Page 861 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 47 Antimycobacterial Drugs 847

clearance is less than 30 mL/min or the patient is on hemodialy- Ethionamide is administered at an initial dose of 250 mg
sis, the dosage is 15 mg/kg two or three times per week. Most once daily, which is increased in 250 mg increments to the
tubercle bacilli are inhibited by streptomycin, 1–10 mcg/mL, recommended dosage of 1 g/d (or 15 mg/kg/d), if possible. The
in vitro. Nontuberculous species of mycobacteria other than 1-g/d dosage, though theoretically desirable, is poorly tolerated
Mycobacterium avium complex (MAC) and Mycobacterium because of gastric irritation and neurologic symptoms, often
kansasii are resistant. All large populations of tubercle bacilli limiting the tolerable daily dose to 500–750 mg. Ethionamide
contain some streptomycin-resistant mutants. On average, 1 is also hepatotoxic. Neurologic symptoms may be alleviated by
8
in 10 tubercle bacilli can be expected to be resistant to strep- pyridoxine.
tomycin at levels of 10–100 mcg/mL. Resistance may be due Resistance to ethionamide as a single agent develops rapidly in
to a point mutation in either the rpsL gene encoding the S12 vitro and in vivo. There can be low-level cross-resistance between
ribosomal protein or the rrs gene encoding 16S ribosomal RNA, isoniazid and ethionamide.
which alters the ribosomal binding site.
Streptomycin penetrates into cells poorly and is active mainly Capreomycin
against extracellular tubercle bacilli. The drug crosses the blood- Capreomycin is a peptide protein synthesis inhibitor antibiotic
brain barrier and achieves therapeutic concentrations with obtained from Streptomyces capreolus. Daily injection of 15 mg/kg
inflamed meninges.
intramuscularly results in peak serum levels of 35–45 mcg/mL
2 hours after a dose. Such concentrations in vitro are inhibitory
Clinical Use in Tuberculosis for many mycobacteria, including multidrug-resistant strains of
Streptomycin sulfate is used when an injectable drug is needed M tuberculosis.
or desirable and in the treatment of infections resistant to other Capreomycin (15 mg/kg/d) is an important injectable agent
drugs. The usual dosage is 15 mg/kg/d intramuscularly or intrave- for treatment of drug-resistant tuberculosis. Strains of M tuber-
nously daily for adults (20–40 mg/kg/d for children, not to exceed culosis that are resistant to streptomycin usually are susceptible
1 g) for several weeks, followed by 15 mg/kg two or three times to capreomycin, though some data suggest cross-resistance with
weekly for several months. Serum concentrations of approxi- strains resistant to amikacin and kanamycin. Resistance to cap-
mately 40 mcg/mL are achieved 30–60 minutes after intramuscu- reomycin, when it occurs, has been associated with rrs, eis, or tlyA
lar injection of a 15 mg/kg dose. Other drugs are always given in gene mutations.
combination to prevent emergence of resistance. Capreomycin is nephrotoxic and ototoxic. Tinnitus, deafness,
and vestibular disturbances occur. The injection causes significant
Adverse Reactions local pain, and sterile abscesses may develop.
Typical dosing of capreomycin is 15 mg/kg/day initially,
Streptomycin is ototoxic and nephrotoxic. Vertigo and hearing which is then reduced to two or three times weekly after an initial
loss are the most common adverse effects and may be permanent. response has been achieved with a daily dosing schedule. The
Toxicity is dose-related, and the risk is increased in the elderly. As intermittent dosing regimen may minimize risk of toxicity.
with all aminoglycosides, the dose must be adjusted according to
renal function (see Chapter 45). Toxicity can be reduced by limit- Cycloserine
ing therapy to no more than 6 months whenever possible.
Cycloserine—a structural analog of d-alanine—inhibits cell
Ethionamide wall synthesis, as discussed in Chapter 43. Concentrations of
15–20 mcg/mL inhibit many strains of M tuberculosis. The usual
Ethionamide is chemically related to isoniazid and similarly blocks dosage of cycloserine in tuberculosis is 0.5–1 g/d in two divided
the synthesis of mycolic acids. It is poorly water soluble and avail- oral doses. The drug is widely distributed to tissues, including
able only for oral use. It is metabolized by the liver. the central nervous system. This drug is cleared renally, and the
dose should be reduced by half if creatinine clearance is less than
H C N 50 mL/min. Alternatively, it may be reduced to 500 mg three
5 2
times weekly.
The most serious toxic effects are peripheral neuropathy and
central nervous system dysfunction, including depression and
C
S NH 2 psychoses. Pyridoxine, 100 mg or more per day, should be given
Ethionamide with cycloserine because this ameliorates neurologic toxicity.
Adverse effects, which are most common during the first 2 weeks
Most tubercle bacilli are inhibited in vitro by ethionamide, of therapy, occur in 25% or more of patients, especially at higher
2.5 mcg/mL or less. Some other species of mycobacteria also are doses leading to peak concentrations greater than 35 mcg/mL.
inhibited by ethionamide, 10 mcg/mL. Serum concentrations in Adverse effects can be minimized by monitoring peak serum
plasma and tissues of approximately 1-5 mcg/mL are achieved by concentrations. The peak concentration is reached 2–4 hours
a dosage of 1 g/d. Cerebrospinal fluid concentrations are equal to after dosing. The recommended range of peak concentrations is
those in serum. 20–35 mcg/mL.