ANTIMYCOBACTERIAL DRUGS Flashcards Preview

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Flashcards in ANTIMYCOBACTERIAL DRUGS Deck (30)
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1
Q

MYCOBACTERIA

A

• Intrinsically resistant to most antibiotics

  • Located intracellularly
  • Quick to develop resistance
  • Therapy can take months or even years

• Combination therapy required

2
Q

TUBERCULOSIS

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

DRUGS FOR TB (1ST LINE, 2ND LINE)

A

• First line drugs

  • 1) ISONIAZID
  • 2) Rifampin
  • 3) Rifabutin (1st line in HIV +ve patients)
  • 4) Ethambutol
  • 5) Pyrazinamide

• Second line drugs

  • Streptomycin
  • Ethionamide
  • Levofloxacin
  • Amikacin
4
Q

GOALS OF THERAPY IN TB

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 time

5
Q

TUBERCULOSIS THERAPY

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

6
Q

LATENT TUBERCULOSIS

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 withTB 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

NOTE: DRUG REGIMINS FOR TREATMENT

1) ISONIAZID USED FOR 6-9 MONTHS
2) RIFAMPIN USED FOR 4 MONTHS (better b/c shorter)

7
Q

ISONIAZID:

A

• Synthetic analog of pyridoxine
• First-line agent
• Most potent antitubercular drug
• PART OF COMBINATION THERAPY
• Sole drug in treatment of latent infection

MOA:

  • Pro-drug (activated by a mycobacterial catalase- peroxidase - KatG)
  • Targets enzymes involved in _mycolic acid synthesis_:

1) • enoyl acyl carrier protein reductase (InhA)
2) • 􏰀-ketoacyl-ACPsynthase(KasA)

PK:

  • Oral, IV & IM
  • Diffuses into all body fluids, cells & caseous material
8
Q

ISONIAZID

ANTIBACTERIAL SPECTRUM +

RESISTANCE

A

ANTIBACTERIAL SPECTRUM:

Bacteriostatic effects against bacilli in stationary phase • Bactericidal against rapidly dividing bacilli

  • _**Specific for M.tuberculosis
  • If used alone**_resistant organisms rapidly emerge

RESISTANCE:

• Chromosomal mutations resulting in:

1) • mutation of deletion of KatG
2) • mutations of acyl carrier proteins

3) • overexpression of inhA

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

9
Q

ISONIAZID

AE

PREGNANCY

A
  • Peripheral neuritis: corrected by pyridoxine supplementation
  • Hepatotoxicity: clinical hepatitis & idiosyncratic

• CYP P450 inhibitor
Lupus-like syndrome: rare

PREGNANCY:

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

10
Q

RIFAMPINS

RIFAMPIN, RIFABUTIN

A

First-line drugs for treatment of all susceptible forms of TB
PART OF COMBINATION THERAPY

  • Bactericidal
  • Resistant strains rapidly emerge
  • USUALLY GIVEN IN COMBINATION

MOA:

• Blocks transcription by binding to 􏰀subunit of bacterial DNA-dependent RNA polymerase

􏰁–> leading to inhibition of RNA synthesis

PK:

  • Oral & parenteral
  • Well distributed (including CSF)
  • Excreted mainly into feces
  • Strong CYP P450 inducer
11
Q

RIFAMPIN

ANTIMICROBIAL SPECTRUM

RESISTANCE

A

ANTIMICROBIAL SPECTRUM

  • Bactericidal for intracellular AND extracellular mycobacteria
  • M.tuberculosis
  • M.kansasii
  • Gram-positive & Gram-negative organisms

RESISTANCE

  • Point mutations in rpoB, the gene for the 􏰀􏰀 subunit of RNA polymerase –> decreased affinity of bacterial DNA-dependent RNA polymerase for drug
  • Decreased permeability
12
Q

RIFAMPIN

CLINICAL APPLICATIONS

A

1) • TB
• Latent TB in INH intolerant patients
2) • Leprosy
3) • Prophylaxis for individuals exposed to meningitis (NOTE THAT CEFTRIAXONE IS USUALLY THE FIRST LINE IN US)

4) • MRSA (with vancomycin)

13
Q

RIFAMPIN

AE

A
  • Light chain proteinuria
  • GI distress
  • Occasional effects: thrombocytopenia, rashes, nephritis, liver dysfunction
  • Imparts harmless orange/red color to bodily fluids

EG) PATIENT COMES BACK COMPLAINS OF RED/ORANGE URINE… AM I OKAY? YES YOU ARE!

–> don’t wear contacts or will dye the contacts!!!

Strongly induces most CYP P450 isoforms

–> b/c it strongly induces CYP P450, and isoniazid is a weak inhibitor, RIFAMPIN WINS this induction

• SAFE IN PREGNANCY

14
Q

RIFABUTIN

A

A RIFAMPIN SUBSTITUTE

Preferred drug for use in HIV patients (due to lesser effects on CYP enzymes)

  • Rifampin substitute to those that are intolerant
  • Insufficient data to recommend use in pregnancy
15
Q

ETHAMBUTOL

everythign + AE

A
  • _*First-line agent* for treatment of all susceptible forms of TB_
  • Specific for most strains of M.tuberculosis & M.kansasii
  • _Inhibits arabinosyl transferases****_

Used in combination with pyrazinamide, izoniazid & rifampin

Resistance occurs rapidly if used alone (mutations in emb gene)

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

16
Q

PYRAZINAMIDE

everything including AE

A

• First-line agent

  • Used in combination with isoniazid, rifampin & ethambutol
  • Must be enzymatically hydrolysed to active pyrazinoic acid
  • Resistant strains lack pyrazinamidase or have increased efflux of drug

PK:

  • Well absorbed orally & well distributed (including CSF)
  • Renal or hepatic insufficiency may require dosage adjustment

AE:

  • Nongouty polyarthralgia (~ 40%)
  • Acute gouty arthritis (rare unless predisposed)
  • Hyperuricemia
  • Hepatotoxicity, myalgia, GI irritation, porphyria, rash, photosensitivity –> must ADJUST DOSE IN RENAL/HEPATIC INSUFFICIENCY!!
  • Recommended for use in pregnancy when benefits outweigh risks
17
Q

STREPTOMYCIN

A

2ND LINE DRUG

• Used for drug-resistant strains
• Used in drug combinations for treatment of ***life-threatening

tuberculous disease:

  1. • meningitis
  2. • miliary dissemination
  3. • severe organ tuberculosis

_• Increasing frequency of resistance to streptomycin limits use of drug***_

18
Q

AMIKACIN

A

2ND LINE DRUG

Used for streptomycin- or multi-drug-resistant strains.

Similar adverse effects to streptomycin.

Teratogenic

19
Q

LEVOFLOXACIN

A

2ND LINE AGENT

Recommended for use when first-line drug-resistant strains are present .

Should always be used in combination.

Teratogenic

20
Q

ETHIONAMIDE

A

2ND LINE AGENT

Congener of INH (no cross-resistance).

Severe GI irritation & adverse neurologic effects.

Also hepatotoxicity & endocrine effects.

Teratogenic

21
Q

ANTI-TB DRUG REGIMEN FOR EMPIRIC TREATMENT OF PULMONARY TB

A

4 DRUG REGIMEN = BETTER B/C SHORTER DURATION

“RIPE”

NO P IN THE 3 DRUG REGIMEN

22
Q

ANTI-TB DRUG REGIMEN TO DRUG RESISTANT STRAINS

RESISTANT TO ISONIAZID (+/- STREPTOMYCIN)

A

RIPE W/O THE “I”

1) RIFAMPIN
2) PYRAZINAMIDE
3) ETHAMBUTAL
- can add fluoroquinolone to strengthen treatement

DURATION OF TREATMENT = 6 MONTHS

23
Q

ANTI-TB DRUG REGIMEN FOR RESISTANT TB TO

ISONIAZID + RIFAMPIN (+/- STREPTOMYCIN)

A

1) FLUOROQUINOLONE
2) PYRAZINAMIDE
3) ETHAMBUTAL
4) + INJECTABLE AGENT (+/- 2ND LINE AGENT)

DURATION OF TREATMENT = 18-24 MONTHS

24
Q

ANTI-TB DRUG REGIMEN WHEN RESISTANT TO:

1) ISONIAZID,
2) RIFAMPIN (+/- STREPTOMYCIN)
3) ETHAMBUTAL OR PYRAZINAMIDE

A

1) FLUOROQUINOLONE (ethambutol or pyrazinamide if active)
2) + INJECTABLE AGENT
3) + TWO 2ND-LINE AGENTS

DURATION OF TREATMENT = 24 MONTHS (2 years)

25
Q

ANTI-TB DRUG REGIMENS RESISTANT TO

1) RIFAMPIN

A

1) ISONIAZID
2) ETHAMBUTOL
3) FLUOROQUINOLONE
4) SUPPLEMENTED with PYRAZINAMIDE for FIRST 2 MONTHS

26
Q

LEPROSY

overview and drugs used

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

DRUGS USED IN LEPROSY

1) • Dapsone
2) • Clofazimine

3) • Rifampin

27
Q

DAPSONE

A

LEPROSY DRUG

  • Structurally related to sulfonamides (SULFA RELATED)
  • Bacteriostatic
  • Inhibits folate synthesis (via dihydropteroate synthetase inhibition)
  • Also _used in treatment of pneumonia ****(P.jiroveci) in HIV +ve patients_

PK:

• Well absorbed & distributed (high levels in skin)

• Acedapsone = repository form of dapsone

ADVERSE EFFECTS:

1) Hemolysis (esp. G6PD deficiency)
_*****2) Erythema nodosum leprosum_ (treated with corticosteroids or thalidomide) –> The dying mycobacterium basically cause this reaction (similar to what happens in syphillus)

• Other effects – GI irritation, fever, hepatitis, methemoglobinemia

• CYP P450 inhibitor (dapsone goes down ie inhibits)

28
Q

CLOFAZIMINE

A

LEPROSY DRUG

  • Phenazine dye
  • Binds to DNA & inhibits replication
  • Redox properties may generate cytotoxic oxygen radicals

• Bactericidal to M.leprae (some activity against M. avium- intracellulare complex)

AE:

• ****Red-brown discoloration of skin

  • GI irritation
  • Eosinophillic enteritis

• ****Erythema nodosum DOES NOT develop (drug has anti- inflammatory action)

29
Q

WHO TREATMENT RECOMMENDATIONS FOR LEPROSY

PAUCI-BACILLARY

VS.

MULTI-BACILLARY

A

PAUCI-BACILLARY: 1-5 SKIN LESIONS

TX: regimen of 2 drugs for 6 MONTHS

1) RIFAMPIN
2) DAPSONE

MULTI-BACILLARY: >5 SKIN LESIONS

TX: regimen of 3 drugs for 12 MONTHS

1) RIFAMPIN
2) DAPSONE
3) CLOFAZIMINE

30
Q

TREATMENT OPTIONS FOR INFECTIONS WITH ATYPICAL MYCOBACTERIA

A