CHEMISTRY AND PHARMACOKINETICS

Aminoglycoside antibiotics are composed of amino sugars linked through glycosidic bonds. The amino groups are highly basic and become extensively protonated and ionized in body fluids. For this reason, the aminoglycosides are poorly absorbed from the gut and must be administered parenterally for the treatment of systemic infections. Occasionally, they are administered orally to treat gastrointestinal infections such as neonatal necrotizing enterocolitis. They are also administered topically to treat infections of the skin, mucous membranes, and ocular tissues.

Because of their highly ionized nature, aminoglycosides do not penetrate tissue cells significantly, and their volumes of distribution are similar to the extracellular fluid volume. Aminoglycosides also have poor penetration of the meninges, even when the meninges are inflamed, and intrathecal administration may be required to treat meningitis.

The aminoglycosides are not metabolized. They are excreted primarily by renal glomerular filtration, with little tubular reabsorption. The renal clearance of aminoglycosides is approximately equal to the creatinine clearance, because creatinine is also filtered at the glomerulus but is not secreted or reabsorbed significantly by the tubules. Because the clearance of aminoglycosides is proportional to the glomerular filtration rate, the dosage of aminoglycosides must be reduced in patients with renal impairment. In most cases, this is accomplished by increasing the interval between doses.

The plasma concentrations of aminoglycosides are routinely measured to ensure adequate dosage and to minimize toxicity. The peak concentration is found about 30 minutes after completing an intravenous infusion of an aminoglycoside, whereas the trough concentration is found immediately before administration of the next dose. Optimal peak and trough concentrations have been established and can be used to guide dosage adjustments for individuals receiving the standard regimen of three daily doses given at 8-hour intervals. For example, therapeutic concentrations of gentamicin and tobramycin are usually between 4 and 8 mg/L. A peak concentration above 12 mg/L or a trough concentration above 2 mg/L is considered toxic and indicates the need to reduce the dosage of gentamicin or tobramycin. Therapeutic concentrations of amikacin are between 16 and 32 mg/L, and the toxic peak and trough concentrations are above 35 mg/L and above 10 mg/L, respectively.

SPECTRUM AND INDICATIONS

The aminoglycosides are highly active against a wide range of aerobic gram-negative bacilli, and these antibiotics are now the most commonly used agents worldwide in the treatment of gram-negative bacterial infections. Gram-negative organisms have become increasingly resistant to β-lactam antibiotics and fluoroquinolones. Consequently, aminoglycosides have undergone resurgence in use.

Of the five aminoglycosides listed in Table 39–2, streptomycin is the least toxic, but it is also the least active against most gram-negative bacilli. Streptomycin is primarily used to treat tuberculosis and infections caused by Yersinia pestis (plague) and Francisella tularensis (tularemia).

Tobramycin is the most active aminoglycoside against many strains of P. aeruginosa, whereas gentamicin is usually more active against members of the family Enterobacteriaceae (Escherichia coli, Klebsiella spp. and others). Gentamicin is also used in combination with a penicillin to treat serious enterococcal, staphylococcal, or viridans group streptococcal infections. Amikacin is more resistant to bacterial enzymes that inactivate aminoglycosides, and it is active against some strains resistant to gentamicin and tobramycin.

BACTERIAL RESISTANCE

Resistance to aminoglycosides is primarily caused by inactivation of the drugs by bacterial enzymes that conjugate the drugs with acetate, phosphate, or adenylate. Resistance to aminoglycosides can also be caused by decreased binding of the drugs to the 30S ribosomal subunit or to decreased uptake of the drugs by porins in bacterial membranes (Table 39–3). Both plasmid and chromosomal genes are involved in resistance to aminoglycosides.

TABLE 39–3 Bacterial Resistance to Protein Synthesis Inhibitors

ADVERSE EFFECTS

The most serious adverse effects of aminoglycosides are nephrotoxicity and ototoxicity. The risk of toxicity is related to the dosage and duration of treatment and varies with the specific drug. Irreversible toxicity can occur, even after use of the drug is discontinued, but serious toxicity is less likely if the offending drug is discontinued at the earliest sign of dysfunction.

Aminoglycosides are the most common cause of drug-induced renal failure. When the drugs accumulate in proximal tubule cells, they can cause acute tubular necrosis. Aminoglycosides also cause glomerular toxicity. These effects impair renal function and lead to a rise in plasma concentrations of the aminoglycosides. The elevated drug concentrations can further impair renal function and contribute to ototoxicity. Hence, it is important to monitor renal function and plasma aminoglycoside concentrations and to adjust the aminoglycoside dosage accordingly. Increasing the interval between doses to 24 hours or longer in persons with impaired renal function decreases the likelihood of toxicity.

Ototoxicity is associated with the accumulation of aminoglycosides in the labyrinth and hair cells of the cochlea, and has been attributed to activation of caspase-dependent apoptosis (programmed cell death) in hair cells. Patients can experience both vestibular and cochlear toxicity. Manifestations of vestibular toxicity include dizziness, impaired vision, nystagmus, vertigo, nausea, vomiting, and problems with postural balance and walking. Cochlear toxicity is characterized by tinnitus and hearing impairment and can lead to irreversible deafness. Often, a delay occurs between drug administration and the onset of symptoms, so many hospitalized patients are ambulatory before signs of toxicity appear.

The aminoglycosides vary in their tendency to cause cochlear or vestibular toxicity. Amikacin produces more cochlear toxicity (deafness), whereas gentamicin and streptomycin cause more vestibular toxicity. Tobramycin appears to cause similar degrees of cochlear and vestibular toxicity.

Neomycin is the most nephrotoxic aminoglycoside, and its use is limited to topical treatment of superficial infections. Neomycin is available in ointments and creams in combination with bacitracin and polymyxin. These triple-antibiotic preparations have been shown to prevent infections after minor skin trauma. Bacitracin provides gram-positive coverage, polymyxin provides gram-negative coverage, and neomycin is active against both gram-positive and gram-negative organisms. Neomycin can elicit hypersensitivity reactions, especially with long-term administration, and products containing only bacitracin and polymyxin are also available.

CHEMISTRY AND PHARMACOKINETICS

The tetracycline antibiotics are four-ring anthracycline compounds produced by Streptomyces species. Doxycycline, minocycline, and tetracycline are semisynthetic derivatives of older tetracyclines, whereas tigecycline is a semisynthetic glycylcycline compound. The properties and clinical uses of these drugs are outlined in Tables 39–1 and 39–2.

The oral bioavailability of the tetracyclines varies from 70% for tetracycline to over 90% for doxycycline and minocycline. All tetracyclines bind divalent and trivalent cations, including calcium, aluminum, and iron. For this reason, their oral bioavailability is reduced if they are taken with foods or drugs containing these ions. Dairy products reduce the oral bioavailability of tetracycline but have little effect on the bioavailability of doxycycline and minocycline. None of the tetracyclines, however, should be taken with antacids or iron supplements.

The tetracycline drugs undergo minimal biotransformation and are excreted primarily in the urine and feces. Unlike other tetracyclines, doxycycline is not dependent on renal elimination, and doses do not need to be adjusted in persons with renal insufficiency.