Anti-TB drugs

Classification
A. First line agents
• Isoniazid (H, INH)
• Rifampicin (= Rifampin, R is the name in USA)
 •or other rifamycins
• Rifabutin
• Rifapentine
• Pyrazinamide (Z, PZA)
• Ethambutol (E)
• Streptomycin(S)

B. 2nd Line agents

•WHO August 2018

•Medicines have been regrouped into three categories

Group A
•Medicines to be prioritised
1. Levofloxacin/moxifloxacin
2. Bedaquiline
3. Linezolid
Group B
•Medicines to be added next
1. Clofazimine
2. Cycloserine/terizidone
GroupC
•Medicines to be included to complete the regimens and when agents from Groups A and B cannot be used
1. Ethambutol
2. Delamanid
3. Pyrazinamide
4. Imipenem-cilastatin
5. Meropenem
6. Amikacin (streptomycin)
7. Ethionamide/prothionamide
8. p-aminosalicylic acid

• 2nd line drugs are for MDR TB

Short treatment regimens: 9-12 months
Long treatment regimens: 10-20 months
• Medicines no longer recommended
 Kanamycin and capreomycin
- Due to increased risk of treatment failure and relapse
• Generally anti-TB drugs are used in combination to prevent resistance

1. Isoniazid

Dr Gichuhi 1
 • It is the most active drug for TB treatment
• Has structural similarity to pyridoxine
• Is bactericidal for actively growing tubercle bacilli
• Less effective against atypical mycobacteria
• Penetrates into macrophages
• Active against both extracellular and intracellular organisms

Mech of action – INH

- Inhibits synthesis of mycolic acids
- These are essential components of mycobacterial cell walls

Mech of resistance
- Various mutations
- Some cause cross-resistance to ethionamide
- Drug-resistant mutants are normally present in susceptible mycobacterial
populations at about 1 bacillus in 106
- Resistant mutants are readily selected if a single anti TB agent is used
- Combination therapy is recommended to prevent emergence of resistance during therapy

P’kinetics - INH
• Oral usually, parenteral (IV, IM in critically ill patients)
• Well absorbed from the GIT
• Distributed into all body fluids and tissues
• The conc in the CNS and CSF range between 20% and 100% of serum concentrations
•Metabolism is in the liver
•Acetylation by N-acetyltransferase, is genetically determined
•Rapid acetylators
•Half life < 1hr
•No clinical significance if appropriate dose given daily
•Subtherapeutic concentrations
•Once-weekly dose
•In malabsorption
•Plasma conc is about one third to one half of that in slow acetylators
•Slow
•Excreted mainly in the urine
•Mainly as metabolites
•Dose not adjusted in renal failure

Use
•TB Rx
•TB prophylaxis
•As a single agent

AEs
•Clinical hepatitis
•Is the most common major toxicity
•Loss of appetite, N, V, jaundice, and right upper quadrant pain
•1% of patients

Dr Gichuhi 2
 •Can be fatal, discontinue INH
•INH is contraindicated after clinical hepatitis
•Increases in liver aminotransferases (up to three or four times normal)
•10–20% of patients
•Usually asymptomatic
•No need to stop Rx

INH-ADRs
Peripheral neuropathy
• 10-20%
• More likely in
 Slow acetylators
 Patients with malnutrition, alcoholism, diabetes, AIDS, and uremia
• Due to pyridoxine deficiency
• INH promotes excretion of pyridoxine
• Reversed by administration of pyridoxine
CNS
•Memory loss
•Psychosis
•Seizures
•May respond to pyridoxine
Immunologic Reactions
•Fever
•Skin rashes
•Drug-induced systemic lupus erythematosus INH-ADRs
Others
•Hematologic abnormalities
•Pyridoxine deficiency anemia
•Tinnitus
•GIT discomfort

INH-Drug interactions
•INH can reduce the metabolism of phenytoin
•increases phenytoin toxicity

2. Rifampicin

•A derivative of rifamycin
•Bactericidal
•Active in vitro against
o Gram-positive and gram-negative cocci
o Some enteric bacteria
o Mycobacteria
o Chlamydiae

Cross-resistance
•To other rifamycin derivatives
•Rifabutin
•Rifapentine
•None to other classes of antimicrobial drugs

Dr Gichuhi 3
Mech Of Action
•Rifampin binds to the β subunit of bacterial DNA dependent RNA polymerase
•Inhibits RNA synthesis
•Human RNA polymerase is not inhibited

Mech of resistance
•Mutations in the gene for the β subunit of DNA dependent RNA polymerase
•Reduces binding of rifampin to the enzyme

P’kinetics
• Oral
• Well absorbed
• Distributed widely in body fluids, most tissues and enters phagocytic cells
• Can kill organisms that are poorly accessible to many other drugs
• Intracellular organisms
• Those sequestered in abscesses and lung cavities
• Highly protein-bound
•Adequate CSF concentrations only in meningeal inflammation
•Excreted mainly through feaces as a metabolite
•It undergoes enterohepatic recirculation
•Small amount excreted in the urine
•No dose adjustment for renal or hepatic insufficiency

Clinical use - Rifampicin

 TB
 Some atypical mycobacterial infections
 Leprosy
 An alternative to INH for latent tuberculosis if
•Unable to take INH
•Exposed to a case of active TB caused by an INHresistant but rifampin-susceptible strain

Clinical use – Rifampicin (Reserved for mycobacteria)

•To eliminate meningococcal carriage
•As prophylaxis in contacts of children with Haemophilus influenzae type b
•To eradicate staphylococcal carriage
•To treat serious staphylococcal infections
•Osteomyelitis
•Prosthetic valve endocarditis

ADRs - Rifampicin
•A harmless orange colour to urine, sweat, tears
•Soft contact lenses may be permanently stained
•Occasional AEs
•Rashes, thrombocytopenia
•Nephritis, acute tubular necrosis
•cholestatic jaundice, hepatitis
AEs -

Dr Gichuhi 4
 •Fever, chills, myalgias
•Anemia, thrombocytopenia

Drug interaction - Rifampicin

•Strongly induces most cytochrome P450 isoforms
•This increases the elimination of many drugs eg
•Anticoagulants
•Anticonvulsants
•Protease inhibitors
•Nevirapine
•Contraceptives

3. Ethambutol
•Activity against
•Mycobacterium tuberculosis
•other mycobacteria
•Inhibits mycobacterial arabinosyl transferases
•This enzyme acts on arabinoglycan which is essential for the mycobacterial cell wall

Mech of resistance
•Mutations resulting in overexpression arabinosyl transferases

•Oral
•Well absorbed
•Crosses the BBB only when the meninges are inflamed
•Excreted in faeces and urine (mainly) in unchanged form
• Reduce dose in severe renal failure

Adverse Effects - ethambutol

•The most common serious adverse event is retrobulbar neuritis. It results in loss of
•Visual acuity
•Red-green colour blindness
•Hypersensitivity is rare

4. Pyrazinamide (PZA)

•Used only for TB

•Inactive at neutral pH
•At pH 5.5 it inhibits MTB
•Is taken up by macrophages
•Activity against mycobacteria in the acidic environment of lysosomes
•Is a “sterilizing” agent
•Acts on residual intracellular organisms that may cause relapse

•Pyrazinamide is a prodrug
•Converted to pyrazinoic acid by mycobacterial pyrazinamidase

Mech of action
•Pyrazinoic acid disrupts mycobacterial cell membrane metabolism and transport functions

•Mech of Resistance

Dr Gichuhi 5
•? Impaired uptake of pyrazinamide
•Mutations in gene for pyrazinamidase
•Impairs metabolism of PZA to its active form
•No cross-resistance with other antimycobacterial drugs

•Oral administration
•Well absorbed
•Widely distributed in body tissues, including inflamed meninges
•Half-life is 8–11 hours
•Metabolized by the liver
•Metabolites excreted through kidney
•Dose adjusted in renal failure

ADR
•Hepatotoxicity in 1–5%
•N, V
•Drug fever
•Hyperuricemia
•May cause gouty arthritis

5. Streptomycin

•An aminoglycoside
•Activity against
•MTB
•Mycobacterium avium complex (MAC)
•Mycobacterium kansasii
•Other non tuberculous mycobacteria are resistant
•Resistance is due to mutation of genes which alter the ribosomal binding site
•IM, IV
•Penetrates into cells poorly
•Active mainly against extracellular tubercle bacilli
•Crosses the BBB
•Therapeutic concentrations with inflamed meninges
•Dose adjusted in renal failure

ADRs
•Ototoxic
•Vertigo and hearing loss are the most common ADRs
•May be permanent
•Nephrotoxic

2nd line anti-TB agents

•Usually considered only if

•Resistance to first-line agents
•Failure of clinical response to conventional therapy
•Serious treatment-limiting ADRs
•The dosage, emergence of resistance, and long-term toxicity have not been fully established for most drugs

Dr Gichuhi 6
 Ethionamide
•Chemically related to INH
•Cross-resistant with INH
•Blocks the synthesis of mycolic acids
•Oral
•Distributed into tissues
•CSF concs are equal to those in serum
•Metabolized by the liver

Ethionamide - ADRs
•Gastric irritation
•Neurologic symptoms
•May be alleviated by pyridoxine
•Hepatotoxic

Cycloserine
• Inhibits cell wall synthesis
• Dose adjusted in renal failure

ADRs
• Most common during the first 2 weeks of therapy
• Affect 25%
• Associated with high doses, monitor peak serum concs

•Peripheral neuropathy
•CNS
•Depression and psychosis
•Pyridoxine used to ameliorate neurologic toxicity

Aminosalicylic acid (PAS)

•A folate synthesis antagonist
•Structurally similar to p-amino-benzoic acid (PABA) and to the sulfonamides

•Oral
•Widely distributed in tissues and body fluids except CSF
PAS - ADRs
•GIT symptoms are common
•PUD
•Haemorrhage
•May be diminished by giving the drug with meals and antacids
•Very high concentrations of aminosalicylic acid in the urine
•Can cause crystalluria

Fluoroquinolones
•Have activity against many gram-positive and gramnegative bacteria
•MTB
•Atypical mycobacteria
•Moxifloxacin is the most active against MTB in vitro

Dr Gichuhi 7
Linezolid
•Achieves good intracellular concs
•ADRs
•Bone marrow suppression
•Irreversible peripheral and optic neuropathy

Rifabutin
•A rifamycin
•Bacterial RNA polymerase inhibitor
•Activity against
•MTB
•MAC
•Mycobacterium fortuitum
•Activity is similar to that of rifampin
•Cross-resistance with rifampin is virtually complete Rifabutin
•Rifabutin is an inducer of CYP450 enzymes
•It is a less potent inducer than rifampin
•Use instead of rifampin in TB and HIV if receiving
•a protease inhibitor or
•NVP

Rifapentine
•Active against both MTB and MAC
•A bacterial RNA polymerase inhibitor
•Cross-resistance between rifampin and rifapentine is complete
•Also an inducer of CYP450 enzymes
•Drug interaction similar to rifampicin
•Toxicity is similar to that of rifampicin

Bedaquiline
•It inhibits ATP synthase in mycobacteria
•Has invitro activity against both replicating and nonreplicating bacilli
•Bactericidal
•No cross-resistance with other anti-TB Bedaquiline
•Administer with food
•High-fat food doubles peak plasma conc
•Metabolized by CYP3A4 mainly
•Check for interactions
•Excreted mainly via the feces
•Terminal half-life of bedaquiline & metabolite (M2) = about 5.5 months
•Slow release of bedaquiline and M2 from peripheral tissues
•ADRs
•Hepatotoxicity
•Cardiac toxicity

Dr Gichuhi 8