ANTIMYCOBACTERIAL DRUGS Flashcards Preview

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Flashcards in ANTIMYCOBACTERIAL DRUGS Deck (30):
1

MYCOBACTERIA

• Intrinsically resistant to most antibiotics

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

• Combination therapy required

2

TUBERCULOSIS

• 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

DRUGS FOR TB (1ST LINE, 2ND LINE) 

• 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

GOALS OF THERAPY IN TB

• 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

TUBERCULOSIS THERAPY

• 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

LATENT TUBERCULOSIS

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

ISONIAZID:

• 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

ISONIAZID

ANTIBACTERIAL SPECTRUM + 

RESISTANCE

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

ISONIAZID

AE 

PREGNANCY

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

RIFAMPINS

RIFAMPIN, RIFABUTIN

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

RIFAMPIN

ANTIMICROBIAL SPECTRUM

RESISTANCE

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

RIFAMPIN

CLINICAL APPLICATIONS 

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

RIFAMPIN

AE

• 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

RIFABUTIN

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

ETHAMBUTOL

everythign + AE

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

PYRAZINAMIDE

everything including AE 

• 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

STREPTOMYCIN

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

AMIKACIN

2ND LINE DRUG

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

Similar adverse effects to streptomycin.

Teratogenic

19

LEVOFLOXACIN

2ND LINE AGENT

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

Should always be used in combination.

Teratogenic

20

ETHIONAMIDE

2ND LINE AGENT

Congener of INH (no cross-resistance).

Severe GI irritation & adverse neurologic effects.

Also hepatotoxicity & endocrine effects.

Teratogenic

21

ANTI-TB DRUG REGIMEN FOR EMPIRIC TREATMENT OF PULMONARY TB

4 DRUG REGIMEN = BETTER B/C SHORTER DURATION

"RIPE" 

 

NO P IN THE 3 DRUG REGIMEN 

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22

ANTI-TB DRUG REGIMEN TO DRUG RESISTANT STRAINS

RESISTANT TO ISONIAZID (+/- STREPTOMYCIN) 

RIPE W/O THE "I"

1) RIFAMPIN

2) PYRAZINAMIDE

3) ETHAMBUTAL

-can add fluoroquinolone to strengthen treatement 

 

DURATION OF TREATMENT = 6 MONTHS

23

ANTI-TB DRUG REGIMEN FOR RESISTANT TB TO

ISONIAZID + RIFAMPIN (+/- STREPTOMYCIN) 

 

1) FLUOROQUINOLONE

2) PYRAZINAMIDE

3) ETHAMBUTAL

4) + INJECTABLE AGENT (+/- 2ND LINE AGENT)

 

DURATION OF TREATMENT = 18-24 MONTHS 

24

ANTI-TB DRUG REGIMEN WHEN RESISTANT TO: 

1) ISONIAZID,

2) RIFAMPIN (+/- STREPTOMYCIN)

3) ETHAMBUTAL OR PYRAZINAMIDE

1) FLUOROQUINOLONE (ethambutol or pyrazinamide if active)

2) + INJECTABLE AGENT 

3) + TWO 2ND-LINE AGENTS 

 

DURATION OF TREATMENT = 24 MONTHS (2 years) 

25

ANTI-TB DRUG REGIMENS RESISTANT TO

1) RIFAMPIN

1) ISONIAZID

2) ETHAMBUTOL

3) FLUOROQUINOLONE

4) SUPPLEMENTED with PYRAZINAMIDE for FIRST 2 MONTHS

26

LEPROSY

overview and drugs used

• 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

DAPSONE

 

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)

 

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28

CLOFAZIMINE

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

WHO TREATMENT RECOMMENDATIONS FOR LEPROSY

 

PAUCI-BACILLARY 

VS. 

MULTI-BACILLARY

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

TREATMENT OPTIONS FOR INFECTIONS WITH ATYPICAL MYCOBACTERIA

 

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