How should amikacin be dosed and adjusted in a patient with impaired renal function, including loading dose, maintenance intervals based on creatinine clearance, therapeutic drug monitoring, and alternatives if severe renal impairment?

Amikacin Dosing in Renal Impairment

In patients with impaired renal function, administer a full loading dose of 7.5 mg/kg (or 15 mg/kg daily dose equivalent), then adjust maintenance dosing by extending the interval rather than reducing the dose, using either the serum creatinine × 9 method for interval calculation or proportional creatinine clearance reduction for fixed-interval dosing, with mandatory therapeutic drug monitoring to maintain peak levels of 35-45 μg/mL (daily dosing) or 65-80 μg/mL (intermittent dosing) and trough levels below 5-10 μg/mL. 1, 2

Initial Loading Dose Strategy

• Always give a full loading dose of 7.5 mg/kg regardless of renal function to achieve adequate initial peak concentrations, as aminoglycosides exhibit concentration-dependent bactericidal activity 1
• The loading dose is identical to what would be calculated for patients with normal renal function 1
• For newborns, use 10 mg/kg as the loading dose, followed by 7.5 mg/kg every 12 hours 1

Maintenance Dosing Adjustment Methods

Method 1: Extended Interval with Normal Dose (Preferred for Stable Patients)

• Calculate the dosing interval in hours by multiplying the patient's serum creatinine (mg/dL) by 9 1
  • Example: If serum creatinine = 2 mg/dL, give 7.5 mg/kg every 18 hours
  • Example: If serum creatinine = 3 mg/dL, give 7.5 mg/kg every 27 hours
• This method maintains the full individual dose to preserve concentration-dependent killing 1

Method 2: Reduced Dose at Fixed 12-Hour Intervals

• First, administer the full 7.5 mg/kg loading dose 1
• Calculate maintenance dose using the formula:
  • Maintenance Dose (mg) = (Observed CrCl ÷ Normal CrCl) × Calculated Loading Dose 1
  • Where Normal CrCl is typically 100 mL/min
• Alternative simplified calculation: Divide the normally recommended dose by the patient's serum creatinine level 1
• This method is used when fixed-interval dosing is clinically necessary 1

Specific Recommendations for Severe Renal Impairment (CrCl <30 mL/min)

• For daily dosing regimens: Reduce dose or increase dosing interval to 15 mg/kg administered 2-3 times per week 2
• For intermittent (thrice-weekly) dosing: Use 15-25 mg/kg per dose, 2-3 times per week, adjusted according to drug level monitoring 2
• The ATS/ERS/ESCMID/IDSA guidelines specifically recommend this approach for NTM treatment, which is applicable to other indications 2

Hemodialysis Patients

• Do NOT use either dosing adjustment method during active dialysis 1
• Administer amikacin after hemodialysis sessions to avoid premature drug removal 2
• Use extended interval dosing (e.g., 15 mg/kg 2-3 times per week after dialysis) 2
• Approximately 40% of aminoglycosides are removed when given just before hemodialysis 2

Mandatory Therapeutic Drug Monitoring

Target Levels:

• Peak concentrations (30-90 minutes after infusion):
  • Daily dosing: 35-45 μg/mL 2
  • Intermittent dosing (thrice weekly): 65-80 μg/mL 2
• Trough concentrations (just before next dose): <5 μg/mL (ideally <10 μg/mL maximum) 2, 1

Monitoring Requirements:

• Measure serum amikacin concentrations whenever possible in renal impairment 1
• Avoid peak concentrations above 35 μg/mL and trough concentrations above 10 μg/mL 1
• Monitor renal function (serum creatinine or creatinine clearance) periodically during therapy 1
• For treatment beyond 10 days, monitor amikacin serum levels plus renal, auditory, and vestibular functions 1

Critical Pitfalls to Avoid

• Never reduce the loading dose in renal impairment – this compromises initial bacterial killing due to concentration-dependent activity 1
• Do not use fixed dosing nomograms without individualization – these do not account for the wide variability in aminoglycoside clearance in renal dysfunction 3
• Avoid administering aminoglycosides before dialysis – this results in significant drug removal and subtherapeutic levels 2
• Do not rely solely on creatinine clearance for interval adjustment – the ratio of amikacin clearance to creatinine clearance decreases during therapy even with stable renal function, requiring dose reduction 4
• Never exceed 15 mg/kg/day total daily dose by all routes of administration 1

Alternative Considerations for Severe Renal Impairment

• When creatinine clearance is severely reduced (<10-20 mL/min), consider alternative antibiotics if clinically appropriate 5
• For patients with CrCl 10-20 mL/min, a dosage of 17 mg/kg every 48 hours may be appropriate based on population pharmacokinetic modeling 5
• The revised Lund-Malmö (rLM) and CKD-EPI equations show superior predictive performance for amikacin elimination compared to Cockcroft-Gault, though rLM requires careful evaluation in renal failure 6