Gentamicin

GENTAMICIN

Gentamicin is an aminoglycoside (Figure 45–2) isolated from Micromonospora purpurea. It is effective against both gram-positiveand gram-negative organisms, and many of its properties resemble those of other aminoglycosides. Sisomicin is very similar to the C_1a component of gentamicin.

Antimicrobial Activity

Gentamicin sulfate, 2–10 mcg/mL, inhibits in vitro many strains of staphylococci and coliforms and other gram-negative bacteria. It is active alone, but also as a synergistic companion with β-lactam antibiotics, against Escherichia coli, Proteus, Klebsiella pneumoniae,Enterobacter, Serratia, Stenotrophomonas, and other gram-negativerods that may be resistant to multiple other antibiotics. Like all aminoglycosides, it has no activity against anaerobes.

Resistance

Streptococci and enterococci are relatively resistant to gentamicin owing to failure of the drug to penetrate into the cell. However, gentamicin in combination with vancomycin or a penicillin pro-duces a potent bactericidal effect, which in part is due to enhanced uptake of drug that occurs with inhibition of cell wall synthesis. Resistance to gentamicin rapidly emerges in staphylococci during monotherapy owing to selection of permeability mutants. Ribosomal resistance is rare. Among gram-negative bacteria, resistance is most commonly due to plasmid-encoded aminoglycoside-modifying enzymes. Gram-negative bacteria that are gentamicin-resistant usu-ally are susceptible to amikacin, which is much more resistant to modifying enzyme activity. The enterococcal enzyme that modifies gentamicin is a bifunctional enzyme that also inactivates amikacin, netilmicin, and tobramycin, but not streptomycin; the latter is modified by a different enzyme. This is why some gentamicin-resistant enterococci are susceptible to streptomycin.

Clinical Uses

A. Intramuscular or Intravenous Administration

Gentamicin is used mainly in severe infections (eg, sepsis and pneumonia) caused by gram-negative bacteria that are likely to be resistant to other drugs, especially P aeruginosa, Enterobacter sp, Serratia marcescens, Proteus sp, Acinetobacter sp, and Klebsiella sp.It usually is used in combination with a second agent because an aminoglycoside alone may not be effective for infections outside the urinary tract. For example, gentamicin should not be used as a single agent to treat staphylococcal infections because resistance develops rapidly. Aminoglycosides also should not be used for single-agent therapy of pneumonia because penetration of infected lung tissue is poor and local conditions of low pH and low oxygen tension contribute to poor activity. Gentamicin 5–6 mg/kg/d traditionally is given intravenously in three equal doses, but once-daily administration is just as effective for some organisms and less toxic (see above).

Gentamicin, in combination with a cell wall-active antibiotic, is also indicated in the treatment of endocarditis caused by gram-positive bacteria (streptococci, staphylococci, and enterococci). The synergistic killing achieved by combination therapy may achieve bactericidal activity necessary for cure or allow for the shortening of the duration of therapy. The doses of gentamicin used for synergy against gram-positive bacteria are lower than tra-ditional doses. Typically the drug is administered at a dose of 3 mg/ kg/day in three divided doses. Peak levels should be approximately 3 mcg/mL, while trough levels should be < 1 mcg/mL. There are limited data to support administering the 3-mg/kg dose as a single daily injection in the treatment of streptococcal endocarditis.

B. Topical and Ocular Administration

Creams, ointments, and solutions containing 0.1–0.3% gentami-cin sulfate have been used for the treatment of infected burns, wounds, or skin lesions and in attempts to prevent intravenous catheter infections. The effectiveness of topical preparations for these indications is unclear. Topical gentamicin is partly inacti-vated by purulent exudates. Ten mg can be injected subconjuncti-vally for treatment of ocular infections.

C. Intrathecal Administration

Meningitis caused by gram-negative bacteria has been treated by the intrathecal injection of gentamicin sulfate, 1–10 mg/d. However, neither intrathecal nor intraventricular gentamicin was beneficial in neonates with meningitis, and intraventricular gen-tamicin was toxic, raising questions about the usefulness of this form of therapy. Moreover, the availability of third-generation cephalosporins for gram-negative meningitis has rendered this therapy obsolete in most cases.

Adverse Reactions

Nephrotoxicity is usually reversible and mild. It occurs in 5–25% of patients receiving gentamicin for longer than 3–5 days. Such toxicity requires, at the very least, adjustment of the dosing regi-men and should prompt reconsideration of the need for the drug,particularly if there is a less toxic alternative agent. Measurement of gentamicin serum levels is essential. Ototoxicity, which tends to be irreversible, manifests itself mainly as vestibular dysfunction. Loss of hearing can also occur. The incidence of ototoxicity is in part genetically determined, having been linked to point muta-tions in mitochondrial DNA, and occurs in 1–5% for patients receiving gentamicin for more than 5 days. Hypersensitivity reac-tions to gentamicin are uncommon.