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Two-point Kinetic Calculations for Traditional or Synergy Dosing with Gentamicin and Tobramycin

Two-point Kinetic Calculations for Traditional or Synergy Dosing with Gentamicin and Tobramycin - Clinical Hub, UW Health Clinical Tool Search, UW Health Clinical Tool Search, Clinical Practice Guidelines, Infection and Isolation, Related


Copyright ©2017 University of Wisconsin Hospitals and Clinics Authority
Contact: CCKM@uwhealth.org Last Revised: 5/2017
Appendix D. Two-point kinetic calculations for traditional or synergy dosing with
gentamicin and tobramycin 30-minute infusions
From: PK/PD Dose Optimization of Antibiotics for the Treatment of Gram-negative Infections – Adult –
Inpatient Clinical Practice Guideline
Last Reviewed 5/2017; Last Updated 5/2017
Contact: Erin McCreary, PharmD, BCPS; emccreary@uwhealth.org or Marie Pietruszka, PharmD,
BCPS; mpietruszka@uwhealth.org
Aminoglycoside Pharmacokinetic and Pharmacodynamic Properties1,2
ξ Hydrophilic (volume of distribution approximates the volume of extracellular fluid)
ξ Rapidly bactericidal and concentration-dependent activity
ξ Post-antibiotic effect (bactericidal activity persists even after serum concentrations fall below minimum
inhibitory concentration)
ξ Trough concentrations above target correlate to toxicities (e.g. ototoxicity, nephrotoxicity)
ξ Factors leading to faster drug clearance (e.g. dehydration, children)
o ↑ 𝐶𝐿 (𝑟𝑒𝑛𝑎𝑙 𝑓𝑢𝑛𝑐𝑡𝑖𝑜𝑛)
𝑦𝑖𝑒𝑙𝑑𝑠
→ ↑ 𝑘𝑒
o ↓ 𝑉𝑑 (𝑓𝑙𝑢𝑖𝑑 𝑣𝑜𝑙𝑢𝑚𝑒)
𝑦𝑖𝑒𝑙𝑑𝑠
→ ↑ 𝑘𝑒
ξ Factors leading to slower drug clearance (e.g. edema, ascites, sepsis, obesity)
o ↓ 𝐶𝐿
𝑦𝑖𝑒𝑙𝑑𝑠
→ ↓ 𝑘𝑒
o ↑ 𝑉𝑑
𝑦𝑖𝑒𝑙𝑑𝑠
→ ↓ 𝑘𝑒
Definitions for calculations (note: all times are in hours)
𝑡 = 𝑖𝑛𝑓𝑢𝑠𝑖𝑜𝑛 𝑡𝑖𝑚𝑒
𝑡1 = 𝑡𝑖𝑚𝑒 𝑓𝑟𝑜𝑚 𝐶1 (𝑡𝑟𝑜𝑢𝑔ℎ) 𝑡𝑜 𝑠𝑡𝑎𝑟𝑡 𝑜𝑓 𝑖𝑛𝑓𝑢𝑠𝑖𝑜𝑛
𝑡2 = 𝑡𝑖𝑚𝑒 𝑓𝑟𝑜𝑚 𝑒𝑛𝑑 𝑜𝑓 𝑖𝑛𝑓𝑢𝑠𝑖𝑜𝑛 𝑡𝑜 𝐶2 (𝑝𝑒𝑎𝑘)
𝜏 = 𝑑𝑜𝑠𝑖𝑛𝑔 𝑖𝑛𝑡𝑒𝑟𝑣𝑎𝑙
𝑇′ = (𝜏 − [𝑡 + 𝑡1 + 𝑡2])
𝐶1 = 𝑚𝑒𝑎𝑠𝑢𝑟𝑒𝑑 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 30 𝑚𝑖𝑛𝑢𝑡𝑒𝑠 𝒑𝒓𝒊𝒐𝒓 𝑡𝑜 𝑡ℎ𝑒 𝑑𝑜𝑠𝑒 (𝑙𝑎𝑏 𝑟𝑒𝑝𝑜𝑟𝑡𝑒𝑑 𝑣𝑎𝑙𝑢𝑒); 𝑟𝑒𝑝𝑟𝑒𝑠𝑒𝑛𝑡𝑠 𝑡𝑟𝑜𝑢𝑔ℎ
𝐶2 = 𝑚𝑒𝑎𝑠𝑢𝑟𝑒𝑑 c𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 30 𝑚𝑖𝑛𝑢𝑡𝑒𝑠 𝒂𝒇𝒕𝒆𝒓 𝑒𝑛𝑑 𝑜𝑓 𝑖𝑛𝑓𝑢𝑠𝑖𝑜𝑛(𝑙𝑎𝑏 𝑟𝑒𝑝𝑜𝑟𝑡𝑒𝑑 𝑣𝑎𝑙𝑢𝑒); 𝑟𝑒𝑝𝑟𝑒𝑠𝑒𝑛𝑡𝑠 𝑝𝑒𝑎𝑘
𝐶𝑚𝑎𝑥 = 𝑐𝑎𝑙𝑐𝑢𝑙𝑎𝑡𝑒𝑑 𝑝𝑒𝑎𝑘 (𝑡𝑟𝑢𝑒 𝑝𝑒𝑎𝑘); 𝑝ℎ𝑎𝑟𝑚𝑎𝑐𝑜𝑘𝑖𝑛𝑒𝑡𝑖𝑐 𝑡𝑎𝑟𝑔𝑒𝑡 𝑎𝑡 𝑠𝑡𝑒𝑎𝑑𝑦 𝑠𝑡𝑎𝑡𝑒
𝐶𝑚𝑖𝑛 = 𝑐𝑎𝑙𝑐𝑢𝑙𝑎𝑡𝑒𝑑 𝑡𝑟𝑜𝑢𝑔ℎ (𝑡𝑟𝑢𝑒 𝑡𝑟𝑜𝑢𝑔ℎ); 𝑝ℎ𝑎𝑟𝑚𝑎𝑐𝑜𝑘𝑖𝑛𝑒𝑡𝑖𝑐 𝑡𝑎𝑟𝑔𝑒𝑡 𝑎𝑡 𝑠𝑡𝑒𝑎𝑑𝑦 𝑠𝑡𝑎𝑡𝑒
𝐾𝑒 = 𝑒𝑙𝑖𝑚𝑖𝑛𝑎𝑡𝑖𝑜𝑛 𝑟𝑎𝑡𝑒 𝑐𝑜𝑛𝑠𝑡𝑎𝑛𝑡 (ℎ𝑟-1)
𝑉𝑑 = 𝑣𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝑑𝑖𝑠𝑡𝑟𝑖𝑏𝑢𝑡𝑖𝑜𝑛 (𝑟𝑒𝑝𝑜𝑟𝑡𝑒𝑑 𝑖𝑛 𝐿 𝑜𝑟 𝐿/𝑘𝑔)
Copyright © 2017 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 05/2017CCKM@uwhealth.org

Copyright ©2017 University of Wisconsin Hospitals and Clinics Authority
Contact: CCKM@uwhealth.org Last Revised: 5/2017
Selecting an appropriate initial gentamicin or tobramycin dosing regimen (to be infused over 30
minutes) based on desired PK target regimen (traditional dosing)1,2
1. Choose an appropriate dosing weight
a. Use ideal body weight unless total body weight is below ideal body weight, then use total body
weight.
b. If total body weight is greater than 20% in excess of ideal body weight, use adjusted body weight.
2. Calculate patient specific CrCl (in mL/min) using appropriate equation
3. Estimate 𝑘𝑒
𝑘𝑒 = [(
0.00293
ℎ𝑟
) × 𝐶𝑟𝐶𝑙] + 0.014
4. Estimate 𝑡½
𝑡½ = (
0.693
𝑘𝑒
)
5. Estimate 𝑉𝑑 using dosing weight established in Step 1
𝑉𝑑 (𝑑𝑒ℎ𝑦𝑑𝑟𝑎𝑡𝑖𝑜𝑛) = 0.20𝐿/𝑘𝑔
𝑉𝑑 (𝑛𝑜𝑟𝑚𝑎𝑙 𝑎𝑛𝑑 𝑜𝑏𝑒𝑠𝑖𝑡𝑦) = 0.26𝐿/𝑘𝑔
𝑉𝑑(𝑒𝑑𝑒𝑚𝑎, 𝑎𝑠𝑐𝑖𝑡𝑒𝑠, 𝐶𝐻𝐹 𝑒𝑥𝑐𝑒𝑟𝑏𝑎𝑡𝑖𝑜𝑛)~0.35 𝐿/𝑘𝑔
** NOTE: If both fluid overloaded and obese, use 0.26L/kg to avoid overestimating Vd
6. Calculate initial dosing interval 𝜏
𝜏 = [
ln (𝐶max𝑑𝑒𝑠𝑖𝑟𝑒𝑑 𝐶min𝑑𝑒𝑠𝑖𝑟𝑒𝑑⁄ )
𝑘𝑒
] + 𝑡
** NOTE: If patient is HD-dependent, administer dose after each dialysis session. Round dosing interval to
nearest 8, 12, 18, 24, 36, or 48 hours.
See guideline for target Cmax (peak) and Cmin (trough) based on infection site
7. Calculate initial loading dose (based on desired Cmax, which is the PK peak target) and subsequent
maintenance dose required to maintain desired target peak concentration
𝐿𝑜𝑎𝑑𝑖𝑛𝑔 𝐷𝑜𝑠𝑒 (𝑚𝑔) = [(𝐶𝑚𝑎𝑥) × (𝑉𝑑)]  Use only for life-threatening infections
𝑀𝑎𝑖𝑛𝑡𝑒𝑛𝑎𝑛𝑐𝑒 𝐷𝑜𝑠𝑒 (𝑚𝑔) = [(𝐶𝑚𝑎𝑥) × (𝑉𝑑)] × (1 − 𝑒−𝑘𝜏)
** NOTE: Consider aiming for the lower end of the PK range (Cmax) for initial dose estimation for patients with
BMI > 30 kg/m2 to avoid overestimating the dose required for this population. For example, aim for a peak of 8
mcg/mL for pneumonia instead of 10 mcg/mL.
8. Round calculated maintenance dose to nearest 10 mg or available stock bag dose, then recalculate
the estimated Cmax based on rounded dose
estimated 𝐶𝑚𝑎𝑥 = 𝐶max𝑑𝑒𝑠𝑖𝑟𝑒𝑑 × [
rounded dose
calculated dose
]
9. Estimate Cmin (trough) as a safety check
estimated 𝐶𝑚𝑖𝑛 = estimated 𝐶𝑚𝑎𝑥 × (𝑒−𝑘(T))
T = estimated time between peak and trough (e.g. plug in 7 hours if the patient has an 8-hour dosing interval)
Copyright © 2017 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 05/2017CCKM@uwhealth.org

Copyright ©2017 University of Wisconsin Hospitals and Clinics Authority
Contact: CCKM@uwhealth.org Last Revised: 5/2017
Evaluating gentamicin and tobramycin steady state concentrations and making recommendations
for dose adjustments (traditional or synergy dosing)1,2
1. Verify administration time, duration of infusion (should be 30 minutes) and sampling time
2. Calculate patient-specific 𝑘𝑒
𝑘𝑒 =
𝑙𝑛 (𝐶2 𝐶1
⁄ )
T′
3. Calculate patient specific 𝑡½ (using patient-specific 𝑘𝑒)
𝑡½ = (
0.693
𝑘𝑒
)
4. Calculate 𝐶𝑚𝑎𝑥 & 𝐶𝑚𝑖𝑛 (using patient-specific 𝑘𝑒)
𝐶𝑚𝑎𝑥 = (𝐶2) × (𝑒𝑘𝑡2) 𝐶𝑚𝑖𝑛 = (𝐶1) × (𝑒−𝑘𝑡1)
5. Calculate patient-specific 𝑉𝑑 (using patient-specific 𝑘𝑒)
𝑉𝑑 =
(𝐷𝑜𝑠𝑒/𝑡) × (1 − 𝑒−𝑘𝑡)
[(𝐶𝑚𝑎𝑥 − (𝐶𝑚𝑖𝑛𝑒−𝑘𝑡)] × (𝑘𝑒)
6. Calculate new patient-specific dosing interval 𝜏 (using patient specific 𝑘𝑒)
𝜏 = [
ln (𝐶max𝑑𝑒𝑠𝑖𝑟𝑒𝑑 𝐶min𝑑𝑒𝑠𝑖𝑟𝑒𝑑⁄ )
𝑘𝑒
] + 𝑡 + 𝑡2
**Note: Round dosing interval to nearest 8, 12, 18, 24, 36, or 48 hours.
7. Calculate new dose (using patient-specific 𝑘𝑒 𝑎𝑛𝑑 𝑉𝑑)
𝐷𝑜𝑠𝑒 = 𝐶𝑚𝑎𝑥(𝑑𝑒𝑠𝑖𝑟𝑒𝑑) × 𝑉𝑑(1 − 𝑒−𝑘𝜏)
8. Dose check : Use calculated dose, patient specific Vd, patient specific ke and calculated dosing
interval to verify expected 𝐶𝑚𝑎𝑥 (estimated peak) and 𝐶𝑚𝑖𝑛 (estimated trough) with the new dosing
regimen
𝐶𝑚𝑎𝑥 = (
𝐷𝑜𝑠𝑒
𝑉𝑑
) × (1 − 𝑒−𝑘𝜏) 𝐶𝑚𝑖𝑛 =
(
𝐷𝑜𝑠𝑒
𝑉𝑑
) × (𝑒−𝑘𝜏)
(1 − 𝑒−𝑘𝜏)
Copyright © 2017 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 05/2017CCKM@uwhealth.org

Copyright ©2017 University of Wisconsin Hospitals and Clinics Authority
Contact: CCKM@uwhealth.org Last Revised: 5/2017
Graphical representations of steady-state aminoglycoside dosing regimens with
adjustments
Copyright © 2017 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 05/2017CCKM@uwhealth.org

Copyright ©2017 University of Wisconsin Hospitals and Clinics Authority
Contact: CCKM@uwhealth.org Last Revised: 5/2017
Copyright © 2017 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 05/2017CCKM@uwhealth.org

Copyright ©2017 University of Wisconsin Hospitals and Clinics Authority
Contact: CCKM@uwhealth.org Last Revised: 5/2017
References:
1. Bauer, Larry A. The Aminoglycoside Antibiotics In: Weitz M, Pancotti R eds. Applied Clinical
Pharmacokinetics. 2nd ed. New York McGraw Hill; 2008:97-115.
2. MacDougall C, Chambers HF. Aminoglycosides In: Brunton L, Chabner B, Knollamn B eds.
Goodmans and Gillman's The Pharmacological Basis of Therapeutics. 12th ed. New York
McGraw Hill;2011:1507-1512.
Copyright © 2017 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 05/2017CCKM@uwhealth.org