Systematic review of high-dose amikacin regimens for the treatment of Gram-negative infections based on EUCAST dosing recommendations

Background Amikacin is an aminoglycoside with activity against Gram negative pathogens. Updated EUCAST amikacin breakpoints for Enterobacterales and Pseudomonas aeruginosa included revised dosing recommendations of 25-30mg/kg to achieve key pharmacokinetic/pharmacodynamic parameters, higher than recommended in the British National Formulary. We undertook a literature review to report preferred dosing regimens, monitoring and toxicities associated with the use of amikacin at doses ≥20mg/kg/day. Methods This literature search was conducted in electronic databases for any study reporting adult participants treated with amikacin at doses ≥20mg/kg/day. Data were extracted for pharmacokinetic parameters and clinical outcomes, while papers were assessed for bias using the ROBINS-I tool. Results Nine papers were identified and included, eight of which were observational studies; assessment of bias showed substantial flaws. Dosing regimens ranged from 25-30mg/kg/day. Six studies adjusted the dose in obesity when participants BMI ≥30 kg/m2. Target peak serum concentrations ranged from 60mg/L-80mg/L and 59.6-81.8% of patients achieved these targets. Two studies reported the impact of high dose amikacin on renal function. No studies reporting auditory or vestibular toxicity were identified. Conclusions Dosing amikacin at 25-30mg/kg achieved peak concentration targets in the majority of patients, but there was no information on clinical outcomes. There is little information about the impact on renal function or ototoxicity; caution with use of high dose regimens in older patients for prolonged periods is recommended. Given the paucity of information, there is a need for a consensus guideline for high dose amikacin or a prospective study. What is already known on this topic Amikacin is receiving increased interest as an antibiotic option for multidrug resistant organisms Amikacin and other aminoglycosides require therapeutic drug monitoring to minimise the risk of nephrotoxicity Increasing prevalence of antimicrobial resistance in key pathogens has led to changes to susceptibility breakpoints and theoretical dosing recommendations in European-wide guidelines, including a recommendation for high-dose amikacin for certain pathogens What this study adds The current literature reporting data and outcomes with high-dose amikacin regimens has a high degree of bias and is confounded by poor study design and as a result there in insufficient evidence base to provide guidance on how to manage high-dose amikacin. Appropriate dosing weight for obese patients, adjustment for renal impairment, monitoring interval, potential toxicity and key PK/PD targets to guide treatment with high-dose amikacin regimens remain poorly defined in the current literature. How this study might affect research, practice or policy Further evidence and/or consensus guidelines based on expert judgement are required to ensure patients can receive optimal therapy when amikacin is the treatment of choice.