Review of Pharmacology - 9E (2015)

CHAPTER
14
Chemotherapy B: Antimicrobials
for Specific Conditions
Anti-Mycobacterial Antibiotics
Mycobacterium causes tuberculosis and leprosy. Several atypical mycobacteria may also
cause infection in humans especially in the immunocompromised patients.
Tuberculosis
It is caused by Mycobacterium tuberculosis. The drugs used for tuberculosis are
First line
Essential Supplementary Thiacetazone
Second line
Isoniazid (H) Streptomycin (S) Paraaminosalicylic acid Ofloxacin
Rifampicin (R ) Rifabutin Ethionamide Levofloxacin
Pyrazinamide (Z) Rifapentine Cycloserine Moxifloxacin
Ethambutol (E) Kanamycin Linezolid
Capreomycin
Amikacin
Clarithromycin
Isoniazid (H)
• It is a prodrug activated by catalase-peroxidase (coded by KatG). Active metabolite
inhibits the enzyme ketoenoylreductase (coded by inh A), required for mycolic acid
synthesis, an essential component of mycobacterial cell wall. It acts by O 2
dependent
pathway such as catalase peroxidase reaction.
• It is the single most important drug used in tuberculosis. Mycobacterial strains are
assumed to be susceptible to isoniazid, if the resistance is less than 4%.
• It is bacteriostatic against resting and bactericidal against rapidly multiplying organisms.
• It is effective against intra- as well as extra-cellular mycobacteria.
• Action is most marked against rapidly multiplying bacilli (less effective against slow
multipliers).
• It is widely distributed in the body including CSF.
• It is effective orally and metabolized by ACETYLATION which is genetically
controlled. Fast acetylators require high dose and slow acetylators are predisposed to
toxicity (particularly peripheral neuritis).
• It is an essential component of multi-drug therapy of tuberculosis and is drug of
choice (used solely) for prophylaxis of tuberculosis and for treatment of latent
tuberculosis infection.
• Resistance occurs due to mutation in Kat G (gene for catalse-peroxidase) or inhA.
Mutation in kat G is responsible for high level resistance whereas mutation in inhA
confers cross resistance to ethionamide.
• It causes peripheral neuritis that can be prevented and treated by pyridoxine.
• It is also hepatotoxic and can cause hemolysis in G-6 PD deficient patients. Incidence
of hepatotoxicity increases with age, daily alcohol consumption and in post partum
(3 months) period.
• Isoniazid also inhibits MAO-A; thus can result in cheese reaction.
• Rash, fever, anemia, optic atrophy, seizures, lupus like syndrome, psychosis and
gynaecomastia has also been reported with this drug.
Mycobacteria Most
effective
drug
1. Rapidly H
growing
(wall of
cavitary
lesion)
2. Slow growing Z
(intracellular)
3. Spurters R
(within caseous
material)
Isoniazid is metabolized by
ACETYLATION which is
genetically controlled. Slow
acetylators are predisposed to
toxicity particularly peripheral
neuritis.
Drug
H
R
Z
E
S
Action
CIDAL
CIDAL
CIDAL
STATIC
CIDAL
Hepatotoxic
Yes
Yes
Yes
No
No
Bacteria
Inhibited
Both
Both
Intracellular
Both
Extra
cellular
Rifampicin (R)
• It is a derivative of rifamycin (other derivatives are rifabutin and rifapentine). It is
bactericidal against both dividing and non-dividing mycobacterium and acts by
inhibiting DNA dependent RNA polymerase.
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