Quick Guide for Once-Daily Aminoglycoside Dosing

July 25, 2016

Extended interval dosing provides the patient with higher dose as well as less frequent dosing interval.

What are the benefits of once-daily aminoglycoside dosing over traditional dosing?

First, it provides a higher dose with less frequent administration, whereas traditional dosing involves a lower dose with more frequent administration. Study results show that longer dosing intervals translate to continuous aminoglycoside bactericidal activity with lower odds of resistance. Traditional dosing, on the other hand, involves frequent aminoglycoside exposure, resulting in decreased bacterial killing.

Second, it allows for a more rapid killing of the organism. This is because aminoglycosides are concentration-dependent killers. Study results show that lower trough levels may be associated with less overall toxicity, and once-daily administration results in significantly less nephrotoxicity than traditional dosing, and possibly less or equal ototoxicity.

Finally, it offers greater convenience than traditional dosing. It’s a simpler dosing process with less chance for calculation errors that’s less time consuming and more cost-effective.

What are the exclusion criteria for once-daily dosing?

If patients meet any of the following exclusion criteria, they aren’t candidates for once-daily aminoglycoside dosing and must refer to traditional dosing:

  • Severe renal disease (creatinine clearance [CrCl] <30 mL/min)
  • Dialysis
  • Cystic fibrosis
  • Older than 70
  • Ascites/severe liver disease
  • Cirrhosis
  • Extensive burns (>20% of total body SA)
  • History or signs of vestibular toxicity and/or hearing loss
  • Pregnancy or postpartum lactating
  • Younger than 12 (because of lack of studies)
  • Febrile neutropenic
  • Synergy for Gram-positive infections
  • Enterococcal endocarditis

What are the indications for once-daily dosing?

Documented or suspected Gram-negative infections, urinary tract infection (UTI), pyelonephritis, sepsis, meningitis, open fracture, osteomyelitis, suspected Pseudomonas infection, pneumonia, pelvic inflammatory disease, wound infections, intraabdominal infections, bacteremia, and/or cystitis.

How do you estimate CrCl using the Cockroft-Gault equation?

Once the patient’s ideal body weight (IBW) is determined, it should be plugged into the Cockroft-Gault equation in order to calculate CrCl.

If the patient isn’t obese, IBW is used. However, if the patient’s total body weight is >120% of IBW, adjusted body weight must be calculated and used. If the patient’s total body weight is less than IBW, total body weight is used for the dosing weight.

How do you determine initial dose?

This depends on the indication and type of aminoglycoside initiated. Amikacin offers the broadest spectrum and is often reserved to treat resistant pathogens developed during therapy. It’s the preferred agent to treat all mycobacterial infections except Mycobacterium chelonae, for which tobramycin is recommended. Tobramycin is reserved for P. aeruginosa. Gentamicin is widely used, but resistance is an issue. Overall, gentamicin is more active against Serratia marcescens.

If the patient is started on either gentamicin or tobramycin and has a suspected Pseudomonas infection, pneumonia, osteomyelitis, meningitis, or sepsis, 7 mg/kg is used to calculate the initial dose. The 7 mg/kg dose uses the Hartford nomogram for interval adjustment.

If patient is started on either gentamicin or tobramycin and has a UTI, open fracture/surgery prophylaxis, cystitis, wound infections, pyelonephritis, or intraabdominal/pelvic infection, 5 mg/kg is warranted. The 5 mg/kg dose uses the Barnes-Jewish Hospital nomogram for interval adjustments.

The 7 mg/kg and 5 mg/kg dosing intervals are both based on time from the start of infusion and are rounded to the nearest 20 mg dose. Measurement of serum level can be repeated if plot of serum concentration is beyond the 48-hour section of the nomogram.

If the patient is initiated on amikacin, the starting dose is 15 mg/kg, which is rounded to the nearest 25 mg. This also uses Hartford nomogram for interval adjustment.

How do you determine dosing interval?

The dosing interval for gentamicin, tobramycin, and amikacin is based on CrCl:

  • CrCl ≥60 mL/min: every 24-hour interval
  • CrCl 40-59 mL/min: every 36-hour interval
  • CrCl 20-39 mL/min: every 48-hour interval
  • CrCl <20 mL/min: high-dose, extended-interval isn’t recommended

How do you monitor these patients?

It’s recommended to obtain a random serum level 6 to 14 hours (for Hartford nomogram) and 8 to 12 hours (for Barnes-Jewish nomogram) after the start of the initial infusion. The resultant level is then plotted on the nomogram, in which optimal dosing interval can be determined.

The desired/target trough levels for gentamicin and tobramycin is <1 mcg/mL or undetectable, but for amikacin, it’s less than 4 mcg/mL or undetectable. The desired/target peak levels for gentamicin and tobramycin is 16-20 mcg/mL, but for amikacin, it’s 40-60 mcg/mL.

If the trough is undetectable or the patient has no renal dysfunction, it’s recommended to check the patient’s trough at minimum once-weekly and serum creatinine and BUN twice-weekly. If the patient is unstable or renal dysfunction is present, it’s recommended to check trough, serum creatinine, and BUN more frequently. Trough is monitored for toxicity in renal insufficiency patients, those with a serum creatinine increase of 0.5 mg/dL, and those with >30% from baseline when taking aminoglycoside.

How do you monitor for toxicity?

Nephrotoxicity and ototoxicity are the most common toxicities associated with aminoglycosides.

Nephrotoxicity is reversible, and serum creatinine must be measured at least twice-weekly. If the serum creatinine increases by 0.5 mg/dL or 30% increase from baseline, traditional dosing is warranted. Study results show that aminoglycoside administration during afternoon time periods have the lowest occurrence of nephrotoxicity.

For ototoxicity, it’s suggested that patients get screened biweekly. It’s also recommended to check patients’ baseline visual acuity using the Snellen pocket card by having them shake their head and re-read the card. If patient loses 2 lines of visual acuity, audiology exam is warranted.