Antimicrobial Stewardship (AMS)

Resources to help you ensure the safe and effective use of antimicrobials in NSHA patients.

Vancomycin

  • Serious infections due to beta-lactam resistant, Gram-positive microorganisms such as:
    • Methicillin resistant Staphylococcus aureus (MRSA) 
    • Ampicillin resistant Enterococcus spp.
    • Methicillin resistant coagulase-negative staphylococci
    • Ceftriaxone resistant S. pneumoniae (meningitis)
  • Infections due to Gram-positive microorganisms or surgical prophylaxis in patients with a history of severe delayed skin reactions/organ dysfunction to beta-lactam antimicrobials: 
    • e.g. Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia & systemic symptoms (DRESS)

Last reviewed June 2021

  • Nephrotoxicity: more likely if trough levels persistently 15–20 mg/L 
  • Cytopenias especially neutropenia and thrombocytopenia
  • Ototoxicity with prolonged use
  • Histamine-release causes a vancomycin flushing reaction characterized by an immediate, generalized erythema during rapid infusion which disappears when the infusion stops. It is not a true allergy. Refer to the IV manual for recommended minimum infusion time. 

Last reviewed June 2021

  • Oral vancomycin administration is suitable only for C. difficile infection as it is not absorbed from the GI tract. Do not use oral vancomycin as stepdown therapy for IV vancomycin.
  • Vancomycin is a less effective choice than a beta-lactam antimicrobial for methicillin-susceptible staphylococcal (MSSA) infections. 
  • S. aureus with an MIC of greater than or equal to 2 mg/L has a high failure rate; consider an ID consult.

Last reviewed June 2021

  • Loading dose of 25–30 mg/kg IV x 1 (round to the nearest 250mg. Use actual body weight, maximum dose 3000 mg) if
    • Serious MRSA infections or serious MSSA infections with absolute contraindication to beta-lactams where rapid attainment of target trough level is desired, e.g., pneumonia, epidural abscess, septic shock, meningitis.
    • Patients with significant renal dysfunction in order to decrease the time required to attain target trough level.
  • For other indications, start with maintenance dose as the loading dose as below
Maintenance Dose 15 mg/kg
Round to the nearest 250mg
Use actual body weight, maximum dose 2000mg
Consider ID consult if more than 4000mg/day
  CrCl (mL/min)   Dosing Interval
≥ 60 Q12h*
30-59 Q24h
< 30 Q48h
 Hemodialysis  Usually dosed after each dialysis, consult pharmacist
and dialysis order sets.

*If targeting a higher trough, near 15 mg/L, and patient’s creatinine clearance is ≥ 90mL/min and < 60 years old, may use 15mg/kg q8h for critically ill patients

 

THERAPEUTIC DRUG MONITORING (TDM)

Trough Target

Target serum trough concentration 10-15 mg/L for most infections

 

Endocarditis:

  • 10-20 mg/L for enterococci or staphylococci 
  • 10-15 mg/L for viridans group streptococci
Invasive infections: CNS infections,
osteomyelitis, pneumonia, and
other deep seated MRSA infections
Suggest target trough concentrations in higher range, around 15 mg/L
  • The IDSA has recommended against using target trough concentrations of 15-20 mg/L 
  • Serum trough levels in the 15-20mg/L range have increased risk of renal toxicity with minimal evidence of increased efficacy.

Trough Monitoring

  • Pre-vancomycin (trough) level within 30 min prior to 4th dose (or 3rd dose for q24h dosing) if patient is expected to be on vancomycin for longer than 48 hours
    • For patients receiving q 48-hour dosing, draw a trough level prior to the second dose to ensure level is not above target range.
    • Monitor levels more frequently in patients with variable kidney function, altered volume of distribution (e.g.: burns, cystic fibrosis, sepsis, critical care, pregnancy), requiring larger doses, and/or addition of nephrotoxic drug or agent (e.g.: IV contrast)
    • Do not hold further scheduled vancomycin doses while trough level is pending, unless there has been an acute deterioration in the patient's creatinine clearance
  • If level outside desired range, contact clinical pharmacist for assistance with dosing and interpretation of levels as required
    • Usually adjust dose in increments of 250mg and/or the frequency to q12h, q24h, or q48h as appropriate
    • If pre 3rd or 4th level is low but near target, can maintain the dose and repeat level, since vancomycin level will likely increase with subsequent doses
  • Repeat pre-vancomycin level at least weekly to ensure it is within desired range once target trough is achieved and serum creatinine is stable

Other Monitoring

  • Serum creatinine- baseline and at least weekly while on therapy, provided creatinine is stable
  • Complete blood count with differential (for cytopenias) - baseline and weekly while on therapy
  • May monitor laboratory values more frequently if warranted by clinical scenario

Last reviewed June 2021

1. SHS-UHN Antimicrobial Stewardship Program: https://www.antimicrobialstewardship.com/antimicrobials

2. Sunnybrook Guidelines: https://sunnybrook.ca/glossary/item.asp?i=1164&p=1341&page=

3. Rybak MJ, Le J, Lodise TP, et al. Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: A revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm. 2020;77(11):835-864.

4. Baddour LM, Wilson WR, Bayer AS, et al. Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association [published correction appears in Circulation. 2015 Oct 27;132(17):e215] [published correction appears in Circulation. 2016 Aug 23;134(8):e113] [published correction appears in Circulation. 2018 Jul 31;138(5):e78-e79]. Circulation. 2015;132(15):1435-1486.

5. Stewart JJ, Jorgensen SCJ, Dresser L, et al. A Canadian Perspective on the Revised 2020 ASHP/IDSA/PIDS/SIDP Guidelines for Vancomycin AUC Based Therapeutic Drug Monitoring for Serious MRSA Infections. JAMMI. 2021; 6(1):3-9

6. Claeys, KC, Brade, KD, Pro, ELH, Jorgensen, SC, Dresser, LD, & Con, BRD (2020). Should Therapeutic Monitoring of Vancomycin Based on Area under the Curve Become Standard Practice for Patients with Confirmed or Suspected Methicillin-Resistant Staphylococcus aureus Infection? [published correction appears in Can J Hosp Pharm. 2020 Fall;73(4):298]. Can J Hosp Pharm. 2020;73(3):232-237.

Last reviewed June 2021

Aminoglycoside Dosing and Monitoring

Tobramycin, gentamicin (agent of choice for Gram-positive synergy), amikacin

Last reviewed Jan 2023

  • Treatment of serious infections caused by susceptible Gram-negative microorganisms such as Pseudomonas
  • Synergy for some Gram-positive infections (i.e. infective endocarditis)

Last reviewed Jan 2023

  • Cranial nerve VIII toxicity
    • Usually NOT reversible 
    • Cochlear: hearing loss, tinnitus
    • Vestibular: nausea, vertigo, balance
    • Must inform patients and monitor for toxicity
      • Daily assessment of hearing, balance, dizziness
      • Audiogram Monitoring: Baseline and serial audiograms should be ordered for patients whose therapy is anticipated to exceed 14 days or in those at high risk for toxicity.
  • Nephrotoxicity
    • May be reversible, single dose safe in sepsis
  • Neuromuscular blockade
    • Rare, flaccid paralysis, respiratory muscle weakness, contraindicated in myasthenia gravis

Risk factors for toxicity: more than 3 days of therapy, renal insufficiency, elevated trough levels, elderly, volume depletion, concomitant nephrotoxic or ototoxic drugs (i.e. amphotericin B, cisplatin), pre-existing hearing/vestibular disorder, prior aminoglycoside exposure (within 3 months).

Last reviewed Jan 2023

  1. Preferred: Extended interval dosing (once daily dosing)
  2. Traditional dosing
  3. Cystic fibrosis dosing
  4. Dosing for synergy in Gram-positive infections

*Note: cystic fibrosis patients often require higher dosing regimens; consult with CF team

Last reviewed Jan 2023

  • Preferred dosing strategy: similar efficacy and less toxicity than traditional dosing
  • Exclusion criteria:
    • Renal failure  (CrCl less than 20mL/min)    
    • Burns (greater than 20% BSA)    
    • Synergistic therapy
    • Surgical prophylaxis
    • Ascites

Step 1. Calculate dosing rate

Non- obese: Dose based on actual body weight
Obese: if body weight is 30% above ideal body weight (IBW), calculate Dosing Weight
  Dosing Weight: IBW + 0.4 x (actual body weight - IBW)
  Ideal body weight (IBW) equation:
  • IBW (male) = 50 kg + 2.3 kg*(each inch above 5 feet)
  • IBW (female) = 45.5 kg + 2.3 kg*(each inch above 5 feet)

Step 2. Calculate maintenance dose

Use dosing weight:

  • Tobramycin/gentamicin: 5-7 mg/kg (round to nearest 20mg)
    • 5mg/kg for less severe infections or urinary infections
  • Amikacin: 15 mg/kg (round to nearest 50mg)

Step 3. Choose dosing interval based on creatinine clearance

Creatinine Clearance (mL/min) Dosing Interval
Greater than 60 q24h
40-59 q36h
20-39 q48h
Less than 20 Avoid once daily dosing

Step 4. Therapeutic drug monitoring

  • TROUGH level 6 hours prior to 2nd dose
  • Repeat at least once weekly*
Drug Target Trough
Tobramycin/Gentamicin Less than 1 mg/L
Amikacin Less than 2.5 mg/L

*If initial trough level on target and renal function stable (i.e., not expecting drug accumulation or toxicity), may draw future troughs 30 minutes prior to dose for practicality

Other Monitoring:

Serum creatinine 2 or more times per week; daily clinical assessment of acute changes to hearing or balance/dizzines; audiogram as necessary.

Last reviewed Jan 2023

  • Use if patient meets exclusion criteria for extended interval dosing

Step 1. Calculate dosing weight

Non-Obese: Dose based on actual body weight
Obese: if body weight is 30% above ideal body weight (IBW), calculate Dosing Weight
  Dosing Weight: IBW + 0.4 x (actual body weight - IBW)
  Ideal body weight (IBW) equation:
  • IBW (male) = 50 kg + 2.3 kg*(each inch above 5 feet)
  • IBW (female) = 45.5 kg + 2.3 kg*(each inch above 5 feet)

Step 2. Calculate and give loading dose

Use dosing weight:    

  • Tobramycin/gentamicin: 2 mg/kg (round to nearest 20mg)
  • Amikacin: 7.5 mg/kg (round to nearest 5 mg)

Step 3. Calculate maintenance dose and choose dosing interval based on creatinine clearance (CrCl)

Tobramycin/gentamicin: 1.7 mg/kg  
(round to nearest 20mg)
Amikacin: 5 mg/kg (round to nearest 50mg)
CrCl (mL/min) Dosing Interval CrCl (mL/min) Dosing Interval
Greater than or equal to 60 q8h Greater than or equal to 40 q12h
40-59 q12h Less than 40 q24h
20-39 q24h HD After each HD
Less than 20* Once, then based on levels CRRT q24-48h
HD After each HD    
CRRT q24-48h*    

*Give one dose, check level in 24h, re-dose when level less than 2 mg/L

Step 4. Therapeutic drug monitoring

  • TROUGH level 30 minutes prior to 4th dose
  • PEAK level 30-60 minutes after the end of the 4th dose infusion
  • Repeat once weekly or more
  Indication Tobramycin/Gentamicin Amikacin
Desired Peak* UTIs 3-5 mg/L 16-20 mg/L
Serious Infections 5-10 mg/L 20-25 mg/L
Desired Trough Less than 2 mg/L Less than 8 mg/L

*Target peak may need to be in excess of 10 mg/L (greater than 25mg/L for amikacin) for patients with severe Gram-negative infections

Other Monitoring:

  • Serum creatinine 2 times or more per week; daily clinical assessment of acute changes to hearing or balance/dizziness; audiogram as necessary

Last reviewed Jan 2023

  • Should discuss with CF team as soon as possible
  • Tobramycin is preferred agent – round to nearest 20mg
  • Infusion should be over 1 hour
  • If  CrCl less than 60 mL/min: avoid or consult the CF team

^ or use previous known dose if no change in weight or kidney function
*After the end of the infusion

Obese Dosing

  • If body weight is 30% above ideal body weight (IBW), calculate Dosing Weight 
  • IBW (male) = 50 kg + 2.3 kg x (each inch above 5 feet)
  • IBW (female) = 45.5 kg + 2.3 kg x (each inch above 5 feet)
  • Dosing Weight: IBW + 0.4 x (actual body weight - IBW)

Other Monitoring 

  • Creatinine at least 3 times a week, daily if over 40 years or kidney injury
  • Daily assessment of acute changes to hearing or balance. Inform patient of risks of ototoxicity and to report any symptoms

Consult CF team or pharmacy for dose adjustments

  • If trough level pre 3rd dose is greater than 1mg/mL, change dosing interval to q36 hours
  • If both levels are low, increase dose by 40-100 mg.
  • If both levels are high, decrease dose by 40-100 mg.
  • If levels are discordant, consult CF physician and/or clinical pharmacist.
  • If dose is changed, repeat levels after new third dose.
  • If levels are within the therapeutic range, recheck levels twice a week.

Last updated January 2023

Ensure gentamicin synergy susceptible by high-level aminoglycoside resistance testing (HLAR)

  • Used for:
    • Enterococcus spp. 
    • Staphylococcal prosthetic valve endocarditis
      • NOT indicated for Staphylococcal native valve endocarditis
    • Some Streptococcal spp. depending on penicillin MIC
  • Recommend consulting Infectious Diseases 

Step 1. Calculate dosing rate

Non- obese: Dose based on actual body weight
Obese: if body weight is 30% above ideal body weight (IBW), calculate Dosing Weight
  Dosing Weight: IBW + 0.4 x (actual body weight - IBW)
  Ideal body weight (IBW) equation:
  • IBW (male) = 50 kg + 2.3 kg*(each inch above 5 feet)
  • IBW (female) = 45.5 kg + 2.3 kg*(each inch above 5 feet)

Step 2. Calculate maintenance dose

Use dosing weight:

  • Gentamicin: 1 mg/kg (round to nearest 20mg)

Step 3. Choose dosing interval based on creatinine clearance

Creatinine Clearance (mL/min) Dosing Interval
Greater than 60 q8h
40-59 q12h
20-39 q24h
Less than 20 Once, then based on levels
HD After each HD
CRRT q24-48h

Step 4. Therapeutic drug monitoring

  • TROUGH level 30 minutes prior to 4th dose
  • PEAK level 30-60 minutes after the end of the 4th dose infusion
  • Repeat once weekly or more
  Desired Peak Desired Trough
Gentamicin 3-5 mg/L Less than 2 mg/L

Other Monitoring:

  • Serum creatinine 2 or more times per week; daily clinical assessment of acute changes to hearing or balance/dizziness; audiogram as necessary

Last reviewed Jan 2023

1. Ali MZ et al. A Meta-Analyis of the Relative Efficacy and Toxicity of Single Daily Dosing Versus Multiple Daily Dosing of Aminoglycosides. Clin Infect Dis. 1997;24(5):796-809.

2. Bailey TC et al. A meta-analysis of extended-interval dosing versus multiple daily dosing of aminoglycosides. Clin Infect Dis. 1997;24(5):786-795.

3. Barza M et al. Single or multiple daily doses of aminoplycosides:a meta-analysis. BMJ. 1996;312(7027):338-45.

4. Stankowicz MS et al. Once-daily aminoglycoside dosing: An update on current literature. Am J Health Syst Pharm. 2015;72(16):1357-64.

5. Pharmacy Services, QEII Health Sciences Centre. Clinical Pharmacokinetic Handbook. 2005.

6. Antimicrobial Stewardship, Sunnybrook Health Sciences Centre. Antimicrobial Guideline: Aminoglycosides. 2019. https://sunnybrook.ca/glossary/item.asp?g=5&c=0&i=1463&page=. Accessed January 2020.

7. SHS + UHN Antimicrobial Stewarship Program. Initiating Aminoglycosides Safely – an Interactive Algorithm. 2016. https://www.antimicrobialstewardship.com/antimicrobials. Accessed January 2020.

8. Lee J et al. Predictive performance of gentamicin dosing nomograms. Drug Des Devel Ther. 2014;8:1097-1106.

9. Ryback MJ et al. Prospective Evaluation of the Efect of an Aminoglycoside Dosing Regimen on Rates of Observed Nephrotoxicity and Ototoxicity.Antimicrob Agents Chemother. 1999;43(7):1549-55.

Last reviewed Jan 2023