KDIGO Clinical Practice Guideline for Acute Kidney Injury
Patients with Normal Kidney Function in Steady State: Recommendations and Rationale

• 3.8.2: We suggest that, in patients with normal kidney function in steady state, aminoglycosides are administered as a single dose daily rather than multiple-dose daily treatment regimens. (2B)

Rationale

Aminoglycoside demonstrates concentration-dependent bactericidal activity, with a prolonged ‘‘postantibiotic effect’’, thereby permitting extended interval dosing in an effort to optimize efficacy and minimize toxicity. This dosing strategy and a number of other measures to limit aminoglycoside uptake in renal tubular cells, prevent apoptosis, limit oxygen injury, and protect mitochondrial function have all been recommended to minimize the risk of AKI and preserve the therapeutic value of these important antimicrobial agents.^280-296 Single-dose daily or extended-interval dosing of aminoglycosides offer a number of theoretical and practical advantages to maintain antimicrobial activity while limiting possible nephrotoxicity. This convenient and inexpensive aminoglycoside dosing strategy has been widely adopted at many centers when using this potentially toxic, yet highly effective, class of antibiotics.

When feasible in patients with normal and stable kidney function, once-daily (often referred to as extended-interval) dosing of aminoglycosides should be used to limit aminoglycoside nephrotoxicity. The pharmacokinetic and pharmacodynamic properties of aminoglycosides favor high dosing strategies with extended intervals between doses. The key therapeutic parameter for efficacy is peak blood level divided by minimum inhibitory concentration (MIC) of the infecting organism (C_max/MIC) in an effort to obtain > 10-fold C_max/MIC. Aminoglycosides induce a prolonged postantibiotic effect (inhibition of bacterial growth after blood levels have fallen below the MIC of the organism). The length of the postantibiotic effect is directly related to the peak blood levels. These pharmacokinetic/ pharmacodynamic parameters make single-dose daily strategies an attractive option when using aminoglycosides.

The nephrotoxicity of aminoglycosides has been very well studied^{280–282,284–293,295,296}and is primarily related to uptake of aminoglycosides through a receptor known as megalin, expressed on epithelial cells along the proximal convoluted tubule.²⁹³ Aminoglycosides are concentrated in the proximal convoluted tubules, where they bind avidly to polyanionic, phospholipid-containing membranes. Aminoglycosides induce myeloid body formation, impair protein synthesis, degrade mitochondrial function, and culminate in apoptosis and eventual necrosis of renal tubular epithelial cells. Direct glomerular injury can occur²⁸⁸ but is usually a secondary consequence of aminoglycoside-induced tubular impairment. As the receptor uptake of aminoglycosides is saturable, highlevel intermittent doses of aminoglycosides actually reduced the daily uptake and accumulation of aminoglycosides when compared to multiple-daily dosing strategies. This should limit the risk of nephrotoxicity, at least in principle.

The potential efficacy of single-dose daily regimens (or other extended dosing treatment programs) of aminoglycosides vs. multiple-daily dosing strategies has been extensively studied in numerous controlled and uncontrolled clinical studies over many years^297-308, and the subject has been the focus of a number of formal meta-analyses.^309-314 These investigations include pediatric populations, elderly populations, empirical therapy, targeted therapy, treatment directed towards Gram-negative bacterial pathogens and Grampositive bacterial pathogens.

The cumulative results of this evidence-based review and numerous meta-analyses indicate that once-daily dosing strategies generally tend to result in less AKI when compared to multiple-dose dosing strategies, although the benefit accrued by the single-daily dose strategy is modest and inconsistent across a number of these studies. For this reason, a level 2 recommendation is suggested in support of the use of single-daily dose strategies over multiple-dose daily strategies. It should be noted that multiple-daily dosing strategies continue to be the standard of care for enterococcal endocarditis; no detailed, randomized trials have been reported comparing single-daily vs. multiple-daily regimens for enterococcal endocarditis.^{272,315–317}

The use of single-daily dosing of aminoglycosides is generally well-tolerated but bolus infusions of aminoglycosides should be avoided. The high-dose, once-daily aminoglycoside regimens should be administered over 60 minutes to avoid untoward events such as neuromuscular blockade. This recommendation is particularly important when patients are receiving other potential neuromuscular blocking agents, or have underlying disorders affecting neuromuscular transmission (e.g., myasthenia gravis).