Gram-negative bacteria display concentration-dependent killing with an optimal Peak/MIC ratio of ~10 or an AUC/MIC of 70-127 mg·h/L per day for gentamicin/tobramycin and AUC 210-380 mg·h/L per day for amikacin. Aminoglycosides are also used for synergistic effects with certain aerobic gram-positive bacteria.
| Bioavailability (F) | Oral absorption is negligible; therefore these agents are given IV |
| Fraction | IV: 1, IM: 1, Intraperitoneal: 0.55, Hypodermoclysis: 1 |
| Salt | 1 |
| Vd (Volume of Distribution) | 0.25 L/kg Ideal Body Weight + (0.4 (Total Body Weight - Ideal body weight) if total body weight is greater than lean body weight. Critical care patients may have an expanded Vd. Aminoglycosides distribute into extracellular fluid. |
| Cl (Clearance) | 1.4 L/kg/hr, which is similar to creatinine clearance with a small amount of non-renal elimination |
| K (Elimination Rate Constant) | 0.0026 × (Creatinine clearance based on IBW) + 0.014 |
| T' (Infusion Period) | 0.5-1 hour |
| Protein Binding | No plasma protein binding |
| Time to Peak | End of infusion, 1.5 hours post IM dose and hypodermoclysis |
| Usual Interval | Traditional dosing: every 8, 12, 16, 24, 36, 48 hours; Pulse dosing/extended interval dosing: every 24, 36, or 48 hours. Usually, 3-4 half-lives lapse from peak to trough for traditional dosing, and > 6 half-lives for pulse dosing. |
| Toxicity | Nephrotoxicity and ototoxicity |
Large infrequent doses are thought to have equal efficacy with decreased nephrotoxicity and ototoxicity. Dosage intervals of ~ 6 half-lives are used to allow serum level to fall to very low levels before the next dose.
As peak levels are increased, lower trough levels are recommended to keep the AUC in the therapeutic range. Trough levels less than 1 mcg/ml have the lowest rates of nephrotoxicity. The percentage increase in the AUC is greater as troughs increase as compared to peaks. Increasing the peak rather than the trough is recommended for efficacy. Efficacy is related to the peak and toxicity is related to the AUC and troughs. Higher peak to MIC ratios are associated with clinical response. Peak/MIC ratio of 6-10/1 are recommended.
Extended spectrum penicillins such as carbenicillin, ticarcillin, and less so with piperacillin, inactivate gentamycin and tobramycin in patients with poor renal function and decrease their half-lives. Serum aminoglycosides levels should be drawn when serum levels of the penicillin are at a minimum, and the levels should be assayed right away or refrigerated.
Dosage calculations and predictions are best when samples are drawn close to steady state, after 3-5 doses for traditional doses. In order to avoid the distribution phase when administering large doses such as pulse doses or once-daily doses in cystic fibrosis patients, peaks should be drawn at least two hours from the start of the dose.
Draw both levels after the same dose. Peak 0.5-1 hours post-dose, Trough before the next dose
Peak 0.5-1 hour post-dose, Trough 0.5 hours before the next dose. Both levels after the same dose. If post-dialysis levels are drawn, wait at least 2 hours post-dialysis, as redistribution occurs after dialysis and levels will be falsely low if drawn too early.
Peak 4 hours post dose, Trough when level is expected to be approximately 2 mcg/ml. Single midpoint level 10-14 hours post-dose to ensure the level is low enough to be within assay range and high enough to differentiate elimination rate curves. Do not draw true troughs as the levels will be very low as elimination lines for different renal function capacities will converge and it will be impossible to determine the correct dosing interval. If a peak level is drawn, at least two hours post-infusion to avoid the distribution phase.
Daily renal function monitoring is suggested. Note if renal function changes, aminoglycoside levels will change quicker than serum creatinine levels as creatinine's Vd is larger and half-life is longer.
One-compartment open model:
Aminoglycosides have been modeled with 1, 2, and 3-compartment models. If the peak is drawn 0.5-1 hours post-dose for traditional dosing and 2 hours post-dose for pulse dosing, a one-compartment model is adequate for pharmacokinetic calculations and dosing.
Calculations are most accurate when two levels are drawn with or without Bayesian methods. When traditional dosing is employed, a peak and trough may be drawn as noted above. When pulse dosing is employed, the time of a peak needs to be further from the administration time, when the level is expected to be in the assay's reportable range, 4 hours post dose, and the trough should be at a time when the level is expected to be 2 mcg/ml or higher. Serum levels should be drawn a minimum of two half-lives apart to ensure accurate calculations.
Aminoglycosides display concentration-dependent killing, time-dependent toxicity, and a prolonged post-antibiotic effect. Peaks of 8-10 times the MIC of the gram-negative pathogens are desired to optimize dose-dependent killing or concentration-dependent killing and to prevent the emergence of resistant pathogens. A dosage interval of approximately 5-6 half-lives is recommended.
A dose of gentamicin/tobramycin 5 mg/kg is recommended for pathogens with a MIC ≤ 1 mcg/ml and will achieve a peak of 15-20 mcg/ml, and a dose of 7 mg/kg is recommended for pathogens with a MIC of approximately 2 mcg/ml and will achieve a peak of 25-30 mcg/ml. A 3 mg/kg pulse dose may be used for lower urinary tract infections.
Gentamicin and tobramycin true troughs less than 0.5 mcg/ml for approximately 4-8 hours are desired to allow for redistribution from tissues and elimination. The initial dosing interval is based on creatinine clearance, then a single level post-dose level is plotted on the graphic to determine if the dosing interval needs to be changed. True troughs should not be measured as the elimination rate curves converge, dosing interval determination cannot be made, and the level may be below the assay range.
Two authors, J Lee 2014 and AW Wallace 2012, reviewed the predicted performance of pulse dosing methods. Both authors found that nomograms performed poorly and recommended serum level monitoring or individualizing dosing methods. Monitor serum levels by obtaining a peak 2 hours post-infusion to avoid the distribution phase and a 10-hour post-dose level to calculate kinetic parameters (elimination rate constant, volume of distribution) to individualize dosing using one-compartment model equations.
Patients with cystic fibrosis have higher clearance rates than patients of similar demographics without CF. Tobramycin is usually prescribed due to lower MICs for pseudomonas aeruginosa which is the usual pathogen. The most common dose for patients over 5-8 years of age is 10 mg/kg per day either as divided doses three times a day or once daily. Some studies have used 15 mg/kg/day as divided doses three times a day or once daily.
The goal peak is 10 times the MIC of the pathogen or AUC/MIC of 70-100.
Peaks 2 hours from the start of the dose are recommended to ensure the prolonged distribution phase is over and allow a one-compartment model to be used for dosing adjustments. Serum levels 2 hours and 10 hours from the start of infusion are used to calculate the elimination rate constant and volume of distribution using the method of Sawchuk and Zaske.
K (1/hours) = ln(Cmax(mcg/ml) / Cmin(mcg/ml)) / Time between levels in hours
Vd (L) = S × F × Dose(mg) × (1 - exp(-K × T')) × exp(-K × Time post-dose) / (Cmax × K × T' × (1 - exp(-K × Tau)))
T' = infusion period in hours
Dosing Weight (kg) = LBWkg + (0.4 × (Total Body Weightkg - LBWkg)) if TBW > LBW
K (1/hours) = 0.0026 × (CrCl) + 0.014
See: Aminoglycoside Creatinine Clearance Versus Half-Life
Tau (hours) = (ln(Cmaxss(mcg/ml) desired) / Cminss(mcg/ml) desired) / K + T'
Vd (L) = 0.25 × Dosing weight (kg)
Loading Dose (mg) = Cp(mg/L)desired × Vd × K × T' / (1 - e(-K × T'))
Maintenance Dose (mg) = Cpmaxss desired × (Vd × K × T' × (1 - e(-K × Tau))) / (S × F × (1 - e(-K × T')))