few hours at room temperature, imipenem faster; piperacillin-tazobactam, flucloxacillin and ceftazidime are stable for about 24 hours in appropriate diluents.

Strategies.

• More frequent dosing, extended infusion (over 3 to 4 hours) or continuous infusion after a first dose given over 30 minutes.
• Examples: piperacillin-tazobactam 4.5 g over 4 hours every 8 hours; meropenem 1 to 2 g over 3 hours every 8 hours; ceftazidime 2 g loading then 6 g over 24 hours; flucloxacillin 12 g over 24 hours (continuous infusion by pump); benzylpenicillin continuous infusion for CNS or endovascular infection.
• A large randomised study of continuous infusion of piperacillin-tazobactam or meropenem in sepsis reported lower 90-day mortality, whereas earlier smaller studies were neutral; benefit is greatest in critical illness and with higher-MIC organisms.

Selection. Use extended or continuous infusion in severe sepsis, febrile neutropenia, Pseudomonas infection, augmented renal clearance, CNS infection and endocarditis. A dedicated line is needed, since many antibiotics are incompatible when mixed.

Risks. Prolonged infusions occupy venous access and need compatible diluents; dose calculations must account for stability; continuous infusion of high doses in renal impairment increases neurotoxicity (seizures with cefepime, carbapenems, high-dose penicillins).

Monitoring. Renal function daily in critical illness; free beta-lactam levels where available (target 4 times the MIC); neurological state; clinical response by 48 to 72 hours.

Special groups. Critical illness with augmented clearance: avoid under-dosing and use extended infusion. Renal impairment: reduce the daily dose, not the loading dose. Obesity: do not cap the dose at usual weight values without clinical review. Children: weight-based extended infusion is used with care. Region: where infusion pumps are lacking, frequent intermittent dosing, with a full first dose, is the practical alternative.