Streptococci and enterococci are relatively resistant to gentamicin owing to failure of the drug to penetrate into the cell. However, gentamicin in combination with some penicillins or vancomycin produces 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 usually 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.
A. Intramuscular or Intravenous Administration
Gentamicin is used mainly in severe infections 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. Aminoglycosides should not be used as single agents for therapy of pneumonia because penetration of infected lung tissue is poor and local conditions of low pH and low oxygen tension contribute to limited activity. Gentamicin 5–7 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, may also be indicated in the treatment of endocarditis caused by Gram-positive bacteria (streptococci, staphylococci, and enterococci) as discussed earlier.
B. Topical and Ocular Administration
Creams, ointments, and solutions containing 0.1–0.3% gentamicin 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 inactivated by purulent exudates. Gentamicin can be injected intraocularly for treatment of certain eye 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 gentamicin 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. It may be used in cases of drug-resistant meningitis or severe β-lactam allergy.