Basic Pharmacokinetic terminology: 

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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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.

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Initial evaluation

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

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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.

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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.

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(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

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    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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(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.

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(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

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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.

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(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.

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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. 
      IN: Dipiro JT, Talbert, Hayes PE et al (Eds): Pharmacotherapy a 
      Pathophysiologic Approach.

(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 
        conventional administration of gentamicin and tobramycin. 
        Pharmacoecon 1996;10:494-503.

(13) Maller R, Isaksson B, Nilsson L, et al. A study of amikacin given once 
        versus twice daily in serious infections. 
        J Antimicrob Chemother 1988;22:75-9.

(14) Nordstrom L, Ringberg H, Cronberg S, et al. Does administration of an 
        aminoglycoside in a single daily dose affect its efficacy and toxicity? 
        J Antimicrob Chemother 1990;25:159-73.

(15) Parker SE & Davey PG: Once-daily aminoglycoside administration 
        in gram-negative sepsis. Pharmacoeconomics 1995; 7:393-402.

(16) Preston SL & Briceland LL: Single daily dosing of aminoglycosides. 
        Pharmacotherapy 1995; 15:297-316.

(17) Santre C, Georges J, Jacquier JM et al: Amikacin levels in bronchial 
        secretions of 10 pneumonia patients with respiratory support treated once 
        daily versus twice daily. Antimicrob Agents Chemother 1995; 39:264-267.

(18) Ter Braak EW, De Vries PJ, Bouter KP et al: Once-daily dosing regimen 
        for aminoglycoside plus beta-lactam combination therapy of serious 
        bacterial infections: combination trial with netilmicin plus ceftriaxone. 
        Am J Med 1990; 89:58-66.

(19) Prins JM, Buller HR, Kuijper EJ, et al. Once versus twice daily gentamicin
        in patients with serious infections. Lancet 1993;341:335-9.

(20) Winters ME (Ed): Basix Clinical Pharmacokinetics, 2nd ed. 
        Applied Therapeutics, Inc, Spokane, WA, 1988.

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