47
C H A P T E R
Antimycobacterial Drugs
Camille E. Beauduy, PharmD, &
Lisa G. Winston, MD*
C ASE STUDY
A 60-year-old man presents to the emergency department
with a 2-month history of fatigue, weight loss (10 kg), fevers,
night sweats, and a productive cough. He is currently living
with friends and has been intermittently homeless, spending
time in shelters. He reports drinking about 6 beers per day.
In the emergency department, a chest x-ray shows a right
apical infiltrate. Given the high suspicion for pulmonary
Mycobacteria are intrinsically resistant to most antibiotics.
Because they grow more slowly than other bacteria, antibiotics
that are most active against rapidly growing cells are relatively
ineffective. Mycobacterial cells can also be dormant and, thus,
resistant to many drugs or killed only very slowly. The lipid-rich
mycobacterial cell wall is impermeable to many agents. Mycobac-
terial species are intracellular pathogens, and organisms residing
within macrophages are inaccessible to drugs that penetrate these
cells poorly. Finally, mycobacteria are notorious for their ability
to develop resistance. Combinations of two or more drugs are
required to overcome these obstacles and to prevent emergence of
resistance during the course of therapy. The response of mycobac-
terial infections to chemotherapy is slow, and treatment must be
administered for months to years, depending on which drugs are
used. The drugs used to treat tuberculosis, atypical mycobacterial
infections, and leprosy are described in this chapter.
■ DRUGS USED IN TUBERCULOSIS
Isoniazid (INH), rifampin (or other rifamycin), pyrazinamide,
and ethambutol are the traditional first-line agents for treatment
of tuberculosis (Table 47–1). Isoniazid and rifampin are the most
∗
The authors thank Henry F. Chambers, MD and Daniel H. Deck,
PharmD for their contributions to previous editions.
842
tuberculosis, the patient is placed in respiratory isolation.
His first sputum smear shows many acid-fast bacilli, and an
HIV test returns with a positive result. What drugs should
be started for treatment of presumptive pulmonary tubercu-
losis? Does the patient have a heightened risk of developing
medication toxicity? If so, which medication(s) would be
likely to cause toxicity?
active drugs. An isoniazid-rifampin combination administered for
9 months will cure 95–98% of cases of tuberculosis caused by sus-
ceptible strains. An initial intensive phase of treatment is recom-
mended for the first 2 months due to the prevalence of resistant
strains. The addition of pyrazinamide during this intensive phase
allows the total duration of therapy to be reduced to 6 months
without loss of efficacy. In practice, therapy is usually initiated
with a four-drug regimen of isoniazid, rifampin, pyrazinamide,
and ethambutol until susceptibility of the clinical isolate has
been determined. In susceptible isolates, the continuation phase
consists of an additional 4 months with isoniazid and rifampin
(Table 47–2). Neither ethambutol nor other drugs such as strep-
tomycin adds substantially to the overall activity of the regimen
(ie, the duration of treatment cannot be further reduced if another
drug is used), but the fourth drug provides additional cover-
age if the isolate proves to be resistant to isoniazid, rifampin,
or both. If therapy is initiated after the isolate is known to be
susceptible to isoniazid and rifampin, ethambutol does not
need to be added. The prevalence of isoniazid resistance among
clinical isolates in the USA is approximately 10%. Prevalence
of resistance to both isoniazid and rifampin (which is termed
multidrug resistance) ranged from 1 to 1.6% from the years
2000 to 2013 in the USA. Multidrug resistance is much more
prevalent in many other parts of the world. Resistance to
rifampin alone is rare.
 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.
1
Drug Typical Adult Dosage

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
Ethambutol 15–25 mg/kg/d activated form of isoniazid forms a covalent complex with an acyl
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
Clofazimine 200 mg/d in protection of the cell from oxidative stress; and mutations in
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
Moxifloxacin 400 mg/d mycobacterial populations at about 1 bacillus in 106. Since
Rifabutin2 300 mg/d tuberculous lesions often contain more than 108 tubercle bacilli,
3 resistant mutants are readily selected if isoniazid or any other
Rifapentine 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
6 6 12
2
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.
3
magnitude greater than the number of infecting organisms.
No longer recommended, but may be considered in selected cases if HIV-uninfected
without cavitation on chest radiograph. Thus, at least two (or more in certain cases) active agents should
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.
CONHNH2 Metabolism of isoniazid, especially acetylation by liver
Isoniazid
N-acetyltransferase, is genetically determined (see Chapter 4).
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-
CH3
tively. More rapid clearance of isoniazid by rapid acetylators is
OH usually of no therapeutic consequence when appropriate doses
HOH2C
are administered daily, but subtherapeutic concentrations may
CH2OH 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
844 SECTION VIII Chemotherapeutic Drugs

TABLE 47–2 Recommended treatment for drug-susceptible tuberculosis.

Intensive Phase Continuation Phase
Regimen (min duration = 8 weeks) (min duration = 18 weeks)1  
(in order of
preference) Drugs Dosing Interval Drugs Dosing Interval Comments

1 INH 7 days per week2 INH 7 days per week2 Preferred regimen.
RIF RIF
PZA
EMB
2 INH 7 days per week2 INH 3 days per week Preferred alternative if less frequent DOT is
RIF RIF needed.
PZA
EMB
3 INH 3 days per week INH 3 days per week Caution in patients with HIV and/or cavitary
RIF RIF disease due to concerns for treatment
failure, relapse, drug resistance.
PZA
EMB
4 INH 7 days per week × INH 2 days per week Avoid in patients with HIV or those with
RIF 2 weeks, then RIF smear-positive and/ or cavitary disease.
PZA 2 days per week ×
EMB 6 weeks
1
Experts recommend prolonged continuation phase (31 weeks) for patients with cavitation on initial chest radiograph and positive cultures at the end of the intensive
treatment phase.
2
May consider 5 days per week if needed for DOT. No studies compare 5 versus 7 doses per week, but extensive experience suggests efficacy of this regimen.
DOT, directly observed therapy; EMB, ethambutol; HIV, human immunodeficiency virus; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin.

preexisting hepatic insufficiency and should be guided by serum A. Immunologic Reactions

concentrations if a reduction in dose is contemplated. Isoniazid
inhibits several cytochrome P450 enzymes, leading to increased
concentrations of such medications as phenytoin, carbamazepine,
and benzodiazepines. However, when used in combination with
rifampin, a potent CYP enzyme inducer, the concentrations of
these medications are usually decreased.
Clinical Uses
The typical dosage of isoniazid is 5 mg/kg/d; a typical adult dose is
300 mg given once daily. Up to 10 mg/kg/d may be used for seri-
ous infections or if malabsorption is a problem. A 15-mg/kg dose,
or 900 mg, may be used in a twice to three times-weekly dosing
regimen in combination with a second antituberculous agent (eg,
rifampin, 600 mg). Pyridoxine, 25–50 mg/d, is recommended
for those with conditions predisposing to neuropathy, an adverse
effect of isoniazid. Isoniazid is usually given by mouth but can be
given parenterally in the same dosage.
Isoniazid as a single agent is also indicated for treatment
of latent tuberculosis. The dosage is 300 mg/d (5 mg/kg/d) or
900 mg twice weekly, and the duration is usually 9 months.
Adverse Reactions
The incidence and severity of untoward reactions to isoniazid are
related to dosage and duration of administration.
Fever and skin rashes are occasionally seen. Drug-induced sys-
temic lupus erythematosus has been reported.
B. Direct Toxicity
Isoniazid-induced hepatitis is the most common major toxic effect.
This is distinct from the minor increases in liver aminotransferases
(up to three or four times normal), which do not require cessa-
tion of the drug and which are seen in 10–20% of patients, who
usually are asymptomatic. Clinical hepatitis with loss of appetite,
nausea, vomiting, jaundice, and right upper quadrant pain occurs
in 1% of isoniazid recipients and can be fatal, particularly if the
drug is not discontinued promptly. There is histologic evidence of
hepatocellular damage and necrosis. The risk of hepatitis depends
on age. It occurs rarely under age 20, in 0.3% of those age 21–35,
1.2% of those age 36–50, and 2.3% for those age 50 and above.
The risk of hepatitis is greater in individuals with alcohol depen-
dence and possibly during pregnancy and the postpartum period.
Development of isoniazid hepatitis contraindicates further use of
the drug.
Peripheral neuropathy is observed in 10–20% of patients given
dosages greater than 5 mg/kg/d, but it is infrequently seen with
the standard 300-mg adult dose. Peripheral neuropathy is more
likely to occur in slow acetylators and patients with predisposing
conditions such as malnutrition, alcoholism, diabetes, AIDS, and
uremia. Neuropathy is due to a relative pyridoxine deficiency.

Isoniazid promotes excretion of pyridoxine, and this toxicity is
readily reversed by administration of pyridoxine in a dosage as low
as 10 mg/d. Central nervous system toxicity, which is less com-
mon, includes memory loss, psychosis, ataxia, and seizures. These
effects may also respond to pyridoxine.
Miscellaneous other reactions include hematologic abnormali-
ties, provocation of pyridoxine deficiency anemia, tinnitus, and
gastrointestinal discomfort.
RIFAMPIN
Rifampin is a semisynthetic derivative of rifamycin, an antibi-
otic produced by Amycolatopsis rifamycinica, formerly named
Streptomyces mediterranei. It is active in vitro against Gram-positive
organisms, some Gram-negative organisms, such as Neisseria and
Haemophilus species, mycobacteria, and chlamydiae. Susceptible
organisms are inhibited by less than 1 mcg/mL. Resistant mutants
are present in all microbial populations at approximately 1 in
6
10 organisms and are rapidly selected out if rifampin is used as
a single drug, especially in a patient with active infection. There
is no cross-resistance to other classes of antimicrobial drugs, but
there is cross-resistance to other rifamycin derivatives, eg, rifabutin
and rifapentine.
Mechanism of Action, Resistance, &
Pharmacokinetics
Rifampin binds to the β subunit of bacterial DNA-dependent
RNA polymerase and thereby inhibits RNA synthesis. Resistance
results from any one of several possible point mutations in rpoB,
the gene for the β subunit of RNA polymerase. These muta-
tions result in reduced binding of rifampin to RNA polymerase.
Human RNA polymerase does not bind rifampin and is not
inhibited by it. Rifampin is bactericidal for mycobacteria. It read-
ily penetrates most tissues and penetrates into phagocytic cells. It
can kill organisms that are poorly accessible to many other drugs,
such as intracellular organisms and those sequestered in abscesses
and lung cavities.
Rifampin is well absorbed after oral administration and
excreted mainly through the liver into bile. It then undergoes
enterohepatic recirculation, with the bulk excreted as a deacylated
metabolite in feces and a small amount excreted in the urine.
Dosage adjustment for renal or hepatic insufficiency is not neces-
sary. Usual doses result in serum levels of 5–7 mcg/mL. Rifampin
is distributed widely in body fluids and tissues. The drug is
relatively highly protein-bound, and adequate cerebrospinal fluid
concentrations are achieved only in the presence of meningeal
inflammation.
Rifampin strongly induces most cytochrome P450 isoforms
(CYP1A2, 2C9, 2C19, 2D6, and 3A4), which increases the elimi-
nation of numerous other drugs including methadone, antico-
agulants, cyclosporine, some anticonvulsants, protease inhibitors,
some nonnucleoside reverse transcriptase inhibitors or integrase
strand transfer inhibitors, contraceptives, and a host of others
CHAPTER 47 Antimycobacterial Drugs 845
(see Chapters 4 and 66). Co-administration of rifampin results in
significantly lower serum levels of these drugs.
Clinical Uses
A. Mycobacterial Infections
Rifampin, usually 600 mg/d (10 mg/kg/d) orally, must be
administered with isoniazid or other antituberculous drugs to
patients with active tuberculosis to prevent emergence of drug-
resistant mycobacteria. In some short-course therapies, 600 mg
of rifampin is given twice weekly. Rifampin, 600 mg daily or
twice weekly for 6 months, also is effective in combination with
other agents in some atypical mycobacterial infections and in
leprosy. Rifampin, 600 mg daily for 4 months as a single drug,
is an alternative to isoniazid for patients with latent tuberculosis
who are unable to take isoniazid or who have had exposure to
a case of active tuberculosis caused by an isoniazid-resistant,
rifampin-susceptible strain.
B. Other Indications
Rifampin has other uses in bacterial infections. An oral dosage
of 600 mg twice daily for 2 days can eliminate meningococcal
carriage. Rifampin, 20 mg/kg (maximum 600 mg) once daily
for 4 days, is used as prophylaxis in contacts of children with
Haemophilus influenzae type b disease. Rifampin combined
with a second agent is sometimes used to eradicate staphy-
lococcal carriage. Rifampin combination therapy is also used
for treatment of serious staphylococcal infections such as
osteomyelitis, prosthetic joint infections, and prosthetic valve
endocarditis.
Adverse Reactions
Rifampin imparts a harmless orange color to urine, sweat, and
tears (soft contact lenses may be permanently stained). Occasional
adverse effects include rashes, thrombocytopenia, and nephritis.
Rifampin may cause cholestatic jaundice and occasionally hepa-
titis, and it commonly causes light-chain proteinuria. If adminis-
tered less often than twice weekly, rifampin may cause a flu-like
syndrome characterized by fever, chills, myalgias, anemia, and
thrombocytopenia. Its use has been associated with acute tubular
necrosis.
ETHAMBUTOL
Ethambutol is a synthetic, water-soluble, heat-stable compound,
the dextro-isomer of the structure shown below, dispensed as the
dihydrochloride salt.
CH2OH C2H5
H C NH (CH2)2 NH C H
C2H5 CH2OH
Ethambutol
846 SECTION VIII Chemotherapeutic Drugs
Mechanism of Action & Clinical Uses
Ethambutol inhibits mycobacterial arabinosyl transferases, which
are encoded by the embCAB operon. Arabinosyl transferases are
involved in the polymerization reaction of arabinoglycan, an
essential component of the mycobacterial cell wall. Resistance to
ethambutol is due to mutations resulting in overexpression of emb
gene products or within the embB structural gene. Susceptible
strains of Mycobacterium tuberculosis and other mycobacteria are
inhibited in vitro by ethambutol, 1–5 mcg/mL.
Ethambutol is well absorbed from the gut. After ingestion
of 25 mg/kg, a blood level peak of 2–5 mcg/mL is reached in
2–4 hours. About 20% of the drug is excreted in feces and 50% in
urine in unchanged form. Ethambutol accumulates in renal failure,
and the dose should be reduced to three times weekly if creatinine
clearance is less than 30 mL/min. Ethambutol crosses the blood-
brain barrier only when the meninges are inflamed. Concentrations
in cerebrospinal fluid are highly variable, ranging from 4% to 64%
of serum levels in the setting of meningeal inflammation.
As with all antituberculous drugs, resistance to ethambutol
emerges rapidly when the drug is used alone. Therefore, etham-
butol is always given in combination with other antituberculous
drugs. Ethambutol hydrochloride, 15–25 mg/kg, is usually given
as a single daily dose in combination with isoniazid, rifampin, and
pyrazinamide during the initial intensive phase of active tuber-
culosis treatment. The higher dose may be used for treatment of
tuberculous meningitis. Higher doses have been used with inter-
mittent dosing regimens for directly observed therapy; for example,
25–30 mg/kg three times weekly or 50 mg/kg administered twice
weekly. Ethambutol is also used in combination with other agents
for the treatment of nontuberculous mycobacterial infections, such
as Mycobacterium avium complex (MAC) or M. kansasii; the typical
dose for these infections is 15 mg/kg once daily.
Adverse Reactions
Hypersensitivity to ethambutol is rare. The most common serious
adverse event is retrobulbar neuritis, resulting in loss of visual acu-
ity and red-green color blindness. This dose-related adverse effect
is more likely to occur at dosages of 25 mg/kg/d continued for
several months. At 15 mg/kg/d or less, visual disturbances occur in
approximately 2% of patients, typically after at least one month of
treatment. Experts recommend baseline and monthly visual acu-
ity and color discrimination testing, with particular attention to
patients on higher doses or with impaired renal function. Etham-
butol is relatively contraindicated in children too young to permit
assessment of visual acuity and red-green color discrimination.
PYRAZINAMIDE
Pyrazinamide (PZA) is a relative of nicotinamide, and it is used
only for treatment of tuberculosis. It is stable and slightly soluble in
water. It is inactive at neutral pH, but at pH 5.5 it inhibits tubercle
bacilli at concentrations of approximately 20 mcg/mL. The drug is
taken up by macrophages and exerts its activity against mycobacte-
ria residing within the acidic environment of lysosomes.
O
N
C NH2
N
Pyrazinamide (PZA)
Mechanism of Action & Clinical Uses
Pyrazinamide is converted to pyrazinoic acid—the active form of
the drug—by mycobacterial pyrazinamidase, which is encoded
by pncA. Pyrazinoic acid disrupts mycobacterial cell membrane
metabolism and transport functions. Resistance may be due
to impaired uptake of pyrazinamide or mutations in pncA that
impair conversion of PZA to its active form.
Serum concentrations of 30–50 mcg/mL at 1–2 hours after
oral administration are achieved with dosages of 25 mg/kg/d.
Pyrazinamide is well absorbed from the gastrointestinal tract and
widely distributed in body tissues, including inflamed meninges.
The half-life is 8–11 hours. The parent compound is metabolized
by the liver, but metabolites are renally cleared; therefore, PZA
should be administered at 25–35 mg/kg three times weekly (not
daily) in hemodialysis patients and those in whom the creatinine
clearance is less than 30 mL/min. In patients with normal renal
function, a dose of 30–50 mg/kg is used for thrice-weekly or
twice-weekly treatment regimens.
Pyrazinamide is an important front-line drug used in conjunc-
tion with isoniazid and rifampin in short-course (ie, 6-month)
regimens as a “sterilizing” agent active against residual intracellular
organisms that may cause relapse. Tubercle bacilli develop resis-
tance to pyrazinamide fairly readily, but there is no cross-resistance
with isoniazid or other antimycobacterial drugs.
Adverse Reactions
Major adverse effects of PZA include hepatotoxicity (in 1–5%
of patients), nausea, vomiting, drug fever, photosensitivity, and
hyperuricemia. The latter occurs uniformly and is not a reason to
halt therapy if patients are asymptomatic.
SECOND-LINE DRUGS FOR
TUBERCULOSIS
The alternative drugs listed below are usually considered only (1)
in case of resistance to first-line agents; (2) in case of failure of
clinical response to conventional therapy; and (3) in case of serious
treatment-limiting adverse drug reactions. Expert guidance is desir-
able in dealing with the toxic effects of these second-line drugs. For
many drugs listed in the following text, the dosage, emergence of
resistance, and long-term toxicity have not been fully established.
Streptomycin
The mechanism of action and other pharmacologic features of
streptomycin, an aminoglycoside, are discussed in Chapter 45.
The typical adult dosage is 1 g/d (15 mg/kg/d). If the creatinine

clearance is less than 30 mL/min or the patient is on hemodialy-
sis, the dosage is 15 mg/kg two or three times per week. Most
tubercle bacilli are inhibited by streptomycin, 1–10 mcg/mL,
in vitro. Nontuberculous species of mycobacteria other than
Mycobacterium avium complex (MAC) and Mycobacterium
kansasii are resistant. All large populations of tubercle bacilli
contain some streptomycin-resistant mutants. On average, 1
in 108 tubercle bacilli can be expected to be resistant to strep-
tomycin at levels of 10–100 mcg/mL. Resistance may be due
to a point mutation in either the rpsL gene encoding the S12
ribosomal protein or the rrs gene encoding 16S ribosomal RNA,
which alters the ribosomal binding site.
Streptomycin penetrates into cells poorly and is active mainly
against extracellular tubercle bacilli. The drug crosses the blood-
brain barrier and achieves therapeutic concentrations with
inflamed meninges.
Clinical Use in Tuberculosis
Streptomycin sulfate is used when an injectable drug is needed
or desirable and in the treatment of infections resistant to other
drugs. The usual dosage is 15 mg/kg/d intramuscularly or intrave-
nously daily for adults (20–40 mg/kg/d for children, not to exceed
1 g) for several weeks, followed by 15 mg/kg two or three times
weekly for several months. Serum concentrations of approxi-
mately 40 mcg/mL are achieved 30–60 minutes after intramuscu-
lar injection of a 15 mg/kg dose. Other drugs are always given in
combination to prevent emergence of resistance.
Adverse Reactions
Streptomycin is ototoxic and nephrotoxic. Vertigo and hearing
loss are the most common adverse effects and may be permanent.
Toxicity is dose-related, and the risk is increased in the elderly. As
with all aminoglycosides, the dose must be adjusted according to
renal function (see Chapter 45). Toxicity can be reduced by limit-
ing therapy to no more than 6 months whenever possible.
Ethionamide
Ethionamide is chemically related to isoniazid and similarly blocks
the synthesis of mycolic acids. It is poorly water soluble and avail-
able only for oral use. It is metabolized by the liver.
N dose should be reduced by half if creatinine clearance is less than
H5C2
C central nervous system dysfunction, including depression and
S NH2
Ethionamide
Most tubercle bacilli are inhibited in vitro by ethionamide,
2.5 mcg/mL or less. Some other species of mycobacteria also are
inhibited by ethionamide, 10 mcg/mL. Serum concentrations in
plasma and tissues of approximately 1-5 mcg/mL are achieved by
a dosage of 1 g/d. Cerebrospinal fluid concentrations are equal to
those in serum.
CHAPTER 47 Antimycobacterial Drugs 847
Ethionamide is administered at an initial dose of 250 mg
once daily, which is increased in 250 mg increments to the
recommended dosage of 1 g/d (or 15 mg/kg/d), if possible. The
1-g/d dosage, though theoretically desirable, is poorly tolerated
because of gastric irritation and neurologic symptoms, often
limiting the tolerable daily dose to 500–750 mg. Ethionamide
is also hepatotoxic. Neurologic symptoms may be alleviated by
pyridoxine.
Resistance to ethionamide as a single agent develops rapidly in
vitro and in vivo. There can be low-level cross-resistance between
isoniazid and ethionamide.
Capreomycin
Capreomycin is a peptide protein synthesis inhibitor antibiotic
obtained from Streptomyces capreolus. Daily injection of 15 mg/kg
intramuscularly results in peak serum levels of 35–45 mcg/mL
2 hours after a dose. Such concentrations in vitro are inhibitory
for many mycobacteria, including multidrug-resistant strains of
M tuberculosis.
Capreomycin (15 mg/kg/d) is an important injectable agent
for treatment of drug-resistant tuberculosis. Strains of M tuber-
culosis that are resistant to streptomycin usually are susceptible
to capreomycin, though some data suggest cross-resistance with
strains resistant to amikacin and kanamycin. Resistance to cap-
reomycin, when it occurs, has been associated with rrs, eis, or tlyA
gene mutations.
Capreomycin is nephrotoxic and ototoxic. Tinnitus, deafness,
and vestibular disturbances occur. The injection causes significant
local pain, and sterile abscesses may develop.
Typical dosing of capreomycin is 15 mg/kg/day initially,
which is then reduced to two or three times weekly after an initial
response has been achieved with a daily dosing schedule. The
intermittent dosing regimen may minimize risk of toxicity.
Cycloserine
Cycloserine—a structural analog of d-alanine—inhibits cell
wall synthesis, as discussed in Chapter 43. Concentrations of
15–20 mcg/mL inhibit many strains of M tuberculosis. The usual
dosage of cycloserine in tuberculosis is 0.5–1 g/d in two divided
oral doses. The drug is widely distributed to tissues, including
the central nervous system. This drug is cleared renally, and the
50 mL/min. Alternatively, it may be reduced to 500 mg three
times weekly.
The most serious toxic effects are peripheral neuropathy and
psychoses. Pyridoxine, 100 mg or more per day, should be given
with cycloserine because this ameliorates neurologic toxicity.
Adverse effects, which are most common during the first 2 weeks
of therapy, occur in 25% or more of patients, especially at higher
doses leading to peak concentrations greater than 35 mcg/mL.
Adverse effects can be minimized by monitoring peak serum
concentrations. The peak concentration is reached 2–4 hours
after dosing. The recommended range of peak concentrations is
20–35 mcg/mL.
848 SECTION VIII Chemotherapeutic Drugs
Aminosalicylic Acid (PAS)
Aminosalicylic acid is a folate synthesis antagonist that is active
almost exclusively against M tuberculosis. It is structurally similar
to p-amino-benzoic acid (PABA) and is thought to have a similar
mechanism of action to the sulfonamides (see Chapter 46). In the
USA, PAS is commercially available as a 4-g packet of delayed-
release granules. In order to protect the integrity of the delayed-
release coating, the granules must be administered sprinkled over
applesauce or yogurt, or swirled in fruit juice and swallowed
whole.
COOH
OH
NH2
Aminosalicylic acid (PAS)
Tubercle bacilli are usually inhibited in vitro by aminosalicylic
acid, 1–5 mcg/mL. The granule formulation of aminosalicylic
acid results in improved absorption from the gastrointestinal
tract. Peak serum levels are expected to be 20–60 mcg/mL 6 hours
after a 4 g oral dose. The dosage is 8–12 g/d orally for adults and
300 mg/kg/d for children, administered in two or three divided
doses. The drug is widely distributed in tissues and body fluids
except the cerebrospinal fluid. Aminosalicylic acid is rapidly
excreted in the urine, in part as active PAS and in part as the
acetylated compound and other metabolic products. To avoid
accumulation in renal impairment, the maximum dose is 4 g twice
daily when creatinine clearance is less than 30 mL/min. Very high
concentrations of aminosalicylic acid are reached in the urine,
which can result in crystalluria.
Aminosalicylic acid is used infrequently in the USA because
other oral drugs are better tolerated. Gastrointestinal symptoms
are common but occur less frequently with the delayed-release
granules; they may be diminished by giving the drug with meals
and with antacids. Peptic ulceration and hemorrhage may occur.
Hypersensitivity reactions manifested by fever, joint pains, skin
rashes, hepatosplenomegaly, hepatitis, adenopathy, and granulo-
cytopenia often occur after 3–8 weeks of PAS therapy, making it
necessary to stop administration temporarily or permanently.
Kanamycin & Amikacin
The aminoglycoside antibiotics are discussed in Chapter 45.
Kanamycin had been used for treatment of tuberculosis caused by
streptomycin-resistant strains, but it is no longer available in the
USA, and less toxic alternatives (eg, capreomycin and amikacin)
have taken its place.
Amikacin is playing a greater role in the treatment of tuberculo-
sis due to the prevalence of multidrug-resistant strains. Prevalence
of amikacin-resistant strains is low (<5%), and most multidrug-
resistant strains remain amikacin-susceptible. M tuberculosis is
inhibited at concentrations of 1 mcg/mL or less. Amikacin is also
active against atypical mycobacteria. There is no cross-resistance
between streptomycin and amikacin, but kanamycin resistance
often indicates resistance to amikacin as well. Peak serum con-
centrations of 30–45 mcg/mL are achieved 30–60 minutes after
a 15-mg/kg intravenous infusion or intramuscular injection.
Amikacin is indicated for treatment of tuberculosis suspected
or known to be caused by streptomycin-resistant or multidrug-
resistant strains. This drug must be used in combination with at
least one and preferably two or three other drugs to which the
isolate is susceptible for treatment of drug-resistant cases. The
recommended dosage is 15 mg/kg once daily initially, followed by
intermittent dosing two or three times per week.
Fluoroquinolones
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
M tuberculosis at concentrations less than 2 mcg/mL. They are
also active against atypical mycobacteria. Moxifloxacin is the
most active against M tuberculosis in vitro. Levofloxacin tends to
be slightly more active than ciprofloxacin against M tuberculo-
sis, whereas ciprofloxacin is slightly more active against atypical
mycobacteria.
Fluoroquinolones are an important addition to the drugs avail-
able for tuberculosis, especially for strains that are resistant to first-
line agents. The World Health Organization recommends using a
later generation fluoroquinolone such as moxifloxacin or levoflox-
acin. Resistance, which may result from one of several single point
mutations in the gyrase A subunit, develops rapidly if a fluoroqui-
nolone is used as a single agent; thus, the drug must be used in
combination with two or more additional active agents. Typically,
resistance to one fluoroquinolone indicates class resistance. How-
ever, moxifloxacin may retain some activity in strains resistant to
ofloxacin. The dosage of levofloxacin is 500–750 mg once a day,
and some clinicians increase to 1000 mg daily if tolerated. The
dosage of moxifloxacin is 400 mg once a day. Some experts rec-
ommend checking peak serum concentrations. Expected levels at
about two hours post-dose are 8–12 mcg/mL for levofloxacin and
3–5 mcg/mL for moxifloxacin.
Linezolid
Linezolid (discussed in Chapter 44) inhibits strains of M tuberculosis
in vitro at concentrations of 4–8 mcg/mL. It achieves good intra-
cellular concentrations, and it is active in murine models of
tuberculosis. Linezolid has been used in combination with other
second- and third-line drugs to treat patients with tuberculosis
caused by multidrug-resistant strains. Conversion of sputum
cultures to negative was associated with linezolid use in these
cases. Significant adverse effects, including bone marrow suppres-
sion and irreversible peripheral and optic neuropathy, have been
reported with the prolonged courses of therapy that are necessary
for treatment of tuberculosis. A 600-mg (adult) dose administered
once a day (half of that used for treatment of other bacterial infec-
tions) seems to be sufficient and may limit the occurrence of these
adverse effects. Experts recommend supplemental pyridoxine for
patients treated with linezolid. Although linezolid may prove to

be an important new agent for treatment of tuberculosis, at this
point it should be used only for multidrug-resistant strains that
also are resistant to several other first- and second-line agents. It is
generally avoided in patients on concomitant serotonergic agents
due to concern for serotonin syndrome.
Rifabutin
Rifabutin is derived from rifamycin and is related to rifampin.
It has significant activity against M tuberculosis, MAC, and
Mycobacterium fortuitum (see below). Its activity is similar to
that of rifampin, and cross-resistance with rifampin is virtually
complete. Some rifampin-resistant strains may appear susceptible
to rifabutin in vitro, but a clinical response is unlikely because
the molecular basis of resistance, rpoB mutation, is the same.
Rifabutin is both substrate and inducer of cytochrome P450
enzymes. Because it is a less potent inducer, rifabutin is often
used in place of rifampin for treatment of tuberculosis in patients
with HIV infection who are receiving antiretroviral therapy with
a protease inhibitor, a nonnucleoside reverse transcriptase inhibi-
tor (eg, efavirenz), or an integrase strand transfer inhibitor (eg
dolutegravir), drugs that also are cytochrome P450 or UDP gluc-
uronosyltransferase (UGT) substrates.
The typical dosage of rifabutin is 300 mg/d unless the patient
is receiving a protease inhibitor, in which case the dosage should
be reduced, typically by half. If efavirenz (also a cytochrome
P450 inducer) is used, the recommended dosage of rifabutin is
600 mg/d. Rifabutin may accumulate in severe renal impairment,
and the dose should be reduced by half if creatinine clearance is
less than 30 mL/min. Rifabutin is associated with similar rates
of hepatotoxicity or rash compared to rifampin; it can also cause
leukopenia, thrombocytopenia, and optic neuritis.
Rifapentine
Rifapentine is another analog of rifampin. It is active against both
M tuberculosis and MAC. As with all rifamycins, it is a bacterial
RNA polymerase inhibitor, and cross-resistance between rifampin
and rifapentine is complete. Like rifampin, rifapentine is a potent
inducer of cytochrome P450 enzymes, and it has the same drug
interaction profile; however, when rifapentine is administered
intermittently, induction of metabolism of other medications is
less pronounced compared to rifampin. Toxicity is similar to that
of rifampin. Rifapentine and its microbiologically active metabo-
lite, 25-desacetylrifapentine, have an elimination half-life of
13 hours. Rifapentine, 600 mg (10 mg/kg) once or twice weekly,
has been used for treatment of tuberculosis caused by rifampin-
susceptible strains during the continuation phase (ie, after the
first 2 months of therapy and ideally after conversion of sputum
cultures to negative); however, this regimen has decreased efficacy
compared with the standard rifampin-based regimen. Revised
guidelines for treatment of drug-susceptible tuberculosis pub-
lished in 2016 recommend against it. In particular, its use should
be avoided in patients at higher risk of failure, including those
with positive cultures at the end of the intensive treatment phase
and those with evidence of cavitation on chest radiographs. Rifa-
pentine should not be used to treat active tuberculosis in patients
CHAPTER 47 Antimycobacterial Drugs 849
with HIV infection because of an unacceptably high relapse rate
with rifampin-resistant organisms. Rifapentine in combination
with isoniazid, typically both dosed at 900 mg once weekly for
3 months (12 doses each in total), is an effective short course treat-
ment for latent tuberculosis infection.
Bedaquiline
Bedaquiline, a diarylquinoline, is the first drug with a novel mech-
anism of action against M tuberculosis to be approved since 1971.
Bedaquiline inhibits adenosine 5′-triphosphate (ATP) synthase
in mycobacteria, has in vitro activity against both replicating and
nonreplicating bacilli, and has bactericidal and sterilizing activity
in the murine model of tuberculosis. Cross-resistance has been
reported between bedaquiline and clofazimine, likely via upregu-
lation of the multisubstrate efflux pump, MmpL5.
Peak plasma concentration and plasma exposure to bedaquiline
increase approximately twofold when administered with high-fat
food. Bedaquiline is highly protein-bound (>99%), is metabolized
chiefly through the cytochrome P450 system, and is excreted
primarily via the feces. The mean terminal half-life of bedaquiline
and its major metabolite (M2), which is four to six times less
active in terms of antimycobacterial potency, is approximately
5.5 months. This long elimination phase probably reflects slow
release of bedaquiline and M2 from peripheral tissues. CYP3A4 is
the major isoenzyme involved in the metabolism of bedaquiline,
and potent inhibitors or inducers of this enzyme cause clinically
significant drug interactions.
Current recommendations state that bedaquiline, in combina-
tion with at least three other active medications, may be used for
24 weeks of treatment in adults with laboratory-confirmed pul-
monary tuberculosis if the isolate is resistant to both isoniazid and
rifampin. The recommended dosage for bedaquiline is 400 mg
once daily orally for 2 weeks, followed by 200 mg three times a
week for 22 weeks taken orally with food in order to maximize
absorption. The most common adverse effects, occurring at rates
of 25% or more, are nausea, arthralgia, and headache. Bedaquiline
has been associated with both hepatotoxicity and cardiac toxicity.
The FDA has issued a black-box warning related to the risk of
QTc prolongation and associated mortality. It should be reserved
for patients who do not have other treatment options and used
with caution in patients with other risk factors for cardiac conduc-
tion abnormalities.
■ DRUGS ACTIVE AGAINST
NONTUBERCULOUS
MYCOBACTERIA
Many mycobacterial infections seen in clinical practice in the
United States are caused by nontuberculous mycobacteria (NTM),
formerly known as “atypical mycobacteria.” These organisms have
distinctive laboratory characteristics, are present in the environ-
ment, and are generally not communicable from person to person.
As a rule, these mycobacterial species are less susceptible than
M tuberculosis to antituberculous drugs. On the other hand, agents
850 SECTION VIII Chemotherapeutic Drugs
TABLE 47–3 Clinical features and treatment options for infections with atypical mycobacteria.
Species Clinical Features
M kansasii Resembles tuberculosis
M marinum Granulomatous cutaneous disease
M scrofulaceum Cervical adenitis in children
M avium complex Pulmonary disease in patients with chronic
(MAC) lung disease; disseminated infection in AIDS
M chelonae Abscess, sinus tract, ulcer; bone, joint, tendon
infection
M fortuitum Abscess, sinus tract, ulcer; bone, joint, tendon
infection
M ulcerans Skin ulcers
such as macrolides, sulfonamides, and tetracyclines, which are not
active against M tuberculosis, may be effective for infections caused
by NTM. Emergence of resistance during therapy is also a prob-
lem with these mycobacterial species, and active infection should
be treated with combinations of drugs. M kansasii is susceptible
to rifampin and ethambutol, partially susceptible to isoniazid, and
completely resistant to pyrazinamide. A three-drug combination
of isoniazid, rifampin, and ethambutol is the conventional treat-
ment for M kansasii infection. A few representative pathogens,
with the clinical presentation and the drugs to which they are
often susceptible, are given in Table 47–3.
M avium complex (MAC), which includes both M avium
and M intracellulare, is an important and common cause of dis-
seminated disease in late stages of AIDS (CD4 counts < 50/µL).
MAC is much less susceptible than M tuberculosis to most anti-
tuberculous drugs. Combinations of agents are required to sup-
press the infection. Azithromycin, 500–600 mg once daily, or
clarithromycin, 500 mg twice daily, plus ethambutol, 15 mg/kg/d,
is an effective and well-tolerated regimen for treatment of dissemi-
nated disease. Some authorities recommend use of a third agent,
especially rifabutin, 300 mg once daily. Other agents that may be
useful are listed in Table 47–3. Azithromycin and clarithromycin
are the prophylactic drugs of choice for preventing disseminated
MAC in AIDS patients with CD4 cell counts less than 50/µL.
Rifabutin in a single daily dose of 300 mg has been shown to
reduce the incidence of MAC bacteremia but is less effective than
macrolides.
■ DRUGS USED IN LEPROSY
Mycobacterium leprae has never been grown in vitro, but animal
models, such as growth in injected mouse footpads, have permit-
ted laboratory evaluation of drugs. Only those drugs with the wid-
est clinical use are presented here. Because of increasing reports of
dapsone resistance, treatment of leprosy with combinations of the
drugs listed below is recommended.
Treatment Options
Amikacin, clarithromycin, ethambutol, isoniazid, moxifloxacin, rifampin,
streptomycin, trimethoprim-sulfamethoxazole
Amikacin, clarithromycin, ethambutol, doxycycline, levofloxacin, minocycline,
rifampin, trimethoprim-sulfamethoxazole
Amikacin, erythromycin (or other macrolide), rifampin, streptomycin
(Surgical excision is often curative and the treatment of choice.)
Amikacin, azithromycin, clarithromycin, ethambutol, moxifloxacin, rifabutin
Amikacin, doxycycline, imipenem, linezolid, macrolides, tobramycin
Amikacin, cefoxitin, ciprofloxacin, doxycycline, imipenem, minocycline,
moxifloxacin, ofloxacin, trimethoprim-sulfamethoxazole
Clarithromycin, isoniazid, streptomycin, rifampin, minocycline, moxifloxacin
(Surgical excision may be effective.)
DAPSONE & OTHER SULFONES
Several drugs closely related to the sulfonamides have been used
effectively in the long-term treatment of leprosy. The most widely
used is dapsone (diaminodiphenylsulfone). Like the sulfon-
amides, it inhibits folate synthesis. Resistance can emerge in large
populations of M leprae, eg, in lepromatous leprosy, particularly
if low doses are given. Therefore, the combination of dapsone,
rifampin, and clofazimine is recommended for initial therapy of
lepromatous leprosy. A combination of dapsone plus rifampin is
commonly used for leprosy with a lower organism burden. Dap-
sone may also be used to prevent and treat Pneumocystis jiroveci
pneumonia in AIDS patients.
O
NH2 S NH2
O
Dapsone
Sulfones are well absorbed from the gut and widely distributed
throughout body fluids and tissues. Dapsone’s half-life is 1–2 days,
and drug tends to be retained in skin, muscle, liver, and kidney. Skin
heavily infected with M leprae may contain several times more drug
than normal skin. Sulfones are excreted into bile and reabsorbed
in the intestine. Excretion into urine is variable, and most excreted
drug is acetylated. In renal failure, the dose may have to be adjusted.
The usual adult dosage in leprosy is 100 mg daily. For children, the
dose is proportionately less, depending on weight.
Dapsone is usually well tolerated. Many patients develop some
hemolysis, particularly if they have glucose-6-phosphate dehydro-
genase deficiency. Methemoglobinemia is common but usually
is not clinically significant. Gastrointestinal intolerance, fever,
pruritus, and rash occur. During dapsone therapy of lepromatous
leprosy, erythema nodosum leprosum often develops. It is some-
times difficult to distinguish reactions to dapsone from manifesta-
tions of the underlying illness. Erythema nodosum leprosum may
be suppressed by thalidomide (see Chapter 55).
 CHAPTER 47 Antimycobacterial Drugs 851

RIFAMPIN and a major portion of the drug is excreted in feces. Clofazimine

Rifampin (see earlier discussion) in a dosage of 600 mg daily is
highly effective in leprosy and is given with at least one other drug
to prevent emergence of resistance. Even a dose of 600 mg per
month may be beneficial in combination therapy.
CLOFAZIMINE
Clofazimine is a phenazine dye used in the treatment of multi-
bacillary leprosy, which is defined as having a positive smear from
any site of infection. Its mechanism of action has not been clearly
established. Absorption of clofazimine from the gut is variable,
is stored widely in reticuloendothelial tissues and skin, and its
crystals can be seen inside phagocytic reticuloendothelial cells. It
is slowly released from these deposits, so the serum half-life may
be 2 months. A common dosage of clofazimine is 100–200 mg/d
orally. The most prominent adverse effect is discoloration of the
skin and conjunctivae. Gastrointestinal side effects are common.
This medication is no longer commercially available, but it can
be obtained through established programs. For example, an inves-
tigational new drug (IND) program is established in the USA
through the National Hansen’s Disease Program. Internation-
ally, ministries of health can make requests directly to the World
Health Organization.

SUMMARY First-Line Antimycobacterial Drugs

Pharmacokinetics, Toxicities,
Subclass, Drug Mechanism of Action Effects Clinical Applications Interactions

ISONIAZID Inhibits synthesis of mycolic
acids, an essential
component of mycobacterial
cell walls
Bactericidal activity against
susceptible strains of
M tuberculosis
First-line agent for
against nontuberculous
mycobacteria
Toxicity:
Hepatotoxic, peripheral neuropathy (give
pyridoxine to prevent)

RIFAMYCINS

Inhibits DNA-dependent RNA Bactericidal activity against First-line agent for

polymerase, thereby blocking
production of RNA
susceptible bacteria and
rapidly emerges when used
as a single drug in the
treatment of active infection
mycobacterial infections Toxicity: Rash,
nephritis, thrombocytopenia, cholestasis,
meningococcal colonization, flu-like syndrome with intermittent
staphylococcal infections dosing

Rifabutin: Oral; similar to rifampin but less cytochrome P450 induction and fewer drug interactions
Rifapentine: Oral; long-acting analog of rifampin that may be given once weekly in select cases during the continuation phase of tuberculosis treatment or for treatment
of latent tuberculosis

PYRAZINAMIDE Bacteriostatic activity against “Sterilizing” agent used

pyrazinamide is converted to susceptible strains of during first 2 months of metabolites are renally cleared so use
the active pyrazinoic acid M tuberculosis 3 doses weekly if creatinine clearance
under acidic conditions in bactericidal against actively duration of therapy to be Toxicity: Hepatotoxic,
macrophage lysosomes dividing organisms shortened to 6 months hyperuricemia

ETHAMBUTOL Inhibits mycobacterial Bacteriostatic activity against Given in four-drug initial

arabinosyl transferases, which
are involved in the
polymerization reaction of
arabinoglycan, an essential
component of the
mycobacterial cell wall
susceptible mycobacteria combination therapy for
tuberculosis until drug Toxicity: Retrobulbar neuritis
used for nontuberculous
mycobacterial infections
852 SECTION VIII Chemotherapeutic Drugs

P R E P A R A T I O N S Centers for Disease Control and Prevention (CDC): Update: Adverse event data
and revised American Thoracic Society/CDC recommendations against
*
A V A I L A B L E the use of rifampin and pyrazinamide for treatment of latent tubercu-
losis infection—United States, 2003. MMWR Morb Mortal Wkly Rep
2003;52:735.
GENERIC NAME AVAILABLE AS
Curry International Tuberculosis Center and California Department of Public
DRUGS USED IN TUBERCULOSIS Health, 2016: Drug-Resistant Tuberculosis: A Survival Guide for Clinicians,
Aminosalicylic acid Paser Third Edition [1-305].
Bedaquiline fumarate Sirturo Gillespie SH et al: Early bactericidal activity of a moxifloxacin and isoniazid
combination in smear-positive pulmonary tuberculosis. J Antimicrob
Capreomycin Capastat Chemother 2005;56:1169.
Ethambutol Generic, Myambutol Griffith DE et al: An official ATS/IDSA statement: Diagnosis, treatment, and
Ethionamide Trecator, Trecator-SC prevention of nontuberculous mycobacterial disease. Am J Respir Crit Care
Isoniazid Generic Med 2007;175:367.
Hugonnet J-E et al: Meropenem-clavulanate is effective against extensively drug-
Pyrazinamide Generic
resistant Mycobacterium tuberculosis. Science 2009;323:1215.
Rifabutin Generic, Mycobutin Jasmer RM, Nahid P, Hopewell PC: Latent tuberculosis infection. N Engl J Med
Rifampin Generic, Rifadin, Rimactane 2002;347:1860.
Rifapentine Priftin Kinzig-Schippers M et al: Should we use N-acetyltransferase type 2 genotyping to
Streptomycin Generic personalize isoniazid doses? Antimicrob Agents Chemother 2005;49:1733.
Lee M et al: Linezolid for treatment of chronic extensively drug-resistant tubercu-
DRUGS USED IN LEPROSY
losis. N Engl J Med 2012;367:1508.
Clofazimine Lamprene Mitnick CD et al: Comprehensive treatment of extensively drug-resistant tubercu-
Dapsone Generic losis. N Engl J Med 2008;359:563.
*
Nahid P et al: Official American Thoracic Society/Centers for Disease Control
Drugs used against nontuberculous mycobacteria are listed in Chapters 43–46. and Prevention/Infectious Diseases Society of America Clinical Practice
Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis
REFERENCES 2016;63:e147.
Sulochana S, Rahman F, Paramasivan CN: In vitro activity of fluoroquinolones
Centers for Disease Control and Prevention (CDC): Provisional CDC Guidelines against Mycobacterium tuberculosis. J Chemother 2005;17:169.
for the use and safety monitoring of bedaquiline fumarate (Sirturo) for the
treatment of multidrug-resistant tuberculosis. MMWR Morb Mortal Wkly Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J
Rep 2013;62:1. Respir Crit Care Med 2000;161(4 Part 2):S221.
Centers for Disease Control and Prevention (CDC): Recommendations for use Zhang Y, Yew WW: Mechanisms of drug resistance in Mycobacterium tuberculosis.
of an isoniazid-rifapentine regimen with direct observation to treat latent Int J Tuberc Lung Dis 2009;13:1320.
Mycobacterium tuberculosis infection. MMWR Morb Mortal Wkly Rep Zumla A et al: Current concepts—Tuberculosis. N Engl J Med 2013;368:745.
2011;60:1650.

C ASE STUDY ANSWER

The patient should be started on four-drug therapy with
rifampin, isoniazid, pyrazinamide, and ethambutol. He should
also be started on antiretroviral therapy for HIV. If a protease-
inhibitor-based antiretroviral regimen is used to treat his HIV,
rifabutin should replace rifampin because of the serious drug-
drug interactions between rifampin and protease inhibitors.
If dolutegravir is chosen, it must be administered twice daily
due to the interaction with rifampin; alternatively, rifabutin
can be used in place of rifampin, and dolutegravir can be
dosed once daily. The patient is at increased risk of developing
hepatotoxicity from both isoniazid and pyrazinamide given
his history of alcohol use.

Antimycobacterial Drugs
The chemotherapy of infections caused by Mycobacterium
tuberculosis, M leprae, and M avium-intracellulare is compli-
cated by numerous factors, including (1) limited information
about the mechanisms of antimycobacterial drug actions;
(2) the development of resistance; (3) the slow growth
& intracellular location of mycobacteria; (4) the chronic
Antimycobacterial agents
Drugs used in
tuberculosis
First-line drugs Alternative drugs
(isoniazid, rifampin, (amikacin,
ethambutol, ciprofloxacin,
pyrazinamide, ethionamide,
streptomycin) p-aminosalicylate)
DRUGS FOR TUBERCULOSIS
The major drugs used in tuberculosis are isoniazid (INH), rifampin,
ethambutol, pyrazinamide, and streptomycin. Actions of these
agents on M tuberculosis are bactericidal or bacteriostatic depending
on drug concentration and strain susceptibility. Appropriate drug
treatment involves antibiotic susceptibility testing of mycobacterial
isolates from that patient. Initiation of treatment of pulmonary
tuberculosis usually involves a 3- or 4-drug combination regimen
depending on the known or anticipated resistance to isoniazid
(INH). Directly observed therapy (DOT) regimens are recom-
mended in noncompliant patients and in drug-resistant tuberculosis.
A. Isoniazid
1. Mechanisms—Isoniazid (INH) is a structural congener of
pyridoxine. Its mechanism of action involves inhibition of the
Trevor_Ch47_p397-p403.indd 397
47
C H A P T E R
nature of mycobacterial disease, which requires protracted
drug treatment and is associated with drug toxicities; and
(5) patient compliance. Chemotherapy of mycobacterial
infections almost always involves the use of drug combinations
to delay the emergence of resistance and to enhance antimy-
cobacterial efficacy.
Drugs used Drugs used for
in leprosy nontuberculous mycobacteria
Acedapsone, Azithromycin,
dapsone, clarithromycin,
clofazimine, moxifloxacin
rifampin
synthesis of mycolic acids, essential components of mycobacterial
cell walls. Resistance can emerge rapidly if the drug is used
alone. High-level resistance is associated with mutations in the
katG gene that codes for a catalase-peroxidase involved in the
bioactivation of INH. Low-level resistance occurs via deletions
in the inhA gene that encodes the target enzyme, an acyl car-
rier protein reductase. INH is bactericidal for actively growing
tubercle bacilli, but is less effective against dormant organisms.
2. Pharmacokinetics—INH is well absorbed orally and
penetrates cells to act on intracellular mycobacteria. The liver
metabolism of INH is by acetylation and is under genetic control.
Patients may be fast or slow inactivators of the drug. INH half-life
in fast acetylators is 60–90 min; in slow acetylators it may be 3–4 h.
Fast acetylators may require higher dosage than slow acetylators
for equivalent therapeutic effects.
397
7/13/18 6:50 PM
 398 PART VIII Chemotherapeutic Drugs
3. Clinical use—INH is the single most important drug used
in tuberculosis and is a component of most drug combination
regimens. In the treatment of latent infection (formerly known as
prophylaxis), including skin test converters and for close contacts
of patients with active disease, INH is given as the sole drug.
4. Toxicity and interactions—Neurotoxic effects are common
and include peripheral neuritis, restlessness, muscle twitching, and
insomnia. These effects can be alleviated by administration of pyr-
idoxine (25–50 mg/d orally). INH is hepatotoxic and may cause
abnormal liver function tests, jaundice, and hepatitis. Fortunately,
hepatotoxicity is rare in children. INH may inhibit the hepatic
metabolism of drugs (eg, carbamazepine, phenytoin, warfarin).
Hemolysis has occurred in patients with glucose-6-phosphate
dehydrogenase (G6PDH) deficiency. A lupus-like syndrome has
also been reported.
B. Rifampin
1. Mechanisms—Rifampin, a derivative of rifamycin, is
bactericidal against M tuberculosis. The drug inhibits DNA-
dependent RNA polymerase (encoded by the rpo gene) in
M tuberculosis and many other microorganisms. Resistance via
changes in drug sensitivity of the polymerase often emerges
rapidly if the drug is used alone.
2. Pharmacokinetics—When given orally, rifampin is well
absorbed and is distributed to most body tissues, including the
central nervous system (CNS). The drug undergoes enterohepatic
cycling and is partially metabolized in the liver. Both free drug
and metabolites, which are orange colored, are eliminated mainly
in the feces.
3. Clinical uses—In the treatment of tuberculosis, rifampin is
almost always used in combination with other drugs. However,
rifampin can be used as the sole drug in treatment of latent
tuberculosis in INH-intolerant patients or in close contacts of
patients with INH-resistant strains of the organism. In leprosy,
rifampin given monthly delays the emergence of resistance to
dapsone. Rifampin may be used with vancomycin for infections
due to resistant staphylococci (methicillin-resistant Staphylococcus
aureus [MRSA] strains) or pneumococci (penicillin-resistant
Streptococcus pneumoniae [PRSP] strains). Other uses of rifampin
include the meningococcal and staphylococcal carrier states.
4. Toxicity and interactions—Rifampin colors sweat, urine
and tears orange. It is harmless, though contact lenses can be
permanently stained. Rifampin commonly causes light-chain pro-
teinuria and may impair antibody responses. Occasional adverse
effects include skin rashes, thrombocytopenia, nephritis, and liver
dysfunction. If given less often than twice weekly, rifampin may
cause a flu-like syndrome and anemia. Rifampin strongly induces
liver drug-metabolizing enzymes and enhances the elimination
rate of many drugs, including anticonvulsants, contraceptive
steroids, cyclosporine, ketoconazole, methadone, terbinafine, and
warfarin.
Trevor_Ch47_p397-p403.indd 398
5. Other rifamycins—Rifabutin is equally effective as an anti-
mycobacterial agent and is less likely to cause drug interactions
than rifampin. It is usually preferred over rifampin in the treat-
ment of tuberculosis or other mycobacterial infections in AIDS
patients, especially those treated with cytochrome P450 substrates
including protease inhibitors or efavirenz. Rifapentine has kinet-
ics that allow for once-weekly dosing and can be used with iso-
niazid for treatment of latent infections. Rifaximin, a rifampin
derivative that is not absorbed from the gastrointestinal tract, has
been used in traveler’s diarrhea.
SKILL KEEPER: GENOTYPIC VARIATIONS IN
DRUG METABOLISM (SEE CHAPTERS 4, 5)
Genotypic variants occur with regard to the metabolism
of isoniazid. What other drugs exhibit such variation, and
what enzymes are involved in their metabolism? What are
the clinical consequences of genetic polymorphisms in drug
metabolism?
The Skill Keeper Answers appear at the end of the
chapter.
C. Ethambutol
1. Mechanisms—Ethambutol (ETB) inhibits arabinosyltrans-
ferases (encoded by the embCAB operon) involved in the synthe-
sis of arabinogalactan, a component of mycobacterial cell walls.
Resistance occurs rapidly via mutations in the emb gene if the
drug is used alone.
2. Pharmacokinetics—The drug is well absorbed orally and
distributed to most tissues, including the CNS. A large fraction
is eliminated unchanged in the urine. Dose reduction is necessary
in renal impairment.
3. Clinical use—The main use of ethambutol is in tuberculosis,
and it is always given in combination with other drugs.
4. Toxicity—The most common adverse effects are dose-dependent
visual disturbances, including decreased visual acuity, red-green
color blindness, optic neuritis, and possible retinal damage (from
prolonged use at high doses). Most of these effects regress when
the drug is stopped. Other adverse effects include headache, con-
fusion, hyperuricemia, and peripheral neuritis.
D. Pyrazinamide
1. Mechanisms—The mechanism of action of pyrazinamide is
not known; however, its bacteriostatic action appears to require
metabolic conversion via pyrazinamidases (encoded by the pncA
gene) present in M tuberculosis. Resistance occurs via mutations
in the gene that encodes enzymes involved in the bioactivation of
pyrazinamide and by increased expression of drug efflux systems.
7/13/18 6:50 PM

This develops rapidly when the drug is used alone, but there is
minimal cross-resistance with other antimycobacterial drugs.
2. Pharmacokinetics—Pyrazinamide is well absorbed orally
and penetrates most body tissues, including the CNS. The drug is
partly metabolized to pyrazinoic acid, and both parent molecule
and metabolite are excreted in the urine. The plasma half-life of
pyrazinamide is increased in hepatic or renal failure.
3. Clinical use—The combined use of pyrazinamide with other
antituberculous drugs is an important factor in the success of
short-course treatment regimens.
4. Toxicity—Approximately 40% of patients develop nongouty
polyarthralgia. Hyperuricemia occurs commonly but is usually
asymptomatic. Other adverse effects are myalgia, gastrointestinal
irritation, maculopapular rash, hepatic dysfunction, porphyria,
and photosensitivity reactions. Pyrazinamide should be avoided
in pregnancy.
E. Streptomycin
This aminoglycoside is now used more frequently than before
because of the growing prevalence of strains of M tuberculosis
resistant to other drugs. Streptomycin is used principally in drug
combinations for the treatment of life-threatening tuberculous
disease, including meningitis, miliary dissemination, and severe
organ tuberculosis. The pharmacodynamic and pharmacokinetic
properties of streptomycin are similar to those of other aminogly-
cosides (see Chapter 45).
F. Alternative Drugs
Several drugs with antimycobacterial activity are used in cases that
are resistant to first-line agents; they are considered second-line
drugs because they are no more effective, and their toxicities are
often more serious than those of the major drugs.
Amikacin is indicated for the treatment of tuberculosis
suspected to be caused by streptomycin-resistant or multidrug-
resistant mycobacterial strains. To avoid emergence of resistance,
amikacin should always be used in combination drug regimens.
Ciprofloxacin and ofloxacin are often active against strains of
M tuberculosis resistant to first-line agents. The fluoroquinolones
should always be used in combination regimens with two or more
other active agents.
Ethionamide is a congener of INH, but cross-resistance does
not occur. The major disadvantage of ethionamide is severe
gastrointestinal irritation and adverse neurologic effects at doses
needed to achieve effective plasma levels.
p-Aminosalicylic acid (PAS) is rarely used because primary
resistance is common. In addition, its toxicity includes gastro-
intestinal irritation, peptic ulceration, hypersensitivity reactions,
and effects on kidney, liver, and thyroid function.
Other drugs of limited use because of their toxicity include
capreomycin (ototoxicity, renal dysfunction) and cycloserine
(peripheral neuropathy, CNS dysfunction).
Trevor_Ch47_p397-p403.indd 399
CHAPTER 47 Antimycobacterial Drugs 399
Bedaquiline inhibits ATP synthase in mycobacteria. It is
approved for TB resistant to both isoniazid and rifampin. Adverse
effects include nausea, arthralgia, headache, cardiotoxicity, and
hepatotoxicity.
G. Antitubercular Drug Regimens
1. Standard regimens—For empiric treatment of pulmonary
TB (in most areas of <4% INH resistance), an initial 3-drug
regimen of INH, rifampin, and pyrazinamide is recom-
mended. If the organisms are fully susceptible (and the patient
is HIV negative), pyrazinamide can be discontinued after
2 mo and treatment continued for a further 4 mo with a 2-drug
regimen.
2. Alternative regimens—Alternative regimens in cases of fully
susceptible organisms include INH plus rifampin for 9 mo, or INH
plus ethambutol for 18 mo. Intermittent (2 or 3 × weekly) high-
dose 4-drug regimens are also effective.
3. Resistance—If resistance to INH is higher than 4%, the
initial drug regimen should include ethambutol or streptomycin.
Tuberculosis resistant only to INH (the most common form of
resistance) can be treated for 6 mo with a regimen of rifampin
plus pyrazinamide plus ethambutol or streptomycin. Multidrug-
resistant organisms (resistant to both INH and rifampin) should
be treated with 3 or more drugs to which the organism is sus-
ceptible for a period of more than 18 mo, including 12 mo after
sputum cultures become negative.
DRUGS FOR LEPROSY
A. Sulfones
Dapsone (diaminodiphenylsulfone) remains the most active
drug against M leprae. The mechanism of action of sulfones may
involve inhibition of folic acid synthesis. Because of increasing
reports of resistance, it is recommended that the drug be used
in combinations with rifampin and/or clofazimine (see below).
Dapsone can be given orally, penetrates tissues well, undergoes
enterohepatic cycling, and is eliminated in the urine, partly as
acetylated metabolites. Common adverse effects include gastro-
intestinal irritation, fever, skin rashes, and methemoglobinemia.
Hemolysis may occur, especially in patients with G6PDH
deficiency.
Acedapsone is a repository form of dapsone that provides
inhibitory plasma concentrations for several months. In addi-
tion to its use in leprosy, dapsone is an alternative drug for
the treatment of Pneumocystis jirovecii pneumonia in AIDS
patients.
B. Other Agents
Drug regimens usually include combinations of dapsone with
rifampin (or rifabutin, see prior discussion) with or without
clofazimine. Clofazimine, a phenazine dye that may interact
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 400 PART VIII Chemotherapeutic Drugs
with DNA, causes gastrointestinal irritation and skin discolor-
ation ranging from red-brown to nearly black.
DRUGS ACTIVE AGAINST
NONTUBERCULOUS MYCOBACTERIA
(NTM)
Nontuberculous mycobacteria (NTM) were formerly known
as atypical mycobacteria. One example is Mycobacterium avium
complex (MAC), a cause of disseminated infections in AIDS
patients. Currently, clarithromycin or azithromycin with or
without rifabutin is recommended for primary prophylaxis in
patients with CD4 counts less than 50/µL. Treatment of MAC
infections requires a combination of drugs, one favored regimen
consisting of azithromycin or clarithromycin with ethambutol
and rifabutin. Infections resulting from other nontuberculous
mycobacteria (eg, M marinum, M ulcerans), though sometimes
asymptomatic, may be treated with the described antimycobac-
terial drugs (eg, ethambutol, INH, rifampin) or other antibiotics
(eg, amikacin, cephalosporins, fluoroquinolones, macrolides, or
tetracyclines).
QUESTIONS
1. A 45-year-old homeless man presents to the emergency depart-
ment with fever, weight loss, and a productive cough. Chest
x-ray shows right apical infiltrate and TB is suspected. He is
started on empiric INH, rifampin, and pyrazinamide. The pri-
mary reason for the use of drug combinations in the treatment
of this patient’s TB is:
(A) Delay or prevent the emergence of resistance
(B) Ensure patient compliance with the drug regimen
(C) Increase antibacterial activity synergistically
(D) Provide prophylaxis against other bacterial infections
(E) Reduce the incidence of adverse effects
Questions 2–5. A 21-year-old woman from Southeast Asia has
been staying with family members in the United States for the
last 3 mo and is looking after her sister’s preschool children dur-
ing the day. Because she has difficulty with the English language,
her sister escorts her to the emergency department of a local
hospital. She tells the staff that her sister has been feeling very
tired for the last month, has a poor appetite, and has lost weight.
The patient has been feeling somewhat better lately except for a
cough that produces a greenish sputum, sometimes specked with
blood. With the exception of rales in the left upper lobe, the
physical examination is unremarkable and she does not seem to
be acutely ill. Laboratory values show a white count of 12,000/µL
and a hematocrit of 33%. Chest x-ray film reveals an infiltrate in
the left upper lobe with a possible cavity. A Gram-stained smear
of the sputum shows mixed flora with no dominance. An acid-
fast stain reveals many thin rods of pinkish hue. A preliminary
diagnosis is made of pulmonary tuberculosis. Sputum is sent to
the laboratory for culture.
Trevor_Ch47_p397-p403.indd 400
2. At this point, the most appropriate course of action is to
(A) Hospitalize the patient and start treatment with
4 antitubercular drugs
(B) Hospitalize the patient and start treatment with rifampin
(C) Prescribe isoniazid for prophylaxis and send the patient
home to await culture results
(D) Provide no drugs and send the patient home to await
culture results
(E) Treat the patient with isoniazid plus rifampin
3. Which drug regimen should be initiated in this patient when
treatment is started?
(A) Amikacin, isoniazid, pyrazinamide, streptomycin
(B) Ciprofloxacin, cycloserine, isoniazid, PAS
(C) Ethambutol, isoniazid, pyrazinamide, rifampin
(D) Isoniazid, pyrazinamide, rifampin, streptomycin
(E) PAS, pyrazinamide, rifabutin, streptomycin
4. Which statement concerning the possible use of isoniazid
(INH) in this patient is false?
(A) Dyspnea, flushing, palpitations, and sweating may occur
after ingestion of tyramine-containing foods
(B) In fast acetylators, lower maintenance doses are necessary
(C) Peripheral neuritis may occur during treatment
(D) The patient should take pyridoxine daily
(E) The risk of the patient developing hepatitis from INH is
less than 2%
5. On her release from the hospital, the patient is advised not
to rely solely on oral contraceptives to prevent pregnancy
because they may be less effective while she is being main-
tained on antimycobacterial drugs. The agent most likely to
interfere with the action of oral contraceptives is
(A) Amikacin
(B) Ethambutol
(C) Isoniazid
(D) Pyrazinamide
(E) Rifampin
6. A patient with AIDS and a CD4 cell count of 100/µL has
persistent fever and weight loss associated with invasive
pulmonary disease due to M avium complex (MAC). Optimal
management of this patient is to
(A) Choose an antibiotic based on drug susceptibility of the
cultured organism
(B) Initiate a two-drug regimen of INH and pyrazinamide
(C) Prescribe rifabutin because it prevents the development
of MAC bacteremia
(D) Start treatment with the combination of azithromycin,
ethambutol, and rifabutin
(E) Treat with trimethoprim-sulfamethoxazole
7. A 10-year-old boy has uncomplicated pulmonary tubercu-
losis. After initial hospitalization, he is now being treated
at home with isoniazid, rifampin, and ethambutol. Which
statement about this case is accurate?
(A) A baseline test of auditory function test is essential
before drug treatment is initiated
(B) His mother, who takes care of him, does not need INH
prophylaxis
(C) His 3-year-old sibling should receive INH prophylaxis
(D) Polyarthralgia is a potential adverse effect of the drugs
the boy is taking
(E) The potential nephrotoxicity of the prescribed drugs
warrants periodic assessment of renal function
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8. Which statement about antitubercular drugs is accurate?
(A) Antimycobacterial actions of streptomycin involve inhi-
bition of arabinosyltransferases
(B) Cross-resistance of M tuberculosis to isoniazid and
pyrazinamide is common
(C) Ocular toxicity of ethambutol is prevented by thiamine
(D) Pyrazinamide treatment should be discontinued imme-
diately if hyperuricemia occurs
(E) Resistance to ethambutol involves mutations in the
emb gene
9. Once-weekly administration of which of the following anti-
biotics has prophylactic activity against bacteremia caused by
M avium complex in AIDS patients?
(A) Acedapsone
(B) Azithromycin
(C) Clarithromycin
(D) Kanamycin
(E) Rifabutin
10. Risk factors for multidrug-resistant tuberculosis include
(A) A history of treatment of tuberculosis without rifampin
(B) Recent immigration from Asia and living in an area of
over 4% isoniazid resistance
(C) Recent immigration from Latin America
(D) Residence in regions where isoniazid resistance is known
to exceed 4%
(E) All of the above
ANSWERS
1. Although it is sometimes possible to achieve synergistic
effects against mycobacteria with drug combinations, the
primary reason for their use is to delay the emergence of
resistance. The answer is A.
2. Despite the fact that this patient does not appear to be
acutely ill, she would in most cases be treated with 4 drugs
that have activity against M tuberculosis. This is because
organisms infecting patients from Southeast Asia are com-
monly INH-resistant, and coverage must be provided with
3 other antituberculosis drugs in addition to isoniazid. This
patient should be hospitalized for several reasons, including
potential difficulties with compliance regarding the drug regi-
men and the fact that young children are in the home where
she is living. The answer is A.
3. Sputum cultures will not be available for several weeks, and
no information is available regarding drug susceptibility of
the organism at this stage. For optimum coverage, the initial
regimen should include INH, rifampin, pyrazinamide, and
ethambutol. INH-resistant organisms are usually sensitive
to both rifampin and pyrazinamide. Streptomycin is usu-
ally reserved for use in severe forms of tuberculosis or for
infections known to be resistant to first-line drugs. Likewise,
amikacin and ciprofloxacin are possible agents for treatment
of multidrug-resistant strains of M tuberculosis. Cycloserine,
PAS, and rifabutin are alternative second-line drugs that
may be used in cases of failed response to more conventional
agents. The answer is C.
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CHAPTER 47 Antimycobacterial Drugs 401
4. Fast acetylators may require higher doses of the drug than
others. Peripheral neuropathy caused by INH is due to
pyridoxine deficiency. It is more common in the diabetic,
malnourished, or AIDS patient and can be prevented by
a daily dose of 25–50 mg of pyridoxine. INH can inhibit
monoamine oxidase type A and has caused tyramine reac-
tions. Hepatotoxicity is age-dependent, with an incidence of
0.3% in patients aged 21–35 years and greater than 2% in
patients older than 50 years. The answer is B.
5. Rifampin induces the formation of several microsomal drug-
metabolizing enzymes, including cytochrome P450 isoforms.
This action increases the rate of elimination of a number of
drugs, including anticoagulants, ketoconazole, methadone,
and steroids that are present in oral contraceptives. The phar-
macologic activity of these drugs can be reduced markedly in
patients taking rifampin. The answer is E.
6. Combinations of antibiotics are essential for suppression of
disease caused by M avium complex in the AIDS patient,
and treatment should be started before culture results are
available. Although rifabutin is prophylactic against MAC
bacteremia when it is used as sole therapy in active disease,
resistant strains of the organism emerge rapidly. MAC is
much less susceptible than M tuberculosis to conventional
antimycobacterial drugs. Currently, the optimum regimen
consists of azithromycin (or clarithromycin) with ethambutol
and rifabutin. The answer is D.
7. A baseline test of ocular (not auditory) function may be use-
ful before starting ethambutol. None of the drugs prescribed
is associated with nephrotoxicity. Polyarthralgia is a common
adverse effect of pyrazinamide that was not prescribed in
this case. Periodic tests of liver function may be advisable in
younger patients who are treated with INH plus rifampin,
especially if higher doses of these drugs are used. Prophylaxis
with INH is advisable for all household members and very
close contacts of patients with active tuberculosis, especially
young children. The answer is C.
8. Arabinosyltransferase is inhibited by ethambutol (not strep-
tomycin) and resistance involves alterations in the emb gene.
Ocular adverse effects of ethambutol are dose-dependent and
usually reversible when the drug is discontinued. Thiamine
is not protective. There is minimal cross-resistance between
pyrazinamide and other antimycobacterial drugs. Pyrazin-
amide uniformly causes hyperuricemia, but this is not a rea-
son to halt therapy even though the drug may provoke gouty
arthritis in susceptible persons. The answer is E.
9. Because of its long elimination half-life (3–4 d), weekly
administration of azithromycin has proved to be equivalent
to daily administration of clarithromycin when used for
prophylaxis against M avium complex in AIDS patients.
Acedapsone is a repository form of dapsone used in leprosy.
The answer is B.
10. Multidrug-resistant tuberculosis (MDR-TB) is defined as
resistance to 2 or more drugs. All the risk factors are rel-
evant. In the case of resistance to both INH and rifampin,
initial regimens still include both drugs, plus ethambutol,
pyrazinamide, streptomycin (or other aminoglycoside), and
a fluoroquinolone. Continuation therapy should include at
least 3 drugs shown to be active in vitro against the infect-
ing strain. The appropriate duration of therapy has not been
established. The answer is E.
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 402 PART VIII Chemotherapeutic Drugs

SKILL KEEPER ANSWER: GENOTYPIC VARIATIONS IN DRUG METABOLISM (SEE CHAPTERS 4, 5)

Examples of genotypic variations in drug metabolism include succinylcholine (pseudocholinesterase) and isoniazid (N-acetyltransferase).
Genetic polymorphisms also occur in isoforms of cytochrome P450 and contribute to variability in the rates of metabolism of phenformin,
dextromethorphan, and metoprolol. Variants in the CYP2D6 isoform have been implicated in excessive responses to codeine and
nortriptyline, and variants in CYP2C9 may be responsible for unusual sensitivity to the anticoagulant effects of warfarin.
Enzyme Drugs Clinical Consequences
Aldehyde dehydrogenase Ethanol Facial flushing, emesis, and cardiovascular symptoms in Asians with
low enzyme activity
N-acetyltransferase Isoniazid Increased dose requirement in fast acetylators
  Hydralazine Increased risk of lupus-like syndrome in slow acetylators
  Procainamide Increased cardiotoxicity in fast acetylators
Pseudocholinesterase Succinylcholine Deficiencies may lead to prolonged apnea

CHECKLIST

When you complete this chapter, you should be able to:

❑ List 5 special problems associated with chemotherapy of mycobacterial infections.
❑ Identify the characteristic pharmacodynamic and pharmacokinetic properties of
isoniazid and rifampin.
❑ List the typical adverse effects of ethambutol, pyrazinamide, and streptomycin.
❑ Describe the standard protocols for drug management of latent tuberculosis,
pulmonary tuberculosis, and multidrug-resistant tuberculosis.
❑ Identify the drugs used in leprosy and in the prophylaxis and treatment of
M avium-intracellulare complex disease.

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