This calculator may be used to calculate aminoglycoside (using either once-daily and conventional dosing strategies) dosing. The calculations utilized to arrive at these dosages as well as the rationale for each dosing strategy are described below.
The theoretical benefits of high-dose, extended-interval dosing are to:
The rationale for high-dose extended-interval dosing of aminoglycosides is rooted in the following observations:
Concentration-Dependent Killing: The bactericidal action of aminoglycosides is concentration dependent, i.e., the higher the peak/MIC ratio the higher the kill rate. The conventional dosing regimen usually results in relatively low peak/MIC ratios (<5), while the same total daily dose given as a single bolus results in much higher ratios (>10).
Nephrotoxicity: Aminoglycoside uptake into renal tubule cells and the inner ear appears to be saturated at relatively low serum levels, suggesting that higher peaks do not necessarily result in a greater risk of toxicity. Also, serum troughs that are at or near zero may promote tissue drug disposition, shorten tissue exposure, and promote recovery. In addition to the well-known risk factors (age, volume depletion, liver disease, co-administration of certain drugs, etc.), duration of exposure to the aminoglycoside appears to be a more important determinant of toxicity than the serum aminoglycoside level. Although definitive evidence is still lacking, animal and human studies strongly suggest that once-daily dosing is less nephrotoxic.
PAE: Aminoglycosides exhibit a significant PAE against aerobic gram- negative bacteria. The PAE refers to the continued suppression of bacterial growth despite the decline of the antimicrobial concentration to zero. The duration of this effect (2 - 8 hours) depends on several factors, chief among them the height of the preceding aminoglycoside peak. The PAE phenomenon suggests that the aminoglycoside serum level may be allowed to fall below the MIC of the pathogen without compromising antimicrobial efficacy.
Adaptive Resistance: In vitro studies indicate that more frequent dosing of aminoglycosides tends to reduce their uptake into the bacterial cell of aerobic GNB. This phenomenon ("adaptive post-exposure resistance") is observed as an apparent increase in the MIC90 (i.e., reduced efficacy). Longer dosing intervals appear to shorten the time required for the MIC to revert to its original value. These observations may have significant clinical implications. The persistent low-level exposure of the target organism, as occurs with multiple daily dosing, may markedly reduce the antimicrobial activity of aminoglycosides.
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