Aminoglycosides

Aminoglycosides are poorly absorbed orally but are well absorbed from the peritoneum, pleural cavity, joints, and denuded skin.

Aminoglycosides are usually given IV but may be given IM if IV access is unavailable. Aminoglycosides are distributed well into extracellular fluid except for vitreous humor, cerebrospinal fluid, respiratory secretions, and bile (particularly in patients with biliary obstruction). Intravitreous injection is required to treat endophthalmitis. Intraventricular injection is often required to reach intraventricular cerebrospinal fluid levels high enough to treat meningitis.

Aminoglycosides are excreted by glomerular filtration and have a serum half-life of 2 to 3 hours; the half-life increases exponentially as the glomerular filtration rate falls (eg, in renal insufficiency, in older adults).

Aminoglycosides are used for

• Serious gram-negative bacillary infections

Aminoglycosides are active against most gram-negative aerobic and facultative anaerobic bacilli but lack activity against anaerobes and most gram-positive bacteria, except for most staphylococci; however, some gram-negative bacilli and staphylococci are resistant.

Aminoglycosides are infrequently used alone, except when used for plague and tularemia. They are usually used with a broad-spectrum beta-lactam for severe infection suspected to be due to a gram-negative bacillary species. However, because of increasing aminoglycoside resistance, a fluoroquinolone can be substituted for the aminoglycoside in initial empiric regimens depending on the susceptibility patterns to fluoroquinolones in the local community. If the pathogen is found to be susceptible to the accompanying antibiotic, the aminoglycoside can be stopped after 2 to 3 days.

endocarditisgentamicingentamicinstreptomycin; in such cases, streptomycin should be used if these strains are susceptible to high levels of streptomycin.

ampicillin plus ceftriaxone rather than ampicillin plus gentamicin for Enterococcus faecalis endocarditis, even for strains without aminoglycoside resistance, because efficacy is similar and toxicity is less.

tularemia and plague and, with other antibiotics, to treat tuberculosis. Kanamycin may still play a role in the treatment of certain cases of multidrug-resistant tuberculosis in combination with other antibiotics.

Neomycin is available for eye, ear, oral, and rectal use and as a bladder irrigant. Oral neomycin is used topically against intestinal microbiota to prepare the bowel before surgery and to treat hepatic coma.

Aminoglycosides are contraindicated in patients who are allergic to them.

Aminoglycosides enter breast milk but are not well absorbed orally. Thus, they are considered compatible with use during breastfeeding.

All aminoglycosides cause

• Renal toxicity (often reversible)

• Vestibular and auditory toxicity (often irreversible)

• Prolongation of effects of neuromuscular blockers

Symptoms and signs of vestibular damage are vertigo and ataxia.

Risk factors for renal, vestibular, and auditory toxicity are

• Frequent or very high doses

• Very high blood levels of the drug

• Long duration of therapy (particularly > 3 days)

• Older age

• A preexisting renal disorder

• Coadministration of vancomycin, cyclosporine, amphotericin B, iodinated contrast agents, or other nephrotoxins

• For auditory toxicity, a genetic predisposition, preexisting hearing problems, and coadministration of loop diuretics

High doses given over a long period of time typically cause more concern about renal toxicity, but even low doses given for a short time can worsen renal function.

Patients receiving aminoglycosides for > 2 weeks and those at risk of vestibular and auditory toxicity should be monitored with serial audiography. At the first sign of toxicity, the medication should be stopped (if possible), or dosing should be adjusted.

Hypersensitivity reactions are uncommon except for contact dermatitis due to topical neomycin

Because toxicity depends more on duration of therapeutic levels than on peak levels and because efficacy is concentration-dependent rather than time-dependent, frequent doses are avoided. Once/day IV dosing is preferred over traditional intermittent dosing for most indications. Once/day dosing may not be preferred when used for gram-positive synergy (eg, enterococcal endocarditis) or in patients who are pregnant, have significant burns (> 20% of body surface area), or have renal failure (creatinine clearance < 40 mL/minute). IV aminoglycosides are typically infused over 30 to 60 minutes.

If a patient is below their ideal body weight (IBW), their total body weight (TBW) should be used to calculate doses. If TBW is greater than IBW but less than 120% of IBW, dosing should be based on IBW. If TBW is greater than 120% of IBW, adjusted body weight (ABW) should be used to calculate doses:

• IBW in kg (males): 50 + (2.3 × inches above 60 inches)

• IBW in kg (females): 45.5 + (2.3 × inches above 60 inches)

• ABW in kg: IBW + [0.4 × (TBW – IBW)]

In patients with normal renal function, once/day dosing is

If patients respond to the 7-mg/kg dose of gentamicin or tobramycin clinically and renal function continues to be normal, the once/day dose can be reduced to 5 mg/kg after the first few days of treatment.

In critically ill patients, peak serum levels should be determined after the first dose. In all patients, peak and trough levels are measured after the second or third dose (when the daily dose is divided) or when therapy lasts > 3 days, as well as after the dose is changed. Serum creatinine is measured every 2 to 3 days, and, if it is stable, serum aminoglycoside levels do not need to be measured again. Peak concentration is the level 60 minutes after an IM injection or 30 minutes after the end of a 30-minute IV infusion. Trough levels are measured during the 30 minutes before the next dose.

gentamicin (33.44 to 50.16 micromol/L) and tobramycingentamicin and tobramycin, trough levels should be < 1 mcg/mL (< 2.09 micromol/L for gentamicin and < 2.14 micromol/L for tobramycin) at 18 to 24 hours after the first dose with once/day dosing and between 1 and 2 mcg/mL (between 2.09 and 4.18 micromol/L for gentamicin and between 2.14 and 4.28 micromol/L for tobramycin) with traditional intermittent dosing.

For patients with renal insufficiency on traditional intermittent dosing, the loading dose is the same as that for patients with normal renal function; usually, the dosing interval is increased rather than the dose decreased. Guidelines for maintenance doses based on serum creatinine or creatinine clearance values are available, but they are not precise, and measurement of blood levels is preferred.

If patients are taking a high dose of a beta-lactam and an aminoglycoside, the high serum levels of the beta-lactam can inactivate the aminoglycoside in vitro in serum specimens obtained to determine drug levels unless the specimen is assayed immediately or frozen. If patients with renal failure are concurrently taking an aminoglycoside and a high-dose beta-lactam, the serum aminoglycoside level may be lower because interaction in vivo is prolonged.