Objectives:

What is tuberculosis?

• A multi-systemic desease with myriad

• 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 ()

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

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

• Supplemental first line

Second Line

Fluroquinones

Other oral drugs

Injectible drugs

Other classification

• 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
• 

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