Antimycobacterial Drugs

Question 1

Nicotinic acid derivative (isonicotinic acid hydrazide)

Answer 1

Isoniazid

Question 2

Isoniazid - MoA

Answer 2

Inhibition of mycolic acid synthesis (needed for cell wall)

katG gene

Question 3

Isoniazid - Clinical use

Answer 3

1st line TB.
Bactericidal: M.tuberculosis and M.kansaii
Little activity: M.avium-intracellulare.
Not active: M. leprae.

Given to prevent TB in neonates and children who have had close contact with persons in whom active TB was recently diagnosed

Active and latent TB

Question 4

Isoniazid - Adverse effects

Answer 4

Hepatotoxicity (from metabolite acetylhydrazine)

Peripheral neuritis (paresthesias, numbness of fingers and toes, in vit B6 deficiency, effect individuals with slow acetylator phenotype)

Toxic encephalopathy
Seizures

Hematologic abnormalities (granulocytosis, anemia, thrombocytopenia)

Hepatitis (highest prevalence for persons over 50 years, elevated serum transaminase)

Question 5

Isoniazid - Interactions

Answer 5

Alcohol + rifampin: increased risk of hepatotoxicity.

Increases carbamazepine and phenytoin levels.

Aluminum salts: inhibits absorption

Question 6

Isoniazid - Special considerations

Answer 6

Genetically different rate of acetylation of drug causes different plasma concentrations.

Question 7

Synthetic butanol derivative

Answer 7

Ethambutol

Question 8

Ethambutol - MoA

Answer 8

Bacteriostatic for mycobacteria

Inhihits arabinosyl transferase and the synthesis of arabinogalactam required for mycobacterial cell wall formation

Question 9

Ethambutol - Clinical use

Answer 9

1st line TB.
Bacteriostatic activity

M. avium-intracellulare infections

Question 10

Ethambutol - Adverse effects

Answer 10

Dose dependent optic neuritis and impaired red-green color discrimination

Hyperuricemia
Gout
Hepatitis
Thrombocytopenia

Question 11

Ethambutol - Special consideration

Answer 11

Monitor visual color discrimination regularly

Question 12

Ethambutol - Contraindications

Answer 12

Children too young to permit assessment of visual acuity and red-green discrimination

Question 13

Synthetic Nicotinamide derivatie

Answer 13

Pyrazinamide

Question 14

Pyrazinamide - MoA

Answer 14

disrupts mycobacterial cell membrane metabolism and transport functions

M. tuberculosis: inhibits the growth by inhibiting fatty acid synthesis required for cell membrane function.

Inhibits also RNA

Question 15

Pyrazinamide - Clinical use

Answer 15

1st line TB.

Rapid bactericidal action

Question 16

Pyrazinamide - Adverse effects

Answer 16

Hepatits
Hyperuricemia and gout
Arthalgia
Hematologic toxicity
Fever
Increase in Fe serum concentration

Question 17

Rifamycin derivatives

Answer 17

Rifampin
Rifapentine
Rifabutin

Question 18

Rifampin - MoA

Answer 18

Binds to DNA-dependent RNA polymerase, preventing DNA transcription and RNA synthesis

Question 19

Rifampin - Clinical use

Answer 19

Broad-spectum, gram (+), (-) and acid fast bacilli

1st line TB.
Combined with isoniazid, ethambutol, pyrazinamide to treat TB.
Combined with sulfone or clofazimine to treat leprosy.

Alternative to INH if resistance.

Meningitis prophylaxis
H. influenzae B inf
Prevent meningococcal disease
Tubercular meningtiis
Eliminate staph.coccal carriage,
Staph endocarditis (in comb. with vancomycin and gentamicin)
Legionella pneumphila (in comb with macrolide/fluoroquinolone)

Question 20

Rifampin - Special considerations

Answer 20

Penetrates inflamed meninges

Liver function tests must be done evere 2-4 weeks of treatment.

Never use alone in active infection

Question 21

Rifampin - Adverse effects

Answer 21

Impaired liver function
Elevate serum bilirubin and transaminase levels
Hepatitis
Hypersensitivity: chills, fever, fatigue, headache (50 % of patients!)
High dose: renal disease, leukopenia, thrombocytopenia, purpura
Reddish-orange to brown discoloration of saliva, tears, and urine
Light-chain proteinuria

If administered less often than twice weekly: flu-like syndrome (fever, chills, myalgias, anemia, thrombocytopenia)

Question 22

Rifampin - Interactions

Answer 22

Alcohol consumption appears to increase the risk of hepatitis and should be avoided in persons being treated for TB.

Rifampin induces cytochrome p450 isozymes, CYP1A2, CYP2C9 and CYP3A4, and can thereby accelerate the metabolism of other drugs and reduce their serum concentrations and therapeutic effectiveness

These drugs include: macrolides, benzodiazepines, Ca channel blockers, digoxin, estrogens, sulfonylureas, theophylline, warfarin.

Question 23

Rifapentine - Clinical use

Answer 23

Pulmonary TB by M. tuberculosis
Twice-weekly combined with isoniazid, ethambutol, and pyrazinamide for 2 months, and once-weekly with isoniazid for an additional 4 months.

Question 24

Rifabutin - Clinical use

Answer 24

Preferred for treating TB in HIV patients (protease inhibitors can be used).
M. avium intracellulare
M. fortuitum

Question 25

Rifabutin - Interactions and Adverse effects

Answer 25

Cytochrome P450 and GI irritation

Question 26

Streptomycin (antimycobacterial) - Clinical use

Answer 26

TB: Resistance to other TB drugs Active against M. avium complex, M. kansasii

Question 27

Streptomycin (antimycobacterial) - Adverse effects

Answer 27

Nephrotoxicity, ototoxicity

Question 28

Amikacin (antimycobacterial) - Clinical use

Answer 28

2nd line TB Multidrug resistant tuberculosis strains, atypical mycobacteria. Combined with at least one other drug

Question 29

Dapsone - MoA

Answer 29

Inhibits folic acid synthesis

Question 30

Dapsone - Clinical use

Answer 30

Leprosy (both types) Bacteriostatic

Question 31

Dapsone - Adverse effects

Answer 31

``` GI disturbances Peripheral neuropathy Optic neuritis and blurred vision Proteinuria Nephrotic syndrome SLE-like syndrome Hematologic toxicity G6PD-def: hemolytic anemia ```

Question 32

Clofazimine - Clinical use

Answer 32

Bactericidal: M. tuberculosis Bacteriostatic: M. leprae + avium-intracellulare. Erythema nodosum leprosum (in lepromatous leprosy)

Question 33

Dapsone - Contraindications

Answer 33

Glucose 6 phosphate dehydrogenase deficiency

Question 34

Clofazimine - Adverse effects

Answer 34

``` GI distress Photosensitivity Skin discolorations Discoloration of body fluids Elevation of hepatic enzyme levels Hepatitis ```

Question 35

Clofazimine - Contraindications

Answer 35

Hepatic disease

Question 36

Thalidomide - Clinical use

Answer 36

TB Leprosy Erythema nodosum leprosum

Question 37

Antimycobacterial drugs - Administration

Answer 37

Generally Oral Isoniazid: + IM Rifampim: + IV Streptomycin: Only IM

Question 38

Bedaquiline - MoA

Answer 38

Blocks the proton pump for ATP synthase in M. tuberculosis

Question 39

Bedaquiline - Clinical use

Answer 39

MDR-TB in adults and children when another effective treatment cannot be provided. Adm. Once daily for 2 weeks, then 3 times per week for 22 weeks.

Question 40

Bedaquiline - Advers effects

Answer 40

Prolonged QT - arrhythmias, sudden death Liver reactions; nausea, headache

Question 41

Bedaquiline - Special considerations

Answer 41

Used with at least 3 other drugs Patients must have an electrocardiogram before treatment is begun, and at regular intervals thereafter Patients should be monitored for adverse liver reactions

Question 42

Bedaquiline - Interactions

Answer 42

Cytochrome P450

Question 43

Isoniazid - Contraindications

Answer 43

Vitamin B6 deficiency