Mycobacterial Agents Pharmacology

Question 1

Mtb

Answer 1

• Mycobacterium tuberculosis
• Slow-growing, aerobic bacteria with lipid-rich cell wall
• Can remain dormant for long periods of time
• Mycolic acid makes up 60% of cell wall, relatively impermeable
• Intracellular - lives inside non-activated macrophages
• Need to use multiple or combination drugs to decrease emergence of resistant strains

Question 2

TB

Answer 2

Tuberculosis

Question 3

BCG

Answer 3

• Bacillus of Calmette and Guerin vaccine

- Contains live, attenuated preparation of the BCG strain of Mycobacterium bovis

Question 4

MAC

Answer 4

• M. avium mycobacterium

- Contains M. avium and M. intrecellulare

Question 5

NTM

Answer 5

Non-tuberculosis mycobacterium

Question 6

PPD

Answer 6

• Purified Protein Derivative
• Intradermal tuberculin testing
• Cell-free purified protein fraction obtains from human strain of Mycobacterium tuberculosis

Question 7

Mycobacterial Infections + Organisms

Answer 7

• Tuberculosis - Mtb
• Leprosy - M. leprae
• MAC => chronic cough, SoB, fatigue

Question 8

Active Tuberculosis

Answer 8

• Becomes active if immune system doesnt prevent growth
• These bacteria begin to multiply in the body => active TB disease
• Can be spread to others
• Localized = lungs, Disseminated = Fulminant

Question 9

Latent TB Infection

Answer 9

• LTBI
• Exposed to bacteria but becomes inactive
• Lives in body but becomes active later
• Many who have LTBI never develop active TB
• No symptoms or physical findings that suggest TB
• Respiratory smear/culture will be negative

Question 10

Pulmonary TB Disease

Answer 10

• Symptoms: fever, cough, night sweats, weight loss, fatigue, hemoptysis, decreased appetite
• Respiratory smears are usually culture positive (~50%)

Question 11

Asymptomatic Diagnosis

Answer 11

• Based on immune response to Mtb antigens
• PPD Skin test: purified protein derivative, delayed hypersensitivity
• QuantiFERON - TB-Gold standard, blood test, immune cell memory resposne

Question 12

5 Principles of TB Treatment

Answer 12

1. Multiple drugs MUST be used
2. Drug sensitivity testing is mandatory
3. Single daily dosing of drugs is preferred
4. Prolonged therapy is necessary (>6 mo)
5. Monitoring for patient compliance and toxicity is required (DOT)

Question 13

Initiation Phase

Answer 13

• Bactericidal, intensive phase
• Use: isoniazid, rifampin, pyrazinamide, and ethambutol
• Administer for 2 months

Question 14

Continuation Phase

Answer 14

• Sterilizing/continuation phase
• Use: isoniazid and rifampin
• Continued for 4-7 months IF cavitation on chest x-ray, positive acid fast bacillus smear, and positive culture

Question 15

TB First Line Agents

Answer 15

-Greatest level of efficacy with acceptable toxicity

Drugs

• Isoniazid (INH)
• Ethambutol (EMB)
• Pyrazinamide (PZA)
• Rifampin (RIF)

RIPE!!!

Question 16

Isoniazid

Answer 16

• Inhibits synthesis of mycolic acids
• Primary agent in therapeutic/prophylactic programs
• Bactericidal
• Enters phagocytic cells of the host and kills bacilli

Question 17

Isoniazid + Pro-drug

Answer 17

• Pro-drug activated inside mycobacterium
• Enters via passive diffusion and is then activated by katG
• Becomes a range of radicals/reactive species that attacks multiple targets including mycolic acid synthesis
• Other targets: Lipid peroxidation, DNA damage, and NAD metabolism
• Resistance: mutations in katG or inhA promotor region (increased expression)

Question 18

Isoniazid ADME

Answer 18

• Orally absorbed that can be interfered with by aluminum containing antacids
• Hepatic acetylation for metabolism that determines [drug] and half-life
• Excreted in urine (don’t adjust for renal impairment)

Question 19

Isoniazid + AE

Answer 19

• Allergic rxns
• Peripheral neuropathy at high doses
• Elevated hepatic enzymes (more common)
• Box warning: INH induced hepatitis (rare) - monitor monthly (LFTs)

Question 20

Isoniazid + Peripheral Neuropathy

Answer 20

• INH metabolites attach to inactive vitamin B6
• Vitamin B6 (pyridoxine) used to produce GABA
• When deficient, this could cause seizures and peripheral neuropathy
• Supplement with pyroxidine

Question 21

Ethambutol

Answer 21

• Inhibits mycobacterial cell wall synthesis but enhances activity of lipophilic drugs mainly
• Inhibits arabinosyl transferase which blocks polysaccharide synthesis and mycolic acid transfer to cell wall
• Enhances activity of lipophilic drugs like RIF

Question 22

Ethambutol ADME

Answer 22

• Orally absorbed, aluminum antacids can interfere
• Hepatic metabolism
• Excreted in urine: DOSE ADJUST

Question 23

Ethambutol Toxicity

Answer 23

• Optic neuritis is most common AE
• Results in diminished visual acuity and loss of red/green discrimination
• Decreased ureate excretion => Gout if predisposed

Question 24

Ethambutol Alternative

Answer 24

• Streptomycin
• Inhibits protein synthesis (binds to 30S ribosome, aminoglycoside)
• Poorly absorbed orally
• Not distributed in CSF, good otherwise
• Dose adjust with renal impairment, excrete urine
• Neuro and nephrotoxic

Question 25

Pyrazinamide

Answer 25

• Enters Mtb as a pro-drug by passive diffusion
• Converted to POA by nicotinamidase/pyrazinamidase
• Disrupts intracellular pH and membrane transport (exact MoA unresolved)

Question 26

Pyrazinamide ADME

Answer 26

• Well absorbed
• Widely distributed, CSF
• Hepative metabolism
• Excreted in urine (DOSE ADJUST)

Question 27

Pyrazinamide AE

Answer 27

• Liver injury with jaundice, rarely fatal
• Don’t use with decreased liver function
• Monitor LFTs

Question 28

Rifampin MoA

Answer 28

• Binds to B-subunit of bacterial DNA-dependent RNA polymerase
• Inhibits RNA synthesis
• Bactericidal

Question 29

Rifampin ADME

Answer 29

• Oral administration (food/antacids decrease)
• Distributes to all body fluids and organs, includes CNS
• Induces hepatic mixed-function oxidases, increases its own and other drugs’ metabolism (contraceptives)
• Fecal elimination, orange-red discoloration
• Tears may permanently stain contacts red/orange

Question 30

Rifampin Toxicity

Answer 30

• STRONG inducer of CYP1A2, 2C9, 2C19, and 3A4
• Flu-like symptoms, skin rashes, and itching, jaundice/hepatitis, hepatic enzyme elevation
• Potential DDI, includes several HIV protease inhibitors

Question 31

MDR TB

Answer 31

• Multidrug resistant TB
• Resistant to at least two of the best anti-TB drugs, isoniazid and rifampicin
• XDR (extensively DR) is rare, same as MDR as well as resistant to any FQ and at least one of the three injectable second-line drugs

Question 32

Bedaquiline

Answer 32

• Sirturo
• 1st new TB drug in over 40 years
• MoA: inhibits proton pump for mycobacterial ATP synthase
• Hepatic metabolism
• Feces excretion

Question 33

Bedaquiline Boxed Warnings

Answer 33

• Increased mortality

- QT prolongation

Question 34

Pretomanid

Answer 34

• Approved in 2019 for XDR TB
• Nitroimidazole drug
• Blocks mycolic acid synthesis
• Use in combination with Bedaquiline and Linezolid
• AE: peripheral neuropathy, acne/rash, low blood sugar, vomiting, diarrhea, liver inflammation
• 16 hour half life
• Excreted in urine