# Aminoglycoside Calculator

### Drug Parameters

 Aminoglycoside Gentamicin Tobramycin Amikacin Dosing Method Extended Conventional Goal peak Goal trough

### Patient Parameters

 Age years Height in cm Weight kg lbs Gender Male Female Creatinine mg/dL µmol/L

### Dose by Level

Press 'Calculate' to view calculation results.

This aminoglycoside calculator uses a variety of published pharmacokinetic equations and principles to estimate an appropriate aminoglycoside regimen. This regimen can be completely empiric, where the dose is based on body weight, height, and creatinine clearance, or a regimen may be calculated based on one or more drug levels.

This calculator was specifically designed to help students and clinicians understand the process of calculating an aminoglycoside regimen. When a regimen is calculated, each step in the dosing process is fully enumerated and visible by clicking the "Equations" tab.

After calculating a dose, click on 'Progress Note' for a pharmacokinetic template or 'Equations' for a step-by-step explanation of the recommended dosing regimen.

#### Population Estimate of Kel

Because aminoglycosides are primarily renally eliminated, the elimination constant (Kel) is directly related to the creatinine clearance:1

$$\\ K_{el} = 0.00293*(CrCl\;in\;mL\min) + 0.014 \\ K_{el}\;(simplified) = 0.003*(CrCl\;in\;mL\min) + 0.01$$

This calculator uses the above equation to estimate aminoglycoside clearance. The second (simplified) equation may be used at the bedside, which contains coefficients that are easier to memorize. It is important to note that this method relies on an accurate creatinine clearance; therefore, this method may not be appropriate in patients with unstable renal function or those with difficult-to-estimate creatinine clearance.

#### Actual, Ideal, and Adjusted Body Weight

Aminoglycosides weight-based dosing should be based on ideal or adjusted body weight. The following criteria are used by this calculator to determine an aminoglycoside dosing weight:

• In underweight patients (less than ideal body weight), actual weight is used.
• In normal-weight patients (100-120% ideal weight), ideal body weight is used:2
$$\\Ideal\;BW\;(men)\; = 50 + 2.3*(height\;over\;60\;inches) \\Ideal\;BW\;(women)\; = 45.5 + 2.3*(height\;over\;60\;inches)$$
• In overweight patients (>120% ideal weight), a 40% adjustment factor is used:3
$$\\AdjustedBW\; = IdealBW + (0.4*(ActualBW - IdealBW))$$

#### Inappropriate Populations for Extended-Interval Dosing

Extended-interval dosing may not be appropriate in certain patient populations that have significantly altered pharmacokinetic parameters or in patients with disease states where very high peak levels are not appropriate. These populations include:

• Pediatrics
• Creatinine clearance < 20 mL/min
• Dialysis (peritoneal or hemodialysis)
• Cystic fibrosis
• Burn > 20% BSA
• Significant ascites
• Pregnancy
• Gram positive synergy (Enterococcal endocarditis)

#### Extended-Interval Nomograms

This calculator uses four extended-interval nomograms. You may select a specific nomogram by clicking the "Config" icon in the top, right-hand corner of this webpage.

#### Hartford Nomogram (1995)3

The Hartford nomogram was one of the first published extended-interval nomograms. Unlike other nomograms, it uses the highest dose of gentamicin/tobramycin (7 mg/kg versus 5 mg/kg), which achieves a 40% higher peak. Although this higher dose has not been shown to improve clinical outcomes, it may be beneficial for institutions with higher average MICs to gentamicin or tobramycin.

#### Barnes-Jewish4

Although the Barnes-Jewish nomogram has not been formally published, it is commonly used as an extended-interval nomogram. The nomogram is no longer available as a webpage via the Barnes-Jewish Hospital (St. Louis, MO), but it is available as an appendix in a meta-analysis that was published from the same institution.4

#### Rochester (1997)5

The Rochester nomogram is slightly more conservative than other nomograms in that it suggests excluding patients with a creatinine clearance less than 30 mL/min (rather than 20 mL/min) and de-emphasizes the use of Q48h dosing in favor of verifying that a pre-dose trough level is < 1 mcg/mL. Furthermore, this nomogram uses the highest dose of amikacin (20 mg/kg versus 15 mg/kg), which achieves a 33% higher amikacin peak.

#### Urban-Craig (1997)6

The Urban-Craig nomogram was developed with an option for Q12h dosing, which is especially useful in younger patients with high aminoglycoside clearance who may have an inappropriately long interval of subtherapeutic drug levels. With the addition of the Q12h interval, the nomogram should be designed to maintain at least 4 hours of drug level below 1 mcg/mL (gentamicin/tobramycin) with a maximal post-antibiotic effect of 16 hours.

#### Relative Potency of Amikacin to Gentamicin/Tobramycin

There is a significant discrepancy in the literature regarding the relative potency between amikacin and gentamicin/tobramycin. Consider the following:

• Most extended-interval nomograms are developed for gentamicin/tobramycin and are "converted" to an equivalent amikacin serum drug level. The Hartford nomogram3 uses a relative potency of 2:1 (amikacin:gentamicin/tobramycin), but the Barnes-Jewish4, Rochester5, and Urban-Craig 6 nomograms use a ratio of 3:1.
• Although the Barnes-Jewish4, Rochester5, and Urban-Craig6 nomograms use the same gentamicin/tobramycin dose (5 mg/kg), they have discrepant amikacin doses (15 mg/kg or 20 mg/kg) even though they all use the same 3:1 ratio for converting an amikacin concentration to "fit" onto the gentamicin/tobramycin nomograms.
• The CLSI-accepted MIC susceptibility cut-off of most gram negative organisms to gentamicin and tobramycin is 2 mcg/mL, whereas the susceptibility cut-off for amikacin to the same organisms is generally 8 mcg/mL (a 4:1 ratio).
• The original literature involving amikacin (then named BB-K8) showed that the relative potency of amikacin to gentamicin was between 2.5:1 and 4:1 depending on the isolated organism.7
• There is no clear standard conversion between the potency of amikacin and gentamicin/tobramycin. Given the CLSI breakpoint is a 4:1 ratio, this calculator uses a conversion of 4:1 for the purposes of converting serum drug levels between gentamicin/tobramycin and amikacin unless otherwise specified by and extended-interval nomogram.

#### Proposed Benefits of Extended-Interval Dosing

There are a number of proposed benefits to extended-interval dosing compared to conventional dosing:5,6

• Aminoglycosides are concentration-dependent antibiotics -- the more drug given, the higher the bacterial kill rates. Because extended-interval dosing guarantees a very high peak:MIC ratio, efficacy may be improved.
• Bacteria exposed to high levels of aminoglycosides without intervals of low drug concentrations develop adaptive post-exposure resistance, which results in less bacterial uptake of the aminoglycoside molecule. Less frequent dosing with longer periods of low or drug-free intervals may reduce the incidence or extent of adaptive post-exposure resistance.
• Aminoglycoside exhibit a post-antibiotic effect (PAE) in which bacterial growth is inhibited even though drug levels have dropped below the organism's MIC. The PAE is highly dependent on the height of the aminoglycoside peak. In patients who are not neutropenic who have very high aminoglycoside peaks, the PAE can last as long as 8-15 hours. By taking advantage of a longer PAE, extended-interval dosing may provide reduced toxicity without compromising efficacy by having lower or undetectable trough levels.
• Aminoglycosides are both nephrotoxic and ototoxic (vestibular and auditory). Uptake of aminoglycosides into renal and vestibular cells is saturated at a low concentration, meaning that very high peaks (extended-interval dosing) are not likely to cause more toxicity than traditional peak levels (conventional dosing).

#### Clinical Evidence of Conventional vs. Extended-Interval Dosing

There have been numerous clinical trials published attempting to determine whether extended-interval dosing is superior in efficacy or safety to conventional dosing. A recent meta-analysis of 9 meta-analyses, including 30+ clinical trials, concluded that extended-interval dosing may be slightly superior in efficacy (5 of 9 meta-analyses), equally nephrotoxic (6 of 9 meta-analyses), and equally ototoxic (9 of 9 meta-analyses).8

Given the controversial and conflicting data, the significant heterogeneity of the primary literature, and the variety of different definitions for efficacy, nephrotoxicity, and ototoxicity, it is difficult to form an informed, definite conclusion regarding the benefit of extended-interval dosing versus conventional dosing. Regardless, a conservative conclusion is that extended-interval dosing is at least as beneficial and safe, if not better, than conventional dosing. Furthermore, extended-interval dosing provides for simpler mathematical calculations and reduced need for drug levels, which may reduce the risk of medication errors.

1. Bauer LA. Chapter 4. The Aminoglycoside Antibiotics. In: Bauer LA, ed. Applied Clinical Pharmacokinetics. 2nd ed. New York: McGraw-Hill; 2008.
2. Devine BJ. Gentamicin therapy. Drug Intell Clin Pharm. 1974;8:650–655.
3. Nicolau DP, Freeman CD, Belliveau PP, et al. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother. 1995;39(3):650-5. PMID 7793867.
4. Bailey TC, Little JR, Littenberg B, et al. A meta-analysis of extended-interval dosing versus multiple daily dosing of aminoglycosides. Clin Infect Dis. 1997;24(5):786-95. PMID 9142771.
5. Anaizi N. Once-daily dosing of aminoglycosides. A consensus document. Int J Clin Pharmacol Ther. 1997;35(6):223-6. PMID 9208335.
6. Urban AW, Craig WA. Daily dosage of aminoglycosides. Curr Clin Top Infect Dis. 1997;17:236-55. PMID 9189668.
7. Yu PK, Washington JA. Comparative in vitro activity of three aminoglycosidic antibiotics: BB-K8, kanamycin, and gentamicin. Antimicrob Agents Chemother. 1973;4(2):133-9. PMID 4208506.
8. Barclay ML, Kirkpatrick CM, Begg EJ. Once daily aminoglycoside therapy. Is it less toxic than multiple daily doses and how should it be monitored? Clin Pharmacokinet. 1999;36(2):89-98. PMID 10092956.