Anti-mycobacterial Drugs

Question 1

What are mycobacteria?

Answer 1

Gram-positive bacteria

Rod-shaped aerobic bacilli

Lacking true outer membrane

Contain a layer of peptidoglycan

Question 2

Mycobacteria cell walls?

Answer 2

Contain Mycolic acid

High lipophilic cell walls that stain poorly with gram stain

Acid-fast bacilli

Question 3

Genus Mycobacterium classes?

Answer 3

M.tuberulosis

M.leprae

Question 4

Mnemonic for the four first-line antimycobacterial drugs?

Answer 4

HRZE

Question 6

Defense mechanism of mycobacteria?

Answer 6

Contains porins in their outer lipid layer, have a potential space (periplasm). They’re neither gram+ nor gram-

Abundance of efflux pumps in the cell membrane

Some of the bacilli hide inside the patient’s cells (extra physicochemical barrier) that antimicrobial agents must cross to be effective

Question 7

What are the drug targets and drug names for each target?

Answer 7

Mycolic acid inhibitors - Isoniazid, Delamanid, Ethionamide (DIE)

Arabinogalactan Inhibitors- arabinifuranosyl transferases
Ethambutol (EMB), Ethylenediamine

Peptidoglycan inhibitor: Cycloserine

Question 8

MOA of Fluoroquinolone

Answer 8

Inhibits DNA Synthesis and supercoiling by targeting topoisomerase

Question 9

Moa of Rifamycin

Answer 9

Inhibits RNA synthesis by targeting RNA Polymerase

Question 10

Moa of Streptomycin

Answer 10

Inhibits protein synthesis by targeting the 30S ribosomal subunit

Question 11

Moa of Macrolides

Answer 11

Target 23S ribosomal RNA, inhibiting peptidyl transferases

Question 12

Moa of Isoniazid

Answer 12

Inhibits mycolic acid synthesis

Question 13

Moa of Ethionamide

Answer 13

Inhibits mycolic acid synthesis

Question 14

Moa of Ethambutol

Answer 14

Inhibits cell wall synthesis

Question 15

Moa of Pyrazinamide

Answer 15

Inhibits cell membrane synthesis and trans-translation

Question 16

Moa of Bicyclic nitromidazoles

Answer 16

Inhibit mycolic acid and protein biosynthesis

Generate reactive nitrogen species

Question 17

Moa of Bedaquiline

Answer 17

Inhibits ATP Synthesis

Question 18

Moa of Oxazolidinones

Answer 18

Inhibit initiation of protein synthesis by binding to 50S ribosomal subunit

Question 19

Mechanism of resistance

Answer 19

Drugs unable to penetrate cell wall

Mutations in DNA repair genes lead to multiple drug resistance

Anaerobic conditions lead to dormant/nonreplicating state; drugs that block metabolic processes have no effect during state of dormancy
(EXCEPTION: Rifamycin, Fluoroquinolone, Nitoimidazoles) (NFR)

Question 20

Mechanism of resistance and the drug

Answer 20

Low pH renders drug inactive - Streptomycin

Drug exported from cell before it reaches target - Streptomycin, Isoniazid, Ethambutol (SIE)

Alteration of enzyme prevents conversion of prodrug to active form - Pyrazinamide, Isoniazid

Alteration of target protein structure prevents drug recognition - Rifamycin, Ethambutol, Streptomycin, Fluoroquinolone, Macrolide (MR SEF)

Question 21

Tuberculosis is transmitted through

Answer 21

Inhalation of infected droplet nuclei

Question 22

What organ is infected first in tb

Answer 22

Lung

Question 23

Symptoms of Tb

Answer 23

Low-grade fever
Night sweats
malaise
fatigue
weight loss
blood-streaked productive cough

Question 24

Other Mycobacterium Species

Answer 24

M.Africanum (common in West Africa)

M.cannetti (rare cause in East Africa)

M.bovis (in cattles, spread to humans via them)

M.Microti (rodents)

M.Pinipedii (seals)

Question 25

Clinical manifestation of Tb

Answer 25

The preclinical/latent stage, no signs or symptoms About 90-95% of infected individuals develop latent Tb infection (LTBI) and only a few, especially immunocompromised, will develop active TB. Latent may be reactivated to active Tb, several weeks to many decades

Question 26

Lab findings during latent Tb?

Answer 26

Chest x-ray is normal Tuberculin test may be positive

Question 27

Lab findings during active Tb?

Answer 27

Clinical manifestation Signs and symptoms depend on the site of infection

Question 28

Signs and symptoms of TB Pulmonary TB

Answer 28

Coughing blood Fever Chest pain Chills Weight loss Night sweats Long term cough No appetite Fatigue

Question 29

Extrapulmonary Tb Common ones

Answer 29

Superficial lymph nodes in the cervical or supraclavicular region Pleural Tb Genitourinary system Bones and Joints Peritoneum Pericardium

Question 30

Diagnosis of Tb

Answer 30

AFB staining Culture Tuberculin skin test/Mantoux test Nucleic acid amplification techniques NOTE: The GeneXpert MTB/RIF is the commonly used Nucleic acid amplification method and is recommended by WHO In addition, this technique also detects rifampicin resistance

Question 31

Method of Management of TB

Answer 31

All TB treatment must be given under (DOT) Directly Observer Treatment using (FDC) Fixed-dose combination tablets

Question 32

What are the First-Line drugs in the Management of TB

Answer 32

Isoniazid (H) Rifampicin (R) Pyrazinamide (Z) Ethambutol (E) (RIPE) Additional first-line drug Streptomycin

Question 33

What are the Second-Line drugs in the Management of TB

Answer 33

(SACK BF) Fluoroquinolones Injectable drugs- streptomycin, kanamycin, amikacin, capreomycin (SACK) Other drugs- BEDAQUILINE, others

Question 34

WHO recommended multi-drug therapy What is the regimen?

Answer 34

6 MONTH REGIMEN for txt of all pt. with Tb regardless of disease site or HIV status (RIPE) HRZE FOR THE FIRST 2 MONTHS (INTENSIVE PHASE) Rifampicin Isoniazid Pyrazinamide Ethambutol FOLLOWED BY Rifampicin + Isoniazid for next 4 months (CONTINUATION PHASE) The strategy is called 2HRZE/4HR

Question 35

Objective of MDT

Answer 35

To make the pt. Non-infectious as early as possible To prevent development of drug resistant bacilli To prevent relapse To reduce the total duration of treatment

Question 36

Overview of Isoniazid

Answer 36

The most active drug for Tb txt caused by susceptible strains Structurally similar to Pyridoxine Penetrate into macrophages and active against both extracellular and intracellular organisms Highly effective against rapidly growing bacilli Cheapest Bactericidal First line drug

Question 37

Moa of Isoniazid

Answer 37

Prodrug, activated by catalase peroxidase (KatG) - inhibits the reductase enzyme (Ketoenonylreductase) involved in the synthesis of mycolic acid Inhibits the biosynthesis of MYCOLIC ACIDS which are ESSENTIAL CONSTITUENTS OF THE MYCOBACTERIAL CELL WALL

Question 38

MOR of Isoniazid

Answer 38

Mutation of KatG gene - results in loss of the catalase peroxidase enzyme required for activation of Isoniazid Mutation or deletion of KatG (confers high-level resistance to INH) Overexpression of genes for InhA (confers low-level resistance to INH) Increased expression of Efflux pump Cross-resistance to ethionamide

Question 39

Adverse effects of Isoniazid

Answer 39

Hepatotoxicity - more in chronic alcoholics, older people and repair acetylators Peripheral neuritis - dose-related toxicity (paresthesia, numbness, burning, and pain in extremities) Pyridoxine 10mg/day is routinely given with INH to reduce the risk and also for B6 deficiency Others- fever, skin rashes, arthralgia, GI disturbance, psychosis and rarely convulsions

Question 40

Drug interaction of isoniazid

Answer 40

Aluminium Hydroxide (Antacid) inhibits the absorption of INH Alcohol increases the risk of hepatitis INH inhibits the metabolism of phenytoin and carbamazepine

Question 41

Use of Rifampicin/Rifamycin

Answer 41

First-line anti-tubercular drug Effective against intracellular and extracellular bacilli Bactericidal effective against