Tuberculosis

Objectives: [[Pasted image 20210624140716.png]]

What is tuberculosis?

  • A multi-systemic desease with myriad

[[Pasted image 20210624140856.png]]

  • Inhalation of aerosol droplets containing M. tuberculosis with subsequent deposition in lungs:
  • Immediate clearance of the organism ° Primary disease: immediate onset of active disease ° Latent infection
  • Reactivation disease: onset of active disease many years following a period of latent infection

Tubercle bacilli -> carried in droplets small enough to reach alveolar space (5-10 microns) -> innate host defense system fails to eliminate -> proliferate inside alveolar macrophages -> migrate away from lungs to

Essentials of Diagnosis

  • Fatigue, weight loss, fever, night sweats, and cough (dry or productive)
  • Risk factors for acquisition:
  • Chest radiograph: pulmonary
  • Acid-fast bacili

Goals of treatment

  • Decrease mortality and long-term morbidity
  • To effect a permanent cure, prevent relapses and decrease transmission
  • To minimize development of drug resistance
  • To achieve the above while minimizing side-effects

Management consists of a patient-centered approach in which the patient, provider, public health and laboratory enter into a relationship that assures that the goals of treatment are met.

Drug Susceptibility Testing

  • Positivie cultures should be followed by drug susceptibility testing
  • Symptoms and radiographic findings do not differentiate between MDR-TB from fully susceptible TB
  • Suspect MDR-TB if:
    • History of previous treatment for TB
    • Lived in a country with a high prelavance of MDR-TB
    • In contact with a case of MDR-TB infected
    • PH ([[Pasted image 20210624142045.png]])

Anti-tubercular drugs

Classification

First Line

HRZE - abbreviation for Isoniazid, Rifampin, Pyrazinamide, Ethambutol

  • Streptomycin is considered as a reserve drug

Isoniazid

  • Abbreviated as H / INH
  • Essential of all tubercular therapy
  • Primarily tuberculoidal
  • Fast multiplying organisms are rapidly killed, but quiescent are only inhibited
  • Acts on extracellular and intracellular TB (bacilii present within macrophages)
  • Equally active in acidic or alkaline medium (during inflammation env. turns acidic)
  • Cheapest antitubercular drugs

Mechanism

  • Inhibition of synthesis of mycolic acids (unique fatty acid components of mycobacterial cell wall)
  • Targets -> Two gene products called InhA and KasA (resistance develops at this point)
    • About 1 in million (10^6) is inherently resistant to INH
    • IF INH is given alone, such bacili proliferate selectively and after 2-3 months increase resistant infection
    • Mechanism
      • Mutation of catalase peroxidase (KatG) -> Resistance cannot be overcome -> Stop INH
      • Mutation of inhA gene -> Low-level INH resistance -> can be overcome by using ‘high-dose’ INh
  • no cross resistance

Pharmacokinetics:

  • N-acetylation metabolism extensively in liver
    • Fast acetylators [30-40% indians] t-half 1 hour
    • Slow acetylators [60-70%] t-half of 3 hour Acetylator status does not matter if INH is taken daily

Adverse effects:

  • Peripheral neuritis

    • Dose dependent
    • Prevented by pyridoxine (10mg/day)
    • Treatment by pyridoxidine (100mg/day) [10x prophylaxis]
  • Hepatitis

    • Rare in children
    • Reversible
    • Common in older and alcoholics

Rifampicin

  • A.k.a Rifampin
  • Obtained from Streptomyces mediterranei
  • Bactericidal against M. tuberculosis and leprae
    • And also Many other gram-positive and gram-negative bacteria like Staph. aureus, N. meningitidis, H. influenzae, E. coli, Klebsiella, Pseudomonas, Proteus and Legionella
  • Acts best on slowly/intermittently dividing ones (spurters)
  • both extra and intracellular bacilii

MOA

  • Inhibits RNA synthesis by binding to mycobacterial DNA-dependent RNA polymerase (encoded by rpoB gene) and blocking its polymerizing function
  • Mammalian RNA polymerase does not avidly bind to rifampicin

Resistance

  • Resistance develops rather rapidly
  • Incidence of resistant bacili 10^-7
  • Primary rifampin resistant tubercular infection is unusual
  • In india - 2%
  • It is due to mutation in rpoB gene reducing its affinity
  • No cross resistance with other antituberculars except

PK

  • Orally
  • Bioavailability - 70%
  • Food decreases absorption -> thus taken on empty stomach
  • Penetrates intracellulary -> enters tubercular cavities, caseous masses and placenta
  • Crosses meninges and largely lpumped out from P
  • Metabolized in liver -> Excreted in bile and urine

Drug interactions

  • Induces several CYP450 isoenzymes
    • Increases metabolism of many drugs including itself [[Pasted image 20210624144457.png]]

Adberse

  • Hepatotoxicity
    • Dose related
    • If jaundice - continues
  • Minor reaction [does not requiring drug withdrawal]
    • Cutaneous: flushing, pruritus + rash, redness and watering eyes
    • Flu like symptoms: chills,
    • Abdominal cramps, nausea, vomiting, diarrhoea
    • Urine/secretions may become orange-red -> Harmless

Other uses

  • Leprosy
  • prophylaxis of
  • 2nd/3rd DOC of
  • Doxycyline + rifampacin -> first in Brucellossis

Pyrazinamide (Z)

  • Tuberculocidal but weaker than ING

  • More active in acidic medium

  • Highly effective during first 2 months when inflammatory changes are present

  • Good sterilziing activity

  • Inclusion of pyrazinamide

    • Shortened duration of treatment
    • Reduces risk of relapse

MOA

  • Not well established
  • Pyrazinamide -> pyraz

ADR

  • Hepatotoxicity
    • Dose related
    • Less common in Indian population
    • Daily dose is limited to 25-30

Ethambutol

  • Only tuberculostatic in FL
  • Fast

MOA

  • Not fully understood
  • Interferes wit MAcid incorparation into wall

ADR

  • Retrobulbar neuritis:
    • Loss of visual acuity/color vision, field defects
    • Stop at first indication of visual impairment
    • Young children were previously contraindicated, but now wit
    • Early recognition + stoppage -> Largely reverisble
    • Safe in pregnancy

Useful in MAC

Streptomycin

[[Pasted image 20210624145607.png]]

  • Supplemental first line

Second Line

Fluroquinones

Other oral drugs

Injectible drugs

Other classification

[[Pasted image 20210624142434.png]]

  • Bactericidal: drugs that kill the bacilli in vivo
    • All first line drugs are bactericidal except Ethambutol (which is bacteriostatic)

Bacteriostatic: Inhibits multiplication -> their destruction depends on the immune mechanism of the host: - Ethambutol - Thioacetazone

Two phase therapy

  • Intensive Phase
    • Aims for rapid killing of bacili
  • Continuation Phase
    • Sterilizing smaller number of dormant/persistent bacilii
    • Multi-drug regimens and DOT necessary (unless R not used) even though the risk of drug resistence

Ramycing

Fluroquinolines

Rifabutin

  • Less active against M. Tuberculosis, more active against MAC
  • Less potential for drug interactions
  • Prevention of dissemin
  • [[Pasted image 20210626081226.png]]

Rifapentine

  • Potent enzyme inducer
  • Not suitable for use during the intensive phase
  • Indication (600 mg once/twice weekly)
  • Mechanism

Bedaquiline

  • Novel mechanism: Inhibits mycobacterial ATP synthase thereby limiting energy production within mycobacteria
  • Human ATPsynthase: 20000 less sensitive than mycobacterial enzyme
  • Strong bactericidial sterilizing activity - M. tuberculosis
  • Kill both rapid and dormant
  • Resistance:
    • Mutation
    • BDQ efflux’
  • Fatty meals improves absorption
  • Highly plasma protein bound
  • ADR
    • Nausea, headache, arthalgia
    • Potential to cause hepatotoxicity

To use only for pulmonary MDR-18 in adukts (>18 years) Women should be non-pregnant and should not be during

  • In combination with at least 3 other anti-TB

  • To be used only when an effective regiment

  • Dise: first 2 weeks, 400 mg

  • 3rd-22nd week 200 mg 3 times a week

  • Each BDQ tablet should be swallowed whole with meals - DO NOT BREAK THE TABLET

  • Not to be used for drug-sensitive TB, such as extrapulmonaryTB or non-tubercular

Operational Guidelines for Rx inititation

[[Pasted image 20210626083625.png]]