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SGU Pharm deck -term4 > Antimycobacterial > Flashcards

Antimycobacterial Flashcards

1
Q

Factors that

make mycobacterial therapy challenging ?

A
  • Located intracellularly
  • Intrinsically resistant to most antibiotics
  • Quick to develop resistance
  • Therapy can take months or even years
  • Combination therapy required
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2
Q

TB overview

A

Mycobacterium tuberculosis
• Small aerobic non-motile bacillus
• Divides every 16-20 h
• 1/3 world’s population is thought to be infected
•New infections occur at rate of 1 per second (can be latent or active)
•Can lead to serious infections of the lungs, genitourinary tract, skeleton & meninges

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3
Q

list first line drugs of TB ?

A
  • First line drugs
  • Isoniazid
  • Rifampin
  • Rifabutin (1st line in HIV +ve patients)
  • Ethambutol
  • Pyrazinamide
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4
Q

List second line drugs of TB

A
  • Second line drugs
  • Streptomycin
  • Ethionamide
  • Levofloxacin
  • Amikacin
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5
Q

Goals of TB therapy

A

• Kill tubercle bacilli
• Prevent emergence of drug resistance
•Eliminate persistent bacilli from host’s tissue to prevent relapse
To accomplish these goals, multiple drugs must be taken for a sufficiently long tim

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6
Q

TB therapy guidelines

A
  • Antibiotic susceptibility testing of mycobacterial isolates required
  • 3-4 drug combination regimen
  • Directly Observed Therapy (DOT) regimens are recommended in noncompliant patients or resistant strains
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7
Q

two risk groups for TB therapy

A

Generally, persons at high risk for developing TB disease fall into two categories and will receive prophylaxis / treatment

  1. Persons who have been recently infected with TB bacteria, eg:
    • Close contacts of a person with infectious TB •Persons who have immigrated from an area with a high rate of TB
    • Children <5 who have a positive TB test
    • Groups with high rates of TB transmission
2. Persons with medical conditions that weaken the immune system, eg: 
• HIV 
• Substance abuse 
• Diabetes mellitus 
• Organ transplants 
• Severe kidney disease
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8
Q

List the features of TB cell wall X7

A 
Mycolic acid 
arabinogalactan 
peptidoglycan 
cell membrane 
lipoarabinomannan 
porin 
glycolipids
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9
Q

isoniazid overveiw

A
  • Synthetic analog of pyridoxine
  • First-line agent
  • Most potent antitubercular drug
  • Part of COMBINATION THERAPY for active infections
  • Sole drug in treatment of latent infection
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10
Q

isoniazid MOA

A
  • Pro-drug (activated by a mycobacterial catalaseperoxidase - KatG)
  • Targets enzymes involved in mycolic acid synthesis:
  • enoyl acyl carrier protein reductase (InhA)
  • b-ketoacyl-ACP synthase (KasA)
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11
Q

isoniazid antibacterial spectrum

A
  • Bacteriostatic effects against bacilli in stationary phase
  • Bactericidal against rapidly dividing bacilli
  • Specific for M.tuberculosis
  • If used alone resistant organisms rapidly emerge
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12
Q

isoniazid resistance

A
  • Chromosomal mutations resulting in:
  • mutation of deletion of KatG
  • mutations of acyl carrier proteins
  • overexpression of inhA

•Cross-resistance between other anti-tuberculosis drugs DOES NOT OCCUR

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13
Q

isoniazid pk? AE ? pregnancy ?

A
  • Oral, IV & IM
  • Diffuses into all body fluids, cells & caseous material
AE-->
•Peripheral neuritis: corrected by 
 pyridoxine supplementation
• Hepatotoxicity: clinical hepatitis &amp; idiosyncratic
• CYP P450 inhibitor
• Lupus-like syndrome: rare

Safe in pregnancy (however, hepatitis risk is increased, pyridoxine supplementation is recommended

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14
Q

rifamycins overview

A
  • Rifampin & rifabutin
  • First-line drugs for treatment of all susceptible forms of TB
  • Part of COMBINATION THERAPY for active infections
  • Sole drug in treatment of latent infection (2nd line)
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15
Q

rifampin overview and MOA

A
  • Antimicrobial and antimycobacterial
  • Bactericidal
  • Resistant strains rapidly emerge
  • USUALLY GIVEN IN COMBINATION

•Blocks transcription by binding to b subunit of bacterial DNA-dependent RNA polymerase
→ leading to inhibition of RNA synthesis

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16
Q

rifampin antimicrobial spectrum

A
  • Bactericidal for intracellular AND extracellular mycobacteria • M.tuberculosis • M.kansasii
  • Active against Gram-positive & Gram-negative organisms
  • Activity against MRSA
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17
Q

rifampin resistance

A
  • Point mutations in rpoB, the gene for the b subunit of RNA polymerase → decreased affinity of bacterial DNA-dependent RNA polymerase for drug
  • Decreased permeability
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18
Q

Rifampin clinical applications

A
  • Active TB infections
  • Latent TB in isoniazid intolerant patients
  • Leprosy (delays resistance to dapsone)
  • Prophylaxis for individuals exposed to meningitis
  • Prophylaxis in contacts of children with H.influenzae type B
  • MRSA (with vancomycin)
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19
Q

Rifampin PK ?

A
  • Oral & parenteral
  • Well distributed (including CSF)
  • Excreted mainly into feces
  • Strong CYP P450 inducer
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20
Q

rifampin AE

A
  • Light chain proteinuria
  • GI distress
  • Occasional effects: thrombocytopenia, rashes, nephritis, liver dysfunction
  • Imparts harmless orange/red color to bodily fluids
  • Strongly induces most CYP P450 isoforms
  • SAFE IN PREGNANCY
21
Q

rifabutin overview and uses

A
  • Preferred drug for use in HIV patients (due to less induction of CYP enzymes)
  • Rifampin substitute to those that are intolerant
  • Insufficient data to recommend use in pregnancy
22
Q

Ethambutol

A
  • First-line agent for treatment of all susceptible forms of TB
  • Specific for most strains of M.tuberculosis & M.kansasii
  • Used in combination with pyrazinamide, izoniazid & rifampin
  • Resistance occurs rapidly if used alone (mutations in emb gene)
23
Q

Ethambutol MOA ? AE

A

Inhibits arabinosyltransferase leading to decreased carbohydrate polymerization of cell wal

AE–>
•Dose-dependent visual disturbances (eg, red/green color blindness) – cannot be used in children too young to receive sight tests
•Headache, confusion, hyperuricemia, peripheral neuritis (rare)
• Safe in pregnancy

24
Q

pyrazinamide ? PK ?

A
  • First-line agent
  • Used in combination with isoniazid, rifampin & ethambutol
  • Must be enzymatically hydrolysed to active pyrazinoic acid. Mechanism of action remains unclear
  • Resistant strains lack pyrazinamidase or have increased efflux of drug
  • Well absorbed orally & well distributed (including CSF)
  • Renal or hepatic insufficiency may require dosage adjustment
25
Q

pyrazinamide AE

A
  • Nongouty polyarthralgia (~ 40%)
  • Acute gouty arthritis (rare unless predisposed)
  • Hyperuricemia
  • Hepatotoxicity, myalgia, GI irritation, porphyria, rash, photosensitivity
  • Recommended for use in pregnancy when benefits outweigh risks
26
Q

streptomycin

A
  • Aminoglycoside (same MOA and adverse effects)
  • Used for drug-resistant strains
  • Used in drug combinations for treatment of life-threatening tuberculous disease: • meningitis • miliary dissemination • severe organ tuberculosis
  • Increasing frequency of resistance to streptomycin limits use of drug
27
Q

Amikacin

A

Used for streptomycin- or multi-drug-resistant strains. Similar adverse effects to streptomycin. Teratogenic

2nd line drug

28
Q

Levofloxacin

A

Recommended for use against first-line drugresistant strains. Should always be used in combination. Teratogenic

2nd line drug

29
Q

Ethionamide

A

Congener of INH (no cross-resistance). Severe GI irritation & adverse neurologic effects. Also hepatotoxicity & endocrine effects. Teratogenic

2nd line drug

30
Q

drug regimen for treatment of latent TB

A

Drug and Duration of Treatment
1- Isoniazid 6-9 months
2- Rifampin 4 months

31
Q

anti TB drug regimens for initial phase and continuation phase

A

initial phase
1- isoniazid, rifampin, pyrazinamide and thambutol for 8 weeks follwed by continuation phase with isoniazid and rifampin for 18 weeks

or

2- isoniazid, rifampin and ethambutol for 8 weeks intially followed by isoniazid and rifampin for 31 weeks

32
Q

leprosy

A
  • aka Hansen’s disease
  • Caused by Mycobacterium leprae & Mycobacterium lepromatis
  • Primarily granulomatous disease of peripheral nerves & mucosa of upper respiratory tract
  • ~ 70 % cases are in India
33
Q

drugs for leprosy

A

WHO recommends 3 drugs to be used in combination:

• Dapsone • Clofazimine • Rifampin

34
Q

dapsone

A
  • Structurally related to sulfonamides
  • Bacteriostatic
  • Inhibits folate synthesis (via dihydropteroate synthetase inhibition)
  • Also used in treatment of pneumonia (P.jiroveci) in HIV +ve patients
35
Q

dapsone PK and AE ?

A
  • Well absorbed & distributed (high levels in skin)
  • Acedapsone = repository form of dapsone

AE –>
• Hemolysis (esp. G6PD deficiency)
•Erythema nodosum leprosum (treated with corticosteroids or thalidomide)
•Other effects – GI irritation, fever, hepatitis, methemoglobinemia
• CYP P450 inhibitor

36
Q

clofazimine

A
  • Phenazine dye
  • Binds to DNA & inhibits replication
  • Redox properties may generate cytotoxic oxygen radicals
  • Bactericidal to M.leprae (some activity against M. aviumintracellulare complex)
37
Q

Clofazimine AE ?

A

• Red-brown discoloration of skin • GI irritation • Eosinophillic enteritis •Erythema nodosum DOES NOT develop (drug has antiinflammatory action

38
Q

Pauci-bacillary (PB): 1-5 skin lesions

regimen

A

Regimen of 2 drugs: Rifampin + dapsone (6 months)

39
Q

Multi-bacillary: > 5 skin lesions

regimen

A

Regimen of 3 drugs: Rifampin, clofazimine + dapsone (12 months)

40
Q

Pattern of Drug Resistance (Isoniazid (+/Streptomycin)

Suggested Regimen

A

Rifampin, pyrazinamide, ethambutol (can add fluoroquinolone to strengthen treatment)
6 months

41
Q

pattern of drug resistance - suggested regimen Isoniazid & rifampin (+/Streptomycin)

A

Fluoroquinolone, pyrazinamide, ethambutol + injectable agent +/- second-line agent
18-24 months

42
Q

pattern of drug resistance - suggested regimen for –>Isoniazid, rifampin (+/streptomycin), + ethambutol or pyrazinamide

A

Fluoroquinolone (ethambutol or pyrazinamide if active) + injectable agent +/- two second-line agents
24 months

43
Q

pattern of drug resistance - suggested regimen for –>Rifampin

A

Isoniazid, ethambutol, fluoroquinolone, supplemented with pyrazinamide for first 2 months
12-18 months

44
Q

M kansaii clinical features and treatments

A

Resembles TB Isoniazid + rifampin + ethambutol

45
Q

clinical features and treatments for for M marinum

A

Granulomatous cutaneous disease

2 drug combination (rifampin, ethambutol, clarithromycin, minocycline, doxycycline, sulfonamides)

46
Q

clinical features and treatments for M avium complex

A

Pulmonary disease Clarithromycin + ethambutol +/- rifabutin

47
Q

clinical features and treatments for M chelonae

A

Abscess, sinus tract, ulcer; bone, joint, tendon infection

Clarithromycin (monotherapy usually adequate)

48
Q

clinical features and treatments for M fortuitum

A

Abscess, sinus tract, ulcer; bone, joint, tendon infection

Amikacin, cefoxitin, levofloxacin, sulfonamides, imipenem

SGU Pharm deck -term4 (10 decks)

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