463

Antimycobacterial Agents
38  Richard J. Wallace, Jr., Julie V. Philley, and David E. Griffith

SHORT VIEW SUMMARY

Therapy for Tuberculosis (Mycobacterium
tuberculosis) (see Chapter 251)
• Isoniazid, rifampin, pyrazinamide, and
ethambutol are first-line agents for drug-
susceptible tuberculosis. Doses of antiretroviral
agents may need adjustment (see Table 38-3).
• Initiation of treatment for HIV infection may
need to be delayed in patients starting
treatment for tuberculosis (see Table 38-2 and
http://aidsinfo.nih.gov/guidelines).
• Streptomycin is a potent but more toxic
first-line agent.
• Rifabutin is used instead of rifampin in
patients receiving protease inhibitors for HIV
infection (see Table 38-5).
• Rifapentine is recommended for directly
observed therapy along with isoniazid, both
given once weekly for 12 weeks for latent
tuberculosis.
• Once-a-week administration of rifapentine and
isoniazid can be used for the continuation
phase of noncavitary pulmonary tuberculosis
in patients without HIV infection whose smear
is negative at 2 months.
• Capreomycin, a polypeptide antibiotic,
amikacin, kanamycin, para-aminosalicylic
acid, quinolones, cycloserine, linezolid,
and ethionamide are second-line agents
used for drug-resistant M. tuberculosis
infection.
• Bedaquiline is a recently marketed drug for
drug-resistant tuberculosis.
Therapy for Leprosy (Mycobacterium
leprae) (see Chapter 252)
• Dapsone, rifampin, and clofazimine are
first-line agents. Clofazimine use is restricted
(see text).
Therapy for Other Mycobacterial
Infections
• Tetracyclines, macrolides, and quinolones are
discussed more extensively in Chapters 26, 29,
and 34.

Drugs for mycobacterial infections are discussed in three groups: those
primarily for the treatment of infections caused by Mycobacterium
tuberculosis, drugs for infections caused by nontuberculous (atypical)
mycobacteria (NTM), and agents principally for the treatment of
leprosy. Approaches to antituberculous chemotherapy have been
affected by the increasing prevalence of multidrug-resistant M. tuber-
culosis (MDR-TB), defined as resistance to at least isoniazid (INH) and
rifampin,1-5 and extensively drug-resistant M. tuberculosis (XDR-TB),
defined as resistance to at least INH and rifampin, resistance to any
fluoroquinolone, and resistance to at least one second-line injectable
drug,5-10 and by the special impact on M. tuberculosis of those infected
with human immunodeficiency virus (HIV).5,11,12
MDR-TB and XDR-TB strains have necessitated the use of drugs
that are considered second-line agents, as well as drugs that must be
administered by injection.13 The list of agents active against MDR-TB
and XDR-TB strains remains limited; however, recent development
and introduction of new antituberculous drugs has significantly
improved the outlook for successful treatment of M. tuberculosis
strains resistant to “standard” first-line and second-line agents. The
current pace of new tuberculosis drug development is unprecedented
and cause for optimism even in the presence of increasing MDR-TB
and XDR-TB disease prevalence. It still must be emphasized that to
prevent the emergence of acquired drug resistance and to treat opti-
mally both drug-susceptible and drug-resistant M. tuberculosis infec-
tion universal supervised therapy is essential.14,15
MDR-TB and XDR-TB infections are of increased concern in
persons immunologically disabled by HIV with or without acquired
immunodeficiency syndrome (AIDS) because the host contribution to
controlling the infection is severely diminished. HIV-infected indi-
viduals have a number of other special problems. They are especially
prone to adverse drug reactions.16,17 The susceptibility of protease
inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors
(NNRTIs) to hepatic metabolism induced by rifamycins, especially
rifampin and rifapentine, necessitates the ongoing need for regimens
that exclude these agents.16,17 In addition, malabsorption of antituber-
culous drugs can occur in AIDS patients, resulting in suboptimal anti-
tuberculous serum drug levels, which predisposes to acquired drug
resistance.18
The early years of HIV disease saw a dramatic increase in the preva-
lence and severity of infections caused by M. avium and other NTM,
especially in their disseminated forms. Fortunately, the combination
of the macrolide-azalide group with ethambutol was active against
M. avium and other NTM, even in patients with markedly impaired
cell-mediated immune defenses. In recent years, with great advance-
ment in antiretroviral therapy and the use of disseminated M. avium
prophylaxis, the incidence of disseminated disease in advanced HIV
infection has markedly declined. The effects of HIV infection and
AIDS on leprosy and its chemotherapy do not appear to be as great as
expected.
Traditionally, antimicrobial agents for tuberculosis have been clas-
sified as first-line drugs, having superior efficacy with acceptable toxic-
ity, and second-line drugs, having less efficacy and greater toxicity.
Several excellent reviews of antimycobacterial agents and therapy are
available,13,19-24 including guidelines for therapy for MDR-TB infec-
tion.13,19,21 Effective treatment of both MDR-TB and XDR-TB strains
requires detailed information about extended drug susceptibilities to
guide individualized treatment regimens.8,13,25
Antituberculous drugs differ in their mechanism of bactericidal
action and in their delivery to tuberculous lesions. Three of the first-
line agents—INH, rifampin, and ethambutol—are active against the
large populations of tubercle bacilli in cavities. Streptomycin (now
considered a second-line agent), other aminoglycosides, and capreo-
mycin penetrate cells poorly and are inactive at acidic pH. Pyrazin-
amide (PZA; the fourth first-line agent), which is inactive at the neutral
or slightly alkaline pH that may occur extracellularly, is active only in
acidic environments such as within macrophages. Slowly replicating
organisms in necrotic foci are killed by rifampin and somewhat less
readily by INH.
First-line antituberculous agents, except ethambutol, are bacteri-
cidal. The bactericidal activities of both INH and rifampin against
tubercle bacilli in cavitary, intracellular, or necrotic foci provide the
basis for the efficacy of short-course INH-rifampin regimens. A com-
bination of three bactericidal agents that are active against intracellular
organisms—INH, rifampin, and PZA—is essential for the 2-month
initiation phase of the standard 6-month regimen currently recom-
mended for drug-susceptible disease in the United States. A residual
population consisting of virtually nonreplicating dormant tubercle
bacilli within necrotic foci is especially difficult to eradicate, perhaps
explaining the minimum of 4 months of continuation phase therapy
needed even in persons with competent immune defenses.
463
 463.e1
KEYWORDS
amikacin; bedaquiline; clofazimine; cycloserine; dapsone; delamanid;
directly observed therapy; ethionamide; isoniazid; linezolid; PA-824;

Chapter 38  Antimycobacterial Agents

para-aminosalicylic acid; quinolones; rifabutin; rifampin; rifapentine;
streptomycin
 464
Much of the following discussion of individual antimycobacterial
agents is taken from existing guidelines. In collaboration with other
organizations, the Centers for Disease Control and Prevention (CDC)
will be updating treatment guidelines for latent M. tuberculosis infec-
Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases
resistant in over 70% of cases treated with INH monotherapy for 3
months. Resistance results from selection under antimicrobic pressure
of resistant mutants of M. tuberculosis that number 1 in 106 among
untreated bacillary populations. Large populations like the 109 to 1010

tion (LTBI) and established tuberculosis probably close to the publica-
tion of this volume. Additionally, new technologies such as the widely
available TB GeneXpert and gene sequencing (available through the
CDC) offer the clinician the ability to rapidly (within days) detect
drug-resistant M. tuberculosis strains to avoid ineffective and toxic
empirical second-line medication regimens for tuberculosis. The
reader is strongly encouraged to monitor the CDC website for timely
review of the anticipated new guidelines and details about the indica-
tions and procedures for utilizing the tubercular drug resistance rapid
identification technologies.
Chemical structures of the major drugs discussed in this chapter
are shown in Figure 38-1.
FIRST-LINE ANTITUBERCULOUS
DRUGS
Isoniazid
Derivation and Structure.  Isoniazid, isonicotinic acid hydrazide
(INH), a synthetic agent, was introduced in 1952.
Mechanism of Action.  Isoniazid is bactericidal against actively
growing M. tuberculosis and bacteriostatic against nonreplicating
organisms. It acts by inhibition of synthetic pathways of mycolic acid,
an important constituent of mycobacterial cell walls. It also likely
inhibits the catalase-peroxidase enzyme, coded for by the gene katG.
Antimicrobial Activity and Resistance.  Against M. tuberculosis,
0.025 to 0.05 µg/mL of INH is inhibitory, and higher concentrations
are bactericidal against replicating organisms. When INH is adminis-
tered alone as monotherapy in the presence of active tubercular disease,
resistance to INH will emerge. Initially susceptible isolates become
bacilli in pulmonary cavities are especially likely to contain significant
numbers of inherently resistant tubercle bacilli. Low-level INH resis-
tance, defined as an INH minimal inhibitory concentration (MIC) for
M. tuberculosis of greater than 0.1 µg/mL but less than 1.0 µg/mL is
most commonly associated with point mutations or short deletions
within the catalase-peroxidase gene (katG), which still produces some
enzymatic activity, whereas high-level resistance, defined as an INH
MIC for M. tuberculosis of greater than 1.0 µg/mL, is associated with
major deletions within the gene with loss of all enzymatic activity.26,27
Resistance in the regulatory region of a second gene involved in
mycolic acid synthesis (inhA) also confers INH resistance.26,27 The inci-
dence of INH resistance among new cases of tuberculosis in 2011 was
7% in persons born in the United States and 11% in persons born
outside the United States, including immigrants from Africa, Southeast
Asia, Eastern Europe, and Central America, where INH resistance is
more common.11,12,28
Pharmacology.  INH is well absorbed orally or intramuscularly
and is distributed throughout the body. Cerebrospinal fluid (CSF)
levels are generally about 20% of plasma concentrations but may
approach plasma levels in the presence of meningeal inflammation.
Co-administration with vitamin C appears to inactivate INH suspen-
sions markedly.29
Metabolism of INH occurs initially by hepatic N-acetyltransferase.
Diminished acetylation capacity is inherited as an autosomal recessive
trait that varies from a 5% prevalence rate in Canadian Eskimos to
83% in Egyptians. Ten percent to 15% of Asians are “slow” acetylators,
as are 58% of American whites. Six hours after a 4-mg/kg oral dose,
slow acetylators exhibit plasma INH levels of more than 0.8 µg/mL and

Me Me
O HO

Me
Me O OH O
H OH OH Me
O N Me Me
NH2 MeO NH OH
H
N Me N
N N Me
O H
N O OH N
O Me OH
Me
A B C

Me Me
O HO

Me
Me O OH O
OH OH Me Me Me
Me Me
MeO NH O HO

Me
Me O OH O
O NH OH OH Me
Me Me
O N MeO NH
O
Me O
N
N Me N
O N
N NH2
O OH
Me O
Me N
D E F
FIGURE 38-1  Structures of major antimycobacterial agents. A, Isoniazid. B, Rifampin. C, Ethambutol. D, Rifabutin. E, Rifapentine. F, Pyrazinamide.
 465
H2N NH
H 2N NH
NH
HO

Chapter 38  Antimycobacterial Agents

HN OH Cl
OH
O
OHC
O
Me Me
Me O O
O
H S N N Cl
HO O
HO N Me
HO
H2N NH2 N N
H
G H I

R
O O NH2
H
H 2N N NH2
N N
H H
O
NH O
H
N NH NH2 CO2H
O
OH S NH2
O O O
NH NH
H
Capreomycin
N NH IA (R  OH),
H Me
IB (R  H) NH2 H2N O N

J K L M
FIGURE 38-1, cont’d  G, Streptomycin. H, Dapsone. I, clofazimine. J, Capreomycin. K, Para-aminosalicylic acid. L, Cycloserine. M, Ethionamide.

dosage modifications for INH and other antituberculous drugs in

TABLE 38-1  Need for Dosage Modification for
hepatic or renal failure.
Antituberculous Drugs in Hepatic or Renal Failure
Adverse Reactions
ANTIMICROBIAL MODIFY IN MODIFY IN Hepatitis.  INH has infrequent major toxicities, most notably hepatitis.
DRUG HEPATIC FAILURE RENAL FAILURE Ten to 20 percent of INH recipients have asymptomatic minor eleva-
Isoniazid No No tions in serum aspartate aminotransferase levels that usually resolve
Pyrazinamide Yes Yes even with continued therapy.30 A meta-analysis of six studies estimated
Ethambutol No Yes the rate of clinical (symptomatic) hepatitis in patients given INH alone
Rifampin ?Yes No to be approximately 0.6%.31 Recent data indicate that the incidence of
Rifabutin ?Yes No clinical hepatitis is even lower. Hepatitis occurred in only 0.1% to
Amikacin No Yes 0.15% of 11,141 persons receiving INH alone as treatment for LTBI in
Capreomycin No Yes
an urban tuberculosis control program.32 Early estimates of the inci-
dence of severe or major INH hepatotoxicity were provided from the
Kanamycin No Yes
results of a large multicenter U.S. National Institutes of Health (NIH)–
Streptomycin No Yes
sponsored trial. Fatal hepatitis occurred in 8 of nearly 14,000 patients
Quinolones No Yes (levofloxacin, not receiving INH.33 All but one of the deaths occurred in one study center,
moxifloxacin)
and patients did not receive routine monitoring for toxicity during the
Para-aminosalicylic acid No Yes
trial.33 More recent studies, however, suggest that the rate of fatal INH-
Ethionamide Yes No related hepatitis is substantially lower.32,34,35 The likely explanation is
Cycloserine No Yes the adoption in the early 1980s of uniform clinical toxicity monitoring
for patients receiving INH for treatment of LTBI.34,35 Hepatotoxicity
can occur at any time but generally occurs after weeks to months of
therapy rather than days to weeks after treatment is begun. INH hepa-
rapid acetylators have levels of less than 0.2 µg/mL.20 The striking totoxicity is correlated with age, presumably owing to a diminished
bimodal distribution of plasma half-lives of INH depending on acety- capacity for repair of INH-induced hepatocellular damage in the
lator status generally does not affect the outcome with daily therapy, elderly. Undernutrition may also play a role in the expression of INH
because plasma levels are maintained well above inhibitory concentra- hepatotoxicity.36 Hepatotoxicity is increased in several groups: alco-
tions. Metabolically altered INH is principally excreted in urine along holic patients; patients with preexisting liver damage33; pregnant
with lesser amounts of unaltered drug. Dosage modification in renal women and women up to 3 months postpartum37; patients also taking
insufficiency is not necessary. The benefit of dosage adjustment with INH in combination with acetaminophen38; patients receiving other
significant hepatic disease is not established. Table 38-1 summarizes potentially hepatotoxic agents such as rifampin35; patients with active
 466
hepatitis B; and HIV-seropositive patients on highly active antiretro-
viral therapy.39 Histologically, hepatocellular damage can progress to
submassive necrosis. Although active hepatitis B is considered a con-
tributing factor to INH hepatotoxicity,40,41 INH has been safely admin-
Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases
istered to some with acute hepatitis42 and for LTBI to persons
chronically infected with hepatitis B and C.39,43,44 Educating patients
about the recognition of symptoms of INH-induced liver disease is key
in preventing its progression. As noted, routine clinical monitoring of
patients receiving INH is mandatory.35 Routine monitoring of serum
hepatic enzyme concentrations is not indicated for all patients at the
start of treatment of LTBI. Baseline testing is recommended for patients
whose initial evaluation suggests a liver disorder, patients infected with
HIV who are receiving highly active antiretroviral therapy, pregnant
women and those in the immediate postpartum period (i.e., within 3
months of delivery), persons with a history of chronic liver disease
(e.g., hepatitis B or C, alcoholic hepatitis, or cirrhosis), persons who
use alcohol regularly, and others who are at risk for chronic liver
disease.35,39 Baseline testing is no longer routinely indicated in persons
older than 35 years of age.35,39 Laboratory monitoring during treatment
of LTBI is indicated for patients whose baseline liver function test
results are abnormal and for other persons at risk for hepatic
disease.35,39,45 Although biochemical monitoring may contribute to
patient confidence and adherence with the treatment regimen, the
contribution of routine biochemical monitoring to the safety of INH
administration is not proven. The importance of routine clinical moni-
toring is clear, however, and must be applied rigorously with or without
biochemical monitoring.
The most feared INH-related toxicity is fulminant hepatic failure
necessitating liver transplantation or resulting in death. The CDC con-
ducted a detailed analysis of 17 patients with severe INH-related hepa-
toxicity over a 4-year period.46 The estimated incidence of death and
liver transplantation was 1/150,000 to 1/220,000 patients receiving
INH therapy for LTBI. Although continuation of INH after the onset
of hepatitis-related symptoms was associated with severe hepatotoxic-
ity, some patients still developed severe hepatotoxicity after stopping
INH within days to a week of symptom onset. Although it is not uni-
versally protective, patients should be strongly advised to discontinue
INH therapy at the onset of symptoms consistent with incipient hepa-
titis, such as nausea, loss of appetite, and dull midabdominal pain.
Perhaps most disconcerting, there were two children younger than 15
years of age in this series of patients. The overall conclusions of this
analysis were that severe hepatotoxicity was idiosyncratic, occurred at
any time during INH treatment, occurred even with careful clinical
and biochemical monitoring and with appropriate (recommended)
doses of INH, and could occur in children.46
Most hepatotoxicity subsides after INH discontinuation. Cautious
readministration of INH after a resolution of hepatitis for selected
patients has been reported to be well tolerated and safe,47 although
consideration should be given in these patients to alternative therapies
for LTBI, such as rifampin.35,39 Recognition of the frequency and sever-
ity48 of INH hepatotoxicity has not curtailed therapeutic usage but has
led to a revision of indications for treatment of LTBI, with special
caution indicated for groups identified at high risk for INH hepatotox-
icity (see earlier discussion).35,39,48
Neurotoxicity.  Peripheral neuropathy has been described in 17%
of recipients of 6 mg/kg/day of INH but is less frequent when adults
receive the standard dose of 300 mg/day. Poor nutrition or underlying
alcoholism, diabetes mellitus, or uremia predisposes to neuropathy,
which is more frequent in slow acetylators who have higher plasma
levels of unaltered drug. Increased pyridoxine excretion is promoted
by INH. Pyridoxine, 10 to 50 mg daily, can ameliorate the neuropathy
without interfering with the antimycobacterial effect. Current guide-
lines suggest that pyridoxine use is necessary only for patients with
underlying predispositions for neuropathy, as outlined earlier, but pyri-
doxine use is essentially universal for patients receiving INH. It is
noteworthy that neuropathy is a manifestation of excessive pyridoxine
dosing.
INH-induced central nervous system (CNS) toxicity can produce
aberrations ranging from memory loss to psychosis or seizures. Optic
neuropathy has been reported and can be confused with ethambutol-
related optic neuritis in patients receiving both drugs. Toxic CNS
reactions are not necessarily related to pyridoxine deficiency but have
responded to its administration.20
Hypersensitivity Reactions.  Fever, which may be sustained or
“spiking,” skin eruptions, or hematologic abnormalities can occur. INH
recipients can develop positive antinuclear antibody reactions and
rarely manifest a lupus-like syndrome that is reversible on discontinu-
ation of the INH.
Miscellaneous Adverse Reactions.  INH-associated arthritic dis-
orders have included Dupuytren’s contracture and shoulder-hand syn-
drome.20,24 Pellagra can occur in malnourished INH recipients.20,49
Pyridoxine deficiency–related anemia can occur in children or adults.50
Overdose.  Accidental ingestion of INH by children or ingestion
during a suicide attempt may result in metabolic acidosis, hyperglyce-
mia, seizures, and coma. High-dose pyridoxine usually reverses these
toxicities.
Significant Drug Interactions.  Particular caution is indicated
when administering INH to those with a seizure disorder. INH may
alter metabolism of antiseizure medications, so it is important to
monitor the blood levels of seizure medications for patients taking
INH. Phenytoin (Dilantin) toxicity is potentiated by INH. Mental
changes, nystagmus, and ataxia can result, especially in slow acetylators
whose high INH levels inhibit phenytoin metabolism. Theophylline
toxicity has been reported with co-administration of INH. INH
decreases the efficacy of clopidogrel by decreasing the metabolism of
the parent compound to the more biologically active metabolite. Com-
bined INH and rifampin therapy predisposes to elevation of plasma
hepatic enzymes. Plasma INH concentrations are increased by para-
aminosalicylic acid (PAS) through interference with acetylation.
Although significant drug interactions are less frequent with INH than
with rifampin, it is important to check for all potential drug-drug
interactions for any patient taking INH.
Usage.  INH is indicated for all clinical forms of tuberculosis. It is
used alone for therapy for LTBI for selected purified protein derivative
(PPD) skin test or interferon-γ release assay (IGRA) reactors at high
risk for developing active tuberculosis disease.35 The most recent CDC/
American Thoracic Society (ATS) guidelines state that INH is consid-
ered safe in pregnancy, but the risk for hepatitis may be increased both
before and after delivery. Supplementation with pyridoxine is recom-
mended if INH is administered during pregnancy.19,35 It is approved
for treating active tuberculosis in pregnant patients, but it should be
given with caution, and then only for selected high-risk patients with
LTBI (e.g., HIV-seropositive patients or recent contacts to individuals
with active tuberculosis).35
Availability and Dosage.  INH is available generically (tablets,
syrup, injectable solutions) and under brand names—INH tablets or
Nydrazid injectable solution. Dosage forms include 100- and 300-mg
tablets; syrup containing 10 mg/mL; 100 mg/mL solution for paren-
teral injection; and combination capsules combining 150 mg of INH
with 300 mg of rifampin (Rifamate) or tablets of 50 mg with 120 mg
of rifampin and 300 mg of PZA (Rifater). The usual adult dosage is
5 mg/kg/day (preferably 300 mg once daily). A higher dosage (10 to
15 mg/kg; maximum, 300 mg/day) has been recommended for infants
and children.
With the routine use of directly observed therapy for all patients,
twice- or three-times-weekly high-dose INH, 15 mg/kg orally (maxi-
mum 900 mg), is combined with rifampin, 10 mg/kg (maximum
600 mg orally), and PZA, 50 mg/kg (maximum 4 g), after an initial
period of daily drug therapy for drug-susceptible tuberculosis. For
most patients in the United States with tuberculosis, these drugs
are combined with ethambutol, 50 mg/kg orally (maximum 4 g)
twice weekly, or streptomycin, 20 mg/kg intramuscularly, until sus­
ceptibilities are available. A reliable urine test is available to confirm
INH ingestion.51 Although the preferred parenteral route is intra­
muscular injection, INH for injection can be administered safely
intravenously.52
Rifampin (see also Chapter 27)
Derivation and Structure.  Rifampin (termed rifampicin in the United
Kingdom) is a semisynthetic derivative of a complex macrocyclic anti-
biotic, rifamycin B, produced by Streptomyces mediterranei. It was
introduced for clinical trials in tuberculosis in 1967.

Mechanism of Action.  Rifampin inhibits DNA-dependent RNA
polymerase; human RNA polymerase is insensitive.
Antimicrobial Activity and Resistance.  Rifampin is bactericidal
against actively replicating M. tuberculosis to a degree comparable to
467
no recommendations for rifampin dosage modification (i.e., dose
reduction) with either hepatic or renal insufficiency. Rifampin is
removed by hemodialysis or peritoneal dialysis.57
Adverse Reactions.  Minor adverse reactions are rather frequent

Chapter 38  Antimycobacterial Agents

INH with MICs of 0.005 to 0.2 µg/mL. It is also active against intracel-
lular, slowly replicating bacilli and somewhat against nearly dormant
organisms in necrotic foci. Rifampin’s efficacy is indicated in suscep-
tible pulmonary tuberculosis by sputum conversion 2 weeks earlier
with rifampin-containing regimens than with regimens without the
drug. Resistance emerges rapidly if the drug is given as monotherapy.
Approximately 95% of resistance to rifampin results from a point muta-
tion or deletion within an 81-base pair region of the gene encoding the
β-subunit of RNA polymerase (rpoB).27,53 Mutations in the rpoB gene
can be rapidly detected with the tuberculosis GeneXpert technology
that is widely available in the United States. The prevalence of rifampin
resistance among new cases of tuberculosis in the United States is cur-
rently less than 1%.4,11,12 Isolated resistance to rifampin in the United
States has been strongly associated with HIV infection.54 Resistance to
rifampin is associated in all instances with cross-resistance to rifapen-
tine and in most instances with rifabutin, especially in the presence of
high-level resistance. Rifampin resistance coupled with resistance to
INH and other antituberculous agents defines either MDR-TB or
XDR-TB isolates, depending on the number and type of antitubercu-
lous agents to which the M. tuberculosis isolate is resistant.5
Pharmacology.  Rifampin is well absorbed orally, yielding peak
plasma concentrations of 7 to 8 µg/mL after a dose of 600 mg. It is
widely distributed throughout the body. CSF concentrations range
from undetectable to 0.5 µg/mL in healthy persons and reach 50% of
plasma concentrations with meningeal inflammation. Rifampin’s high
lipid solubility enhances phagosomal penetration. Rifampin is deacety-
lated to an active form that undergoes biliary excretion and enterohe-
patic recirculation. Because of autoinduction of rifampin metabolism
(cytochrome P-450–coupled),55 biliary excretion increases with contin-
ued therapy. Induction of rifampin’s metabolism with consequent
reduction in its half-life and plasma concentrations becomes maximal
after approximately six doses.56 Excretion is primarily into the gastro-
intestinal tract, with lesser amounts in the urine. The plasma concen-
tration and urinary excretion increase in hepatic failure. Probenecid
blocks hepatic uptake, causing decreased biliary excretion. There are
with rifampin, but cessation of therapy because of adverse effects was
necessary in only 6 of 372 patients taking the drug for 20 weeks.58
Hepatitis.  Rifampin’s major adverse effect is hepatitis. Minimal
abnormalities in liver function tests are common in those taking
rifampin and usually resolve, possibly because of autoinduction of its
metabolism even with continuation of the drug. Characteristically,
elevations of bilirubin and alkaline phosphatase levels result, whereas
elevation of hepatocellular enzyme concentrations can be caused by
rifampin, INH, or both. Alcoholic patients with preexisting liver
damage appear to be especially prone to rifampin-induced liver reac-
tions. There is no clear evidence that rifampin monotherapy for LTBI
is associated with fulminant hepatic failure as reported with INH
therapy for LTBI.
Effects on Immune Parameters.  Rifampin has widespread effects
on humoral and cell-mediated immunity, but they appear to be of no
clinical significance.
Hypersensitivity Reactions.  Flushing, fever, pruritus without
rash, urticaria, cutaneous vasculitis, eosinophilia, thrombocytopenia,
hemolysis, or renal failure due to interstitial nephritis can occur
because of rifampin. A systemic flulike syndrome, at times associated
with thrombocytopenia, has been described almost exclusively with
intermittent, high-dose therapy.
Miscellaneous Adverse Reactions.  Widespread distribution of
rifampin is reflected in an orange color appearing in urine, feces, saliva,
sputum, pleural effusions, tears, soft contact lenses, sweat, semen, and
CSF. With overdosage, a red man syndrome of skin discoloration has
been described. Gastrointestinal upset is frequent but is usually ame-
liorated by a temporary reduction in dosage.
Significant Drug Interactions.  By induction of microsomal cyto-
chrome P-450–mediated enzymatic activities, rifampin causes
increased hepatic metabolism of many substances. Rifampin interac-
tion with more than 100 drugs has been described.16,17,59-61 A compila-
tion of this expanding list of compounds is given in Table 38-2. The
induction period with rifampin may last for weeks after the drug is
discontinued. The recent introduction of PIs and NNRTIs for the

TABLE 38-2  Mycobacterium tuberculosis Disease in Human Immunodeficiency Virus (HIV) Coinfection
• The principles for treatment of active tuberculosis (TB) disease in HIV-infected patients are the same as those for HIV-uninfected patients.
• All HIV-infected patients with diagnosed active TB should be started on TB treatment as soon as possible.
• All HIV-infected patients with diagnosed active TB should be treated with antiretroviral therapy (ART).
• In patients with CD4 counts <50 cells/mm3, ART should be initiated within 2 weeks of starting TB treatment.
• In patients with CD4 counts ≥50 cells/mm3 who present with clinical disease of major severity as indicated by clinical evaluation (including low Karnofsky score, low
body mass index, low hemoglobin, low albumin, organ system dysfunction, or extent of disease), ART should be initiated within 2 to 4 weeks of starting TB treatment.
The strength of this recommendation varies on the basis of CD4 cell count:
○ CD4 count 50 to 200 cells/mm3 (BI)
○ CD4 count >200 cells/mm3 (BIII)
• In patients with CD4 counts ≥50 cells/mm3 who do not have severe clinical disease, ART can be delayed beyond 2 to 4 weeks of starting TB therapy but should be
started within 8 to 12 weeks of TB therapy initiation. The strength of this recommendation also varies on the basis of CD4 cell count:
○ CD4 count 50 to 500 cells/mm3 (AI)
○ CD4 count >500 cells/mm3 (BIII)
• In all HIV-infected pregnant women with active TB, ART should be started as early as feasible, both for maternal health and for prevention of mother-to-child
transmission of HIV.
• In HIV-infected patients with documented multidrug-resistant and extensively drug-resistant TB, ART should be initiated within 2 to 4 weeks of confirmation of TB drug
resistance and initiation of second-line TB therapy.
• Despite pharmacokinetic drug interactions, a rifamycin (rifampin or rifabutin) should be included in TB regimens for patients receiving ART, with dosage adjustment if
necessary.
• Rifabutin is the preferred rifamycin to use in HIV-infected patients with active TB disease on a protease inhibitor (PI)-based regimen because the risk for substantial
drug interactions with PIs is lower with rifabutin than with rifampin (AII).
• Co-administration of rifampin and PIs (with or without ritonavir boosting) is not recommended (AII).
• Rifapentine is not recommended in HIV-infected patients receiving ART for treatment of latent TB infection or active TB, unless in the context of a clinical trial (AIII).
• Immune reconstitution inflammatory syndrome (IRIS) may occur after initiation of ART. Both ART and TB treatment should be continued while managing IRIS (AIII).
• Treatment support, which can include directly observed therapy of TB treatment, is strongly recommended for HIV-infected patients with active TB disease (AII).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional.
Rating of Evidence: I = data from randomized controlled trials; II = data from well-designed nonrandomized trials or observational cohort studies with long-term clinical
outcomes; III = expert opinion
Modified from Department of Health and Human Services: Guidelines for the Use of Antiretroviral Agents in HIV-1 Adolescents and Adults. Last updated 3/27/2012. For
the most up-to-date guidelines, see http://aidsinfo.nih.gov/guidelines.
 468

TABLE 38-3  Recommendations for Co-administering Antiretroviral Drugs with Rifampin

RECOMMENDED CHANGE IN DOSE OF RECOMMENDED CHANGE
ANTIRETROVIRAL DRUG IN DOSE OF RIFAMPIN COMMENTS
Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

Non-nucleoside Reverse Transcriptase Inhibitors

Efavirenz None (some experts recommend 800 mg for patients No change (600 mg/day) Efavirenz AUC ↓ by 22%; no change in
>60 kg) rifampin concentration. Efavirenz
should not be used during the first
trimester of pregnancy.
Nevirapine Nevirapine and rifampin should not be used together Nevirapine AUC ↓ 37%-58% and Cmin ↓ 68% with 200 mg twice daily
Rilpivirine Rifampin and Rilpivirine should not be used together Rilpivirine AUC ↓ by 80%
Etravirine Etravirine and rifampin should not be used together Marked decrease in etravirine predicted, based on data on the interaction
with rifabutin
Single Protease Inhibitors
Ritonavir Rifampin and ritonavir should not be used together Significantly ↓ PI exposure (>75%)
despite ritonavir boosting
Fosamprenavir Rifampin and fosamprenavir should not be used
together
Atazanavir Rifampin and atazanavir should not be used together Atazanavir AUC ↓ by >95%
Indinavir Rifampin and indinavir should not be used together Indinavir AUC ↓ by 89%
Nelfinavir Rifampin and nelfinavir should not be used together Nelfinavir AUC ↓ 82%
Saquinavir Rifampin and saquinavir should not be used together Saquinavir AUC ↓ by 84%
Dual Protease-Inhibitor Combinations
Saquinavir/ritonavir Saquinavir 400 mg + ritonavir 400 mg twice daily No change (600 mg/day) Use with caution; the combination of
saquinavir (1000 mg twice-daily),
ritonavir (100 mg twice-daily), and
rifampin caused unacceptable rates of
hepatitis among healthy volunteers
Lopinavir/ritonavir Increase the dose of lopinavir/ritonavir (Kaletra) to 4 No change (600 mg/day) Use with caution; this combination
(Kaletra) tablets (200 mg of lopinavir with 50 mg of resulted in hepatitis in all adult healthy
ritonavir) twice daily volunteers in an initial study
“Super-boosted” Lopinavir/ritonavir (Kaletra)—2 tablets (200 mg of No change (600 mg/day) Use with caution; this combination
lopinavir/ritonavir lopinavir with 50 mg of ritonavir) + 300 mg of resulted in hepatitis among adult
(Kaletra) ritonavir twice daily healthy volunteers. However, there are
favorable pharmacokinetic and clinical
data among young children.
Atazanavir/ritonavir The standard dose of ritonavir-boosted atazanavir Atazanavir trough concentration ↓
(300 mg once daily with 100 mg of ritonavir) by >90%
should not be used with rifampin
Tipranavir/ritonavir Rifampin and tipranavir/ritonavir should not be used together
Darunavir/ritonavir Rifampin and darunavir/ritonavir should not be used together
CCR-5 Receptor Antagonists
Maraviroc Increase maraviroc to 600 mg twice daily No change (600 mg/day) Maraviroc Cmin ↓ by 78%. No reported
clinical experience with ↑ dose of
maraviroc with rifampin.
Integrase Inhibitors
Raltegravir No change No change (600 mg/day) Increase raltegravir dose to 800 mg orally
twice daily; monitor for antiretroviral
efficacy or switch to rifabutin
Elvitegravir/cobicistat/ Co-administration should be avoided Cobicistat and elvitegravir concentrations
tenofovir/emtricitabine may be significantly ↓. Consider an
(Stribild) alternative antimycobacterial or
alternative antiviral regimen.

AUC, area under the curve; PI, protease inhibitor.

Modified from UpToDate, 2013. For the most up-to-date information, see http://www.aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf

treatment of HIV infection has complicated the treatment of tubercu-
losis in this setting (see Table 38-2). Because rifampin induces metabo-
lism of PIs and NNRTIs, rifampin should not be co-administered with
these agents.16,17,62 The most recent guidelines for co-administration of
rifamycins with antiretroviral agents are summarized in Table 38-3 and
can be found on the NIH website (http://aidsinfo.nih.gov/guidelines),
which is a “living document” with ongoing updates.17 Assistance can
also be found at the CDC website (www.cdc.gov/tb/publications/
guidelines/TB_HIV_Drugs/default.htm).17 As new antiretroviral
agents and more pharmacokinetic data become available, treatment
recommendations are likely to be modified, so the reader is encouraged
to check these websites periodically for updates.
In general, the co-administration of antituberculosis drugs and
antiretroviral drugs should be initiated and guided by clinicians expe-
rienced in the treatment of these patients and familiar with the poten-
tial drug-drug interactions.
Competition for excretion with contrast agents used for biliary tract
imaging may cause inability to visualize the gallbladder. Probenecid
interferes with renal excretion, whereas PAS may interfere with gastro-
intestinal absorption.
Usage.  Rifampin is indicated for treatment of all forms of pulmo-
nary and extrapulmonary tuberculosis. It is recommended for treat-
ment of LTBI as an alternative choice to INH.35 The available data
suggest that the efficacy of rifampin for treating LTBI appears compa-
rable to that of INH, and, as noted, it appears to be less frequently
associated with severe hepatotoxicity. Rifampin in combination with
PZA was shown to be effective in HIV-positive patients for prophylaxis
when given for only 2 months,63 but for reasons that have yet to
be elucidated the combination of rifampin and PZA for treatment
of LTBI was associated with an unanticipated high rate (almost 6%)
of severe or fatal hepatotoxicity, especially in HIV-seronegative
patients.64,65 The rifampin/PZA combination is, therefore, not currently

recommended for treatment of LTBI, although the use of this regimen
might rarely be indicated for carefully selected patients under very
unusual and stringent circumstances with close clinical and biochemi-
cal monitoring and supervision by experienced clinicians. Rifampin
469
50 µg/mL, with a half-life of 12 hours, making once-daily or less fre-
quent dosing practical. PZA crosses inflamed meninges and has been
recommended in combination regimens for tuberculous meningitis.71
It is metabolized by the liver, and metabolic products, including prin-

Chapter 38  Antimycobacterial Agents

is a category C drug, but it is approved for use in pregnant patients cipally pyrazinoic acid, are excreted mainly by the kidneys, requiring
with active tuberculosis. It should only be used in pregnancy (as with dosage modification in renal failure. PZA is dialyzable, so dosing is
INH) for high-risk patients with LTBI, and then only if INH is not recommended after dialysis sessions consistent with dosing recom-
appropriate. mendations for INH, rifampin, and ethambutol.57
Availability and Dosage.  Rifampin is supplied in the United States Adverse Reactions.  The most common side effects are nausea and
as Rifadin, available in 150- or 300-mg capsules and in combination vomiting. Hepatotoxicity occurred in nearly 15% of PZA recipients in
300-mg capsules with 150-mg INH (Rifamate) or in 120-mg tablets early trials that employed dosages of 40 to 50 mg/kg/day for prolonged
with 50-mg INH and 300 mg of PZA (Rifater). Rifampin for intrave- periods. Current regimens of 20 to 35 mg/kg/day are safer,72 although
nous infusion (600 mg/vial, Rifadin) should not be used intramuscu- recent data suggest that PZA is the most common cause of hepatotoxic-
larly. The usual oral dosage is 10 mg/kg/day (maximum, 600 mg) for ity in multidrug regimens also containing INH and rifampin.73,74
adults and 10 to 20 mg/kg/day for children (not to exceed 600 mg/ Patients with preexisting liver disease should have symptoms and
day). A 600-mg twice-weekly schedule generally has been well toler- hepatic function tests monitored closely. PZA is also a frequent cause
ated. The current rifampin dosing recommendations have raised con- of hypersensitivity reactions and nongouty polyarthralgia in these mul-
cerns that some patients may be receiving suboptimal rifampin doses.66 tidrug regimens.73 Other adverse reactions (1% of patients or less)
For instance, with current recommendations for 10-mg/kg, maximal include interstitial nephritis,75 rhabdomyolysis with myoglobinuric
600 mg, dosing, a 60-kg individual would receive the same rifampin renal failure,76 and photosensitivity. Asymptomatic urate retention
dose as a 100-kg person. Studies are ongoing to investigate the safety occurs in 50% of PZA recipients, with symptomatic gout usually occur-
and efficacy of weight-adjusted rifampin doses higher than the 600-mg ring in patients with preexisting gout.72
dose. Rifampin from opened capsules can be suspended (usually Significant Drug Interactions.  As just noted, the combination of
10 mg/mL) in simple or flavored sugar syrups that should not include rifampin and PZA for treatment of LTBI is associated with a high rate
ascorbic acid, which can inactivate rifampin.29 Suspensions can be of severe or fatal hepatotoxicity.63-65 There are no other significant drug
refrigerated up to 2 weeks. interactions with PZA.
Usage.  PZA is included as an essential component of multidrug
Pyrazinamide 6-month short-course chemotherapy.19,73 Without PZA for the first 2
Derivation and Structure.  PZA is a synthetic pyrazine analogue of months initiation phase of therapy, relapse rates after 6 months of
nicotinamide. therapy are unacceptable.19 Efficacy with intermittent administration
Mechanism of Action.  The mechanism of action of PZA remains makes PZA suitable for directly observed therapy regimens. PZA is a
unknown. class C drug and should be used with caution in pregnancy. Although
Antimicrobial Activity and Resistance.  PZA is bactericidal for PZA is recommended for routine use in pregnant women by the World
tubercle bacilli at 12.5 µg/mL. Its optimal activity appears to be against Health Organization (WHO), the drug has not been recommended for
semi-dormant organisms in an acid pH environment, like that existing general use in pregnant women in the United States by the Food and
intracellularly in phagolysosomes. Despite good activity at acid pH in Drug Administration (FDA) and the CDC because of insufficient data
vitro and inhibitory concentrations within monocytes,67 PZA exhibits to determine safety.19 The practical consequence of this policy is that
low activity alone in pretreated macrophages.68 Resistance rapidly pregnant women in the United States with active tuberculosis require
evolves if PZA is used alone. Primary resistance is seen in less than 1% 9 months of therapy, because PZA is not included in the first 2 months
of isolates, but nearly 50% of INH-rifampin–resistant MDR-TB isolates of therapy.
are PZA resistant.2 Most isolates resistant to PZA have mutations in Availability and Dosage.  PZA is available in 500-mg tablets or as
the gene encoding pyrazinamidase (pncA) (Table 38-4).69,70 This results 300-mg tablets in combination with INH (50 mg) and rifampin
in the loss of pyrazinamidase activity, an enzyme that converts PZA to (120 mg) (Rifater). Dosage is 20 to 25 mg/kg/day (maximum, 2.0 g)
the active form of pyrazinoic acid. orally once or in two divided doses. PZA has been well tolerated in a
Pharmacology.  Well-absorbed orally, PZA is widely distributed twice-weekly dosage of 50 mg/kg (not to exceed 4 g/day) for short-
throughout the body, attaining concentrations above that needed to course regimens.
inhibit tubercle bacilli. Peak plasma concentrations are approximately
Ethambutol
Derivation and Structure.  Ethambutol (ethylenediiminobutanol)
was discovered in 1961 among synthetic compounds screened for anti-
TABLE 38-4  Mechanism of Action and tuberculous activity.
Recognized Mutational Resistance in Commonly Mechanism of Action.  Ethambutol inhibits arabinosyl transferase
Used Antituberculous Agents enzymes that are involved in arabinogalactan and lipoarabinomannan
MECHANISM OF SITE OF MUTATIONAL biosynthesis within the cell wall.77
DRUG ACTION RESISTANCE (GENE) Antimicrobial Activity and Resistance.  Ethambutol is bacterio-
Isoniazid Inhibits mycolic acid synthesis inhA (regulatory region) static in vitro or within macrophages67 at concentrations of 1 µg/mL
(mycolic acid gene) against susceptible strains of M. tuberculosis. Primary ethambutol
Catalase/peroxidase enzyme katG (catalase/peroxidase gene) resistance in the United States is only approximately 2%.11,12 Ethambu-
Rifampin Inhibits RNA polymerization β subunit rpoB (RNA tol’s principal role has been as a “companion” drug to curtail resistance.
polymerase gene) However, resistance rates as high as 80% for ethambutol in INH-
Pyrazinamide Unknown pncA (pyrazinamidase gene) rifampin–resistant isolates from New York City apparently indicate
Ethambutol Inhibits cell wall synthesis embB (gene for arabinosyl limited utility against MDR-TB.2 Ethambutol resistance relates to point
(blocks arabinosyl transferase enzyme) mutations in the arabinosyl transferase enzyme EmbB, which is coded
transferase) for by the embB gene.78
Streptomycin Inhibits protein synthesis rpsL (gene for ribosomal S12 Pharmacology.  Ethambutol administered orally is 75% to 80%
protein); 16-S ribosomal absorbed, yielding peak plasma concentrations of 5 µg/mL after a
RNA gene
dose of 25 mg/kg. It is distributed throughout the body, including
Amikacin Inhibits protein synthesis 16-S ribosomal RNA gene (?
amikacin-binding site)
the CSF. Although little ethambutol crosses normal meninges, levels
10% to 50% of those in plasma occur in CSF with meningeal inflam-
Capreomycin Inhibits cell wall synthesis Unknown
mation. After conversion of approximately 25% of absorbed ethambu-
Quinolones Inhibits DNA structure gyrA (gyrase A gene)
tol to inactive metabolites, 80% of the parent drug, together with
 470
metabolites, is excreted in urine. Consequently, it becomes necessary
to modify the dosage in significant renal failure.
Adverse Reactions.  The major toxicity of ethambutol is neuropa-
thy, including peripheral neuropathy and retrobulbar optic neuritis.
Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases
Characteristically, patients complain of bilateral blurry vision and are
found to have impairment of visual acuity and red-green color vision.
Common in association with high-dose (50 mg/kg/day) therapy with
prolonged administration, and more common with 25 mg/kg/day than
with 15 mg/kg/day dosing, retrobulbar neuritis is usually slowly
reversible. Visual loss has rarely occurred in elderly persons receiving
as little as 15 mg/kg/day.79 The administration of ethambutol at 25 mg/
kg on a three times weekly basis appears to be associated with a reduced
risk for visual toxicity in this patient population compared with daily
dosing at 15 mg/kg.80 This observation is important because baseline
visual acuity is often impaired in the elderly and associated with other
diseases such as cataracts that are associated with blurred vision.
Recipients of ethambutol should be instructed to report symptoms of
blurry vision promptly and to discontinue the drug until confirmatory
visual testing can be done. Visual acuity and red-green color percep-
tion testing is recommended at baseline, whenever a change in visual
symptoms occurs, and monthly for patients taking ethambutol for
more than 2 months or at higher than usual doses.19 Monthly testing
in patients on 15 mg/kg can be useful in establishing the range of visual
abnormalities in those already visually impaired.
Gastrointestinal intolerance is infrequent. Hyperuricemia occurs
because of decreased renal uric acid excretion. Hypersensitivity reac-
tions are rare and include dermatitis, arthralgias, and fever.
Significant Drug Interactions.  There are no significant drug
interactions with ethambutol.
Usage.  Ethambutol is routinely included as the fourth drug along
with INH, rifampin, and PZA in initial therapy for tuberculosis before
the availability of drug susceptibility information. Ethambutol is
included to protect against the emergence of rifampin resistance in
patients with occult INH resistance who, if receiving only INH,
rifampin, and PZA, would be functionally on only INH and PZA. It is
also routinely used in treatment regimens for patients with isolates
resistant to INH or rifampin, or both. Ethambutol has no detectable
effects on the fetus and is approved for treatment of tuberculosis in the
United States.
Availability and Dosage.  Ethambutol is available as ethambutol
hydrochloride (Myambutol) supplied in 100- or 400-mg tablets. The
usual dosage is 15 to 25 mg/kg/day initially, followed after 60 days by
15 mg/kg/day (maximum, 1600 mg) as a single daily dose.
Streptomycin
Derivation, Structure, and Pharmacology.  Streptomycin, an amino-
glycoside antibiotic introduced in the 1940s, was the first drug to
reduce tuberculosis mortality. Its structure, mechanism of action, and
pharmacology are covered in other chapters. Briefly, intramuscular
injection of 1 g yields peak plasma concentrations of 25 to 45 µg/mL.
It is virtually excluded from the CNS.
Antimicrobial Activity and Resistance.  Streptomycin is bacteri-
cidal against M. tuberculosis in vitro but is inactive against intracellular
tubercle bacilli. Concentrations of 4 to 10 µg/mL of plasma are inhibi-
tory. The rapid emergence of resistance to streptomycin was quickly
recognized as a consequence of single-drug therapy. Approximately 1
in 106 tubercle bacilli is spontaneously resistant to streptomycin.
Primary resistance to streptomycin is seen most often in patient popu-
lations having a high incidence of INH resistance. In MDR-TB disease
outbreaks, approximately 80% of INH-rifampin–resistant isolates are
also streptomycin resistant.2 Streptomycin resistance relates to muta-
tional changes involving ribosomal binding protein or the ribosomal
binding site.27,81,82 Isolates resistant to streptomycin are not cross-
resistant to amikacin, kanamycin, or capreomycin.
Adverse Reactions.  Streptomycin toxicity is like that of other ami-
noglycoside antibiotics but with less renal and auditory toxicity and
greater vestibular toxicity than more commonly used aminoglycosides.
Patients receiving streptomycin should be instructed to be aware of
tinnitus, decreased hearing, and problems with balance, and they
should be instructed to notify their caregiver immediately if such reac-
tions occur.
Unlike other aminoglycosides, allergic or hypersensitivity reactions
can be seen with streptomycin. These include fever, chills, eosinophilia,
and rash.
Significant Drug Interactions.  There are no significant drug
interactions with streptomycin.
Usage.  Streptomycin is indicated as the fourth drug along with
INH, rifampin, and PZA in patients at significant risk for drug resis-
tance. It is also used for multidrug therapy for drug-resistant tubercu-
losis. Dosages of greater than 1 g/day should be avoided. Dosage
reduction or frequency of administration, or both, are indicated in
patients older than 50 years, those with low body weight, and those
in whom renal function is impaired. Streptomycin blood levels may
be useful for guiding streptomycin dosing in these circumstances.
Special care must be taken when streptomycin is used in combination
with other nephrotoxic or ototoxic drugs, such as capreomycin or
amikacin. It is a category D drug in pregnancy because of fetal
ototoxicity.
Availability and Dosage.  Streptomycin sulfate for intramuscular
injection is provided in 1-g single-injection vials. The recommended
dosage in younger adults (<50 years) with normal renal function is
15 mg/kg/day or 0.5 to 1 g daily to 1 g twice weekly. Children receive
20 to 40 mg/kg/day (maximum, 1 g) in divided doses every 12 hours.
Although not approved for such use, the drug can be safely given
intravenously when needed. Streptomycin is currently available in the
United States, but its supply has been interrupted in the past.
ALTERNATIVES TO RIFAMPIN
Rifabutin
Derivation and Pharmacology.  Several spiropiperidyl rifamycins
have activity against mycobacteria, including M. tuberculosis, M.
avium-intracellulare complex, and M. kansasii.83-87 Rifabutin (Mycobu-
tin), a derivative of rifamycin-S, is more active in vitro and more effec-
tive on a weight basis in experimental murine tuberculosis than is
rifampin.86 The mechanism of action is inhibition of RNA polymerase,
as it is with rifampin. It has a long plasma half-life (45 hours) in
humans and marked tissue tropism, producing tissue concentrations
5-fold to 10-fold greater than in serum. Peak serum concentrations of
rifampin (5 to 10 µg/mL) are 5-fold to 10-fold higher than those of
rifabutin (0.5 µg/mL).88
Adverse Reactions.  A polymyalgia syndrome, a yellowish tan dis-
coloration of the skin (pseudojaundice), and anterior uveitis have
occurred in patients taking rifabutin, usually at doses exceeding
300 mg daily.89,90 Almost all persons with these side effects have also
been receiving clarithromycin, fluconazole, or ritonavir. Symptoms of
uveitis include ocular pain and blurred vision.90 Neutropenia occurs
infrequently when rifabutin is used to treat tuberculosis but has been
reported in one third of patients receiving therapy for pulmonary M.
avium complex disease.91 The incidence of rash, hepatitis, and gastro-
intestinal distress appears comparable to that with rifampin. It also can
produce an orange-red discoloration of urine, saliva, tears, and contact
lenses similar to that of rifampin.
Significant Drug Interactions.  Rifabutin induces the hepatic
cytochrome P-450 system but only about 50% of that seen with
rifampin. This induction produces lowered serum levels of numerous
drugs normally metabolized in the liver, including the PIs (Table
38-5).16,17 Concurrent administration of delavirdine or saquinavir with
rifabutin is not recommended for this reason.92 Rifabutin is also
metabolized by this same system, so enzyme inhibitors such as the PIs
fluconazole and clarithromycin increase plasma rifabutin concentra-
tions (see Table 38-3).16,17,89,92
Usage.  Rifabutin appears as effective as rifampin in the treatment
of drug-susceptible tuberculosis.93,94 In patients with HIV infection,
rifampin is replaced by rifabutin if PIs are used (amprenavir, atazana-
vir, darunavir, fosamprenavir, nelfinavir, lopinavir-ritonavir [Kaletra],
tipranavir-ritonavir, darunavir-ritonavir, and ritonavir).16,17 Current
guidelines suggest that rifabutin should be given as 300 mg three times
a week or every other day with the option for monitoring rifabutin
levels.17 Rifabutin’s potential for treatment of infection with MDR-TB
is of interest because approximately 25% of rifampin-resistant tuber-
culosis strains are inhibited by low concentrations of rifabutin and
there are some data suggesting that rifabutin adds to the efficacy
 471

TABLE 38-5  Recommendations for Co-administering Antiretroviral Drugs with Rifabutin

ANTIRETROVIRAL RIFABUTIN DOSE
DOSE CHANGE CHANGE COMMENTS

Chapter 38  Antimycobacterial Agents

Non-nucleoside Reverse-Transcriptase Inhibitors
Efavirenz No change To 450-600 mg (daily or Rifabutin AUC ↓ by 38%. Effect of efavirenz + protease inhibitor(s)
intermittent) on rifabutin concentration has not been studied. Efavirenz
should not be used during the first trimester of pregnancy.
Nevirapine No change No change (300 mg daily or Rifabutin and nevirapine AUC not significantly changed
3 times/wk)
Rilpivirine Rifabutin and rilpivirine should not be used together Rilpivirine AUC ↓ by 46%
Etravirine No change No change (300 mg daily or No clinical experience; etravirine Cmin ↓ by 45%, but this was not
3 times/wk) thought to warrant a change in dose
Single Protease Inhibitors
Fosamprenavir No change ↓ to 150 mg/day No published clinical experience
or
300 mg 3 times/wk
Atazanavir No change ↓ to 150 mg every other day No published clinical experience. Rifabutin AUC ↑ by 250%
or 3 times/wk
Indinavir 1000 mg q8h ↓ to 150 mg/day Rifabutin AUC ↑ by 170%; indinavir concentrations ↓ by 34%
or
300 mg 3 times/wk
Nelfinavir No change ↓ to 150 mg/day Rifabutin AUC ↑ by 207%; insignificant change in nelfinavir
or concentration
300 mg 3 times/wk
Dual Protease Inhibitor Combinations
Lopinavir/ritonavir (Kaletra) No change ↓ to 150 mg every other day Rifabutin AUC ↑ by 303%; 25-O-desacetyl rifabutin AUC ↑ by
or 3 times/wk 47.5-fold
Ritonavir (any dose) with saquinavir, No change ↓ to 150 mg every other day Rifabutin AUC and 25-O-desacetyl rifabutin AUC ↑, by varying
indinavir, amprenavir, fosamprenavir, or 3 times/wk degrees
atazanavir, tipranavir, or darunavir
CCR-5 Receptor Antagonists
Maraviroc No change No change No clinical experience; a significant interaction is unlikely
Integrase Inhibitors
Raltegravir No change No change No clinical experience; a significant interaction is unlikely
Elvitegravir/cobicistat/tenofovir/ Co-administration should be avoided Consider an alternative antimycobacterial or alternative antiviral
emtricitabine (Stribild) regimen. If used, consider rifabutin 150 mg once daily or every
other day. Monitor rifabutin concentrations and adjust dose
accordingly. Elvitegravir AUC ↓ 21%, Cmin ↓ 67%; rifabutin
active metabolite (25-O-desacetyl rifabutin) AUC ↑ 625%.

AUC, area under the curve.

Modified from UpToDate, 2013. For the most up-to-date information, see http://www.aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf.

of treatment regimens in this circumstance.95,96 It remains controver-
sial whether rifampin-resistant/rifabutin-susceptible M. tuberculosis
patients can be treated for shorter durations than other rifampin-
resistant patients, especially those with concomitant INH resistance.
Until there is more supportive evidence, it seems prudent to include
rifabutin in the regimens of these patients but not to assume it has
activity in this situation comparable to its activity for M. tuberculosis
isolates without rpoB mutations.97
Rifapentine
Derivation and Pharmacology.  With the microbiologic success of
rifabutin but problems with low serum levels and complex adverse
reactions, investigators searched for other rifamycin compounds. The
most promising agent so far is rifapentine.98-101 In the study leading to
licensure in 1998, rifapentine, 600 mg twice weekly, was compared
with rifampin, 450 to 600 mg, when both were given with daily isonia-
zid, pyrazinamide, and ethambutol for 2 months, followed by rifapen-
tine, 600 mg, plus isoniazid once weekly or rifampin, 450 to 600 mg,
plus isoniazid twice weekly. Results after 6 months were comparable,
although the rifapentine relapse rate was slightly higher (10% vs. 5%).99
When given with a fatty meal, peak blood levels after the administra-
tion of 600 mg rifapentine are 15 µg/mL of native drug and 6 µg/mL
of 25-desacetyl rifapentine, the active metabolite. The half-life of rifa-
pentine is 13 hours.
Adverse Drug Reactions.  The adverse effects of rifapentine are
similar to those associated with rifampin.
Significant Drug Interactions.  Rifapentine appears to be a more
potent inducer of the cytochrome P-450 system than rifabutin but less
than rifampin. It therefore may increase metabolism of co-administered
drugs that are metabolized by these enzymes.
Usage.  Rifapentine has recently been approved for once-weekly
use with INH in the continuation phase of therapy for HIV-negative
patients without cavitation on chest radiograph and negative acid-fast
bacilli smears at 2 months.19 The drug should be avoided in HIV-
positive patients on antiretroviral therapy because of interaction with
PIs and NNRTIs and the unexplained development of rifamycin
monoresistance in some patients.17,102 Rifapentine in combination with
INH given once weekly for 12 weeks (12 total doses) has recently been
shown to be as effective and safe as INH with higher treatment comple-
tion rates than INH for treating LTBI in HIV-seronegative and HIV-
seropositive patients not on antiretroviral therapy. This form of LTBI
therapy should be administered by directly observed therapy.103,104
Availability and Dosage.  Rifapentine is available in 150-mg
tablets. The recommended dosage for adults in the continuation phase
of therapy for tuberculosis has been 10 mg/kg or a maximum 600 mg
per week, although studies are ongoing to determine the optimal dose
for rifapentine with active tubercular disease. The recommended dose
for LTBI therapy is 900 mg per week, but weekly doses as high as
1200 mg appear to be tolerated reasonably well. The drug is not
approved for use in children or pregnant women. The pharmacokinet-
ics of rifapentine have not been evaluated in patients with renal impair-
ment. Only about 17% of an administered dose is excreted via the
kidneys. The clinical significance of impaired renal function in the
disposition of rifapentine is unknown. Similarly, the clinical signifi-
cance of impaired hepatic function in the disposition of rifapentine
and its 25-desacetyl metabolite is not known.
 472
SECOND-LINE ANTITUBERCULOUS
DRUGS
Quinolones (see Chapter 34)
Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases
Mechanism of Action.  Emerging outbreaks of MDR-TB disease2-6
have stimulated the investigation of fluorinated quinolones for their
activity against mycobacteria.105-111 Some are bactericidal against M.
tuberculosis, presumably by inhibition of its DNA gyrase at concentra-
tions within achievable serum levels.106
Antimicrobial Activity and Resistance.  Ciprofloxacin and ofloxa-
cin inhibit more than 90% of strains of drug-susceptible tubercle bacilli
at concentrations of 0.5 and 1.0 µg/mL, respectively.107-109 Fluoroqui-
nolones, particularly sparfloxacin, have produced additive effects with
other antituberculous drugs in vitro and in animals. Clinical trials of
ofloxacin in combination with INH and rifampin indicate activity
comparable to that of ethambutol.111 Ofloxacin used alone in a dose
of 300 mg/day in patients infected with MDR-TB has produced
decreases in sputum colony counts, with sputum conversion in 26%.112
In nonconverters, ofloxacin resistance emerged. Usage as a single
agent in animal models or in human trials with inactive drugs has
led to the rapid emergence of resistance. Resistance appears to result
from mutations in the genes responsible for DNA configuration (DNA
gyrase).27,113
Of the fluoroquinolones, gatifloxacin (no longer marketed in the
United States), moxifloxacin, and levofloxacin, in that order, have the
most activity against M. tuberculosis,114 with significant early bac­
tericidal activity against M. tuberculosis relative to first-line anti­
tuberculous drugs.115 Cross-resistance has been demonstrated among
ciprofloxacin, ofloxacin, and levofloxacin.
Two phase II studies sponsored by the CDC have been conducted
recently evaluating the effect of moxifloxacin substitution for either
ethambutol or isoniazid during the first 2 months of treatment of newly
diagnosed tuberculosis.116,117 In the first trial, moxifloxacin substitution
for ethambutol resulted in no apparent effect on 2-month sputum
conversion rates to negativity but did show a faster median time to
sputum conversion.116 In a second trial, moxifloxacin substituted for
INH in the first 2 months of treatment of tuberculosis had no effect on
2-month sputum conversion rates.117 These studies suggest that substi-
tution of moxifloxacin for ethambutol or isoniazid during the first 2
months of therapy is no less efficacious than standard intensive-phase
therapy and may result in more rapid clearance of M. tuberculosis from
the lungs. Ongoing trials will investigate if moxifloxacin, as part of a
first-line regimen, will shorten treatment duration.
Usage.  Quinolones are now routinely incorporated into treatment
regimens for MDR-TB disease along with other agents and are the
cornerstones of therapy for quinolone-susceptible MDR-TB isolates.
The usual dosage is levofloxacin, 750 to 1000 mg/day, or moxifloxacin,
400 mg/day. The use of quinolones in children and adolescents has not
been approved, but most experts agree that the drugs should be con-
sidered for children with MDR-TB disease. This class of drugs should
be avoided in pregnancy. Fluoroquinolones are cleared primarily by
the kidney, and dosage adjustment is recommended if creatinine clear-
ance is less than 50 mL/min. They are not cleared by hemodialysis, so
supplemental doses after dialysis are not necessary. Drug levels are not
affected by hepatic disease. There is also ongoing concern about the
use of quinolones as first-line therapy for community-acquired pneu-
monia, which is the most common misdiagnosis applied to missed
cases of tuberculosis. It appears that either multiple or prolonged
courses of quinolones are required to promote quinolone-resistant
tuberculosis, which is unfortunately not a circumstance without
precedence.
Adverse Reactions.  The adverse effects for levofloxacin (these
apply to most of the quinolones) include nausea and bloating, dizzi-
ness, insomnia, tremulousness, headache, rash, pruritus, and photo-
sensitivity. There are limited data on the safety and tolerability of
long-term moxifloxacin and gatifloxacin at 400 mg/day. One issue of
long-term safety for the newer quinolones is their cardiac effect on the
QT interval, resulting in a ventricular tachycardia known as torsades
de pointes. The optimal approach for monitoring possible cardiac tox-
icity in patients on long-term quinolone therapy is not established.
Whether to continue a quinolone in the presence of QT-interval
prolongation or whether to add another agent that also may prolong
the QT interval is clearly a risk-benefit decision especially for patients
with MDR-TB disease for which the quinolone may be the most
important drug in the treatment regimen. Tendonitis and tendon
rupture are also concerns with fluoroquinolones, which has prompted
a special warning by the FDA on package inserts for fluoroquinolone
use. As with potential cardiac toxicity, the decision to continue a qui-
nolone in a patient with tendonitis requires an individualized risk-
benefit analysis.
Significant Drug Reactions.  Because antacids and other medica-
tions containing divalent cations markedly decrease absorption of fluo-
roquinolones, it is important that fluoroquinolone not be administered
within 2 hours of such medication.
Linezolid (see Chapter 32)
Linezolid is an oxazolidinone with activity against drug-resistant
gram-positive bacteria.118 It has been shown to inhibit all strains of
M. tuberculosis at concentrations of less than 1 µg/mL in vitro.
Although it has potentially severe toxicity with long-term use, it has
been shown to have significant activity in multidrug regimens for
MDR-TB and XDR-TB. In a recent series of 41 XDR-TB patients unre-
sponsive to therapy, linezolid at initial doses of 600 mg/day followed
by either 600 mg/day or 300 mg/day was associated with a sputum
conversion rate of 87%. Acquired linezolid resistance occurred in less
than 10% of patients with both 300 mg and 600 mg linezolid dosing.
Remarkably, 82% of patients had clinically significant adverse events
but only 3 patients permanently discontinued linezolid because of drug
toxicity.119
Linezolid is marketed as Zyvox and is available as 600-mg tablets
and infusions. The usual daily dose for bacterial infections has been
600 mg twice daily. However, the usual dose for tuberculosis is 300 to
600 mg once daily. The oral form is almost 100% bioavailable. The
emergence of mutational resistance is not surprising because the drug
inhibits the ribosome and M. tuberculosis only has one copy of this
gene. Significant adverse reactions have emerged associated with long-
term administration, especially bone marrow suppression, peripheral
neuropathy, and blindness, which, combined with the high cost of the
drug, may limit its use. However, the poor efficacy and significant side
effects of other second-line drugs such as PAS and cycloserine, make
linezolid a relatively attractive choice for initial MDR-TB and XDR-TB
disease treatment regimens rather than as a salvage agent after patients
have failed therapy with older second-line drugs. All patients with
MDR-TB and XDR-TB disease should have their treatment guided by
physicians experienced in the management of these diseases.
Capreomycin, Amikacin, and Kanamycin
Capreomycin, amikacin, and kanamycin are considered as a group
because all are administered by intramuscular or intravenous injection,
have similar pharmacokinetics and toxicities, and are excreted by the
renal route. These drugs have been used principally as alternative
agents for MDR-TB disease. All have additive ototoxicity and nephro-
toxicity and in that regard should be given cautiously, just like strep-
tomycin or other aminoglycosides.
Capreomycin
Antimicrobial Activity and Resistance.  Capreomycin, a polypeptide
antibiotic obtained from Streptomyces capreolus, is active against M.
tuberculosis, including most MDR-TB strains,2 at concentrations of 1
to 50 µg/mL (usually 10 µg/mL). Average peak plasma concentrations
of 30 µg/mL are achievable. There is no cross-resistance between strep-
tomycin and capreomycin,120 but some isolates resistant to kanamycin
or amikacin are cross-resistant to capreomycin. The site of mutational
change resulting in capreomycin resistance is unknown.
Adverse Reactions.  Capreomycin can cause hearing loss, tinnitus,
and decreased renal function but is considered less toxic than amika-
cin, and especially kanamycin.
Significant Drug Interactions.  There are no significant drug
interactions with capreomycin.
Usage.  Capreomycin has emerged as the first-line injectable agent
in regimens for the treatment of drug-resistant tuberculosis, especially
when there is streptomycin resistance.

Availability and Dosage.  Capreomycin sulfate is supplied as
Capastat. The dosage is the same as with streptomycin, with a range of
500 mg to 1 g deep intramuscularly five times weekly for 2 to 4 months
in those younger than 50 years and having normal renal function. The
dose is thereafter reduced to 1 g two to three times weekly. It is a cat-
egory C pregnancy drug.
Amikacin
Antimicrobial Activity and Resistance.  In vitro and in animals, ami-
kacin is among the most active aminoglycosides against M. tuberculo-
sis. Because of its expense and greater toxicity, it has in the past been
considered after streptomycin and capreomycin for the treatment of
MDR-TB. However, several factors have made it the preferred paren-
teral agent, including (1) the high rate of streptomycin resistance in
MDR-TB isolates and (2) the ready availability of amikacin levels facili-
tating amikacin dosing that does not cause early severe toxicity and
loss of the parenteral agent for long-term use. It has generally replaced
kanamycin in the United States. There is cross-resistance to amikacin
and kanamycin that results from an A-G change at base pair 1408 of
the 16-S ribosomal RNA gene.121
Adverse Reactions.  Common side effects include tinnitus, hearing
loss, and nonoliguric renal failure. Hypersensitivity events are rare.
Usage.  Amikacin is an alternative injectable agent for the treat-
ment of resistant M. tuberculosis infections. The customary dose is 7
to 10 mg/kg (not to exceed 1 g) five times weekly. Because most pathol-
ogy laboratories can determine blood levels of amikacin but not kana-
mycin, streptomycin, or capreomycin, amikacin is especially suited
when parenteral therapy is required in patients with renal failure or in
elderly patients with preexisting hearing loss. It is a category D drug
in pregnancy.
Kanamycin
Kanamycin is an aminoglycoside that has activity against most strains
of streptomycin-resistant tubercle bacilli. Except for its lower cost,
kanamycin offers no advantage over amikacin in combination therapy
and has substantial ototoxicity. In addition, serum levels are not readily
available.
Availability and Dosage.  Kanamycin sulfate is available as
Kantrex, 0.5 g/2 mL, 1 g/3 mL, or 75 mg/2 mL (pediatric formula-
tion) for intramuscular injection. The usual dose is 15 mg/kg (maxi-
mum, 1.0 g), generally limited to 500 mg/day in adults because of
ototoxicity.
Para-aminosalicylic Acid
Derivation, Structure, and Pharmacology.  As a calcium or sodium
salt, this synthetic compound inhibits the growth of tubercle bacilli by
the impairment of folate synthesis. PAS is incompletely absorbed orally.
A 4-g dose yields plasma concentrations of 70 to 80 µg/mL. Eighty-five
percent of absorbed PAS is excreted in urine as various metabolic
products.
Adverse Reactions.  Chief among PAS side effects is gastrointesti-
nal intolerance, which is often severe and results in poor compliance.
PAS can cause reversible drug-induced lupus-like reactivity and, when
given as the sodium salt, sodium overload. It can produce lymphoid
hyperplasia, and recipients can develop mononucleosis-like syndromes
with fever, rash, hepatosplenomegaly, occasionally toxic hepatitis, and
adenopathy. Hypersensitivity to PAS is frequent.
Usage.  PAS has retained a limited role in multidrug therapy in
developing countries because of its low cost. However, it is becoming
less favored because of poor compliance and primary resistance. Its use
in the United States is limited to the treatment of MDR-TB and
XDR-TB disease.
Availability and Dosage.  PAS in the United States is available from
the CDC (www.cdc.gov). Dosage forms include 500-mg tablets or 4-g
resin packets. The usual dosage is 10 to 12 g/day in three or four
divided doses for adults (6 to 8 g/day of the sodium-potassium–free
ascorbate) and, in children, 200 to 300 mg/kg/day in divided doses.
Cycloserine
Derivation and Mechanism of Action.  By virtue of inhibiting cell
wall synthesis, cycloserine possesses antimicrobial activity against a
473
broad range of prokaryotic organisms including mycobacteria. From 5
to 20 g/mL inhibits susceptible M. tuberculosis in vitro.
Pharmacology.  Cycloserine is readily absorbed orally. Serum con-
centration measurements aiming for a peak concentration of 20 to
Chapter 38  Antimycobacterial Agents
35 mg/L are often useful in determining the optimum dose for a given
patient. Widely distributed among tissues, no blood-brain barrier
exists to cycloserine.19 Little of the drug is metabolized, and approxi-
mately two thirds is excreted unchanged by the kidneys.
Adverse Reactions.  Cycloserine levels are essential for optimal use
of this toxic drug. Peak serum concentrations of cycloserine should be
kept between 20 and 35 µg/mL.19 Cycloserine can cause peripheral
neuropathy or CNS dysfunction, including confusion, irritability, som-
nolence, headache, nervousness, vertigo, dysarthria, and seizures.
Behavioral alterations include severe depression with suicidal ideation.
Cycloserine is contraindicated in patients with a history of seizures or
those with severe underlying depression. Because the CNS toxicity
appears to be dose related and only a few specialized laboratories do
serum drug levels, the drug is generally avoided, even by clinicians
experienced in treating tuberculosis, unless no other options are avail-
able, such as with some patients infected with MDR-TB and XDR-TB
strains.
Usage.  Cycloserine is one of several alternatives for re-treatment
regimens or for treatment of primary drug-resistant M. tuberculosis. It
does not appear to have great activity against MDR-TB strains.2 It is
classified as a category C drug in pregnancy.
Availability and Dosage.  Cycloserine is provided in the United
States as Seromycin in 250-mg pulvules. The usual dosage is 500 to
1000 mg/day in two divided doses, with 500 mg/day commonly used.
Cycloserine levels can be obtained to guide drug dosage and minimize
toxicity.
Ethionamide
Derivation, Mechanism of Action, and Resistance.  Ethionamide, a
derivative of isonicotinic acid, was first synthesized in 1956. It is tuber-
culostatic at 0.6 to 2.5 µg/mL against susceptible strains, presumably
by inhibition of oxygen-dependent mycolic acid synthesis.122 The
mechanism of ethionamide resistance is unknown, but some isolates
are resistant to both INH and ethionamide and harbor mutations in
the region of the inhA gene, which is involved in mycolic acid
biosynthesis.26
Pharmacology.  Ethionamide is absorbed well orally, yielding peak
plasma concentrations of 20 µg/mL. It is widely distributed and pene-
trates both normal and inflamed meninges to yield CSF concentrations
equivalent to those in plasma. It is metabolized by the liver, with metab-
olites renally excreted. Ethionamide interferes with INH acetylation.
Adverse Reactions.  Gastrointestinal distress with nausea and
vomiting frequently leads to poor compliance and drug discontinu-
ance. Various neurologic disorders have been caused by ethionamide,
including peripheral neuropathy and psychiatric disturbances. Neuro-
logic side effects have been reported to be alleviated by pyridoxine or
nicotinamide. Reversible hepatotoxicity occurs in approximately 5% of
ethionamide recipients. A hypersensitivity-type rash and poor diabetic
control are infrequent complications. Its usage is limited also by a high
frequency of severe gastrointestinal intolerance. Hypothyroidism is a
recognized complication of ethionamide use and is more common
when ethionamide is combined with PAS. Patients should have peri-
odic screening for hypothyroidism in patients receiving ethionamide
long term.
Usage.  Ethionamide is among the agents that can be chosen for the
treatment of drug-resistant tuberculosis. It appears to be active against
most MDR-TB isolates; although there is some similarity in the mode
of action of ethionamide with INH, their mode of actions are suffi-
ciently different so that cross-resistance with clinical M. tuberculosis
isolates usually does not occur. Regardless, confirmation of in vitro
susceptibility to ethionamide for INH-resistant isolates must be
obtained.
Availability and Dosage.  Ethionamide is available in the United
States as Trecator-SC in 250-mg coated tablets. The initial dosage is
250 mg twice daily (or as a single dose at bedtime), which is increased
by 250 mg daily until 1 g/day in divided doses is reached. Usually, 500
to 750 mg is the maximal tolerated dose.
 474
β-Lactams
All mycobacteria produce β-lactamase. M. tuberculosis is protected
from β-lactam antibiotics through its potent β-lactamase–encoded
gbya gene called BlaC. Several β-lactamase–resistant β-lactam antibi-
Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases
otics are active in vitro against M. tuberculosis.122-125 Clavulanate in
particular has demonstrated in vitro the capacity to inhibit the activity
of BlaC-encoded products. Meropenem, a carbapenem offering a
limited substrate to hydrolysis, has demonstrated high bactericidal in
vitro activity when combined with clavulanate against susceptible
MDR-TB and XDR-TB strains.126 Reports of β-lactam success for treat-
ing TB have been sporadic, but in a recent study of 31 patients,
meropenem-clavulanate was added to a linezolid-containing regimen
for treating MDR-TB/XDR-TB. The patients receiving meropenem-
clavulanate had a higher percentage of smear and culture conversion
than patients who did not.127 Unfortunately, activity of β-lactam agents
against intracellular mycobacteria is generally poor.128,129 In concentra-
tions as high as 50 µg/mL in a macrophage model, ceforanide, active
in vitro, was unable to inhibit tubercle bacilli.
Amithiozone
Amithiozone (thiacetazone), a thiosemicarbazole, is active against
many strains of M. tuberculosis.20 Because of its low cost, amithiozone
has been employed as a first-line drug, particularly in East Africa.20
However, because of severe toxicity in HIV-infected recipients there,
clinical usage no longer appears appropriate.17
New Drugs for Tuberculosis
This is an era of unprecedented interest and activity in the development
of new antituberculous drugs. Currently there are more than 15 new
compounds with potential antituberculosis activity in the preclinical
or clinical phases of development. Approximately twice that number
of other interesting molecules have been identified in screening, lead
identification, or lead optimization.
The diarylquinoline bedaquiline (also referred to as TMC207 or
Sirturo) is a novel compound that acts by inhibiting the M. tuberculosis
adenosine triphosphate (ATP) synthase.130,131 This compound demon-
strates significant in vitro potency against M. tuberculosis—both drug-
susceptible and multidrug-resistant strains as well as multiple other
mycobacteria.130 Animal studies suggested that bedaquiline has signifi-
cant potential to shorten treatment duration for both drug-susceptible
and drug-resistant strains.132 In initial and follow-up reports of a ran-
domized trial of bedaquiline versus placebo in multidrug regimens for
newly diagnosed patients with MDR-TB disease, the patients receiving
bedaquiline had significantly reduced time to sputum conversion with
an increased proportion of patients with sputum conversion. Bedaqui-
line also prevented resistance against companion drugs in the course
of treatment.133,134 The only side effect that occurred more frequently
with bedaquiline than placebo was nausea. Bedaquiline is also known
to prolong the QT interval. One caveat that has emerged from data
filed with the FDA is that in a larger cohort of patients, the bedaquiline
treatment arm was associated with five times the number of deaths
compared with the placebo arm.135 Investigation of these deaths has
shown that half of them were due to progressive tuberculosis and that
to date there is no direct pathophysiologic link between bedaquiline
and the other deaths. The FDA has approved bedaquiline for treatment
of drug-resistant tuberculosis with a black box warning relating to
possible cardiac toxicity and sudden death. As with the quinolones, a
risk-benefit analysis is necessary for any patient to receive bedaquiline,
but it would seem difficult to withhold bedaquiline to patients with few
other antibiotic choices even in the presence of a prolonged QT inter-
val on an electrocardiogram.
OPC-67683, or delamanid, is a new agent derived from the nitro-
dihydro-imidazooxazole class of compounds that inhibits mycolic acid
synthesis and has shown potent in vitro and in vivo activity against
both drug-susceptible and drug-resistant M. tuberculosis strains.136,137
In one assessment of early bactericidal activity of delamanid in tuber-
culosis patients, doses of 200 and 300 mg daily resulted in decreased
sputum M. tuberculosis burden of a magnitude similar to that of
rifampin.138 In a recent placebo-controlled trial of delamanid, 100 mg/
day or 200 mg/day, administered over 2 months as part of a multidrug
regimen for MDR-TB,139 both delamanid doses were associated with a
significant increase in sputum-culture conversion at 2 months. Most
adverse events were mild to moderate in severity and were evenly
distributed across groups. QT-interval prolongation was reported sig-
nificantly more frequently in the groups that received delamanid.
PA-824 is a nitroimidazole that has undergone extensive testing in
animal models and is currently being studied, primarily in MDR-TB
patients.140-143 The mechanism of action of delamanid and PA-824 are
not yet known, but they appear to generate radicals with toxic effects
on mycolic acids and protein biosynthesis.144 PA-824 is potent in vitro
against drug-susceptible and drug-resistant TB strains and appears to
have activity against nonreplicating or slowly replicating strains.
PA-824 has undergone initial dose-ranging monotherapy studies and
has shown dose-related early bactericidal activity.140 In a recent study
involving patients with drug-susceptible tuberculosis, the combination
of PA-824, moxifloxacin, and PZA had a 14-day antituberculosis activ-
ity in sputum comparable with that of the current standard regimen
for drug susceptible tuberculosis.143 The important implication is that
this regimen is effective and does not contain rifampin; therefore, there
is a low interaction potential with antiretroviral regimens. PA-824
would also be suitable for MDR-TB isolates. Trials of longer-duration
PA-824 administration are ongoing.
MAJOR DRUGS FOR THE
TREATMENT OF
NONTUBERCULOUS
MYCOBACTERIAL INFECTIONS
(SEE CHAPTERS 253 AND 254)
Nontuberculous mycobacteria (NTM) vary greatly in susceptibility to
antimicrobial agents.145-148 Some, such as M. kansasii, are susceptible to
agents used principally for the treatment of tuberculosis; others, such
as M. fortuitum and M. chelonae, respond to antibiotics used more
commonly for pyogenic bacterial infections; and still others, especially
M. avium-intracellulare, are broadly resistant. Susceptibility testing of
the NTM has been greatly facilitated by the publication in 2003 and
2011 of national guidelines for testing by the Clinical Laboratory Stan-
dards Institute (CLSI).149,150 Hence, chemotherapy for NTM infections
based on susceptibility results is now feasible for many species. An
important exception is that susceptibility testing has no clinically pre-
dictive value in infections due to M. avium-intracellulare except for the
newer macrolide clarithromycin.148
Macrolides (see Chapter 29)
Antimicrobial Activity and Resistance.  Pretreatment strains of
M. kansasii, M. marinum, M. haemophilum, M. malmoense, M. avium-
intracellulare, M. chelonae, and M. abscessus are susceptible to
achievable therapeutic concentrations of the newer macrolides clar-
ithromycin and azithromycin. This has resulted in a dramatic change
in therapy for NTM infections, with a macrolide now part of the
treatment regimen for most species. Clarithromycin inhibits almost
all species with the exception of 20% of M. fortuitum and M. simiae
at 4 µg/mL or less.151-155 Initial therapeutic results have indicated
that these agents are clinically efficacious as well, including against
both pulmonary and disseminated M. avium-intracellulare infec-
tions.148,156,157 Both macrolides have proved efficacious for the preven-
tion of disseminated M. avium infection in patients with AIDS.158,159
Macrolides should not be used as monotherapy because of the rapid
emergence of resistance, which results from a point mutation at
adenine 2058 or 2059 on the 23-S ribosomal RNA gene, the presumed
macrolide-binding site, and produces cross-resistance to all macro-
lides.160,161 Intrinsic resistance due to a series of chromosomal erm
(erythromycin methylase) genes has recently been described in M.
fortuitum, M. smegmatis, and M. abscessus, but in none of the slowly
growing species.162
Pharmacology.  Clarithromycin is metabolized in the liver, and
significant concentrations of the 14-OH metabolite are detectable in
the serum.163 Clarithromycin is also excreted in part by the kidneys,
and a reduction in dosage is required in elderly patients, patients with
low body weights, and reduced renal failure.
Adverse Reactions.  The most common side effects are nausea,
vomiting, and diarrhea, which are generally dose related.164 A toxic

hepatitis occurs with daily doses above 1.0 g and is associated with
elevated levels of alkaline phosphatase and γ-glutamyltransferase.164
Temporary hearing loss may also occur with high doses of
azithromycin.145
Significant Drug Interactions.  Clarithromycin is metabolized by
the cytochrome P-450 enzyme system, and serum levels are dramati-
cally reduced by enzyme inducers such as rifampin.163 Clarithromycin
is an inhibitor of the P-450 enzyme system, and its use results in
increased serum levels and potential increased toxicities of multiple
drugs metabolized by these enzymes, including rifabutin,86,87 carbam-
azepine, cisapride, astemizole, terfenadine, and theophylline. Clar-
ithromycin inhibits the metabolism of PIs as well. In contrast,
azithromycin is not metabolized by the cytochrome P-450 system and
has no significant drug interactions.165
Dosage.  The usual therapeutic doses are 500 mg twice daily for
clarithromycin and 250 mg once daily for azithromycin. For M. avium
complex lung disease, the usual clarithromycin dose is 500 mg morning
and evening, and for azithromycin the dosage is 500 mg given three
times weekly. For disseminated M. avium prophylaxis, the dosage of
azithromycin is 1200 mg once a week.159
Rifampin
Antimicrobial Activity.  Rifampin is employed for the treatment of
many slowly growing NTM infections. In vitro, all untreated strains
of M. kansasii, M. marinum, M. haemophilum, and M. xenopi are
inhibited by 0.25 to 1.0 µg/mL.148,166,167 Other species are much less
susceptible. Only one half of M. avium-intracellulare strains are inhib-
ited in vitro by 4 to 16 µg/mL of rifampin. Synergy between rifampin
and other agents has been demonstrable for a number of species in
vitro. Its role as a single agent is discouraged because resistance will
occur.167
Pharmacology, Adverse Events, and Significant Drug Interac-
tions.  See the earlier discussion in the section on tuberculosis.
Usage.  The excellent response of M. kansasii infections to rifampin-
containing regimens has made rifampin a recommended component
of most treatment regimens.148 Rifampin doses are the same as those
for treatment of tuberculosis. For patients with HIV infection on PIs,
rifabutin (150 mg three times per week) or clarithromycin (500 mg
twice daily) is recommended over rifampin,148 because of its lesser
effect on the cytochrome P-450 system.
Rifabutin
Antimicrobial Activity.  Rifabutin is inhibitory against 90% of strains
of M. avium-intracellulare at a concentration of 2 µg/mL.83,84 It is con-
centrated severalfold in tissue and, like rifampin, has gastrointestinal
toxicity as its most common adverse effect. Rifabutin at a dose of
300 mg/day has been shown to reduce by 50% the incidence and rate
of dissemination of M. avium-intracellulare infections in AIDS patients
having CD4 counts of less than 200,168 although it is probably not as
effective as the newer macrolides.
Pharmacology, Adverse Events, and Significant Drug Interac-
tions.  The reader is referred to the earlier discussion in the section on
tuberculosis.
Usage.  Rifabutin is used in place of rifampin in HIV-infected
patients on PIs, although it is not recommended with saquinavir or
delavirdine.17 Rifabutin is frequently used in the multidrug regimen for
treatment of M. avium-intracellulare lung disease, especially in patients
who may have failed a regimen containing rifampin.148 However, for
disseminated disease in patients with AIDS, a placebo-controlled study
showed that through 16 weeks of follow-up, a dose of 300 mg daily did
not increase the culture conversion rate over clarithromycin and eth-
ambutol alone but did protect against the development of macrolide
resistance.169
Aminoglycosides
Aminoglycoside antibiotics have been used extensively for the treat-
ment of rapidly growing and some slow-growing NTM infections.
Among M. kansasii strains, 86% demonstrated streptomycin suscepti-
bility. Forty-four percent of strains of M. avium-intracellulare have
been susceptible to streptomycin. Rapidly growing mycobacteria,
including M. fortuitum and M. abscessus, are resistant.
475
Amikacin is the most active aminoglycoside against the
NTM.148,170-172 However, marked variability exists between mycobacte-
rial species in susceptibility. All strains of M. marinum, M. kansasii,
and M. fortuitum are susceptible to 4 µg/mL or less,166,171,172 whereas
Chapter 38  Antimycobacterial Agents
isolates of M. chelonae, M. abscessus, and M. avium-intracellulare are
more resistant but are usually inhibited by 8 to 32 µg/mL of amika-
cin.171,172 Doses for streptomycin and amikacin are generally the same
as those for treatment of tuberculosis. Tobramycin is the most active
aminoglycoside and is the recommended aminoglycoside for treat-
ment of M. chelonae.171,172 Other aminoglycosides, such as gentamicin,
are less active and are generally not clinically useful.
Mutational resistance to amikacin on therapy is rare, probably
because of relatively high toxicity, which limits therapy. Resistance has
been described with M. abscessus and results from the same 16-S ribo-
somal RNA gene mutation described with M. tuberculosis.173
Ethambutol
Ethambutol has good in vivo activity against M. avium complex and
is included as part of treatment regimens for these organisms.148 It
also has activity against most other slowly growing NTM, including
M. kansasii, M. marinum, and M. xenopi. Species of rapidly growing
mycobacteria are all highly resistant, with the exception of the M.
smegmatis.
LESS FREQUENTLY USED
MISCELLANEOUS ANTIMICROBIAL
AGENTS FOR TREATMENT OF
NONTUBERCULOUS
MYCOBACTERIA
Isoniazid
Drugs such as INH used principally for treatment of M. tuberculosis
were evaluated relatively early for their activity against NTM. INH
inhibits nearly 90% of strains of M. kansasii at concentrations of 1 to
5 µg/mL, as contrasted to only 10% to 30% of M. avium-intracellulare
strains. At present, INH is included routinely in the therapy for M.
kansasii in the United States,148 M. xenopi, and M. szulgai. It has been
replaced by more active agents for therapy for other species, including
M. avium-intracellulare.
Tetracyclines
Approximately 50% of isolates of the rapidly growing species M. for-
tuitum and 20% of M. chelonae are susceptible to tetracycline.172 Mino-
cycline and doxycycline are twofold to fourfold more active than
tetracycline171 and have been effective in therapy when the isolates were
susceptible in vitro.129 Minocycline and doxycycline are also active
against M. marinum166,174,175 and have been used successfully in M.
marinum infections.148,174 A parenteral tetracycline, tigecycline, with
activity against all rapidly growing mycobacteria, has been marketed.
It is frequently used as part of combination therapy for M. abscessus
lung disease; however, little data are available evaluating its efficacy in
this role.176
Sulfonamides
Sulfamethoxazole is active against M. fortuitum but not against M.
chelonae or M. abscessus.171,172 Localized infections have been cured
with sulfamethoxazole alone or in combination with trimethoprim.129 M.
marinum infections have responded to therapy with trimethoprim-
sulfamethoxazole,148 but strains are susceptible in vitro only against a
low inoculum.155
Both M. marinum and M. kansasii exhibit very similar drug sus-
ceptibilities. Sulfamethoxazole is also active against isolates of M. kan-
sasii. It has been curative in combination regimens used for the
treatment of rifampin-resistant M. kansasii infections.167
Limited experience indicates some in vitro activity and clinical
efficacy of sulfonamides against M. terrae complex, M. haemophilum,
M. simiae, and M. avium-intracellulare.148
Quinolones
The newer fluorinated quinolones (ciprofloxacin, ofloxacin, moxifloxa-
cin, levofloxacin) have in vitro activity against a number of NTM at
 476
achievable serum levels.101,102,172,177 M. fortuitum strains are the most
susceptible, with ciprofloxacin MICs of 0.25 µg/mL or less and good
responses clinically.177 Recent studies have shown levofloxacin to
have comparable activity to ciprofloxacin, while the newer quinolone
Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases
moxifloxacin has twofold to fourfold lower MICs than these older
agents.178 A number of species are inhibited by intermediate concen­
trations of ciprofloxacin (1 to 4 µg/mL). These include M. chelonae
(25%), M. malmoense, M. marinum, M. xenopi, M. kansasii, M. hae-
mophilum, and some strains of M. avium-intracellulare. Again, the
newer quinolones gatifloxacin and moxifloxacin are more active than
ciprofloxacin.158 The clinical efficacy of the quinolones for these
species has yet to be established. Resistance to ciprofloxacin after
monotherapy has been described179 and presumably involves the same
DNA gyrase mutations observed with quinolone resistance with M.
tuberculosis.108
Linezolid
Recent studies have shown that many NTM are inhibited by 8 µg/mL
(susceptible MICs) of linezolid, including M. fortuitum, M. kansasii,
M. marinum, and M. haemophilum. Isolates of M. chelonae are all
susceptible or intermediate to linezolid, and in vitro it is the most active
oral drug available for this species after the macrolides. Isolates of M.
avium complex and M. simiae are usually resistant.180
β-Lactams
All mycobacteria produce β-lactamase, although it can be difficult to
detect in M. avium complex. β-Lactams or combinations of β-lactam/
β-lactamase inhibitors have been shown to be active or useful clini-
cally, however, only for the M. fortuitum complex. Cefoxitin, cef­
metazole, and imipenem-cilastatin are active in vitro against
approximately 80% of M. fortuitum strains and most isolates of M.
abscessus at clinically achievable plasma concentrations.120,181
Clofazimine
Discussed more fully later in the section “Drugs for Treatment of
Leprosy (Hansen’s Disease),” clofazimine (Lamprene) possesses in vitro
activity against M. chelonae, M. abscessus, and M. avium-intracellulare.
Most strains are inhibited by 1.6 to 2.0 µg/mL.148 Clinical experience
with clofazimine in therapy against M. avium in AIDS has been disap-
pointing.148 Clinical experience with M. avium-intracellulare lung
disease has been infrequently reported, although it is used for this
indication with some frequency.
Susceptibility Tests
Standardized methods for susceptibility testing of the NTM were
approved for the first time in 2003 by the CLSI.129 In vitro susceptibility
of NTM drugs is no guarantee of therapeutic efficacy. Previously cited
failures of clofazimine in M. avium-intracellulare infections indicate
limitations in extrapolating in vitro data to clinical experience. As
a rule, favorable therapeutic results are likely when drugs are used
to which NTM are susceptible in vitro, and poor outcomes can be
anticipated when there is in vitro resistance. Least predictable are
outcomes of M. avium-intracellulare infections, for which routine sus-
ceptibility testing is not recommended except for clarithromycin (or
azithromycin).129,130,148
DRUGS FOR TREATMENT OF
LEPROSY (HANSEN’S DISEASE)
Background
The special parasite-host relationship of M. leprae (Hansen’s bacillus),
characterized by persistence of the organism in tissue for years, has
mandated prolonged chemotherapy to prevent relapse. For years,
chemotherapy for leprosy mainly consisted of dapsone alone, which
produced gratifying clinical results and was affordable. However,
because of self-supervised monotherapy, resistance of leprosy bacilli,
both secondary and now primary, became a problem worldwide.182
Currently, multidrug therapy is the rule for both multibacillary and
paucibacillary disease, and this has markedly increased cure rates
and decreased the incidence of drug resistance. The principal agents
used in therapeutic multidrug regimens are dapsone, rifampin, and
clofazimine.
Dapsone
Derivation and Structure.  Dapsone (4,4′-diaminophenyl sulfone), a
synthetic compound, was demonstrated to be effective in rat leprosy
in 1941 and soon thereafter was used successfully in human trials.
Mechanism of Action.  Sulfones inhibit bacterial dihydropteroate
synthase, as do sulfonamides, and presumably inhibit M. leprae by the
same mechanism.
Antimicrobial Activity.  By mouse foot pad inoculation, as little as
0.003 µg/mL of dapsone is estimated to inhibit multiplication of M.
leprae. Dapsone has been described as “weakly bactericidal” for sus-
ceptible leprosy bacilli. In humans, it has been estimated that 99.9% of
bacillary populations are killed after 3 to 4 months of dapsone
therapy.183 In lepromatous (multibacillary) patients on monotherapy,
secondary dapsone resistance often emerges 5 to 24 years after begin-
ning therapy.184 Before the usage of current standard multidrug regi-
mens, secondary resistance occurred in approximately 20% of cases.
Pharmacology.  Dapsone is well absorbed orally. Distributed
throughout body fluids, tissue concentrations are approximately 2 µg/
mL. The plasma half-life of dapsone is 21 to 44 hours, with some drug
retention for up to 3 weeks. Dapsone becomes acetylated, with 70% to
80% excreted as metabolites in urine. The dosage should be reduced
accordingly in renal failure.
Adverse Reactions.  An oxidant drug, dapsone produces dose-
dependent hemolysis, which is not of clinical consequence in patients
without a hematologic disorder taking dapsone 50 to 100 mg daily.
Hemolysis is greatly enhanced in patients with glucose-6-phosphate
dehydrogenase deficiency, especially in its severe forms. Gastrointesti-
nal intolerance occurs with resulting anorexia, nausea, or vomiting.
Hematuria, fever, pruritus, rashes, and granulocytopenia can occur.
Dapsone is now being used in AIDS patients as prophylaxis and
treatment of Pneumocystis jirovecii pneumonia. These patients usually
have preexisting anemia, making dapsone-induced hemolysis less
well tolerated. Conversion of up to 20% of erythrocyte hemoglobin
to methemoglobin can occur with dapsone doses of 100 mg daily.
Although methemoglobinemia is usually asymptomatic, it may become
of clinical consequence if the patient develops hypoxemia from lung
disease. Rash is common in this patient population. In one study using
dapsone, 100 mg daily, for prophylaxis, 33 of 47 patients discontinued
the drug.185
In leprosy patients, reactions with dapsone may be difficult to extri-
cate from the reactions attendant with the disease itself.186 A sulfone
syndrome occurring 5 to 6 weeks after the initiation of therapy can be
characterized by fever, jaundice, dermatitis, and lymphadenopathy—a
presentation not unlike that of infectious mononucleosis.187 During
initial dapsone therapy, erythema nodosum leprosum reactions com-
monly become manifest in those with multibacillary disease.
Usage.  Dapsone and rifampin are the principal therapeutic agents
for the treatment of both multibacillary and paucibacillary M. leprae
infections. Usage in prophylaxis or treatment of P. jirovecii pneumonia
(PCP) is discussed in Chapter 271. Dapsone is also useful in dermatitis
herpetiformis, a subject beyond the scope of this chapter.
Availability and Dosage.  Dapsone is available generically in
tablets of 25 or 100 mg. The adult daily dose is 100 mg, and for children
it is 1.0 to 1.5 mg/kg/day. It is administered daily for 6 months in
paucibacillary disease and for a minimum of 2 years in multibacillary
disease.
Rifampin
Mechanism of Action and Resistance.  The mechanism of action of
rifampin is presumed to be inhibition of M. leprae DNA-dependent
RNA polymerase that produces a relatively rapid bactericidal effect. Its
inhibitory concentration of human strains of M. leprae tested in mice
is 0.3 µg/mL. Acquired rifampin resistance is caused by mutational
changes in RNA polymerase.188
Usage.  Clinical usage of rifampin has confirmed that it is more
bactericidal by several orders of magnitude than all other antileprosy
drugs either alone or in combination. It is considered the only rapidly
bactericidal drug against M. leprae. Using a skin biopsy assay, a single
1500-mg dose of rifampin was determined to reduce the viability of
leprosy bacilli to undetectable levels by 3 to 5 days.189 Despite such a
dramatic impact on numbers of tissue M. leprae, rifampin must be

employed with one or more companion drugs to prevent the develop-
ment of resistance.183 The high cost of rifampin has discouraged daily
usage in economically disadvantaged regions. However, once-monthly
therapy with 600 to 1200 mg of rifampin in combination drug regi-
mens has produced satisfactory clinical responses with a minimum of
adverse reactions.190 Current recommendations are that rifampin
should be administered in a single monthly supervised dose of 600 mg.
This dosage is continued for 6 months in paucibacillary disease and for
a minimum of 2 years in multibacillary disease. In the United States,
rifampin is given as a 600-mg daily dose in both of the settings
described. Reversal and erythema nodosum leprosum reactions with
rifampin have been comparable or less severe than with sulfones alone.
Daily rifampin treatment may reduce both the serum levels and sub-
sequently the beneficial effects of corticosteroids for reactions by
inducing hepatic microsomal enzymes.
Clofazimine (Lamprene)
Derivation and Structure.  Clofazimine is a phenazine dye.
Mechanism of Action and Antimicrobial Activity.  Clofazimine’s
precise mechanism of action is unknown. Highly lipophilic and bound
to mycobacterial DNA, clofazimine is weakly bactericidal against M.
leprae. Its action may relate to iron chelation with resulting production
of nascent oxygen radicals intracellularly.191 The inhibitory concentra-
tion of clofazimine in mouse tissue is between 0.1 and 1.0 mg/kg. A
delay of some 50 days ensues before tissue antimicrobic activity can be
demonstrated in humans. Owing to new limited availability in the
United States, the drug is now available only under a research protocol
and in that respect is again considered “investigational” despite many
years of use as a routine antibiotic.
Pharmacology.  Clofazimine pharmacokinetics are complex.
Absorption is quite variable, with 9% to 74% of an administered dose
appearing in feces. Oral administration results in plasma concentra-
tions of 0.4 to 3 µg/mL with a half-life of approximately 70 days.
Clofazimine is widely distributed throughout reticuloendothelial
tissues, especially liver, spleen, lung, adrenals, adipose tissue, and skin
lesions. Red-orange phagocytized crystals of clofazimine are observed
microscopically in macrophages. It is largely unmetabolized and sub-
sequently slowly excreted with less than 1% in urine. Biliary excretion
appears to be the major route of excretion. Excretion also occurs in
breast milk. Dosage of 100 mg/day has been calculated to result even-
tually in a total accumulation of at least 10 g in human tissue.
Adverse Reactions.  Gastrointestinal intolerance (anorexia, diar-
rhea, abdominal pain) is the most common therapy-limiting side effect
and is generally dose related. Dry mouth and skin may occur. Skin
pigmentation is quite common, resulting from drug accumulation and
producing red-brown to nearly black discoloration, especially in dark-
skinned persons. It is only partly reversible.
Usage.  Clofazimine’s current role is principally in combination
with rifampin and dapsone for multibacillary disease. It is also used in
combination for sulfone-resistant infections and for individuals who
are intolerant to sulfones, usually because of severe sulfone-associated
erythema nodosum leprosum or reversal reactions. Such reactions
occur much less often with clofazimine than with dapsone,192 possibly
because of anti-inflammatory properties of clofazimine.
Availability and Dosage.  Clofazimine is supplied in 50- and
100-mg capsules. For multibacillary disease, it is administered in a
dosage of 50 mg/day for a minimum of 2 years in combination with
rifampin and dapsone. A dapsone alternative dosage has usually been
100 to 300 mg/day.
Additional or Second-Line Drugs
Thiacetazone (Amithiozone)
Thiacetazone’s efficacy is greater in tuberculoid (paucibacillary) than
in lepromatous (multibacillary) disease. It can be administered when
sulfones are not tolerated. Considerable cross-resistance occurs with
sulfones. Thiacetazone is unavailable in the United States.
Ethionamide and Protionamide
Ethionamide (Trecator-SC) is described under “Second-Line Antitu-
berculous Drugs.” It and its congener protionamide (which is unavail-
able in the United States) possess similar pharmacokinetics and dosing
477
and provide alternatives to clofazimine in multidrug regimens for mul-
tibacillary disease in those who are unable to tolerate clofazimine or
refuse it because of skin pigmentation. Ethionamide and protionamide
are apparently weakly bactericidal against M. leprae. Ethionamide is
Chapter 38  Antimycobacterial Agents
provided in 250-mg tablets. The usual dosage is 250 mg daily. Both
agents are expensive and cause considerable gastrointestinal intoler-
ance and occasional hepatitis.
Other Substituted Rifamycins
Rifabutin (Mycobutin) and rifapentine (Priftin) are substituted rifamy-
cins that are active against M. leprae. Both are approved for the treat-
ment of tuberculosis by the FDA. In mice, these compounds are even
more active than rifampin,193 which raises interest in their use, espe-
cially in intermittent regimens.
Other Sulfones
Acedapsone
Acedapsone (4,4′-diacetyldiaminodiphenyl sulfone) is a long-acting
intramuscular repository derivative of dapsone. The parent compound
possesses little activity against M. leprae but is metabolized into active
dapsone. Its half-life is 46 days, and that of the derived dapsone is 43
days.194 A 300-mg intramuscular dose maintains dapsone levels in
volunteers above the inhibitory concentration for M. leprae for approx-
imately 100 days. Microbiologic and clinical responses are somewhat
slower than those for daily dapsone. Long-term studies with acedap-
sone by injection five times yearly have yielded encouraging results.
Acedapsone shows promise especially in regions where, or in patients
in whom, long-term oral therapy is not practical.
Sulfoxone
Less well absorbed and more expensive than dapsone, sulfoxone, a
disubstituted sulfone, may be better tolerated gastrointestinally. It is
formulated in 165-mg enteric-coated tablets, with a usual daily dosage
of 300 mg.194
Newer Agents
Several other agents have shown promising activity against M. leprae
in mouse foot pad models and early clinical trials. Among these are
included minocycline (Minocin),195 clarithromycin (Biaxin),195 and
fluorinated quinolones—pefloxacin, ofloxacin (Floxin),196 and espe-
cially sparfloxacin.197 Their roles in replacing drugs in existing multi-
drug regimens remain to be determined, although none of these agents
appears to be as bactericidal against M. leprae as rifampin and neither
pefloxacin nor sparfloxacin is on the market. Current efforts with these
newer agents are also focusing on short-course therapy198 rather than
the current standard 2-year regimens.
Chemotherapy-Associated Reactions  
in Leprosy
Febrile reactions in leprosy can be ameliorated with acetylsalicylic acid
(aspirin) in conventional dosage. Immunologic reactions are common
during chemotherapy. “Reversal” reactions associated with swelling
and edema in preexisting skin lesions or peripheral neuropathy in
more severe reactions usually occur in the first year of therapy. Corti-
costeroids such as prednisone, 40 to 80 mg/day initially with subse-
quent tapering of dosage, have been reasonably efficacious for reversal
reactions. Thalidomide is not used for reversal reactions.
For patients with erythema nodosum leprosum reactions, thalido-
mide in an initial dosage of 100 mg four times a day is the treatment
of choice. Its beneficial effect for these reactions appears to be mediated
by the inhibition of tumor necrosis factor-α.199 Treatment is initiated
at 400 mg/day to attain control of the disease but should then be
tapered over the first week, with a maintenance dose of 50 to 100 mg/
day. Thalidomide is commercially available for the treatment of leprosy,
but its usage is tightly regulated (see Chapter 252). Because of its
marked teratogenicity, thalidomide should never be administered to
women of childbearing potential. In patients with erythema nodosum
leprosum for whom thalidomide is unacceptable, high-dose predni-
sone offers an alternative. Patients who manifest puzzling or severe
reactions are best managed by specialists such as those at the Hansen’s
Disease Clinic in Carville, Louisiana.166
 478
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