Page 857 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 47 Antimycobacterial Drugs 843

TABLE 47–1 Antimicrobials used in the treatment of growing tubercle bacilli. It is less effective against nontuberculous
tuberculosis. mycobacteria. Isoniazid penetrates into macrophages and is active
against both extracellular and intracellular organisms.
Drug Typical Adult Dosage 1
First-line agents Mechanism of Action & Basis of Resistance
Isoniazid 300 mg/d Isoniazid inhibits synthesis of mycolic acids, which are essential
Rifampin 600 mg/d components of mycobacterial cell walls. Isoniazid is a prodrug that
Pyrazinamide 25 mg/kg/d is activated by KatG, the mycobacterial catalase-peroxidase. The
activated form of isoniazid forms a covalent complex with an acyl
Ethambutol 15–25 mg/kg/d
carrier protein (AcpM) and KasA, a beta-ketoacyl carrier protein
Second-line agents
synthetase, which blocks mycolic acid synthesis. Resistance to
Amikacin 15 mg/kg/d isoniazid is associated with mutations resulting in overexpression
Aminosalicylic acid 8–12 g/d of inhA, which encodes an NADH-dependent acyl carrier pro-
Bedaquiline 400 mg/d tein reductase; mutation or deletion of the katG gene; promoter
Capreomycin 15 mg/kg/d mutations resulting in overexpression of ahpC, a gene involved
in protection of the cell from oxidative stress; and mutations in
Clofazimine 200 mg/d
kasA. Overproducers of inhA express low-level isoniazid resis-
Cycloserine 500–1000 mg/d, divided
tance and cross-resistance to ethionamide. KatG mutants express
Ethionamide 500–750 mg/d high-level isoniazid resistance and often are not cross-resistant to
Levofloxacin 500–750 mg/d ethionamide.
Linezolid 600 mg/d Drug-resistant mutants are normally present in susceptible
6
Moxifloxacin 400 mg/d mycobacterial populations at about 1 bacillus in 10 . Since
8
Rifabutin 2 300 mg/d tuberculous lesions often contain more than 10 tubercle bacilli,
resistant mutants are readily selected if isoniazid or any other
Rifapentine 3 600 mg once weekly
drug is given as a single agent. The use of two independently
Streptomycin 15 mg/kg/d acting drugs in combination is much more effective. The
1 Assuming normal renal function. probability that a bacillus is initially resistant to both drugs is
2 6 6 12
150 mg/d if used concurrently with a protease inhibitor or cobicistat; 600 mg/d with approximately 1 in 10 × 10 , or 1 in 10 , several orders of
efavirenz. magnitude greater than the number of infecting organisms.
3
No longer recommended, but may be considered in selected cases if HIV-uninfected Thus, at least two (or more in certain cases) active agents should
without cavitation on chest radiograph.
always be used to treat active tuberculosis to prevent emergence
of resistance during therapy.
ISONIAZID
Pharmacokinetics
Isoniazid is the most active drug for the treatment of tuberculosis Isoniazid is readily absorbed from the gastrointestinal tract,
caused by susceptible strains. It is a small molecule (molecular optimally on an empty stomach; peak concentrations may be
weight 137) that is freely soluble in water. The structural similarity decreased by up to 50% when taken with a fatty meal. A 300 mg
to pyridoxine is shown below.
oral dose (5 mg/kg in children) achieves peak plasma concentra-
N tions of 3–5 mcg/mL within 1–2 hours. Isoniazid diffuses readily
into all body fluids and tissues. The concentration in the central
nervous system and cerebrospinal fluid ranges between 20% and
100% of simultaneous serum concentrations.
Metabolism of isoniazid, especially acetylation by liver
CONHNH 2
N-acetyltransferase, is genetically determined (see Chapter 4).
Isoniazid
The average plasma concentration of isoniazid in rapid acetyl-
ators is about one third to one half of that in slow acetylators,
N and average half-lives are less than 1 hour and 3 hours, respec-
CH 3 tively. More rapid clearance of isoniazid by rapid acetylators is
OH usually of no therapeutic consequence when appropriate doses
HOH 2 C
are administered daily, but subtherapeutic concentrations may
CH 2 OH occur if drug is administered as a once-weekly dose or if there is
Pyridoxine malabsorption.
Isoniazid metabolites and a small amount of unchanged drug
In vitro, isoniazid inhibits most tubercle bacilli at a concen- are excreted in the urine. The dosage need not be adjusted in renal
tration of 0.2 mcg/mL or less and is bactericidal for actively failure. Dose adjustment is not well defined in patients with severe