Amikacin dosing and therapeutic drug monitoring: a single tertiary centre quality improvement audit

Amikacin is increasingly being used as a firstline aminoglycoside in the empirical treatment of sepsis.1 It is typically given once daily with the goal of achieving a peak plasma concentration (Cmax) to minimum inhibitory concentration (MIC) ratio of 8–10.2 However, optimal dosing strategies for amikacin remain a matter of debate.3, 4 Recent updates from the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST)5, 6 effectively lowered susceptibility breakpoints for Pseudomonas aeruginosa and Enterobacterales. Pharmacokinetic modelling data suggested that a dose of amikacin between 25 and 30 mg/kg would be required to achieve a therapeutic Cmax for most Gram-negative pathogens based on these new breakpoints.7 These predictions are in contrast to other studies suggesting that 15–20 mg/kg achieves appropriate therapeutic levels.2 In 2023, our institutional aminoglycoside guidelines were updated to transition from gentamicin to amikacin 15–20 mg/kg for actual body weight once daily, with adjustments for renal impairment, in accordance with our antibiogram. We aimed to evaluate this change to ensure adequate Cmax to MIC ratios were achieved. This retrospective cohort study was conducted at a tertiary hospital in Australia. All adult inpatients who received at least one dose of amikacin with a dosing regimen of 15–20 mg/kg and had an appropriately timed Cmax level collected between November 2023 and September 2024 were included. Given that amikacin was mostly used empirically, MIC values for individual isolates were rarely available. Therefore, the 95th percentile MIC for Enterobacterales in our local hospital antibiogram, generated using the VITEK 2 automated system (bioMérieux, France), was selected as a surrogate, which was 4 mg/L. This was chosen to reflect a conservative estimate of local resistance patterns and ensure that dosing strategies are assessed against clinically relevant local data. The primary outcome was an amikacin Cmax-to-MIC ratio of ≥8.8 Secondary outcomes were all-cause mortality at 30 days, readmission rate at 30 days, acute kidney injury and length of stay. The source of infection was identified from review of documentation by the treating team. Amikacin was predominantly prescribed empirically at the time of suspected sepsis before a source of infection was clinically established. Of the 39 patients identified for inclusion, 37 (95%) achieved the target ratio with a Cmax of 32 mg/L or more (Table 1). The median amikacin Cmax was 52.1 mg/L (interquartile range (IQR) 40.4–63.3). Amikacin was predominantly used as short-duration empiric treatment, with a median of two doses (IQR 1–3) among patients who achieved the target ratio. At 30 days the all-cause mortality was 5 (14%) (Table 2). There were eight (22%) patients that had an acute kidney injury, and the median length of stay was 5 days (IQR 4.5–49.5). Where a source was identified, urinary was the most common (18 (49%) patients). Based on our local Enterobacterales antibiogram, the majority of patients that are dosed with 15–20 mg/kg dosing regimen achieve a satisfactory Cmax-to-MIC ratio of 8 or higher. Amidst evolving resistance patterns and revised breakpoints, our data support the clinical validity of our dosing approach, suggesting that even conservative doses within the 15–20 mg/kg range can achieve pharmacodynamic targets. We acknowledge the small sample sizes and use of surrogate MIC values. Future research incorporating the gold standard of area under the curve-based monitoring may help clarify exposure–response relationships in more detail. Despite these limitations, our findings suggest that our current local empirical dosing guidelines are appropriate for our patient population and pathogen profile, achieving pharmacodynamic targets in most patients. AI-assisted technology (ChatGPT, OpenAI) was used for formatting and spelling checks. The authors affirm full responsibility for the accuracy and integrity of the manuscript content. The data that support the findings of this study are available from the corresponding author upon reasonable request.