Reference: Chapter 47. Basic and Clinical Pharmacology . 13th Edition. Katzung and Trevor.

Lec Guide

Mycobacteria ▪ Prevalence of resistance to both isoniazid and rifampin (which is termed

▪ intrinsically resistant to most antibiotics multidrug resistance) is about 3%.
▪ grow more slowly than other bacteria so antibiotics that are most active against ▪ Resistance to rifampin alone is rare.
rapidly growing cells are relatively ineffective
▪ Mycobacterial cells can also be dormant and thus completely resistant to many Drug Typical Adult Dosage
drugs or killed only very slowly. First-line agents (in approximate order of preference) (RIPES)
▪ The lipid-rich mycobacterial cell wall is impermeable to many agents. Isoniazid 300 mg/d
▪ Mycobacterial species are intracellular pathogens, and organisms residing within Rifampin 600 mg/d
macrophages are inaccessible to drugs that penetrate these cells poorly. Pyrazinamide 25 mg/kg/d
▪ notorious for their ability to develop resistance Ethambutol 15–25 mg/kg/d
▪ Combinations of two or more drugs are required to overcome these obstacles and
Streptomycin 15 mg/kg/d
to prevent emergence of resistance during the course of therapy.
Second-line agents
▪ The response of mycobacterial infections to chemotherapy is slow, and treatment
must be administered for months to years, depending on which drugs are used. Amikacin 15 mg/kg/d
Agents: Aminosalicylic acid 8–12 g/d
1. Drugs used in Tuberculosis Bedaquiline 400 mg/d
2. Drugs used in Atypical mycobacteria Capreomycin 15 mg/kg/d
3. Drugs used in Leprosy Ciprofloxacin 1500 mg/d, divided
Clofazimine 200 mg/d
Cycloserine 500–1000 mg/d, divided
Ethionamide 500–750 mg/d
▪ Streptomycin is no longer recommended as first-line therapy in most settings. Levofloxacin 500–750 mg/d
▪ Isoniazid and rifampin are the most active drugs.
Moxifloxacin 400 mg/d
▪ An isoniazid/rifampin combination administered for 9 months will cure 95–98% of
Rifabutin 300 mg/d
cases of tuberculosis caused by susceptible strains.
Rifapentine 600 mg once or twice weekly
▪ The addition of pyrazinamide to an isoniazid-rifampin combination for the first 2
months allows the total duration of therapy to be reduced to 6 months without
loss of efficacy. Recommended duration of therapy for tuberculosis
▪ In practice, therapy is usually initiated with a four-drug regimen of (RIPE) Regimen
Duration in Months
isoniazid, rifampin, pyrazinamide, and ethambutol until susceptibility of the (in Approximate Order of Preference)
clinical isolate has been determined. Isoniazid, rifampin, pyrazinamide 6
▪ Neither ethambutol nor other drugs such as streptomycin adds substantially to Isoniazid, rifampin 9
the overall activity of the regimen (ie, the duration of treatment cannot be Rifampin, ethambutol, pyrazinamide 6
further reduced if another drug is used), but the fourth drug provides additional Rifampin, ethambutol 12
coverage if the isolate proves to be resistant to isoniazid, rifampin, or both. Isoniazid, ethambutol 18
▪ The prevalence of isoniazid resistance among clinical isolates in the United States All others ≥ 24
is approximately 10%.

RIFAMPIN
▪ semisynthetic derivative of rifamycin, an antibiotic produced by Streptomyces mediterranei.
▪ active in vitro against gram-positive and gram-negative cocci, some enteric bacteria, mycobacteria, and chlamydiae.
▪ Susceptible organisms are inhibited by less than 1 mcg/mL.
▪ Resistant mutants are present in all microbial populations at approximately 1 in 10 6 organisms and are rapidly selected out if rifampin is used as a single drug, especially in a patient
with active infection.
▪ There is no cross-resistance to other classes of antimicrobial drugs, but there is cross-resistance to other rifamycin derivatives, eg, rifabutin and rifapentine.

Pharmacokinetics Mechanisms of Action & Resistance Clinical Uses Adverse Effects & Drug Interactions

▪ 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.
▪ well absorbed after oral administration
▪ Excreted mainly through the liver into
bile  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.
▪ Usual doses result in serum levels of 5–7
mcg/mL.
▪ Rifampin is distributed widely in body
fluids and tissues.
▪ The drug is relatively highly protein-
bound, and adequate cerebrospinal fluid
concentrations are achieved only in the
presence of meningeal inflammation.
▪ Binds to the β subunit of bacterial A. Mycobacterial Infections ▪ harmless orange color to urine, sweat, and
DNA-dependent RNA polymerase ▪ usually 600 mg/d (10 mg/kg/d) orally tears (soft contact lenses may be
 inhibits RNA synthesis ▪ must be administered with isoniazid or other permanently stained)
▪ Resistance results from any one of antituberculous drugs to patients with active
several possible point mutations in tuberculosis to prevent emergence of drug- ▪ Occasional adverse effects include: rashes,
rpoB, the gene for the β subunit of resistant mycobacteria thrombocytopenia, and nephritis,
RNA polymerase  result in ▪ In some short-course therapies, 600 mg of rifampin cholestatic jaundice and occasionally
reduced binding of rifampin to RNA is given twice weekly. hepatitis, and it commonly causes light-
polymerase. ▪ Rifampin, 600mg daily or twice weekly for 6 months chain proteinuria.
▪ Human RNA polymerase does not - also effective in combination with other agents in ▪ Flu-like syndrome characterized by fever,
bind rifampin and is not inhibited some atypical mycobacterial infections and in chills, myalgias, anemia, and
by it. leprosy. thrombocytopenia. If administered less
▪ Rifampin is bactericidal for ▪ Rifampin, 600mg daily for 4 months as a single drug often than twice weekly
mycobacteria. - latent tuberculosis who are unable to take ▪ Associated with acute tubular necrosis.
isoniazid ▪ Rifampin strongly induces most
- who have had exposure to a case of active cytochrome P450 isoforms (CYP1A2, 2C9,
tuberculosis caused by an isoniazid-resistant, 2C19, 2D6, and 3A4), which increases the
rifampin-susceptible strain. elimination of numerous other drugs
including methadone, anticoagulants,
B. Other Indications cyclosporine, some anticonvulsants,
▪ Eliminate meningococcal carriage protease inhibitors, some nonnucleoside
 oral dosage of 600 mg twice daily for 2 days reverse transcriptase inhibitors,
▪ Prophylaxis in contacts of children with contraceptives, and a host of others
Haemophilus influenzae type b disease ▪ Co-administration of rifampin results in
 Rifampin, 20 mg/kg/d for 4 days significantly lower serum levels of these
▪ Eradicate staphylococcal carriage drugs.
 Rifampin combined with a second agent
▪ Treatment of serious staphylococcal infections
such as osteomyelitis and prosthetic valve
endocarditis
 Rifampin combination therapy
ISONIAZID
▪ most active drug for the treatment of tuberculosis caused by susceptible strains
▪ a small molecule (MW 137)
▪ freely soluble in water
▪ structurally similar to pyridoxine
▪ In vitro, isoniazid inhibits most tubercle bacilli at a concentration of 0.2 mcg/mL or less
▪ bactericidal for actively growing tubercle bacilli.
▪ less effective against atypical mycobacterial species.
▪ Penetrates into macrophages and is active against both extracellular and intracellular organisms.
Chemistry & Pharmacokinetics Mechanisms of Action & Resistance Clinical Uses Adverse Effects & Drug Interactions
▪ readily absorbed from the gastrointestinal ▪ inhibits synthesis of mycolic acids, which ▪ Typical dosage: 5 mg/kg/d, 300 mg given A. Immunologic Reactions
tract are essential components of mycobacterial once daily (adult dose) ▪ Fever and skin rashes( occasional)
▪ A 300 mg oral dose (5 mg/kg in children) cell walls. ▪ For serious infections or if malabsorption is ▪ Drug-induced SLE (systemic lupus
achieves peak plasma concentrations of 3– ▪ a prodrug that is activated by KatG, the a problem  Up to 10 mg/kg/d may be erythematosus)
5 mcg/mL within 1–2 hours. mycobacterial catalase-peroxidase. used
▪ Isoniazid diffuses readily into all body fluids ▪ activated form of isoniazid forms a covalent ▪ In combination with a second B. Direct Toxicity
and tissues. complex with an acyl carrier protein antituberculous agent (rifampin, 600mg)  ▪ Isoniazid-induced hepatitis
▪ The concentration in the CNS and CSF (AcpM) and KasA, a beta-ketoacyl carrier 15 mg/kg dose or 900 mg, may be used in a  most common major toxic effect
ranges between 20% and 100% of protein synthetase, which blocks mycolic twice-weekly dosing regimen  distinct from minor increases in liver
simultaneous serum concentrations. acid synthesis. ▪ With conditions predisposing to aminotransferases (up to three or four
▪ Metabolism of isoniazid, especially neuropathy(an adverse effect of isoniazid) times normal) - do not require cessation of
acetylation by liver N-acetyltransferase, is Resistance to isoniazid is associated with  Pyridoxine(25–50 mg/d) is the drug, seen in 10–20% of patients, who
genetically determined mutations resulting in: recommended for those usually are asymptomatic.
▪ average plasma concentration of isoniazid 1. overexpression of inhA, which ▪ Isoniazid is usually given by mouth but can  Clinical hepatitis with loss of appetite,
in rapid acetylators is about 1/3 to ½ of encodes an NADH-dependent acyl be given parenterally in the same dosage. nausea, vomiting, jaundice, and right
that in slow acetylators carrier protein reductase. ▪ Isoniazid as a single agent is also indicated upper quadrant pain occurs in 1% of
▪ Average half-lives: (Overproducers of inhA express low- for treatment of latent tuberculosis. (300 isoniazid recipients and can be fatal,
✓ rapid acetylators: less than 1 hour level isoniazid resistance and cross- mg/d (5 mg/kg/d) or 900 mg twice weekly particularly if the drug is not discontinued
✓ slow acetylators: 3 hours resistance to ethionamide) for 9 months) promptly.
▪ More rapid clearance of isoniazid by rapid 2. mutation or deletion of the katG gene  Hepatocellular damage and necrosis.
acetylators is usually of no therapeutic (KatG mutants express high-level  Risk of hepatitis depends on age.
consequence when appropriate doses are isoniazid resistance and often are not ✓ Rare: under age 20
administered daily, but subtherapeutic cross-resistant to ethionamide) ✓ 0.3% of those aged 21–35
concentrations may occur if drug is 3. overexpression of ahpC, a gene ✓ 1.2% of those aged 36–50
administered as a once-weekly dose or if involved in protection of the cell from ✓ 2.3% for those aged 50 and above
there is malabsorption. oxidative stress  greater in individuals with alcohol
▪ Isoniazid metabolites and a small amount 4. mutations in kasA dependence and possibly during
of unchanged drug are excreted mainly in pregnancy and the postpartum period.
the urine. ▪ Resistant mutants are readily selected if  Development of isoniazid hepatitis
▪ The dosage need not be adjusted in renal isoniazid or any other drug is given as a contraindicates further use of the drug.
failure. single agent.
▪ Dose adjustment is not well defined in ▪ At least two (or more in certain cases) ▪ Peripheral neuropathy
patients with severe preexisting hepatic active agents should always be used to  observed in 10–20% of patients given
insufficiency and should be guided by treat active tuberculosis to prevent dosages greater than 5 mg/kg/d
serum concentrations if a reduction in dose emergence of resistance during therapy.  infrequently seen with the standard 300
is contemplated. mg adult dose.
 More likely to occur in slow acetylators
and patients with predisposing
conditions such as malnutrition,
alcoholism, diabetes, AIDS, and uremia.
 due to a relative pyridoxine deficiency.
 Isoniazid promotes excretion of
pyridoxine, and this toxicity is readily
reversed by administration of pyridoxine
in a dosage as low as 10 mg/d.
▪ Central nervous system toxicity
 less common
 includes memory loss, psychosis, and
seizures.
 these effects may also respond to
pyridoxine.
▪ Miscellaneous other reactions:
✓ hematologic abnormalities
✓ provocation of pyridoxine deficiency
anemia
✓ tinnitus
✓ gastrointestinal discomfort.
▪ Reduce the metabolism of phenytoin,
increasing its blood level and toxicity.
 PYRAZINAMIDE (PZA)
✓ a relative of nicotinamide
✓ used only for treatment of tuberculosis
✓ 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.
Pharmacokinetics Mechanisms of Action & Resistance
▪ Serum concentrations of 30–50 mcg/mL at MOA:
1–2 hours after oral administration are ▪ Pyrazinamide is converted to pyrazinoic
achieved with dosages of 25 mg/kg/d. acid—the active form of the drug—by
▪ Pyrazinamide is well absorbed from the mycobacterial pyrazinamidase, which is
gastrointestinal tract encoded by pncA.
▪ widely distributed in body tissues, ▪ Pyrazinoic acid disrupts mycobacterial cell
including inflamed meninges. membrane metabolism and transport ▪ Tubercle bacilli develop resistance to
▪ Half-life is 8–11 hours functions.
▪ The parent compound is metabolized by
the liver, but metabolites are renally Resistance:
cleared ▪ due to impaired uptake of pyrazinamide or ▪ In hemodialysis patients and those in whom arthritis.
mutations in pncA that impair conversion
of PZA to its active form.
ETHAMBUTOL
✓ synthetic, water-soluble, heat-stable compound
✓ dispensed as the dihydrochloride salt
Pharmacokinetics Mechanisms of Action & Resistance
▪ Ethambutol is well absorbed from the gut. ▪ Ethambutol inhibits mycobacterial
▪ After ingestion of 25 mg/kg, a blood level arabinosyl transferases, which are
peak of 2–5 mcg/mL is reached in 2–4 encoded by the embCAB operon.
hours. ▪ Arabinosyl transferases are involved in the
▪ About 20% of the drug is excreted in feces polymerization reaction of arabinoglycan,
and 50% in urine in unchanged form. an essential component of the
▪ Ethambutol accumulates in renal failure, mycobacterial cell wall.
and the dose should be reduced by half if ▪ Susceptible strains of Mycobacterium
creatinine clearance is less than 10 tuberculosis and other mycobacteria are
mL/min. inhibited in vitro by ethambutol, 1–5
▪ Ethambutol crosses the blood-brain barrier mcg/mL.
only when the meninges are inflamed.
▪ Concentrations in CSF are highly variable, Resistance:
ranging from 4% to 64% of serum levels in ▪ Due to mutations resulting in
the setting of meningeal inflammation. overexpression of emb gene products or
within the embB structural gene.
▪ As with all antituberculous drugs,
resistance to ethambutol emerges rapidly
when the drug is used alone.
STREPTOMYCIN
Pharmacokinetics Resistance
▪ Streptomycin penetrates into cells poorly ▪ Nontuberculosis species of mycobacteria
and is active mainly against extracellular other than Mycobacterium avium
tubercle bacilli. complex (MAC) and Mycobacterium
▪ The drug crosses the bloodbrain barrier kansasii are resistant.
and achieves therapeutic concentrations ▪ All large populations of tubercle bacilli
with inflamed meninges. contain some streptomycin-resistant
▪ Serum concentrations of approximately 40 mutants.
mcg/mL are achieved 30–60 minutes after ▪ On average, 1 in 108 tubercle bacilli can be
intramuscular injection of a 15 mg/kg dose. expected to be resistant to streptomycin
at levels of 10–100 mcg/mL.
▪ Resistance may be due to a point
mutation in either the rpsL gene encoding
the S12 ribosomal protein or the rrs gene
encoding 16S ribosomal RNA, which alters
the ribosomal binding site.
▪ Other drugs are always given in
combination to prevent emergence of
resistance.
Clinical Uses
▪ Pyrazinamide is an important front-line ▪ Major adverse effects of PZA:
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.
pyrazinamide fairly readily, but there is no
cross-resistance with isoniazid or other
antimycobacterial drugs.
the creatinine clearance is less than 30
mL/min, PZA should be administered at 25–
35 mg/kg three times weekly (not daily)
▪ In patients with normal renal function, a
dose of 40–50 mg/kg is used for thrice-
weekly or twice-weekly treatment
regimens.
Clinical Uses
▪ Ethambutol is always given in combination
with other antituberculous drugs.
▪ Ethambutol hydrochloride, 15–25 mg/kg, is
usually given as a single daily dose in
combination with isoniazid or rifampin for
the treatment of active tuberculosis.
▪ treatment of tuberculous meningitis -
higher dose may be used
▪ The dose of ethambutol is 50 mg/kg when a
twice-weekly dosing schedule is used.
Clinical Uses
▪ Streptomycin sulfate is used when an
injectable drug is needed or desirable and in
the treatment of infections resistant to
other drugs.
Dosage:
▪ If the creatinine clearance is less than 30
mL/min or the patient is on hemodialysis,
the dosage is 15 mg/kg two or three times
per week.
▪ Most tubercle bacilli are inhibited by
streptomycin, 1–10 mcg/mL, in vitro.
▪ Usual dosage: 15 mg/kg/d (1 g/d) IM or IV
daily for adults (20–40 mg/kg/d, not to
exceed 1–1.5 g for children) for several
weeks, followed by 1–1.5 g two or three
times weekly for several months.
Adverse Effects & Drug Interactions
1. hepatotoxicity (1–5% of patients)
2. nausea
3. vomiting
4. drug fever
5. hyperuricemia
▪ The latter occurs uniformly and is not a
reason to halt therapy.
▪ Hyperuricemia may provoke acute gouty
Adverse Effects & Drug Interactions
▪ Hypersensitivity to ethambutol is rare.
▪ Retrobulbar neuritis
 Most common serious adverse event
 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
are very rare.
▪ Periodic visual acuity testing is desirable if
the 25 mg/kg/d dosage is used.
▪ Ethambutol is relatively contraindicated in
children too young to permit assessment
of visual acuity and redgreen color
discrimination.
Adverse Effects & Drug Interactions
▪ Streptomycin is ototoxic and nephrotoxic.
▪ Vertigo and hearing loss are the most
common adverse effects and may be
permanent.
▪ Toxicity is dose-related, and the risk is
increased in the elderly.
▪ As with all aminoglycosides, the dose must
be adjusted according to renal function
▪ Toxicity can be reduced by limiting therapy
to no more than 6 months whenever
possible.
 ▪ The alternative drugs are usually considered only
(1) in case of resistance to first-line agents
(2) in case of failure of clinical response to conventional therapy
(3) in case of serious treatment-limiting adverse drug reactions.
Ethionamide ▪ Chemically related to isoniazid and similarly blocks the synthesis of mycolic
acids.
P:
▪ It is poorly water soluble and available only in oral form.
▪ It is metabolized by the liver.
▪ Most tubercle bacilli are inhibited in vitro by ethionamide, 2.5 mcg/mL or less.
▪ Some other species of mycobacteria also are inhibited by ethionamide, 10
mcg/mL.
▪ Serum concentrations in plasma and tissues of approximately 20 mcg/mL are
achieved by a dosage of 1 g/d.
▪ Cerebrospinal fluid concentrations are equal to those in serum.
Capreomycin ▪ Capreomycin is a peptide protein synthesis inhibitor antibiotic obtained from
Streptomyces capreolus.
Cl:
▪ Daily injection of 1 g intramuscularly results in blood levels of 10 mcg/mL or
more.
▪ Such concentrations in vitro are inhibitory for many mycobacteria, including
multidrug-resistant strains of M tuberculosis.
▪ Capreomycin (15 mg/kg/d) is an important injectable agent for treatment of
drug-resistant tuberculosis.
R:
▪ Strains of M tuberculosis that are resistant to streptomycin or amikacin
usually are susceptible to capreomycin.
▪ Resistance to this drug, when it occurs, may be due to an rrs mutation.
Cycloserine MOA: inhibitor of cell wall synthesis
C:
▪ Concentrations of 15–20 mcg/mL inhibit many strains of M tuberculosis.
▪ The dosage of cycloserine in tuberculosis is 0.5–1 g/d in two divided oral
doses.
P:
▪ This drug is cleared renally, and the dose should be reduced by half if
creatinine clearance is less than 50 mL/min.
▪ The peak concentration is reached 2–4 hours after dosing.
▪ The recommended range of peak concentrations is 20–40 mcg/mL.
Aminosalicylic ▪ Aminosalicylic acid is a folate synthesis antagonist that is active almost
exclusively against M tuberculosis.
Acid (PAS) ▪ It is structurally similar to p-amino-benzoic acid (PABA) and to the
sulfonamides
▪ Tubercle bacilli are usually inhibited in vitro by aminosalicylic acid, 1–5
mcg/mL.
P:
▪ Aminosalicylic acid is readily absorbed from the gastrointestinal tract.
▪ Serum levels are 50 mcg/mL or more after a 4 g oral dose.
▪ The dosage is 8–12 g/d orally for adults and 300 mg/kg/d for children.
▪ The drug is widely distributed in tissues and body fluids except the
cerebrospinal fluid.
▪ Aminosalicylic acid is rapidly excreted in the urine, in part as active PAS and in
part as the acetylated compound and other metabolic products.
Kanamycin & ▪ Kanamycin had been used for treatment of tuberculosis caused by
streptomycin-resistant strains, but the availability of less toxic alternatives
Amikacin (eg, capreomycin and amikacin) has rendered it obsolete.
▪ Amikacin is playing a greater role in the treatment of tuberculosis due to the
prevalence of multidrug-resistant strains.
▪ Prevalence of amikacin-resistant strains is low (< 5%), and most
multidrugresistant strains remain amikacin-susceptible.
▪ M tuberculosis is inhibited at concentrations of 1 mcg/mL or less.
▪ Amikacin is also active against atypical mycobacteria.
▪ There is no cross-resistance between streptomycin and amikacin, but
kanamycin resistance often indicates resistance to amikacin as well.
Fluoroquinolones Ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin
▪ In addition to their activity against many gram-positive and gram-negative
bacteria, inhibit strains of M tuberculosis at concentrations less than 2
mcg/mL.
▪ active against atypical mycobacteria.
▪ Moxifloxacin is the most active against M tuberculosis in vitro.
▪ Levofloxacin tends to be slightly more active than ciprofloxacin against M
tuberculosis
▪ Ciprofloxacin is slightly more active against atypical mycobacteria.
D:
▪ Administered at an initial dose of 250 mg once daily, which is increased in
250-mg increments to the recommended dosage of 1 g/d (or 15 mg/kg/d), if
possible.
▪ The 1 g/d dosage, though theoretically desirable, is poorly tolerated because
of gastric irritation and neurologic symptoms, often limiting the tolerable
daily dose to 500–750 mg.
AE:
▪ Ethionamide is also hepatotoxic.
▪ Neurologic symptoms may be alleviated by pyridoxine.
R:
▪ Resistance to ethionamide as a single agent develops rapidly in vitro and in
vivo. There can be low-level cross-resistance between isoniazid and
ethionamide.
AE:
▪ Capreomycin is nephrotoxic and ototoxic.
▪ Tinnitus, deafness, and vestibular disturbances occur.
▪ The injection causes significant local pain, and sterile abscesses may
develop.
D:
▪ Dosing of capreomycin is the same as that of streptomycin.
▪ Toxicity is reduced if 1 g is given two or three times weekly after an initial
response has been achieved with a daily dosing schedule.
AE:
▪ Most serious toxic effects are peripheral neuropathy and CNS dysfunction,
including depression and psychotic reactions.
▪ Pyridoxine, 150 mg/d, should be given with cycloserine because this
ameliorates neurologic toxicity.
▪ Adverse effects, which are most common during the first 2 weeks of therapy,
occur in 25% or more of patients, especially at higher doses.
▪ Adverse effects can be minimized by monitoring peak serum concentrations.
AE:
▪ Very high concentrations of aminosalicylic acid are reached in the urine, which
can result in crystalluria.
▪ Aminosalicylic acid is used infrequently because other oral drugs are better
tolerated.
▪ GI symptoms are common and may be diminished by giving the drug with
meals and with antacids.
▪ Peptic ulceration and hemorrhage may occur.
▪ Hypersensitivity reactions manifested by fever, joint pains, skin rashes,
hepatosplenomegaly, hepatitis, adenopathy, and granulocytopenia often
occur after 3–8 weeks of PAS therapy, making it necessary to stop
administration temporarily or permanently.
▪ Serum concentrations of 30–50 mcg/mL are achieved 30–60 minutes after a
15 mg/kg intravenous infusion.
▪ Amikacin is indicated for treatment of tuberculosis suspected or known to be
caused by streptomycin- resistant or multidrug-resistant strains.
▪ This drug must be used in combination with at least one and preferably two
or three other drugs to which the isolate is susceptible for treatment of drug-
resistant cases.
▪ The recommended dosages are the same as those for streptomycin
R:
▪ Fluoroquinolones are an important addition to the drugs available for
tuberculosis, especially for strains that are resistant to first-line agents.
▪ Resistance, which may result from one of several single point mutations in
the gyrase A subunit, develops rapidly if a fluoroquinolone is used as a single
agent; thus, the drug must be used in combination with two or more other
active agents.
D:
▪ Ciprofloxacin: 750 mg orally twice a day
▪ Levofloxacin: 500–750 mg once a day
▪ Moxifloxacin: 400 mg once a day
Linezolid ▪ Linezolid inhibits strains of M tuberculosis in vitro at concentrations
of 4–8 mcg/mL.
▪ achieves good intracellular concentrations
▪ active in murine models of tuberculosis.
▪ Linezolid has been used in combination with other second- and
third-line drugs to treat patients with tuberculosis caused by
multidrug-resistant strains.
Rifabutin ▪ 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.
▪ Some rifampin-resistant strains may appear susceptible to rifabutin
in vitro, but a clinical response is unlikely because the molecular
basis of resistance, rpoB mutation, is the same.
▪ Rifabutin is both substrate and inducer of cytochrome P450
enzymes.
Rifapentine ▪ Rifapentine is an analog of rifampin.
▪ It is active against both M tuberculosis and MAC.
▪ As with all rifamycins, it is a bacterial RNA polymerase inhibitor, and
cross-resistance between rifampin and rifapentine is complete.
▪ Like rifampin, rifapentine is a potent inducer of cytochrome P450
enzymes has the same drug interaction profile
▪ Toxicity is similar to that of rifampin.
▪ Rifapentine and its microbiologically active metabolite, 25-
desacetylrifapentine, have an elimination half-life of 13 hours.
Bedaquiline ▪ a diarylquinoline
▪ first drug with a novel mechanism of action against M tuberculosis
to be approved since 1971.
▪ Bedaquiline inhibits adenosine 5′-triphosphate (ATP) synthase in
mycobacteria
▪ has in vitro activity against both replicating and nonreplicating
bacilli
▪ has bactericidal and sterilizing activity in the murine model of
tuberculosis.
▪ No cross-resistance has been found between bedaquiline and other
medications used to treat tuberculosis.
▪ Peak plasma concentration and plasma exposure of bedaquiline
increase approximately twofold when administered with high-fat
food.
▪ Bedaquiline is highly protein-bound (> 99%)
▪ metabolized chiefly through the cytochrome P450 system
▪ excreted primarily via the feces
AE:
▪ Significant adverse effects, including bone marrow suppression and irreversible
peripheral and optic neuropathy, have been reported with the prolonged courses
of therapy that are necessary for treatment of tuberculosis.
▪ A 600 mg (adult) dose administered once a day (half of that used for treatment of
other bacterial infections) seems to be sufficient and may limit the occurrence of
these adverse effects.
▪ Although linezolid may prove to be an important new agent for treatment of
tuberculosis, at this point it should only be used for multidrug-resistant strains that
also are resistant to several other first- and second-line agents.
▪ Because it is a less potent inducer, rifabutin is indicated in place of rifampin for
treatment of tuberculosis in patients with HIV infection who are receiving
antiretroviral therapy with a protease inhibitor or a nonnucleoside reverse
transcriptase inhibitor (eg, efavirenz), drugs that also are cytochrome P450
substrates.
D:
▪ The typical dosage of rifabutin is 300 mg/d unless the patient is receiving a protease
inhibitor, in which case the dosage should be reduced.
▪ If efavirenz (also a cytochrome P450 inducer) is used, the recommended dosage of
rifabutin is 450 mg/d.
▪ Rifapentine, 600 mg (10 mg/kg) once or twice weekly, is indicated for treatment of
tuberculosis caused by rifampin-susceptible strains during the continuation phase
only (ie, after the first 2 months of therapy and ideally after conversion of sputum
cultures to negative).
▪ Rifapentine should not be used to treat patients with HIV infection because of an
unacceptably high relapse rate with rifampin-resistant organisms.
▪ Rifapentine, given once weekly for 3 months in combination with isoniazid, is an
effective short course treatment for latent tuberculosis infection.
▪ Mean terminal half-life of bedaquiline and its major metabolite (M2), which is four
to six times less active in terms of antimycobacterial potency, is approximately 5.5
months.
▪ This long elimination phase probably reflects slow release of bedaquiline and M2
from peripheral tissues.
▪ CYP3A4 is the major isoenzyme involved in the metabolism of bedaquiline and
potent inhibitors or inducers of this enzyme cause clinically significant drug
interactions.
▪ Current recommendations state that bedaquiline, in 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.
▪ Bedaquiline has been associated with both hepatotoxicity and cardiac toxicity
(prolongation of the QTc interval), so patients must be closely monitored during
treatment.
TREATMENT OF TB
Nontuberculous or “atypical” mycobacteria
Guidelines for national programme 3rd ed. WHO-Geneva June 2004 ▪ Cause of many mycobacterial infections seen in clinical practice
I – isoniazid ▪ These organisms have distinctive laboratory characteristics
P – pyrazinamide ▪ present in the environment
R – rifampicin ▪ not communicable from person to person.
E – ethambutol ▪ As a rule, these mycobacterial species are less susceptible than M tuberculosis to
S – streptomycin antituberculous drugs.
Km – kanamycin Macrolides, sulfonamides, and tetracyclines
Cs – cycloserine ▪ not active against M tuberculosis, may be effective for infections caused by atypical
Q – quinolone (ciprofloxacin or ofloxaxin) mycobacteria.
Et – ethionamide ▪ Emergence of resistance during therapy is also a problem with these mycobacterial
PAS – Para Amino Salicylic acid species, and active infection should be treated with combinations of drugs.
M kansasii
Example of TB regimen: ▪ susceptible to rifampin and ethambutol, partially susceptible to isoniazid, and
▪ New case: completely resistant to pyrazinamide.
2 IRPE / 4 (HR)3 or 2 (IR) PE / 6 (IE) ▪ Conventional treatment for M kansasii infection - three-drug combination of
▪ Resistant to all essential drugs: isoniazid, rifampin, and ethambutol
1 inj. + 1 Q + 2 of these 3 oral drugs (PAS , Et , Cs) X 6 mos. then same drug M avium complex (MAC)
except inj. X 18 mos. ▪ includes both M avium and M intracellulare
▪ If susceptibility testing is not available: ▪ important and common cause of disseminated disease in late stages of AIDS (CD4
Km + Et + Q + P +/- E X 6 mos. counts < 50/μL).
then: Et + Q + P +/- E X 12-18 mos. ▪ MAC is much less susceptible than M tuberculosis to most antituberculous drugs.
Combinations of agents are required to suppress the infection.
TB Diagnostic Category Treatment ▪ is an effective and well-tolerated regimen for treatment of disseminated disease.
▪ Some authorities recommend use of a third agent, especially rifabutin, 300 mg once
Category I ▪ new pulmonary smear (+) cases 2 IRPE / 4 IR
daily.
▪ new seriously ill pulmonary ▪ Azithromycin and clarithromycin are the prophylactic drugs of choice for
smear (-) cases with extensive
preventing disseminated MAC in AIDS patients with CD4 cell counts less than 50/μL.
lung lesions on CXR
▪ Rifabutin in a single daily dose of 300 mg has been shown to reduce the incidence
▪ new extrapulmonary TB of MAC bacteremia but is less effective than macrolides.
▪ concomitant HIV infection
Species Clinical Features Treatment Options
Category II ▪ failure cases 2 IRPES/ 1 IREP/ 5 IRE
M kansasii Resembles tuberculosis Ciprofloxacin, clarithromycin,
▪ relapse cases but milder ethambutol, isoniazid, rifampin,
▪ return after default RAD trimethoprimsulfamethoxazole
▪ (smear +) other (smear + or -) 1st line: INH + Rifampicin + Ethambutol
2nd line: ethionamide, cycloserine,
Category III ▪ new smear (-) but with minimal 2 IRP(E)*/ 4 IR clarithromycin, amikacin, streptomycin
pulmonary TB on CXR as Resistant to Pyrazinamide
assessed by TB diagnostic * : E may be omitted for
committee non-cavitary, smear M marinum Granulomatous Amikacin, clarithromycin, ethambutol,
negative, fully susceptible cutaneous disease doxycycline, minocycline, rifampin,
cases trimethoprimsulfamethoxazole

Skin infections 1st line: Rifampicin + Ethambutol

Category IV : ▪ Chronic (still smear-positive after refer to specialized facility
2nd line:
supervised re-treatment) or DOTS center
TMP-SMX, Clarithromycin, Amikacin,
Kanamycin, Minocycline, Doxycycline
M Cervical adenitis in Amikacin, erythromycin (or other
D.O.T.S
scrofulaceum children macrolide), rifampin, streptomycin
▪ stands for Directly-Observed Treatment Short course. TOC: Surgical excision
▪ It is a comprehensive strategy endorsed by the World Health Organization (WHO) M avium Pulmonary disease in Amikacin, azithromycin, clarithromycin,
to detect and cure TB patients.
complex patients with chronic ciprofloxacin, ethambutol, rifabutin
▪ Five elements of DOTS: (MAC) lung disease;
a. political commitment disseminated infection
b. quality sputum microscopy for diagnosis in AIDS
c. regular supply of anti-TB drugs
d. standardized recording and reporting of TB data 1st line:
e. supervised treatment by a treatment partner Azithromycin 500 mg OD or
clarithromycin 500 mg BID + ethambutol
According to the WHO Report on the TB Epidemic, 1997: 15–25 mg/kg/d OR Clofazimine or
a. DOTS cure TB patients and it can produce cure rates as high as 95% even in Ciprofloxacin 750mg BID or Amikacin
the poorest countries. 2nd line: Rifabutin 300mg OD;
b. DOTS prevent new infections among children and adults Rifampicin; Ethionamide; Cycloserine;
c. DOTS can stop resistance to anti-TB drugs. Imipenem
d. DOTS is cost-effective. Prophylaxis in AIDS pt: Rifabutin 300 mg
OD
TB and pregnancy M chelonae Abscess, sinus tract, Amikacin, doxycycline, imipenem,
▪ INH, Rifampin, Ethambutol x 9 mos. + vitamin B6 10-25mg orally ulcer; bone, joint, macrolides, tobramycin
▪ PZA’s risk of teratogenicity – not yet defined tendon infection
▪ breastfeeding is not C/I M fortuitum Abscess, sinus tract, Amikacin, cefoxitin, ciprofloxacin,
▪ infant should be given 3 mos. INH prophylaxis; delay BCG immunization ulcer; bone, joint, doxycycline, ofloxacin,
tendon infection trimethoprimsulfamethoxazole
Chronic lung disease & 1st line: amikacin + doxycycline
skin/soft tissue infection 2nd line: Cefoxitin, rifampicin, TMP-
SMX, Ciprofloxacin, ofloxacin,
imepenem, clarithromycin
M ulcerans Skin ulcers Isoniazid, streptomycin,rifampin,
minocycline (Surgical excision may be
effective.)
 ▪ Methemoglobinemia is common but usually is not a problem clinically.
▪ Gastrointestinal intolerance, fever, pruritus, and various rashes occur.
▪ During dapsone therapy of lepromatous leprosy, erythema nodosum leprosum
Leprosy often develops.
While all of this is scary, researchers estimate that leprosy is not highly contagious, and ▪ It is sometimes difficult to distinguish reactions to dapsone from manifestations of
that 95% of exposures do not result in disease. the underlying illness.
▪ Caused by M. leprae ▪ Erythema nodosum leprosum may be suppressed by thalidomide.
▪ Tropical, warm temperate regions
▪ Skin and nerve predilection RIFAMPIN
▪ Depends upon cell-mediated immunity ▪ In a dosage of 600 mg daily is highly effective in leprosy
▪ Dx: biopsy; slit skin smears ▪ given with at least one other drug to prevent emergence of resistance.
▪ Mode of transmission: nasal secretions ▪ Even a dose of 600 mg per month may be beneficial in combination therapy.
▪ mere touching of a person infected with leprosy cannot immediately transfer
leprosy to another. CLOFAZIMINE
▪ In the Biblical times, people who were infected with leprosy were cursed, taunted ▪ A phenazine dye
and ignored. ▪ Use: Treatment of multibacillary leprosy, which is defined as having a positive
smear from any site of infection.
Clinical types of Leprosy: ▪ Absorption of clofazimine from the gut is variable, and a major portion of the drug
1. Tuberculoid leprosy – skin macules with clear centers and well defined margins; is excreted in feces.
anesthetic; no Virchow cells; (+) lepromin test ▪ stored widely in reticuloendothelial tissues and skin, and its crystals can be seen
2. Borderline tuberculoid inside phagocytic reticuloendothelial cells.
3. Borderline disease ▪ It is slowly released from these deposits, so the serum half-life may be 2 months.
4. Borderline lepromatous ▪ Dosage: 100 mg/d orally.
5. Lepromatous – impaired cell immunity; atrophy of skin, muscles; amputations; ▪ Most prominent untoward effect: discoloration of the skin and conjunctivae.
spontaneous ulcerations ▪ Gastrointestinal side effects are also common.
▪ Ethionamide – a substitute for clofazimine, dose: 250 -375mg/day
Based on Ridley-Jopling Classification:
A. Borderline vs Indeterminate Jarisch-Herxheimer reaction:
B. Tuberculoid vs. Lepromatous ▪ exacerbation of lepromatous leprosy
▪ is induced 5-6 wks. after initiation of treatment
Treatment principles for leprosy ▪ fever, malaise, exfoliative dermatitis, jaundice with hepatic necrosis,
The major goals of the leprosy control program are: lymphadenopathy, methemoglobinemia, anemia
(1) early detection of patients;
(2) appropriate treatment; and
(3) adequate care for the prevention of disabilities and rehabilitation. Because
leprosy is an infectious disease, antibiotic therapy plays a pivotal role in the
management of newly diagnosed patients.

DRUGS FOR MYCOBACTERIUM LEPRAE

1. Dapsone (diaphenylsulfone, DDS),
2. rifampicin (RFP),
3. clofazimine (CLF),
4. ofloxacin (OFLX), and
5. minocycline (MINO) constitute the backbone of the multidrug therapy (MDT)
regimen recommended by WHO.

Other chemotherapeutic agents:

• Levofloxacin (LVFX), sparfloxacin (SPFX), and clarithromycin
• WHO has designed very practical kits containing medication for 28 days,
dispensed in blister packs, for both Pauci Bacillary and Multi Bacillary leprosy. The
blister pack medication kit for Single Lesion Pauci Bacillary leprosy contains the
exact dose for the one-time administration of the three components of the Multi
Drug Therapy regimen.

DAPSONE
▪ diaminodiphenylsulfone
▪ several drugs closely related to the sulfonamides have been used effectively in the
long-term treatment of leprosy.
▪ Like the sulfonamides, it inhibits folate synthesis.
▪ Resistance can emerge in large populations of M leprae in lepromatous leprosy,
particularly if low doses are given.
▪ Uses:
✓ Initial therapy of lepromatous leprosy: Dapsone + rifampin + clofazimine
✓ Leprosy with a lower organism burden – Dapsone plus rifampin
✓ Prevent and treat Pneumocystis jiroveci pneumonia in AIDS patients.
Pharmacokinetics:
▪ 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.
AE:
▪ Dapsone is usually well tolerated.
▪ Many patients develop some hemolysis, particularly if they have glucose-6-
phosphate dehydrogenase (G6PD) deficiency