Therapeutics 2 course

1. Therapeutics 2 course N.B Tuberculosis

2. TB is caused by Mycobacterium tuberculosis, which can produce either a silent, latent infection or a progressive, active disease. • Risk Factors for Infection: • Location and Place of Birth: TB is most prevalent in large urban areas, places such as prisons, shelters, or nursing homes, abuse or illicit drug use • Race, Ethnicity, Age, and Gender: Hispanic Asians, blacks, primarily in the 25- to 44-year age group, male predominance increases with each decade of life after 15 years old • Coinfection with Human Immunodeficiency Virus N.B

3. Children younger than 2 years of age and adults older than 65 years • Patients with underlying immune suppression Transmission • M. tuberculosis is transmitted from person to person by coughing or other activities that cause the organism to be aerosolized. N.B Reactivation Disease • within 2 years of infection, The apices of the lungs are the most common sites for reactivation (85% of cases)

4. Extrapulmonary Tuberculosis • Extrapulmonary TB without concurrent pulmonary disease is uncommon in normal hosts but more common in HIV-infected patients • Lymphatic and pleural diseases are the most common forms of extrapulmonary TB, followed by bone, joint, genitourinary, meningeal, and other forms. N.B

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6. The Elderly • Positive skin tests, fevers, night sweats, sputum production, or hemoptysis may be absent, making TB hard to distinguish from other bacterial or viral infections or chronic lung diseases. mental status changes are twice as common in the elderly, and CNS disease must be considered when TB is entertained. Mortality is six times higher in the elderly, in part owing to delays in diagnosis. • Children • TB in children may present as atypical bacterial pneumonia, and often involves the lower and middle lobes. Extrapulmonary TB is more common in children. N.B

7. TREATMENT • The desired outcomes during the treatment of TB are: 1. Rapid identification of a new TB case 2. Initiation of specific anti-TB treatment 3. Prompt resolution of the signs and symptoms of disease 4. Achievement of a noninfectious state in the patient, thus ending isolation 5. Adherence to the treatment regimen by the patient 6. Cure of the patient as quickly as possible (generally at least 6 months of treatment) N.B

8. Monotherapy can be used only for infected patients who do not have active TB (latent infection, as shown by a positive skin test). • Once active disease is present, a minimum of two drugs, and generally three or four drugs, must be used • The duration of treatment depends on the condition of the host, extent of disease, presence of drug resistance, and tolerance of medications. The shortest duration of treatment generally is 6 months, and 2 to 3 years of treatment may be necessary for cases of MDR-TB N.B

9. Non-pharmacologic Therapy • Prevent the spread of TB • Find where TB has already spread using contact investigation • Replenish the weakened (consumptive) patient to a state of normal weight and well-being. • Fitted respirators, and closing doors to “negative-pressure” rooms. • Some may need nutritional support • Surgery may needed to remove damaged tissues in the lung and lesions N.B

10. Pharmacological therapy ……Drugs • Primary Antituberculosis Drugs: • Isoniazid, Rifampin, Pyrazinamide, and Ethambutol • Secondary line therapy: • Streptomycin, Cycloserine, Ethionamide, Clofazimine, Quinolones • New Drugs and Delivery Systems: • nitroimidazole derivatives, diarylquinoline, corticosteroids, N.B

11. Primary Antituberculosis Drugs: • Isoniazid is one of the two most important TB drugs • Isoniazid should be given on an empty stomach, and antacids should be avoided within 2 hours of dosing. • Pregnant women, alcoholics, and patients with poor diets who are treated with isoniazid should receive pyridoxine (vitamin B6) 10 to 50 mg daily to reduce the incidence of CNS effects or peripheral neuropathies. • Without rifampin, treatment is generally 18 months or longer. N.B

12. Rifampin usually is given orally, but it also can be give as a 30-minute IV infusion. Oral doses are best given on an empty stomach • women who use oral contraceptives must use another form of contraception during therapy because increased clearance of the hormones may lead to unexpected pregnancies. • Patient records should be reviewed for potential drug interactions before dispensing rifampin. Rifampin may turn urine and other secretions orange-red and may permanently stain some types of contact lenses. N.B

13. Adding pyrazinamide to the first 2 months of treatment with isoniazid and rifampin shortens the duration to 6 months for most patients. • Ethambutol It is used as a fourth drug for TB while awaiting susceptibility data. • Ethambutol should not be given with antacids, Patients may complain of a change in visual acuity, the inability to see the color green, or both. N.B

14. Second-Line Antituberculosis Drugs: • Streptomycin is one of three aminoglycoside antibiotics (along with amikacin and kanamycin) that are active against mycobacteria. • Streptomycin occasionally causes nephrotoxicity, causing ototoxicity … older or long duration … permanent deafness • Cycloserine is only used to treat MDR-TB • Cycloserine can produce dose-related CNS toxicity • addition of pyridoxine 50 mg daily may improve patient tolerance of cycloserine. N.B

15. Ethionamide is not used in the United States…GI toxicity, may cause goiter, gynecomastia, alopecia, impotence, menorrhagia, photodermatitis, and acne. • Levofloxacin, gatifloxacin (outside of the United States), and moxifloxacin are sometimes used to treat MDR-TB because of their excellent activity against M. tuberculosis N.B

16. New Drugs and Delivery System: • The nitroimidazole derivatives are related to metronidazole and work through inhibiting mycolic acid synthesis. • diarylquinoline TMC207 (bedaquiline) works through targeting the ATP synthase pump, and does not demonstrate cross-resistance with existing TB drugs. • Liposomes have been investigated as delivery systems for various agents against mycobacteria, including isoniazid, rifampin, and the aminoglycosides. N.B

17. Adjunctive therapy with corticosteroids may be of benefit for some patients with tuberculous meningitis or pericarditis to relieve inflammation and pressure. They should be avoided in most other circumstances because they detract from the immune response to TB. N.B

18. Pharmacological treatment...Latent Infection N.B

19. Isoniazid is the preferred drug for treating LTBI. Generally, isoniazid alone is given for 9 months. • Young children, the elderly, and HIV-positive patients are at greater risk of active disease once infected with M. tuberculosis. • Isoniazid adult doses are usually 300 mg daily (5 to 10 mg/kg of body weight) • Rifampin 600 mg daily for 4 months can be used when isoniazid resistance is suspected or when the patient cannot tolerate isoniazid N.B

20. There is a growing body of evidence that 4 months of rifampin may be a safer and more cost-effective alternative to 9 months of isoniazid. • The combination of pyrazinamide plus rifampin is no longer recommended because of higher than expected rates of hepatotoxicity. • It should be noted that hypersensitivity reactions were more common with the isoniazid/rifapentine regimen and close clinical follow up should be undertaken. N.B

21. Treatment algorithm for tuberculosis N.B

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23. treatment initiated with isoniazid, rifampin, pyrazinamide, and ethambutol for the initial 2 months. • A repeat smear and culture should be performed when 2 months of treatment has been completed. • In HIV-uninfected patients having no cavitation on chest radiograph and negative acid-fast smears at completion of 2 months of treatment, the continuation phase may consist of either once-weekly isoniazid and rifapentine, or daily or twice-weekly isoniazid and rifampin, to complete a total of 6 months N.B

24. Drug susceptibility testing should be done on the initial isolate for all patients with active TB. • The standard TB treatment regimen is isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and rifampin for 4 months, a total of 6 months of treatment. • If susceptibility to isoniazid, rifampin, and pyrazinamide is shown, ethambutol can be stopped at any time. Without pyrazinamide, a total of 9 months of isoniazid and rifampin treatment is required. N.B

25. Pharmacological treatment... Active Infection N.B

26. Special groups of patients • Children: TB in children may be treated with regimens similar to those used in adults, although some physicians still prefer to extend treatment to 9 months. • Pregnancy: • Women with TB should be cautioned against becoming pregnant • the usual treatment is isoniazid, rifampin, and ethambutol for 9 months • B vitamins are particularly important during pregnancy and should be provided to women being treated for TB. Rifampin is associated rarely with birth defects, including limb reduction and CNS lesions N.B

27. Streptomycin use during pregnancy may lead to hearing loss in the newborn, including complete deafness. • Ethionamide may cause premature delivery and congenital deformities when used during pregnancy. • cycloserine generally cannot be recommended during pregnancy • Ciprofloxacin, levofloxacin, moxifloxacin, and the other quinolones are associated with permanent damage to cartilage in the weight-bearing joints of immature animals N.B

28. Pregnant women with LTBI are not at the same level of risk compared with those with active disease. Therapy with isoniazid for LTBI may be delayed until after pregnancy or, if recent skin-test conversion has occurred, started during the second trimester of pregnancy. • Although most anti- TB drugs are excreted in breast milk, the amount of drug received by the infant through nursing is insufficient to cause toxicity. • Quinolones should be avoided in nursing mothers, if possible. N.B

29. Renal Failure: • For nearly all patients, isoniazid and rifampin do not require dose modification in renal failure. They are eliminated primarily by the liver. • Pyrazinamide and ethambutol typically require a reduction in dosing frequency from daily to three times weekly. • Ciprofloxacin and moxifloxacin are approximately 50% cleared by the kidneys but may not require a change in dose from once daily, as used for TB. N.B

30. BacilleCalmette-Guérin Vaccine • The BCG vaccine is an attenuated, hybridized strain of M. bovis. • Vaccination with BCG produces a subclinical infection resulting in sensitization of T lymphocytes and cross-immunity to M. tuberculosis, as well as cutaneous hypersensitivity and, in many cases, a positive tuberculin skin test. • In the United States, BCG vaccination is recommended only for uninfected children who are at unavoidable risk of exposure to TB and for whom other methods of prevention and control have failed or are not feasible N.B

31. WHO Policy Recommendations 2016 • In patients with rifampicin-resistant or multidrug-resistant TB who have not been previously treated with second-line drugs and in whom resistance to fluoroquinolones and second-line injectable agents has been excluded or is considered highly unlikely, a shorter MDR-TB regimen of 9-12 months may be used instead of a conventional regimen. • In patients with rifampicin-resistant or multidrug-resistant TB, a regimen with at least five effective TB medicines during the intensive phase is recommended, including pyrazinamide and four core second-line TB medicines - one chosen from group A, one from group B, and at least two from group C N.B

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33. Case example • H.G. is a 35-year-old Hispanic man who presents with a 4-week history of a productive cough. The cough was initially nonproductive but became productive of yellow sputum after 2 weeks. The patient has been self-medicating with over-the-counter antitussives without relief, but he experienced hemoptysis this morning. He also complains of subjective fevers, chills, night sweats, dyspnea on exertion, fatigue, and an unintentional 15-pound weight loss during the last 2 months. He immigrated to the United States from Mexico when he was 12 years old, but he has not traveled outside the United States for more than a decade. N.B

34. He currently works as a laborer on new home construction projects, and several of his coworkers, who moved to the United States from Mexico within the past year, have similar respiratory symptoms. He is currently married with 3 children. The patient has a 20-pack-year smoking history and drinks alcohol on the weekends but denies illicit drug use. • On physical examination, H.G. is a thin-appearing man in mild respiratory distress. His heart rate is 94 beats/minute, his respiratory rate is 24 breaths/minute, and his temperature is 38.9◦C. Bronchial breath sounds are noted in the right upper lobe on chest auscultation, and the chest radiograph shows extensive patchy infiltrates in the right upper lobe. N.B

35. Significant laboratory data include the following: White blood cell count, 13,200/μL (72% polymorphonuclear leukocytes, 3% bands, 12% lymphocytes, 13% monocytes) Red blood cell count, 3.7 × 106/μL, Hemoglobin, 11.2 g/dL, Hematocrit, 34%, Platelets, 269 × 103/μL, Serum electrolytes, renal function, and hepatic functionare within normal limits. • He is 69 inches tall, and his weight is 68 kg. The remainder of his physical examination is unremarkable. • What signs and symptoms consistent with active TB disease are present in H.G.? N.B

36. What risk factors for TB are present in H.G.? • H.G.’s HIV test is negative. How should treatment be initiated in H.G., pending the results of sputum culture and susceptibility testing? Can he transmit M. tuberculosis to others during treatment? • Four weeks later, H.G.’s initial sputum cultures were reported to be positive for M. tuberculosis. Drug susceptibility testing to isoniazid and rifampin revealed susceptibility to both agents. What drug regimen should be used for continued treatment of H.G.? How long should treatment be continued? N.B

37. References • Pharmacotherapy, Principles & Practice,4th ed, 2016 • WHO treatment guidelines for drug-resistant tuberculosis 2016 update • Pharmacotherapy, physiological approach, 2014, Chapter 90 • Applied therapeutics, 2013, Chapters 65 N.B