Aminoglycosides

AMINOGLYCOSIDES

The aminoglycosides are a large group of broad-spectrum antibiotics possessing significant activity against many Gram-negative bacteria and a more limited range of Gram-positive organisms. The antibiotics are all bactericidal and administered by injection because they are poorly absorbed from the gastrointestinal tract. They are cationic, water-soluble drugs that interfere with protein synthesis in bacteria by binding to the 30S ribosome subunit (which is not possessed by mammals).

The earliest aminoglycoside was streptomycin, discovered in 1944, and at least 10 more were discovered over the next 30 years although not all were marketed. However, their susceptibility to resistance development by inactivating enzymes and other mechanisms, and their potential to cause damage to the kidneys and the eighth cranial nerve (to the ear) limited the use of the naturally occurring aminoglycosides and lead to the development of several semisynthetic members of the group.

Streptomycin was the first effective antibiotic for the treatment of tuberculosis and it is still used as a second line drug for that purpose, although it now has few other applications. Neomycin was also discovered in the 1940s, but its high toxicity curtailed its use as a systemic drug and it is now largely restricted to ophthalmic and topical products, although in this limited field its use is widespread, and it is often encountered with other antibiotics or with steroids in antibiotic/anti-inflammatory creams. Oral preparations of neomycin are employed, again often in combination with other antibiotics, to reduce the bacterial population of the colon prior to surgery.

Three of the most important aminoglycosides currently available are gentamicin, tobramycin and amikacin. The first two of these are naturally occurring drugs discovered in the 1960s, whilst amikacin is a semisynthetic derivative of kanamycin, which it has superseded. Gentamicin, the drug of choice in the UK, is used alone or in combination with β-lactam antibiotics (with which it exhibits synergy) both for ‘blind’ therapy of infections prior to identification of the infecting organism, and for the treatment of bacterial endocarditis and serious Gram-negative infections; in common with other members of the group, it has no activity against anaerobes. Amikacin has similar applications, but is more stable to inactivation by bacterial enzymes, though rather less potent, than gentamicin. All three antibiotics possess useful activity against Ps. aeruginosa and are particularly valuable, again with β-lactams, for the eradication or suppression of this organism in the lungs of cystic fibrosis patients; tobramycin is slightly more active than gentamicin against Ps. aeruginosa and for this reason it is more frequently used for this purpose than any other.

Aminoglycosides have in the past often been administered twice or three times per day, but the more recent trend has been towards a single, higher, daily dose. Although not suitable in all situations, once-daily dosing is undoubtedly more convenient and considered to be at least as safe and efficacious. Regardless of the dosing schedule however, monitoring of serum levels during treatment to avoid potential toxic high concentrations or ineffective low ones is still an integral part of aminoglycoside therapy.