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What is a common strategy used to overcome drug resistance in tuberculosis treatment?
What is a common strategy used to overcome drug resistance in tuberculosis treatment?
Which of the following medications is considered a first-line treatment option for tuberculosis?
Which of the following medications is considered a first-line treatment option for tuberculosis?
Which of the following is a known adverse effect associated with rifamycins?
Which of the following is a known adverse effect associated with rifamycins?
Rifampin is known to primarily function by which mechanism of action?
Rifampin is known to primarily function by which mechanism of action?
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What characterizes multidrug-resistant tuberculosis (MDR-TB)?
What characterizes multidrug-resistant tuberculosis (MDR-TB)?
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Which second-line treatment option is categorized as an aminoglycoside?
Which second-line treatment option is categorized as an aminoglycoside?
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What is a characteristic of nontuberculosis mycobacteria (NTM) infections?
What is a characteristic of nontuberculosis mycobacteria (NTM) infections?
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What factor contributes to the resistance of mycobacteria to most antibiotics?
What factor contributes to the resistance of mycobacteria to most antibiotics?
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What is a significant characteristic of rifabutin compared to rifampin in treating TB patients co-infected with HIV?
What is a significant characteristic of rifabutin compared to rifampin in treating TB patients co-infected with HIV?
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Which of the following adverse effects is associated with both rifampin and rifabutin?
Which of the following adverse effects is associated with both rifampin and rifabutin?
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Which drug primarily serves as a second-line treatment for multi-drug resistant tuberculosis (MDR-TB) by inhibiting protein synthesis?
Which drug primarily serves as a second-line treatment for multi-drug resistant tuberculosis (MDR-TB) by inhibiting protein synthesis?
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What is the mechanism of action of ethambutol in tuberculosis treatment?
What is the mechanism of action of ethambutol in tuberculosis treatment?
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Which of the following is NOT a typical adverse effect of pyrazinamide?
Which of the following is NOT a typical adverse effect of pyrazinamide?
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For a patient receiving isoniazid, what is the significance of using rifapentine?
For a patient receiving isoniazid, what is the significance of using rifapentine?
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Which second-line treatment for TB disrupts D-alanine incorporation into the bacterial cell wall?
Which second-line treatment for TB disrupts D-alanine incorporation into the bacterial cell wall?
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In cases of drug resistance, which second-line agent may be used for streptomycin-resistant organisms?
In cases of drug resistance, which second-line agent may be used for streptomycin-resistant organisms?
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Which adverse effect is commonly associated with the treatment of tuberculosis?
Which adverse effect is commonly associated with the treatment of tuberculosis?
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Which drug is preferred to avoid drug interactions when treating tuberculosis?
Which drug is preferred to avoid drug interactions when treating tuberculosis?
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Which property is true regarding the mechanism of action of Rifamycins?
Which property is true regarding the mechanism of action of Rifamycins?
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What is a major concern regarding drug resistance in tuberculosis therapy?
What is a major concern regarding drug resistance in tuberculosis therapy?
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What is a potential central nervous system effect of tuberculosis medications?
What is a potential central nervous system effect of tuberculosis medications?
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Which statement about the anti-leprosy drug Clofazimine is accurate?
Which statement about the anti-leprosy drug Clofazimine is accurate?
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What is the correct dosage regimen for Rifampicin in Multibacillary (MB) leprosy treatment?
What is the correct dosage regimen for Rifampicin in Multibacillary (MB) leprosy treatment?
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Which adverse reaction can occur from using Dapsone in TB treatment?
Which adverse reaction can occur from using Dapsone in TB treatment?
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Study Notes
Rifamycins
- Rifampin, rifabutin, and rifapentine are all rifamycins
- Rifabutin is used for TB patients with HIV who are receiving protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs)
- Rifabutin is a weaker inducer of drug metabolism than rifampin
- Rifabutin has similar side effects as rifampin but can also cause uveitis, skin hyperpigmentation, and neutropenia
- Rifapentine is more active than rifampin and has a longer half-life
- Rifapentine is used in combination with isoniazid once weekly for latent TB infection (LTBI) and in select HIV-negative patients with minimal pulmonary TB
Pyrazinamide
- Short-course oral agent used for the first 2 months of TB treatment
- Its mechanism of action is unknown
- Effective against tuberculosis bacilli in acidic lesions and macrophages
- It is metabolized to pyrazinoic acid, which is the active drug
- Well distributed throughout the body, including the cerebrospinal fluid (CSF)
- Can cause liver toxicity and uric acid retention, which can rarely precipitate gouty attacks
Ethambutol
- Bacteriostatic drug specific for mycobacteria
- Inhibits arabinosyl transferase, which is involved in cell wall synthesis
- Well distributed, but has low penetration into the central nervous system (CNS)
- Excreted in urine
- Most common side effect is optic neuritis, which can lead to diminished visual acuity and difficulty distinguishing between red and green
- Risk of optic neuritis increases with higher doses and in patients with renal impairment
- Decreases uric acid excretion, so monitor gout patients
Second-Line Treatment for TB
- Streptomycin is used against extracellular organisms
- Streptomycin-resistant organisms may be treated with kanamycin or amikacin
- Para-aminosalicylic acid (PAS) was a standard regimen for 18 months from the 1950s to the 1960s and is now used to treat multidrug-resistant TB (MDR-TB)
- Capreomycin should be avoided with streptomycin
- Capreomycin inhibits protein synthesis and is reserved for MDR-TB, requiring therapeutic drug monitoring (TDM) to monitor for nephrotoxicity and ototoxicity
- Cycloserine disrupts d-alanine incorporation into the bacterial cell wall and is well distributed, including in the CSF
- Ethionamide is an analog of isoniazid
- Ethionamide disrupts mycolic acid synthesis in a different pathway than isoniazid and is widely distributed, including in the CSF
- Fluoroquinolones such as moxifloxacin and levofloxacin are used for MDR-TB
- Macrolides, such as azithromycin, are preferred over clarithromycin to avoid drug interactions
- Second-line agents are less effective and more toxic than first-line agents
Mycobacteria
- They are intracellular pathogens that can survive inside macrophages
- They are resistant to many antibiotics due to their lipid-rich cell wall and slow cell division (18-24 hours)
- Most antibiotics target fast-growing bacteria
- Humans are mainly affected by Mycobacterium tuberculosis and Mycobacterium leprae (leprosy)
- Nontuberculosis mycobacteria (NTM) infections are increasing, particularly M. avium-intracellulare.
Tuberculosis
- Most initial infections are asymptomatic (latent tuberculosis)
- This can become a chronic illness and cause extensive scarring in the upper lobes of the lungs
- Early lung lesions heal without residual changes, except occasional pulmonary/tracheobronchial lymph node calcification
- Extrapulmonary tuberculosis is when the infection spreads outside the lungs
- More common in immunocompromised individuals and children
Strategies to Overcome Drug Resistance
- Multidrug therapy is used to rapidly reduce the bacterial population to prevent emergence of drug-resistant bacteria
- First-line drugs include isoniazid, rifampin, ethambutol, and pyrazinamide (short-course chemotherapy)
- Rifabutin or rifapentine can replace rifampin
- Second-line drugs for MDR-TB (resistant to at least isoniazid and rifampin) include: aminoglycosides (streptomycin, kanamycin, or amikacin) or capreomycin, fluoroquinolones (levofloxacin or moxifloxacin), remaining active first-line drugs, and cycloserine, ethionamide, or p-aminosalicylic acid.
Anti-Leprosy Drugs
- Dapsone inhibits dihydropteroate synthetase in the folate synthesis pathway (bacteriostatic)
- It is also used to treat Pneumocystis jirovecii pneumonia in immunosuppressed patients
- Well absorbed orally and distributed, with a concentration in the skin
- It undergoes hepatic acetylation and both parent drug and metabolites are eliminated in urine
- Adverse reactions include hemolysis (especially in G6PD patients), methemoglobinemia, and peripheral neuropathy
Clofazimine
- Binds to DNA, blocking DNA synthesis
- Also generates cytotoxic oxygen radicals to kill bacteria
- Active against M. tuberculosis and NTM
- Well absorbed orally and distributed, but doesn't enter the CNS
- Accumulates in tissues, allowing for intermittent therapy
- Half-life is 70 days
- Possesses anti-inflammatory properties to control Type II lepra reaction (erythema nodosum leprosum)
- Side effects include pink to brownish-black discoloration of the skin
WHO Recommended Multidrug Treatment Regimen for Leprosy
-
Multibacillary (MB) leprosy:
- Rifampicin: 600 mg once a month
- Dapsone: 100 mg daily
- Clofazimine: 300 mg once a month and 50 mg daily
- Duration: 12 months
-
Paucibacillary (PB) leprosy:
- Rifampicin: 600 mg once a month
- Dapsone: 100 mg daily
- Duration: 6 months
-
Single Skin Lesion Paucibacillary leprosy:
- Rifampicin: 600 mg
- Ofloxacin: 400 mg
- Minocycline 100 mg
- Single dose
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