Antimycobacterial Drugs

TONY LIWA MD, PHD

JUNE 2023
 Introduction
Most antibiotics are more effective against rapidly growing organisms
than against slowly growing ones.
Because mycobacteria are very slowly growing organisms, they are
relatively resistant to antibiotics.
Mycobacterial cells can also be dormant and thus completely resistant
to many drugs-or killed only very slowly by the few drugs that are
active.

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 Introduction
The lipid-rich mycobacterial cell wall is impermeable to many agents.
A substantial proportion of mycobacterial organisms are intracellular,
residing within macrophages, and inaccessible to drugs that penetrate
poorly.
Finally, mycobacteria are notorious for their ability to develop
resistance to any single drug.

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Cell structure

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 What should be done
Combinations of 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, and Rx must be administered for months to years
depending on which drugs are used.

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 Drugs Used in Tuberculosis
Isoniazid (INH), rifampin, pyrazinamide (PZA), ethambutol
(ETH), and streptomycin are the five first-line agents for Rx of TB.
INH and rifampin are the two most active drugs.
An INH-rifampin combination administered for 9 months will cure
95–98% of cases of TB caused by susceptible strains.
The addition of PZA to an INH-rifampin combination for the first 2
months allows the total duration of therapy to be reduced to 6 months
without loss of efficacy.
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 Drugs Used in Tuberculosis
In practice, therapy is initiated with a four-drug regimen of
INH, RIF, PZA, and either ETH or streptomycin until
susceptibility of the clinical isolate has been determined.
Neither ETH nor streptomycin adds substantially to the overall
activity of the regimen (but they do provide additional coverage
should the isolate prove to be resistant to INH, rifampin, or
both).
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 First line agents in approximate order of
preference

Isoniazid 300 mg/d

Rifampin 600 mg/d
Pyrazinamide 25 mg/kg/d
Ethambutol 15–25 mg/kg/d
Streptomycin 15 mg/kg/d

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 Second line agents
Amikacin 15 mg/kg/d
Para-Aminosalicylic acid 8–12 g/d
Capreomycin 15 mg/kg/d
Ciprofloxacin 1500 mg/d, divided
Clofazimine 200 mg/d
Cycloserine 500–1000 mg/d, divided
Ethionamide 500–750 mg/d
Levofloxacin 500 mg/d
Rifabutin 300 mg/d
Rifapentine 600 mg once or twice weekly

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 Isoniazid (INH)

INH is the most active drug for the Rx of Tb caused by susceptible

strains.
It is a small (MW 137), simple molecule freely soluble in water.
In vitro, INH inhibits most tubercle bacilli in a concentration of 0.2
μg/mL or less and is bactericidal for actively growing tubercle bacilli.
INH is able to penetrate into phagocytic cells and thus is active against
both extracellular and intracellular organisms.

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 Mechanism of action
INH inhibits synthesis of mycolic acids, which are essential
components of mycobacterial cell walls.
INH is a prodrug that is activated by KatG, the mycobacterial
catalase-peroxidase.
The activated form of INH exerts its lethal effect by forming a
covalent complex with an acyl carrier protein (AcpM) and KasA, a
beta-ketoacyl carrier protein synthetase, which blocks mycolic acid
synthesis.
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 Basis of Resistance
Resistance to INH has been associated with mutations resulting in
overexpression of inhA, which encodes an NADH-dependent acyl
carrier protein reductase;
Mutation or deletion of katG;
Promoter mutations resulting in overexpression of ahpC, a putative
virulence gene involved in protection of the cell from oxidative stress;
and mutations in kasA.

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 Basis of Resistance
Overproducers of inhA express low-level isoniazid
resistance and cross-resistance to ethionamide.
KatG mutants express high-level isoniazid resistance and
are usually not cross-resistant to ethionamide.

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 Pharmacokinetics
INH is readily absorbed from the gastrointestinal tract.
The administration of a 300-mg oral dose (5 mg/kg in children)
results in peak plasma concentrations of 3–5 μg/mL within 1–2 hours.
INH diffuses readily into all body fluids and tissues.
The concentration in the CNS and CSF ranges between 20% and
100% of simultaneous serum concentrations.

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 Pharmacokinetics
Metabolism of INH, especially acetylation by liver N-
acetyltransferase, is genetically determine.
The average concentration of INH in the plasma of 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.

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 Pharmacokinetics
Rapid clearance of INH by fast acetylators is 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.
INH metabolites and a small amount of unchanged drug are excreted
mainly in the urine.
The dose need not be adjusted in renal failure, but 1/3 to ½ of the
normal dose is recommended in severe hepatic insufficiency.

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 Adverse effects
Allergic Reactions
Fever and skin rashes are occasionally seen.
Drug-induced systemic lupus erythematosus (SLE) has been
reported.
Direct Toxicity
Isoniazid-induced hepatitis is the most frequent major toxic
effect.
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 Adverse effects
Hepatitis is distinct from the minor increases in liver
aminotransferases, seen in 10-20% of patients, who usually are
asymptomatic. Such increases do not require cessation of the
drug.
Clinical hepatitis with loss of appetite, nausea, vomiting,
jaundice, and right upper quadrant pain occurs in 1% of
INH recipients and can be fatal, particularly if the drug is not
discontinued promptly.
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 Adverse effects
Peripheral neuropathy is observed in 10–20% of patients given
dosages greater than 5 mg/kg/d but is infrequently seen with the
standard 300 mg adult dose.
It is more likely to occur in slow acetylators and patients with
predisposing conditions such as malnutrition, alcoholism, diabetes,
AIDS, and uremia.
Neuropathy is due to a relative pyridoxine deficiency.

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 Adverse effects
Isoniazid promotes excretion of pyridoxine, and this toxicity
is readily reversed by administration of pyridoxine in a dosage
as low as 10 mg/d.
CNS toxicity, which is less common, includes memory loss,
psychosis, and seizures. These may also respond to
pyridoxine.

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 Adverse effects
Miscellaneous other reactions include hematologic
abnormalities, provocation of pyridoxine deficiency anemia,
tinnitus, and git discomfort.
Isoniazid can reduce the metabolism of phenytoin, increasing
its blood level and toxicity.

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 Rifampicin
Rifampin is a large (MW 823), complex semisynthetic
derivative of rifamycin, an antibiotic produced by
Streptomyces mediterranei.
It is active in vitro against gram-positive and gram negative
cocci, some enteric bacteria, mycobacteria, and chlamydia.

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 Antimycobacterial Activity
Rifampin binds strongly to the β-subunit of bacterial
DNA-dependent RNA polymerase and thereby inhibits
RNA synthesis.
Human RNA polymerase does not bind rifampin and is
not inhibited by it.
 Rifampin is bactericidal for mycobacteria.

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 Resistance
Resistance results from one of several possible point
mutations in rpoB, the gene for the beta subunit of RNA
polymerase.
These mutations prevent binding of rifampin to RNA
polymerase.

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 Pharmacokinetics
It readily penetrates most tissues and 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.

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 Pharmacokinetics
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 in the urine.
Dosage adjustment for renal insufficiency is not necessary.

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 Clinical Use-Mycobacterial Infections
Rifampin is effective in some atypical mycobacterial infections and in
leprosy when used together with a sulfone.
Rifampin is an alternative to INH prophylaxis for patients who are
unable to take INH or who have had close contact with a case of active
Tb caused by an INH-resistant, rifampin-susceptible strain .

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 Other Indications
An oral dosage of 600 mg twice daily for 2 days can eliminate
meningococcal carriage.
 Rifampin, 20 mg/kg/d for 4 days, is used as prophylaxis in contacts of
children with Haemophilus influenzae type B disease.
Rifampin combined with a second agent is used to eradicate
staphylococcal carriage.

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 Other indications
Rifampin combination therapy is also indicated for Rx of serious
staphylococcal infections such as osteomyelitis and prosthetic valve
endocarditis.
Rifampin has been recommended also for use in combination with
ceftriaxone or vancomycin in Rx of meningitis caused by highly
penicillin-resistant strains of pneumococci.

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 Adverse reaction
Rifampin imparts a harmless orange color to urine, sweat, tears, and
contact lenses (soft lenses may be permanently stained).
Occasional adverse effects include rashes, thrombocytopenia, and
nephritis.
It may cause cholestatic jaundice and occasionally hepatitis.

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 Adverse reaction
Rifampin may cause a flu-like syndrome characterized
by fever, chills, myalgias, anemia, thrombocytopenia,
and sometimes is associated with acute tubular
necrosis.

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 Adverse reaction
Rifampin strongly induces most CYP450 isoforms (CYP1A2,
CYP2C9, CYP2C19, CYP2D6, and CYP3A4), which increases the
elimination of numerous other drugs including anticoagulants, some
anticonvulsants, protease inhibitors, and contraceptives.
Ketoconazole may reduce rifampin serum concentrations by
interfering with absorption.

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 Ethambutol
ETH is a synthetic, water-soluble, heat-stable compound, dispensed as the
dihydrochloride salt.
ETH is an inhibitor of mycobacterial arabinosyl transferases, which are
encoded by the embCAB operon.
Arabinosyl transferases are involved in the polymerization reaction of
arabinoglycan, an essential component of the mycobacterial cell wall.
Resistance to ETH is due to mutations resulting in overexpression of emb gene
products or within the embB structural gene.

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 Pharmacokinetics
EtH is well absorbed from the gut. Following ingestion of 25
mg/kg, a blood level peak of 2–5 μg/mL is reached in 2–4 hours.
About 20% of the drug is excreted in feces and 50% in urine in
unchanged form.
ETH accumulates in renal failure, and the dose should be
reduced by half if creatinine clearance is less than 10 mL/min.

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 Pharmacokinetics
ETH crosses the blood-brain barrier only if the meninges are inflamed.
Concentrations in CSF are highly variable, ranging from 4% to 64% of
serum levels in the setting of meningeal inflammation.
As with all anti-TB drugs, resistance to ETH emerges rapidly when the
drug is used alone.
Therefore, ETH is always given in combination with other anti-TBs
drugs.

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 Adverse reactions
Hypersensitivity to ETH is rare.
The most common serious adverse event is retrobulbar neuritis
causing loss of visual acuity and red-green color blindness.
This dose-related side effect is more likely to occur at a dosage of 25
mg/kg/d continued for several months.
With dosages of 15 mg/kg/d or less, visual disturbances are very rare.

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 Adverse reactions
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 red-green color
discrimination.

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 Pyrazinamide
PZA is a relative of nicotinamide, stable, slightly soluble in water, and
quite inexpensive.
At neutral pH, it is inactive in vitro, but at pH 5.5 it inhibits tubercle
bacilli and at concentrations of approximately 20 μg/mL.
Drug is taken up by macrophages and exerts its activity against
intracellular organisms residing within this acidic environment.

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 Pyrazinamide
PZA is converted to pyrazinoic acid, the active form of the drug, by
mycobacterial pyrazinamidase, which is encoded by pncA.
The drug target and mechanism of action are unknown.
Resistance is due to mutations in pncA that impair conversion of PZA
to its active form.
Impaired uptake of PZA may also contribute to resistance.

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 Pyrazinamide
PZA is an important front-line drug used in conjunction with INH and
rifampin in short-course (i.e., 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 with INH or other antimycobacterial drugs.

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 Pharmacokinetics
Serum concentrations of 30–50 μg/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.

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 Adverse Reactions
Major adverse effects of PZA include hepatotoxicity (in 1–
5% of patients), nausea, vomiting, drug fever, and
hyperuricemia.
The latter occurs uniformly and is not a reason to halt therapy.
Hyperuricemia may provoke acute gouty arthritis.

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 Streptomycin
Most tubercle bacilli are inhibited by streptomycin, 1–10 g/mL, in
vitro.
Non tuberculosis species of mycobacteria other than Mycobacterium
avium complex (MAC) and Mycobacterium kansasii are resistant.
All large populations of tubercle bacilli contain some streptomycin-
resistant mutants.
On average, 1 in 108 tubercle bacilli can be expected to be resistant to
streptomycin at levels of 10–100 g/mL.

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 Streptomycin
Streptomycin penetrates into cells poorly, and consequently it is
active mainly against extracellular tubercle bacilli.
Additional drugs are needed to eliminate intracellular
organisms, which constitute a significant proportion of the total
mycobacterial burden.
Streptomycin crosses the blood-brain barrier and achieves
therapeutic concentrations with inflamed meninges.

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 Clinical use in Tb
Streptomycin sulfate remains an important drug in the treatment of
Tb.
It is employed when an injectable drug is needed or desirable,
principally in individuals with severe, possibly life threatening forms of
Tb, eg, meningitis and disseminated disease, and in Rx of infections
resistant to other drugs.
Other drugs are always given simultaneously to prevent emergence of
resistance.

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 Adverse reaction
Streptomycin is ototoxic and nephrotoxic.
Vertigo and hearing loss are the most common side 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.
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