Terms in this set (62)
What complications prevent easy treatment of mycobacterial infection?
1. Limited info about the mechanisms of drug actions
2. Mycobacteria are intrinsically resistant to most drugs
3. Intracellular location of mycobacteria (hard to treat)
4. Chronic nature of disease, which requires protracted drug treatment (month-years) and is associated with toxicities
5. Patient compliance.
What form of therapy is required in non-compliant patients or in drug-resistant tuberculosis?
Directly observed therapy (DOT) regimens are recommended in noncompliant patients and in drug-resistant tuberculosis. This is when a trained healthcare individual confirms patient compliance by observing the taking of every drug dose.
What is the mechanism of action of isoniazid?
Isoniazid is a structural
analogue of pyridoxine (B6) activated by a mycobacterial catalase-peroxidase (KatG)
. The activated drug targets enzymes involved in mycolic acid synthesis:
Enoyl acyl carrier protein reductase (AcpM; InhA)
β-ketoacyl-ACP synthase (KasA)
Which antimycobacterial is first-line therapy for HIV+ patients with tuberculosis?
The indicated treatment is with Rifabutin.
Which drugs are indicated as first-line treatment of tuberculosis?
2. Rifamycins (rifampin, rifabutin)
Which drugs are indicated as second-line treatment of tuberculosis?
What is the most potent anti-tubercular drug?
Isoniazid is the best drug.
Is isoniazid a bacteriostatic or bactericidal drug?
Isoniazid is bactericidal for actively growing mycobacteria, but is less effective against dormant organisms. It has bacteriostatic effects against bacilli in the stationary phase.
What are the causes of isoniazid resistance?
High-level resistance emerges rapidly if isoniazid is used alone. Resistance occurs due to chromosomal mutations resulting in:
1. Deletion of KatG;
2. Changes to acyl carrier protein reductase binding sites
3. Overexpression of the acyl carrier protein reductase.
What is the treatment for latent tuberculosis?
For the treatment of latent infection, isoniazid is given as the sole drug.
True or false: cross-resistance between anti-tuberculosis drugs is common.
False: Cross-resistance between other anti-tuberculosis drugs DOES NOT OCCUR.
How is isoniazid metabolized?
The liver metabolism of the drug is by acetylation and is under genetic control (fast or slow inactivators). 'Fast-acetylators' may require higher dosage than slow acetylators for equivalent therapeutic effects.
What are the adverse effects of isoniazid?
• Neurotoxic effects (peripheral neuritis, restlessness)
• Hepatotoxicity: clinical hepatitis and idiosyncratic hepatotoxicity (rare in children)
• CYP P450 inhibitor: may increase levels of warfarin and phenytoin.
• Lupus-like syndrome: ANA antibodies develop in approximately 20 % of patients.
What is the antidote for the neurotoxic effects of isoniazid?
These effects can be corrected by supplementing the patient with pyridoxine.
Is isoniazid approved for pregnancy?
Isoniazid is safe in pregnancy, but the risk of hepatitis is increased. Pyridoxine supplementation is recommended in ALL pregnant women.
What is the mechanism of action for rifamycins?
The rifamycins (rifampin and rifabutin) are bactericidal against intracellular and extracellular mycobacteria and many other microorganisms.
They block transcription by binding to the β-subunit of bacterial DNA-dependent RNA polymerase, leading to inhibition of RNA synthesis.
How does rifamycin resistance develop?
Resistance strains emerge rapidly, especially if the drugs are used alone. Resistance occurs due to either:
• Point mutations in rpoB (encoding β-subunit of RNA polymerase)
• Decreased permeability.
What forms of mycobacterial infection is rifampin indicated for?
In combination with other drugs for TB
• In latent infection
as the sole drug in isoniazid-intolerant patients or in close contact with isoniazid-resistant strains of the organism.
• In leprosy to delay the emergence of resistance to dapsone.
• Prophylaxis of meningitis in exposed individuals.
• In combination with vancomycin for MRSA or PRSP.
• Rifabutin is less likely to cause drug interactions than rifamycin thus is the preferred drug for the treatment of TB in HIV positive patients.
Which two mycobacteria are best treated with rifampin?
• M. tuberculosis
• M. kansasii
How are rifamycins metabolized?
The drugs undergo enterohepatic cycling and both parent drug and metabolites (which are orange colored) are excreted mainly in the feces.
How does rifamycin interact with other drugs?
Rifampin is a strong inducer of cytochrome P450 enzymes and increases the elimination of many drugs, including anticonvulsants, contraceptives, methadone and warfarin. Rifabutin is a less effective inducer of the cytochrome enzymes and thus is less likely to cause drug interactions.
What are the adverse effects of rifamycins?
• Light chain proteinuria may impair antibody responses
• GI distress - nausea, vomiting, and diarrhea
• Thrombocytopenia, rashes, nephritis, liver dysfunction
• CYP P450 inducer (Rifampin)
• Orange-colored secretions (HOW COOL IS THAT?!)
Is rifampin safe for pregnancy?
Rifampin is safe in pregnancy, but there is insignificant data to recommend rifabutin.
Your patient has HIV and requires treatment for tuberculosis. What is the correct treatment?
Give the patient rifabutin because it has less of an effect on cytochromes.
What are the clinical applications of ethambutol?
Ethambutol is used in combination with other drugs for the treatment of TB. It is specific for most strains of M. tuberculosis and M. kansasii.
What is the mechanism of action for ethambutol?
(encoded by the emb gene) which are involved in the synthesis of mycobacterial cell wall components.
What is the cause of resistance to ethambutol?
Resistance strains emerge rapidly due to mutations in the emb gene, especially if it is used alone.
What are the adverse effects of ethambutol?
Dose-dependent visual disturbances like decreased visual acuity, red-green color blindness, optic neuritis, possible retinal damage (from prolonged use at high dosage)
• Headache, confusion, hyperuricemia, peripheral neuritis.
In which patients is ethambutol contraindicated?
Ethambutol should not be used in children too young for vision tests.
Is ethambutol safe in pregnancy?
Is pyrazinamide used in pregnancy?
Pyrazinamide is only recommended in pregnancy when the benefits outweigh the risks (Category C).
What are the adverse effects of pyrazinamide?
• Non-gouty polyarthralgia (~40% of patients)
• Acute gouty arthritis (rare unless predisposed)
• Hyperuricemia (common but usually asymptomatic)
• Hepatotoxicity, myalgia, GI irritation, porphyria, rash, photosensitivity.
Describe the pharmacokinetics of pyrazinamide.
Pyrazinamide is partly metabolized in the urine and then excreted via the urine. Both renal and hepatic insufficiency can require dosage adjustments.
What is the mechanism of action for pyrazinamide?
The exact mechanism of action of pyrazinamide is unknown, but is
thought to be due to the conversion of the drug to pyrazinoic acid
(by pyrazinamidase), in susceptible strains of M. tuberculosis,
which lowers the pH of the environment.
What is the cause of pyrazinamide resistance?
Resistant strains lack pyrazinamidase or have increased efflux of the drug.
What is streptomycin used for?
Streptomycin is an aminoglycoside recommended for use in
drug-resistant strains of TB
. It is used in combination with other drugs for the treatment of life-threatening tuberculous disease, including meningitis, miliary dissemination, and severe organ tuberculosis. Due to the increasing levels of streptomycin-resistant strain of TB its use is limited.
How do pharmacokinetics and side effects of streptomycin differ from other aminoglycosides?
Pharmacokinetics and adverse effects of streptomycin are similar to those of other aminoglycosides.
What is amikacin?
Amikacin is an aminoglycoside used, in combination with other drugs, for streptomycin- or multi-drug resistant strains of TB.
What is levofloxacin?
Levofloxacin is a fluoroquinolone that is recommended, in combination, for use against first-line drug-resistant strains of TB. It is not recommended for use in pregnant women or children under the age of 18.
What is ethionamide?
Ethionamide is a congener of isoniazid but shares no cross-resistance. It is
used, in combination, for drug-resistant strains of TB
. The major disadvantage of the drug is that it can cause severe gastrointestinal irritation and adverse neurologic effects.
What is the treatment regimen for latent tuberculosis?
• Isoniazid for 6-9 months
• Rifampin for 4 months
What are the standard regimens for empiric treatment of pulmonary TB?
For the first 8 weeks, give:
• Isoniazid, rifampin, ethambutol, and pyrazinamide
• Isoniazid, rifampin, ethambutol
Follow this with 18 weeks of isoniazid and rifampin (if pyrazinamide given prior) or 36 weeks (if not given).
If a patient's TB is isoniazid resistant (+/- streptomycin resistant), how should they be treated?
Use rifampin, ethambutol, and pyrazinamide with a fluoroquinolone for 6 months.
If a patient has rifampin and isoniazid resistant TB, how should they be treated?
Use a fluoroquinolone, pyrazinamide, ethambutol
and an injectable agent +/- second-line agent for 18-24 months.
If a patient has rifampin, ethambutol or pyrazinamide (but not both), and isoniazid resistant TB, how should they be treated?
Use fluoroquinolone (ethambutol or pyrazinamide if active) + injectable agent +/- two second-line agents for 24 months.
If someone has rifampin resistant TB, what should be given?
Give isoniazid, ethambutol, fluoroquinolone, supplemented with pyrazinamide for first 2 months, for 12-18 months total.
According to the WHO, how should leprosy be treated?
The WHO currently recommends three drugs:
What is the mechanism of action of dapsone?
Dapsone is structurally related to the sulfonamides and its mechanism of action involves the inhibition of folate synthesis (via
dihydropteroate synthetase inhibition
What are the adverse effects of dapsone?
• Hemolysis (especially in G6PD deficient patients).
• Erythema nodosum leprosum
• GI irritation, fever, methemoglobinemia, hepatitis
• Cytochrome P450 inhibitor
What is erythema nodosum leprosum?
It's an inflammatory complication of leprosy that results in painful skin lesions on the arms and legs and face. It can be
treated/prevented with either corticosteroids or thalidomide.
What is acedapsone?
Acedapsone is a repository form of dapsone that provides inhibitory plasma concentrations for several months.
What is dapsone used for?
Dapsone is used in combination with rifampin +/- clofazimine for the treatment of leprosy; it's also used an alternative in the treatment of AIDS-related PCP.
What is the mechanism of action for clofazimine?
Clofazimine is a phenazine dye that binds to DNA to inhibit replications. It also has redox properties that may lead to the generation of cytotoxic oxygen radicals.
What is clofazimine used for?
Clofazimine is bactericidal to M.leprae and also has some activity against M. avium-intracellulare complex. It's is used in combination with dapsone and rifampin for the treatment of leprosy.
What are the adverse effects of clofamizine?
• Red-brown discoloration of the skin (harmless)
• GI irritation
• Eosinophilic enteritis
Your leprosy patient has four skin lesions. What is the appropriate treatment?
Use rifampin and dapsone for six months if the person has pauci-bacillary leprosy (1-5 lesions).
Your leprosy patient has six skin lesions. What is the appropriate treatment?
Use rifampin, clofazimine, and dapsone for twelve months if the person has multi-bacillary leprosy (5+ lesions).
What is the treatment for M. fortuitum?
Use amikacin, cefoxitin, levofloxacin, sulfonamides, and imipenem.
How do you treat M. chelonae?
Use clarithromycin (mono therapy is usually adequate).
How do you treat the M. avium complex?
Use clarithromycin and ethambutol +/- rifabutin.
How do you treat M. marinum?
Use a two-drug combination of rifampin, ethambutol, clarithromycin, minocycline, doxycycline, or sulfonamides.
How do you treat M. kansasii?
Treat with a combination of isoniazid, rifampin, and ethambutol.