Antimycobacterials

Question 1

Mycobacterium has its own family, Mycobacteriaceae. Mycobacteria includes pathogens known to cause serious diseases in mammals, including TB and Leprosy. Tx of infections caused by mycobacteria is complicated by numerous factors, including:

Answer 1

1. Limited information about the mechanisms of antimycobacterial drug actions
2. Mycobacteria are intrinsically resistant to most antimicrobials
3. Intracellular location of mycobacteria
4. Chronic nature of mycobacterial disease, associated with chronic use and therefore toxicities
5. Patient compliance

Question 2

Chemotherapy of mycobacterial infections almost always is associated with what?

Answer 2

Combination therapy

–delays the emergency of resistance and enhance antimycobacterial efficacy

Question 3

First mycobacterium we will focus on is Tuberculosis caused by Mycobacterium Tuberculosis. What are some features?

Answer 3

Lungs = major site of infection
Spread through air when ppl who have an active infection cough, sneeze or transmit saliva through air
Most infections are asymptomatic and latent and about 1 in 10 latent infections progress to active disease.

Question 4

Describe mycobacterium tuberculosis in terms of organism

Answer 4

Small, aerobic, non motile bacteria
Divides slowly (requires months of tx)
Have a cell wall so gram +

Question 5

Now going into the treatment of TB, this involves use of anti-mycobacterial drugs. Effective tx is very difficult due to the unusual structure and chemical composition of the cell wall. How is latent vs active TB treated?

Answer 5

Latent TB: single drug
Active TB: tx with combination therapy
5 to 10% of infected persons who do not receive tx for latent TB will develop TB disease

Question 6

Persons at high risk for developing TB disease fall into what two categories?

Answer 6

1. Persons who have been recently infection with TB

2. Persons with medical conditions that weaken the immune system

Question 7

Persons who have been recently infected with TB include?

Answer 7

1. Close contacts of a person w/infectious TB
2. Persons who have immigrated from area w/high TB
3. Children less than 5 who have a + TB test
4. Groups with high rates of TB transmission (homeless HIV)
5. Persons who work or reside with people who are at high risk for TB in facilities or institutions (hospitals, homeless shelters, jails)

Question 8

Persons with medical conditions that weaken the immune system include?

Answer 8

1. Babies and young children often have weak immune systems
2. HIV
3. Substance abuse
4. Silicosis
5. DM
6. Severe kidney disease
7. Low body weight
8. Organ transplants
9. Head and neck cancer
10. Medical tx with steroids
11. specialized tx for RA and Crohns Disease

Question 9

What are the goals of TB therapy?

Answer 9

To kill mycobacteria
To prevent emergency of drug resistance
To eliminate persistent mycobacteria from the host’s tissues to prevent relapse

Question 10

What are the 1st and 2nd line drugs for TB?

Answer 10

1st Line: Isoniazid, Rifamycins, Ethambutol, Pyrazinamide
2nd Line: Streptomycin, Ethionamide, Levofloxacin, Amikacin
–initiation of therapy usually involves three or four drug combo regiment depending on the known or anticipated rate of resistance to isoniazid

Question 11

What is Directly Observed Therapy (DOT)?

Answer 11

DOT: regimens are recommended in non compliant patients and in drug resistant TB

Question 12

What are the standard regiments for empiric tx of pulmonary TB?

Answer 12

Initial Phase:
Drugs: Isoniazid, Rifampin, Pyrazinamide and Ethambutol (duration 8 weeks)
or
Drugs: Isoniazid, Rifampin, Ethambutol
(duration 8 weeks)
Continuation Phase:
Drugs: Isoniazid and Rifampin (duration: 18 weeks)
or
Drugs: Isoniazid and Rifampin (duration: 31 weeks)
–depends on drug resistance profile and immune status of patient

Question 13

What are the drug regiments for tx of latent TB?

Answer 13

Isoniazid: 6-9 months
Rifampin: 4 months

Question 14

Lets discuss each individual drugs. First is Isoniazid. What is the MOA?

Answer 14

Analogue of Pyridoxine (Vit B6)
–pro drug activated by mycobacterial catalase peroxidase (KatG)
–active form of drug targets enzymes that are involved in mycolic acid synthesis (component of cell wall)
–enzymes: enoyl acyl carrier protein reductase (AcpM) and B-ketoacyl-ACP synthase (KasA)
Bactericidial: actively growing organisms

Question 15

Resistance is a big problem and emerges rapidly if isoniazid is used alone. Resistance occurs due to chromosomal mutations resulting in?

Answer 15

1. Deletion of KatG
2. Changes in binding sites on acyl carrier protein reductase
3. Overexpression of the acyl carrier protein reductase

Question 16

What is the spectrum of activity and clinical applications?

Answer 16

Single most important drug used in TB

For latent infections given as a single drug

Question 17

What are the pharmacokinetics of isoniazid?

Answer 17

Orally, IV or iM
Liver metabolism via acetylation
Fast acetylators is 60-90 minutes (higher dosage for equal therapeutic effects)
Slow acetylators is 3-4 hours

Question 18

What are adverse effects and contraindications for isoniazid?

Answer 18

Neurotoxic effects: corrected by supplementing with pyridoxine
Hepatotoxicity
CYP450 inhibitor: increase plasma levels of drugs
Lupus like syndrome: anti nuclear antibodies
Contraindications:
Safe in pregos but risk of hepatitis so need to give pyridoxine to all prego women

Question 19

Next drug in the treatment of TB is Rifamycins (rifampin and rifabutin). What is the MOA and resistance?

Answer 19

Bactericidal against intracellular and extracellular mycobacteria and many other organisms
–block transcription by binding to the beta subunit of bacterial DNA dependent RNA polymerase = inhibition of RNA synthesis
Resistance:
point mutations in rpoB (gene for beta subunit of RNA polymerase) = decrease affinity for drug
decreased permeability

Question 20

What is the spectrum of activity and clinical applications of Rifamycin?

Answer 20

Combo therapy for TB
Tx of latent infection :given as sole drug in isoniazid intolerant patients
In leprosy: given monthly delays the emergency of resistance to dapsone
Used for prophylaxis of meningitis in exposed individuals and also in combo with vancomycin for MRSA and PRSP
Rifabutin is preferred in tx of TB patient with HIV

Question 21

What are the pharmacokinetics of Rifamycin?

Answer 21

Orally or parenterally
Well distributed (including CSF)
Enterohepatic cycling and both parent drug and metabolites (orange in color) are excreted in feces
Inducer of Cytochrom P450 enzymes and increases the elimination of many drugs (rifampin stronger induced)

Question 22

what are adverse effects of Rifamycin as well as pregnancy use?

Answer 22

AE:
Light chain proteinuria
GI distress
CYP450 inducer
Orange Colored Secretions: urine, tears Sweat
Pregnancy: Rifampin is safe but not enough data on rifabutin

Question 23

Next drug for TB is Ethambutol, what is the MOA and resistance?

Answer 23

Inhibits arabinosyl transferases (encoded by emb gene) (involved in the synthesis of mycobacterial cell wall components)
Resistance strains emerge due to mutations in the emb gene

Question 24

What is the spectrum of activity and clinical applications of Ethambutol?

Answer 24

Used in combo for tx of TB ( M. Tuberculosis and M. Kansaii)

Question 25

What are the pharmacokinetics for ethambutol?

Answer 25

Well absorbed orally and well distributed

Eliminated unchanged in the urine

Question 26

What are the AE, Pregnancy status and Contraindications in ethambutol?

Answer 26

Dose dependent visual disturbances: red green color blindness (will be the first sign of visual changes therefore not for kids under 5)
Safe for pregos
Not for kids under 5

Question 27

The last first line drug for the tx of TB is Pyrazinamide. What is the MOA and Resistance?

Answer 27

Unknown exact mechanism

Resistant strains lack pyrazinamidase or have increased efflux of the drug

Question 28

What is the spectrum of activity, clinical application and pharmacokinetics for pyrazinamide?

Answer 28

Used in combo with other drugs for tx of TB

Partly metabolized in the urine and then excreted via the urine

Question 29

What are the adverse effects and pregnancy status for pyrazinamide?

Answer 29

Non-gouty polyarthralgia
Acute gouty arthritis
Hyperuricemia
Only recommended in pregnancy when the benefits outweigh the risks

Question 30

Lastly lets go through the second line drugs for the Tx of TB. There are 4, each card will go through one. Streptomycin, what are some features?

Answer 30

Aminoglycoside
Use in drug resistant strains of TB
Used in combo with other drugs for tx of life threatening TB, including meningitis, military dissemination
Pharmacokinetics and AE similar to aminoglycoside
Use is limited due to resistance

Question 31

Next second line agent is Amikacin. What are some features?

Answer 31

Aminoglycoside used in combo with other drugs for streptomycin or multi drug resistant strains of TB

Question 32

Third second line agent is Levofloxacin. What are some features?

Answer 32

Fluoroquinolone, used in combo, for use against first line drug resistant strains
–not for used in pregos or children under 8

Question 33

The fourth second line agent for tx of TB is Ethionamide. What are some features?

Answer 33

Congener of isoniazid but shares no cross resistance
Used in combo for drug resistant strain of TB
Causes severe GI irritation and adverse neurologic effects