DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

consequently, gentamicin-resistant strains of enterococci
may be susceptible to streptomycin.
Resistance owing to mutations that alter ribosomal structure and
reduce aminoglycoside binding is relatively uncommon. Missense
mutations in Escherichia coli that substitute a single amino acid in a crucial
ribosomal protein may prevent binding of streptomycin. 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. Resistance in ~50% of
streptomycin-resistant strains of enterococci is attributable to ribosomal
mutations (Eliopoulos et al., 1984). Because ribosomal resistance
usually is specific for streptomycin, these strains of enterococci remain
sensitive to a combination of penicillin and gentamicin in vitro.
Antibacterial Spectrum of the Aminoglycosides. The
antibacterial activity of gentamicin, tobramycin,
kanamycin, netilmicin, and amikacin is directed primarily
against aerobic gram-negative bacilli. Kanamycin,
like streptomycin, has a more limited spectrum compared
with other aminoglycosides; in particular, it should not be
used to treat infections caused by Serratia or P. aeruginosa.
The aerobic gram-negative bacilli vary in their susceptibility
to the aminoglycosides (Table 54–1).
Tobramycin and gentamicin exhibit similar activity
against most gram-negative bacilli, although tobramycin
usually is more active against P. aeruginosa and some
Proteus spp., whereas gentamicin is usually more active
against Serratia. 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 aminoglycosideinactivating
enzymes.
Aminoglycosides have little activity against anaerobic
microorganisms or facultative bacteria under anaerobic
conditions. Their action against most gram-positive
bacteria is limited, and they should not be used as single
agents to treat infections caused by gram-positive
bacteria. In combination with a cell wall–active agent,
such as a penicillin or vancomycin, an aminoglycoside
produces a synergistic bactericidal effect in vitro.
Clinically, the superiority of aminoglycoside combination
regimens over β-lactams alone is not proven except
in relatively few infections (discussed later).
Absorption, Distribution, Dosing, and
Elimination of the Aminoglycosides
Absorption. The aminoglycosides are highly polar cations and therefore
are very poorly absorbed from the GI tract. Less than 1% of a
dose is absorbed after either oral or rectal administration. The drugs
are not inactivated in the intestine and are eliminated quantitatively
in the feces. Long-term oral or rectal administration of aminoglycosides
may result in accumulation to toxic concentrations in patients
with renal impairment. Absorption of gentamicin from the GI tract
may be increased by GI disease (e.g., ulcers or inflammatory bowel
disease). Instillation of these drugs into body cavities with serosal
surfaces also may result in rapid absorption and unexpected toxicity
(i.e., neuromuscular blockade). Similarly, intoxication may occur
when aminoglycosides are applied topically for long periods to large
Table 54–1
Typical Minimal Inhibitory Concentrations of Aminoglycosides That Will Inhibit 90% (MIC 90
) of Clinical
Isolates for Several Species
MIC 90
μg/ml
SPECIES KANAMYCIN GENTAMICIN NETILMICIN TOBRAMYCIN AMIKACIN
Citrobacter freundii 8 0.5 0.25 0.5 1
Enterobacter spp. 4 0.5 0.25 0.5 1
Escherichia coli 16 0.5 0.25 0.5 1
Klebsiella pneumoniae 32 0.5 0.25 1 1
Proteus mirabilis 8 4 4 0.5 2
Providencia stuartii 128 8 16 4 2
Pseudomonas aeruginosa >128 8 32 4 2
Serratia spp. >64 4 16 16 8
Enterococcus faecalis — 32 2 32 ≥64
Staphylococcus aureus 2 0.5 0.25 0.25 16
Adapted with permission from Wiedemann B, Atkinson BA. Susceptibility to antibiotics: Species incidence and trends. In: Antibiotics in
Laboratory Medicine, 3rd ed. (Lorian V, ed.), Lippincott Williams & Wilkins, Baltimore, 1991, pp. 962–1208.)