Amikacin Dosing in Severe Sepsis and Septic Shock
Loading Dose
Administer a loading dose of ≥25 mg/kg based on total body weight to achieve therapeutic peak concentrations in patients with severe sepsis or septic shock. 1
Patients with severe sepsis and septic shock have significantly expanded extracellular volume from aggressive fluid resuscitation, increasing the volume of distribution to approximately 0.41 L/kg (range 0.29–0.51 L/kg), which necessitates higher loading doses than standard regimens. 1
Even with 25 mg/kg dosing, only 70% of septic patients achieve the target peak concentration of >64 mg/L (corresponding to 8× the MIC breakpoint for Enterobacteriaceae and Pseudomonas aeruginosa). 1
The remaining 30% of patients fail to reach therapeutic peaks even at 25 mg/kg, highlighting the need for therapeutic drug monitoring to guide further dose escalation. 1
The loading dose is not affected by renal function—give the full weight-based dose regardless of baseline creatinine clearance. 2
Administration Method
Therapeutic Drug Monitoring Targets
Target a peak concentration (Cpeak) that achieves a Cpeak/MIC ratio ≥8 to ≥10 for optimal bactericidal activity. 3, 4
For organisms with MIC = 8 mg/L (EUCAST susceptibility breakpoint), the target peak is ≥64 mg/L. 1
For less susceptible organisms (e.g., MIC = 16 mg/L), target peaks of 128–160 mg/L may be required. 3
Draw the peak concentration 1 hour after completion of the 30-minute infusion to assess adequacy of the loading dose. 1, 2
Trough concentrations (Cmin) should be <5 mg/L to minimize nephrotoxicity risk. 4
In patients with impaired renal function at baseline, trough levels frequently exceed 5 mg/L after the loading dose, requiring interval prolongation. 4
Perform therapeutic drug monitoring within 24 hours of the loading dose to guide maintenance dosing adjustments. 4
Dosing Interval and Maintenance Strategy
After the loading dose, extend the dosing interval based on renal function and measured trough concentrations rather than administering fixed 24-hour intervals. 4
In septic patients with normal baseline renal function, the median elimination half-life is 4.6 hours (range 3.2–7.8 hours), but this varies widely. 1
In patients receiving continuous renal replacement therapy (CRRT), the elimination half-life extends to a median of 6.5 hours (range 4.5–279.6 hours), and the median time to reach Cmin <5 mg/L is 34 hours (range 14–76 hours). 2
Only 17% of septic patients require no dose or interval adjustment during amikacin therapy, emphasizing the necessity of individualized TDM-guided dosing. 4
Alternative Dosing Strategy for Resistant Organisms
For multidrug-resistant Gram-negative organisms, consider a moderate-dose, non-extended-interval regimen of 12.5 mg/kg every 12 hours to maintain time above MIC (T>MIC) >60% of the dosing interval, which may reduce resistance development compared to extended-interval dosing. 5
This regimen targets Cpeak >40 mg/L and T>MIC >60%, and demonstrates less tubular injury (measured by NGAL) compared to 25 mg/kg every 24 hours. 5
Renal Function Adjustments
Do not reduce the initial loading dose based on renal impairment—only maintenance doses and intervals require adjustment. 2
In patients with baseline renal dysfunction (elevated creatinine or reduced eGFR), the loading dose of 25 mg/kg remains necessary to achieve therapeutic peaks. 2, 4
After the loading dose, measure trough concentrations before administering the next dose; if Cmin >5 mg/L, delay the next dose until the trough falls below this threshold. 4
In patients on CRRT, drug clearance is highly variable (median 1.26 mL/min/kg, range 0.1–3.30 mL/min/kg) and does not correlate with CRRT parameters, mandating TDM-guided dosing. 2
Patients with pre-existing renal impairment who receive amikacin are at increased risk of further acute kidney injury (AKI); 24% of septic patients developed AKI during therapy, with 80% of these having baseline renal dysfunction. 4
Clinical Outcomes and Monitoring
Early achievement of optimal Cpeak/MIC ratio (≥8) is associated with significantly improved clinical cure rates (86% vs. 70%, P = 0.18) and microbiological eradication (83% vs. 61%, P = 0.07). 4
Clinical cure rates improve progressively as Cpeak/MIC increases (P = 0.006). 4
Delayed time to achieving optimal Cpeak/MIC is associated with worse microbiological and clinical outcomes. 4
Monitor serum creatinine daily during therapy, especially in patients with baseline renal impairment or those receiving concomitant nephrotoxic agents. 4
Common Pitfalls to Avoid
Do not use standard 15 mg/kg dosing in septic shock—this consistently fails to achieve therapeutic peaks due to expanded volume of distribution. 1
Do not assume 25 mg/kg will be adequate in all patients—approximately 30% require higher doses to reach target peaks. 1
Do not administer subsequent doses at fixed 24-hour intervals without measuring trough concentrations—83% of patients require dose or interval adjustment. 4
Do not withhold the loading dose in patients with renal impairment—subtherapeutic early concentrations are associated with treatment failure. 2, 4
In patients on CRRT, do not assume standard dosing recommendations apply—pharmacokinetic variability is extreme and TDM is mandatory. 2