M

ÇaQ Acetylase CAO Adenylase

Phosphorylase X Protected from enzyme

FIGURE 45-1 Sites of activity of various plasmid-mediated enzymes capable of inactivating aminoglycosides.

The symbol X indicates regions of the molecules that are protected from the designated enzyme. In gentamicin Cp R1=R2=CH3; in gentamicin C2, R1=CH3, R2=H; in gentamicin C1a, R1=R2=H.

The primary site of action of the aminoglycosides is the 30S ribosomal subunit; some aminoglycosides also bind to several sites on the 50S ribosomal subunit. Aminoglycosides disrupt the normal cycle of ribosomal function by interfering with the initiation of protein synthesis, leading to the accumulation of abnormal initiation complexes (Figure 45-2). Aminoglycosides also cause misreading of the mRNA template and incorporation of incorrect amino acids into the growing polypeptide chains. Aminoglycosides vary in their capacity to cause misreading, presumably owing to differences in their affinities for specific ribosomal proteins; bactericidal activity and the ability to induce misreading are strongly correlated.

microbial resistance to the aminoglycosides Bacteria may be resistant to aminoglycosides because of failure of the antibiotic to penetrate intracellularly, low affinity of the drug for the bacterial ribosome, or—most commonly—drug inactivation by moditying enzymes acquired by conjugative transfer of resistance plasmids. These enzymes phosphorylate, adenylate, or acetylate specific hydroxyl or amino groups (Figure 45-1), preventing binding to ribosomes. Amikacin is modified by only a few of these inactivating enzymes; thus, strains that are resistant to other aminoglycosides may remain susceptible to amikacin.

Mature protein

Growing polypeptide

Mature protein

FIGURE 45-2 Effects of aminoglycosides on protein synthesis. A. Aminoglycoside (represented by closed circles) binds to the 30S ribosomal subunit and interferes with initiation of protein synthesis by fixing the 30S-50S riboso-mal complex at the start codon (AUG) of mRNA. As 30S-50S complexes downstream complete translation of mRNA and detach, the abnormal initiation complexes, so-called streptomycin monosomes, accumulate, blocking further translation of the message. Aminoglycoside binding to the 30S subunit also causes misreading of mRNA, leading to B. premature termination of translation with detachment of the ribosomal complex and incompletely synthesized protein or C. incorporation of incorrect amino acids (indicated by the X), resulting in the production of abnormal or nonfunctional proteins.

Blocks initiation of protein synthesis

Blocks further 3' translation and elicits premature termination mRNA translation aminoglycoside = •

UU Incorporation of incorrect amino acid

FIGURE 45-2 Effects of aminoglycosides on protein synthesis. A. Aminoglycoside (represented by closed circles) binds to the 30S ribosomal subunit and interferes with initiation of protein synthesis by fixing the 30S-50S riboso-mal complex at the start codon (AUG) of mRNA. As 30S-50S complexes downstream complete translation of mRNA and detach, the abnormal initiation complexes, so-called streptomycin monosomes, accumulate, blocking further translation of the message. Aminoglycoside binding to the 30S subunit also causes misreading of mRNA, leading to B. premature termination of translation with detachment of the ribosomal complex and incompletely synthesized protein or C. incorporation of incorrect amino acids (indicated by the X), resulting in the production of abnormal or nonfunctional proteins.

Many clinical isolates of Enterococcus faecalis and E. faecium are highly resistant to all aminoglycosides. Infections caused by aminoglycoside-resistant strains of enterococci can be especially difficult to treat because of the loss of the synergistic bactericidal activity between a penicillin or vancomycin and an aminoglycoside and because these strains often also are cross-resistant to van-comycin and penicillin. Resistance to gentamicin indicates cross-resistance to tobramycin, amikacin, kanamycin, and netilmicin because one enzyme inactivates all of these drugs; this enzyme does not modify streptomycin, which is inactivated by another enzyme; consequently, gentamicin-resistant strains of enterococci may be susceptible to streptomycin. Natural resistance to aminoglycosides may be caused by failure of the drug to penetrate the cytoplasmic (inner) membrane. Penetration of drug across the outer membrane of gram-negative microorganisms into the periplasmic space can be slow, but resistance on this basis is unimportant clinically. Transport of aminoglycosides across the cytoplasmic membrane is an oxygen-dependent active process. Strictly anaerobic bacteria thus are resistant to these drugs because they lack the necessary transport system. Similarly, facultative bacteria are resistant when grown under anaerobic conditions. Resistance owing to mutations that alter ribosomal structure is relatively uncommon. Missense mutations in Escherichia coli that substitute a single amino acid in a crucial ribosomal protein may prevent streptomycin binding. Although highly resistant to streptomycin, these strains are not widespread in nature. Similarly, only 5% of strains of Pseudomonas aeruginosa exhibit such ribosomal resistance to streptomycin. It has been estimated that ~50% of the streptomycin-resistant strains of enterococci are ribosomally resistant. Because ribosomal resistance usually is specific for streptomycin, these strains remain sensitive to a combination of penicillin and gentamicin.

ANTIBACTERIAL SPECTRUM OF THE AMINOGLYCOSIDES The antibacterial activity of most aminoglycosides is directed primarily against aerobic gram-negative bacilli. Kanamycin, like streptomycin, has a more limited spectrum than the other aminoglycosides. Aminoglycosides have little activity against anaerobic microorganisms or facultative bacteria under anaerobic conditions. They should not be used as single agents for infections caused by gram-positive bacteria. Combined with a cell wall-active agent, such as a penicillin or vancomycin, aminoglycosides produce synergistic bactericidal effects against enterococci, streptococci, and staphylococci.

Aerobic gram-negative bacilli vary in their susceptibility to the aminoglycosides. Tobramycin and gentamicin exhibit similar activity against most gram-negative bacilli, although tobramycin usually is more active against P. aeruginosa and some Proteus spp. Many gram-negative bacilli that are resistant to gentamicin because of plasmid-mediated inactivating enzymes also are resistant to tobramycin. Amikacin, and in some instances netilmicin, retain their activity against gentamicin-resistant strains because they are a poor substrate for many of the aminoglycoside-inactivating enzymes.

ABSORPTION, DISTRIBUTION, DOSING, AND ELIMINATION OF THE AMINOGLYCOSIDES ABSORPTION

The aminoglycosides are highly polar and, thus, poorly absorbed from the gastrointestinal (GI) tract. Instillation of these drugs into body cavities with serosal surfaces may result in rapid absorption and unexpected toxicity (e.g., neuromuscular blockade). Toxic levels also may result from sustained topical application to large wounds, burns, or cutaneous ulcers, particularly with renal insufficiency. Long-term oral or rectal administration of aminoglycosides may result in accumulation to toxic concentrations in patients with renal impairment.

Aminoglycosides are absorbed rapidly after intramuscular injection. In critically ill patients, especially those in shock, drug absorption from intramuscular sites may be reduced by poor perfusion.

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