Pharmacokinetics overview of the aminoglycosides and vancomycin for pharmacists, physicians, and students.

Pharmacokinetic Overview

D. McAuley, GlobalRPh Inc

Pharmacokinetics (Def.)	Volume of distribution (VD)	Bioavailability (F)	Steady State
Elimination rate constant	Half-Life	Creatinine clearance	First order elimination
PK properties (Overview)	Mechanism of action	Elimination (route)	Distribution
Initial Evaluation	Follow-up Evaluation	Adverse effects	Monitoring for toxicity
Serum Drug levels (Indications)	Patients not requiring levels	Frequency of serum levels	When to draw levels..
Dosing (Step by step)	Ideal body weight	Adjusted body weight	Kel determination
Vd determination	Desired Levels	Time of infusion	Loading Dose
Calculate Interval (T)	Calculate Maint dose	Calculate Cmax, Cmin	Chart Documentation
Sample problem	Once daily dosing (Exclusions)	Once daily dosing (Weight determination)	Once daily dosing (Dosing regimens)
Once daily dosing (Goals of therapy)	References

Basic Pharmacokinetic terminology:

Pharmacokinetics: Concerned with the study and characterization
     of the time course of drug absorption, distribution, metabolism and
     excretion, and with the mathematical relationships required to
     develop models to interpret such date.

Clinical pharmacokinetics: A health science discipline dealing with the
    application of pharmacokinetics to the safe and effective therapeutic
    management of the individual.

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Volume of Distribution (Vd)
      (a)    Non-physiologic volume into which the drug disperses after it is
                  absorbed.
      (b)    Does not represent a real body space. Vd may be affected by:
              1.      Body size and composition-fat, muscle, total body water,
                          extracellular water.
              2.      Physical-chemical characteristics of drugs-pka, molecular weight,
                           solubility.
              3.      Tissue binding.
              4.      Plasma protein binding.

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Bioavailability (F) = 0 to 1
        (a)    Extent to which drug reaches the general circulation or becomes
        systemically available.
        (b)    Vancomycin & aminoglycosides given intravenously: F=1 (100%).

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Steady State
        (a)    5 half-lives to be approximately 97% of steady state.
        (b)    At steady state the rate of drug administration is equal to drug
                   elimination and the mean concentration remains constant.

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Elimination Rate Constant (kel)
(a) The fraction of the amount of drug in the body eliminated per unit time.
(b) For drugs eliminated by first-order kinetics

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Half-life
       (a) Time required for serum concentration to decrease by one-half the
              original value.
       (b) T1/2 = 0.693/kel

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Creatinine Clearance (ml/min)
       (a) Creatinine is a metabolic by-product of muscle and an individual's
              muscle mass or lean body weight primarily determines its rate
              of formation.
       (b) Cockcroft and Gault equation:
                 CrCl: (140 - age) x IBW / (Scr x 72) (x 0.85 for females)
                 IBW (Ideal body weight)
                         Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet.
                         Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet.

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First Order Elimination
       (a) Rate of biotransformation is proportional to the amount of drug in the
              apparent compartment in which the site of biotransformation is located.
       (b) A direct proportionality exists between drug concentration at any specified
             time and the size of the dose.
       (c) Kel (elimination rate constant) is equal to the slope of the line of
              [Log conc vs time plot].
       (d) One-compartment model: Immediate and uniform, complete drug
               distribution into a single compartment followed by elimination.
       (e) Two-compartment model: Distribution initially into a central compartment,
              followed by a gradual equilibration with a peripheral compartment.

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Pharmacokinetic Properties

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Overview:
Aminoglycosides: not absorbed orally; IV route primary route of
administration-occasionally given IM; quite hydrophilic-distributes primarily in
extracellular fluid~25% of body weight; relatively poor tissue penetration;
protein binding (20-30%)-not clinically significant; well distributed except
for the eye, CNS, CSF. Must be given intrathecally for CNS infections.
Increased Vd seen in CHF, peritonitis, ascites, acute burn injury, s/p
surgery, immediately post partum patients.
Exhibits concentration dependent bactericidal activity.
MIC: (Tobra/Gent): Susceptible: < 4 mg/l Intermediate: 8 Resistant: >16.
Increasing the peak, will result in an increased post-antibiotic effect.

Vancomycin: Given IV only (IM very painful). Exhibits time-dependent or
concentration independent bactericidal activity.
MIC's: Susceptible: <4 mcg/ml. Intermediate: 4-16 mcg/ml. Resistant: > 16 mcg/ml.
Protein binding: 30-55%; Vd (range): 0.5 to 0.9 L/kg.
Follows a two-compartment model (prolonged distribution-well distributed);
Serum levels: Peak (30-40)-goal = 8 x MIC. Trough: 5-15 mcg/ml (goal= 2x MIC).

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Mechanism of Action
(a) Aminoglycosides are rapidly bactericidal. They irreversibly bind to the
30 s bacterial ribosome; protein synthesis is thereby inhibited and cell death
ensues. Uptake into bacterial cells is facilitated by cell wall inhibitors
(Vancomycin and beta-lactams).

(b) Vancomycin is bactericidal against most sensitive organisms except
enterococci. Vancomycin inhibits bacterial cell wall synthesis by interfering with
glycopeptide synthesis.

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Elimination
(a) Aminoglycosides: Glomerular filtration
(b) Vancomycin: Glomerular filtration

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Distribution
Aminoglycosides enter most body fluids well approximating
extracellular fluid. (excluding pulmonary tissue, fatty tissue, abscess).
Vancomycin is widely distributed throughout the body.
The volume of distribution of the aminoglycosides and vancomycin can be
quite variable and can vary widely from patient to patient. It is one of the
key factors in the determination of the peak and trough concentration.

Any factor that can alter the extracellular fluid can affect the volume of
distribution.
*Dehydration: Decreased Vd.
*Chronic renal failure, CHF, ascites, obesity: Increased Vd. <Top>

Initial evaluation

Is the drug appropriate?
Is the dose appropriate?

Specific patient parameters
     (a) Age, sex, height, weight, IBW.
     (b) Allergies
     (c) Current antibiotic therapy
     (d) Infectious diagnosis
     (e) Renal and hepatic function
     (f ) Concurrent disease states/diagnoses that may impact therapy
             (eg. cachexia, diabetes mellitus, bilateral AKA, etc.)
     (g) Clinical signs and symptoms (Temp, RR, HR etc)
     (h) Laboratory tests: gram stains, culture and sensitivity results, CBC & diff,
           Scr, BUN, WBC, I/O (past 24 hours)
     (i ) Determination of optimal blood levels based on diagnosis.

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Follow-up Evaluation
Is the drug working?
Is the patient experiencing any adverse effects from the drug?

Treatment failure:
Temperature or WBC increasing; symptoms increasing.
Note: changes in renal function may not reflect nephrotoxicity.
Other causes of acute renal failure occurring
in hospitalized patients, include:
    - Severe or prolonged hypotension (decreased renal perfusion)
    - Surgery
    - Other nephrotoxic drugs: amphotericin, cisplatin, etc.
    - Acute cardiovascular dysfunction

<Top> Is the patient responding to treatment?
Look for reversal of initial signs and symptoms.
    -Is the patient's temperature decreasing?
     Culture results negative?
    -Heart rate and respiratory rate returning to normal?
    -Is the white blood cell count decreasing?
    -Normalization of blood gases?

    Is the current regimen appropriate?
    Is the patients renal function stable?
   Are current serum levels (peak and trough) appropriate?
    Is the drug still required?

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Overview of adverse effects:

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Aminoglycosides:
Major: Vestibular toxicity; auditory toxicity;
renal toxicity (reversible); neuromuscular toxicity (post-synaptic
curare-like action).
Minor: skin rash; drug induced fever.
What to look for: Changes in urine output; BUN,
creatinine, ototoxicity (hearing tests).]

Vancomycin:
Red man syndrome (histamine-like reaction characterized by flushing,
tingling, pruritis, tachycardia, and a red rash on the face,neck,upper
torso, back and arms.
Management: slow rate of infusion, dilute drug in sufficient diluent,
anti-histamine prophylaxis); Nephrotoxicity (reversible)-incidence
(<5%); ototoxicity (may be irreversible); neutropenia; thrombophlebitis;
skin rash.

<Top> Monitoring for toxicity:
1. Auditory and neuromuscular toxicity are not evaluated in most patients.
    If prolonged courses of aminoglycosides are anticipated, baseline and
    periodic assessment of hearing with audiometry are recommended.
    Neuromuscular toxicity is most likely in patients with preexisting
    neuromuscular disease or patients with hypocalcemia.

2. Serum creatinine and BUN determinations 2-3 times/week should monitor
     renal toxicity. More frequent determinations are advised for patients with
     changing renal function. Creatinine clearance, I/O's, urinalysis, when
     available will help to identify patients with possible nephrotoxicity.

3. Risk factors for Nephrotoxicity: Age, renal insufficiency, elevated trough
    concentrations, total daily dose, cumulative dose, concurrent nephrotoxic
    drugs, prior aminoglycoside exposure, duration of treatment.

4. Toxicity usually takes 5-7 days to develop. Mechanism: damage occurs
     to the cells lining the proximal tubules.

5. The process of nephrotoxicity (uptake by cells) is saturable and the
    number of insults determines toxicity. It is imperative to minimize the
    number of insults and allow the tubular cells a relatively drug free
    period in which to regenerate cells.

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Criteria for Selecting the Appropriate times for Collecting
Serum Drug levels

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Indications for serum concentration monitoring:
(1) Patients with compromised renal function (CrCl <50 ml/min) and/or
      unstable renal function (an increase or decrease in serum creatinine
      > 0.3 mg/dl).
(2) Projected courses of therapy of > 7 days.
(3) Suspected treatment failures.

Patients not requiring levels include those in whom the assessed
dosage regimen is adequate and (1) CrCl >50 ml/min and stable
(< 0.3 mg/dl changes in serum creatinine) and
(2) Projected course of therapy is < 7 days, and infections are unlikely
      to be complicated.

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Frequency of serum level determinations:
A. Weekly levels are advised for patients with stable renal function
     as noted above.
B. Levels may be advised more frequently than once weekly in patients
     exhibiting conditions predisposing them to pharmacokinetic variability
     such as:
      (1) Fluid overload or dehydration
      (2) Rises in serum creatinine above baseline of > 0.3 mg/dl
      (3) Acute cardiac, and/or renal decompensation.
      (4) Severe hypotension (decreased renal perfusion)
      (5) Hyperalimentation
      (6) Ascites (increased Vd)
      (7) Burn patients (usually see increases in kel)
      (8) Cystic fibrosis patients (increases in kel)
      (9) Surgery patients

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Draw levels off the third dose for:
-Patients with normal renal function based on Creatinine/Bun, I/O's,
medical history; concomitant drug therapy, and hydration status.
When to draw levels:
Aminoglycoside: Peak/trough: 30 minutes before
        and after a 30 minute infusion.
Vancomycin: Peak: 60 minutes after the infusion. Trough: 30
        minutes prior to next dose.
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Draw levels off the first dose for:
- Patients with abnormal renal function based on BUN/SCR; I/O's,
    edema, history of renal or cardiac disease.
- Patients receiving other nephrotoxic drugs.
- Patient is neutropenic, febrile, and/or unstable.
- Patient has unstable or increasing serum creatinine.
When to draw levels:
1st level: aminoglycoside: 30 minutes post infusion. Vanco: 60 minutes post
infusion. 2nd level: at least one
half-life (depending on drug) after the 1st level.

Aminoglycoside / Vancomycin Worksheet
(Step by Step)

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(1) Obtain baseline data:
Patient age, sex, height, weight, allergies, diagnosis, infection site, current
drug therapy, I/O's for past 24 hours, Tmax, WBC with diff, albumin,
Past medical history, Lab work-up: Scr, Bun, cultures etc.

(2) Estimate Ideal body weight in (kg)
     Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet.
     Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet.

(3) If the actual body weight is greater than 25 - 30% of the calculated
     IBW, calculate the adjusted body weight (ABW):
           ABW = IBW + 0.4(Total body weight - IBW)

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(4) Estimate Creatinine Clearance: (ml/min)
       Cockcroft and Gault equation:
       CrCl: (140 - age) x IBW / (Scr x 72)       (x 0.85 for females)
       Note: if the ABW (actual body weight) is less than the IBW use the
       actual body weight for calculating the CRCL. If the patient is >65yo and
       creatinine<1, use 1 to calculate the creatinine clearance.

<Top> (5) Estimate kel (Elimination rate constant):
     Amikacin /Gentamicin/Tobramycin: Kel = (0.00285 x CrCl) + 0.015
         May also use: (0.003 x CrCl) + 0.01
     Vancomycin: kel = 0.0016 x Crcl

     The above equations provide an estimate of the elimination rate
     constant based on population kinetics. The following may decrease
     the usefulness of these equations:
          *Renal failure, CHF, Burn patients, cystic fibrosis, severe
            hypotension, rapidly changing renal function. (Burn victims
            and patients with cystic fibrosis usually have increased
            rates of elimination. Patients with CHF or severe hypotension
            will have decreased rates of elimination due to decreased
            renal perfusion).

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    Kel determination from reported levels:
      kel = (Ln C1 / C2) / (t2 - t1)
      C1= actual or extrapolated Peak; or post peak level
      C2= actual or extrapolated trough; or random level
      Drawn at least 1.5 x estimated half-life after first level.
      (t2 - t1) = Time difference between levels.

(6) Estimate half-life (T1/2) in hours:
      T1/2 = 0.693 / Kel

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(7) Estimate Volume of Distribution (Vd): (Liters)
Aminoglycosides:
    Use IBW unless obese, then use ABW= 0.4 x (TBW-IBW) + IBW
    Vd (Normal) = 0.25 to 0.3 L/kg
    Bun/Cr ratio 10 to 15:1 (nml). Patient normally hydrated or a
    patient that will return rapidly to normal status.

    Vd (dehydrated) = 0.2 to 0.25 L/kg
    Bun/Cr ratio > 20:1; acute weight loss; decreased skin turgor; dry
   mucous membranes, thirst, massive hemorrhage, acute diuresis.

    Vd (overhydrated) = 0.35 to 0.4 L/kg.
    Bun/Cr ratio < 10:1 , patients with ascites; edema, chronic renal
   failure, severe hypalbuminemia (less than 2.5 gm/dl)-promotes
    edema.

Vancomycin:
    [Use actual body wt unless obese (> 30% over IBW)-then use adjusted
    body weight = 0.4(TBW- IBW) + IBW.]
    Vd (Normal): 0.6 to 0.7 L/kg (usually 0.65)
    (dehydrated): 0.5 to 0.6 L/kg
    (overhydrated): 0.7 to 0.85 L/kg

<Top>     Volume of distribution calculation based on actual or
      extrapolated peak and trough concentrations:
         Vd = MD x (1-e-kti) / (k) (ti) [Cmax - (Cmin e-kti)]

(8) Desired Peak___ (mcg/ml) Desired trough___.
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Infection	Gent/Tobra		Amikacin		Vanco
Infection	Peak	Trough	Peak	Trough	Peak	trough
Abdominal	6-7	<1	25-35	4-6	25-30	<10
Cystitis	4-5	<1	20-25	4-6
Endocarditis	4-15*	<1.5	35-45	<8	35-40	<15
Osteomyelitis	6-7	<1	25-35	4-6	30-40	<10
Pneumonia	8-10	<1.5	30-35	<8	30-40	<15
Pyelonephritis	6-7	<1	25-35	4-6	25-35	<10
Sepsis	7-8	<1	25-30	4-6	25-35	<10
Soft Tissue	6-7	<1	20-25	<6	25-30	<10
Synergy	4-6	<1	20-25	4-6
Wound	6-7	<1	25-30	<6	25-35	<10
* A wide range of levels are supported depending on the MIC of the infecting organism and the degree of infiltration. Highly resistant strains will require much higher levels to ensure adequate therapy is rendered. Consultation with an infectious disease specialist is recommended.

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(9). Select Time of Infusion (ti):
(a) Aminoglycosides: 30 minutes (0.5 hrs)
(b) Vancomycin: 0-500 mg/ 0.5 hrs ; 501 to 1250 mg/ 1 hour ;
        1251 to 1750/ 1.5 hrs ; >1750/ 2 hours.
(10) Calculate Loading Dose:___________(mg).

   Gentamicin/Tobra: 1.5-2.5 mg/kg x ABW (usually 2 mg/kg)
   Amikacin: 6-7.5 mg/kg x ABW
   Vancomycin: Loading doses are not usually administered since
   concentrations following the first maintenance dose are normally
   well above the usual MIC's.

<Top> (11) Calculate Dosing Interval (T)    hrs.
    T = Ln (Cmax/Cmin) / kel + ti or estimated T = 3 x T1/2

(12) Calculate Maintenance dose (MD):_____mg.
   MD = [(kel) x (Vd) x (ti) x (Cpeak desired) x (1 - e^-kT)] / (1 - e^-kti)
     or MD = (Cpeak desired) x Vd (eg: C = D/V, therefore D=C*V)

(13). Calculate Predicted Peak and Trough at Steady State.
          Cmax = [Dose * 1-e^-kti] / (kel)(Vd)(ti) 1-e^-kT
          Cmin = Cmax * e^-k(T-ti)
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Summary: Chart Documentation
(All documentation should follow this format).
(Example):
(1) Identify service: "Pharmacokinetic dosing service" or "Clinical
       Pharmacy note"
(2) Record time and date.
(3) List day of therapy for all antibiotics

<Top> Pharmacokinetic Dosing Service -Gentamicin Day #2
8/6/99 @1500
O: (Objective) Patient is an 86yo, M, 5'6" , 140# (65kg), IBW= 65kg.
     (Pt has S/Sx of pneumonia). Dx: Pneumonia   BUN: 12
     Creat: 1.2 WBC =16.1 Tmax: 102.2     I/O= 3850/ 3640 (24hrs)
     Current antibiotic regimen: Ancef 1 gram ivpb q8h and
     Gent 80mg ivpb q12h.
    * (Normally include patient age, sex, admission diagnosis, medical
      history, allergies, current drug therapy, and reason for
      placing pt on the consult drug).

A: (Assessment) Estimated CrCl= 34 ml/min yielding a Gent T1/2 of
      7.2 hrs suggesting an 18hr dosing interval. A gent peak of 8 mcg/ml
      is desirable for adequate pulmonary penetration. Bun/Scr =22:
      Somewhat dehydrated-should result in smaller Vd. Albumin wnl.
    *(Under assessment-may include: Ht, Wt, IBW, BUN/Cr, I/O's,
      albumin, other pertinent lab data, pharmacokinetic parameters,
      and predicted drug concentrations. Should also include specific
      data relating to infectious process: WBC, cultures & sensitivities,
      chest X-ray etc.)
R: (Recommendations/Plan)
     (1) Change gent to 100mg q18h for
           estimated peak of 7.7 and trough of 0.9.
     (2) Obtain Peak and trough on
           Friday around 0600 dose (30 min before and 30min post infusion).
     (3) Decrease Ancef to 1gram q12h
     (4) Monitor BUN and creat 3 x weekly.
     Thank you for the consult, will continue to follow.
            John Doe R.Ph.

<Top> (Overview of recommendation: Based on patient data and disease state
recommend a dosing regimen on the consult drug. Indicate the predicted
concentrations. Recommend the appropriate times to measure drug
concentrations. Evaluate the patient's other medications and recommend
dosing adjustments as necessary. Contact the physician and verbally
state the recommendations and document this in the patient's medical
record.)

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Example: Follow-up note:
· Pharmacokinetic Dosing Service-Gent day#6
· O: Tmax 99, I/O: 3600/3550 (24hrs), WBC: 8.6
· BUN: 12, Creat: 1.0
· Sputum culture + Kleb pneumo (s)Gent (s)ancef
· Gent 100mg q18h. Gent peak: 5.8 Gent trough: 1.3
·
· A: Patient responding to therapy, renal function stable.
· True gent peak: 6.0, True trough: 1.2 based on Pharmacokinetic
· extrapolation. Vd= 0.31 L/kg, T1/2= 7.6 hrs.
·
· R: Suggest:
· 1. Change gent to 140mg q24h for estimated pk: 8 trough: 0.9
· 2. Repeat levels in 7 days.
· 3. will continue to follow.
· John Doe, R.Ph. <Top>

Sample Problems

Mr. Smith is a 43 yo male. Diagnosis : aspiration pneumonia. Social history:
chronic alcoholic. Height: 6'2" Weight: 70kg. Scr: 0.7 mg/dl. Bun: 12 mg/dl.
Patient is started on Piperacillin 3 grams q4h and gentamicin 140 mg load.
Physician requests consult.
   (1) Estimated IBW= 50 kg + (2.3 x 14) = 82.2 kg

   (2) Estimated Crcl = (140-age) x IBW / 72 x SCR =
          [(140- 43) x 70] / 72 x 1.0 = 94.3 ml/min
          (Note: used ABW because ABW<IBW. Also rounded SCR to 1,
          in order to compensate for "cachectic" nature of patient.)

   (3) Estimate Kel: = (0.00285 x crcl) + 0.015 = 0.283 hr-1

   (4) Estimate T1/2 = Ln(2)/ Kel = 2.44 hrs.

   (5) Estimate Vd: BUN/Scr = 17 (assume nml hydration).
        Vd= 0.25 L/kg x 70 kg = 17.5 liters. (may use 0.25 to 0.3)

   (6) Select infusion time: Use 0.5 hrs for aminoglycosides.

   (7) Determine desired peak and trough concentrations:
         For the treatment of pneumonia, higher levels are req'd in order to
         to get adequated pulmonary penetration.
         Desired Cpeak: 8-10 mcg/ml    Cmin<1 mcg/ml ideally.

   (8) Calculate dosing interval (T):
        (a) Quick method: T = 3 x T1/2 = 3 x 2.44 = 7.3 hrs (Interval =8hrs)
        (b) Longer method: T= Ln (Cmax/Cmin) / Kel + ti
               = Ln(8/1)/0.284 + 0.5 = 7.82 hrs (Interval = 8 hrs)

   (9) Maintenance dose (MD):
           Quick method: MD = Concentration desired x Vd
              = 8 mcg/ml x 17.5 liters = 140 mg

(10) Determine if the regimen is appropriate by plugging the values into
          the Cmax and Cmin equations. These equations will predict the
          concentrations that will be achieved at steady state.
·
              Cmax = [140mg x 1- e^{- (0.284 x 0.5)}] /
                  [0.284 x 17.5 x 0.5 x 1 -e^{-(0.284 x 8hr)}]
                        = 8.3 mcg/ml (Expected peak)

              Cmin= Cmax x e^-kel(T-ti) = 8.3 x e^{- 0.284 (8 - 0.5)} = 0.99= ~1.0

              Regimen is therefore appropriate.

   (11) Recommendation: Give gentamicin 140 mg ivpb q8h. Infuse over
           30 minutes. Estimated Cpeak= 8-8.5 mcg/ml. Ctrough ~ 1 mcg/ml.
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Once Daily Dosing Protocol:

(Exclusions: Check all that apply: If there are any checks do not use
   once-daily dosing-use conventional dosing.
     (1) Patient has febrile neutropenia
     (2) Burn patient
     (3) Spinal cord injury
     (4) R/O meningitis or endocarditis
     (5) CrCl < 40 ml/min
     (6) Age < 18 or >70
     (7) History of ototoxicity
     (8) Pregnant
     (9) Being used for synergy for staph or strept infection.

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Calculation of Dosing weight
If not obese, Use IBW. ( If actual wt is < IBW use actual instead.)
If obese use the adjusted body weight.
      Patient Total body weight (TBW)=___________kg

      Calculate Ideal body weight=_______________kg
           IBW (male) = 50 kg + 2.3 kg for each inch over 60"
                   (Female)= 45.5 kg + 2.3 kg for each inch over 60"

      Calculate Adjusted body weight (ABW) for obese patients.
          (Use if TBW >20% over IBW)=______kg.
            ABW = 0.4(TBW - IBW) + IBW

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Dosing:
    * Mild infection: 4mg x dosing weight in kg. (Cystitis etc)

    * Moderate infection: 5 mg/kg of dosing weight (wound infection,
           Pyelonephritis, intraabdominal or pelvic infections
          , osteomyelitis, etc.)

    * Severe infection: 6 mg/kg of dosing weight. (Gram negative
           pneumonia, septic shock, etc.)

    * Life-threatening: 7 mg/kg of dosing weight.

          (Round dose to the nearest 20 mg)
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Goals of therapy:
   Desired trough for once daily dosing
    Trough concentration: The trough may be measured at 18 or 24 hours.
     If measured after 18 hours, the trough concentration must be less< 1
     or < 0.5 mcg/ml if measured after 24 hours. If these goals are not met,
     initiate standard dosing.

Peak concentrations: (Once daily dosing)
     Mild: (Gent/tobra: 12-16 . Amik: 30-40)
     Moderate: (Gent/tobra: 16-20. Amikacin: 40-50 )
     Severe: (Gent/Tobra: 20-24 Amikacin: 50-60)
     Life-threatening: (Gent/Tobra: 24-28 Amikacin: 60-70)

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Monitoring:
Monitor Bun & Serum creatinine at least q3 days (more frequently if
unstable). Order initial level to be drawn 18 to 24 hours after the dose.

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References

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(1) Bates RD and Nahata MP. Once daily administration of aminoglycosides.
     Ann Pharmacotherapy 1994;28:757-765.
(2) Bauer LA: Clinical pharmacokinetics and individualization of drug therapy.
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(3) Chan GL: Alternative dosing strategy for aminoglycosides: impact on
      efficacy, nephrotoxicity, and ototoxicity.
      Drug Inell Clin Pharm 1989; 23:788-794.
(4) Christensen S, Ladefoged K & Frimodt-Moller N: Experience with once
      daily dosing of gentamicin: considerations regarding dosing and monitoring.
      Chemother 1997; 432:442-450.
(5) Cooke RPD, Grace RJ & Gover PA et al: Audit of once-daily dosing
      gentamicin therapy in neutropenic fever. IJCP 1997; 51(4):229-231.
(6) Debroe, Verpooten GA. Influence of dosage schedule on renal accumulation
      of amikacin and tobramycin in man. J Antimicrob Chemother 1991;27
      (Suppl C):41-47.
(7) Evans WE, Schentag JJ & Jusko WJ (Eds): Applied Pharmacokinetic
      Principles of Therapeutic Drug Monitoring, 2nd ed. Applied Therapeutics,
      Spokane, WA, 1986.
(8) Ellis-pegler RB, Chambers S, Begg EJ et al: Aminoglycoside dosing:
      Time to change. Aust NZ J Med 1994; 24:359-360.
(9) Hatala R, Dinh T, and Cook DJ. Once daily aminoglycoside dosing in
      immunocompetent adults. A meta analysis.
     Ann Intern Med 1996;124:717-725.
(10) Labovitz E, Levison ME & Kaye D: Single dose daily gentamicin therapy
        in urinary tract infection. Antimicrob Agents Chemother 1974; 6:465-470.
(11) Nicolau DP, Belliveau PP, Freeman CD, et al. Experience with a once
        daily aminoglycoside program administered to 2,184 adult patients.
        Antimicrob Agent Chemother 1995;39:650-5
(12) Mithani H and Brown G. The economic impact of once daily versus
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Pharmacokinetic Overview

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