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**Pulse Dosing also known as Extended Interval Dosing or Once-daily Dosing Overview: **

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 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. Gentamicin and tobramycin true troughs less than 0.5 mcg/ml for approximately 4-8 hours are desired to allow for redistribute 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 (below) 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 can not 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 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 a one-compartment model equations. When a one-compartment model is used the calculated/extrapolated peak will be lower than the true peak immediately post-infusion, the Vd calculated will be higher, and the AUC calculated will also be lower than the true AUC when the medication follows a two-compartment model. When making dosing adjustments keep in mind that the true peak will be higher, dosage interval calculated will be longer than needed if the true peak is used rather than the extrapolated peak in the calculations. A peak level, immediately post-infusion, during the distribution phase, would be useful to see if the goal peak is being achieved. Any changes in dose will produce proportional changes in the post-infusion peak. Dosage interval adjustments may be based on K calculated and the extrapolated peak from the original dose.

**Hartford Nomogram commentary:**
The nomogram was designed to cover pseudomonas aeruginosa (median gentamicin MIC
2 mcg/ml) which is not a common pathogen. The linear dosing nomogram was
developed from a very small set of 20 patients' data. The mean volume of
distribution was 0.39 l/kg which is large compared to approximately 0.25-0.27
l/kg in most references and other studies. This would cause an under-prediction
of serum levels. Using a linear regression analysis of non-linear data is less
than optimal and creates additional errors in the model allowing a shorter dosing interval to be
selected than an exponential decay curve would suggest. Dosing patients with a creatinine clearance
of less than 30 ml/min will most likely result in high trough
levels.

**Cystic Fibrosis(CF):**

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. Target levels for pulse dosing 20-30 mcg/ml and trough levels less than 1 mcg/ml. Target levels for three times a day dosing is 10-12 mcg/ml and trough less than 2 mcg/ml. The infusion period for pulse dosing is 60 minutes and 0.5 hours for three times a day dosing. Peaks 2 hours from the start of the dose are recommended to ensure the prolonged distribution phase is over and allow a once-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((-KT')*exp(-K*Time post-dose) / (Cmax*K*T'*(1-exp(-K*Tau)))

**Aminoglycoside Dosing Tools**

Excel
Aminoglycoside Bayesian Dosing Calculator, open compartment open model, for steady
state or Non-Steady State dosing using the method of superposition. The tool
creates a data file of data fittings that may be used to perform Medication
Usage Evaluations and parameter optimization. The Solver Add-in must be available for
the file to run. In Excel do the following: Click File, Click Options, Click Add-ins, Manage Excel Add-in
Click Go, Check Solver Add-in, and select OK.

Excel Program Instructions

Aminoglycosides Once-daily Dosing: Pharmacy
& Therapeutics
Review

Amikacin Once-daily Dosing
15 mg/kg Graphic Tool

Gentamicin & Tobramycin Once-daily Dosing 3 mg/kg Graphic Tool

Gentamicin &
Tobramycin Once-daily Dosing
5 mg/kg Graphic Tool

Gentamicin & Tobramycin Once-daily Dosing 7 mg/kg Graphic Tool

Aminoglycoside*
O nce-daily*

Aminoglycoside

**Aminoglycoside Pharmacokinetic Dosing Information****Spectrum of activity:** Gram-negative bacteria
display concentration-dependent killing with an optimal Peak/MIC ratio of ~10 or
an AUC/MIC of 80-120 per day. Aminoglycosides are also used for synergistic effect with certain gram-positive bacteria

**Bioavailability (F):**
Oral absorption is negligible, therefore
these agents are given IV

Fraction IV: 1, IM: 1

**Salt: **1

**Vd: **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.

**Cl: **1.4 L/kg/hr, which is similar to creatinine clearance with a
small amount of non-renal elimination

**K:** 0.0026*(Creatinine clearance based on IBW) + 0.014

**T':** 0.5-1 hour**Usual Interval: **Traditional dosing: every
8,12, 16, 24, 36, 48 hours; Pulse dosing/extended interval dosing: every 24, 36, or 48 hours

**Usual Dose:**

**Traditional Dosing:**

*Gentamicin/Tobramycin:*

Load: 2 mg/kg, Maintenance:1-1.5 mg/kg

*Amikacin:*

Load: 7.5 mg/kg, Maintenance: 5 mg/kg

**Pulse Dosing:**

Large infrequent doses are thought to have equal efficacy and decrease toxicity.

*Gentamicin/Tobramycin:*

Maintenance: 5 mg/kg for pathogens with MIC <= 1-2 mcg/ml, 7 mg/kg for
pathogens with MIC of up to 2 mcg/ml.

*Amikacin:*

Maintenance: 15 mg/kg**Hemodialysis Dosing:***Gentamicin/tobramycin:*
Loading dosing: 2 mg/kg, Maintenance Dose: 1-1.5 mg/kg post dialysis depending on
the severity of infection. Mild UTI: Re-dose when the pre-hemodialysis trough is less than 1 mcg/ml,
moderate to severe UTI re-dose when the trough < 1.5-2 mcg/ml, for systemic gram-negative infections, 1.5-2 mg/kg and re-dose when
the pre-hemodialysis trough is less than 3-5 mcg/ml.

*Amikacin:*
Loading dose 5-7.5 mg/kg, Maintenance Dose: 3-5 mg/kg depending on
the severity of infection. Mild UTI: Re-dose when the pre-hemodialysis trough is less than
3 mcg/ml, moderate to severe UTI re-dose when the trough < 5 mcg/ml, for systemic gram-negative infections 5 mg/kg and re-dose when pre-hemodialysis trough is less than
10 mcg/ml re-dose.

**Therapeutic Levels**

*Gentamicin/tobramycin:*

Traditional dosing: systemic infection: peak 6-10 mcg/ml,
Trough: < 1.5 mcg/ml; UTI peak 4-6 mcg/ml, trough less than 1 mcg/ml

Hemodialysis: Mild UTI: Re-dose when
the pre-hemodialysis trough is less than 1 mcg/ml,
moderate to severe UTI re-dose when trough < 1.5-2 mcg/ml, for systemic gram-negative infections, re-dose when
the pre-hemodialysis trough is less than 3-5 mcg/ml.

Pulse dosing: peak ~ 20 mcg/ml, trough less than 0.5 mcg/ml

*Amikacin:*

Traditional dosing: systemic infection: peak 20-30 mcg/ml,
Trough < 5 mcg/ml; UTI peak 15 mcg/ml; trough less than 5 mcg/ml

Pulse dosing: peak ~ 60 mcg/ml, trough less than 0.9 mcg/ml

**Serum Sampling Times: **

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.

Traditional dosing:

Draw both levels after the same dose. Peak 0.5-1 hour post-dose, Trough before the next dose

Hemodialysis: 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.

Pulse Dosing: Draw 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.

**Pharmacokinetic Model: one-compartment open: **

Aminoglycosides have been modeled with 1, 2, and 3-compartment models. If the
peak is drawn 0.5-1 hour post-dose for traditional dosing and 2 hours post-dose
for pulse dosing, a one-compartment model is adequate
for pharmacokinetic calculations and dosing.

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 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. Gentamicin and tobramycin true troughs less than 0.5 mcg/ml for approximately 4-8 hours are desired to allow for redistribute 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 (below) 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 can not 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 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 a one-compartment model equations. When a one-compartment model is used the calculated/extrapolated peak will be lower than the true peak immediately post-infusion, the Vd calculated will be higher, and the AUC calculated will also be lower than the true AUC when the medication follows a two-compartment model. When making dosing adjustments keep in mind that the true peak will be higher, dosage interval calculated will be longer than needed if the true peak is used rather than the extrapolated peak in the calculations. A peak level, immediately post-infusion, during the distribution phase, would be useful to see if the goal peak is being achieved. Any changes in dose will produce proportional changes in the post-infusion peak. Dosage interval adjustments may be based on K calculated and the extrapolated peak from the original dose.

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. Target levels for pulse dosing 20-30 mcg/ml and trough levels less than 1 mcg/ml. Target levels for three times a day dosing is 10-12 mcg/ml and trough less than 2 mcg/ml. The infusion period for pulse dosing is 60 minutes and 0.5 hours for three times a day dosing. Peaks 2 hours from the start of the dose are recommended to ensure the prolonged distribution phase is over and allow a once-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

Vd

**Dosage Calculations: **

**Lean Body Weight: **

LBW_{(kg)}
Adult Males (18 years and older) in kg: 50 kg + 2.3*(Height in inches-60)

LBW_{(kg)} Adult Female (18 years and older): 45.5 + 2.3*(Height in
inches-60)

Dosing Weight_{(kg)} = LBW_{kg }+ (0.4
(Total Body Weight_{kg} - LBW_{kg}) if TBW > LBW)

**Creatinine Clearance: **

Adult
Males: Creatinine Clearance _{(mL/min)}= (140-age_{(years)})*LBW /(serum creatinine_{(mg/dl)}*72)

Adult
Females: Creatinine Clearance _{(mL/min)} = 0.85 *( (140-age_{(years)})*LBW /(serum creatinine_{(mg/dl)}*72))

**K**_{(1/hours)}=:** **0.0026(Crcl)+0.014,
Aminoglycoside Creatinine Clearance Versus Half-Life

**Tau**_{(hours)} = ((ln(Cmaxxss_{(mcg/ml)} desired)/Cminss_{(mcg/ml)} desired))/K) + T'

**Vd**_{(L)} = 0.25*Dosing weight_{(kg)}

**Loading Dose _{(mg)}** = Cp

**Pulse Dosing (also known as larger dose extended
interval)**

**Dialysis Dosing**

Elimination occurs during and between dialysis. Bolus
dosing equations may be applied because little drug elimination occurs during
the medication infusion. Clearance in units of L/hr is recommended as clearance
is not weight-related. Use L/hr
and Vd in liters in the equations below to calculate K and individualize dosing. The graphics below,
of post-dialysis dosing or doses at the end of dialysis, demonstrate that using a set dose in mg/kg achieves dissimilar levels and
that the dose should be individually calculated using clearance and Vd. Larger
patients need lower doses in mg/kg to obtain similar trough levels to
smaller patients. Standard or fixed doses have similar pre-dialysis troughs but
have varying peaks. Dosing before dialysis allows for high peaks and troughs
that are lower.

Cpmaxss = S*F*D/(Vd*(1-e^{(-((Krenal*Tau)+(Kdialysis*Tdialysis))})),
assuming dialysis every Tau

Cpminsspredialysis = Cpmaxss*e^{(-Krenal*(Tau-Tdialysis))}
, assume trough drawn just before dialysis and dialysis is at end of dosage
interval.

As dialysis is usually 3 days a week the method of superposition would give a more accurate
representation of levels.

Cpmax after Dose1-3 = S*F*D/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3))})),
each dose administered once weekly, with 3 dialysis sessions.

The highest level of the week is after the
dose on the last dialysis day of M/W/F or T/Th/S series.
The highest trough is before the third dialysis in the series. The lowest tough is
before the first dialysis in the series.

Highest Peak
in the series. Dose1 is Monday or Tuesday depending on series.

Cmax1
=D1/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))e^{(-(Krenal*24*4+Kdialysis*Tdialysis*2))
}

Cmax2 =D2/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))e^{(-(Krenal*24*2+Kdialysis*Tdialysis*1))}

Cmax3 =D3/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))

*Highest Cmaxss* in series =
Cmax1+Cmax2+Cmax3*Lowest Trough* in series is just before first
dialysis is the series = *Highest Cmaxss in series**e^{(-(Krenal*(3*24)-Tdialysis))}

The lowest trough and peak are just before and after the
dose in the first dialysis in
M/W/F or T/Th/S
series.

Lowest Peak in the series. Dose1
is Wednesday or Thursday in the series.

Cmax1 =D1/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))e^{(-(Krenal*24*5+Kdialysis*Tdialysis*2))}

Cmax2 =D2/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))e^{(-(Krenal*24*3+Kdialysis*Tdialysis*1))}

Cmax3 =D3/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))

*Lowest
Cmaxss in series* = Cmax1+Cmax2+Cmax3

The highest trough is just
before the third dialysis in
M/W/F or T/Th/S
series.

Highest trough in the series.
Dose1 is Friday or Saturday in the series.

Cmax1 =D1/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))e^{(-(Krenal*24*5+Kdialysis*Tdialysis*2))}

Cmax2 =D2/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))e^{(-(Krenal*24*2+Kdialysis*Tdialysis*1))}

Cmax3 =D3/(Vd*(1-e^{(-((Krenal*7*24)+(Kdialysis*Tdialysis*3)))}))

*Cmaxss after middle dose in series* = Cmax1+Cmax2+Cmax3 *Highest trough
in series* = Cmax after middle dose *e^{(-(Krenal*(2*24)-Tdialysis))}

**Serum sampling for dialysis**

**High Flux Dialysis Dosing Give After or At End of
Dialysis**

**Aminoglycoside High Flux Dialysis Fixed Dosing**