Anti-TB Drugs and Antifungals

Main Cause of TB

*M. tuberculosis*

Rare Causes of TB

Very rare causes are the closely related M. tuberculosis complex (*M. bovis*, *M. africanum*, *M. microti*)

Mycobacterial Cell Wall Characteristics

Know that mycobacterial cell wall is thicker and more complex than that of other types of bacteria, has __**high lipid content**__ and rich in mycolic acids

Mycobacterial Characteristics

* Weak "Gram-positive”, __**intracellular**__
* Divides every 16 to 20 hours, __**extremely slow**__
* __**Very hardy**__, able to survive adverse conditions
* Resistant to drying and disinfectants

Mycobacterial Transmission

Human to human via aerosol

Describe the major components/layers of the cell wall

* __**High lipid content**__ and hydrophobicity
* Rich in mycolic acids
* __**Thicker and more complex**__
* Peptidoglycan
* Arabinogalactan
* Lipoarabinomannan

Mycobacterial Cell Wall Target

Cell wall is the target of several anti-TB agents

Latent TB

* No symptoms, do not spread
* Can develop into active TB disease
* Immunocompromised people at high A

Active TB

* With symptoms and infectious
* May resulted from reinfection or reactivation of latent TB

Antimycobacterials

* Anti-TB drugs
* Antibiotics

Antimycobacterials: Anti-TB Drugs

* Isoniazid (INH)
* Rifampin (Rif)
* Ethambutol (EMB)
* Pyrazinamide (PZA)

Antimycobacterials: Antibiotics

* Streptomycin
* Fluoroquinolones
* Cycloserine

Name the three anti-TB drugs of choice for latent TB infection

* Isoniazid (INH)
* Rifampin (RIF)
* Rifapentine (RPT)

Name the four first-line anti-TB drugs for active TB disease

Active TB __**(drug-sensitive)**__

* Isoniazid (INH)
* Rifampin (Rif)
* Ethambutol (EMB)
* Pyrazinamide (PZA)

Efficacy of Active TB (Drug-Sensitive) Regimen

90% effective for drug-sensitive TB

Isoniazid (INH) MOA

__**Inhibition of mycolic acid synthesis → inhibition of cell wall**__

What biological process does isoniazid (INH) inhibit?

Inhibition of cell wall

Is isoniazid bactericidal or bacteriostatic for actively replicating/dividing susceptible mycobacteria?

* __Bactericidal__ for actively dividing mycobacterial cells
* __Bacteriostatic if slow-growing__

What are the major therapeutic uses of isoniazid?

* __**Most active agent for drug-sensitive TB**__
* __**Used alone for prevention**__
* With rifampicin, pyrazinamide, and either streptomycin or ethambutol for active TB

Isoniazid (INH) Adverse Effects

* CNS: __**peripheral neuropathy**__
* Hepatic: liver toxicity
* Hematologic

Rifamycins MOA

__**Inhibits bacterial RNA polymerase → inhibits RNA synthesis**__

What biological process does rifamycins inhibit?

Inhibits RNA synthesis

Is rifamycins bactericidal or bacteriostatic for actively replicating/dividing susceptible mycobacteria?

__Bactericidal__ for mycobacteria

Most Commonly Used Rifamycins

Rifampin (Rif)

What are the major therapeutic uses of this rifamycins?

* __**DOC for meningitis form of TB**__
* Prophylaxis of meningococcal or H. influenzae meningitis

Any issues when rifamycin is used alone? How do you resolve the issues?

* Resistance emerges rapidly when used alone
* Use with isoniazid (INH) or other anti-TB drugs for active TB to prevent drug resistance

Rifamycin Adverse Effects

* Changes body fluid to turn reddish brownish color (NOT harmful)
* DDIs with antibiotics and antiretroviral drugs

Pyrazinamide (PZA) MOA

PZA is converted to pyrazinoic acid (active form) → __**disrupt mycobacterial cell membrane metabolism and functions**__

What biological process does pyrazinamide (PZA) inhibit?

Mycobacterial cell membrane metabolism and functions

Is pyrazinamide (PZA) bactericidal or bacteriostatic for replicating/dividing mycobacteria?

Tuberculocidal (__bactericidal__) in replicating M. tuberculosis only

What are the major therapeutic uses of this pyrazinamide (PZA)?

An important __**front-line drug used in conjunction with INH and Rif in short-course regimens**__ against residual TB bacteria

Any issues when pyrazinamide (PZA) is used alone? How do you resolve the issues?

* Rapid resistance when used alone
* Used in combination with other drugs to overcome resistance

Pyrazinamide (PZA) Adverse Effects

* Hepatotoxicity
* Nausea/vomiting
* Drug fever
* Hyperuricemia

Ethambutol (EMB) MOA

__**Inhibits arabinogalactan polymerization → inhibits mycobacterial cell wall synthesis**__

What biological process does ethambutol (EMB) inhibit?

Mycobacterial cell wall synthesis

Is ethambutol (EMB) bactericidal or bacteriostatic for actively replicating/dividing cells susceptible mycobacteria?

Tuberculostatic (__bacteriostatic__)

What are the major therapeutic uses of ethambutol (EMB)?

* Against infections caused by *M. tuberculosis*
* *M. bovis*
* *MAC*

Any issues when ethambutol (EMB) is used alone? How do you resolve the issues?

* Rapid resistance when used alone
* Used in combination with other anti-TB drugs

Ethambutol (EMB) Adverse Effects

__Optic neuropathy (up to 5%) that can progress to irreversible blindness__

Clinical Management of TB

* __**Combination therapy**__ necessary to suppress resistance
* __**Prolonged therapy**__ (6 months or longer)
* Slow down bacterial replication
* Most agents are not tuberculocidal when mycobacterial cells are inactive

Clinical Management of TB: Major Issue

* __**Compliance**__ us major therapeutic issue
* __**MAJOR cause of drug-resistant TB**__

Clinical Management of TB: Preferred Empiric Therapy

__**RIPE**__

* Rif + INH + PZA + EM

7 Possible Causes of Resistance

1) Drug unable to penetrate cell wall

2) Low pH renders drug inactive (streptomycin)

3) Anaerobic conditions lead to dormant/non-replicating state; drugs that block metabolic processes have no effect during state of dormancy (EXCEPT rifamycin, fluoroquinolone)

4) Alteration of enzyme prevents conversion of pro-drug to active form (pyrazinamide, isoniazid)

5) Drug exported from cell before it reaches target (streptomycin, isoniazid, ethambutol)

6) Mutations in DNA repair genes lead to multiple drug resistance

7) Alteration of target protein structure prevents drug recognition (rifamycin, ethambutol, streptomycin, fluoroquinolone, macrolide)

Drug-Resistant TB Treatment Regimens

* Multidrug-resistant TB (MDR-TB)
* Extensively multidrug-resistant TB (XDR-TB)

Multidrug-resistant TB (MDR-TB)

* Resistant to at least one first-line anti-TB drug AND INH and Rif
* Add or substitute group 2 and/or 3 agents
* Group 2 drugs: Kanamycin, Amikacin, Capreomycin, Streptomycin
* Treat for up to 24 months after conversion

Extensively Multidrug-Resistant TB (XDR-TB)

* MDR-TB + any in group 2 + any fluoroquinolones (group 3)
* Group 2 drugs: Kanamycin, Amikacin, Capreomycin, Streptomycin
* Extremely difficult to treat

Bedaquiline: WHO Reccomendation

Bedaquiline be reeerved for MDR-TB when other regimen cannot be designed

Bedaquiline MOA

Blocks the proton pump\] for ATP synthase of myobacteria

Where is TB Drug-Resistance Common?

Resistance common in Africa, Asia, Central or South America, and even U.S

TB Prophylaxis

* Chemoprophylaxis
* INH (+pyridoxine) for 6-12 months
* pyridoxine = vitamin B6 to prevent peripheral neuropathy from INH

TB Prophylaxis Criteria

* __**Positive tuberculin test without active disease**__
* __**Household contacts with activeTB**__
* Comorbidity (esp. HIV)
* Old fibrotic scars on chest X-ray

TB Prevention by Vaccine

* Bacillus Calmette-Guérin (BCG) vaccine
* WHO Model List of Essential Medicines
* __**Most effective in preventing severe forms of TB in children**__
* __**Limited effectiveness in adults**__
* Standard of care for patients with __**bladder cancer**__ since 1977

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