Aminoglycosides bind to the aminoacyl site of 16S ribosomal RNA and disrupt bacterial peptide elongation, which is usually bactericidal against susceptible aerobic gram-negative bacilli. Microbiologic activity is pH-dependent, and acidic environments like those found in the lung and bronchial secretions may decrease the antimicrobial effect.
The emergence of aminoglycoside resistance during the treatment of gram-negative infections is infrequent. Still, it can occur through bacterial production of enzymes that inactivate the drug or methylate the target 16S ribosomal RNA and through an efflux system that decreases aminoglycoside accumulation.
Aminoglycosides are most frequently used with another antibacterial agent for empiric therapy of septicemia, nosocomial respiratory tract infections, complicated urinary tract infections, complicated intraabdominal infections, and osteomyelitis caused by aerobic gram-negative bacilli. They are often discontinued in favor of less toxic antibiotics once organism identity and susceptibility have been confirmed.
Combination therapy with gentamicin is frequently used to treat invasive infections caused by enterococci in the absence of high-level resistance.
Parenteral aminoglycosides are also used as part of a regimen for mycobacterial infections and, as a single agent, for treating tularemia, plague, and uncomplicated urinary tract infections caused by drug-resistant gram-negative organisms.
Optimal dosing of aminoglycosides should lead to rapid attainment of therapeutic concentrations, correlated with improved outcomes while minimizing toxicity. The first steps in aminoglycoside administration include determining the dosing weight and estimating renal function.
Parenteral aminoglycosides can be administered using a traditional intermittent dosing strategy that uses smaller doses given several times each day or an extended-interval dosing strategy that uses high doses administered at an extended time interval. These two strategies have comparable efficacy and safety. High dose extended-interval administration takes advantage of the pharmacodynamic properties of aminoglycosides. It offers greater ease of preparation, administration, and monitoring.
For most patients with suspected or documented moderate to severe infections due to gram-negative aerobic bacteria in whom an aminoglycoside is being administered and who are expected to exhibit more predictable aminoglycoside pharmacokinetics, extended-interval rather than traditional intermittent dosing is preferred. Certain patient groups may exhibit altered aminoglycoside pharmacokinetics, rendering extended-interval dosing less useful or effective.
Traditional intermittent dosing of gentamicin and tobramycin in adults involves administration of a loading dose based on indication, administration of a maintenance dose at a specific interval several times daily depending on renal function, and subsequent monitoring of serum concentrations to guide dose adjustments.
Extended-interval dosing of gentamicin and tobramycin in adults involves administration of a higher dose administered at an extended interval based upon the estimated or measured creatinine clearance. Extended-interval dosing targets a peak serum concentration of 15 to 20 mcg/mL and trough concentrations less than 1 mcg/mL. Dose adjustments can be made using a published nomogram or through individualized monitoring with the assistance of a pharmacist.
Target serum concentrations for amikacin are a peak of 20 to 30 mcg/mL and a trough of at least < 8 mcg/mL (often targeted at 1 to 4 mcg/mL). Higher peak concentrations up to 40 mcg/mL are often recommended for serious, life-threatening infections. For patients receiving traditional intermittent dosing of amikacin, the usual loading dose is 7.5 mg/kg, with a subsequent maintenance dose of 15 mg/kg per day in two or three divided doses. A 15 mg/kg dose is administered for patients receiving extended-interval dosing of amikacin. The initial dosing interval is based upon the estimated or measured creatinine clearance.
Specific or additional dosing adjustments are indicated in certain populations, including children, patients on dialysis, burn patients, the elderly, and those receiving aminoglycosides as == therapy with beta-lactams for serious gram-positive infections. Septic patients undergoing aggressive fluid resuscitation in resolving or evolving acute renal failure often warrant especially close monitoring.
For serious infections due to typical gram-negative bacteria, except uncomplicated lower urinary tract infections, aminoglycosides are generally used with other agents that have gram-negative activity regardless of the dosing method.
Aminoglycosides demonstrate both post-antibiotic effect and concentration-dependent killing. Aminoglycosides reach concentrations in the urine 25 to 100 fold that of serum. Still, they have poor penetration into the CSF, biliary tree, and bronchial secretions. They are effectively removed by both hemodialysis and peritoneal dialysis.
The primary toxicities of aminoglycosides are nephrotoxicity, which is generally reversible, and ototoxicity, both vestibular and cochlear. Neuromuscular blockade is a rare but serious adverse effect, and myasthenia gravis is an absolute contraindication to aminoglycoside use.