Ch34 : Anti-mycobacterial

Tasneem Smerat
 Mycobacterium Tuberculosis

• Tuberculosis (TB) remains the leading cause of death worldwide from a single
infectious disease agent.

• WHO estimates that eight million people get TB every year, of whom 95% live in
developing countries. An estimated 2 million people die from TB every year.

• TB is an ancient infectious disease caused by mycobacterium tuberculosis.

• Pulmonary tuberculosis is a disease of respiratory transmission,
patients with the active disease (bacilli) expel them into the air by:
• Coughing,
• Sneezing,
• Shouting,
• Or any other way that will expel bacilli into the air
Once inhaled by a tuberculin free person, the bacilli multiply 4 -6 weeks and spreads
throughout the body. The bacilli implant in areas of high partial pressure of oxygen:
 Lung
 Renal cortex
 Reticuloendothelial system

 This is known as the primary infection. The patient will heal and a scar will appear in
the infected loci. There will also be a few viable bacilli/spores may remain in these
areas (particularly in the lung). The bacteria at this time goes into a dormant state, as
long as the person's immune system remains active and functions normally this
person isn't bothered by the dormant bacillus.
 When a person's immune system is depressed., A secondary reactivation occurs. 85-
90% of the cases seen which are of secondary reactivation type occurs in the lungs.
Treatment of Mycobacteria Infections

Species First line therapy

M. tuberculosis Isoniazid + Rifampin +

Pyrazinamide + Ethambutol

M. avium Clarithromycin + Ethambutol

M. leprae Dapsone + rifampin

 clofazimine

From: Goodman & Gilman, 9th ed., 1996

 Chemotherapy for tuberculosis
• TB treatment generally includes four
first-line drugs.

• Second-line drugs They are used for

patients who cannot tolerate the first-
line drugs or who are infected with
resistant TB . (less effective, more toxic, and
less extensively studied) .

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• M. tuberculosis is slow growing and requires treatment for months to years.

• LTBI can be treated for 9 months with isoniazid (INH) monotherapy or with
12 once-weekly doses of INH (900 mg) and rifapentine (900 mg).

• In contrast, active TB disease must be treated with several drugs.

• Treatment for drug-susceptible TB lasts for at least 6 months, while

treatment of multidrug-resistant TB (MDR-TB) typically lasts for about 2
years

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 Although clinical improvement can occur in the
first several weeks of treatment, therapy is
continued much longer to eradicate persistent
organisms and to prevent relapse.

• Standard short-course chemotherapy for

tuberculosis includes
 Isoniazid, rifampin, ethambutol, and
pyrazinamide for 2 months (the intensive
phase),
 followed by isoniazid and rifampin for 4
months.

• Once susceptibility data are available, the drug

regimen can be individually tailored 8
• Second line regimens for MDR-TB (TB resistant to at least isoniazid
and rifampin) normally include:

• An aminoglycoside (streptomycin, kanamycin, or amikacin) (all injectable

agents)

• A fluoroquinolone (typically levofloxacin or moxifloxacin),

• Any first-line drugs that remain active, and

• One or more of the following: Cycloserine, ethionamide, or

paminosalicylic acid.

• For extensively drug resistant TB (XDR-TB), Clofazimine, Linezolid, and other

drugs may be employed empirically
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 Isoniazid MOA
• Considered the drug of choice for the chemotherapy of TB. Discovered in 1945 a
hydrazide of isonicotonic acid.

• Is bacteriostatic for resting bacilli, Bactericidal for growing bacilli.

• Isoniazid is a prodrug activated by a mycobacterial catalase–peroxidase (KatG).

• Isoniazid targets the enzymes (acyl carrier protein reductase (InhA) and β-ketoacyl-
ACP synthase (KasA),) which are essential for the synthesis of mycolic acid.

• Inhibiting mycolic acid leads to a disruption in the bacterial cell wall.

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 Adverse effects of Isoniazide
• Hepatitis: the most serious adverse effect.

 If hepatitis goes unrecognized, and if isoniazid is continued, it can be fatal.

 The incidence increases with age (greater than 35 years old), among patients who
also take rifampin, or among those who drink alcohol daily.

• Peripheral neuropathy: (manifesting as paresthesia of the hands and feet) appears

to be due to a relative pyridoxine deficiency.

 This can be avoided by supplementation of 25 to 50 mg per day of

pyridoxine (vitamin B6).

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 Adverse effects of Isoniazide
• Central nervous system (CNS) adverse effects: including
convulsions in patients prone to seizures.
• Inhibits of drug metabolism: e.g. carbamazepine and phenytoin

Note :
The main excretory product- acetylisoniazid. This is a result of enzymatic
acetylation, very important in terms of metabolism, Isoniazid is under genetic
control, there are 2 groups of people .Fast and slow acetylators.
Those that have high acetyl transferase activity are fast acetylators, may produce
more of the toxic intermediate.
This is an inherited trait ==> Autosomal dominant.

Ethnicity- Eskimos,native American Indians, and Asians are fast aceytlators.

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 Rifamycins: rifampin, rifabutin, and rifapentine

• They are first-line oral agents for tuberculosis.

• Rifampin: Rifampin has broader antimicrobial activity than

isoniazid and can be used as part of treatment for several different
bacterial infections.

• Because resistant strains rapidly emerge during monotherapy, it is

never
given as a single agent in the treatment of active tuberculosis

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 Rifampin MOA
• Rifampin blocks RNA transcription by interacting with the β subunit of
mycobacterial DNA-dependent RNA polymerase.

Antimicrobial spectrum of Rifampin

• It is bactericidal for both intracellular and extracellular mycobacteria,

including M. tuberculosis and M. leprae

• Frequently used prophylactically for individuals exposed to meningitis

caused by meningococci or Haemophilus influenzae.

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 Pharmacokinetics of Rifampin
• Distribution of rifampin occurs to all body fluids and organs.

• Rifampin can induce hepatic cytochrome P450 enzyme leading to numerous drug
interactions

• Urine, feces, tears and other secretions have an orange-red color

Rifampin adverse effects

Hepatitis and death due to liver failure (rare) (Incidence of hepatic dysfunction
increases when Rifampin is co- administered with Isoniazid )

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 Note
Active disease always requires treatment with multidrug regimens, and
preferably three or more drugs with proven in vitro activity against the
isolate.

Rifampin and Isoniazid are the most effective drugs for the treatment of
TB. The drug enjoys high patient compliance and acceptability. But these 2
drugs should never be given alone! They are always used in combination
because resistance occurs to one drug alone very rapidly. They are used in
combination with each other initially as well as other drugs. Bacilli must
become resistant to two drugs in order to remain viable. Statistically, the
chances are very small of the bacilli becoming resistant to both.
 Rifabutin

• Antimicrobial spectrum – broad

• Therapeutic uses
 Used to treat TB in HIV patients on HAART (Highly Active
Antiretroviral Therapy), as it has less interference with
drug metabolism
– works better against Mycobacterium avium-intracellulare
complex (MAC)
– less active against tuberculosis.

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 Rifapentine
• Antimicrobial spectrum – broad
• Has longer half life than rifampicin or rifabutin
• Therapeutic uses: used to treat TB

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 Ethambutol
• Spectrum of coverage
– Mycobacterium tuberculosis
– M. kansasii
– MAC

• Mechanism of action: inhibits arabinosyl transferases involved in

cell wall synthesis

• Mechanisms of resistance: mutation in arabinosyl transferase gene

• Therapeutic Uses: Tuberculosis

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 Ethambutol Adverse effects
• Optic neuritis (uncommon):
 Dose dependent (more drug = worse symptoms)
 Diminished visual acuity + inability to tell red from green

• Miscellaneous symptoms (rare) – rash, itching, GI upset, etc.

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 Pyrazinamide

– Used in combination with isoniazid, rifampin, and ethambutol

– Spectrum of coverage: Mycobacterium tuberculosis

– Mechanism of action: Unclear

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Some characteristics of first-line drugs
used in treating tuberculosis

CBC = complete blood count. GI =

gastrointestinal
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 Alternate second-line drugs

• Streptomycin
• para-aminosalicylic acid
• Ethionamide
• Cycloserine
• Capreomycin
• Fluoroquinolones
• Macrolides

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 Streptomyci
n
– This is the first antibiotic effective in the treatment of tuberculosis
and is discussed with the aminoglycosides

– Its action is directed against extracellular organisms.

– Infections due to streptomycin-resistant organisms may be treated

with kanamycin or amikacin, to which these bacilli remain
sensitive.

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 Capreomyci
n
– This is a peptide that inhibits protein synthesis.

– It is administered parenterally.

– Capreomycin is primarily reserved for the treatment of multidrug-

resistant tuberculosis.

– Careful monitoring of the patient is necessary to prevent its

nephrotoxicity and ototoxicity.

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 Cycloserin
• Orally effective
e
• An analog of d-alanine synthetase, will block bacterial cell wall synthesis.
• Cycloserine is metabolized, and both parent and metabolite are excreted in urine.
• Accumulation occurs with renal insufficiency.

• Adverse effects :

• CNS disturbances
• Epileptic seizure activity may be exacerbated.
• Peripheral neuropathies

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 Ethionamide
• Structural analog of isoniazid

• Mechanism of action: disrupts mycolic acid synthesis.

• It is effective after oral administration and is widely distributed throughout the body,
including the CSF.

• Adverse effects
– Nausea & vomiting
– hepatotoxicity
– Hypothyroidism
– Gynecomastia
– Alopecia
– Impotence
– CNS effects

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 Fluoroquinolones
• Specifically: Ciprofloxacin, Moxifloxacin and Levofloxacin

• Effective in the treatment of:

– Multidrug-resistant tuberculosis.
– Some atypical strains of mycobacteria.

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 Macrolides
• The macrolides, such as Azithromycin and Clarithromycin, are part of
the regimen that includes Ethambutol and Rifabutin used for the
treatment of infections by M. avium-intracellulare complex.

• Azithromycin is preferred for HIV-infected patients because it is least

likely to interfere with the metabolism of antiretroviral drugs.

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 Leprosy
Dapsone + rifampin
± clofazimine

Dapsone: PABA antagonist, Inhibit folate

biosynthesis

Adverse reactions include hemolysis, especially in

patients
with glucose 6-phosphate dehydrogenase defi
ciency, as well as methemoglobinemia,
peripheral neuropathy,
• Clofazimine is a phenazine dye that binds to DNA and prevents it from serving as
a template for future DNA replication.

• Its redox properties may lead to the generation of cytotoxic oxygen radicals that
are also toxic to the bacteria.

• Clofazimine is bactericidal to M. leprae and has some activity against M. avium-

intracellulare complex.
• Patients may develop a red-brown discoloration of the skin.