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Antimyco.pptx
- 1. Antimycobacterials Patricia Tuazon 1st year Resident
- 2. Mycobateria ⢠non-spore-forming, nonmotile, pleomorphic ⢠weakly Gram-positive curved rods ⢠Cell wall contains mycolic acid ⢠âAcid- fastâ bacilli ⢠Mycobacterium tuberculosis. ⢠Mycobacterium Leprae ⢠M avium complex
- 3. Principles of anti Mycobacterial therapy ⢠Single-drug therapy - high likelihood of developing antimicrobial resistance
- 4. The first line 1. Isoniazid 2. Rifampin 3. Pyrazinamide 4. Ethambutol
- 5. Isoniazid ⢠Mechanism of action: inhibit bacterial mycolic acid cell wall synthesis ⢠Targets the enzyme acyl carrier protein reductase (InhA) and B-ketoacyl- ACP synthase, essential for syntesis of mycolic acid ⢠Resistance: ⢠mutations in the INH A gene, and Kat G
- 6. Isoniazid ⢠The pediatric dosage is 10-15 mg/kg/day PO in a single dose not to exceed 300 mg/day ⢠M. tuberculosis, Mycobacterium kansasii, and Mycobacterium bovis ⢠Readily absorbed after oral administration ⢠Impaired when taken with food
- 7. ⢠Major adverse events ⢠hepatotoxicity ⢠dose-related peripheral neuropathy. ⢠Pyridoxine can prevent the peripheral neuropathy -25 to 50 mg Vitamin B6 ⢠Minor adverse events: ⢠rash, worsening of acne, epigastric pain with occasional nausea and vomiting, decreased vitamin D levels, and dizziness.
- 9. Rifamycins ⢠Rifampin, Rifabutin and Rifapentine ⢠Macroclide antibiotics - Streptomyces mediterranei Mechanism of action: ⢠inhibit the DNA dependent RNA polymerase of mycobacteria Pyrazinamide
- 10. Resistance: Alterations in rpoB gene
- 11. Rifamycins ⢠most gram-positive and gram negative bacteria ⢠M. tuberculosis, Mycobacterium leprae, ⢠M. kansasii, and Mycobacterium avium complex. ⢠10-15 mg/kg/day PO in a single dose not to exceed 600 mg/day. ⢠Also used as prophylaxis for individuals exposed to patients with meningitis ⢠Meningococci ⢠Hemophilus influenzae B
- 12. Adverse effects ⢠Generally well tolerated ⢠Transient elevations of liver enzymes; gastrointestinal (GI) upset with cramps, nausea, vomiting, and anorexia; headache; dizziness; and immunologically mediated fever and flu-like symptoms. ⢠turn urine and other secretions (tears, saliva, stool, sputum) orange, which can stain contact lenses Pyrazinamide
- 13. Pyrazinamide Mechanism of action: ⢠bacteria-specific enzyme (pyrazinamidase) converts PZA to pyrazinoic acid, which leads to low pH levels not tolerated by M. tuberculosis. ⢠Resistance ⢠from bacterial pyrazinamidase alterations.
- 14. Pyrazinamide ⢠indicated for the initial treatment phase of active tuberculosis in combination with other antimycobacterial agents. ⢠The pediatric dosage is 15-30 mg/kg/day PO in a single dose, not to exceed 2,000 mg/ day.
- 15. Adverse Reactions -Pyrazinamide ⢠GI upset (e.g., nausea, vomiting, poor appetite) ⢠hepatotoxicity ⢠elevated serum uric acid levels ⢠Minor reactions include arthralgias, fatigue, and, rarely, fever. ⢠Use of PZA in combination with rifampin for short-
- 16. Ethambutol ⢠inhibits RNA synthesis needed for cell wall formation ⢠standard dosages it is bacteriostatic, but at dosages of >25 mg/kg ethambutol has bactericidal activity ⢠The mechanism of resistance to ethambutol is unknown, ⢠develops rapidly when used as a single agent against M. tuberculosis ⢠15-20 mg/kg/day PO in a single dose, twice-weekly dosing is with 50 mg/kg PO in a single dose, not to exceed 2,500 mg/day.
- 17. Adverse effects -Ethambutol ⢠Optic neuritis ⢠Visual changes are reversible ⢠Headache, dizziness, confusion, hyperuicema, Gi upset, peripheral neuropathy, hepatotoxicity and cytopenias ⢠Routine monitoring: baseline and periodic visual acuity and color discrimination testing, CBC, serum uric acid levels, and kidney and liver function tests.
- 19. Alternative second line drugs ⢠Streptomycin ⢠Cycloserine ⢠Ethioamide ⢠Fluoroquinolones ⢠Macrolides -less effective and more toxic than first line agents
- 20. Streptomycin ⢠Streptomycin, an aminoglycoside antibiotic, was one of the first effective agents for TB. ⢠⢠Its action appears to be greater against extracellular organisms.
- 21. Fluoroquinolones ⢠The fluoroquinolones, specifically moxifloxacin and levofloxacin, have an important place in the treatment of multidrug-resistant tuberculosis.
- 22. Macrolides ⢠The macrolides azithromycin and clarithromycin are included in regimens for several NTM infections, including MAC.
- 23. Mycobacterium leprae ⢠Hansenâs disease (also known as leprosy) ⢠affect the nerves, skin, eyes, and lining of the nose (nasal mucosa). ⢠inability to sense touch and pain, which can lead to injuries, like cuts and burn, if left untreated can cause paralysis in both hands and feet
- 24. Dapsone ⢠structurally related to the sulfonamides and similarly inhibits dihydropteroate synthetase in the folate synthesis pathway. ⢠bacteriostatic for M. leprae ⢠Also used in the treatment of pneumonia caused by Pneumocystis jirovecii in immunosuppressed patients. ⢠Pediatric dosage is 1-2 mg/kg/day PO as a single dose, not to exceed ⢠100 mg/day for a duration of 3-10 yr.
- 25. Dapsone Adverse Effects ⢠Hemolytic anemia ⢠Pancreatitis ⢠acute tubular necrosis, acute renal failure, albuminuria ⢠tinnitus, peripheral neuropathy, photosensitivity, ⢠and a hypersensitivity syndrome with fever, rash, hepatic ⢠damage, and malaise. ⢠CBC weekly during the 1st month of therapy, weekly through 6 mo of therapy, and then every 6 mo thereafter. ⢠creatine levels and urinalysis and liver function tests.
- 26. Clofazimine ⢠binding to the mycobacterial DNA at guanine sites. generation of cytotoxic oxygen radicals that are toxic to the bacteria. ⢠Clofazimine is bactericidal to M. leprae, and it has potentially useful activity against M. tuberculosis and NTM. ⢠drug accumulates in tissues, intermittent therapy ⢠1 mg/kg/day PO as a single dose (max 100 mg/day in combination with dapsone rifampin for 2 yr, then as a single agent 1 yr.
- 27. Clofazimine ⢠adverse effect is a dosage-related, reversible pink to tan-brown discoloration of the skin and conjunctiva. ⢠Other adverse effects include a dry, itchy skin rash, headache, dizziness, abdominal pain, diarrhea, vomiting, peripheral neuropathy, and elevated hepatic transaminases. ⢠Routine laboratory monitoring includes periodic liver function
- 28. A 13 y/o male came in for consult for his >3 month history of productive cough, and weight loss. He is currently taking Carbamazepine for seizures. Two weeks ago, he had a positive tuberculosis skin test (PPD test), and a chest radiograph showed evidence of right upper lobe infection. He was started on standard four-drug antimycobacterial therapy. He has come to the clinic complaining of âdrowsiness and dizziness.â Which of the following antimycobacterial drugs is likely to have caused this patientâs symptoms? A. Ethambutol B. Isoniazid. C. Pyrazinamide. D. Rifampin. E. Streptomycin
- 29. ⢠Which of the following is correct regarding clofazimine in the treatment of leprosy? A. Clofazimine should not be used in patients with a deficiency in glucose-6-phosphate dehydrogenase (G6PD). B. Peripheral neuropathy is one of the most common adverse effects seen with the drug. C. Clofazimine may cause skin discoloration over time. D. The risk of erythema nodosum leprosum is increased in patients given clofazimine
- 30. ⢠A 10-year-old male has returned to the clinic for his 1-month check- up after starting treatment for tuberculosis. He is receiving isoniazid, rifampin, pyrazinamide, and ethambutol. He states he feels fine, but now is having difficulty distinguishing the green and red crayons . Which of the following drugs may be causing his decline in vision? A. Isoniazid. B. Rifampin. C. Pyrazinamide. D. Ethambutol.
Hinweis der Redaktion
- Good afternoon, Dr. De Castro, Dr. Cantimbuhan, fellow residents, interns and clerks. For our Infectious Diseases Hour for today, I will be discussing about Antimycobacterials
- What is a Mycobacteria? A hallmark of all mycobacteria is its acid fastnessâthe capacity to form stable mycolate complex with arylmethane dyes (crystal violet, carbolfuchsin, auramine,and rhodamine). They resist decoloration with ethanol and hydrochloric or other acids There are more than 200 mycobacterium species but Mycobacterium tuberculosis ccauses tuberculosis and is a very important pathogen of humans especially in the Philippines Mycobacterium leprae causes leprosy. Mycobacterium avium-intracellulare ( M avium complex, or MAC) and other nontuberculous (NTM) mycobacteria, the opportunistic pathogens in other immunocompromised persons
- The treatment of mycobacterial infection and disease can be challenging. Patients require therapy with multiple agents, the offending pathogens commonly exhibit complex drug resistance patterns, and patients often have underlying conditions that affect drug choice and monitoring. Single-drug therapy of Mycobacterium tuberculosis and nontuberculous mycobacteria is not recommended because of the high likelihood of developing antimicrobial resistance
- needed for the last step of the mycolic acid biosynthesis pathway of cell wall production Isoniazid enters bacilli by passive diffusion. The drug is not directly toxic to the bacillus but must be activated to its toxic form within the bacillus by KatG, a multifunctional catalase-peroxidase. The activated drug forms adducts with bacillar NAD+Â and NADP+Â that inhibit essential steps in mycolic acid synthesis (cell wall) and nucleic acid synthesis (Figure 56â3). Other products of KatG activation of INH include superoxide, H2O2, alkyl hydroperoxides, and the NO radical, which may also contribute to the mycobactericidal effects of INH. Its antibacterial actibity involeves targeting The primary target of INH involves the INH A gene, which encodes the enoyl ACP (acyl carrier, protein) reductase needed for the last step of the mycolic acid biosynthesis pathway of cell wall production. Resistance to INH occurs following mutations in the INH A gene or in other genes encoding enzymes that activate INH, such as kat G INH resistance has been associated with deletions or mutations in the catalase-peroxidase gene (katG); these isolates become catalase negative or have decreased catalase activity. INH resistance has also been associated with alterations in the inhA gene, which encodes an enzyme that functions in mycolic acid synthesis. INH is associated with mutation or deletion of katG, overexpression of the genes for inhA (confers low-level resistance to INH and some cross-resistance to ethionamide) Because TB cavities may contain as many as 107-109Â microorganisms, preexistent resistance can be expected in pulmonary TB cavities of untreated patients. T hese spontaneous mutants will be selected and amplified by monotherapy. Thus, 2 or more agents are usually used. KatG geneâ activates pro drug producing mutants incapable of prodrug activation
- The pediatric dosage is 10-15 mg/ kg/day PO in a single dose not to exceed 300 mg/day. The adult dosage is 5 mg/kg/day PO in a single dose not to exceed 300 mg/day INH is indicated for the treatment of INH needs to be taken 1 hr before or 2 hr after meals because food decreases absorption. Mycobacterium kansasii is a slow-growing, non-tuberculosis mycobacterium (NTM) that, like other mycobacterial species, tends to cause six clinical patterns of infection: pulmonary disease, skin and soft tissue disease, musculoskeletal infections including monoarticular septic arthritis and tenosynovitis, disseminated .
- Major adverse events include hepatotoxicity in 1% of children and approximately 3% of adults (increasing with age) and dose-related peripheral neuropathy. Pyridoxine can prevent the peripheral neuropathy and is indicated for breastfeeding infants and their mothers, children and youth on milk- or meat-deficient diets, pregnant adolescents, and symptomatic HIV-infected children. Minor adverse events include rash, worsening of acne, epigastric pain with occasional nausea and vomiting, decreased vitamin D levels, and dizziness. The liquid formulation of INH contains sorbitol, which often causes diarrhea and stomach upset Routine baseline liver function testing or monthly monitoring is only indicated for persons with underlying hepatic disease or on concomitant hepatotoxic drugs, including other antimycobacterial agents, acetaminophen, and alcohol. Hepatitis is the most serious adverse effect associated with isoniazid incidence increases with age, and those who are alcoholic Peripheral neuropathy , manifesting as paresthesia of the hands and feet, this can be avoided with Vitamin B6 supplementation of 25 to 50 mg per day of pyridoxine
- Because Isoniazid inhibits the metabolism of carbamazepine and phenytoin, isoniazid can potentiate the adverse effects of thi sdrugs, for example nystagmus and ataxia
- are a class of macrolide antibiotics developed from Streptomyces mediterranei The rifamycins inhibit the DNA-dependent RNA polymerase of mycobacteria, resulting in decreased RNA synthesis. They are generally bactericidal at treatment doses, but they may be bacteriostatic at lower doses.  . Rifampin enters bacilli in a concentration-dependent manner, achieving steady-state concentrations within 15 min. The drug binds to the β subunit of DNA-dependent RNA polymerase (rpoB) to form a stable drugâenzyme complex, suppressing chain formation in RNA synthesis.
- Alteration of target protein structure, prevents drug recognition  The prevalence of rifampin-resistant isolates is due to altered rpoB. Mutations in genes involved in DNA repair mechanisms will impair the repair of multiple genes, which may lead to hyper-mutable Antibiotics, endogenous oxidative and metabolic stressors lead to DNA damage, which induces dnaE2. The induction is associated with error-prone DNA repair and leads to higher rates of rifampin resistance. Because resistant strains rapidly emerges from monotherapy, it is never given as a single agent in treatment of active tb
- Â Rifampin inhibits the growth of most gram-positive bacteria as well as many gram-negative microorganisms. Rifampin is active against M. tuberculosis, Mycobacterium leprae, M. kansasii, and Mycobacterium avium complex. Rifampin is an integral drug in standard combination treatment of active M. tuberculosis disease and can be used as an alternative to INH in the treatment of latent tuberculosis infection in children who cannot tolerate INH. The pediatric dosage of rifampin is 10-15 mg/kg/day PO in a single dose, not to exceed 600 mg/day.
- The most common adverse reaction include, nausea, vomiting, rash and flu like syndrome Hepatitis, should be used cautiously in older patients, alcoholics and those with chronic liver disease Increase incidence of hepatic dysfunction when rifampin is co administedre w/ isoniazid Rifampin can be associated with adverse events such as transient elevations of liver enzymes; gastrointestinal (GI) upset with cramps, nausea, vomiting, and anorexia; headache; dizziness; and immunologically mediated fever and flu-like symptoms. All rifamycins can turn urine and other secretions (tears, saliva, stool, sputum) orange, which can stain contact lenses. Patients and families should be warned about this common but otherwise innocuous adverse effect. Rifamycins induce the hepatic cytochrome P450 isoenzyme system and are associated with the increased metabolism and decreased level of several drugs when administered concomitantly. These drugs include digoxin, corticosteroids such as prednisone and dexamethasone, dapsone, fluconazole, phenytoin, oral contraceptives, warfarin, and many antiretroviral agents
- A bacteria-specific enzyme (pyrazinamidase) converts PZA to pyrazinoic acid, which leads to low pH levels not tolerated by M. tuberculosis. Resistance is poorly understood but can arise from bacterial pyrazinamidase alterations. PZA is indicated for the initial treatment
- Adverse events include GI upset (e.g., nausea, vomiting, poor appetite) in approximately 4% of children, dosage-dependent hepatotoxicity, and elevated serum uric acid levels that can precipitate gout in susceptible adults. Approximately 10% of pediatric patients have elevated uric acid levels but with no associated clinical sequelae. Minor reactions include arthralgias, fatigue, and, rarely, fever. Use of PZA in combination with rifampin for short-
- Ethambutol Ethambutol is a synthetic form of ethylenedi-imino-di-1-butanol dihydrochloride that inhibits RNA synthesis needed for cell wall formation. At standard dosages it is bacteriostatic, but at dosages of >25 mg/kg ethambutol has bactericidal activity. The mechanism of resistance to ethambutol is unknown, but resistance develops rapidly when ethambutol is used as a single agent against M. tuberculosis. Ethambutol is indicated for the treatment of infections caused by M. tuberculosis, M. kansasii, M. bovis, and M. avium complex. Ethambutol should only be used as part of a combination treatment regimen for M. tuberculosis. Daily dosing is 15-20 mg/kg PO in a single dose, not to exceed 2,500 mg/day. Twice-weekly dosing is with 50 mg/kg PO in a single dose, not to exceed 2,500 mg/day. Dosage adjustment is needed in renal insufficiency. Ethambutol is available in 100 and 400 mg tablets. The major adverse effect with ethambutol is optic neuritis, and thus ethambutol should generally be reserved for children old enough to have visual acuity and color discrimination reliably monitored. Visual changes are usually dosage dependent and reversible. Other adverse events include headache, dizziness, confusion, hyperuricemia, GI upset, peripheral neuropathy, hepatotoxicity, and cytopenias, especially neutropenia and thrombocytopenia. Routine laboratory monitoring includes baseline and periodic visual acuity and color discrimination testing, CBC, serum uric acid levels
- major adverse effect with ethambutol is optic neuritis, Which results in diminished visual acuity and lnability to discriminate red and green Higher risk of ON for patient w/ renal impairment and thus ethambutol should generally be reserved for children old enough to have visual acuity and color discrimination reliably monitored. Visual changes are usually dosage dependent and reversible. Other adverse events include headache, dizziness, confusion, hyperuricemia (uric acid excretion is decreased by ethambutol, GI upset, peripheral neuropathy, hepatotoxicity, and cytopenias, especially neutropenia and thrombocytopenia. Routine laboratory monitoring includes baseline and periodic visual acuity and color discrimination testing, CBC, serum uric acid levels, and kidney and liver function tests.
- Hansenâs disease (also known as leprosy) is an infection caused by bacteria called Mycobacterium leprae. These bacteria grow very slowly and it may take up to 20 years to develop signs of the infection. The disease can affect the nerves, skin, eyes, and lining of the nose (nasal mucosa). The bacteria attack the nerves, which can become swollen under the skin. This can cause the affected areas to lose the ability to sense touch and pain, which can lead to injuries, like cuts and burns. Usually, the affected skin changes color and either becomes: lighter or darker, often dry or flaky, with loss of feeling, or reddish due to inflammation of the skin. If left untreated, the nerve damage can result in paralysis of hands and feet. In very advanced cases, the person may have multiple injuries due to lack of sensation, and eventually the body may reabsorb the affected digits over time, resulting in the apparent loss of toes and fingers. Corneal ulcers and blindness can also occur if facial nerves are affected. Other signs of advanced Hansenâs disease may include loss of eyebrows and saddle-nose deformity resulting from damage to the nasal septum.
- Dapsone [DAP-sone] is structurally related to the sulfonamides and similarly inhibits dihydropteroate synthetase needed for the bacterial synthesis of folic acid. in the folate synthesis pathway. It is bacteriostatic for M. leprae, and resistant strains may be encountered for microorganism w/ alteration of PABA binding site. Dapsone also is used in the treatment of pneumonia caused by Pneumocystis jirovecii in immunosuppressed patients. Dapsone is used in the treatment of M. leprae in combination with other antileprosy agents (rifampin, clofazimine, ethionamide). The pediatric dosage is 1-2 mg/kg/day PO as a single dose, not to exceed 100 mg/day for a duration of 3-10 yr.
- adverse events, including dosage related hemolytic anemia, especially in patients with glucose-6- phosphate dehydrogenase deficiency, pancreatitis, renal complications (acute tubular necrosis, acute renal failure, albuminuria), increased liver enzymes, psychosis, tinnitus, peripheral neuropathy, photosensitivity, and a hypersensitivity syndrome with fever, rash, hepatic damage, and malaise. A lepra reaction may occur with treatment, which is a nontoxic, paradoxical worsening of lepromatous leprosy with the initiation of therapy. This hypersensitivity reaction is not an indication to discontinue therapy. Dapsone should be used with caution in patients with glucose-6-phosphate dehydrogenase deficiency or taking other folic acid antagonists. Dapsone levels can decrease with concomitant rifampin and can increase with concomitant clotrimazole. Routine laboratory monitoring includes CBC weekly during the 1st mo of therapy, weekly through 6 mo of therapy, and then every 6 mo thereafter. Other periodic assessments include kidney function with creatine levels and urinalysis and liver function tests.
- binding to the mycobacterial DNA at guanine sites. It has a slow bactericidal activity against M. lepra
- Patients typically develop a pink to brownish-black discoloration of the skin and should be informed of this in advance. Eosinophilic and other forms of enteritis, sometimes requiring surgery, have been reported. Clofazimine has some anti-inflammatory and anti-immune activities. Thus, erythema nodosum leprosum may not develop in patients treated with this drug
- Because Isoniazid inhibits the metabolism of carbamazepine and phenytoin, isoniazid can potentiate the adverse effects of thi sdrugs, for example nystagmus and ataxia
- C: adverse effect is a dosage-related, reversible pink to tan-brown discoloration of the skin and conjunctiva. Clofazimine has some anti-inflammatory and anti-immune activities. Thus, erythema nodosum leprosum may not develop in patients treated with this drug