Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Chapter 86 Aminoglycosides: Bactericidal Inhibitors of Protein Synthesis

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.2 Aminoglycosides  Most commonly employed agents  Gentamicin, tobramycin, amikacin  Narrow-spectrum antibiotics  Bactericidal  Use – aerobic gram-negative bacilli  Can cause serious injury to inner ear and kidney  Not absorbed from the GI tract  Microbial resistance

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.3 Aminoglycosides  Adverse effects  Nephrotoxicity  Ototoxicity  Hypersensitivity reactions  Neuromuscular blockade  Blood dyscrasias  Drug Interactions  Penicillins, cephalosporins and vancomycin, ototoxic drugs, nephrotoxic drugs, skeletal muscle relaxants

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.4 Fig Structural formulas of the major aminoglycosides.

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.5 Fig 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 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.

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.6 Serum Levels  Dosing  Single large dose each day or 2-3 smaller doses  Monitoring of serum levels is common – the same aminoglycoside dose can produce very different plasma levels in different patients.  Peak levels must be high enough to kill bacteria; trough levels must be low enough to minimize toxicity.

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.7 Gentamicin (Garamycin)  Used to treat serious infections caused by aerobic gram-negative bacilli  Pseudomonas aeruginosa  Escherichia coli  Klebsiella  Serratia  Proteus mirabilis  Adverse effects  Nephrotoxicity  Ototoxicity

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.8 Fig Plasma gentamicin levels produced with once-daily doses versus divided doses. The curves depict plasma levels of gentamicin produced with (1) a single large dose administered once a day versus (2) the same daily total given as three smaller doses spaced 8 hours apart. Plasma levels with both regimens are high enough to produce good bactericidal effects. The shaded area indicates levels that are low enough to permit washout of the drug from vulnerable cells in the inner ear. Note that, with once-daily dosing, levels are in the washout range for over 12 hours, versus a total of only 6 hours when divided doses are used. As a result, ototoxicity is lower with the once-a-day schedule.

Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc.9 Other Aminoglycosides  Tobramycin (Nebcin)  Amikacin (Amikin)  Neomycin  Kanamycin (Kantrex)  Streptomycin  Paromomycin (Humatin)