Seminar 12 Antimycobacterial drugs PDF

SEMINAR 12 Antimycobacterial drugs 3° MEDICINE Academic year: 2024/25 Professor: Vittoria Carrabs PhD  TUBERCULOSIS Robert Koch isolated several pathogenic bacteria, including...

SEMINAR 12 Antimycobacterial drugs 3° MEDICINE Academic year: 2024/25 Professor: Vittoria Carrabs PhD  TUBERCULOSIS Robert Koch isolated several pathogenic bacteria, including tuberculosis, named Koch's bacillus in his honor. (Mycobacterium tuberculosis) https://youtu.be/I675DCOORMI?si=H7tZUxaMLKP1ZCNS Tuberculosis Epidemiology ✓ It is one of the most serious public health problems worldwide in the 21st century. ✓ It is considered a re-emerging infectious disease. ✓ According to the latest available data from the World Health Organization in 2020, some 10.4 million people developed the disease and 1.7 million died as a result of it; 85% of cases occur in Asia, Africa and Eastern Europe. ✓ In Spain, it is estimated that between 10 and 15 million people are infected. ✓ Resistance to anti-tuberculosis drugs due to non-compliance and/or inadequate treatment is a very serious health problem. Tuberculosis Ethiopathogenesis Chronic lung disease caused by mycobacteria of the Mycobacterium tuberculosis complex (M. Bovis, M. tuberculosis, M. Africanum, M. microti), which mainly affect the lung, although it can cause lesions in any organ and tissue. ROUTE OF TRANSMISSION Airway by inhalation of aerosols, (sneezing, coughing) Tuberculosis Phases of the disease Primary tuberculosis: people who have not been in previous contact with the bacillus and lack an immune response against it are infected. Symptoms are nonspecific; general malaise, weight loss... Secunary tuberculosis : it occurs in previously sensitized subjects. It causes larger areas of necrosis than the primary one and the most characteristic symptom is hemoptoic sputum. Extrapulmonar tuberculosis : Hematogenous spread of the bacilli. Tuberculosis ANTITUBERCULOUS QUIMIOTHERAPY OBJECTIVES: Rapid removal of bacilli Prevent relapse Prevent infection in individuals in close contact with active cases (isolation). To achieve these objectives is important: Treatment with two or more drugs no monotherapy Maintain treatment for three to six months once the sputum analysis is negative With preventive chemotherapy, the objective is to prevent the infection of people in intimate contact with the patient. Tuberculosis PROBLEMS: The increase in AIDS patients is an easy settlement for mycobacteria. Long treatments non-compliance (non-adherence to treatment) and relapses Development of multidrug resistance of the bacillus Tuberculosis RESISTANCE Resistance to several first-line drugs is due to patient non- compliance and/or inadequate treatment. The main resistance is that produced against first-line drugs: isoniazid and rifampin. In these cases, second-line drugs are used. It is more common in patients with AIDS.  Wall structure of Mycobacterium Tubercolosis Outer Membrane Possible drug targets of anti-tuberculosis chemotherapy  ANTITUBERCULOUS DRUGS ► First-line treatment 1. Isoniazid 2. Rifampin 3. Ethambutol 4. Streptomycin 5. Pyrazinamide ► Second line treatment: Aminoglycosides (Kanamycin, Amikacin) Quinolones (Ciprofloxacin, Ofloxacin) Paraamminosalycilic acid (PAS). Etionamide Cycloserine Capreomycin Rifabutin Rifapentin ►Third line treatment : Bedaquiline (approved in 2014) FIRST-LINE ANTI-TUBERCULOSIS DRUGS: ISONIAZID Mechanism of action: It is a prodrug. It acts by altering the walls of mycobacteria, by inhibiting the synthesis of mycolic acids. Its activity is selective on tuberculous mycobacteria, and it lacks action against other microorganisms. Bactericides in tuberculous bacilli in the growth phase. Bacteriostatics in resting tubercle bacilli. Pharmacokinetics Very good absorption orally. It can also be administered parenterally. Diffuses easily to all tissues. It passes through the BBB, placenta and milk. Hepatic metabolisation. It is excreted in the urine. ISONIAZID ADRs (not very toxic) Hepatitis Neurological disturbances and seizures Hypersensitivity reactions haematological alterations Factors that increase the incidence: age, alcoholism, existence of previous liver disease, administration with other hepatotoxic drugs. Clinical use : ** Drug of choice in the treatment and prophylaxis of tuberculosis in all its forms. Dosage: 5mg/Kg/day oral or I.V.  FIRST-LINE ANTI-TUBERCULOSIS DRUGS: RIFAMPIN Mechanism of action Inhibits bacterial RNA synthesis. Bactericidal against M. tuberculosis The appearance of resistance is the reason why treatment fails Pharmacokinetics It is well absorbed orally, also intravenously It crosses the BHE, placenta and breast milk. Hepatic metabolization and short half-life 60-65% is excreted in faeces and the rest in urine. rifampin is an enzyme-inducer. RIFAMPIN ADRs At normal doses (10mg/kg/day) it is well tolerated. Hepatotoxicity: Asymptomatic jaundice, Hepatitis. Flu-like syndrome with dyspnea At high doses: dyspnea, hypotension, and shock. Others: drowsiness, fatigue, gastrointestinal discomfort. It stains all body fluids orange. Contraindications Patients with a history of rifampin hypersensitivity. Liver patients with jaundice. Pregnant during the first 3 months of gestation. Nursing. RIFAMPIN Interactions rifampin = enzyme inducer ▪ Accelerates the metabolism of: ▪ Oral anticoagulants ▪ Estrogens ▪ Oral hypoglycemic agents ▪ Anticonvulsants ▪ Glucocorticoids ▪ Digoxin ▪ Beta-blockers Clinical use ► Tuberculosis Treatment ► Atypical mycobacterial infections. ► In leprosy ► Drug of choice in meningococcal infections and H. influenzae meningitis.  FIRST-LINE ANTI-TUBERCULOSIS DRUGS: Mechanism of action PYRAZINAMIDE Prodrug converted to pyrazinoic acid by the enzyme mycobacterium pyrazinamidase. Pyrazinic acid alters the metabolic and cell membrane transport functions of mycobacteria. Pyrazinic acid accumulates in the cytoplasm of the mycobacterium, generating a lowering of the pH. The acidic pH inactivates the enzyme FAS1 (Fatty Acid Synthase type 1), an enzyme vital for the synthesis of fatty acids present in the bacterium's cell wall. Pharmacokinetics It is well absorbed in the gastrointestinal tract. It crosses the BHE. Excreted in urine ADRs Digestivas: nauseas y vómitos. Hepatotoxicidad Otras: fiebre, urticaria, diarrea, aparición de úlcera péptica. Clinical use En tratamientos de tuberculosis de corta duración y en resistencia a otros fármacos.La pirazinamida combinada con rifampina, permite acortar el tratamiento de 1año a 6 meses. FIRST-LINE ANTI-TUBERCULOSIS DRUGS: ETHAMBUTOL Mechanism of action:Synthetic drug that acts by altering the synthesis of the wall of mycobacteria in the growth phase. Bacteriostatic action. Pharmacokinetics: good oral absorption, it is excreted by kidney. ADRs: Dose-dependent visual disturbances: decreased visual acuity, neuritis, altered color perception (visual examination is recommended before starting treatment). Gastrointestinal disorders Hypersensitivity reactions. Can cause hyperuricemia Clinical use: treatment of tuberculosis. Effective in cases of relapse, and when there is resistance to isoniazid and rifampin. FIRST-LINE ANTI-TUBERCULOSIS DRUGS: STREPTOMYCIN: An aminoglycoside antibiotic, whose use in the treatment of tuberculosis has decreased due to its adverse reactions. To reduce the appearance of resistance, combined treatment with other first-line anti- tuberculosis drugs is necessary.  TREATMENT OF TUBERCULOSIS ► CURATIVE TREATMENT 2+4 Treatment: 1. Initial phase: combination for 2 months of: Rifampin Isoniazid Pyrazinamide 2. Continuation phase: 4 more months with rifampin and isoniazid. Treatment is extended to 9 months (2+7) in cases of HIV-positive patients. Severe cases: treatments of at least 12 months are required. In case of resistance: treatment with isoniazid, rifampin and ethambutol for at least 12 months. In cases of resistance to first-line drugs, second-line drugs should be used. Drug regimen:Medication in a single dose in the morning and on an empty stomach  SECOND-LINE ANTI-TUBERCULOSIS DRUGS: Used only under the following conditions: 1.Resistance to first-choice drugs 2.Lack of clinical response to conventional therapy 3.Serious treatment-limiting adverse drug effects  SECOND-LINE ANTI-TUBERCULOSIS DRUGS: ETHIONAMIDE  Similar to isoniazid, it blocks the synthesis of mycolic acids.  Administration for o.s., hepatic metabolism.  Starting dose of 250 mg 1 time a day, up to the recommended dose of 1g per day  Poorly tolerated due to neurological symptoms, gastric irritation and hepatotoxicity.  Rapid development of resistance when used as monotherapy  SECOND-LINE ANTI-TUBERCULOSIS DRUGS: CAPREOMICIN  Peptide antibiotic obtained from Streptomyces capreolus.  Inhibits mycobacterium protein synthesis  IM administration, dose 15mg/kg/day  Important in the treatment of drug-resistant tuberculosis  Nephrotoxic and ototoxic SECOND-LINE ANTI-TUBERCULOSIS DRUGS: CYCLOSERINE  Inhibitor of cell wall synthesis  Concentrations of 15-20 mg/mL inhibit many strains of M. Tuberculosis. (recommended dose 0.5-1g/day in two doses)  Adverse reactions in the first 2 weeks of therapy: peripheral neuropathy and CNS disorders.  SECOND-LINE ANTI-TUBERCULOSIS DRUGS: AMINOSALICYLIC ACID (PAS)  Antagonist of folate synthesis by analogy with PABA acid, active for M.Tuberculosis.  Mechanism of action like sulfonamides. PAS SULFONAMIDE PABA Rarely used because it is poorly tolerated. SECOND-LINE ANTI-TUBERCULOSIS DRUGS: KANAMYCIN E AMIKACIN  Aminoglycoside antibiotics  Kanamycin is used in streptomycin-resistant strains of M.Tuberculosis, but amikacin is preferred for less toxicity.  IV or IM dose 20-40 mg/kg/day for several weeks, followed by 1-1.5 g 2-3 times a week for several months, always in combination with other anti-TB drugs.  SECOND-LINE ANTI-TUBERCULOSIS DRUGS: FLUOROQUINOLONES  DNA-gyrase inhibitors  Ciprofloxacin dose per o.s. 750 mg twice daily  Levofloxacin dose per o.s. 500-750 mg as a single daily administration  Used in infections caused by multidrug-resistant strains, in combination with two or more other active drugs SECOND-LINE ANTI-TUBERCULOSIS DRUGS: LINEZOLID  Inhibitor of bacterial protein synthesis  Used in infections caused by multidrug-resistant strains, in combination with two or more other active drugs.  Adult dose per o.s. 600 mg once daily THIRD-LINE ANTI-TUBERCULOSIS DRUGS: BEDAQUILINE  Bactericide, inhibitor of bacterial ATP-synthetase.  Administration by o.s., hepatic metabolism (CYP450), elimination through faeces.  In combination with at least 3 active drugs for a 24-week treatment  Dose 400 mg once daily for 2 weeks, followed by 200 mg 3 times weekly for 22 weeks.  Risk of liver and cardiac toxicity  LEPROSY  Infectious disease caused by Mycobacterium Leprae or Hansen's Bacillus.  It mainly affects the skin and peripheral nerves. Nerve involvement causes numbness and weakness in areas controlled by the affected nerves.  Globally, the number of leprosy cases is declining. In 2015, about 80% of cases occurred in India, Brazil, and Indonesia.  In 2015, 178 new cases were reported in the United States. Most cases of leprosy in the United States involve people who have migrated from developing countries. Gerhard Armauer Hansen https://youtu.be/S_dcF0SPYrw?si=WUysJR6VPPiUaR9l  Leprosy Symptoms Leprosy can also be classified according to cellular response and clinical findings:  Tuberculoid leprosy: skin lesions consist of one or a few hypoesthetic, hypopigmented maculae. The areas affected by this eruption are numb due to damage to the underlying peripheral nerves.  Lepromatous leprosy: Most of the skin and many other parts of the body, including the kidneys, nose, and testicles, can be affected. Patients have macules, papules, nodules, or skin plaques that are often symmetrical. Peripheral neuropathy is more severe.  Borderline leprosy: the characteristics of both tuberculoid and lepromatous forms of leprosy are present.  DRUGS FOR THE TREATMENT OF LEPROSY  DAPSONE (AND HIGH SULFONES)  RIFAMPIN in combination  CLOFAZIMINE  DRUGS FOR THE TREATMENT OF LEPROSY DAPSONE  Analogy with sulfonamides. Inhibitor of folate synthesis.  Development of resistance, if given low Dapsone doses of the drug ❑ COMBINATIONS: ❑ Dapsone + rifampin + clofazimine combination for the initial treatment of lepromatous leprosy. ❑ Dapsone + rifampin for the treatment of leprosy with lower microbial load ❑ Dapsone used in the prophylaxis of Pneumocystis jiroveci pneumonia in patients with AIDS Sulfonamide ADRs: well tolerated; hemolysis and allergic reactions  DRUGS FOR THE TREATMENT OF LEPROSY CLOFAZIMINE  Phenazine staining, mechanism of action unknown.  Variable intestinal absorption, elimination via faeces.  Deposits in tissue and skin as crystals (half-life 2 months)  Dose per o.s. 100 mg/day  ADRs: skin and eye discolouration, g.i. disturbances.