ANTI-

MYCOBACTERIAL
DRUGS
Dr. Liaqat Hussain
 Learning
Objectives
 Discussion about Tuberculosis and its causative
agent
 Identify the 1st, 2nd line anti-TB drugs
 Discuss rationale of combination drug therapy in TB
 Detail pharmacology of all these drugs
 Identifying important adverse effects and drug-drug
interaction.
 Discuss emergence of resistance while using anti-
TB drugs.
 Introduction
 It is an infectious bacterial disease that is caused by
the mycobacterium tuberculosis, commonly called
TB. It is chronic granulomatous disease. (as
discussed in pathology).
 It mostly effects lung called pulmonary tuberculosis,
but it can also occur in bones, kidney, intestine,
meninges and genitourinary.
 Mycobacterium tuberculosis is slow growing, obligate
aerobic bacilli, grow in straight or branching chains
 Intrinsically resistant to most antibiotics
 Intracellular organism resides in macrophage
 Can also be dormant and is agile in developing
resistance
Having unique waxy cell wall, offering
impermeability to most of the antibiotics
 Primary phase
 Mycobacterium spread through droplet from infected to healthy
individual----------------taken up by macrophages at this initial stage
macrophages are not activated,
 thus infection continue progressing----------macrophages are activated.
 Ingest bacterium----get segregated-----lesion become enlarged.
 These changes results in formation of a large complex----still the
disease might be asymptomatic
 Latent phase
 This phase usually occurs after 3 weeks of exposure
 stimulation of T-cell mediated immunity
 Formation of granuloma (tubercles) inside tubercles cannot multiply----
may persist for extended time periods might be to years might be
asymptomatic----all depends upon host defense.
 Symptoms (Active TB)
 Weight loss-----fatigue-----weakness------fever especially evening fever and daily basis
 night sweating
 chronic non-productive cough that becomes purulent productive cough with sputum
with passage of time
 Symptoms are organ specific for bone TB different symptoms

■ Risk factors
■ Compromised immunity due to disease like AIDS or taking immunosuppressant
medicines for various diseases like rheumatoid arthritis, SLE,IBD

■ Diagnostic methods
 Blood tests, imaging, bronchoscopy, sputum analysis, skin test
 Mantoux test: PPD (purified protein derivative)
 Mantoux test, which is administered by injecting a 0.1 mL of liquid containing 5 TU
(tuberculin units) PPD (purified protein derivative) into the top layers of skin of the
forearm. Doctors should read skin tests 48-72 hours after the injection.
 Why difficulty to treat Mycobacterium?
 Mycobacteria are intrinsically resistant to most antibiotics.
 Because they grow more slowly than other bacteria, antibiotics that
are most active against rapidly growing cells are relatively ineffective.
 Mycobacterial cells can also be dormant and, thus, resistant to many
drugs or killed only very slowly. The lipid-rich mycobacterial cell wall is
impermeable to many agents.
 Mycobacterial species are intracellular pathogens, and organisms
residing within macrophages are inaccessible to drugs that penetrate
these cells poorly.
 Finally, mycobacteria are notorious for their ability to develop
resistance.
 Combinations of two or more drugs are required to overcome these
obstacles and to prevent emergence of resistance during the course of
therapy.
 The response of mycobacterial infections to chemotherapy is slow,
 Drugs Classification
 1st line agents
 Isoniazid, Rifampin, Pyrazinamide, Ethambutol,

 2nd line agents

 Streptomycin, Ethionamide, capreomycin, cycloserine, Para amino salicylic acid
(PAS), Fluoroquinolones, Amikacin-kanamycin, Rifabutin, Linezolid etc
 Treatment protocols
 Isoniazid and rifampin are the most active drugs.
 An isoniazid-rifampin combination administered for 9 months will cure 95–
98% of cases of tuberculosis caused by susceptible strains.
 An initial intensive phase of treatment is recommended for the first 2
months due to the prevalence of resistant strains.
 The addition of pyrazinamide during this intensive phase allows the total
duration of therapy to be reduced to 6 months without loss of efficacy.
 In practice, therapy is usually initiated with a four-drug regimen.
 In susceptible isolates, the continuation phase consists of an additional 4
months with isoniazid and rifampin.
 Neither ethambutol nor other drugs such as streptomycin adds substantially
to the overall activity of the regimen (ie, the duration of treatment cannot
be further reduced if another drug is used), but the fourth drug provides
additional coverage if the isolate proves to be resistant to isoniazid,
rifampin, or both.
 If therapy is initiated after the isolate is known to be susceptible to isoniazid
 ISONIAZID
 Isoniazid is the most active drug for the treatment of tuberculosis
caused by susceptible strains.
 It is a small molecule that is freely soluble in water.
 In vitro, isoniazid inhibits most tubercle bacilli at a concentration of 0.2
mcg/mL or less and is bactericidal for actively growing tubercle bacilli.
 Isoniazid penetrates into macrophages and is active against both
extracellular and intracellular organisms.
Mechanism of Action & Basis of Resistance
 Isoniazid inhibits synthesis of mycolic acids, which are essential
components of mycobacterial cell walls.
 Isoniazid is a prodrug that is activated by KatG, the mycobacterial
catalase-peroxidase.
 The activated form of isoniazid forms a covalent complex with an acyl
carrier protein (AcpM) and KasA, a beta-ketoacyl carrier protein
synthetase, which blocks mycolic acid synthesis. .
 Resistance
 isoniazid is associated with mutations resulting in
overexpression of inh A,
 which encodes an NADH-dependent acyl carrier protein
reductase;
 mutation or deletion of the katG gene;
 promoter mutations resulting in overexpression of ahpC, a
gene involved in protection of the cell from oxidative stress;
 and mutations in kasA and Overproducers of inhA express
low-level isoniazid resistance and cross-resistance to
ethionamide.
 KatG mutants express high-level isoniazid resistance and
often are not cross-resistant to ethionamide.
 Drug-resistant mutants are normally present in susceptible
■ Since tuberculous lesions often contain more than 108 tubercle bacilli, resistant
mutants are readily selected if isoniazid or any other drug is given as a single
agent.
■ The use of two independently acting drugs in combination is much more
effective.
■ The probability that a bacillus is initially resistant to both drugs is approximately
1 in 106 × 106, or 1 in 1012, several orders of magnitude greater than the
number of infecting organisms.
■ Thus, at least two active agents should always be used to treat active
tuberculosis to prevent emergence of resistance during therapy.
■Pharmacokinetics
■ Isoniazid is readily absorbed from the gastrointestinal tract, optimally on an
empty stomach; peak concentrations may be decreased by up to 50% when
taken with a fatty meal.
■ A 300 mg oral dose (5 mg/kg in children) achieves peak plasma concentrations
of 3–5 mcg/mL within 1–2 hours.
■ Isoniazid diffuses readily into all body fluids and tissues.
■ The concentration in the CNS and CSF ranges between 20% and 100% of
 Metabolism of isoniazid, especially acetylation by liver N-
acetyltransferase.
 The average plasma concentration of isoniazid in rapid
acetylators is about one third to one half of that in slow
acetylators, and average half-lives are less than 1 hour and 3
hours, respectively.
 More rapid clearance of isoniazid by rapid acetylators is
usually of no therapeutic consequence when appropriate
doses are administered daily,
 but sub-therapeutic concentrations may occur if drug is
administered as a once-weekly dose or if there is
malabsorption.
 Isoniazid metabolites and a small amount of unchanged drug
are excreted in the urine.
 The dosage need not be adjusted in renal failure.
 Isoniazid inhibits several cytochrome P450 enzymes, leading
to increased concentrations of such medications as phenytoin,
carbamazepine, and benzodiazepines.
 However, when used in combination with rifampin, a potent
CYP enzyme inducer, the concentrations of these medications
are usually decreased.
 Clinical Uses
 The typical dosage of isoniazid is 5 mg/kg/d; a typical adult
dose is 300 mg given once daily.10 mg/kg/d for serious
infections or if malabsorption is a problem.
 A 15-mg/kg dose, or 900 mg, may be used in a twice to three
times-weekly dosing regimen in combination with a second
anti-tuberculous agent (eg, rifampin, 600 mg).
 Pyridoxine, 25–50 mg/d, is recommended for those with
conditions predisposing to neuropathy, an adverse effect of
 Isoniazid is usually given by mouth but can be given parenterally in
the same dosage.
 Isoniazid as a single agent is also indicated for treatment of latent
tuberculosis. The dosage is 300 mg/d (5 mg/kg/d) or 900 mg twice
weekly, and the duration is usually 9 months.
 Adverse Reactions
 A. Immunologic Reactions
 Fever and skin rashes are occasionally seen.
 Drug-induced systemic lupus erythematosus reported.
 B. Direct Toxicity
 Isoniazid-induced hepatitis is the most common major toxic effect.
 This is distinct from the minor increases in liver aminotransferases
 (up to three or four times normal), 10–20% of patients, who usually
are asymptomatic.
 Clinical hepatitis with loss of appetite, nausea, vomiting, jaundice,
and right upper quadrant pain occurs in 1% of isoniazid recipients
and can be fatal, particularly if the drug is not discontinued
promptly.
 There is histologic evidence of hepatocellular damage and necrosis.
 The risk of hepatitis depends on age. It occurs rarely under age 20,
in 0.3% of those age 21–35, 1.2% of those age 36–50, and 2.3% for
those age 50 and above.
 The risk of hepatitis is greater in individuals with alcohol
dependence and possibly during pregnancy and the postpartum
period.
 Development of isoniazid hepatitis contraindicates further use of
the drug.
 Peripheral neuropathy is observed in 10–20% of patients given
dosages greater than 5 mg/kg/d, but it is infrequently seen with the
standard 300-mg adult dose.
 Isoniazid promotes excretion of pyridoxine, and this toxicity is
readily reversed by administration of pyridoxine in a dosage as
low as 10 mg/d.
 Central nervous system toxicity, which is less common, includes
memory loss, psychosis, ataxia, and seizures.
 These effects may also respond to pyridoxine.
 Miscellaneous other reactions include hematologic abnormalities,
provocation of pyridoxine deficiency anemia, tinnitus, and
gastrointestinal discomfort.
 RIFAMPIN
 Rifampin is a semisynthetic derivative of rifamycin, an
antibiotic produced by Amycolatopsis rifamycinica.
 It is active in vitro against Gram-positive organisms, some
Gram-negative organisms, such as Neisseria and Haemophilus
species, mycobacteria, and chlamydiae.
 Mechanism of Action, Resistance, & Pharmacokinetics
 Rifampin binds to the β subunit of bacterial DNA-dependent
RNA polymerase and thereby inhibits RNA synthesis.
 Resistance results from any one of several possible point
mutations in rpo B, the gene for the β subunit of RNA
polymerase.
 These mutations result in reduced binding of rifampin to RNA
polymerase.
 Human RNA polymerase does not bind rifampin and is not
 Rifampin is bactericidal for mycobacteria.
 It readily penetrates most tissues and penetrates into phagocytic
cells.
 It can kill organisms that are poorly accessible to many other drugs,
such as intracellular organisms and those sequestered in abscesses
and lung cavities.
 Rifampin is well absorbed after oral administration and excreted
mainly through the liver into bile.
 It then undergoes enterohepatic recirculation, with the bulk excreted
as a deacylated metabolite in feces and a small amount excreted in
the urine.
 Dosage adjustment for renal or hepatic insufficiency is not
necessary.
 Rifampin is distributed widely in body fluids and tissues.
 The drug is relatively highly protein-bound, and adequate
cerebrospinal fluid concentrations are achieved only in the presence
 Rifampin strongly induces most cytochrome P450 isoforms
(CYP1A2, 2C9, 2C19, 2D6, and 3A4),
 which increases the elimination of numerous other drugs
including methadone, anticoagulants, cyclosporine, some
anticonvulsants, protease inhibitors, some nonnucleoside reverse
transcriptase inhibitors or integrase strand transfer inhibitors,
contraceptives,
 Co-administration of rifampin results in significantly lower serum
levels of these drugs.
 Clinical Uses
 A. Mycobacterial Infections
 Rifampin, usually 600 mg/d (10 mg/kg/d) orally, must be
administered with isoniazid or other anti-tuberculous drugs to
patients with active tuberculosis to prevent emergence of drug
resistant mycobacteria.
 In some short-course therapies, 600 mg of rifampin is given
 Rifampin, 600 mg daily or twice weekly for 6 months, also is
effective in combination with other agents in some atypical
mycobacterial infections and in leprosy.
 Rifampin, 600 mg daily for 4 months as a single drug, is an
alternative to isoniazid for patients with latent tuberculosis who
are unable to take isoniazid or who have had exposure to a case
of active tuberculosis caused by an isoniazid-resistant, rifampin-
susceptible strain.
 B. Other Indications
 Rifampin has other uses in bacterial infections. An oral dosage of
600 mg twice daily for 2 days can eliminate meningococcal
carriage.
 Rifampin, 20 mg/kg (maximum 600 mg) once daily for 4 days, is
used as prophylaxis in contacts of children with Haemophilus
influenzae type b disease.
 Rifampin combined with a second agent is sometimes used to
 Rifampin combination therapy is also used for treatment of
serious staphylococcal infections such as
 osteomyelitis, prosthetic joint infections, and prosthetic valve
endocarditis.
 Adverse Reactions
 Rifampin imparts a harmless orange color to urine, sweat, and
tears (soft contact lenses may be permanently stained).
 Occasional adverse effects include rashes, thrombocytopenia,
and nephritis.
 Rifampin may cause cholestatic jaundice and occasionally
hepatitis, and it commonly causes light-chain proteinuria.
 If administered less often than twice weekly, rifampin may cause
a flu-like syndrome characterized by fever, chills, myalgias,
anemia, and thrombocytopenia.
 Its use has been associated with acute tubular necrosis.
 ETHAMBUTOL
 Ethambutol is a synthetic, water-soluble, heat-stable compound,
the dextro-isomer of the structure shown above, dispensed as
the dihydrochloride salt.
 Mechanism of Action & Clinical Uses
 Ethambutol inhibits mycobacterial arabinosyl transferases, which
are encoded by the emb CAB operon.
 Arabinosyl transferases are involved in the polymerization
reaction of arabinoglycan, an essential component of the
mycobacterial cell wall.
 Resistance to ethambutol is due to mutations resulting in
overexpression of emb gene products or within the emb B
structural gene.
 Susceptible strains of Mycobacterium tuberculosis and other
mycobacteria are inhibited in vitro by ethambutol, 1–5 mcg/mL.
■ Ethambutol is well absorbed from the gut.
■ After ingestion of 25 mg/kg, a blood level peak of 2–5 mcg/mL is
reached in 2–4 hours.
■ About 20% of the drug is excreted in feces and 50% in urine in
unchanged form.
■ Ethambutol accumulates in renal failure, and the dose should be
reduced to three times weekly if creatinine clearance is less than 30
mL/min.
■ Ethambutol crosses the blood brain barrier only when the meninges
are inflamed.
■ Concentrations in cerebrospinal fluid are highly variable, ranging
from 4% to 64% of serum levels in the setting of meningeal
inflammation.
■ As with all antituberculous drugs, resistance to ethambutol emerges
rapidly when the drug is used alone.
■ Therefore, ethambutol is always given in combination with other
 Ethambutol hydrochloride, 15–25 mg/kg, is usually given as a
single daily dose in combination with isoniazid, rifampin, and
pyrazinamide during the initial intensive phase of active
tuberculosis treatment.
 The higher dose may be used for treatment of tuberculous
meningitis.
 Ethambutol is also used in combination with other agents for the
treatment of nontuberculous mycobacterial infections, such as
Mycobacterium avium complex (MAC) or M. kansasii; the typical
dose for these infections is 15 mg/kg once daily.
 Adverse Reactions
 Hypersensitivity to ethambutol is rare.
 The most common serious adverse event is retrobulbar neuritis,
resulting in loss of visual acuity and red-green color blindness.
 This dose-related adverse effect is more likely to occur at
dosages of 25 mg/kg/d continued for several months.
 At 15 mg/kg/d or less, visual disturbances occur in
approximately 2% of patients, typically after at least one month
of treatment.
 Experts recommend baseline and monthly visual acuity and
color discrimination testing, with particular attention to patients
on higher doses or with impaired renal function.
 Ethambutol is relatively contraindicated in children too young to
permit assessment of visual acuity and red-green color
discrimination.
 PYRAZINAMIDE
 Pyrazinamide (PZA) is a relative of nicotinamide, and it is used
only for treatment of tuberculosis.
 It is stable and slightly soluble in water. It is inactive at neutral
pH, but at pH 5.5 it inhibits tubercle bacilli at concentrations of
approximately 20 mcg/mL.
 The drug is taken up by macrophages and exerts its activity
against mycobacteria residing within the acidic environment of
lysosomes.
 Mechanism of Action & Clinical Uses
 Pyrazinamide is converted to pyrazinoic acid—the active form of
the drug—by mycobacterial pyrazinamidase, which is encoded
by pnc A.
 Pyrazinoic acid disrupts mycobacterial cell membrane
metabolism and transport functions.
 Serum concentrations of 30–50 mcg/mL at 1–2 hours after oral
administration are achieved with dosages of 25 mg/kg/d.
 Pyrazinamide is well absorbed from the gastrointestinal tract and
widely distributed in body tissues, including inflamed meninges.
 The half-life is 8–11 hours.
 The parent compound is metabolized by the liver, but
metabolites are renally cleared; therefore, PZA should be
administered at 25–35 mg/kg three times weekly (not daily) in
hemodialysis patients and those in whom the creatinine
clearance is less than 30 mL/min.
 In patients with normal renal function, a dose of 30–50 mg/kg is
used for thrice-weekly or twice-weekly treatment regimens.
 Pyrazinamide is an important front-line drug used in conjunction
with isoniazid and rifampin in short-course (ie, 6-month)
regimens as a “sterilizing” agent active against residual
intracellular organisms that may cause relapse.
 Tubercle bacilli develop resistance to pyrazinamide fairly
readily, but there is no cross-resistance.
 Adverse Reactions
 Major adverse effects of PZA include hepatotoxicity (in 1–5%
of patients), nausea, vomiting, drug fever, photosensitivity,
and hyperuricemia.
 The latter occurs uniformly and is not a reason to halt
therapy if patients are asymptomatic.
 SECOND-LINE DRUGS FOR TUBERCULOSIS
 The alternative drugs listed below are usually considered only
 (1) in case of resistance to first-line agents;
 (2) in case of failure of clinical response to conventional therapy;
and
 (3) in case of serious treatment-limiting adverse drug reactions.
 Expert guidance is desirable in dealing with the toxic effects of
these second-line drugs.
 For many drugs listed in the following text, the dosage,
emergence of resistance, and long-term toxicity have not been
fully established.
 Streptomycin, Capreomycin, cycloserine, Para aminosalicylic acid
(PSA), Flouroquinolones, linezolid, Rifabutin, Rifapentin,
Bedaquiline
 Capreomycin
 Capreomycin is a peptide protein synthesis inhibitor antibiotic
obtained from Streptomyces capreolus.
 It is an important injectable agent for treatment of drug-resistant
tuberculosis.
 Strains of M tuberculosis that are resistant to streptomycin
usually are susceptible to capreomycin, though some data
suggest cross-resistance with strains resistant to amikacin and
kanamycin.
 Resistance to capreomycin, when it occurs, has been associated
with rrs, eis, or tlyA gene mutations.
 Capreomycin is nephrotoxic and ototoxic.
 Tinnitus, deafness, and vestibular disturbances occur.
 The injection causes significant local pain, and sterile abscesses
may develop.
 Amino salicylic Acid (PAS)
 Amino salicylic acid is a folate synthesis antagonist that is active
almost exclusively against M tuberculosis.
 It is structurally similar to p-amino-benzoic acid (PABA) and is
thought to have a similar mechanism of action to the
sulfonamides .
 PAS is commercially available as a 4-g packet of delayed release
granules.
 In order to protect the integrity of the delayed release coating,
the granules must be administered sprinkled over apple sauce
or yogurt, or swirled in fruit juice and swallowed whole.
 Tubercle bacilli are usually inhibited in vitro by amino salicylic
acid, 1–5 mcg/mL.
 The granule formulation of amino salicylic acid results in
improved absorption from the gastrointestinal tract.
 Peak serum levels are expected to be 20–60 mcg/mL 6 hours
after a 4 g oral dose.
 The dosage is 8–12 g/d orally for adults and 300 mg/kg/d for
children, administered in two or three divided doses.
 The drug is widely distributed in tissues and body fluids except
the cerebrospinal fluid.
 Aminosalicylic acid is rapidly excreted in the urine,
 Very high concentrations of PAS are reached in the urine, which
can result in crystalluria.
 Peptic ulceration and hemorrhage may occur.
 Hypersensitivity reactions manifested by fever, joint pains, skin
rashes, hepatosplenomegaly, hepatitis, adenopathy, and
granulocytopenia often occur after 3–8 weeks of PAS therapy,
 Rifabutin
 Rifabutin is derived from rifamycin and is related to rifampin.
 It has significant activity against M tuberculosis, MAC, and
Mycobacterium fortuitum .
 Its activity is similar to that of rifampin, and cross-resistance with
rifampin is virtually complete..
 it is a less potent inducer of P450 enzymes rifabutin is often
used in place of rifampin for treatment of tuberculosis in patients
with HIV infection
 who are receiving antiretroviral therapy with a protease
inhibitor, a non-nucleoside reverse transcriptase inhibitor (eg,
 Bedaquiline
 Bedaquiline, a di-arylquinoline, is the first drug with a novel
mechanism of action against M tuberculosis.
 Bedaquiline inhibits adenosine 5′-triphosphate (ATP) synthase in
mycobacteria, has in vitro activity against both replicating and
nonreplicating bacilli, and has bactericidal and sterilizing activity
in the murine model of tuberculosis.
 Used in combination with at least three other active
medications, may be used for 24 weeks of treatment in adults
with laboratory-confirmed pulmonary tuberculosis if the isolate is
resistant to both isoniazid and rifampin.
 The recommended dosage for bedaquiline is 400 mg once daily
orally for 2 weeks, followed by 200 mg three times a week for 22
weeks taken orally with food in order to maximize absorption.
 Adverse effects are nausea, arthralgia, and headache.
 DRUGS ACTIVE AGAINST NON-TUBERCULOUS
MYCOBACTERIA
 M avium complex (MAC), which includes both M avium and M
intracellulare, is an important and common cause of
disseminated disease in late stages of AIDS (CD4 counts <
50/μL).
 MAC is much less susceptible than M tuberculosis to most
antituberculous drugs.
 Combinations of agents are required to suppress the infection.
 Azithromycin, 500–600 mg once daily, or clarithromycin, 500 mg
twice daily, plus ethambutol, 15 mg/kg/d, is an effective and
well-tolerated regimen for treatment of disseminated disease.
third agent, especially rifabutin, 300 mg once daily.
 Azithromycin and clarithromycin are the prophylactic drugs of
choice for preventing disseminated MAC in AIDS patients with
CD4 cell counts less than 50/μL.
 DRUGS USED IN LEPROSY
 Mycobacterium leprae has never been grown in vitro, but animal
models, such as growth in injected mouse footpads, have
permitted laboratory evaluation of drugs.
 Because of increasing reports of dapsone resistance, treatment
of leprosy with combinations of the drugs listed below is
recommended.
 DAPSONE & OTHER SULFONES
 The most widely used is dapsone (di-amino-diphenylsulfone).
 Like the sulfonamides, it inhibits folate synthesis.
 Resistance can emerge in large populations of M leprae, eg, in
lepromatous leprosy, particularly if low doses are given.
 Therefore, the combination of dapsone, rifampin, and clofazimine
is recommended for initial therapy of lepromatous leprosy
 A combination of dapsone plus rifampin is commonly used for
 Dapsone may also be used to prevent and treat Pneumocystis
jiroveci pneumonia in AIDS patients.
 Sulfones are well absorbed from the gut and widely distributed
throughout body fluids and tissues.
 Dapsone’s half-life is 1–2 days, and drug tends to be retained in
skin, muscle, liver, and kidney.
 Skin heavily infected with M leprae may contain several times
more drug than normal skin.
 Sulfones are excreted into bile and reabsorbed in the intestine.
 Excretion into urine is variable, and most excreted drug is
acetylated.
 In renal failure, the dose may have to be adjusted.
 The usual adult dosage in leprosy is 100 mg daily.
 For children, the dose is proportionately less, depending on weight.
 Dapsone is usually well tolerated. Many patients develop some
hemolysis, particularly if they have glucose-6-phosphate
dehydrogenase deficiency.
 Methemoglobinemia is common but usually is not clinically
significant.
 Gastrointestinal intolerance, fever, pruritus, and rash occur.
 During dapsone therapy of lepromatous leprosy, erythema
nodosum leprosum often develops.
 It is sometimes difficult to distinguish reactions to dapsone from
manifestations of the underlying illness.
 RIFAMPIN
 Rifampin in a dosage of 600 mg daily is highly effective in leprosy and
is given with at least one other drug to prevent emergence of
resistance.
 Even a dose of 600 mg per month may be beneficial in combination
therapy.
 CLOFAZIMINE
 Clofazimine is a phenazine dye used in the treatment of multibacillary
leprosy, which is defined as having a positive smear from any site of
infection.
 Its mechanism of action has not been clearly established.
 Absorption of clofazimine from the gut is variable, and a major portion
of the drug is excreted in feces.
 Clofazimine is stored widely in reticuloendothelial tissues and skin, and
its crystals can be seen inside phagocytic reticuloendothelial cells.
 It is slowly released from these deposits, so the serum half-life may be
 A common dosage of clofazimine is 100–200 mg/d orally.
 The most prominent adverse effect is discoloration of the skin
and conjunctiva.
 Gastrointestinal side effects are common.
 This medication is no longer commercially available, but it can
be obtained through established programs.
 For example, an investigational new drug (IND) program is
established in the USA through the National Hansen’s Disease
Program. Internationally, ministries of health can make requests
directly to the World Health Organization.
■ Case study:
■ A 60-year-old man presents to the emergency department with a 2-
month history of fatigue, weight loss (10 kg), fevers, night sweats, and
a productive cough. He is currently living with friends and has been
intermittently homeless, spending time in shelters. He reports drinking
about 6 beers per day. In the emergency department, a chest x-ray
shows a right apical infiltrate.
■ Given the high suspicion for pulmonary tuberculosis, the patient is
placed in respiratory isolation. His first sputum smear shows many
acid-fast bacilli, and a HIV test returns with a positive result.
1. What drugs should be started for treatment of presumptive pulmonary
tuberculosis?
2. Does the patient have a heightened risk of developing medication
toxicity?
3. If so, which medication(s) would be likely to cause toxicity?
■ The patient should be started on four-drug therapy with rifampin, isoniazid,
pyrazinamide, and ethambutol. He should also be started on antiretroviral therapy
for HIV.
■ If a protease inhibitor- based antiretroviral regimen is used to treat his HIV, rifabutin
should replace rifampin because of the serious drug-drug interactions between
rifampin and protease inhibitors.
■ If dolutegravir is chosen, it must be administered twice daily due to the interaction
with rifampin; alternatively, rifabutin can be used in place of rifampin, and
dolutegravir can be dosed once daily.
■ The patient is at increased risk of developing hepatotoxicity from both isoniazid and
pyrazinamide given his history of alcohol use.