Page 844 - Basic _ Clinical Pharmacology ( PDFDrive )

830 SECTION VIII Chemotherapeutic Drugs

Ribosomal resistance to streptomycin develops readily, limiting its Resistance
role as a single agent.
Streptococci and enterococci are relatively resistant to gentamicin
Clinical Uses owing to failure of the drug to penetrate into the cell. However,
gentamicin in combination with some penicillins or vancomycin
A. Mycobacterial Infections produces a potent bactericidal effect, which in part is due to
Streptomycin is mainly used as a second-line agent for treatment enhanced uptake of drug that occurs with inhibition of cell wall
of tuberculosis. The dosage is 15 mg/kg/d with a maximum synthesis. Resistance to gentamicin rapidly emerges in staphy-
of 1 g/d (20–40 mg/kg/d for children), and it may be given lococci during monotherapy owing to selection of permeability
intramuscularly or intravenously. It should be used only in com- mutants. Ribosomal resistance is rare. Among Gram-negative
bination with other agents to prevent emergence of resistance. bacteria, resistance is most commonly due to plasmid-encoded
See Chapter 47 for additional information regarding the use of aminoglycoside-modifying enzymes. Gram-negative bacteria that
streptomycin in mycobacterial infections. are gentamicin-resistant usually are susceptible to amikacin, which
is much more resistant to modifying enzyme activity. The entero-
B. Nontuberculous Infections coccal enzyme that modifies gentamicin is a bifunctional enzyme
In plague, tularemia, and sometimes, brucellosis, streptomycin, that also inactivates amikacin, netilmicin, and tobramycin but not
1 g twice daily (15 mg/kg twice daily for children), is given intra- streptomycin; the latter is modified by a different enzyme. This
muscularly in combination with an oral tetracycline. is why some gentamicin-resistant enterococci are susceptible to
Penicillin plus streptomycin is effective for enterococcal endo- streptomycin.
carditis and 2-week therapy of viridans streptococcal endocarditis;
however, for susceptible strains, gentamicin is used more commonly Clinical Uses
when an aminoglycoside is selected as adjunct therapy. Streptomy- A. Intramuscular or Intravenous Administration
cin remains a useful agent for treating gentamicin non-susceptible Gentamicin is used mainly in severe infections caused by Gram-
enterococcal infections, as some isolates that are resistant to gen- negative bacteria that are likely to be resistant to other drugs,
tamicin (and therefore resistant to netilmicin, tobramycin, and especially P aeruginosa, Enterobacter sp, Serratia marcescens,
amikacin) will remain susceptible to streptomycin.
Proteus sp, Acinetobacter sp, and Klebsiella sp. It usually is used
in combination with a second agent because an aminoglycoside
Adverse Reactions alone may not be effective for infections outside the urinary tract.
Fever, skin rashes, and other allergic manifestations may result Aminoglycosides should not be used as single agents for therapy
from hypersensitivity to streptomycin. This occurs most frequently of pneumonia because penetration of infected lung tissue is poor
with a prolonged course of treatment (eg, for tuberculosis). and local conditions of low pH and low oxygen tension contribute
Pain at the injection site is common but usually not severe. to limited activity. Gentamicin 5–7 mg/kg/d traditionally is given
The most serious toxic effect with streptomycin is disturbance of intravenously in three equal doses, but once-daily administration
vestibular function—vertigo and loss of balance. The frequency is just as effective for some organisms and less toxic (see above).
and severity of this disturbance are in proportion to the age of Gentamicin, in combination with a cell wall-active antibiotic,
the patient, the blood levels of the drug, and the duration of may also be indicated in the treatment of endocarditis caused by
administration. Vestibular dysfunction may follow a few weeks of Gram-positive bacteria (streptococci, staphylococci, and entero-
unusually high blood levels (eg, in individuals with impaired renal cocci) as discussed earlier.
function) or months of relatively low blood levels. Vestibular tox-
icity tends to be irreversible. Streptomycin given during pregnancy B. Topical and Ocular Administration
can cause deafness in the newborn. Creams, ointments, and solutions containing 0.1–0.3% genta-
micin sulfate have been used for the treatment of infected burns,
wounds, or skin lesions and in attempts to prevent intravenous
GENTAMICIN catheter infections. The effectiveness of topical preparations for
these indications is unclear. Topical gentamicin is partly inacti-
Gentamicin is a mixture of three closely related constituents, vated by purulent exudates. Gentamicin can be injected intraocu-
C , C , and C (Figure 45–2) isolated from Micromonospora larly for treatment of certain eye infections.
2
1A
1
purpurea. It is effective against both Gram-positive and Gram-
negative organisms, and many of its properties resemble those of C. Intrathecal Administration
other aminoglycosides.
Meningitis caused by Gram-negative bacteria has been treated
by the intrathecal injection of gentamicin sulfate, 1–10 mg/d.
Antimicrobial Activity However, neither intrathecal nor intraventricular gentamicin was
Gentamicin sulfate, 2–10 mcg/mL, inhibits in vitro many beneficial in neonates with meningitis, and intraventricular gen-
strains of staphylococci and Gram-negative bacteria, including tamicin was toxic, raising questions about the usefulness of this
P. aeruginosa and Enterobacteriaceae. Like all aminoglycosides, it form of therapy. Moreover, the availability of third-generation
has no activity against anaerobes. cephalosporins for Gram-negative meningitis has rendered this