(PAS), like the sulfonamides , is a structural analogue of p-aminobenzoic acid (PABA). It is a folate synthesis an-tagonist
that interferes with the incorporation of PABA into folic acid. PAS is
bacteriostatic, and in vitro, most strains of M. tuberculosis are sensitive to a concentra-tion of 1 μg/mL. The antibacterial activity of PAS is
highly specific for M. tuberculosis;
it is not effective against other mycobacterium species.
PAS is readily absorbed from
the GI tract and is widely distributed throughout body fluids except
cere-brospinal fluid. It penetrates tissues and reaches high concentrations in
the tuberculous cavities and caseous tissue. Peak plasma levels are reached
within 1 to 2 hours of drug administration, and the drug has a half-life of
about an hour. PAS is primarily metabolized by hepatic acetylation. When
combined with isoniazid, PAS can function as an alternative substrate and block
hepatic acetylation of isoniazid, thereby increasing free isoniazid levels. Both
the acetylated and unaltered drug are rapidly excreted in the urine. The
concentration of PAS in urine is high and may result in crystalluria.
Use of PAS has diminished
over the years following the introduction of more effective drugs, such as
ri-fampin and ethambutol. At present, therapy with PAS is limited to the
treatment of MDR tuberculosis. Problems with primary resistance, poor
compliance due to GI intolerance, and lupuslike reactions have further
discouraged its use.
Ethionamide (Trecator) is a derivative of
isonicotinic acid and is chemically related to isoniazid. It is a sec-ondary
agent used in combination when primary agents are ineffective or
contraindicated; it is a bacteriostatic antituberculosis agent. Its exact
mechanism of action is unknown but is believed to involve inhibition of
oxygen-dependent mycolic acid synthesis. It is thought that mutations in the
region of the (inhA) gene that are involved in mycolic acid synthesis can cause
both isoni-azid and ethionamide resistance.
Ethionamide is well absorbed
following oral admin-istration. It is rapidly and widely distributed to all
body tissues and fluids, including the cerebrospinal fluid. Metabolism of
ethionamide is extensive, and several di-hydropyridine metabolites are produced.
Less than 1% of the drug is eliminated in the urine unchanged.
GI disturbances, including
nausea, vomiting, and in-tense gastric irritation, are frequent. In addition,
ethion-amide may cause a wide range of neurological side effects, such as
confusion, peripheral neuropathy, psy-chosis, and seizures. Neurological
effects can be mini-mized by pyridoxine supplementation. Other rare side
effects include gynecomastia, impotence, postural hy-potension, and
Cycloserine is a broad-spectrum
antibiotic produced by Streptomyces
orchidaceus. It is structural analogue of D-alanine and acts through a competitive inhibition of the D-alanine that is involved in
bacterial cell wall synthesis. Cycloserine is inhibitory to M.
tuberculosis and active against Escherichia
coli, S. aureus, and Enterococcus,
Nocardia, and Chlamydia spp. It is used in the treatment of MDR tuberculosis and is useful in renal tuberculosis, since
most of the drug is excreted unchanged in the urine.
Cycloserine is readily
absorbed orally and distributes throughout body fluids including the
cerebrospinal fluid. The concentrations of cycloserine in tissues, body fluids,
and the cerebrospinal fluid are approximately equal to the plasma level.
Cycloserine is partially metabolized, and 60 to 80% is excreted unchanged by
Neurological symptoms, which
tend to appear in the first week of therapy, consist of dizziness, confusion,
ir-ritability, psychotic behavioral changes, and even suici-dal ideation.
Cycloserine is contraindicated in patients with underlying psychiatric and
seizure disorders. Other side effects include occasional peripheral neuropathy
and low magnesium levels.
Rifabutin (Mycobutin), an antibiotic related to
ri-fampin, shares its mechanism of action, that is, inhibi-tion of RNA
polymerase. Rifabutin has significant ac-tivity in vitro and in vivo against M. avium-intracellular complex (MAC)
isolates from both HIV-infected and non–HIV-infected individuals. It has better
activity against MAC organisms than rifampin. Rifabutin is ac-tive against M. tuberculosis, including some
rifampin-resistant strains, such as M.
leprae and M. fortuitum. It has a
spectrum of activity against gram-positive and gram-negative organisms similar
to that of rifampin. The mo-lecular basis for resistance to rifabutin is shared
by both rifampin and rifabutin; this explains the virtually com-plete
cross-resistance that occurs between these drugs.
Rifabutin is well absorbed
orally, and peak plasma concentrations are reached in 2 to 3 hours. Because of
its lipophilicity, rifabutin achieves a 5- to 10-fold higher concentration in
tissues than in plasma. The drug has a half-life range of 16 to 96 hours and is
eliminated in urine and bile.
Rifabutin appears as
effective as rifampin in the treatment of drug-susceptible tuberculosis and is
used in the treatment of latent tuberculosis infection either alone or in
combination with pyrazinamide. Clinical use of rifabutin has increased in
recent years, especially in the treatment of HIV infection. It is a less potent
inducer of cytochrome 450 enzymes pathways than ri-fampin and results in less
drug interaction with the protease inhibitors and nonnucleoside reverse
tran-scriptase inhibitors. Rifabutin is therefore commonly substituted for
rifampin in the treatment of tuberculosis in HIV-infected patients. Another
important use of ri-fabutin in the HIV-infected population is prevention and
treatment of disseminated MAC.
The adverse effects that most
frequently result in discontinuation of rifabutin include GI intolerance, rash,
and neutropenia. Rifabutin levels will be increased with concurrent
administration of fluconazole and clar-ithromycin, resulting in anterior
uveitis, polymyalgia syndrome, and a yellowish-tan discoloration of the skin
(pseudojaundice). Other adverse reactions are similar to those of rifampin,
such as hepatitis, red-orange dis-coloration of body fluids, and drug
interactions due to effects on the hepatic P450 cytochrome enzyme system.
Rifapentine is an analogue of
rifampin that is active against M.
tuberculosis and M. avium.
Rifapentine’s mechanism of action, cross-resistance, hepatic induction of P450
enzymes, drug interactions, and toxic profile are similar to those of rifampin.
It has been used in the treatment of tuberculosis caused by
Capreomycin (Capastat) is a polypeptide antibiotic
de-rived from Streptomyces capreolus.
It is bacteriostatic against most strains of M. tuberculosis, including the MDR strain. In addition, it is
active against M. kansasii, M. avium, and in high concentrations,
some gram-positive and gram-negative bacteria. Like other antitu-bercular
drugs, resistance to capreomycin occurs rapidly if the drug is used alone.
There is no cross-resistance be-tween streptomycin and capreomycin, but some
isolates resistant to capreomycin are resistant to viomycin.
Capreomycin is poorly absorbed
from GI tract and so must be given parenterally. It is excreted mainly
un-changed in the urine following glomerular filtration. Capreomycin is a used
as a second-line agent in combi-nation with other drugs. It appears to be
particularly useful in multidrug regimens for the treatment of drug-resistant
tuberculosis, especially with streptomycin re-sistance. Capreomycin is
associated with ototoxicity and nephrotoxicity, and these adverse effects can
be severe in patients with preexisting renal insufficiency.
Amikacin and kanamycin have been used in the treatment of
tuberculosis. Amikacin is very active against several mycobacterium species;
however, it is expensive and has significant toxicity. It is consid-ered in the
treatment of MDR tuberculosis after strep-tomycin and capreomycin. An
additional use of amikacin is in the treatment of disseminated MAC in AIDS
patients. There is no cross-resistance between streptomycin and other
aminoglycosides; most M. tu-berculosis strains
that are resistant to streptomycin aresensitive to kanamycin. The latter drug
may be pre-ferred over viomycin due to its lower toxicity.
Viomycin is a complex
polypeptide antibiotic that is ac-tive against MDR strains of tuberculosis. Cross-resist-ance
between viomycin and kanamycin is less frequent than between viomycin and
Clofazimine has some activity
against M. tuberculosis and is used
as a last resort drug for the treatment of MDR tuberculosis. It is primarily
used in the treatment of M. leprae
and M. avium-intracellulare. Further
details are discussed later, under the treatment of leprosy.
antibiotics clar-ithromycin and
azithromycin have demonstrated in vitro activity against mycobacteria, although
they have limited activity against M.
tuberculosis. Clarithromycin is four times as active as azithromycin
against M. avium-intracellulare in
vitro. Azithromycin’s lower potency may
be compensated for by its greater intracellular pen-etration and its two-fold
higher tissue levels than plasma levels. Clarithromycin with azithromycin, in
combination with other drugs, has gained an important role in the prevention
and treatment of MAC in HIV-infected patients.
Thiacetazone is active
against many strains of M. tuber-culosis.
It is not marketed in the United States.
However, because of its low cost, it is used as a first-line agent in East
Africa, especially in combination with compounds such as isoniazid. The most
common side effects of thiacetazone include GI intolerance and de-velopment of
rashes. It causes significant ototoxicity, es-pecially when coadministered with
hypersensitivity reactions, such as hepatitis, transient marrow aplastic syndromes,
neutropenia, and thrombocytopenia, have been reported.
Most of the fluoroquinolones
antibiotics have activity against M. tuberculosis and M. avium-intracellulare. Ciprofloxacin, ofloxacin, and levofloxacin inhibit 90% of the strains of
susceptible tubercula bacilli at concentrations of less than 2 μg/mL. Levofloxacin is preferred because it is
the active L-optical isomer of ofloxacin and is approved for once-daily use.
Thequinolones act by inhibition of bacterial DNA gyrase. Resistance is the
result of spontaneous mutations in genes that either change the DNA gyrase or
decrease the ability of the drug to cross the cell membrane.
Quinolones are important
recent additions to the therapeutic agents used against M. tuberculosis, espe-cially in MDR strains. Clinical trials of
ofloxacin in com-bination with isoniazid and rifampin have indicated ac-tivity
comparable to that of ethambutol. In addition, quinolones, particularly
ciprofloxacin, are used as part of a combined regimen in HIV-infected patients.
All mycobacteria produce β-lactamase.
In vitro, several β-lactamase-resistant antibiotics or a combination of a β-lactam
with β-lactamase inhibitors, such as clavulanic acid, are active against M. tuberculosis and nontubercu-lous
mycobacteria. However, the activity of β-lactam agents against intracellular
mycobacteria is generally poor. The β-lactam agents may be useful in the
treat-ment of MDR tuberculosis in combination with other antitubercular drugs
but never as monotherapy.