Aminoglycosides: bactericidal inhibitors of protein synthesis

Aminoglycosides: bactericidal inhibitors of protein synthesis

The aminoglycosides are narrow-spectrum antibiotics used primarily against aerobic gram-negative bacilli. These drugs disrupt protein synthesis, resulting in rapid bacterial death. The aminoglycosides can cause serious injury to the inner ear and kidney. Because of these toxicities, indications for these drugs are limited. All of the aminoglycosides carry multiple positive charges. As a result, they are not absorbed from the GI tract, and hence must be administered parenterally to treat systemic infections. In the United States, seven aminoglycosides are approved for clinical use. The agents employed most commonly are gentamicin, tobramycin, and amikacin.

Basic pharmacology of the aminoglycosides

Chemistry

The aminoglycosides are composed of two or more amino sugars connected by a glycoside linkage, hence the family name. At physiologic pH, these drugs are highly polar polycations (ie, they carry several positive charges), and therefore cannot readily cross membranes. As a result, aminoglycosides are not absorbed from the GI tract, do not enter the cerebrospinal fluid, and are rapidly excreted by the kidneys. Structural formulas for the three major aminoglycosides are shown in Figure 87–1.

Figure 87–1 Structural formulas of the major aminoglycosides.

Figure 87–1 Structural formulas of the major aminoglycosides.

Mechanism of action

The aminoglycosides disrupt bacterial protein synthesis. As indicated in Figure 87–2, these drugs bind to the 30S ribosomal subunit, and thereby cause (1) inhibition of protein synthesis, (2) premature termination of protein synthesis, and (3) production of abnormal proteins (secondary to misreading of the genetic code).

Figure 87–2 Mechanism of action of aminoglycosides.
A, Protein synthesis begins with binding of the 50S and 30S ribosomal subunits to messenger RNA (mRNA), followed by attachment of the first amino acid of the new protein to the 50S subunit. As the ribosome moves down the mRNA strand, additional amino acids are added to the growing peptide chain. When the new protein is complete, it separates from the ribosome, and then the ribosomal subunits separate from the mRNA. B, Aminoglycosides bind to the 30S ribosomal subunit and can thereby (1) block initiation, (2) terminate synthesis before the new protein is complete, and (3) cause misreading of the genetic code, which causes synthesis of faulty proteins.

Figure 87–2 Mechanism of action of aminoglycosides.
A, Protein synthesis begins with binding of the 50S and 30S ribosomal subunits to messenger RNA (mRNA), followed by attachment of the first amino acid of the new protein to the 50S subunit. As the ribosome moves down the mRNA strand, additional amino acids are added to the growing peptide chain. When the new protein is complete, it separates from the ribosome, and then the ribosomal subunits separate from the mRNA. B, Aminoglycosides bind to the 30S ribosomal subunit and can thereby (1) block initiation, (2) terminate synthesis before the new protein is complete, and (3) cause misreading of the genetic code, which causes synthesis of faulty proteins.

The aminoglycosides are bactericidal. Cell kill is concentration dependent. Hence, the higher the concentration, the more rapidly the infection will clear. Of note, bactericidal activity persists for several hours after serum levels have dropped below the minimal bactericidal concentration, a phenomenon known as the postantibiotic effect.

Bacterial kill appears to result from production of abnormal proteins rather than from simple inhibition of protein synthesis. Studies suggest that abnormal proteins become inserted in the bacterial cell membrane, causing it to leak. The resultant loss of cell contents causes death. Inhibition of protein synthesis per se does not seem the likely cause of bacterial death. Why? Because complete blockade of protein synthesis by other antibiotics (eg, tetracyclines, chloramphenicol) is usually bacteriostatic—not bactericidal.

Microbial resistance

The principal cause for bacterial resistance is production of enzymes that can inactivate aminoglycosides. Among gram-negative bacteria, the genetic information needed to synthesize these enzymes is acquired through transfer of R factors. To date, more than 20 different aminoglycoside-inactivating enzymes have been identified. Since each of the aminoglycosides can be modified by more than one of these enzymes, and since each enzyme can act on more than one aminoglycoside, patterns of bacterial resistance can be complex.

Of all the aminoglycosides, amikacin is least susceptible to inactivation by bacterial enzymes. As a result, resistance to amikacin is uncommon. To minimize emergence of resistant bacteria, amikacin should be reserved for infections that are unresponsive to other aminoglycosides.

Antimicrobial spectrum

Bactericidal effects of the aminoglycosides are limited almost exclusively to aerobic gram-negative bacilli. Sensitive organisms include Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Proteus mirabilis, and Pseudomonas aeruginosa. Aminoglycosides are inactive against most gram-positive bacteria.

Aminoglycosides cannot kill anaerobes. To produce antibacterial effects, aminoglycosides must be transported across the bacterial cell membrane, a process that is oxygen dependent. Since, by definition, anaerobic organisms live in the absence of oxygen, these microbes cannot take up aminoglycosides, and hence are resistant. For the same reason, aminoglycosides are inactive against facultative bacteria when these organisms are living under anaerobic conditions.

Therapeutic use

Parenteral therapy.

The principal use for parenteral aminoglycosides is treatment of serious infections due to aerobic gram-negative bacilli. Primary target organisms are Pseudomonas aeruginosa and the Enterobacteriaceae (eg, E. coli, Klebsiella, Serratia, Proteus mirabilis).

One aminoglycoside—gentamicin—is now commonly used in combination with either vancomycin or a beta-lactam antibiotic to treat serious infections with certain gram-positive cocci, specifically Enterococcus species, some streptococci, and Staphylococcus aureus.

The aminoglycosides used most commonly for parenteral therapy are gentamicin, tobramycin, and amikacin. Selection among the three depends in large part on patterns of resistance in a given community or hospital. In settings where resistance to aminoglycosides is uncommon, either gentamicin or tobramycin is usually preferred. Of the two, gentamicin is less expensive and may be selected on this basis. Organisms resistant to both gentamicin and tobramycin are usually sensitive to amikacin. Accordingly, in settings where resistance to gentamicin and tobramycin is common, amikacin may be preferred for initial therapy.

Aminoglycosides are not absorbed from the GI tract, and hence oral therapy is used only for local effects within the intestine. In patients anticipating elective colorectal surgery, oral aminoglycosides have been given prophylactically to suppress bacterial growth in the bowel. One aminoglycoside—paromomycin—is used to treat intestinal amebiasis.

Topical therapy.

Neomycin is available in formulations for application to the eyes, ears, and skin. Topical preparations of gentamicin and tobramycin are used to treat conjunctivitis caused by susceptible gram-negative bacilli.

Pharmacokinetics

All of the aminoglycosides have similar pharmacokinetic profiles. Pharmacokinetic properties of the principal aminoglycosides are summarized in Table 87–1.

TABLE 87–1

Dosages and Pharmacokinetics of Systemic Aminoglycosides

		Total Daily Dose (mg/kg)^a^,^b	Half-Life in Adults (hr)	Therapeutic (Peak) Level^c^,^d (mcg/mL)	Safe Trough Level^e^,^f (mcg/mL)
Generic Name	Trade Name	Adults	Children	Therapeutic (Peak) Level^c^,^d (mcg/mL)	Safe Trough Level^e^,^f (mcg/mL)	Normal	Anuric
Amikacin	Amikin	15	15	2–3	24–60	15–30	Less than 5–10
Gentamicin	generic only	3–5^g	6–7.5^g	2	24–60	4–10^h	Less than 1–2ⁱ
Tobramycin	generic only	3–6	6–7.5	2–2.5	24–60	4–10	Less than 1–2ⁱ

^a The total daily dose may be administered as one large dose each day, or as two or three divided doses given at equally spaced intervals around-the-clock.

^b Because of interpatient variability, standard doses cannot be relied upon to produce appropriate serum drug levels, and hence dosage should be adjusted on the basis of serum drug measurements.

^c Measured 30 minutes after IM injection or completing a 30-minute IV infusion.

^d The peak values presented refer to levels obtained when the total daily dosage is given in divided doses, rather than as a single large daily dose.

^e Measured just prior to the next dose.

^f To minimize ototoxicity and nephrotoxicity, drug levels should drop below the listed values between doses.

^g When gentamicin is combined with either vancomycin or a beta-lactam antibiotic to treat certain gram-positive infections, the total daily dose is much lower (eg, about 1 mg/kg for adults).

^h These peak values apply when gentamicin is used to treat gram-negative infections, not when gentamicin is combined with vancomycin or a beta-lactam antibiotic to treat gram-positive infections.

ⁱ For severe infections, the trough may be higher (eg, less than 2-4 mcg/mL).

Absorption.

Because they are polycations, the aminoglycosides cross membranes poorly. As a result, very little (about 1%) of an oral dose is absorbed. Hence, for treatment of systemic infections, aminoglycosides must be given parenterally (IM or IV). Absorption following application to the intact skin is minimal. However, when used for wound irrigation, aminoglycosides may be absorbed in amounts sufficient to produce systemic toxicity.

Distribution.

Distribution of aminoglycosides is limited largely to extracellular fluid. Entry into the cerebrospinal fluid is insufficient to treat meningitis in adults. Aminoglycosides bind tightly to renal tissue, achieving levels in the kidney up to 50 times higher than levels in serum. These high levels are responsible for nephrotoxicity (see below). Aminoglycosides penetrate readily to the perilymph and endolymph of the inner ear, and can thereby cause ototoxicity (see below). Aminoglycosides can cross the placenta and may be toxic to the fetus.

Elimination.

The aminoglycosides are eliminated primarily by the kidney. These drugs are not metabolized. In patients with normal renal function, half-lives of the aminoglycosides range from 2 to 3 hours. However, because elimination is almost exclusively renal, half-lives increase dramatically in patients with renal impairment (see Table 87–1). Accordingly, to avoid serious toxicity, we must reduce dosage size or increase the dosing interval in patients with kidney disease.

Interpatient variation.

Different patients receiving the same aminoglycoside dosage (in milligrams per kilogram of body weight) can achieve widely different serum levels of drug. This interpatient variation is caused by several factors, including age, percent body fat, and pathophysiology (eg, renal impairment, fever, edema, dehydration). Because of variability among patients, aminoglycoside dosage must be individualized. As dramatic evidence of this need, in one clinical study it was observed that, in order to produce equivalent serum drug levels, the doses required ranged from as little as 0.5 mg/kg in one patient to a high of 25.8 mg/kg in another—a difference of more than 50-fold.

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Tags: Pharmacology for Nursing Care

Jul 24, 2016 | Posted by admin in NURSING | Comments Off

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