Page 845 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 45 Aminoglycosides & Spectinomycin 831

therapy obsolete in most cases. It may be used in cases of drug- AMIKACIN
resistant meningitis or severe β-lactam allergy.
Amikacin is a semisynthetic derivative of kanamycin; it is less
Adverse Reactions toxic than the parent molecule (Figure 45–2). It is resistant to
many enzymes that inactivate gentamicin and tobramycin, and,
Nephrotoxicity is usually reversible upon drug discontinuation. It therefore, can be used against some microorganisms resistant to
occurs in 5–25% of patients receiving gentamicin for longer than the latter drugs. Many Gram-negative bacteria, including many
3–5 days. Such toxicity requires, at the very least, adjustment of the strains of Proteus, Pseudomonas, Enterobacter, and Serratia, are
dosing regimen and should prompt reconsideration of the need for the inhibited by 1–20 mcg/mL amikacin in vitro. After injection of
drug, particularly if there is a less toxic alternative agent. Measurement 500 mg of amikacin every 12 hours (15 mg/kg/d) intramuscularly,
of gentamicin serum levels is essential. Ototoxicity, which tends to be peak levels in serum are 10–30 mcg/mL.
irreversible, manifests itself mainly as vestibular dysfunction. Loss of Strains of multidrug-resistant Mycobacterium tuberculosis,
hearing can also occur. Ototoxicity is in part genetically determined, including streptomycin-resistant strains, are usually susceptible
having been linked to point mutations in mitochondrial DNA, and to amikacin. Kanamycin-resistant strains may be cross-resis-
occurs in 1–5% for patients receiving gentamicin for more than tant to amikacin. The dosage of amikacin for tuberculosis is
5 days. Hypersensitivity reactions to gentamicin are uncommon.
10–15 mg/kg/d as a once-daily or two to three times weekly
injection and always in combination with other drugs to which
TOBRAMYCIN the isolate is susceptible.
Like all aminoglycosides, amikacin is nephrotoxic and ototoxic
This aminoglycoside (Figure 45–2) has an antibacterial spectrum (particularly for the auditory portion of the eighth nerve). Serum
similar to that of gentamicin. Although there is some cross- concentrations should be monitored. Target peak serum concen-
resistance between gentamicin and tobramycin, it is unpredictable trations for an every-12-hours dosing regimen are 20–40 mcg/mL,
in individual strains. Separate laboratory susceptibility tests are and trough levels should be maintained between 4 and 8 mcg/mL.
therefore necessary.
NETILMICIN
A. Intramuscular or Intravenous Administration
The pharmacokinetic properties of tobramycin are virtually iden- Netilmicin shares many characteristics with gentamicin and tobra-
tical with those of gentamicin. The daily dose of tobramycin is mycin. However, the addition of an ethyl group to the 1-amino
5–7 mg/kg intramuscularly or intravenously, traditionally divided position of the 2-deoxystreptamine ring (ring II, Figure 45–2)
into three equal amounts and given every 8 hours but now often sterically protects the netilmicin molecule from enzymatic degra-
given as a single daily dose. Monitoring blood levels in renal insuf- dation at the 3-amino (ring II) and 2-hydroxyl (ring III) positions.
ficiency is an essential guide to proper dosing. Consequently, netilmicin may be active against some gentamicin-
Tobramycin has almost the same antibacterial spectrum as gen- resistant and tobramycin-resistant bacteria.
tamicin with a few exceptions. Gentamicin is slightly more active The dosage (5–7 mg/kg/d) and the routes of administration are
against S marcescens, whereas tobramycin is slightly more active against the same as for gentamicin. Netilmicin is largely interchangeable
P aeruginosa; Enterococcus faecalis is susceptible to both gentamicin and with gentamicin or tobramycin but is no longer available in the
tobramycin, but E faecium is resistant to tobramycin. Gentamicin and United States.
tobramycin are otherwise interchangeable clinically.
Like other aminoglycosides, tobramycin is ototoxic and neph-
rotoxic. Nephrotoxicity of tobramycin may be slightly less than NEOMYCIN, KANAMYCIN, &
that of gentamicin. PAROMOMYCIN

B. Inhaled and Ophthalmic Administration Neomycin, kanamycin, and paromomycin have similar pharma-
Tobramycin is formulated in solution (300 mg in 5 mL) for inha- cologic properties.
lation for treatment of P aeruginosa lower respiratory tract infec-
tions complicating cystic fibrosis. The drug is recommended as a Antimicrobial Activity & Resistance
300-mg dose regardless of the patient’s age or weight for admin-
istration twice daily in repeated cycles of 28 days on therapy, fol- Drugs of the neomycin group are active against Gram-positive and
lowed by 28 days off therapy. Serum concentrations 1 hour after Gram-negative bacteria and some mycobacteria. P aeruginosa and
inhalation average 1 mcg/mL; consequently, nephrotoxicity and streptococci are generally resistant. Mechanisms of antibacterial
ototoxicity rarely occur. Caution should be used when adminis- action and resistance are the same as with other aminoglycosides.
tering tobramycin to patients with preexisting renal, vestibular, or The former widespread use of these drugs in bowel preparation for
hearing disorders. Tobramycin is also available as 0.3% ophthal- elective surgery contributed to the selection of resistant organisms
mic ointment and drops for the treatment of superficial eye infec- and some outbreaks of enterocolitis in hospitals. Cross-resistance
tions. These formulations result in minimal systemic absorption between kanamycin and neomycin is complete and may result in
and are unlikely to cause systemic adverse effects. amikacin cross-resistance.