Antitubercular Drugs

Antitubercular Drugs

1. Introduction & the mycobacterial therapeutic problem

• Tuberculosis (TB) is a chronic granulomatous disease caused by Mycobacterium tuberculosis; it surpassed HIV as the leading infectious-disease killer in 2014, and is thought to have killed ~1 in 7 of all humans who have ever lived (G&G 14e Ch.65, p.1267).
• About 1/3 of the world's population is latently infected with M. tuberculosis, of whom 10–15% develop active disease over a lifetime; India is the highest-burden country (~2.2 million of the 9.6 million global new cases in 2014, ~600 deaths/day), and TB kills more Indian adults than any other infectious disease (KDT 8e Ch.56, p.815).
• The M. tuberculosis complex comprises species with 99.9% nucleotide similarity: M. tuberculosis (typus humanus), M. canettii, M. africanum, M. bovis, and M. microti — all cause TB (G&G 14e Ch.65, p.1279).
• Mycobacteria are intrinsically hard to treat because of three natural barriers (G&G 14e Ch.65, p.1267):
  • Waxy lipid cell wall — >60% lipid, mainly mycolic acids (2-branched, 3-hydroxy fatty acids, 76–90 carbon chains); blocks drug penetration to the cell membrane/cytosol.
  • Efflux pumps — abundant membrane transport proteins (e.g. ATP-binding-cassette [ABC] transporters are a full 2.5% of the M. tuberculosis genome) pump out drugs, conferring native resistance.
  • Intracellular + extracellular location — bacilli hide inside host cells AND within necrotic, avascular lesions, so drugs must penetrate both compartments.
• Slow growth and dormancy add to the problem: antibiotics most active against rapidly growing cells are relatively ineffective, and dormant bacilli are killed only very slowly (Katzung 16e Ch.47, p.886).
• Combinations of ≥2 drugs are mandatory — to overcome these barriers AND prevent emergence of resistance during the months-to-years of therapy (Katzung 16e Ch.47, p.886).
• The first randomized controlled trial with concealed allocation in human history was for TB — streptomycin versus bed rest (G&G 14e Ch.65, p.1267).

Historical milestones (G&G 14e Ch.65, p.1267; KDT 8e Ch.56, p.815)

• Para-aminosalicylic acid (PAS) — Lehman, 1943 (2nd effective drug); streptomycin — Waksman & Schatz, 1944 (introduced 1947); thioacetazone — Domagk, 1946; isoniazid — 1952; pyrazinamide — Kushner et al., 1952; rifamycins — Sensi & Margalith, 1957 (rifampin clinically 1962); ethambutol — Lederle, 1961.
• A long pause followed, then a "second wave": bedaquiline (FDA 2012) and delamanid (Europe 2013). The "third wave" is now here, plus repurposed agents (moxifloxacin, levofloxacin, oxazolidinones, β-lactams).