What is the recommended dose of amikacin (an aminoglycoside antibiotic) for a patient with septic shock and Chronic Kidney Disease (CKD) stage 5?

Amikacin Dosing in Septic Shock with CKD Stage 5

In a patient with septic shock and CKD stage 5, administer a full loading dose of amikacin at 25-30 mg/kg based on actual body weight, followed by extended-interval dosing (every 48-72 hours or longer) with mandatory therapeutic drug monitoring to ensure trough levels remain ≤2.5 mg/L before subsequent doses. 1

Loading Dose Strategy

The initial loading dose must NOT be reduced despite severe renal impairment. 1

• Administer 25-30 mg/kg as the loading dose based on actual body weight to achieve optimal peak concentrations (Cmax ≥60 μg/mL or ≥8 × MIC) 1, 2
• The loading dose is unaffected by renal dysfunction because septic shock causes expanded extracellular volume from aggressive fluid resuscitation, increasing the volume of distribution 1
• Failure to achieve adequate peak plasma concentrations on initial dosing is associated with clinical failure in aminoglycoside therapy 1
• Standard 15 mg/kg dosing is insufficient in critically ill patients, with 0% reaching target Cmax >60 μg/mL compared to 76% with 30 mg/kg dosing 2

Maintenance Dosing in CKD Stage 5

Once-daily dosing regimens should NOT be used in patients with severe renal dysfunction where the aminoglycoside is not expected to clear within several days. 1

• After the loading dose, extend the dosing interval significantly (every 48-72 hours or longer) rather than reducing the dose 3, 4
• The specific interval depends on measured drug clearance via therapeutic drug monitoring 3, 5
• For patients on hemodialysis, consider 5 mg/kg every 48 hours with dosing after dialysis sessions 4
• For patients on peritoneal dialysis, consider 4 mg/kg every 48 hours 4

Therapeutic Drug Monitoring (Mandatory)

Therapeutic drug monitoring is essential and should measure both peak and trough concentrations. 3, 5

• Measure peak concentration (Cpeak) 30-90 minutes after infusion completion; target ≥60 μg/mL (or ≥8 × MIC of the pathogen) 1, 3, 6
• Measure trough concentration (Cmin) immediately before the next scheduled dose; must be ≤2.5 mg/L to minimize nephrotoxicity 3, 5, 6
• Peak concentrations above 35 μg/mL and trough concentrations above 10 μg/mL should be avoided according to FDA labeling, though recent evidence suggests higher peaks (≥60 μg/mL) may be necessary for optimal outcomes in septic shock 3, 2
• In CKD stage 5, achieving Cthrough ≤2.5 mg/L at 24 hours occurs with only 20% probability, but increases to 81% at 48 hours, supporting extended-interval dosing 6

Critical Pharmacokinetic Principles

Aminoglycoside efficacy is concentration-dependent, requiring optimization of peak concentrations rather than time above MIC. 1

• The Cpeak/MIC ratio should be ≥8 for optimal clinical and microbiological outcomes 5
• Early achievement of optimal Cpeak/MIC ratio significantly improves clinical cure rates (86% vs 70%) and microbiological eradication (83% vs 61%) 5
• Increased time to achieving optimal Cpeak is associated with worse clinical and microbiological results 5
• Trough levels are associated with effective therapy even in CKD patients, suggesting maintaining some drug exposure between doses may be beneficial 4

Nephrotoxicity Considerations

Pre-existing renal dysfunction increases the risk of further kidney injury with aminoglycosides. 5, 4

• In patients with impaired renal function prior to treatment, amikacin therapy may be associated with further decline in renal function 5
• However, 24% of patients developed acute kidney injury during therapy, with 80% (12/15) already having altered renal function before drug administration 5
• Trough concentrations >5 mg/L are considered potentially nephrotoxic 5
• Lower trough values were associated with survival compared to non-survivors 5
• Avoid nephrotoxic drug combinations (vancomycin, colistin, other aminoglycosides) whenever possible in CKD stage 5 patients 7

Practical Dosing Algorithm

1. Day 1: Administer loading dose of 25-30 mg/kg IV (based on actual body weight) 1, 2
2. Measure Cpeak at 1 hour post-infusion; target ≥60 μg/mL 6, 2
3. Measure Cmin at 24 hours; if >2.5 mg/L, delay next dose 5, 6
4. Continue monitoring Cmin every 24 hours until ≤2.5 mg/L before administering next dose 6
5. Subsequent doses: Administer same mg/kg dose when Cmin ≤2.5 mg/L (typically every 48-72 hours or longer) 4, 6
6. Reassess renal function and drug levels throughout therapy 3

Duration of Therapy

• Limit treatment duration to 7-10 days whenever feasible 3
• If treatment beyond 10 days is necessary, re-evaluate the need for amikacin and intensify monitoring of serum levels, renal function, and auditory/vestibular function 3
• Clinical response should occur within 24-48 hours; if no response within 3-5 days, discontinue and reassess 3