• poor patient compliance (also causes resistance)
• solved via direct observed therapy

• intracellular parasites, and most drugs poorly penetrate macrophage
• impermeable cell wall rich in lipids
• exist in dormant state (lead to antibiotic resistance)
• slow growing organisms (leads to antibiotic resistance)

1. Isoniazid (INH)
2. Rifampin
3. Pyrazinamide
4. Ethambutol
5. Streptomycin

• normal treatment (2 options)
  • INH and Rifampin for 9 months
  • INH, Rifampin for six months with Pyrazinamide being for the initial two months
• HIV- 9 mnths, or 6 mnths after we get negative cultures (whichever is first

• tx- INH, PYZ, ETH for 18-24 mnths
• HIV positive
  • 18-24 mnths, or 12 mnths after negative cultures, whichever is longer

• tx- two options
  • Ripfampin or ethanbutamine for 12 months
  • rifampin, ethanbutamine, pyrazinamide for 12 months
• HIV patient- 18 mnths or 12 mnths after negative cultures, whichever is longer

• tx- at least three drugs for which the organism is sensitive for two years after negative cultures
• HIV positive- same course for two years after negative cultures

• prognosis- high risk for tx failure
• if failing, introduce two new drugs at a time

• bacteriocidal
• mechanism
  1. KatG (a catalse peroxidase) found in the mycobacterium converts INH to active form
  2. INH will then inhibit InhA (protein reductase NADH complex)
     • this enzyme is needed for the synthesis of mycolic acids, so if it is inhibited, the cell wall loses its integrity
• resistance (1:10⁶ organism) via:
  • mutation of InhA
  • loss of catalse peroxidase activity

• bacteriocidal
• mechanism
  • binds to beta unit of bacterial DNA dependent RNA Pol.
  • leads to inhibition of transcription
• resistance (by self 1:10⁶ and with INH its 1:10¹²) mechanism via:
  • mutation of RNA polytermase thereby decreasing drug affinity
  • decrease cell permeability

• bacteriocidal mechanism that is unknown aside from it must be hydrolyzed to pyrazinoic acid via pyrazinamidase to be active
• resistance via loss of pyrazinamidase function

• bacteriostatic
• mechanism
  • inhibit arabinogalactan synthesis (needed for cell wall)
  • weaker cell wall leads to enhanced action of other lipophilic drugs like Rifampin
• resistance mechanism- unknown but frequent and quick if used alone

• absorption- well absorbed from GI tract when administered orally
• distribution- diffuse readily into all tissue
• metabolism (no influence of sex or age)
  • rapid acetylators (inactivators) = half life of one hour
  • slow acetylators (inactivators) = half life of three hours (greater risk for toxicity)
• excretion- kidney as free drug, acetyl version, hydrazones, mono/diacetylhydrazine

• peripheral neuropathy (prevent via coadministration of pyridoxin, vitamin B6)
• liver damage due to N-acetylhydrazine (derived from acetyl INH) undergoing P450 activation to reactive moiety 
  • esp. if over 35, alcoholic, taking other hepatotoxic agents)
• glossitis
• allergic rxn
• GI disturbance
• RARE- if high doses or slow acetylators, reversible CNS effects (can be reversed/ prevented via coadministration of pyridoxine)

• oral administration
• absorption- well absorbed from GI
• half life: 2-5 hrs
• elimination- bile, then to enterohepatic circulation where it undergoes deacetylation and excreted into feces

• hepatic toxicity
• flu like syndrome
• orange red discoloration of urine, saliva, sweat

• orally administered and well absorbed from GI tract
• plasma half life = 4 hrs
• excretion- kidney mainly as unchanged drug
  • some as aldehyde and dicarboxylic acid derivatives

• reversible optic neuritis resulting in decrease visual acuity and loss of red green discrimination

• administered orally
• absorbed well from GI
• excretion- kidney

• ocassional liver damage
• GI disturbance
• decrease urate excretion as well as cause prurits and athralgias, so exacerabate gout

drug interaction of INH and tx

• increase phenytoin toxicity due to decreased liver P450 metabolism of phenytoin
• can decrease effect with aluminum containing antacids (lead to decreased INH absorption)

• induces hepatic microsomal enzymes
• decreases effect of other concurrently administered drugs by increasing their metabolism
  • warfarin
  • predinsone
  • methadone
  • oral contraceptives

• HIV positive
• close contacts
• within first two years after positive tuberculin test
• infants, adolescents
• patients on immunosuppressive therapy

• INH daily alone for 6-12 months (12 months if HIV positive)
  • can be with or w/o ETH
• if its a Multidrug exposure, TB should include
  • PYRZ + ETH
  • PYRZ + Ofloxacin or Ciprofloxacin

• for patients under 35, the benefits are greater to prophylax them
• over 35, the risk of hepatotoxicity is too great unless they have other risk factors (immunosup., lung disease, recent tuberculin conversion)

• M avium complex (MAC)
• M kansasii

CAUSE SERIOUS DISSEMINATED DISEASE IN HIV

• Clarithromycin or Azithromycin + ETH + Rifabutin or Ciprofloxacin

• INH + RIF + ETH or streptomycin

• prevention or in combination with regimens for treatment of disseminated MAC in patients with advanced HIV infection

similar to rifampin

• inhibits bacterial DNA dependent RNA polymerase

• well absorbed from GI tract
• distribution- widely with high conc. in lungs
• metabolism- liver
• excretion- feces and urine
• plasma half life = 45 hrs

• induces microsomal P450 enzymes (less than rifampin)
• decrease AZT

• dapson + rifampin ± clofazimine

• mechanism- like sulfas act as PABA antagonists to inhibit folate biosynthesis
• pharmacokinetics- oral administration excreted by kidney as free drug and glucuronide
• adverse effects
  • ocassiona
    • hemolytic anemia with G6PDH deficiency
    • GI effects: liver toxicity
  • frequently rash

• pharmacokinetics- administer orally
  • very lipid soluble
  • prolonged retention in tissue
• mechanism- bind to DNA and inhibit DNA template function and production of cytotoxic oxygen radicals
• adverse effects
  • frequent- red discoloration of skin, urin, sputum, sweat

• chem. structure- derivative of glutamin acid
• indication- erythema nodosum leprosum
• mechanism- unknown, but anti inflammatory and immuno modulating
• adverse effects- highly teratogenic
  • peripheral neuropathy
  • sedation
  • constipation