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Lec 5: Antimycobacerial Drugs by Dr. Frederick Loyola July 7, 2010

Ma
na

• A prodrug activated by KatG ( mycobacterial

Ya
y
pa catalase-peroxidase)
Je I. Antimycobacterial Agents • Resistance due to:
is A. Isoniazid - overexpression of inhA/changed inhA
av B. Rifampicin gene: low-level res; cross resistance to ethionamide
M C. Pyrazinamide - mutation or deletion of Cat K gene (codes
vs D. Ethambutol for catalase): high-level res; no cross resistance to
E. Streptomycin ethionamide
- overexpression of ahpC
Re
II. Treament Regimen for TB:
- mutation in kasA
ai
DOTs
• readily absorbed from GIT w/ peak concentration
M
n III. Major Side Effects of Drugs
IV. Minor Side Effects of Drugs w/in 1-2 hours; absorption decreased by aluminum
hydroxide
Re
V. Anti-TB Drugs on Pregnancy
• oral absorption complete in fasting state; less with
co
Ri and Lactation
F. VI. Drugs for Non-Tuberculous food and antacids
ul • diffuses into all body fluids and tissues
Pa Anti-Mycobacterials (Anti-TB) • Metabolism genetically determined : fast acetylators
vs First line agents: (t1/2= 1 hr); slow acetylators (t1/2= 3 hrs)
Vi - Isoniazid (H) • Excreted in urine
e - Rifampin (R) • Dose not adjusted in renal failure but in hepatic
en - Pyrazinamide (Z) insufficiency
Arl - Ethambutol (E) • Increases plasma concentration of Phenytoin &
ňa - Streptomycin (S) Carbamazepine
Second line agents:
Ni • Protect drug from light
Amikacin, Aminosalicylic acid, Capreomycin,
• Adverse effects: allergy, hepatitis (age-dependent),
ng
Ciprofloxacin, Moxifloxacin, Cycloserine, Ethionamide,
peripheral neuritis (use B6), CNS, tinnitus, GI
da
kanamycin, Levofloxacin
discomfort, hemolysis in G6PD deficiency, SLE in slow
Da
*H and R: 2 most active drugs
acetylators (rare)
r
he
ac Characteristics of Mycobacterium tuberculosis
• Naturally occurring drug resistant mutants are
B. Rifampicin (R)
Te
co present within large bacterial populations even
Ri before chemotherapy is started • MOA: inhibits RNA synthesis
ie • Replicates slowly, can remain dormant for • Inhibits DNA-dependent RNA polymerase; resistance
ck prolonged periods and can be eradicated only during (changed enzyme) emerges rapidly if used alone
Ni replication • Most potent sterilizing drug available
ad • Bacilli live in several sites within the host and • Bactericidal against rapidly dividing and alowly
Gl each site contains organisms with a different growing bacilli
Je population size, metabolic activity and replication • Active against Gram (+) and gram (-) cocci, some
nz rate enteric bacteria, mycobacteria and chlamydia;
Ay bactericidal
th Principles on Treatment • Acts on extra- & intra-cellular bacillary populations
Ka • Treatment of disease must contain multiple • Resistance: mutations prevent binding of Rifampin to
o drugs to which the organisms are susceptible RNA polymerase
Jh • Drugs must be taken regularly • Well-absorbed orally in the fasting state; distributed
ah • Drug therapy must continue for a sufficient widely; highly protein-bound; t1/2=1.5-5 hrs
en length of time (6 months) to fully eradicate the • CSF concentration. achieved in inflammation
Gi tubercle bacilli to achieve lasting cure • Induces hepatic enzymes
• Excreted through liver into bile; re-circulated and
o
Main Properties of Anti-TB Drugs
excreted in feces and urine
Ed
• Bactericidal Activiy
• No dose adjustment for renal insufficiency
lle
• Streilizing Activity
• Protect drug from light
ce
• Ability to prevent or delay emergence of
• Adverse effects: proteinuria, hepatitis, flu-like
Jo
resistance
syndrome, induction of P450, thrombocytopenia, red-
be

orange metabolites
Jo
z A. Isoniazid (INH)
Iv
• Inhibits mycolic acid synthesis (essential Therapeutic Uses:
component of mycobacterial cell wall ) bactericidal • Tuberculosis: in combination w/ INH etc.
rk

•
Ma
Acts on extra- & intra-cellular bacillary • Atypical mycobacterial infections
populations
el
ch • Leprosy: with sulfone
Ra
” Page 1 of 7
“G
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Ia
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Ni • Meningococcal carriage
• H. influenzae type b prophylaxis Direct Observed Therapy Short-Course (DOTS)
• Staphylococcal carriage: in combination • Political commitment
• Penicillin-resistant pneumococcal meningitis:
combine with Ceftriaxone or Vancomycin • Case detection by sputum smear microscopy

C. Pyrazinamide (Z) • Standardized short course therapy with direct

observation of drug intake
• MOA: unknown, but metabolically activated-bacterial
strains lacking bioactivating enzymes are resistant
• Relative of nicotinamide • Regular uninterrupted supply of all essential
• Exerts activity against intracellular organisms in anti-TB drugs
acidic environment; weakly bactericidal, ”sterilizing
agent” • Standardized recording and reporting system
• Resistance due to mutations in pncA that impair
conversion of pyrazinamide to its active form
• No cross resistance w/ INH or other TREATMENT REGIMEN FOR TB
antimycobacterials REGIMEN PATIENT DOSE ADJ.
• Readily absorbed from GIT; distributed to all fluids (kg)
and tissues Regimen New smear (+) 1 tab INH
• Inactive at neutral pH I New smear (-) (100 mg)
2HRZE/ w/ extensive + PZA
• Serum conc. at 1-2 hrs. after oral intake
4HR parenchymal (500 mg)
• t1/2= 8-11 hrs
involvement + Etham
• Protect drug from light New extra- (400 mg)
• Adverse effects: polyarthralgia-myalgia, hepatitis, pulmonary for > 50 kg
rash, hyperuricemia, phototoxicity, increase porphyrin body wt
synthesis before
D. Ethambutol (E) treatment
• MOA: inhibitor of mycobacterial arabinosyl Regimen Previously
transferases II treated smear
2 HRZES/ (+) PTB w/
• Blocks formation of arabinoglycan, an essential
1HREZ/ relapse,
component of mycobacterial cell wall, by inhibiting
5HRE treatment
arabinosyl transferases
failure,
• Bacteriostatic but with some bactericidal action at
treatment after
higher doses
interruption
• Acts on extra- & intra- cellular bacillary population
Regimen New Smear (-) 1 tab of INH
• Well-absorbed in GIT; conc. reached in 2-4 hours III PTB other than (100 mg)
• Not affected by food but delayed by aluminum 2HRZ/ Cat 1 + PZA
hydroxide and alcohol 4HR Extra- (500 mg)
• t1/2=3-4 hrs pulmonary TB each for
• Resistance due to mutations of emb gene; resistance less severely ill >50 kg
rapid when given alone body wt
• Accumulates in renal failure: dose reduced to half before
• Excretion: feces, urine treatment
• Dose-dependent retrobulbar neuritis – decrease
visual acuity
• Not to be given in children below 6 years because of
unreliable monitoring of visual acuity

E. Streptomycin (S)
• MOA: irreversible inhibitor of protein synthesis by
binding to 30s subunit;
• Resistance & features of aminoglycoside
MAJOR SIDE-EFFECTS OF DRUGS
• Bactericidal to actively multiplying extracellular
bacilli in alkaline medium and in caseous ;ining of the
walls of pulmonary cavitations
• Poor penetration into cells; active against extra-
cellular tubercle bacilli
• Serum conc. achieved 30-60 min. after IM
• Not absorbed in the GIT
• Do not give together with other nephrotoxic or
ototoxic drugs
• Monitor renal function & reduce dose to 50% if with
decrease urine output

Page 2 of 7
 Anti-TB Drugs on Pregnancy and Lactation

• INH, rifampin & ethambutol cross placenta; standard

drugs given to pregnant women
• PAS can be safely used but could be poorly tolerated
• Streptomycin & other aminoglycosides should be
avoided; effect on ear development & function
• Capreomycin, ethiomide, quinolones & cycloserine
not recommended
• PZA avoided; inadequate data on teratogenicity
• Breastfeeding not discouraged; feed infants first
before taking meds
• Drugs in breast milk not considered effective
treatment of tuberculosis in infants

MINOR SIDE-EFFECTS OF DRUGS

Drugs for Non-Tuberculous Mycobacteria

M. avium-intracellulare (MAC)

• Pulmonary diseases in patients with chronic

lung disease, disseminated infections in AIDS

• Prophylaxis: Azithromycin or Clarithromycin

• Treatment: Clarithromycin or Azithromycin +

Ethambutol +/- Rifabutin or Ciprofloxacin

M. kansasii

• Resembles tuberculosis

• Rifamicin, Ethambutol, Isoniazid(±)

Anti-Mycobacterials (Anti-Leprosy)
Dapsone & other sulfones (anti-folate)
• bacteriostatic
• Resistance if very low doses are given; combination
recommended for initial therapy
• t1/2= 1-2 days; tends to be retained in skin, muscle,
liver, kidney
• Dose adjusted in renal failure
• ADR: hemolysis if w/ G6PD deficiency;
methemoglobinemia; GI intolerance; fever; pruritus;
erythema nodosum leprosum

Rifampin :
• effective in lepromatous leprosy
• bactericidal for M. leprae

Clofazimine: unknown MOA (DNA binding)

- stored in reticuloendothelial tissue & skin;
slow release; t1/2= 2 months
- for sulfone-resistant leprosy
- ADR: skin discoloration (red-brown to black)

Prednisone

Thalidomide- inhibits angiogenesis; anti-inflammatory;

immunomodulatory; for multiple myeloma

Recommended Treatment for Leprosy

Page 3 of 7
• Indeterminate- smear (-), flat hyposthetic lesion
usually in face, arms, legs
- single dose Rif + Oflo + Minocycline
• Paucibacillary- smear (-), flat hyposthetic,
hyperpigmented lesions no more
than 5
- Rif once a month + Dapsone OD x 6 mos.
• Multibacillary- smear (+) which are multiple,
erythematous, copper- colored
plaques, nodules w/ or w/o anesthesia
- Rifam + Dapsone + Clofazimine once a
month x 12 months

Page 4 of 7
 ANTIMYCOBACTERIALS (Anti-TB)
Drug Mechanism Toxicity Pharmacoki Indications Notes
netics
First line drugs

Inhibits Allergy; hepatitis (age- Absorbed Isoniazid as a single agent is also indicated for
synthesis of dependent); from the treatment of latent tuberculosis ((+) in tuberculin
Isoniazid (H) mycolic acids peripheral gastrointestin test). Prophylaxis of close contacts of infectious
(bactericidal) neuropathy (usually al tract cases.
in slow acetylators);
CNS; tinnitus; PO/IV
gastrointestinal
discomfort, Pyridoxine
deficiency

Inhibits RNA Proteinuria, hepatitis, PO; excreted Orally, 600 mg/d (10 mg/kg/d) must be
synthesis flu-like syndrome, mainly administered with isoniazid or other
induction of P450, through the antituberculous drugs to patients with active
thrombocytopenia, liver into bile tuberculosis to prevent emergence of drug-
red-orange resistant mycobacteria
Rifampin (R)
metabolites,
Hepatotoxicity An alternative to isoniazid prophylaxis for
patients with latent

Can eliminate meningococcal carriage

Used as prophylaxis in contacts of children with

Haemophilus influenzae type b disease

It is combined with a second agent is used to

eradicate staphylococcal carriage

Rifampin combination therapy is also indicated

for treatment of serious staphylococcal infections
Pyrazinamide such as osteomyelitis and prosthetic valve
(Z) endocarditis.

Unknown Hepatotoxicity; PO; Readily Used in combination with other drugs such as An important front-line
nausea, vomiting, drug absorbed isoniazid and rifampicin in the treatment of drug used in conjunction
fever, and from GIT Mycobacterium tuberculosis with isoniazid and
hyperuricemia; rifampin in short-course
(ie, 6-month) regimens
polyarthralgia-myalgia, as a "sterilizing" agent
hepatitis, rash, active against residual
phototoxicity, intracellular organisms

Page 5 of 7
 increase porphyrin
synthesis Tubercle bacilli develop
Ethambutol (E) resistance to
pyrazinamide fairly
readily

Inhibitor of Retrobulbar neuritis, Well Indicated for the treatment of pulmonary

mycobacterial resulting in loss of absorbed tuberculosis
arabinosyl visual acuity and red- from the gut
transferases green color blindness, (conc. It should not be used as the sole antituberculous
Hypersensitivity- reached in 2- drug, but should be used in conjunction with at
dermatitis, arthralgia, 4 hours) least one other antituberculous drug
fever

irreversible Ototoxic and IM/IV Streptomycin sulfate is used when an injectable

inhibitor of Nephrotoxic, drug is needed or desirable, principally in
Streptomycin protein paresthesia, dizziness, individuals with severe, possibly life-threatening
(S) synthesis nausea, peripheral forms of tuberculosis (eg, meningitis and
neuropathy, allergy disseminated disease)

DRUGS USED IN LEPROSY

Drug Mechanism Toxicity Pharmacoki Indications Notes
netics

Clofazimine unknown but skin discoloration PO Given for sulfone-resistant leprosy or when
may involve (red-brown to black) patients are intolerant to sulfones
DNA binding Combination regimen with dapsone and
rifampicin for multibacillary leprosy
Erythema nodosum leprosum
M. avium infection
All forms of leprosy
Dapsone inhibits folate Hemolysis if w/ G6PD PO May also be used to prevent and treat
(diaminodiphenyl synthesis deficiency; Pneumocystis jiroveci pneumonia in AIDS patients
sulfone) methemoglobinemia;
GI intolerance; fever;
pruritus; erythema
nodosum leprosum

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