Isoniazid (isonicotinic acid
hydrazide, or INH) is the most active drug for the treatment of tuberculosis
caused by susceptible strains. It is a synthetic agent with a structural
similarity to that of pyridoxine.
Isoniazid is active against
susceptible bacteria only when they are undergoing cell division. Susceptible
bacteria may continue to undergo one or two divisions before multiplication is
arrested. Isoniazid can inhibit the syn-thesis of mycolic acids, which are
essential components of mycobacterial cell walls. The mycobacterial enzyme
cata-lase–peroxidase KatG activates
the administered isoni-azid to its biologically active form. The target sites
for the activated isoniazid action are acyl carrier protein AcpM and Kas A, a
-ketoaceyl carrier protein synthetase that blocks mycolic acid synthesis.
Isoniazid exerts its lethal effects at the target sites by forming covalent
Isoniazid is bactericidal
against actively growing M. tu-berculosis
and bacteriostatic against nonreplicating or-ganisms. The minimal
tuberculostatic inhibitory concen-tration (MIC) of isoniazid is 0.025 to 0.05 μg/mL.
The most common mechanism of
isoniazid resistance is the mycobacteria’s formation of mutations in
cata-lase–peroxidase KatG, the enzyme that is responsible for activation of
isoniazid. Another resistance mecha-nism is through a missense mutation related
to the inhA gene involved in mycolic acid biosynthesis.
An active tuberculosis cavity
may contain as many as 107 to 1010 microorganisms. The
frequency of isoni-azid-resistant mutants in a susceptible mycobacterial
population is about 1 bacillus in 106, and this organism is readily
selected out if isoniazid is given as the sole agent. If a second drug having a
similar drug resistance (1in 106) is combined with isoniazid, the
odds that a bacillus is resistant to both drugs become 1 in 1012. Therefore, it is vital to combine at least
two antitubercu-lar agents to which the organism is susceptible.
Isoniazid is water soluble
and is well absorbed when administered either orally or parenterally. Oral
absorp-tion is decreased by concurrent administration of aluminum-containing
Isoniazid does not bind to
serum proteins; it diffuses readily into all body fluids and cells, including
the caseous tuberculous lesions. The drug is detectable in significant
quantities in pleural and ascitic fluids, as well as in saliva and skin. The
concentrations in the central nervous system (CNS) and cerebrospinal fluid are
gen-erally about 20% of plasma levels but may reach close to 100% in the
presence of meningeal inflammation.
Isoniazid is acetylated to
acetyl isoniazid by N-acetyl-transferase,
an enzyme in liver, bowel, and kidney. Individuals who are genetically rapid
acetylators will have a higher ratio of acetyl isoniazid to isoniazid than will
slow acetylators. Rapid acetylators were once thought to be more prone to
hepatotoxicity, but this is not proved. The slow or rapid acetylation of
isoniazid is rarely important clinically, although slow inactivators tend to
develop pe-ripheral neuropathy more readily. Metabolites of isoni-azid and small
amounts of unaltered drug are excreted in the urine within 24 hours of
Isoniazid is among the safest
and most active mycobac-tericidal agents. It is considered the primary drug for
use in all therapeutic and prophylactic regimens for sus-ceptible tuberculosis
infections. It is also included in the first-line drug combinations for use in
all types of tu-berculous infections. Isoniazid is preferred as a single agent
in the treatment of latent tuberculosis infections in high-risk persons having
a positive tuberculin skin re-action with no radiological or other clinical
evidence of tuberculosis. Mycobacterium
kansasii is usually suscep-tible to isoniazid, and it is included in the
standard mul-tidrug treatment regimen.
The incidence and severity of
adverse reactions to iso-niazid are related to dosage and duration of therapy.
Isoniazid-induced hepatitis and peripheral neuropathy are two major untoward
A minor asymptomatic increase
in liver aminotrans-ferase is seen in 10 to 20% of patients, whereas fatal
hepatitis is seen in fewer than 1% of isoniazid recipi-ents. Risk factors for
hepatitis include underlying liver disease, advanced age, pregnancy, and
combination therapy with acetaminophen. Early recognition and prompt
discontinuation of the drug is recommended to prevent further damage to the
Peripheral neuropathy is
observed in 10 to 20% of patients taking more than 5 mg/kg/day of isoniazid.
Patients with underlying chronic disorders such as alco-holism, malnutrition,
diabetes, and AIDS are at particu-lar risk for neurotoxicity; compared with
fast acetyla-tors, neurotoxicity is more frequent in slow acetylators because
slow acetylators achieve higher drug plasma levels. Isoniazid promotes renal excretion
of pyridoxine, resulting in a relative deficiency and neuropathy. CNS toxicity
may range from excitability and seizures to psy-chosis. The neurotoxic effects
are reversed without al-tering the antimycobacterial action by the
administra-tion of 10 to 50 mg/day of pyridoxine. Other adverse reactions
include gastrointestinal (GI) intolerance, ane-mia, rash, tinnitus, and urinary
High isoniazid plasma levels
inhibit phenytoin metabo-lism and potentiate phenytoin toxicity when the two
drugs are coadministered. The serum concentrations of phenytoin should be
monitored, and the dose should be adjusted if necessary.
Rifampin is a semisynthetic
macrocyclic antibiotic pro-duced from Streptomyces
mediterranei. It is a large lipid-soluble molecule that is bactericidal for
both intracellu-lar and extracellular microorganisms. Rifampin binds strongly
to the -subunit of bacterial DNA-dependent RNA polymerase and thereby inhibits
RNA synthesis. Rifampin does not affect mammalian polymerases.
In addition to M. tuberculosis, rifampin is active
against Staphylococcus aureus, Neisseria
meningitidis, Haemo-philus influenzae, Chlamydiae, and certain viruses. Rifampin resistance results from a
point mutation or deletion in rpoB, the gene for the -subunit of RNA
polymerase, thereby preventing the binding of RNA polymerase.
Rifampin is well absorbed
orally, and a peak serum con-centration is usually seen within 2 to 4 hours.
Drug ab- sorption is impaired if rifampin is given concurrently with
aminosalicylic acid or is taken immediately after a meal. It is widely
distributed throughout the body, and therapeutic levels are achieved in all
body fluids, in-cluding cerebrospinal fluid. Rifampin is capable of in-ducing
its own metabolism, so its half-life can be re-duced to 2 hours within a week
of continued therapy. The deacetylated form of rifampin is active and
under-goes biliary excretion and enterohepatic recirculation. Most of the drug
is excreted into the GI tract and a small amount in the urine. Moderate dose
adjustment is required in patients with underlying liver disease.
Rifampin is a first-line
antitubercular drug used in the treatment of all forms of pulmonary and
extrapul-monary tuberculosis. Rifampin is an alternative to iso-niazid in the
treatment of latent tuberculosis infection. Rifampin also may be combined with
an antileprosy agent for the treatment of leprosy and to protect those in close
contact with patients having H. influenza
type b and N. meningitidis infection;
rifampin is also used in methicillin-resistant staphylococcal infections, such
as osteomyelitis and prosthetic valve endocarditis.
The most commonly observed
side effects are GI dis-turbances and nervous system symptoms, such as nau-sea,
vomiting, headache, dizziness, and fatigue. Hepatitis is a major adverse
effect, and the risk is highest in pa-tients with underlying liver diseases and
in slow isoni-azid acetylators; the rate of hepatotoxicity is increased if
isoniazid and rifampin are combined.
Other major untoward
reactions are the result of ri-fampin’s ability to induce hepatic cytochrome
P-450 en-zymes, leading to an increased metabolism of many drugs; this action
has especially complicated the treat-ment of tuberculosis in HIV-infected
patients whose reg-imen includes protease inhibitors and nonnucleoside re-verse
transcriptase. Since rifabutin has relatively little of these effects, it is
commonly substituted for rifampin in the treatment of tuberculosis in
such as pruritus, cuta-neous vasculitis, and thrombocytopenia, are seen in some
patients, and an immune-mediated systemic flulike syn-drome with
thrombocytopenia also has been described. Rifampin imparts a harmless
red-orange color to urine, feces, saliva, sweat, tears, and contact lenses.
Patients should be advised of such discoloration of body fluids.
Pyrazinamide is a synthetic
analogue of nicotinamide. Its exact mechanism of action is not known, although
its target appears to be the mycobacterial fatty acid synthetase involved in
mycolic acid biosynthesis. Pyrazinamide requires an acidic environment, such as
that found in the phagolysosomes, to express its tuber-culocidal activity.
Thus, pyrazinamide is highly effective on intracellular mycobacteria. The
mycobacterial en-zyme pyrazinamidase converts pyrazinamide to pyrazi-noic acid,
the active form of the drug. A mutation in the gene (pncA) that encodes
pyrazinamidase is responsi-ble for drug resistance; resistance can be delayed
through the use of drug combination therapy.
Pyrazinamide is well absorbed
from the GI tract and is widely distributed throughout the body. It penetrates
tissues, macrophages, and tuberculous cavities and has excellent activity on
the intracellular organisms; its plasma half-life is 9 to 10 hours in patients
with normal renal function. The drug and its metabolites are ex-creted
primarily by renal glomerular filtration.
Pyrazinamide is an essential
component of the mul-tidrug short-term therapy of tuberculosis. In combina-tion
with isoniazid and rifampin, it is active against the intracellular organisms
that may cause relapse.
Hepatotoxicity is the major
concern in 15% of pyrazi-namide recipients. It also can inhibit excretion of
urates, resulting in hyperuricemia. Nearly all patients taking pyrazinamide
develop hyperuricemia and possibly acute gouty arthritis. Other adverse effects
include nausea, vomiting, anorexia, drug fever, and malaise. Pyrazinamide is
not recommended for use during pregnancy.
Ethambutol is a
water-soluble, heat-stable compound that acts by inhibition of arabinosyl
transferase en-zymes that are involved in cell wall biosynthesis. Nearly all
strains of M. tuberculosis and M. kansasii and most strains of Mycobacterium avium-intracellulare are
sensi-tive to ethambutol. Drug resistance relates to point mu-tations in the
gene (EmbB) that encodes the arabinosyl transferases that are involved in
mycobacterial cell wall synthesis.
ethambutol is well absorbed (70–80%) from the gut, and peak serum
concentrations are obtained within 2 to 4 hours of drug administration; it has
a half-life of 3 to 4 hours. Ethambutol is widely distributed in all body
fluids, including the cere-brospinal fluid, even in the absence of
inflammation. A majority of the unchanged drug is excreted in the urine within
24 hours of ingestion. Up to 15% is excreted in the urine as an aldehyde and a
dicarboxylic acid metabolite. Ethambutol doses may have to be modified in
patients with renal failure.
Ethambutol has replaced
aminosalicylic acid as a first-line antitubercular drug. It is commonly included
as a fourth drug, along with isoniazid, pyrazinamide, and rifampin, in patients
infected with MDR strains. It also is used in combination in the treatment of M. avium-intracellulare infection in
The major toxicity associated
with ethambutol use is retrobulbar neuritis impairing visual acuity and
red-green color discrimination; this side effect is dose re-lated and reverses
slowly once the drug is discontinued. Mild GI intolerance, allergic reaction,
fever, dizziness, and mental confusion are also possible. Hyperuricemia is
associated with ethambutol use due to a decreased re-nal excretion of urates;
gouty arthritis may result.
aminoglycoside antibiotic, was the first drug shown to reduce tuberculosis mortality.
Streptomycin is bactericidal against M.
tuber-culosis in vitro but is inactive against intracellular organisms. Most M. tuberculosis strains and nontuber-culosis species, such as M. kansasii and M. avium-intracellulare, are sensitive. Spontaneous resistance to streptomycin, seen in approximately 1
in 106 tubercle bacilli, is related to a point mutation that
involves the gene (rpsl or rrs) that encodes for ribosomal proteins and binding
sites. About 80% of strains that are resist-ant to isoniazid and rifampin are
also resistant to strep-tomycin.
Streptomycin is indicated as
a fourth drug in combi-nation with isoniazid, rifampin, and pyrazinamide in
pa-tients at high risk for drug resistance. It is also used in the treatment of
streptomycin-susceptible MDR tuber-culosis.
nephrotoxicity are the major con-cerns during administration of streptomycin
and other aminoglycosides. The toxic effects are dose related and increase with
age and underlying renal insufficiency. All aminoglycosides require dose
adjustment in renal fail-ure patients. Ototoxicity is severe when
aminoglyco-sides are combined with other potentially ototoxic agents.