MOA Side Effects
FIRST LINE
Isoniazid (INH) 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 forms a covalent complex with an acyl
carrier protein (AcpM) and KasA, a beta-ketoacyl carrier
protein synthetase, which blocks mycolic acid synthesis and
kills the cell.
rifampin (or other Rifampin binds to the subunit of bacterial DNA-dependent
rifamycin) RNA polymerase and thereby inhibits RNA synthesis.
Resistance results from any one of several possible point
mutations in rpoB, the gene for the 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 inhibited by it. 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.
pyrazinamide The drug target and mechanism of action are unknown
ethambutol Ethambutol inhibits 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 ethambutol is due to mutations
resulting in overexpression of emb gene products or within
the embB structural gene.
streptomycin irreversible inhibitors of protein synthesis, but the precise
mechanism for bactericidal activity is not known. The initial
event is passive diffusion via porin channels across the outer
membrane (see Figure 43–3). Drug is then actively
transported across the cell membrane into the cytoplasm by
an oxygen-dependent process. The transmembrane
electrochemical gradient supplies the energy for this process,
and transport is coupled to a proton pump. Low extracellular
pH and anaerobic conditions inhibit transport by reducing
Drug Interaction
Fever and skin rashes are occasionally seen. Drug-induced can reduce the metabolism of phenytoin,
systemic lupus erythematosus has been reported. increasing its blood level and toxicity.
Isoniazid-induced hepatitis is the most common major toxic
effect of isoniazid
Peripheral neuropathy
hematologic abnormalities, provocation of pyridoxine
deficiency anemia, tinnitus, and gastrointestinal discomfort.
harmless orange color to urine, sweat, tears, and contact strongly induces most cytochrome P450
lenses (soft lenses may be permanently stained). isoforms (CYPs 1A2, 2C9, 2C19, 2D6, and
3A4), which increases the elimination of
rashes, thrombocytopenia, and nephritis. It may cause numerous other drugs including
cholestatic jaundice and occasionally hepatitis. methadone, anticoagulants,
cyclosporine, some anticonvulsants,
light-chain proteinuria. protease inhibitors, some nonnucleoside
reverse transcriptase inhibitors,
flu-like syndrome characterized by fever, chills, myalgias, contraceptives, and a host of others.
anemia, and thrombocytopenia and sometimes is associated Administration of rifampin results in
with acute tubular necrosis significantly lower serum levels of these
drugs.
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.
retrobulbar neuritis, resulting in loss of visual acuity and red-
green color blindness. This dose-related adverse effect
ototoxic and nephrotoxic. Vertigo and hearing loss are the
most common adverse effects and may be permanent.
Toxicity is dose-related
Fever, skin rashes, and other allergic manifestations may
result from hypersensitivity to streptomycin. This occurs
most frequently with prolonged contact with the drug either
in patients who receive a prolonged course of treatment (eg,
for tuberculosis) or in medical personnel who handle the
 the gradient. Transport may be enhanced by cell wall-active drug. Desensitization is occasionally successful.
drugs such as penicillin or vancomycin; this enhancement Pain at the injection site is common but usually not severe.
may be the basis of the synergism of these antibiotics with The most serious toxic effect with streptomycin is
aminoglycosides. disturbance of vestibular function—vertigo and loss of
Inside the cell, aminoglycosides bind to specific 30S-subunit balance.
ribosomal proteins (S12 in the case of streptomycin). Protein
synthesis is inhibited by aminoglycosides in at least three
ways (Figure 45–3): (1) interference with the initiation
complex of peptide formation; (2) misreading of mRNA,
which causes incorporation of incorrect amino acids into the
peptide and results in a nonfunctional or toxic protein; and
(3) breakup of polysomes into nonfunctional monosomes.
These activities occur more or less simultaneously, and the
overall effect is irreversible and lethal for the cell.

SECOND LINE
Amikacin
Aminosalicylic acid
Capreomycin
Cycloserine
Ethionamide
(Thioamides)
Levofloxacin
SECOND or maybe
3rd LINE
Rifabutin
Rifapentine
Ciprofloxacin
Clofazimine