Treatment of Tuberculosis Flashcards
Why is mycobacterium tuberculosis difficult to treat?
- multiples slowly
- survives in protected intracellular location (i.e. macrophage)
- propensity to develop resistance to antimicrobial agents
- therapy can last up to two years so issues with patient compliance
- issues of drug toxicity and interactions (especially relavent with HIV patients)
Describe first-line therapy for M. tuberculosis and M. avium complex
M. tuberculosis: RIPES - rifampin* (RIF), isoniazid (INH), pyrazinamide (PZA), ethambutol (EMB), streptomycin
M. avium complex: clarithormycin + ethambutol (or clofazimine or ciprofloxacin or amikacin)
* In HIV patients, use of rifabutin can decrease teh drug interactions with PIs and NNRTIs
Describe Rifabutin and Rifapentine vs. Rifampin
Rifabutin and Rifapentine are derivatives of Rifampin
- Rifabutin is a less potent inducer of CYP450 than is Rifampin
- Rifapentine has a longer half-life than Rifampin or Rifabutin so that it may be given on a once-weekly schedule
How do you treat latent TB infection?
Recent evidence shows that 3 month treatment with Isoniazid (INH) and Rifapentine (RPT) with Directly Observed Therapy is effective in preventing TB and is more frequently completed than the US standard of 9 months of INH without DOT.
Who is INH-RPT not recommended for?
- Children <2 y/o
- HIV+ recieving antiretroviral treatmetn
- Pregnant women or women expecting to become pregnant
- Patients with latent TB infection with presumed INH or RIF resistance
Can combination of Rifampin and Pyrazinamide be offered for treatmetn of latent TB?
NO d/t reports of severe liver injury and deaths
What is the basic TB disease regimen for ACTIVE cases of TB?
Initial Phase (8 weeks): INH, RIF, PZA, EMB
- Note: EMB can be discontinued if drug susceptibility studies demonstrate susceptibility to first-line drugs
Continuation Phase (18 weeks): Daily INH and RIF or Twice-weekly INH and RIF
- Once weekly INH/RIF can be used for HIV- patietns without cavities on CXR and who have negative AFB at completion of inital phase
Isoniazid MOA
- Interferes with mycolic acid synthesis (i.e. disrupts cell wall synthesis)
- Bacteriocidal for rapidly dividng bacilli, such as those found in extracellular cavitary lesions
- Bacteriostatic agaisnt organisms found within closed caseous lesions and macrophages that divide slowly and intermittently.
- Penetrates host cells - **effective for intracellular bacilli **
Isoniazid Resistance
- Inability to take up the drug
- Alteration in the target enzyme
- Overproduction of the target enzyme
- Do NOT use as a single agent in ACTIVE TB cases as resistant organisms rapidly emerge
Isoniazid Pharmacology
Absorption: rapidly absorbed from GI tract with oral dose; can be administered IM
Distribution: all tissues and fluids; penetrates inflamed meninges and achieves therapeutic levels in CSF. Crosses placenta and is distributed into breast milk.
Metabolism: metabolized in liver to inactive metabolites, primarily with acetylation via N-acetyl transferase.
- slow vs. fast acetylators affects therapy (plasma concentrations can be 2-3X lower in fast acetylators)
- chronic liver disease will decrease metabolism, so dose must be lowered
Excretion: drug and inactive metabolites excreted in urine
Isoniazid Adverse Effects
PERIPHERAL NEUROPATHY
- Burning or prickling sensation in hands & feet
- Competition between isoniazid and pyridoxal phosphate: corrected with vitamin B6 (pyridoxine) supplementation and is more frequent in malnourished, diabetics and alcoholics
DOSE RELATED HEPATOTOXICITY: the major toxic recation is hepatitis d/t toxic metabolite from acetylation of isoniazid
Allergic rxns non-dose related
Isoniazid Drug Interactions
- Antacids with Al3+ salts decrease absorption (administer 1h before any antacids)
- Corticosteroids decrease effiacy: prednisone reduces plasma [INH] and INH inhibits the hepatic metabolism of cortisol.
- Inhibits P450 isozyme that metabolizes phenytoin, diazepam, fluxetine, nelfinavir, etc
Rifampin MOA, Resistance, and Spectrum
Include Rifampin, Rifabutin, and Rifapentine
MOA: Bactericidal; inhibits DNA dependent RNA polymerase by binding to the beta subunit of the Mb RNA polymerase
Resistance
- Alteration in beta subunit of the RNA polymerase so that it not longer binds drug
- Never given as a single agent becuase resistance emerges rapidly
Spectrum: intra- or extracellular mycobacteria
Rifampin Pharmacology
Absorption: well absorbed from oral administation; impaired by food or para-aminosalicylic acid
Distribution: penetrates all tissues well, including CSF; 75-85% protein bound
Metabolism: deacetylated in liver
Excretion: primarily in bile (30% unchanged) and smal amount via renal tubular secretion. *No adjustment needed for renal insufficiency. *
Rifampin Adverse Effects
- Discolors body fluids (tears, urine, saliva) orange-red
- GI distrubances and nervous system complaints
- Fever, chills and aches
- Hepatotoxicity - more relavent in patients that are slow acetylators; jaundice occurs with chronic liver disease, alcoholics and elderly
Rifampin Drug Interaction
**Induction of CYP450 **
- reduces half life of drug metabolized by P450 enzyme system (prednisone, propranolol, sulfonamides, dapsone, ketoconazole, HIV PI, NNRTIs)
-
Oral anticoagulants and oral contraceptives - less effective
- significant decrease in efficiacy of coumarin type anticoagulants
- reports of reduces plasma [estrogen]
Probenecid increases serum levels of rifampin when taken concurrently
Rifampin Main Therapeutic Usage
First line against mycobacterium tuberculosis (effective against bacili that are rapidly diving in extracelular cavitary lesions, as well as against slowly or intermittenly dividing organisms such as those found in closed caaseous lesions and macrophages)
Does Rifampin have other therapeutic uses besides in TB?
YES!
- MRSA and MRSE (in combination with vancomycin and/or gentamicin)
- Prophylactically for household members expoed to meningitis cuased by meningococci or H. influenzae
- Eradication of staphyloccus in nasal carriers
- Most active antileprosy drug at presnt
Ethambutol MOA
- Disrupts cell wall synthesis by inhibiting arabinosyl transferase, which disrupts arabinogalactan synthesis, which is necessary for synthesis of peptidoglycan units of the cell wall. This results in **increased cell wall permeability **
- Bacteriostatic effect, but may be cidal at high levels
- Effective only agaisnt bacilli athat are actively dividing
- Slow development of resistance
- No cross-resistance
Ethambutol Pharmacology
Absorption: 75% of oral dose
Distributoin: widely
- concentrates in kidneys, lungs, saliva
- therapeutic levels in CSF with inflamed meninges
- crosses placenta
- distributes into breast milk
Elimination: partially metabolized in liver and excreted in urine. *must reduce dose with renal dysfunction *
Ethambutol Adverse Reactions
Dose-Related Optic Neuritis
- decreased visual acuity
- loss of color discrimination
- constriction of visual fields
- monthly visual exams during therapy
- reversible weeks to months after end of therapy
Allergic reactions
Increase in serum urate (hyperuricemia)
Ethambutol Drug Interactions
- Al3+ containing antacids reduce absorption
- Allow 3-4h after antacids before ethambutol dose
Pyrazinamide MOA
- Bacilli convert pyrazinamide to pyrazinoic acid
- Decreases pH below threshold for growth
- Resistant strains may lack the “pyrazinamidase”
- Cidal or static depending on concentration in infected site
- Exerts most significant effect at intracellular sites where M. tuberculosis replicates slowly (e.g. lysosome and macrophage)
Pyrazinamide Pharmacology
Absorption: administerd orall and is rapidly absorbed from GI tract.
Distrubtion: widely distrubted; it penetrates inflamed meninges to reach therapeutic levels in CSF.
Elimination: hydolyzed in liver to pyrazinoic acid (major active metabolite); excreted in urine via glomerular filatration
Pyrazinamide Adverse Effects
- Dose related hepatotoxcity is typically seen with large doses for long periods
- Mild non gouty arthralgias
- Hyperuriciemia d/t inhibition of urate excretion; often asymptomatic. If acute gout develops, discontinue use.
MDR TB occurs when TB bacteria can no longer be killed by at least which two ABXs?
INH and RIF
What is cycloserine and when is it used?
**Second-line, broad spectrum ABX **used in treatment of **active pulmonary **and **extrapulmonary TB **
Only used when others fail and in retreatment (i.e. MDR-TB)
Used for M. avium complex when others don’t work
Rarely used for UTIs
Cycloserine MOA
MOA: structural anaolg of amino acid D-alanine, which is important in synthesis of peptidoglycan
- Competes with D-alanine for two enzymes (L-alanine racemase and D-alanine sythetase) both of which are involved in teh incorporation of D-alanine into bacterial cell walls.
- Inhibits both enzymes and peptidoglycan synthesis, resulting in a **weak cell wall and eventually cell lysis. **
Effective in resistant organisms; no cross-resistance
Cycloserine Pharmacology
Administration: orally with good absorption
Distribution: widely and not protein bound
- lungs, pleural and synovial fluids
- CSF
- Readily croses placenta; distributed in amniotic fluid and breast milk
Excreted unchanged by renal mechanism; *dose adjustment required for renal impairement *
Cycloserine Adverse Effects
Involve CN_S_
- **usually reversible with discontinued therapy **
- headache, tremor, vertigo, confusion, psychotic states with suicidal tendencies, paranoid rxns, seizures; use with caution in pts with hx of depression
- large doses or concurrent use of EtOH increases risk of seizures
- contraindicated in persons with hx of epilepsy
Ethionamide
- Structural analog of isoniazid; works by a different mechanism but same result of **inhibiting protein synthesis. **
- Inactive prodrug that is activated by mycobacterial redux system.
- Oral administration
- Widely distributed, including CSF
- Extensive hepatic metabolism
- Static or cidal depending on concentration
- Reserved as a last line agent beucase of **GI, Neurologic, and Hepatic Toxicity **
- **Pyridoxine **relieves teh neurologic Sx and is commonly given concurrently
Extensively Drug-Resistant TB (XDR-TB)
TB bacteria have changed enough to circumvent the two best ABXs (INH and RIF) as well as most of the alternative drugs used agaisnt MDR-TB.
Second-line drugs include any fluoroquinolone, and at least one of the other three injectable anti-TB drugs: amikacin, kanamycin, or capreomycin.
Needs up to 2 years of drug treatment; challenging!
Capreomycin
- MOA unknown; bacteriostatic
- Administered IM
- Adverse effects: nephrotoxicity, ototoxic
- Reserved as a last line agent (adjunct agent in combination with at least one other, because resistance develops if used alone)
- Effective in XDR-TB
