Page 862 - Basic _ Clinical Pharmacology ( PDFDrive )

848 SECTION VIII Chemotherapeutic Drugs

Aminosalicylic Acid (PAS) between streptomycin and amikacin, but kanamycin resistance
often indicates resistance to amikacin as well. Peak serum con-
Aminosalicylic acid is a folate synthesis antagonist that is active centrations of 30–45 mcg/mL are achieved 30–60 minutes after
almost exclusively against M tuberculosis. It is structurally similar a 15-mg/kg intravenous infusion or intramuscular injection.
to p-amino-benzoic acid (PABA) and is thought to have a similar Amikacin is indicated for treatment of tuberculosis suspected
mechanism of action to the sulfonamides (see Chapter 46). In the or known to be caused by streptomycin-resistant or multidrug-
USA, PAS is commercially available as a 4-g packet of delayed- resistant strains. This drug must be used in combination with at
release granules. In order to protect the integrity of the delayed- least one and preferably two or three other drugs to which the
release coating, the granules must be administered sprinkled over isolate is susceptible for treatment of drug-resistant cases. The
applesauce or yogurt, or swirled in fruit juice and swallowed recommended dosage is 15 mg/kg once daily initially, followed by
whole.
intermittent dosing two or three times per week.
COOH
Fluoroquinolones
OH
In addition to their activity against many Gram-positive and
Gram-negative bacteria (discussed in Chapter 46), ciprofloxacin,
levofloxacin, gatifloxacin, and moxifloxacin inhibit strains of
NH 2 M tuberculosis at concentrations less than 2 mcg/mL. They are
Aminosalicylic acid (PAS) also active against atypical mycobacteria. Moxifloxacin is the
most active against M tuberculosis in vitro. Levofloxacin tends to
Tubercle bacilli are usually inhibited in vitro by aminosalicylic be slightly more active than ciprofloxacin against M tuberculo-
acid, 1–5 mcg/mL. The granule formulation of aminosalicylic sis, whereas ciprofloxacin is slightly more active against atypical
acid results in improved absorption from the gastrointestinal mycobacteria.
tract. Peak serum levels are expected to be 20–60 mcg/mL 6 hours Fluoroquinolones are an important addition to the drugs avail-
after a 4 g oral dose. The dosage is 8–12 g/d orally for adults and able for tuberculosis, especially for strains that are resistant to first-
300 mg/kg/d for children, administered in two or three divided line agents. The World Health Organization recommends using a
doses. The drug is widely distributed in tissues and body fluids later generation fluoroquinolone such as moxifloxacin or levoflox-
except the cerebrospinal fluid. Aminosalicylic acid is rapidly acin. Resistance, which may result from one of several single point
excreted in the urine, in part as active PAS and in part as the mutations in the gyrase A subunit, develops rapidly if a fluoroqui-
acetylated compound and other metabolic products. To avoid nolone is used as a single agent; thus, the drug must be used in
accumulation in renal impairment, the maximum dose is 4 g twice combination with two or more additional active agents. Typically,
daily when creatinine clearance is less than 30 mL/min. Very high resistance to one fluoroquinolone indicates class resistance. How-
concentrations of aminosalicylic acid are reached in the urine, ever, moxifloxacin may retain some activity in strains resistant to
which can result in crystalluria. ofloxacin. The dosage of levofloxacin is 500–750 mg once a day,
Aminosalicylic acid is used infrequently in the USA because and some clinicians increase to 1000 mg daily if tolerated. The
other oral drugs are better tolerated. Gastrointestinal symptoms dosage of moxifloxacin is 400 mg once a day. Some experts rec-
are common but occur less frequently with the delayed-release ommend checking peak serum concentrations. Expected levels at
granules; they may be diminished by giving the drug with meals about two hours post-dose are 8–12 mcg/mL for levofloxacin and
and with antacids. Peptic ulceration and hemorrhage may occur. 3–5 mcg/mL for moxifloxacin.
Hypersensitivity reactions manifested by fever, joint pains, skin
rashes, hepatosplenomegaly, hepatitis, adenopathy, and granulo- Linezolid
cytopenia often occur after 3–8 weeks of PAS therapy, making it
necessary to stop administration temporarily or permanently. Linezolid (discussed in Chapter 44) inhibits strains of M tuberculosis
in vitro at concentrations of 4–8 mcg/mL. It achieves good intra-
Kanamycin & Amikacin cellular concentrations, and it is active in murine models of
tuberculosis. Linezolid has been used in combination with other
The aminoglycoside antibiotics are discussed in Chapter 45. second- and third-line drugs to treat patients with tuberculosis
Kanamycin had been used for treatment of tuberculosis caused by caused by multidrug-resistant strains. Conversion of sputum
streptomycin-resistant strains, but it is no longer available in the cultures to negative was associated with linezolid use in these
USA, and less toxic alternatives (eg, capreomycin and amikacin) cases. Significant adverse effects, including bone marrow suppres-
have taken its place. sion and irreversible peripheral and optic neuropathy, have been
Amikacin is playing a greater role in the treatment of tuberculo- reported with the prolonged courses of therapy that are necessary
sis due to the prevalence of multidrug-resistant strains. Prevalence for treatment of tuberculosis. A 600-mg (adult) dose administered
of amikacin-resistant strains is low (<5%), and most multidrug- once a day (half of that used for treatment of other bacterial infec-
resistant strains remain amikacin-susceptible. M tuberculosis is tions) seems to be sufficient and may limit the occurrence of these
inhibited at concentrations of 1 mcg/mL or less. Amikacin is also adverse effects. Experts recommend supplemental pyridoxine for
active against atypical mycobacteria. There is no cross-resistance patients treated with linezolid. Although linezolid may prove to