Antimycobacterial Flashcards
(48 cards)
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
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
3
Q
list first line drugs of TB ?
A
- First line drugs
- Isoniazid
- Rifampin
- Rifabutin (1st line in HIV +ve patients)
- Ethambutol
- Pyrazinamide
4
Q
List second line drugs of TB
A
- Second line drugs
- Streptomycin
- Ethionamide
- Levofloxacin
- Amikacin
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
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
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
- 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
8
Q
List the features of TB cell wall X7
A
Mycolic acid arabinogalactan peptidoglycan cell membrane lipoarabinomannan porin glycolipids
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
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)
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
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
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 & idiosyncratic • CYP P450 inhibitor • Lupus-like syndrome: rare
Safe in pregnancy (however, hepatitis risk is increased, pyridoxine supplementation is recommended
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)
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
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
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
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)
19
Q
Rifampin PK ?
A
- Oral & parenteral
- Well distributed (including CSF)
- Excreted mainly into feces
- Strong CYP P450 inducer
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
pyrazinamide AE
* 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
streptomycin
* 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
Amikacin
Used for streptomycin- or multi-drug-resistant strains. Similar adverse effects to streptomycin. Teratogenic
2nd line drug
28
Levofloxacin
Recommended for use against first-line drugresistant strains. Should always be used in combination. Teratogenic
2nd line drug
29
Ethionamide
Congener of INH (no cross-resistance). Severe GI irritation & adverse neurologic effects. Also hepatotoxicity & endocrine effects. Teratogenic
2nd line drug
30
drug regimen for treatment of latent TB
Drug and Duration of Treatment
1- Isoniazid 6-9 months
2- Rifampin 4 months
31
anti TB drug regimens for initial phase and continuation phase
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
leprosy
* 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
drugs for leprosy
WHO recommends 3 drugs to be used in combination:
| • Dapsone • Clofazimine • Rifampin
34
dapsone
* 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
dapsone PK and AE ?
* 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
clofazimine
* 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
Clofazimine AE ?
• Red-brown discoloration of skin • GI irritation • Eosinophillic enteritis •Erythema nodosum DOES NOT develop (drug has antiinflammatory action
38
Pauci-bacillary (PB): 1-5 skin lesions
| regimen
Regimen of 2 drugs: Rifampin + dapsone (6 months)
39
Multi-bacillary: > 5 skin lesions
| regimen
Regimen of 3 drugs: Rifampin, clofazimine + dapsone (12 months)
40
Pattern of Drug Resistance (Isoniazid (+/Streptomycin)
| Suggested Regimen
Rifampin, pyrazinamide, ethambutol (can add fluoroquinolone to strengthen treatment)
6 months
41
pattern of drug resistance - suggested regimen Isoniazid & rifampin (+/Streptomycin)
Fluoroquinolone, pyrazinamide, ethambutol + injectable agent +/- second-line agent
18-24 months
42
pattern of drug resistance - suggested regimen for -->Isoniazid, rifampin (+/streptomycin), + ethambutol or pyrazinamide
Fluoroquinolone (ethambutol or pyrazinamide if active) + injectable agent +/- two second-line agents
24 months
43
pattern of drug resistance - suggested regimen for -->Rifampin
Isoniazid, ethambutol, fluoroquinolone, supplemented with pyrazinamide for first 2 months
12-18 months
44
M kansaii clinical features and treatments
Resembles TB Isoniazid + rifampin + ethambutol
45
clinical features and treatments for for M marinum
Granulomatous cutaneous disease
| 2 drug combination (rifampin, ethambutol, clarithromycin, minocycline, doxycycline, sulfonamides)
46
clinical features and treatments for M avium complex
Pulmonary disease Clarithromycin + ethambutol +/- rifabutin
47
clinical features and treatments for M chelonae
Abscess, sinus tract, ulcer; bone, joint, tendon infection
| Clarithromycin (monotherapy usually adequate)
48
clinical features and treatments for M fortuitum
Abscess, sinus tract, ulcer; bone, joint, tendon infection
| Amikacin, cefoxitin, levofloxacin, sulfonamides, imipenem
