Aminoglycosides

General Dosing Guidelines

All DOSAGES MUST BE INDIVIDUALIZED:

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.

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.

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

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 (optional).

Estimate kel (Elimination rate constant):
Amikacin /Gentamicin/Tobramycin: Kel = (0.00285 x CrCl) + 0.015. May also use: (0.003 x CrCl) + 0.01

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).

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.

Mechanism of Action: 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).

Initial and Follow-up 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.

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

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?

Overview of adverse effects:
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).]

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
pperiod in which to regenerate cells.

Serum Level Monitoring

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.

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

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.

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. 2nd level: at least one half-life (depending on drug) after the 1st level.

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.

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

Dosing: (Gent / Tobra)
* 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)

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)

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.

Amikacin (Amikin®)

Dosing (Adults): Conventional dosing (Usual Dose): I.M., I.V.: 5 to 7.5 mg/kg/dose (based on IBW or use adjusted body weight if current weight is greater than 25-30% over IBW) every 8 hours. Note: dose must be individualized.

Renal Dosing: (General guidelines)
CRCL >/=60 mL/minute: Administer every 8 hours
CRCL 40-60 mL/minute: Administer every 12 hours
CRCL 20-40 mL/minute: Administer every 24 hours
CRCL <20 mL/minute: Loading dose, then monitor levels

Dialyzable (50% to 100%). Administer dose postdialysis or administer 2/3 normal dose as a supplemental dose postdialysis and follow levels.

Supplied: Injection, solution: 50 mg/mL (2 mL, 4 mL); 250 mg/mL (2 mL, 4 mL)

Gentamicin

Neomycin

Dosing (Adults):
Preoperative intestinal antisepsis: Oral: 1 g each hour for 4 doses then 1 g every 4 hours for 5 doses; or 1 g at 1 PM, 2 PM, and 11 PM on day preceding surgery as an adjunct to mechanical cleansing of the bowel and oral erythromycin; or 6 g/day divided every 4 hours for 2-3 days.

Hepatic encephalopathy: Oral: 500-2000 mg every 6-8 hours or 4-12 g/day divided every 4-6 hours for 5-6 days

Chronic hepatic insufficiency: Oral: 4 g/day for an indefinite period

Supplied:
Solution, oral: 125 mg/5 ml.
Tablet: 500 mg.

Streptomycin

Dosing (Adults):
Usual dose: 15 mg/kg (or 1 g) IM every 12 hours.

Renal Dosing:
CRCL 10-50 mL/minute: Administer every 24-72 hours.
CRCL <10 mL/minute: Administer every 72-96 hours.

Supplied:
Injection, powder for reconstitution: 1 g

Tobramycin (Tobrex®)

Dosing (Adults): Conventional dosing (Usual dosing range): 1 to 2.5 mg/kg/dose IM or IV every 8-12 hours.

Renal Dosing: (General guidelines for conventional dosing)
CRCL 60 mL/minute: Administer every 8 hours.
CRCL 40-60 mL/minute: Administer every 12 hours.
CRCL 20-40 mL/minute: Administer every 24 hours.
CRCL 10-20 mL/minute: Administer every 48 hours.
CRCL <10 mL/minute: Administer every 72 hours.
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Alternatively (for CRCL < 20): Loading dose, then monitor levels.

Supplied:
Injection, solution:
10 mg/mL (2 mL, 8 mL).
40 mg/mL (2 mL, 30 mL, 50 mL).

Disclaimer

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David F. McAuley, Pharm.D., R.Ph. GlobalRPh Inc.

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