Antimycobacterial Drugs Flashcards

1
Q

Monoresistant TB

A

Resistance to only one first-line drug

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2
Q

Polydrug-resistant TB

A

Resistance to more than one first-line drug (other than BOTH rifampin and isoniazid)

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3
Q

Multidrug-resistant TB (MDR-TB)

A

Resistance to AT LEAST BOTH rifampin and isoniazid

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4
Q

Extensively drug-resistant TB (XDR-TB)

A

Resistance to any fluoroquinolone AND to at least one of the other 2nd-line drugs

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5
Q

Latent vs active tb

A

Active TB has sign, symptoms, radiologic and laboratory evidence. Positive TST/PPD test

Latent TB does not have sign, symptoms, radiologic and laboratory evidence. Positive TST/PPD test

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6
Q

Latent tb treatment depends on measurement and underlying conditions of patient

A
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7
Q

Principles of TB therapy

  • Most sites of disease require ___ months treatment
  • CNS and bone disease require ___ months treatment
  • Standard is a treatment is ___________
  • Dose is dictated by patient ________
A
  • Most sites of disease require 6 months treatment
  • CNS and bone disease require 12 months treatment
  • Standard is a quadruple therapy (RIPE regimen)
  • Dose is dictated by patient weight
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8
Q

Direct Observed Therapy (DOT)

A

ensure adherence and safety and to prevent emergence of drug resistance

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9
Q

First line drugs for TB

A

RIPE

Rifamycins Isoniazid Pyrazinamide Ethambutol

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10
Q

Second line drugs for TB

A

SEAL

Streptomycin, ethionamide, amikacin, levofloxacin

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11
Q

Rifamycins

A
  • Rifampin a.k.a. Rifampicin
  • Rifabutin (mainly used in HIV patients)
  • If used alone, resistance rapidly emerge—> combination therapy
  • Used in the treatment of latent infection
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12
Q

Rifampin MOA and MOR

A

MOA: binds to 𝜷 subunit of bacterial DNA-dependent RNA polymerase leading to inhibition of RNA synthesis
MOR: point mutations in rpoB (gene for the 𝛽 subunit of RNA polymerase)—> Reduced binding to RNA polymerase

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13
Q

Rifampin is

  • administered ________
  • Well distributed (including CSF) in body fluids and tissues
  • Excreted mainly into _______
  • Rifampin is a strong __________________, while Rifabutin is NOT
A
  • Oral & parenteral
  • Well distributed (including CSF) in body fluids and tissues
  • Excreted mainly into feces, small amount in the urine
  • Rifampin is a strong CYP P450 inducer, while Rifabutin is NOT
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14
Q

Rifampin anti microbial spectrum

A
  • Bactericidal against both intracellular and extracellular mycobacteria
  • Bactericidal against both dividing and non-dividing mycobacteria
  • Active against Gram-positive & Gram-negative organisms
  • Activity against MRSA!
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15
Q

Rifampin clinical applications

*remember SMALL P

A
  • Serious staphylococcal infections (osteomyelitis, prosthetic joint infections and prosthetic valve endocarditis)
  • MRSA (with vancomycin)
  • Active TB infections
  • Latent TB in isoniazid intolerant patients
  • Leprosy (delays resistance to dapsone)
  • Prophylaxis for meningitis and H.influenzae type B in exposed individuals
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16
Q

Rifampin adverse effects

A
  • Hepatotoxicity (elevated LFTs)
  • SAFE IN PREGNANCY
  • Red-orange body fluids (urine, sweat and tears) - MOST COMMON & HARMLESS
  • GI upset (anorexia, nausea, abdominal pain)
  • Renal (light-chain proteinuria, nephritis, acute tubular necrosis) - RARE
  • Rashes, anemia, thrombocytopenia are OCCASIONAL
  • Flu-like symptoms
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17
Q
  • Preferred drug for use in HIV patients due to less induction of CYP enzymes
  • Can be a substitute to those patients who are intolerant to rifampin
  • INSUFFICIENT DATA TO RECOMMEND USE IN PREGNANCY
A

Rifabutin

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18
Q

Isoniazid

A
  • Synthetic analog of pyridoxine
  • Abbreviated as INH
  • Most potent anti-TB drug
  • Part of combination therapy for active infections
  • If used alone, resistance rapidly emerge
  • Used in the treatment of latent infection
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19
Q

ISONIAZID

ANTIMICROBIAL SPECTRUM

A
  • Bactericidal against both intracellular and extracellular mycobacteria
  • Bactericidal against actively dividing mycobacteria
  • Bacteriostatic against slowly dividing mycobacteria
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20
Q

ISONIAZID

MECHANISMS OF ACTION

A

Inhibits synthesis of mycolic acid by inhibiting inhA and KasA

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21
Q

ISONIAZID

MECHANISMS OF RESISTANCE

A
  • High level of resistance due to deletion of KatG

* Low level of resistance due to overexpression of inhA and mutations of KasA

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22
Q

Isoniazid is a

  • CYP P450 ____________
  • Metabolized by the ______________ via acetylation (genetically determined)
  • Oral & parenteral
  • Diffuses readily in body fluids, tissues and caseous material
  • Excreted in the urine
A
  • CYP P450 inhibitor
  • Metabolized by the liver N-acetyltransferase via acetylation (genetically determined)
  • Oral & parenteral
  • Diffuses readily in body fluids, tissues and caseous material
  • Excreted in the urine
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23
Q

Isoniazid pharmacokinetics

A
  • Fast acetylators may require higher dosage than slow acetylators for equivalent therapeutic doses
  • No therapeutic consequence when appropriate doses are administered daily, but subtherapeutic concentrations may occur if drug is administered as a once-weekly dose or if there is malabsorption
24
Q

How to alleviate peripheral neuropathy from isoniazid ?

A

alleviated by giving pyridoxine (Vitamin B6)

25
Q

Adverse effects of isoniazid

A

• Neurotoxicity like peripheral neuropathy, restlessness, muscle twitching, seizures, memory loss & insomnia which are more likely to be seen among slow acetylators
alleviated by giving pyridoxine (Vitamin B6)
• GI upset (anorexia, nausea, abdominal pain) and drowsiness
• Hepatotoxicity (INH-induced hepatitis) – MOST COMMON MAJOR TOXIC EFFECT
• Hemolysis in G6PD deficient patients
• Lupus-like syndrome – RARE
• SAFE IN PREGNANCY

26
Q

PYRAZINAMIDE

MECHANISMS OF ACTION & RESISTANCE

A

MOA: must be enzymatically hydrolysed by mycobacterial pyrazinamidase (encoded by pncA) to active pyrazinoic acid

MOR: impaired uptake of pyrazinamide or mutations in pncA

27
Q

PYRAZINAMIDE

PHARMACOKINETICS

A

Works best in acidic pH <6.0 (within phagolysosomes and granulomas)
Metabolized by the liver and excreted in the urine
Given orally

28
Q

PYRAZINAMIDE

ADVERSE EFFECTS

A

• Non-gouty polyarthralgia- MOST COMMON
• Hyperuricemia- COMMON but usually ASYMPTOMATIC
- may precipitate acute gouty arthritis in predisposed patients
• Hepatotoxicity
• Myalgia, GI irritation, maculopapular rash, porphyria, photosensitivity- RARE
• Only given in pregnancy if benefits outweigh the risks, otherwise avoided

29
Q

ETHAMBUTOL

A
  • Part of combination therapy for active infections
  • If used alone, resistance rapidly emerge
  • Bacteriostatic agent which provides synergy with other drugs
  • Least potent against MTB
30
Q

ETHAMBUTOL

MECHANISMS OF ACTION & RESISTANCE

A

MOA: inhibits arabinosyltransferases (encoded by the emb gene) leading to decreased carbohydrate (arabinogalactan) polymerization of cell wall

MOR: mutations (usually overexpression) in the emb gene

31
Q

ETHAMBUTOL

ADVERSE EFFECTS

A

• Visual disturbances (dose dependent)- MOST COMMON and REVERSIBLE

  • decreased visual acuity
  • red-green color blindness - optic neuritis
  • retinal damage
    • Headache, confusion, peripheral neuritis and hyperuricemia- RARE
  • Safe in pregnancy
  • NOT given in children too young to permit assessment of visual acuity and red- green color discrimination
32
Q

STREPTOMYCIN
MOA & CLINICAL USE
• it’s an ______________
• Bactericidal against dividing mycobacteria
• MOA: ________________________________________
• Given parenterally
• Used principally in drug combinations for the treatment of life-threatening tuberculous disease including:
- _______
- _______
- _______

A

STREPTOMYCIN
MOA & CLINICAL USE
• Aminoglycoside
• Bactericidal against dividing mycobacteria
• MOA: inhibits protein synthesis by binding at 30s mycobacterial ribosome
• Given parenterally
• Used principally in drug combinations for the treatment of life-threatening tuberculous disease including:
- TB meningitis
- miliary dissemination
- severe organ TB

33
Q

STREPTOMYCIN

ADVERSE EFFECTS

A

• Ototoxicity (vertigo and hearing loss)- MOST COMMON and may be permanent
• Nephrotoxicity (decreased urine output, elevated BUN & creatinine)
*Toxicities associated are dose-related and can be reduced by limiting therapy to no more than 6 months whenever possible
* Increasing frequency of resistance limits the use of this drug
• TERATOGENIC!

34
Q

ETHIONAMIDE: MOA & ADVERSE EFFECTS
• Chemically related to __________
• MOA: _____________________
• Given orally
• AE: gastric irritation, neurotoxicity (can be alleviated by ____________ supplementation) and hepatotoxicity
• Resistance can develop rapidly if used alone
• NO cross-resistance with Isoniazid

A

ETHIONAMIDE: MOA & ADVERSE EFFECTS
• Chemically related to isoniazid
• MOA: blocks mycolic acid synthesis
• Given orally
• AE: gastric irritation, neurotoxicity (can be alleviated by pyridoxine supplementation) and hepatotoxicity
• Resistance can develop rapidly if used alone
• NO cross-resistance with Isoniazid

35
Q

When is amikacin used

A

Mainly used for streptomycin-resistant or multidrug-resistant mycobacterial strains

36
Q

AMIKACIN: MOA, CLINICAL USE & ADVERSE EFFECTS
• _______________ like streptomycin
• MOA: ___________________________
• Given parenterally
• AE: same as streptomycin (TERATOGENIC!)
• Resistance may still develop if used alone
• Prevalence of amikacin-resistant strains are low (<5%)

A
  • Aminoglycoside like streptomycin
  • MOA: inhibits protein synthesis by binding at 30s mycobacterial ribosome
  • Given parenterally
  • AE: same as streptomycin (TERATOGENIC!)
  • Resistance may still develop if used alone
  • Prevalence of amikacin-resistant strains are low (<5%)
37
Q

Which drug is a fluoroquinolone

A

LEVOFLOXACIN

38
Q

LEVOFLOXACIN MOA

A

interferes with DNA replication by inhibiting DNA gyrase (topoisomerase II)

39
Q

LEVOFLOXACIN AE

A

AE: tendinopathy
• Resistance can rapidly develop if used alone
• TERATOGENIC!

40
Q

LATENT TUBERCULOSIS TREATMENT

A
41
Q

DRUGS FOR LEPROSY

A

Dapsone Rifampin Clofazimine

DR. Clof

42
Q

Dapsone

  • Structurally related to ____________
  • Bacteriostatic
  • Remains to be the most active drug against leprosy
  • MOA:_________________________
  • Given orally and topically
  • Well absorbed and distributed in tissues (high levels in the skin)
  • Also used in the treatment of pneumonia caused by Pneumocystis jirovecii in HIV-AIDS patients
A

• Structurally related to sulfonamides
• Bacteriostatic
• Remains to be the most active drug against leprosy
• MOA: inhibits folate synthesis via dihydropteroate synthase inhibition
• Given orally and topically
• Well absorbed and distributed in tissues (high levels in the skin)
• Also used in the treatment of pneumonia caused by Pneumocystis jirovecii in
HIV-AIDS patients

43
Q

HOW TO TREAT ERYTHEMA NODOSUM LEPROSUM

A

Thalidomide

44
Q

Dapsone AE

A
  • Hemolysis in G6PD deficient patients
  • Methemoglobinemia- COMMON but usually CLINICALLY INSIGNIFICANT
  • GI upset, fever, pruritus and rash can occur
  • Erythema nodosum leprosum often develops during the treatment of lepromatous leprosy which can be treated with Thalidomides
45
Q

Leprosy caused by

A

Caused by Mycobacterium leprae andMycobacterium lepromatis

Disease of peripheral nerves and upper respiratory mucosa

46
Q

_______ is used to treat multi bacillary leprosy

A

Clofazimine

47
Q

CLOFAZIMINE MOA and PK

A
  • MOA: inhibits replication by binding to DNA
  • Given orally
  • Variable absorption and distributed widely in reticuloendothelial tissues and skin
  • Phenazine dye
  • Bactericidal
48
Q

CLOFAZIMINE

ADVERSE EFFECTS

A
  • Discoloration of the skin and conjunctivae - MOST PROMINENT
  • GI irritation- COMMON
  • Does NOT cause erythema nodosum leprosum
49
Q

Treat Pauci-bacillary: 1-5 skin lesions

A

Dapsone + Rifampin (6 months)

50
Q

Treat Multi-bacillary:

> 5 skin lesions

A

Dapsone + Rifampin + Clofazimine (12 months)

51
Q

Treat latent tuberculosis

A
52
Q

Treat active pulmonary tuberculosis

A
53
Q

Treat extra pulmonary tb

A
54
Q

MANAGING DRUG ADVERSE EFFECTS TB

A
55
Q

If patient has HIV. What drug not to give

A

Rifampin.

Use isoniazid instead