Antimicrobials

Administering aminoglycosides in a single, large dose once daily has several advantages:

• More rapid bactericidal activity
• Convenience
• Reduced costs for preparation, administration, monitoring

Once-daily therapy is recommended for treatment of most infections in most patients, with the following exceptions:

Traditional multiple daily dosing of aminoglycosides is recommended in the following circumstances, based on lack of published experience with once-daily therapy.

• Septic shock (during initial hemodynamic instability)
• Renal impairment (estimated creatinine clearance < 40 mL/min)
• Ascites
• Endocarditis
• Meningitis
• Osteomyelitis
• Pregnancy
• Surgical prophylaxis
• Synergistic therapy (with beta-lactam or vancomycin for enterococci)

For dosing tools and calculators, go to Sunnynet, Pharmacy page, click button “Alphabetical Index” and click on link “Aminoglycosides – initial dosing recommendations”. Parameters calculated include: creatinine clearance, ideal body weight, adjusted body weight, dosing weight, and recommended dose (rounded off as per policy).

 Non-Obese Patients

• Gentamicin – 7 mg/kg total body weight once daily
• Tobramycin – 7 mg/kg total body weight once daily
• Amikacin – 15 mg/kg total body weight once daily
  Dose should be rounded off to the nearest 50 mg. If not, pharmacy will automatically convert to nearest 50 mg.

Burn Patients

• Gentamicin – 10mg/kg total body weight once daily
• Tobramycin – 10mg/kg total body weight once daily
• Amikacin – 20mg/kg total body weight once daily
• Dose should be rounded off to the nearest 50mg, if not, pharmacy will automatically convert to nearest 50mg.

Eligible obese Patients

Dosing based on an adjusted body weight, calculated as follows:

• Determine the patient’s actual body weight in kilograms
  
  
• Determine the patient’s ideal body weight (IBD):
  • IBW (male) = 50.0 kg + 2.3 kg (each inch > 5 feet)
  • IBW (female) 45.5 kg + 2.3 kg (each inch > 5 feet)
  • (1 inch = 2.5 cm)
    
    
• If patient’s weight is ≥ 30% above their IBW, then patient is obese and adjusted body weight should be used for dosing.
  
  
• Adjusted body weight (ABW):
  • ABW = IBW + 0.4 (actual body weight – IBW)
    
    

Initial Schedule

• Q24h for estimated CrCl ≥ 60 mL/min
  
  
• Q36h for estimated CrCl 40 – 59 mL/min
  
  
• Estimating CrCl (mL/min):
  • CrCl (Male) = [(140 – age)(actual body weight in kg) x 60 sec/min]/[50 x serum creatinine (µmol/L)]
  • CrCl (Female) = 0.85 x CrCl (Male)

1. Renal Function and Nephrotoxicity
   • BUN, creatinine (SCr) prior to treatment and twice weekly. If SCr rises by 25 mmol/L or by 25% from baseline, re-assess need for aminoglycoside.
   • Obtain repeat peak and 8 – 12 h levels at least weekly during therapy. Elevated trough levels are associated with nephrotoxicity (for target ODA trough levels, see table below (c, ii).
     
     
2. Ototoxicity
• Aminoglycoside therapy may adversely affect cochlear and/or vestibular function. Ototoxicity is not associated with either peak or trough aminoglycoside levels. In order to reduce the risk of ototoxicity, the Medical Advisory Committee has approved a protocol to facilitate monitoring of hearing and balance in patients at the Sunnybrook campus who are alert and deemed to be at high risk for aminoglycoside ototoxicity (testing is current not available at Holland Centre). The algorithm details the procedure for arranging cochlear and vestibular testing.

c. Drug Levels

1.   Initial Levels
   • Obtain peak level following first dose. Peak levels should be drawn 30 minutes after the completion of the infusion.
   • Obtain a second level 8 – 12 hours after the first dose.
     
     
2. Further Levels
   • Obtain a peak level and 8 – 12 hour post-dose level on day 7 at the latest and then weekly thereafter.
   • Following a change in dose or frequency, one set of levels (peak and 8 to 12 hour post-dose) may be obtained to document achievement of desired level range.
     
     
3. Target blood levels for ODA
   • Attainment of the target levels in the table below is recommended for all infections except: (1) urinary tract infection; (2) mycobacterial infections being treated with amikacin.

Please consult a pharmacist to determine the optimal dosage regimen to achieve the desired ODA blood levels.

• Dose Amount (based upon peak level)
  • If peak level is less than desired, increase the dose by proportion. For example, if gentamicin 350 mg results in a peak level of 15 mg/L, then 450 mg should yield a peak level of close to 20 mg/L.
    
    
• Dosing Interval (based on nomogram)
  • The appropriateness of a q24h dosing frequency will be assessed by plotting the exact time and value of the 8 to 12 hr post-dose level as instructed on the nomogram below.

Amikacin level must be halved prior to using nomogram.

• Using an object with a right angle at the corner, place it on the nomogram such that the top edge runs horizontally to intersect the y-axis at the value of 8 to 12 hour post-dose level, and the right edge runs vertically down to intersect the x-axis at the exact time the level was taken.
  
  
• The right upper corner will then fall into one of 5 regions, dictating these responses:
  • Below nomogram (< 2 mg/L): give dose once daily
  • Q24h, q36h, or q48h region: give dose at indicated interval
  • Above nomogram: discontinue ODA and consult pharmacist (x 2529) for advice.

• In non-obese patients, the dose is based on total body weight.
  
  
• In obese patients (actual weight > 30% above ideal body weight), the dose is based on an adjusted body weight (ABW).
  
  

To determine whether patient is obese, follow these steps:

• Determine actual weight (kg)
  
  
• Calculate ideal body weight (IBW) as follows:
  • Male IBW = 50 kg + 2.3 kg (each inch > 5 feet)
  • Female IBW = 45.5 kg + 2.3 kg (each inch > 5 feet)
  • (1 inch = 2.5 cm)
    
    
•  Perform the following calculation:
  • (Actual weight – IBW)/IBW = Z
• If the value of Z above is ≥ 0.3, then patient is obese

• To determine adjusted body weight, perform the following calculation:
  • Adjusted body weight = IBW + 0.4 (Actual weight – IBW)

• The initial dosage according to renal function is indicated in the table below:

*If dose of gentamicin or tobramycin is not rounded up to nearest 20 mg, Pharmacy will automatically do so (MAC approved auto-sub policy).

When gentamicin is used in the setting of endocarditis for synergy with a beta-lactam or vancomycin against enterococcus, staphylococcus or streptococcus, use 1 mg/kg dosing at interval determined by creatinine clearance and aim for a target peak of 3 – 5 mg/L and trough < 1 mg/L.

Uncomplicated lower urinary tract infection may be treated with a lower dose of aminoglycoside. Gentamicin or tobramycin may be given in a dose of 1 mg/kg q8h or q12h, depending on renal function.

1. Renal Function and Nephrotoxicity
   • BUN, creatinine (SCr) prior to treatment and twice weekly
   • If SCr rises by 25 mmol/L or by 25% from baseline, re-assess need for aminoglycoside
   • Elevated trough levels are associated with increased risk of nephrotoxicity (see table below for target blood levels)
     
     
2. Ototoxicity
   • Aminoglycoside therapy may adversely affect cochlear and/or vestibular function. Ototoxicity is not associated with either peak or trough aminoglycoside levels. In order to reduce the risk of ototoxicity, the Medical Advisory Committee has approved a protocol to facilitate monitoring of hearing and balance in patients at the Sunnybrook campus who are alert and deemed to be at high risk for aminoglycoside ototoxicity (testing is current not available at Holland Centre). The algorithm on page 31 details the procedure for arranging cochlear and vestibular testing.
     
     
3. Obtaining Drug Levels
   1. Initial Levels
      • Obtain a trough level just prior to the third dose.
      • Obtain a peak level 30 min after completion of the 3rd dose infusion
      • In patients with CrCl < 40 mL/min, contact Pharmacy for assistance with initial levels.
        
        
   2. Further Levels
      • Obtain a set of peak and trough levels at least every 7 days during therapy or if renal status changes.
      • Consult pharmacy.
        
        
4. Target blood levels for traditional therapy*
   
   

   Aminoglycoside	Peak (mg/L)	Trough (mg/L)
   Gentamicin	4 – 10	< 2
   Tobramycin	4 – 10	< 2
   Amikacin	15 – 30	< 10

   *Target serum levels should be individualized according to the site of infection, susceptibility of causative organisms, and clinical status of the patient. Peak levels are targeted for efficacy and trough levels are targeted to avoid nephrotoxicity.

5. Dosage Adjustment
   Assistance with the Therapeutic Drug Monitoring (TDM) of aminoglycosides may be obtained by writing “Pharmacist to see re: Aminoglycoside Dosing” on the Doctor’s Order Sheet, or by contacting the liaison pharmacist (x 2529)