Aminoglycoside Antibiotics: Pharmacokinetics

PHARMACOKINETICS

The blood plasma drug concentrations achieved during multiple daily dose therapy with aminoglycosides usu-ally correlates with clinical outcome in patients with bacteremia and in patients with pneumonia. Raising the aminoglycoside plasma concentration to its in vitro minimum inhibitory concentration against the isolated pathogen is a useful indicator of the adequacy of amino-glycoside dosing.

Both the rate and extent of gastrointestinal absorp-tion of individual aminoglycosides are generally quite low. For example, more than 95% of an oral dose of neomycin is excreted unchanged in the feces. The sys-temic bioavailability of the aminoglycosides is low across other membranes as well. For example, gentam-icin is poorly absorbed from a topical ophthalmic preparation, and there is little systemic absorption of ei-ther inhaled tobramycin or aminoglycosides instilled into the urinary bladder. Neomycin bioavailability across intact skin is also low, although absorption across damaged skin can be significant: nephrotoxicity can oc-cur in burn patients treated with topical neomycin.

Because of their aqueous solubility and modest binding to plasma and tissue proteins, the distribution of the aminoglycosides corresponds to that of the extra-cellular fluid. Four compartments can be distinguished. The central compartment corresponds to the intravas-cular space; the rapidly equilibrating compartment cor-responds to the extracellular visceral space; the slowly equilibrating compartment largely corresponds to that of skeletal muscle; and the extremely slowly equilibrat-ing compartment presumably corresponds to that of bone, proximal renal tubules, otolymph, and other tissue where binding to phospholipids or mineral matrix oc-curs. Gentamicin fails to reach intraocular fluid or cere-brospinal fluid in significant concentrations after intra-venous injection, although it may reach bactericidal levels in cerebrospinal fluid in patients with meningeal inflammation, such as occurs in meningitis. However, di-rect intrathecal injection of gentamicin may still be re-quired for reliable bactericidal levels.

Most of the enzymes that catalyze the metabo-lism of foreign compounds are found inside cells. As aminoglycosides do not penetrate most cells, they do not undergo any significant metabolism. Nearly all of an intravenous dose is cleared by the kidneys and can be recovered in the urine. Aminoglycoside clearance is ap-proximately equal to that of the glomerular filtration rate, resulting in fairly high urine concentrations; the latter contributes to the efficacy of the aminoglycosides in urinary tract infections.