Mayo Clinic Proceedings

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Title
Mayo Clinic Proceedings
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Mayo Clinic
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Published since 192c'

VOLUME 67

FEBRUARY 1992

NUMBER 2

fl Articles

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109

Mayo Clinic Experience With Allogeneic and Syngeneic Bone
Marrow T ransplantation, 1982 Through 1990

L. Lt lendre, H. C. Hoagland.
S. B. Moore, and others

117

Outcome of Recipients of Bone Marrow Transplants Who Require
Intensive-Care Unit Support

B. Afessa, .4. Teffcri. H. C. Hoagland.
L. Lf lendre. anti S'. G. \ J

123

^Cytogenetic and Molecular Detection of Residual Leukemic Cells
After Alk/gencic Bone Marrow Transplantation in Chronic
Granulocytic Leukemia
Hemorrhagic Cystitis Complicating Bone Marrow Transplantation

D L Graham. 1 Tcfl t. L Lt tend •.
D. A Gdsiincau. H. C, HodgluruJ, and

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a- E. O
e * S -z

128

131

to 1 !>

P. \d< l

L Leiendre, H.
Hoagland, and
M. A. Gertz
D R. Gracey. R. W \d-,: ;no.
J. M. Nacssens, and others

Outcomes of Patients Admitted to a Chronic Ventilator*Dcpendent
Unit in an Atutc-Care Hospital

■ Case Reports
137

Nonoperative Management of Multilevel Lumbar Disk
Herniations in at» Adolescent Athktc

A. M. Wcirum, Jr., and T. D. Ri’zo. Jr.

142

Kayser-Fleischer Rings In a Patient With Basal Cell Carcinoma:
Fortuitous Diagnosis of Presymptomatic Wilson’s Disease

D. G. b rodland and G. R. BailIcy

■ Subject Review
144

Exercise Limitation and Pulmonary Rehabilitat’on in Chronic
Obstructive Pulmonary Disease

C, O. Olopade. K. C. Beck. R IV.
Viggiano, and B. A. Status

■ Symposium on Antimicrobial Agents—Part VI
160

Antiviral Agents

MR.Ke(Hing

179

Antituberculous Agents

7’. E. Van Scoy and C. J. WUkowske
T .'

. 1I

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■ Subspeciaity Clinics: Allergic Diseases

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Management of Insect Sting Hypersensitivity

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J. T. C. Li and J. IV. Yunginger ■

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195 <, Allogeneic Bone Marrow Transplantation: Problems and Prospects

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198

Chronic Ventilator-Dependent Units in Hospitals: Attacking the
Front End of a I-ong-Term Problem

?- At'’’

■ Other Features

F. | §;3'A'

105

Full Table of Contents

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107
10^

Business Information ’
Historical Profiles of Mayo

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158 t Stamp Vignette

lite

ISSN 0025-6196

J. O. A nni’age
W. J. O 'Donohue, Jr.

CorrecGon
*
201 Letters to the Editor
' 203 Meetings Scheduled
206
Book Reviews
158

MACPAJ 67(2)105-210(1992)

Af‘•'7 •

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mayo

Antituberculous Agents

ROBERT E. VAN SCOY, M.D., CONRAD J. WILKOWSKE, M.D.,
Division of Infections Diseases and Internal Medicine

Antituberculous agents have radically improved the prognosis of patients with active tuberculosis.
Generally, 6-month and 9-month antituberculous regimens have been successful, and surgical therapv
is rarely needed. Extrapulmonary tuberculosis should be managed with the same drug regimens as
pulmonary tuberculosis. The major cause of therapeutic failure is poor compliance of the patient in
taking the prescribed medication regularly. A second cause of failure of treatment is resistance of
tubercle bacilli to antimicrobial agents used. When failure of treatment is apparent, careful reassess­
ment by physicians experienced in the treatment of tuberculosis is indicated. A single drug should
never be added to a lading regimen. Isoniazid administered prophylactically for 6 to 12 months is
effective in most cases.

anti,,lbcrcuious aecnls havc r;Klic;i"y
improved (he prognosis of patients with active tuberculosis.
Most patients with tuberculosis can be cured with chemo­
therapy; surgical therapy is rarely necessary. In most cases,
patients can be treated at home and can return to work soon
after treatment has been initiated.
In this article, we discuss live antituberculous drugs—
isoniazid, rifampin, streptomycin, ethambutol, and
pyrazinamide. A few comments are offered about the quin­
olones. including ciprofloxacin. Discussion of other drugs
such as cycloserine, ethionamide, /^-aminosalicylic acid re­
crystallized in vitamin C. thiacetazone. capreomycin, and
aminoglycosides other than streptomycin is beyond the
scope ot this article. Clofazimine, ansamycin. and some f3lactam antimicrobial agents with or without [3-lactamase
inhibitors either have antituberculous activity or arc being
investigated for such activity.
GENERAL COMMENTS
In the United States, conditions are suitable not only for a
major increase in the morbidity and mortality from tubercu­
losis but also for the spread of resistant tuberculosis. This
Individual reprints of this article are not available. The v.iuic
entire
Symposium on Antimicrobial Agents will be available for purchase
as a bound booklet from the Proceeding’s Circulation Office at a
later date.
Uavo Clin Phk- 67:179-1X7. 1992

silu:“ion is ParticuWy tragic because this disease is generally preventable and is certainly treatable. Since 1984. the
expected continued decline in tuberculosis-associated mor­
bidity has not occurred; in fact, in 1986 the morbidity began
to increase.1 Apparently, infections due to human immu­
nodeficiency virus (HIV) arc primarily responsible.'
HIV infection seriously impairs host defenses, especially
the delayed-type hypersensitivity defenses necessary for
combating tuberculosis. HIV is infecting those who abuse
intravenously administered drugs, who are often noncompliant with therapeutic regimens. The result may be not only
more treatment failures but also more cases with resistant or­
ganisms. Infected persons who are not taking medication are
more likely to spread infection to others than are those who
receive consistent treatment.
In 1989, an estimated 10 million persons in the United
Stales were already infected with Mycobacterium tuberculo­
sis (positive reactors to purified protein derivative). Ap­
proximately 21.000 new active clinical cases of tuberculosis
arose from those 10 million. In addition, approximately
20.000 persons became newly infected with the organism,
from which about 2.500 new active clinical cases arose.Certain specific 6-month and 9-month treatment regimens have been successful. In general, extrapulmonary
tubercu|osis should be managed with the drug regimens
outlined for pulmonary tuberculosis. The major cause of
therapeutic failure is poor compliance of the patient in takins’

179

180

ANTITUBERCULOUS AGENTS

the prescribed medication regularly. Most state and county
health departments have nurses and community-outreach
services that will provide free medication and will help in
supervision of therapy; thus, compliance can be improved.
Thorough investigation and follow-up of contacts by health
departments are essential for control of tuberculosis. Physi­
cians and the health department must have an efficient,
cooperative working relationship.
A second cause of therapeutic failure is resistance of
tubercle bacilli to the antimicrobial agents used. When
failure of treatment is apparent, careful reassessment by a
physician experienced in the treatment of tuberculosis is
indicated. A single drug should never be added to a failing
regimen.
Family physicians, internists, and general hospital per­
sonnel have assumed increased responsibility for the diagno­
sis, isolation, treatment, and, particularly, follow-up surveil­
lance of patients with tuberculosis. Nevertheless, problems
have arisen, including misdiagnosis; poor communication
among the hospital staff,~the patient’s physician,
]'
and the
state and county health departments; and inadequate identifi­
cation and investigation of persons exposed to the disease
through contact with the patient.3
Khan and associates4 described the atypical and the typi­
cal chest rocntgenographic features in newly diagnosed
cases of tuberculosis in adults. These findings may include
pleural effusion, hilar adenopathy, and infiltrates of the
lower lobe, as well as more typical manifestations in adults.
Atypical manifestations in patients with acquired immu­
nodeficiency syndrome (AIDS) are common.56
Isoniazid, administered prophylactically for 6 to 12
months, is effective in most cases. Rifampin, 600 mg/day
for 1 year, is recommended for close contacts of those with
isoniazid-resistant organisms.
The Centers for Disease Control and the American Tho­
racic Society have prepared an excellent document entitled
“Core Curriculum on Tuberculosis.”2 Most of the treatment
recommendations in the current article are based on that
document. Several other publications also provide useful
information on the treatment of tuberculosis.7’9

ISONIAZID
Isoniazid, also referred to as INH (isonicotinic acid hydra­
zide), is an almost perfect chemotherapeutic agent. It is
bactericidal, inexpensive, and well absorbed when adminis­
tered orally or parenterally. After several years of clinical
experience with isoniazid, investigators noted that severe
hepatotoxicity developed in a small percentage of patients.
Mode of Action and Main Pharmacologic Properties.—
Isoniazid is a white, water-soluble, crystalline substance. It
acts primarily by inhibiting the synthesis of mycolic acid, an
important component of cell walls.9-10

—«■

Mayo Clin Proc, February 1992, Vol 67

Peak blood concentrations of isoniazid occur 1 to 2 hours
after oral administration. The drug is widely distributed in
the body—variable quantities are found in the pleural fluid,
ascitic fluid, cerebrospinal fluid, caseous material, saliva,
skin, and muscle.
Isoniazid is acetylated by the liver and excreted as a
metabolite by the kidneys; it appears unchanged in the urine.
Other metabolites, including hydrazones, are excreted in the
urine as well. The relative fractions of isoniazid, acetyl­
isoniazid. and hydrazones in the urine vary considerably
among patients.
The duration of tuberculocidal blood levels depends on
the rate of acetylation of isoniazid in the liver, which is
genetically controlled. Among American and northern Eu­
ropean populations, 45 to 65% demonstrate slow inactiva­
tion; Eskimos and Orientals arc more likely to have rapid
inactivation. Rapid acetylation is an autosomal dominant
trait. Both patients with slow and those with rapid inactiva­
tion respond well clinically to standard doses of isoniazid,
Those patients with slow acetylation may be more susccptible to toxic side effects related to higher blood levels (for
example, peripheral neuritis), whereas those with rapidI acctyiation have a higher frequency of hepatotoxicity.
investigators have suggested that the amount of activity
of the liver enzyme cytochrome P-450 may also be related to
isoniazid-induced hepatotoxicity. Results of experimental
studies in animals suggest that single large doses of isoniazid
saturate acetyltransferase and result in lower production of
acetylhydrazine than that which occurs after administration
of multiple small doses. The acetylhydrazine pathway
seems to be related to hepatotoxicity.11 Therefore, studies of
the frequency of hepatotoxicity associated with thriceweekly administration in comparison with daily isoniazid
therapy seems important.12 One study of patients taking
isoniazid and rifampin revealed hepatotoxicity in 5% of
tnose given a daily regimen and in 0 to 1% of those given a
thrice-weekly regimen.13
Spectrum of Activity.—Most strains of M. tuberculosis
are sensitive to isoniazid, whereas almost all strains of M.
avium and M. marinum are resistant. Most strains of M.
kansasii are sensitive to the drug but at higher concentrations
than those effective for M. tuberculosis.
Adverse Effects.—Hepatitis is the most severe side ef­
fect associated with the use of isoniazid. It may be caused
by conversion of isoniazid to acetylhydrazine or related
hepatotoxic derivatives. The frequency of occurrence of
hepatitis increases with advancing age (Table 1), in patients
who also take rifampin, and in those who consume alco­
hol daily. Because of the association between age and the
occurrence of hepatitis, isoniazid prophylaxis is recom­
mended most frequently for patients younger than 35 years
of age.

Mayo Clin Proc, February 1992, Vol 67

Table 1.—Effect of Age on the Occurrence of Hepatitis
in Patients Taking Isoniazid
Age (yr)

Data from the Tuberculosis Advisory Committee report.14
From Van Scoy RE, Wilkowske CJ: Antituberculous agents:
isoniazid, rifampin, streptomycin, ethambutol. and pyrazinamide.
Mayo Clin Proc 58:233-240, 1983

Patients taking isoniazid should be advised about the
symptoms of hepatitis. They should discontinue use of the
drug and consult their physicians immediately if such symp­
toms are noted. Funhermore, some mechanism should be
established for monthly communication with the physician
or health-care worker, regardless of whether monthly deter­
minations of serum glutamic-oxaloacetic or glutamic-pyru­
vic transaminase are obtained. Mild increases in serum
transaminase concentrations will develop in 10% or more of
patients who receive isoniazid, but the levels seldom exceed
2 to 3 times the normal upper limits.15 Most physicians
recommend continuation of isoniazid therapy unless trans­
aminase values exceed 3 to 5 times the normal levels. Some
physicians might advise discontinuation of isoniazid pro­
phylaxis if serum transaminase concentrations are 3 times
the normal level.
Daily consumption of alcohol may increase the metabo­
lism of isoniazid and thereby both increase the risk of hepatotoxicity and decrease the therapeutic effect of the drug.
Aluminum-containing antacids may interfere with the ab­
sorption of isoniazid. Moreover, isoniazid may increase the
blood levels of and the toxicity from phenytoin (Dilantin).
Concurrent administration of disuifiram (Antabuse) and
isoniazid may cause psychotic episodes as a result of altered
metabolism of dopamine.16 Severe acetaminophen-associ­
ated toxicity may occur when large doses are taken by a
patient who is also receiving isoniazid.17
Isoniazid causes increased urinary excretion of pyridox­
ine (vitamin
and may produce symptoms of pellagra,
such as rash, peripheral neuritis, and anemia. This side effect
is particularly prevalent with use of large doses (more than
300 mg/day) in nutritionally deficient persons such as alco­
holics. In such cases, 10 to 50 mg of pyridoxine per day is
recommended. Pyridoxine may also prevent other toxic
reactions in the central nervous system.
As with any drug, the use of isoniazid may be associated
with the occurrence of rash, urticaria, fever, and other hy­
persensitivity reactions. Various other side effects have
been noted, including seizures, optic neuritis, psychotic reac-

■

181

tions, arthralgias, vasculitis, shoulder-hand syndrome, and
agranulocytosis (Table 2). "

Frequency (%)

<20
Rare
20-34
<0.3
35-49
£1.2
______________ >50__________ <2.3________________

■g»r,-rn—1 ■ ■ w

ANTITUBERCULOUS AGENTS

RIFAMPIN
Rifampin is a potent antituberculous drug that also has anti­
biotic activity against other bacteria, antichlamydial activity,
and in vitro activity against some viruses. It is derived from
the bacterium Streptomyces mediterranei. Rifampin seems
to be as potent an antituberculous agent as isoniazid.
Mode of Action and Main Pharmacologic Properties.—
Rifampin is a large, fat-soluble molecule that acts by inhibit­
ing synthesis of RNA. More specifically, it inhibits bacterial
DNA-dependent RNA polymerase.
Rifampin is well absorbed when taken orally. After ad­
ministration of a 600-mg dose in patients with an empty
stomach, peak serum concentrations of about 7 [tg/ml occur
at approximately 2 to 4 hours.10 Although the peak serum
levels are slightly less when the drug is taken after a meal
than in the fasting state, this difference is not known to be
clinically important.
Rifampin penetrates tissues well and reaches therapeutic
levels in the lung, bronchial secretions, cerebrospinal fluid iin
the presence of inflamed meninges, pleural fluid, other cavi­
tary fluids, liver, bile, and urine. The drug crosses the
placental barrier.
Approximately 43% of rifampin is excreted in the bile,
and 30 to 40% is excreted in the urine. As the dose of the
drug is increased, relatively less is excreted in the bile and
relatively more is excreted in the urine. Concomitantly
administered probenecid considerably diminishes the hepatic uptake of rifampin and thereby increases serum levels,
Rifampin is metabolized to the deacetylated form.
Peritoneal dialysis and hemodialysis do not appreciably
eliminate rifampin. The absorption of rifampin may be
delayed by p-aminosalicylic acid; thus, adequate serum lev­
els may not be attained. Therefore, if these two drugs are
used in combination, they should be administered 8 to 12
hours apart.
Spectrum of Activity.—Of note, rifampin has the broad­
est spectrum, in vitro, of any of the primary antituberculous
agents. It inhibits almost all strains of M. tuberculosis, M.
kansasii, and M. marinum and a few strains of M. avium
organisms. It also has activity against other bacteria,
including Neisseria meningitidis, Staphylococcus aureus,
Haemophilus influenzae, and several species of Enterobacteriaceae.
Adverse Effects.—Rifampin can cause numerous side
effects (Table 3).10 Rash may occur in 0.8% of patients,
fever in 0.5%, and nausea and vomiting in 1.5%. The drug
confers an orange-pink color to saliva, tears, urine, and sweat
and may discolor contact lenses. The patient should be
informed about this side effect before therapy is initiated.

182

ANTITUBERCULOUS AGENTS

Mayo Clin Proc. February 1992, Vol 67

Table 2.—Side Effects Associated With Use of Isoniazid
Side effect
Hepatotoxicity

Interactions with
other drugs
Alcohol
Aluminum-containing
antacids
Disulfiram (Antabuse)
Phenytoin (Dilantin)

Pellagra
Rash
Anemia
Involvement of nervous
system (see below)
Nervous system
Peripheral neuritis
Optic neuritis
Seizures
Other
Hypersensitivity

Fever
Rash
Purpura
Urticaria
Other

Comment
Occurrence increases with aging,
the presence of liver disease,
concomitant rifampin therapy,
and daily ingestion of alcohol
Increases metabolism of isoniazid

Decreases absorption of isoniazid
May precipitate psychotic episodes
Increases blood levels and toxicity
of phenytoin

Administration of vitamin o can
prevent or decrease the severity
May be prevented or decreased in
severity by administration of
vitamin B,

See text

From Van Scoy RE, Wilkowske CJ: Antituberculous agents:
isoniazid, rifampin, streptomycin, cthambutol, and pyrazinamide.
Mayo Clin Proc 58:233-240. 1983

Rifampin may cause liver disease; the frequency of oc­
currence of this adverse effect is increased in patients with
slow inactivation of the drug (unlike the situation with
isoniazid), in patients with prior liver disease, and in those
also taking isoniazid. Commonly, liver function tests show
minimal abnormalities, which usually disappear while the
patient continues to take the drug. Patients must be observed
carefully for more <substantial
’
degrees of increased enzymes
and for jaundice, which occurs in 0.6% of patients who take‘
rifampin; if these side effects occur, use of the drug should
be discontinued. In patients taking both isoniazid and ri­
fampin, a predominant increase in serum concentrations of
alkaline phosphatase and bilirubin suggests rifampin-in­
duced toxicity;18 a predominant increase in transaminase
levels may be due to toxicity from isoniazid, rifampin, or
l^oth drugs.
High-dose intermittent therapy or reinstitution of ri­
fampin therapy after a drug-free interval has resulted in
many side effects. Some have been proved to be antibodymediated immune reactions (such as autoimmune anemia

and thrombocytopenia), and others are presumed to be im­
mune reactions (for example, acute renal failure, chills, fe­
ver. myalgia, arthralgia, vomiting, diarrhea, and hepatorenal
syndrome).19 Fatal reactions have been reponed.
Another group of side effects is related to the ability of
rifampin to induce the action of detoxifying or conjugating
liver enzymes. This activity may result in decreased effec­
tiveness of certain medications because they are then ex­
creted more rapidly by the liver. Examples of such ef­
fects include (1) breakthrough bleeding and pregnancy while
the patient is taking birth control pills, (2) adrenal insuffi­
ciency during corticosteroid replacement therapy, (3) de­
creased anticoagulant effect of warfarin drugs, and (4) di­
minished activity of orally administered hypoglycemic
agents, methadone, and digitalis preparations.1'’ Drug-drug
interactions with imidazoles, such as fluconazole, have been
reponed.
Rifampin has been incriminated as a cause of immuno­
suppression. The understanding of all the mechanisms in­
volved and of the extent of immunosuppression is incom­
plete. Currently, this effect docs not seem to be of major
clinical importance. Rifampin may also be associated with
various gastrointestinal disturbances and nervous system
disorders.
STREPTOMYCIN
Streptomycin belongs to the aminoglycoside group of antibi­
otics discussed earlier in this symposium.20 Unfortunately,
at the time of this writing, streptomycin is not available.
Mode of Action and Main Pharmacologic Properties.—
The mode of action and the main pharmacologic properties
of the aminoglycoside antibiotics have been discussed previ­
ously in th>s series.20
Spectrum of Activity.—Streptomycin is active in vitro
against most M. tuberculosis, M. kansasii, and M. marinum
organisms. Most M. avium organisms are resistant to strep­
tomycin.
Adverse Effects.—Edson and Terrell20 have discussed the
adverse effects of the aminoglycosides in general in an earcar
lier contribution in this series. Although streptomycin may
cause renal toxicity, the toxic effects are considerably less
than those associated with other frequently used aminogly­
cosides. Ototoxicity is the major toxic effect of streptomycin
(Table 4). Vestibular toxicity, manifested by vomiting, tin­
nitus, and vertigo (often preceded by headache), is more
common than hearing loss, but hearing loss may also occur
and it may be permanent. Ototoxicity is related to the dosage
of the drug and the duration of treatment. Avoidance of
excessive doses is imperative, particularly in elderly patients
and in those with renal insufficiency.9
Elderly patients adjust to vestibular toxicity less well than
do young persons; therefore, physicians may be hesitant

J

Mayo Clin Proc, February 1992, Vol 67

ANTITUBERCULOUS AGENTS

Table 3.—Side Effects Associated With Use of Rifampin

Side effect
Body fluids become
orange-pink
Liver disease
Transient abnormalities
Severe hepatotoxicity
Associated with intermittent
therapy
Anemia
Thrombocytopenia
Leukopenia
■*
Acute renal failure
I
Chills, fever, myalgia, >
arthralgia, vomiting, I
diarrhea
Interactions between
nfampin and other drugs
Birth control pills
Adrenocorticosteroids
Warfarin
Orally administered
hypoglycemic agents
Methadone
Digitalis derivatives ,
Hypersensitivity
Immunosuppression

Other
Gastrointestinal symptoms
Central nervous system
symptoms

Comment
Warn patients

Immune mechanism
Immune mechanism
Presumed immune mechanism

Induction of activity of
liver enzymes causes
decreased levels of all
these drugs

Mechanism unclear; probably
of little or no importance

Usually mild

From Van Scoy RE. Wilkowske CJ: Antituberculous agents:
isoniazid, rifampin, streptomycin, cthambutol. and pyrazinamide.
Mayo Clin Proc 58:233-240,' 1983

about prescribing streptomycin for older patients.. Periodic
testing with use of audiography and caloric tests of vestibu­
lar function may be helpful, especially in bedridden patients.
Patients may also be tested by having them rapidly turn 180
degrees while walking, to check for loss of balance. Use of
streptomycin should almost always be avoided in pregnant
patients.
ETHAMBUTOL
Ethambutol is a synthetic, orally administered antituber­
culous agent that has essentially replaced p-aminosalicylic
acid as a second, third, or fourth drug in multidrug regimens.
It is bacteriostatic^ Although ethambutol has been admin­
istered to women during pregnancy without detectable ef­
fect on the fetus, the available data are limited, and the risks
must be weighed against the benefits of treatment before
this drug is recommended for use in pregnant women or
women of childbearing age. Ocular toxicity may be diffi­
cult to monitor in children younger than 6 years of age;

183

thus, ethambutol is not recommended for use in this agegroup.
Mode of Action and Main Pharmacologic Properties.—
Ethambutol is the dextro isomer of 2,2'-(ethylenediimino)di1-butanol dihydrochloride. Chemically, it is unlike other
antituberculous agents. The drug is effective against only
actively growing cells.
Ethambutol is well absorbed after oral administration,
and peak serum concentrations of 2 to 5 |ig/ml occur 2 to 4
hours after administration of a single dose of 15 mg/kg.
Absorption is unaffected by the ingestion of food. In pa­
tients with normal renal function, serum levels become un­
detectable 24 hours after the last dose has been taken. The
intraerythrocytic level is approximately twice the plasma
level. About two-thirds of the dose is excreted unchanged in
the urine, and about 15% is excreted in the urine in the form
of various metabolites.10 For patients who are unable to
swallow pills, the manufacturer suggests crushing the tablets
and mixing them with apple juice or applesauce.
Spectrum of Activity.—Although most M. tuberculosis
and M. marinum organisms are sensitive to ethambutol, as
are approximately 50% of M. kansasii organisms. M. avium
is consistently resistant to this agent.
In vitro data may serve as an approximate guide for
therapy, but the clinical response should be the major factor
in monitoring treatment of mycobacteria other than tubercu­
losis (formerly called atypical mycobacterial infections).
The concentrations of 5 to 10 pig/ml used in tabulating the
minimal inhibitory concentrations are at or above the peak
serum levels often achieved.
Adverse Effects.—Ethambutol is a relatively safe drug
when the recommended dosages are used. Ocular toxicity
(decreased visual acuity, loss of green color perception, cen-

Table 4.—Side Effects Associated With Use of Streptomycin
Side effect

Ototoxicity

Neuromuscular blockade
Renal toxicity

Comment
Related to dosage and duration of
administration; vestibular more
common than auditory toxicity;
less well tolerated by elderly
persons than by younger persons
Dose-related effect; uncommon
Milder than that associated with
other aminoglycosides

Hypersensitivity
Rash, urticaria
Fever
Anaphylaxis
Cytopenia
From Van Scoy RE, Wilkowske CI: Antituberculous agents:
isoniazid, rifampin, streptomycin, ethambutol. and pvrazinamide.
Mayo Clin Proc 58:233-240, 1983

184

ANTITUBERCULOUS AGENTS

Mayo Clin Proc. February 1992, Vol 67

Table 5.—Side Effects Associated With Use of Ethambutol
Side effect

Optic neuritis
Hyperuricemia

Comment

Dose-related effect; usually reversible
Attributable to decrease in clearance of
urate

Rash
Anaphylactic shock
Miscellaneous

Difficult to determine whether reactions
are caused by ethambutol or by a
concomitantly administered drug

From Van Scoy RE, Wilkowske CJ: Antituberculous agents:
isoniazid, rifampin, streptomycin, ethambutol, and pyrazinamide.
Mayo Clin Proc 58:233-240, 1983

tral scotomas, or, less commonly, a peripheral visual field
defect) is a dose-related phenomenon that occurs in perhaps
5% or fewer of patients who receive
ive 25 mg/kg per day or
less10 (Table 5). This toxic effect is usually reversible when
use of the drug is promptly discontinued.21 In one report,
ocular toxicity was noted in only 10 of 2.184 patients; in all
but 1 patient, this toxic effect occurred only after the second
month of treatment. Only two patients had symptoms, and
eight cases were detected on a routine examination of the
eyes.22
Patients should be tested for visual acuity and green color
perception before and periodically during therapy with
ethambutol. If a dosage of more than 15 mg/kg per day is
used, tests should be conducted monthly. Because toxicity
may be unilateral, each eye should be tested independently.
Some physicians also advise patients to read the fine print in
newspapers. If the patient notices a difference in visual
acuity in either eye, medical attention should be sought
immediately.
Serum concentrations of uric acid may be increased in
patients who receive ethambutol, probably as a tresult of
decreased clearance of renal urate. Such increases occur by
the third week of therapy.23
As with most drugs, rash and anaphylactic shock may
occur with use of ethambutol. Miscellaneous reactions such
as peripheral neuritis and symptoms involving the gastroin­
testinal and central nervous systems have occurred, but these
may have been due to concomitantly administered drugs
rather than to ethambutol (Table 5). Thrombocytopenia has
recently been reported as an additional side effect.,24

Peak plasma concentrations of 45 pg/ml occur approxi­
mately 2 hours after administration of an oral dose of 1 g.
The major route of excretion of pyrazinamide is by glomeru­
lar filtration, but the drug is also hydrolyzed and then hy­
droxylated. The usual dosage is 15 to 30 mg/kg per day or 50
to 70 mg/kg twice weekly.
In the older medical literature, pyrazinamide was reported
to be hepatotoxic in up to 15% of patients. In recent studies,
however, hepatotoxicity developed in only 1 to 5% of pa­
tients who received isoniazid, rifampin, and pyrazinamide.
Pyrazinamide interferes with the excretion of urate by de­
creasing its tubular secretion. High serum concentrations of
uric acid may result, and clinical manifestations of gout may
become evident. Nausea, vomiting, arthralgias, and druginduced fever may also occur (Table 6).
QUINOLONES (INCLUDING CIPROFLOXACIN)

The quinolone antimicrobial agents are discussed in a sepa­
rate article in this symposium.25 Although norfloxacin has
only minimal activity against mycobacteria, several other
quinolones, including ciprofloxacin and ofloxacin, seem to
have appreciable antimycobactcrial activity. Quinolones
readily penetrate cells, an important criterion for effective
treatment of tuberculosis. A report by Leyscn and co-work­
ers26 presents useful information on the new quinolones.

INDICATIONS FOR
ANTITUBERCULOUS AGENT S
Discussion of treatment of leprosy and mycobacteria
other than tuberculosis is beyond the scope of this article.
Physicians should refer patients with infections due to my­
cobacteria other than tuberculosis, those with drug-resis­
tant tuberculosis, and those who require re-treatment of tu­
berculosis to a medical facility with extensive experience
with these problems.
Relatively new antimycobacterial agents that may be helpful not only against M. tuber­
culosis but also against mycobacteria other than tubercu­
losis include clofazimine, ansamycin, quinolone agents
such as ciprofloxacin and ofloxacin, and certain p-lactam
agents.

Table 6.—Side Effects Associated With Use of Pyrazinamide

______ Side effect_____________________ Comment
Hepatitis

PYRAZINAMIDE
Pyrazinamide, an analogue of nicotinamide, is well absorbed
from the gastrointestinal tract and is widely distributed
throughout the body. Pyrazinamide is considered bacteri­
cidal to actively dividing organisms and eliminates bacilli
that are metabolizing slowly or irregularly.

Gastrointestinal disturbance
Hyperuricemia
'Arthralgias
Drug-induced fever

Little or no increase in hepato­
toxicity when 15 to 30 mg/kg
dose is added to isoniazid
and rifampin
Acute gout uncommon

—

-t-

ANTITUBERCULOUS AGENTS

Mayo Clin Proc, February 1992, Vol 67

185

Table 7.—Recommended Dosages for Initial Treatment of Tuberculosis*

Drug
Isoniazid
Rifampin
Pyrazinamide
Streptomycin
Ethambutolf
Pyridoxine

Daily dose (mg/kg)
Children
Adults

Maximal
Maximal
daily dose (g)

300 mg
5, p.o. or i.m.
10-20, p.o. or i.m.
600 mg
10, p.o.
10-20, p.o.
2-3
15-30,
j).o.
15-30, p.o.
1
15, i.m.
20-40, i.m.
2.5
15-25, p.o.
15-25, p.o.
10-50 mg/day for those patients who are pregnant
or who have diabetes, peripheral neuropathy,
uremia, alcoholism, malnutrition, or seizures or
other conditions in which neurologic disorders
may be likely

Twice-weekly dose (mg/kg)
Children
Adults
20-40; maximum, 900 mg
10-20; maximum, 600 mg
50-70
25-30, i.m.
50

15; maximum, 900 mg
10; maximum, 600 mg
50-70
25-30, i.m.
50

♦Doses should be adjusted for renal insufficiency when appropriate, ii.m. = intramuscularly; p.o. = perorally.
tNot recommended for children younger than 6 years of age.
Modified from Van Scoy RE. Wilkowske CJ: Antituberculous agents. Mayo Clin Proc 62:1129-1136, 1987.

Several general principles arc important in the treat­
ment of tuberculosis. (1) The number ot drugs needed
increases with the number of bacilli found in the lesions.
(2) The number of drugs used can be reduced after a de­
crease in the number of bacilli is evident. (3) A single drug
should never be added to an apparently failing regimen.
(4) Noncompliance of the patient in taking prescribed
medications is the most common reason for therapeutic
failure. (5) The presence of drug resistance should be sus­
pected in patients in whom treatment has failed, patients
who have been exposed to others with resistant organisms,
patients from Africa. Asia, and Central or South America,
patients with cavitary disease or alcoholism, “homeless"
patients, unreliable patients including drug abusers, and
positive after 3 months of
patients in whom cultures remain ]
therapy.
Hospitalization may be necessary for diagnosis and initial
supportive care, but thereafter patients can usually be treated
at home. Early return to work is routine when the patient is
no longer considered contagious. Restriction of activity,
unusual rest periods, and "fresh mountain air are not indi­
cated for the modern-day treatment of tuberculosis.
Treatment Regimens.—Concise reviews of antitubercu­
lous drugs, rationale for use, and treatment regimens have
been published by the Centers for Disease Control and the
American Thoracic Society and others.2-7 As mentioned
earlier, extrapulmonary tuberculosis should be treated with
the same regimens as pulmonary tuberculosis.
Six- and 9-month regimens are recommended. The rec­
ious drugs used for the initial
ommended dosages of the various
treatment of tuberculosis are shown in Table 7. The 6-month
regimen is particularly useful for patients who must be under
surveillance during therapy. The 6-month regimen is as
follows: isoniazid, rifampin, and pvrazinamide daily for 2
months and then isoniazid plus rifampin as either the daily

regimen or the twice-weekly regimen for 4 more months.
The 9-month regimen consists of isoniazid plus rifampin
daily for 2 months, followed by daily or twice-weekly
isoniazid and rifampin for 7 more months, for a total of 9

months of therapy.
Both the 6- and the 9-month treatment regimens apply
only when (1) the organisms arc known to be sensitive to the
drugs used; (2) patients are monitored monthly for compli­
ance and adverse reactions; (3) ethambutol or streptomycin
is added if resistant organisms arc suspected or if life-threat­
ening or extensive disease is present; (4) HIV-infected pa­
tients arc treated with three or four drugs daily during the
first 2 months of therapy; and (5) the duration of treatment
for HIV-infected patients is at least 9 months and is continued for at least 6 months beyond substantiated conversion of
cultures (negative cultures).
Children.—Ethambutol is generally not used in children
whose visual acuity cannot be monitored, such as those
younger than 6 years of age. Hilar adenopathy alone or other
abnormalities evident on the chest roentgenogram necessi­
tate the use of at least two drugs. Drug susceptibility of the
parents of the child is particularly imponant in choosing

regimens for children.
Pregnant Women.—Isoniazid and rifampin can be used
■
’
during
pregnancy,, in conjunction with ethambutol if
isoniazid resistance is suspected. Use of pyrazinamide
should be avoided in pregnant women because the avail­
able data on teratogenicity are inadequate? Therefore, the
6-month regimen cannot be used. Breast-feeding is permitted because toxicity from medication is not a problem.
Preventive Therapy.—The indications for preventive
‘; are summarized in Table 8. Before
therapy for tuberculosis
preventive
therapy
is
initiated,
the presence of active clinical
j
disease should be excluded. Obviously, if the patient has
b«en adequately treated previously, preventive therapy is not

186

ANTITUBERCULOUS AGENTS

Mayo Clin Proc, February 1992, Vol 67

Table 8.—Indications for Preventive Therapy for Tuberculosis*

tPersons with known or suspected HIV infection and PPD >5 mm
•[Close contacts of newly diagnosed cases of infectious tuberculosis and PPD >5 mmt
■[Recent tuberculin skin test converters (>10-mm increase within a 2-yr period if <35 yr
old; >15-mm increase for those 35 yr or older)

TPreviously untreated or inadequately treated persons with chest roentgenograms
that show fibrotic lesions compatible with old healed tuberculosis and PPD >5 mm

tPersons with PPD £10 mm and medical conditions that have been reported to increase
the risk of tuberculosis including:
Intravenous drug use
Diabetes mellitus
Prolonged corticosteroid therapy
End-stage renal disease
Intestinal bypass
Carcinoma of oropharynx
or upper GI tract

Silicosis

Fibrotic lesions on chest roentgenogram
Immunosuppressive therapy
Hematologic disease
Postgastrectomy
10% or more below
ideal body weight

[Persons in the following high-risk groups who are <35 yr of age and PPD >10 mm:
Foreign-bom persons from high-prevalence countries
Low-income populations, including high-risk minorities
Persons in long-term-care facilities (including prisons)

Other persons <35 yr of age and PPD >15 mm
•GI = gastrointestinal; HIV = human immunodeficiency virus; PPD = purified protein
derivative (tuberculin) test.
[Recommendations from the Division of Tuberculosis Control. Center for Prevention
Services. Centers for Disease Control, and the American Thoracic Society.
[Close contacts of infectious cases of tuberculosis, especially children, should be given
3 months of preventive therapy and then have another PPD. If the PPD is again
negative and contact with the infectious case of tuberculosis has ceased, therapy may
be discontinued.

indicated. Patients should be screened for a history of years ofage, serum transaminase should be determined at the
isoniazid-related hepatic injury or discontinuation of onset of therapy and periodically during therapy. If the
isoniazid therapy because of acute liver disease, daily use of transaminase level exceeds 3 to 5 times the upper limit of
alcohol, peripheral neuropathy,
inormal,
’ therapy
’
- "*
. ’. or pregnancy.
.
,•
should be discontinued and further
therapy
The recommended regimen is at least 6 months and pref- planned. No more than a 1-month supply of medication
erably 12 months of isoniazid therapy in a dosage of 10 mg/ should be dispensed at one time.
kg per day (maximal daily dose, 300 mg). A 12-month
Drug-drug interactions, especially with use of rifampin,
regimen is preferred, particularly for those with HIV infec­ should be reviewed; agents frequently incriminated are
tion and those with chest roentgenographic abnormalities prednisone, birth control pills and other hormones, pheconsistent with previous tuberculosis. When directly ob- nytoin, warfarin, cyclosporine, and orally administered hyserved therapy is indicated to ensure <comPliance> 15 mg/kg poglycemic agents. The patient should be advised to expect
up to a maximum of 900 mg twice weekly may be used if a change in color of body fluids and contact lenses during use
resources are inadequate to observe daily therapy.2 Ri­ of rifampin.
fampin, 600 mg/day for 1 year, should be considered for
More than 90% of patients should become culture nega­
close contacts of patients with infectious tuberculosis who tive after 3 months of therapy. If cultures remain positive
excrete isoniazid-resistant organisms.2
after 3 months, careful reevaluation for compliance and re­
Monitoring of Therapy.—Baseline and follow-up as­ sistant organisms is indicated.
sessments are indicated for patients treated for tuberculosis
State and local health departments can be helpful, not
(Table 9). Patients should be counseled to avoid daily use of only in supplying antituberculous medications to patients
alcohol and overall excessive consumption of alcohol and to frequently free of charge—but also in the sometimes tedious
be aware of symptoms of toxicity. If symptoms occur, a job of maintaining careful follow-up surveillance of patients
physician should be consulted. In patients older than 35 and their contacts.

1

i

Mayo Clin Proc, February 1992, Vol 67

Table 9.—Monitoring Assessments During Therapy
for Tuberculosis
Baseline tests
Hepatic enzymes
Bilirubin
Creatinine
Complete blood cell
count

Uric acid (if pyrazinamide is used)
Visual acuity (if ethambutol is used)
Audiometry (if streptomycin is used)

Baseline counseling (see text)
Monthly interviewing for:

Toxicity for hepatitis (nausea, vomiting, loss of appetite,
dark urine, jaundice, fever, abdominal discomfort), bleeding
problems, numbness, paresthesias, visual changes, vertigo,
hearing loss or other ear symptoms (if streptomycin is used)
Other symptoms
Monthly testing for:
Efficacy—sputum, induced sputum, or gastric cultures
Toxicity—laboratory tests based on symptoms elicited,
auditory tests every 2 mo if streptomycin is used

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End of Symposium on Antimicrobial Agents, Part VI.
Part VII will appear in the March issue.
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