Therapeutic drug monitoring of amikacin in septic patients

Introduction: Use of higher than standard doses of amikacin (AMK) has been proposed during sepsis, especially to treat less susceptible bacterial strains. However, few data are available on drug concentrations during prolonged therapy and on potential adverse events related to this strategy. Methods: Sixty-three critically ill patients who required AMK administration for the treatment of severe infection were included in this study. After a loading dose (LD, 18 to 30 mg/kg), the daily regimen was adapted using therapeutic drug monitoring (TDM) of both peak (C-peak) and trough (C-min) concentrations. Target concentrations had to give a ratio of at least 8 between C-peak and the minimal inhibitory concentration (MIC) of the isolated pathogen. A C-min >5 mg/L was considered as potentially nephrotoxic. We recorded clinical and microbiological responses, the development of acute kidney injury (AKI) during therapy and ICU mortality. Results: The median AMK LD was 1500 (750 to 2400) mg, which resulted in a C-peak/MIC >= 8 in 40 (63%) patients. Increasing the dose in the 23 patients with a C-peak/MIC <8 resulted in optimal C-peak/MIC in 15 of these patients (79%). In 23 patients (37%), C-min was >5mg/L after the LD, notably in the presence of altered renal function at the onset of therapy, needing prolongation of drug administration. Overall, only 11 patients (17%) required no dose or interval adjustment during AMK therapy. Clinical cure (32/37 (86%) vs. 16/23 (70%), P = 0.18)) and microbiological eradication (29/35 (83%) vs. 14/23 (61%), P = 0.07) were higher in patients with an initial optimal C-peak/MIC than in the other patients. The proportion of patients with clinical cure significantly improved as the C-peak/MIC increased (P = 0.006). Also, increased time to optimal C-peak was associated with worse microbiological and clinical results. AKI was identified in 15 patients (24%) during AMK therapy; 12 of these patients already had altered renal function before drug administration. Survivors (n = 47) had similar initial C-peak/MIC ratios but lower C-min values compared to nonsurvivors. Conclusions: TDM resulted in adjustment of AMK therapy in most of our septic patients. Early achievement of an optimal C-peak/MIC ratio may have an impact on clinical and microbiological responses, but not on outcome. In patients with impaired renal function prior to treatment, AMK therapy may be associated with a further decline in renal function.