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What are the first line drugs used to treat Mycobacteria tuberculosis?
The first line tuberculosis drugs are "ripes"
Rifampin, Isoniazid, Pyrazinamide, Ethambutol, Streptomycin
What drug is used to treat latent TB?
A patient with latent TB will give a positive TB skin test (mantoux test) but show no clinical signs of the disease. Their TB can be treated with Isoniazid given for 9 months. Remember that TB treatments are long because the bacteria is slow-growing.
While isoniazid is the drug of choice for latent TB, remember that the alternative drug is rifampin (in cases of INH resistance or contraindication)
What is the initial phase of treatment for someone with active tuberculosis?
For someone with active tuberculosis, there are 2 phases of treatment: the Initial phase and the Continuous phase.
Initial treatment is with 4 drugs: "ripe" Rifampin, Isoniazid, Pyrazinamide, and Ethambutol
This treatment is given for 2 months before administering the continuous phase of treatment
What is the continuous phase of tuberculosis treatment?
The continuous phase of treatment is the second phase of the standerd treatment regimen for active tuberculosis. After the initial phase, the patient is checked for the presence of acid fast bacilli, if the smear is negative the continuous treatment is isoniazid and rifampin for another 2 months. If the smear is positive, the continuous phase is carried on for 7 months!
What is the MoA for Isoniazid?
Isoniazid (INH) is given orally. It is a prodrug and is converted into its active form by the enzyme catalase-peroxidase. This means that isoniazid is ineffective against bacteria without catalase-peroxidase. When INH is activated, it inhibits mycolic acid synthesis, thereby blocking mycobacterium cell wall synthesis.
What species of mycobacteria is isoniazid effective against?
Isoniazid is only effective against M. tuberculosis and some atypical mycobacteria.
it is NOT effective against MAC or M. leprae
What are adverse effects of isoniazid?
Isoniazid is converted by acetylation to acetylisoniazid. This is then metabolized to further intermediates, one of them (acetylhydrazine) being hepatotoxic!
Recall the importance of fast and slow acetylators. Some people are naturally fast acetylators and will reduce the plasma levels of isoniazid faster, as well as increase the accumulation of the hepatotoxic metabolite!
Isoniazid is also neurotoxic, and slow acetylators will have increased risk of this because the isoniazid stays in the plasma for longer with them. (treat/prevent with vitamin B6)
Isoniazid can also cause anemia & thrombocytopenia
How is bacterial resistance to isoniazid acquired?
Mutations in the katG gene that codes for catalase-peroxidase confer resistance to isoniazid. Without this enzyme, the bacteria do not convert isoniazid (prodrug) into its active, bactericidal form!
What bacteria does rifampin target?
Rifampin is a broad spectrum antibiotic that inhibits the beta subunit of bacterial RNA polymerase (Recall: isoniazid, because it targets mycolic acid synthesis, acts only against mycobacteria).
Rifampin acts against gram positive, gram negative, and acid fast bacteria!
Specifically, rifampin acts on M. tuberculosis and M. leprae. It is also added to combination therapy for the treatment of staphylococcal endocarditis.
What is the MoA for rifampin?
Rifampin binds the beta subunit of bacterial DNA-dependent RNA polymerase. This inhibits transcription.
A patient started a new antibiotic drug therapy and was worried about reddish-orange discoloration of the urine. It is not due to blood... what antibiotic was likely administered?
Rifampin can turn the patient's urine, sweat, and tears an orange-red.
Other adverse effects include flu-like symptoma and hepatitis.
(all RIPES except streptomycin can cause hepatitis)
List some drug interactions to be aware of with rifampin
Rifampin induces liver microsomal enzymes, thereby decreasing the potency of other drugs metabolized by this system.
For example, rifampin decreases the effect of oral contraceptives, which can lead to unwanted pregnancies. It also decreases the potency of antiepileptic drugs, which can lead to seizures. NNRTI treatment in HIV patients is also negatively impacted.
ALso remember the other classic examples such as theophylline, warfarin, and phenytoin.
Because these have a narrow therapeutic index, a decrease in their plasma concentration can more easily lead to therapeutic failure (just as an increase can more easily lead to toxicity)
How is resistance to rifampin acquired?
Bacteria acquire resistance to rifampin by decreasing the affinity of their RNA polymerase for the drug.
This occurs mainly through methylation of the RNA polymerase.
Which rifampin derivative is effective against MAC?
Recall that rifampin is effective against M. tuberculosis and M. leprae. A derivative of rifampin, Rifabutin, is effective against MAC!
Which first line antimycobacterial is bacteriostatic?
Recall: the first line antimycobacterial are the "RIPES" (rifampin, isoniazid, pyrazinamide, ethambutol, and streptomycin)
All of them are bactericidal except for Ethambutol, which is bacteriostatic.
What is the MoA for Pyrazinamide?
Pyrazinamide is an effective drug against M. tuberculosis. It is converted by the bacteria to pyrazinoic acid, which lowers the pH to a level that inhibits bacterial growth.
It is considered a bactericidal drug.
What are adverse effects of pyrazinamide?
Pyrazinamide, like most first-line antimycobacterials except streptomycin, can cause hepatitis. It can also cause hyperuricemia and gout.
What is the MoA for ethambutol?
Ethambutol inhibits the enzyme arabinosyl transferase, thereby stopping the production of arabinogalactan, a component of the bacterial cell wall.
Ethambutol is the one first line drug that is considered bacteriostatic. It can be used in the treatment of MAC!
What are side effects of ethambutol?
Remember: ethambutol is one of the RIPES drugs, and a first line agent against TB.
It disrupts arabinogalactan synthesis, leading to cell wall permeability.
Ethambutol may cause hepatitis, hyperuricemia, optic neuritis, and thrombocytopenia.
optic neuritis is inflammation of the optic nerve, which leads to a decrease in visual accuity or even total blindness!
What are the side effects of streptomycin?
Streptomycin is an aminoglycoside. Remember: side effects to aminoglycosides include Ototoxicity, Nephrotoxicity, and Neuromuscular blockade!
What are second line drugs against TB?
second line drugs are used only in cases of resistance. They are fluoroquinolones, Rifamycins (rifabutin), amikacin, capreomycin, and kanamycin among others.
When is TB considered extensively drug resistant (XDR-TB)?
TB is considered extensively drug resistant when it is resistant to isoniazid(INH), rifampin, a fluoroquinolone and one of the 3 second line drugs (capreomycin, kanamycin, amikacin)
What is ethionamide?
Ethionamide is a second line TB drug. It is a structural analog of INH. side effects include gastric irritation in 50% of patients.
What is the MoA of cycloserine?
Cycloserine is a cell wall inhibitor. It acts as an analog to D-ala and inhibits the incorporation of D-ala into the pentapeptide during PG synthesis.
Side effects include psychosis and peripheral neuropathy.
Immunocompromised patients, such as those with AIDS, are more likely to suffer what mycobacterial infection?
Disseminated MAC (M. avium-intracellulare complex) infections are seen most commonly in patients with AIDS or a depressed immune system.
Recall that Rifabutin is used instead of Rifampin to treat MAC infections. This is because this infection is more common in AIDS patients. Rifampin induces CYP450 enzymes thereby reducing the efficacy of other co-administered drugs. Of particular importance here would be decreased efficacy of protease inhibitors and NNRTIs, crucial components of anti-retroviral therapy. Rifabutin does not have the same effect on the CYP450 system as Rifampin, which is why it is used instead.
What drugs are used for the prevention of MAC in an HIV patient?
To prevent the development of MAC infection, "CAR" is administered to the HIV+ patient. Clarithromycin, Azithromycin, Rifabutin.
"a MAC truck is a type of CAR"
What drugs are used to treat MAC?
A combination of C-RACE is used to treat MAC: Clarithromycin, Rifabutin, Azithromycin, Ciprofloxacin, and Ethambutol
What drug is the mainstay of treatment for M. leprae?
Dapsone is the mainstay of treatment for leprosy. It is bacteriostatic, and administered orally.
What is the MoA for Dapsone?
Dapsone, the drug used in leprosy, inhibits folate synthesis in a manner similar to sulfonamides.
Remember: sulfonamides inhibit dihydropteroate synthetase, which joins PABA with dihydropteroate diphosphate...
What are some adverse effects of dapsone?
Dapsone, like sulfonamides, can cause hemolytic anemia in G6PDH deficient patients.
It can also cause GI disturbance, neuropathy, nephrotic syndrome, and lupus-like reactions.
What drug is combined with other antileprosy drugs to help prevent resistance?
Rifampin is added to antileprosy regimens. It is bactericidal against M. leprae.
What is clofazimine?
Clofazimine is a bactericidal drug against M. leprae. It is also effective against the other mycobacteria M. tuberculosis and MAC!!
Additionally, clofazimine has anti-inflammatory effects and is used to treat Erythema Nodosum Leprosum ( a side effect of antileprosy therapy produced by the lysis of leprae bacteria)
What drugs are used in the management of Erythema Nodosum Leprosum (ENL)
ENL is managed by the drug clofazimine. Thalidomide can also be used to manage ENL.
Clofazimine is used in the multi-drug treatment of leprosy involving Rifampicin, Dapsone, and Clofazimine. It has an anti-inflammatory effect, which is beneficial in ENL treatment. Side effects include a pink/brown skin discoloration and myelosuppression.
What are side effects of clofazimine?
Clofazimine is a drug used in the treatment of leprosy. Remember it also has an anti-inflammatory action and can help with mild Erythema nodosum leprosum. 75-100% of patients on clofazimine suffer skin pigmentation (pink-brownish black discoloration)
They also suffer GI intolerance.
What is Erythema Nodosum Leprosum?
ENL is an antibody- immune complex reaction. It results from a reaction to mycobacterial antigens released upon lysis of the bacteria during therapy. It is characterized by painful nodules and plaques.
Thalidomide is the treatment of choice for severe forms. Less severe forms can be treated with clofazimine and corticosteroids.
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