When should a loading dose be administered?

When to Give a Loading Dose

Loading doses should be administered for critically ill patients requiring rapid achievement of therapeutic drug concentrations, particularly for antimicrobials with low volumes of distribution (polymyxins, beta-lactams, vancomycin) and for all patients receiving continuous infusions of beta-lactam antibiotics, regardless of renal function or severity of illness. 1

Antimicrobials Requiring Loading Doses

Polymyxins (Colistin and Polymyxin B)

• Colistin requires a loading dose of 6-9 million IU in all patients, including those with renal dysfunction, because plasma concentrations remain suboptimal for 2-3 days before reaching steady state without a loading dose 1
• Polymyxin B requires a loading dose of 2-2.5 mg/kg to achieve optimal plasma levels on the first day 1
• The loading dose is mandatory regardless of renal function status 1

Beta-Lactam Antibiotics

• All critically ill patients should receive a loading dose when starting beta-lactam therapy, independent of whether continuous or intermittent administration is planned 1
• The loading dose should equal the standard intermittent dose (e.g., 4g piperacillin if planning 12g/24h continuous infusion) 1
• Without a loading dose, continuous infusions may result in plasma concentrations remaining below the MIC for several hours after starting the infusion 1
• Meta-analysis data shows mortality reduction only occurs when loading doses precede continuous infusions (RR 0.63 vs 0.56 without loading dose) 1
• The rationale is that critically ill patients have increased volumes of distribution due to capillary permeability and fluid resuscitation, making loading doses essential even in patients with organ failure 1

Vancomycin

• For seriously ill patients with suspected MRSA infection, administer a loading dose of 25-30 mg/kg (actual body weight) 2
• Loading doses enable rapid achievement of therapeutic concentrations in critically ill patients with expanded extracellular volume from fluid resuscitation 2, 3
• Loading doses are not affected by renal dysfunction and should be given regardless of kidney status 3
• Do not give a loading dose if the patient is already receiving vancomycin therapy unless pre-existing levels are subtherapeutic in severe sepsis/septic shock 3

Teicoplanin

• Loading dose of 25-30 mg/kg is recommended for critically ill patients to rapidly achieve therapeutic levels 4
• For serious infections, use the higher end of the dosing range (10-12 mg/kg) for loading doses 4
• Loading doses are not affected by alterations in renal function 4

Cardiovascular Medications

Antiarrhythmics

• Esmolol requires a loading dose of 500 mcg/kg (0.5 mg/kg) over 1 minute before starting maintenance infusion to rapidly control heart rate in tachyarrhythmias 1
• Amiodarone requires 150 mg over 10 minutes as a loading dose for stable narrow-complex tachycardias or pre-excited atrial arrhythmias 1
• Digoxin requires 8-12 mcg/kg total loading dose, with half administered initially over 5 minutes 1

Antiepileptic Drugs

Phenytoin

• Oral loading doses of 1 gram divided into three doses (400 mg, 300 mg, 300 mg) at two-hour intervals should be reserved for clinic or hospital settings with close serum level monitoring 5
• Patients with renal or liver disease should not receive oral loading regimens 5
• Intravenous phenytoin loading dose of 18 mg/kg infused over 20 minutes achieves therapeutic unbound concentrations within 5-20 minutes 6

Key Principles for Loading Dose Administration

Volume of Distribution Considerations

• Loading doses are essential for drugs with low volumes of distribution in critically ill patients because these patients have expanded extracellular volumes from fluid resuscitation 1, 2, 3
• The loading dose should be calculated based on the volume of distribution at the time of peak effect (tmax) to accurately achieve target concentrations without unexpected adverse effects 7

Renal Function Independence

• Loading doses are not affected by renal dysfunction and should be administered at full doses even in patients with acute kidney injury or chronic kidney disease 1, 3, 4
• Only maintenance doses require adjustment for renal function 1

Common Pitfalls to Avoid

• Never use fixed 1-gram doses for vancomycin loading as this results in underdosing in most patients, especially those weighing >70 kg 2
• Do not skip loading doses when initiating continuous infusions of beta-lactams, as this delays achievement of therapeutic concentrations and may contribute to treatment failure 1
• Avoid giving loading doses to patients already on maintenance therapy unless levels are documented to be subtherapeutic 3
• For phenytoin oral loading, never use this approach in outpatient settings or in patients with hepatic or renal disease 5