1. Anti-TB Drugs
Roy Krishna, Ph.D. FCP.

2. Etiology
Mycobacteria comprise a group of organisms known as acid fast bacilli (AFB)
Mycobacterium tuberculosis (MTB)
Mycobacterium leprae
Many others
Humans are primary reservoir
Thick, impermeable wall.
Long dormancy.
Slow replication cycle

3. Overview of TB Treatment
Treatment can be divided into 3 separate approaches:
Latent TB infection treatment (LTBI)
aka “preventive therapy” and/or “chemoprophylaxis”
Active disease treatment
Extrapulmonary disease
Pleural, lymphatic, bone/joint, GU tract, meningitis, peritonitis
Develops in 10-20% of untreated cases

4. Pharmacotherapy of LTBI
Three regimens recommended for treatment of LTBI
Isoniazid X 9 months
Isoniazid X 6 months
Rifampin X 4 months
Appropriate treatment of LTBI is essential to controlling/eradicating the disease

5. Active TB Treatment Active disease treatment
Treatment can be divided into 3 separate approaches:
Latent TB infection treatment (LTBI)
aka “preventive therapy” and/or “chemoprophylaxis”
Active disease treatment
Extrapulmonary disease
Pleural, lymphatic, bone/joint, GU tract, meningitis, peritonitis
Develops in 10-20% of untreated cases

6. Empiric Treatment of Active TB
Multiple drugs required initially as unknown resistance
General approach (with exceptions) is:
“Initial phase”
2 months with 4 drugs, then:
“Continuation phase”
4-7 months with 2 drugs to equal 6-9 months total therapy
2 basic combinations for treating adults who:
Have never been treated previously
Have unknown resistance/sensitivity

7. M. tuberculosis
Theorized that there are 3 subpopulations of M. tuberculosis in an infected host:
Rapid growing
Slow growing (semi-dormant)
Spurts of growth followed by periods of dormancy (dormant)
Different TB agents work on different subpopulations
Combining drugs increases chances of success

8. Treatment of Active TB Major first line drugs
Isoniazid (INH)
Rifampin (RIF)
Pyrazinamide (PZA)
Ethambutol (EMB)
Special circumstance first line drugs
Rifabutin*
Rifapentine
*Not FDA approved for treatment of TB

9. Place in Therapy/Pharmacokinetics
First-line agent as monotherapy for treatment of LTBI
First-line agent combined w/ PZA, RIF, & EMB for treatment of active TB
Works best against rapidly growing M. tuberculosis
Also works against slower/intermittent growing
Available IV/PO
Rarely used IV
Hepatically metabolized w/ some renal excretion
No adjustment needed for renal dysfunction
Generally avoided in active liver disease

10. INH MOA Works via competitive antagonism
Much like sulfonamides compete with PABA
Inhibits mycolic acid synthesis
Necessary component of cell wall
Mycolate synthetase
Generally considered safe in pregnancy

11. Major Adverse Effects Adverse effects of INH
Most notable side effects involve the liver
Effects range from mild to severe
Asymptomatic elevation of aminotransferases
Clinical hepatitis
Fatal hepatitis

12. Major Adverse Effects Adverse effects of INH
Most notable side effects involve the liver
Effects range from mild to severe
Asymptomatic elevation of aminotransferases
Clinical hepatitis
Fatal hepatitis

13. Adverse Effects of INH Asymptomatic elevation of aminotransferases
AST/ALT elevation up to 5Xs the ULN occur in 10-20% of those on INH alone
Most cases occur w/in first 2 mo. of therapy & do not require discontinuation
Enzyme levels usually return to normal even with continued administration
Guidelines recommend:
Stop if LFTs increased w/ symptoms of liver failure
Stop if AST>5Xs upper limit of normal w/o symptoms

14. Adverse Effects of INH Clinical hepatitis & Fatal hepatitis
Newer data indicate rate of clinical hepatitis may be lower than previously thought
Current rate %
Risk depends largely on several factors which increase risk
Age, alcohol use, pre-existing liver disease, other hepatotoxic meds

15. Adverse Effects of INH Other adverse effects of INH
Peripheral neuropathy
Dose related; INH interferes with pyridoxine metabolism
Occurs in 0.2-2% of patients at normal dosages
Risk factors for peripheral neuropathy
DM, HIV, ESRD, malnutrition, alcoholism, pregnancy
Supplement with pyridoxine 25mg po QD in above to avoid
CNS effects, anemia, lupus, GI intolerance also seen

16. Rifamycins
Rifamycins include 2 agents which may be exchanged with rifampin in special circumstances
Rifabutin
Use if intolerable side effects with rifampin
Use rifabutin if unacceptable drug interactions; esp. HIV+ patients on certain therapy
Rifampin OK w/ certain HIV meds
Rifabutin OK w/ others
Rifapentine
As part of once-weekly continuation therapy in select patients

17. Place in Therapy/Pharmacokinetics
Second-line agent as monotherapy for treatment of LTBI
First-line agent combined with INH, PZA, & EMB for treatment of active TB
Works best against slower/intermittent growing M. tuberculosis
Also works against rapidly growing
Available PO/IV
Extensively hepatically metabolized
Excreted mostly in bile
No adjustment needed in renal dysfunction
Usually only hepatotoxic agent used in active liver disease

18. RIF MOA Inhibits DNA-dependent RNA polymerase Other uses
Binds to a subunit of enzyme
Protein synthesis impaired
Other uses
Also covers gram + organisms
Prophylaxis of bacterial meningitis & LTBI are only times should be used by itself
Usually part of combination therapy for gram-positive infections
Prosthetic-valve endocarditis
Osteomyelitis (implant infections)
Watch CYP450 induction!
Considered safe in pregnancy

20. Major Adverse Effects Adverse effects of RIF Hepatotoxicity
Transient asymptomatic hyperbilirubinemia
Clinical hepatitis %
Thrombocytopenia
CBC, platelets, AST, ALT, bilirubin recommended at baseline
Flu-like syndrome
Rash
Orange discoloration of bodily fluids

21. Major Adverse Effects Patient counseling issues
Discoloration of body fluids
May harmlessly change urine, sputum, tears, sweat orange
Can discolor contact lenses, clothing
Avoid alcohol/signs and sx of liver disease
Drug interactions
Need for MD/lab monitoring
CBC, platelets, AST, ALT, bilirubin at baseline; afterward

22. Pyrazinamide
First-line agent combined with INH, RIF, & EMB for treatment of active TB
Works best against dormant and semi-dormant M. tuberculosis
Available PO only
About 70% renally excreted
Dose adjustment needed in renal dysfunction
No good data in pregnancy, assumed to be safe

23. Major Adverse Effects Hepatotoxicity GI symptoms
About 1%
Less common than INH and RIF
Effects more severe than RIF
GI symptoms
Anorexia, nausea, vomiting
Arthralgias/Gouty arthrits
Arthralgias up to 40%
Use in gout is contraindicated

24. Ethambutol
First-line agent combined with INH, RIF, & PZA for treatment of active TB
Works best against rapidly dividing M. tuberculosis
Available PO only
Primarily renally excreted
Dose adjustment needed for renal dysfunction
Generally considered safe in pregnancy

25. EMB MOA Exact mechanism is unknown
Ethambutol inhibits arabinosyltransferases
Mycobacterial enzyme which produces arabinogalactans
Arabinose, Arabinomannan and Lipoarabinomannan
Components of cell wall

26. Major Adverse Effects Retrobulbar neuritis No Hepatotoxicity
Decreased visual abilities, change in red-green discrimination
One or both eyes
Damage can be permanent
Monthly vision tests recommended
Drug not recommended in children where visual changes cannot be monitored
No Hepatotoxicity

27. Treatment of Active TB Second line drugs
Generally reserved for drug intolerance/resistance
Fluoroquinolones* (po/IV)
Levofloxacin (Levaquin®)
Moxifloxacin (Avelox®)
Streptomycin (IV/IM, drug formerly first-line)
Amikacin/kanamycin* (IV/IM)
Capreomycin (IV/IM)
Cycloserine (po)
Ethionamide (po)
P-Aminosalicylic acid (PAS) (po)
*Not FDA approved for treatment of TB

28. Fluoroquinolones and Aminoglycosides
Already covered in protein synthesis inhibitors
Just like all second-line agents, resistance, toxicities, clinical experience help determine when to utilize
Remember pregnancy restrictions
Items of note:
Moxifloxacin, levofloxacin have best data
If resistant to one FQ, assume resistance to all
Amikacin/kanamycin
Cross resistance 100%
Less vestibular dysfunction than streptomycin
Streptomycin
Often works against strains resistant to amikacin/kanamycin
Less nephrotoxicity than amikacin/kanamycin

29. Cycloserine Works against many gram + and gram – organisms
Used almost exclusively for M. tuberculosis
Works on the cell wall
Inhibits Alanine Racemase
Ultimately prevents peptide bond formation
Adjust dose for renal dysfunction
Only use in pregnancy if no other option

30. Major Adverse Effects CNS effects
Headache, restlessness to psychosis, seizures
May exacerbate underlying seizure disorders, mental illness
Pyridoxine may help
mg/day
Monitor neuropsychiatric status

31. Ethionamide Works similar to INH
No adjustment needed for renal dysfunction
Do not use in pregnancy

32. Major Adverse Effects Gastrointestinal symptoms Hepatotoxicity
Nausea, vomiting, metallic taste, anorexia, abdominal pain
Hepatotoxicity
About 2%
Structurally similar to INH
Neurotoxicity
Peripheral and optic neuropathy
1-2%

33. PAS Works similar to sulfonamides
Competes with PABA
No adjustment needed in renal dysfunction
Use in pregnancy only if no other options

34. Major Adverse Effects Hypothyroidism Gastrointestinal symptoms
Thyroid hormone replacement may be needed
Gastrointestinal symptoms
Upset stomach, diarrhea
Up to 11%
Hepatotoxicity %