Antimycobacterial drugs

Question 1

Description of Isoniazid

Answer 1

Most important first-line agent for TX of tuberculosis; structurally related to pyridoxine

Can be used prophylactically as single agent for skin test converters or if contacting patients with active disease

Question 2

Mechanism of Action of Isoniazid

Answer 2

Enters bacilli as a prodrug, activated to an isonicotinoyl radical by KatG, a mycobacterial heme-containing catalase-peroxidase enzyme; the isonicotinoyl radical reacts with NAD and NADP to produce a dozen adducts

An isonicotinoyl-NAD adduct inhibits enoyl acyl carrier protein reductase (InhA) and β-ketoacyl acyl carrier protein synthase (KasA), decreasing the synthesis of mycolic acid and leading to cell death

An isonicotinoyl-NADP adduct inhibits DHFR to reduce nucleic acid synthesis

Question 3

Pharmacokinetics of Isoniazid

Answer 3

Usually administered PO; food decreases absorption so best taken on an empty stomach; widely distributed into all body fluids and tissues
Dosing is fairly long-term, e.g., 300 mg QD for 6-12 months
Metabolized mainly by acetylation (genetically variable); ca. 75% of drug and metabolites are excreted in the urine (rapid vs. slow acetylators need different doses).

Question 4

Adverse reactions and counterindications of isoniazid

Answer 4

Elevated LFTs (10-20%), hepatitis (1%, DC if symptoms of hepatitis occur)

Peripheral neuropathy via pyridoxine depletion (2%; occurs more frequently at high doses and in malnourished patients, diabetics, and alcoholics): twitching, paresthesias

Hepatitis; monitor LFTs; avoid alcohol and acetaminophen
Administer vitamin B6 to avoid neuropathy

Question 5

Description of Rifampin

Answer 5

One of a group of rifamycin-class antibiotics
First-line anti-TB agent; available alone or in combination with INH
Broad-spectrum antibiotic, active in most gram-positive and many gram-negative bacteria and mycobacteria; a DOC for leprosy, DOC for prophylaxis of H. influenzae meningitis and meningococcal disease

Question 6

Mechanism of Action of rifampin

Answer 6

Bactericidal; binds to bacterial b subunit of RNA polymerase thereby inhibiting RNA synthesis with consequent decreased protein synthesis
Resistance arises from point mutations in rpoB gene coding for b subunit of RNA polymeras

Question 7

Pharmacokinetics of rifampin

Answer 7

Administered PO and IV; best taken on an empty stomach
Usual dose for TB is 600 mg PO QD for 6-9 months; for meningitis and meningococcal prophylaxis, dosing is for 2-4 days; in leprosy TX, dosing is 600 mg Q month
Rifampin and its metabolite are primarily excreted (60%) in feces via biliary elimination; and up to 30% is excreted in urine

Question 8

Adverse reactions and counterindications of rifampin

Answer 8

GI: NVD, cramps, hepatitis
Strong inducer of most hepatic CYPs → many drug interactions, ↓ bioavailability over time
Flu-like hypersensitivity reaction (50%): fever, chills, headache, fatigue
Harmless reddish-orange or reddish-brown discoloration of bodily fluids

Hepatic disease: hepatitis, jaundice; alcoholism; monitor LFTs (No frank hepatoxicity like isoniazid)
In HIV+ PX receiving protease inhibitors or nonnucleoside reverse transcriptase inhibitors, replace rifampin with rifabutin

Question 9

Description of Ethambutol

Answer 9

First-line anti-TB agent, used in combination with INH, pyrazinamide, rifampin

Question 10

Mechanism of action of ethambutol

Answer 10

Complex mechanism of action: blocks arabinosyl transferase III involved in cell wall biosynthesis; appears to inhibit RNA synthesis, resulting in impaired protein synthesis; may interfere with mycolic acid biosynthesis
Ethambutol is only effective against bacilli that are actively dividing (bacteriostatic)

Question 11

Pharmacokinetics of ethambutol

Answer 11

Administered PO, usually 15 mg/kg QD for 6-9 months
Well-absorbed, widely distributed
Metabolism via sequential oxidation of alcohols resulting in dicarboxylic acid metabolite
Parent drug and its metabolites are excreted primarily in the urine (50-65%), with 20-25% excreted unchanged in the feces

Question 12

Adverse reactions and precautions against ethambutol

Answer 12

The most common adverse effect is a dose-dependent (but rare at standard doses), usually reversible, optic neuritis resulting in decreased visual acuity and red-green color blindness

Optic neuritis
Monitor visual function; avoid ethambutol in young children in whom visual assessment is not reliable
Adjust dosage with renal impairment: if CrCL 10-50 mL/min: extend dosing interval to every 24-36 hr; if CrCL

Question 13

Description of pyrazinamide

Answer 13

First-line anti-TB agent, used in combination with INH, ethambutol, rifampin

Question 14

Mechanism of action of pyrazinamide

Answer 14

Requires metabolic activation (hydrolysis) to pyrazinoic acid by M. tuberculosis pyrazinamidase enzyme
Exact MOA unknown but three proposed mechanisms are 1) inhibition of eukaryotic-like fatty acid synthetase I of M. tuberculosis, 2) reduction of intracellular pH 3) disruption of membrane transport
Bacteriostatic at low concentrations and bactericidal at high concentrations

Question 15

Pharmacokinetics of ethambutol

Answer 15

Administered PO, 15-30 mg/kg QD, usually for 2 months if bacilli are not resistant
Well-absorbed, widely distributed, peak plasma concentration achieved within 2 hours
Pyrazinamide and its metabolites (liver) are excreted in the urine (70%), mainly via glomerular filtration

Question 16

Adverse reactions and precautions against pyrazinamide

Answer 16

Hepatotoxicity is the most serious adverse reaction of pyrazinamide, manifesting as hepatitis, jaundice, elevated LFTs, but hepatotoxicity is uncommon (1-5%) with current regimens
Hyperuricemia; interferes with uric acid excretion
Skin: rash, photosensitivity
Arthralgia (40-70%)

Hepatic disease: hepatitis, jaundice, alcoholism; monitor LFTs
Interferes with urine ketone determination (Ketostix®, etc.)
Gout

Question 17

Second line therapies for TB include:

Answer 17

Ethionamide (blocks mycolic acid synthesis like isoniazid)

para-Aminosalycilic acid (mimics PABA, inhibits dihydropteroate synthase to decr purine synthesis)

Cycloserine (d-ala analog to inhibit alanine racemase to decr cell wall synthesis)

Capreomycin (cyclic peptide protein synthesis inhibitor)

Aminoglycoside antibiotics (bind 30S ribosome subunits)

Fluoroquinolone antibiotics (inhibits topoisomerases)

Question 18

Description of aminoglycosides

Answer 18

Primary agents: amikacin, gentamicin, kanamycin, neomycin, tobramycin, streptomycin; all are amino sugars
Active mainly vs. aerobic, gram-negative bacilli including Escherichia coli, Klebsiella sp., Enterobacter sp., Proteus sp., Pseudomonas sp

Question 19

Mechanism of action of aminoglycosides

Answer 19

Bactericidal: inhibit protein synthesis; bind to 30S ribosomal subunit
Resistance via inactivating enzymes, increased expression of efflux pumps, mutations in 30S subunit components 16S mRNA and ribosomal protein S12

Question 20

Pharmacokinetics of aminoglycosides

Answer 20

Polar compounds; not well-absorbed orally, so usually given parenterally or used topically
Major elimination route is via glomerular filtration; excretion is directly proportional to creatinine clearance and adjustments must be made in patients with renal insufficiency
Plasma drug levels often monitored to make dosing adjustments

Question 21

Toxicity of aminoglycosides

Answer 21

Ototoxicity, nephrotoxicity, NMJ blockade (curare-like), allergic skin rxn or contact dermatitis, pregnancy category D.

Question 22

Description of Moxifloxacin

Answer 22

Broad spectrum fluoroquinolone antibacterial agent for oral and intravenous administration
Used as adjunctive second-line tuberculosis therapy in relapse, treatment failure, or M. tuberculosis resistant to isoniazid, rifampin, or when first-line drugs cannot be tolerated

Question 23

Mechanism of action of moxifloxacin

Answer 23

Interferes with bacterial DNA function by stabilizing topoisomerase II- and topoisomerase IV-DNA cleavage complexes, inhibiting DNA duplication, transcription, repair, and recombination
Resistance (1.8 x 10–9 to

Question 24

Pharmacokinetics of moxifloxacin

Answer 24

Formulated as 400 mg tablets and in NS for IV infusion, given as 400 mg QD for 12-18 months if rifampin-resistant strain is involved; 18-24 months if isoniazid- and rifampin-resistant strains are involved, 24 months if strain is resistant to isoniazid, rifampin, ethambutol, and/or pyrazinamide
F = 0.9, widely distributed; peak plasma concentration achieved within 3-4 hr, t1/2 ca. 12 hr
Metabolized (ca. 50%) via glucuronide (urine) and sulfate (feces) conjugation, no CYP involvement; remainder is excreted as unchanged drug

Question 25

Adverse reactions and precautions for moxifloxacin

Answer 25

Well-tolerated; most-frequent adverse effects have a GI emphasis: NVD, abdominal discomfort
Joint swelling, tendinitis, tendon rupture
CNS: nervousness, dizziness, insomnia
CV: QT prolongation (6-7 msec)
Worsening of myasthenia gravis due to neuromuscular blockade

Patients with prolonged QT interval, hypokalemia, or receiving class IA or III antiarrhythmic drugs
Myasthenia gravis

Question 26

Description of Bedaquiline

Answer 26

FDA approved December 2012 for multidrug-resistant tuberculosis
Used in adults with MDR tuberculosis as part of combination therapy with at least 3 other drugs if TB isolate demonstrates in vitro susceptibility or with 4 other drugs if in vitro testing is not available

Question 27

Mechanism of action of bedaquiline

Answer 27

Binds to mycobacterial ATP synthase subunit c, supplemented with residues from subunit a; inhibits ATP biosynthesis by preventing rotation of subunits c

Question 28

Pharmacokinetics of bedaquiline

Answer 28

Supplied as 100 mg tabs for PO dosing
400 mg QD for weeks 1-2
200 mg three times per week for weeks 3-24
Food increases F by 2-fold, so all doses are taken with meals
CYP3A4 is the major isozyme involved in metabolism
Long half-life of about 5 ½ months; main route of excretion is via feces with only 0.001% excreted in the urine as parent drug

Question 29

Adverse reactions and precautions for bedaquiline

Answer 29

GI: nausea (38%)
MSK: arthralgia (33%)
Headache (28%)
CV: QT prolongation (10-23 ms)

Obtain ECG at baseline and at weeks 2, 12, and 24; DC if QT interval > 500 ms is obtained
Hepatic impairment; monitor LFTs, avoid alcohol, acetaminophen; DC if LFTs > 8x ULN

Question 30

Description of dapsone

Answer 30

Active vs. M. leprae; a DOC for leprosy in multidrug regimens
Very versatile, used as an antiinfective for Pneumocystis carinii pneumonia and prophylaxis of malaria, and as an immunosuppressive agent for relapsing cartilage inflammation and systemic lupus erythematosus; also used to treat various dermatologic disorders

Question 31

Mechanism of action of dapsone

Answer 31

Similar to sulfonamides, dapsone inhibits dihydropteroate synthase → ↓ folic acid → ↓ DNA synthesis

Question 32

Pharmacokinetics of dapsone

Answer 32

Administered PO, usually 50-100 mg QD for leprosy
TX for years and sometimes for lifetime; usually given with monthly rifampin and clofazimine
Metabolized by acetylation and undergoes enterohepatic cycling

Question 33

Adverse reactions and precautions against dapsone

Answer 33

GI disturbances, hepatitis
Blood: hemolysis is reported in the majority of patients receiving > 200 mg QD, also anemia, leukopenia

Hepatic disease: hepatitis, jaundice; alcoholism; monitor LFTs
Monitor CBC