Lippincott Chapter 41: Antimycobacterial Drugs

Question 1

TB drugs

Answer 1

Ethambutol MYAMBUTOL
Isoniazid
Pyrazinamide
Rifabutin MY
Rifapentin
Rifampin

Question 2

2nd line TB drugs

Answer 2

DRUGS USED TO TREAT TUBERCULOSIS
(2nd line)
Aminoglycosides
Aminosalicylic acid PASER
Capreomycin CAPASTAT
Cycloserine SEROMYCIN
Ethionamide TRECATOR
Fluoroquinolones
Macrolides

Question 3

Drugs for leprosy

Answer 3

Clofazimine LAMPRENE
Dapsone
Rifampin (Rifampicin) RIFADIN

Question 4

Isoniazid

Answer 4

Isoniazid
Isoniazid [eye-so-NYE-a-zid], along with rifampin, is one of the two
most important TB drugs.
1. Mechanism of action: Isoniazid is a prodrug activated by a
mycobacterial catalase–peroxidase (KatG). Isoniazid targets the
enzymes acyl carrier protein reductase (InhA) and β-ketoacyl-ACP
synthase (KasA), which are essential for the synthesis of mycolic
acid. Inhibiting mycolic acid leads to a disruption in the bacterial
cell wall.
2. Antibacterial spectrum: Isoniazid is specific for treatment of
M. tuberculosis, although M. kansasii may be susceptible at higher
drug concentrations. Most NTM are resistant to INH. The drug
is particularly effective against rapidly growing bacilli and is also
active against intracellular organisms.

Resistance: Resistance follows chromosomal mutations, includ-
ing 1) mutation or deletion of KatG (producing mutants incapa-
ble of prodrug activation), 2) varying mutations of the acyl carrier
proteins, or 3) overexpression of the target enzyme InhA. Cross-
resistance may occur between isoniazid and ethionamide.
4. Pharmacokinetics: Isoniazid is readily absorbed after oral
administration. Absorption is impaired if isoniazid is taken with
food, particularly high-fat meals. The drug diffuses into all body
fluids, cells, and caseous material (necrotic tissue resembling
cheese that is produced in tuberculous lesions). Drug concentra-
tions in the cerebrospinal fluid (CSF) are similar to those in the
serum. Isoniazid undergoes N-acetylation and hydrolysis, result-
ing in inactive products. [Note: Isoniazid acetylation is genetically
regulated, with the fast acetylators exhibiting a 90-minute serum
half-life, as compared to 3 to 4 hours for slow acetylators (Figure
41.4).] Excretion is through glomerular filtration and secretion, pre-
dominantly as metabolites (Figure 41.5). Slow acetylators excrete
more of the parent compound.

Question 5

Isoniazid adverse effects

Answer 5

Adverse effects: Hepatitis is the most serious adverse effect
associated with isoniazid. If hepatitis goes unrecognized, and if
isoniazid is continued, it can be fatal. The incidence increases with
age (greater than 35 years old), among patients who also take
rifampin, or among those who drink alcohol daily. Peripheral neu-
ropathy (manifesting as paresthesia of the hands and feet) appears
to be due to a relative pyridoxine deficiency. This can be avoided by
supplementation of 25 to 50 mg per day of pyridoxine (vitamin B6
).
Central nervous system (CNS) adverse effects can occur, includ-
ing convulsions in patients prone to seizures. Hypersensitivity reac-
tions with isoniazid include rashes and fever. Because isoniazid
inhibits the metabolism of carbamazepine and phenytoin (Figure
41.6), isoniazid can potentiate the adverse effects of these drugs
(for example, nystagmus and ataxia).

Question 6

Rifamycin

Answer 6

Rifamycins: rifampin, rifabutin, and rifapentine
Rifampin, rifabutin, and rifapentine are all considered rifamycins, a
group of structurally similar macrocyclic antibiotics, which are first-line
oral agents for tuberculosis.
1. Rifampin: Rifampin [ri-FAM-pin] has broader antimicrobial activ-
ity than isoniazid and can be used as part of treatment for sev-
eral different bacterial infections. Because resistant strains rapidly
emerge during monotherapy, it is never given as a single agent in
the treatment of active tuberculosis.
a. Mechanism of action: Rifampin blocks RNA transcription by
interacting with the β subunit of mycobacterial DNA-dependent
RNA polymerase.
b. Antimicrobial spectrum: Rifampin is bactericidal for both
intracellular and extracellular mycobacteria, including M. tuber-
culosis, and NTM, such as M. kansasii and Mycobacterium
avium complex (MAC). It is effective against many gram-positive
and gram-negative organisms and is used prophylactically for individuals exposed to meningitis caused by meningococci or
Haemophilus influenzae. Rifampin also is highly active against
M. leprae.
c. Resistance: Resistance to rifampin is caused by mutations in
the affinity of the bacterial DNA-dependent RNA polymerase
gene for the drug.
d. Pharmacokinetics: Absorption is adequate after oral admin-
istration. Distribution of rifampin occurs to all body fluids and
organs. Concentrations attained in the CSF are variable, often
10% to 20% of blood concentrations. The drug is taken up
by the liver and undergoes enterohepatic recycling. Rifampin
can induce hepatic cytochrome P450 enzymes and transport-
ers (see Chapter 1), leading to numerous drug interactions.
Unrelated to its effects on cytochrome P450 enzymes, rifampin
undergoes autoinduction, leading to a shortened elimination
half-life over the first 1 to 2 weeks of dosing. Elimination of
rifampin and its metabolites is primarily through the bile and
into the feces; a small percentage is cleared in the urine
(Figure 41.7). [Note: Urine, feces, and other secretions have an
orange-red color, so patients should be forewarned. Tears may
even stain soft contact lenses orange-red.]

Question 7

Rifamycin adverse effects and drug interactions

Answer 7

Adverse effects: Rifampin is generally well tolerated. The
most common adverse reactions include nausea, vomiting, and
rash. Hepatitis and death due to liver failure are rare. However,
the drug should be used judiciously in older patients, alcoholics,
or those with chronic liver disease. There is a modest increase
in the incidence of hepatic dysfunction when rifampin is coad-
ministered with isoniazid. When rifampin is dosed intermittently,
especially with doses of 1.2 g or greater, a flu-like syndrome
can occur, with fever, chills, and myalgia, sometimes extending
to acute renal failure, hemolytic anemia, and shock.
f. Drug interactions: Because rifampin induces a number of
phase I cytochrome P450 enzymes and phase II enzymes (see
Chapter 1), it can decrease the half-lives of coadministered
drugs that are metabolized by these enzymes (Figure 41.8).
This may necessitate higher dosages for coadministered drugs,
a switch to drugs less affected by rifampin, or replacement of
rifampin with rifabutin.

Question 8

Rifabutin

Answer 8

Rifabutin: Rifabutin [rif-a-BYOO-tin], a derivative of rifampin, is
preferred for TB patients coinfected with the human immunode-
ficiency virus (HIV) who are receiving protease inhibitors (PIs)
or several of the non-nucleoside reverse transcriptase inhibitors
(NNRTIs). Rifabutin is a less potent inducer (approximately 40%
less) of cytochrome P450 enzymes, thus lessening certain drug
interactions. Rifabutin has adverse effects similar to those of
rifampin but can also cause uveitis, skin hyperpigmentation, and
neutropenia.

Question 9

Rifapentin

Answer 9

Rifapentine: Rifapentine [rih-fa-PEN-teen] has activity greater
than that of rifampin in animal and in vitro studies, and it also has
a longer half-life. In combination with isoniazid, rifapentine may be used once weekly in patients with LTBI and in select HIV-negative
patients with minimal pulmonary TB.

Question 10

Pyrazinamide

Answer 10

Pyrazinamide
Pyrazinamide [peer-a-ZIN-a-mide] is a synthetic, orally effective short-
course agent used in combination with isoniazid, rifampin, and eth-
ambutol. The precise mechanism of action is unclear. Pyrazinamide
must be enzymatically hydrolyzed by pyrazinamidase to pyrazinoic
acid, which is the active form of the drug. Some resistant strains lack
the pyrazinamidase enzyme. Pyrazinamide is active against tubercu-
losis bacilli in acidic lesions and in macrophages. The drug distributes
throughout the body, penetrating the CSF. Pyrazinamide may con-
tribute to liver toxicity. Uric acid retention is common but rarely pre-
cipitates a gouty attack. Most of the clinical benefit from pyrazinamide
occurs early in treatment. Therefore, this drug is usually discontinued
after 2 months of a 6-month regimen.

Question 11

Ethambutol

Answer 11

Ethambutol
Ethambutol [e-THAM-byoo-tole] is bacteriostatic and specific for
mycobacteria. Ethambutol inhibits arabinosyl transferase—an
enzyme important for the synthesis of the mycobacterial cell wall.
Ethambutol is used in combination with pyrazinamide, isoniazid, and
rifampin pending culture and susceptibility data. [Note: Ethambutol
may be discontinued if the isolate is determined to be susceptible
to isoniazid, rifampin, and pyrazinamide.] Ethambutol is well distrib-
uted throughout the body. Penetration into the CNS is minimal, and it
is questionably adequate for tuberculous meningitis. Both the parent
drug and metabolites are primarily excreted in the urine. The most
important adverse effect is optic neuritis, which results in diminished
visual acuity and loss of ability to discriminate between red and green.
The risk of optic neuritis increases with higher doses and in patients
with renal impairment. Visual acuity and color discrimination should
be tested prior to initiating therapy and periodically thereafter. Uric
acid excretion is decreased by ethambutol, and caution should be
exercised in patients with gout.

Question 12

Streptomycin

Answer 12

Alternate second-line drugs
Streptomycin [strep-toe-MY-sin], para-aminosalicylic [a-mee-noe-
sal-i-SIL-ik] acid, capreomycin [kap-ree-oh-MYE-sin], cycloserine
[sye-kloe-SER-een], ethionamide [e-thye-ON-am-ide], fluoroquino-
lones, and macrolides are second-line TB drugs. In general, these
agents are less effective and more toxic than the first-line agents.
Figure 41.10 summarizes some of the characteristics of second-line
drugs.
1. Streptomycin: Streptomycin, an aminoglycoside antibiotic, was
one of the first effective agents for TB (see Chapter 39). Its action
appears to be greater against extracellular organisms. Infections
due to streptomycin-resistant organisms may be treated with
kanamycin or amikacin, to which these bacilli usually remain
susceptible.

Question 13

Para-aminosalicylate acid

Answer 13

Para-aminosalicylic acid: Para-aminosalicylic acid (PAS) was
another one of the original TB medications. From the early 1950s
until well into the 1960s, isoniazid, PAS, plus streptomycin was
the standard 18-month treatment regimen. While largely replaced
by ethambutol for drug-susceptible TB, PAS remains an important
component of many regimens for MDR-TB.

Question 14

Capreomycin

Answer 14

Capreomycin: This is a parenterally administered polypeptide
that inhibits protein synthesis. Capreomycin is primarily reserved
for the treatment of MDR-TB. Careful monitoring is necessary to
minimize nephrotoxicity and ototoxicity.

Question 15

Ethionamide

Answer 15

Ethionamide: This is a structural analog of isoniazid that also
disrupts mycolic acid synthesis. The mechanism of action is not
identical to isoniazid, but there is some overlap in the resistance
patterns. Ethionamide is widely distributed throughout the body,
including the CSF. Metabolism is extensive, most likely in the liver,
to active and inactive metabolites. Adverse effects that limit its
use include nausea, vomiting, and hepatotoxicity. Hypothyroidism,
gynecomastia, alopecia, impotence, and CNS effects also have
been reported.

Question 16

Fluoroquinolones

Answer 16

Fluoroquinolones: The fluoroquinolones, specifically moxifloxa-
cin and levofloxacin, have an important place in the treatment of
multidrug-resistant tuberculosis. Some NTM also are susceptible.
These drugs are discussed in detail in Chapter 40.

Question 17

Macrolides

Answer 17

Macrolides: The macrolides azithromycin and clarithromycin are
included in regimens for several NTM infections, including MAC.
Azithromycin may be preferred for patients at greater risk for drug
interactions (clarithromycin is a both a substrate and inhibitor of
cytochrome P450 enzymes). Details about the pharmacology of
macrolides are found in Chapter 39.

Question 18

Bedaquiline

Answer 18

Bedaquiline: Bedaquiline [bed-AK-wi-leen], an ATP synthase
inhibitor, is the first in a new class of drugs approved for the treat-
ment of MDR-TB. Bedaquiline is administered orally, and it is active
against many types of mycobacteria. Bedaquiline may cause QT
prolongation, and monitoring of the electrocardiogram is recom-
mended. This agent is a CYP3A4 substrate, and administration
with strong CYP3A4 inducers (for example, rifampin) should be
avoided.

Question 19

Dapsone

Answer 19

Leprosy (or Hansen’s disease) is uncommon in the United States; how-
ever, worldwide it is a much larger problem (Figure 41.11). Leprosy can
be treated effectively with dapsone and rifampin, adding clofazimine in
multibacillary cases (Figure 41.12).
A. Dapsone
Dapsone [DAP-sone] is structurally related to the sulfonamides and
similarly inhibits dihydropteroate synthetase in the folate synthesis
pathway. It is bacteriostatic for M. leprae, and resistant strains may
be encountered. Dapsone also is used in the treatment of pneumonia
caused by Pneumocystis jirovecii in immunosuppressed patients. The
drug is well absorbed from the gastrointestinal tract and is distributed throughout the body, with high concentrations in the skin. The parent
drug undergoes hepatic acetylation. Both parent drug and metabo-
lites are eliminated in the urine. Adverse reactions include hemolysis
(especially in patients with glucose-6-phosphate dehydrogenase defi-
ciency), methemoglobinemia, and peripheral neuropathy.

Question 20

Clofazimine

Answer 20

Clofazimine
Clofazimine [kloe-FAZ-i-meen] is a phenazine dye. Its mechanism of
action may involve binding to DNA, although alternative mechanisms
have been proposed. Its redox properties may lead to the generation
of cytotoxic oxygen radicals that are toxic to the bacteria. Clofazimine
is bactericidal to M. leprae, and it has potentially useful activity against
M. tuberculosis and NTM. Following oral absorption, the drug accu-
mulates in tissues, allowing intermittent therapy but does not enter the
CNS. Patients typically develop a pink to brownish-black discoloration
of the skin and should be informed of this in advance. Eosinophilic
and other forms of enteritis, sometimes requiring surgery, have been
reported. Clofazimine has some anti-inflammatory and anti-immune
activities. Thus, erythema nodosum leprosum may not develop in
patients treated with this drug.