1. PHARMACOTHERAPY III PHCY 510
University of Nizwa
College of Pharmacy and Nursing
School of Pharmacy
PHARMACOTHERAPY III
PHCY 510
Lecture 6 Infectious Diseases “Tuberculosis” Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy, CPN University of Nizwa

2. Course Outcome
Upon completion of this lecture the students will be able to
Describe risk factors, etiology, clinical presentation (signs and symptoms, diagnosis), transmission, diagnosis, treatment strategies, and follow up of tuberculosis.
Individualize the treatments for special populations with tuberculosis infections.

3. Tuberculosis (TB) is a communicable infectious disease caused by Mycobacterium species
Mycobacterium tuberculosis
Mycobacterium bovis
Mycobacterium africanum
Globally, 2 billion are infected, 2 to 3 million people die from TB each year.
M. tuberculosis is transmitted from person to person by coughing or sneezing.
Human immunodeficiency virus (HIV) is the most important risk factor for active TB.

4. Primary infection is initiated by the alveolar implantation of organisms in droplet nuclei that are small enough (1 to 5 mm) to escape the ciliary epithelial cells of the upper respiratory tract and reach the alveolar surface.
Once implanted, the organisms multiply and are ingested by pulmonary macrophages, where they are killed, or, they continue to multiply.
Incubation period from infection to occurrence of primary lesions ranges from 2 to 10 weeks.
Early diagnosis and prompt treatment can reduce the period of infectivity to other people.

5. Latent tuberculosis infection (LTBI) is a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens without evidence of clinically manifested active TB.
Latent tuberculosis is not transmittable to others.
90% of patients who experience primary disease have no further clinical manifestations other than a positive skin test.

6. Tissue necrosis and calcification of the originally infected site forms a radiodense area referred to as a Ghon complex.
Widely disseminated disease and granuloma formation known as miliary TB.
Mycobacteria are rod-shaped, non-spore-forming, slow growing (4 to 6 weeks) aerobic bacteria.
The bacilli do not stain freely, but once stained they resist decolorization with acid alcohol, which led to their classification as acid-fast bacilli (AFB).

7. Clinical Presentation
Signs and symptoms
Weight loss, fatigue, a productive cough, fever, and night sweats.
Frank hemoptysis.
Physical examination
Dullness to chest percussion, rales, and increased vocal fremitus are observed frequently on auscultation.
Laboratory tests
Moderate elevations in the white blood cell count with a lymphocyte predominance.
Tuberculin test (Mantoux test - purified protein derivative (PPD)) is used to detect latent TB infection.
Chest radiograph
Patchy or nodular infiltrates in apical area of upper lobes or the superior segment of the lower lobes.
Cavitation that may show air-fluid levels as infection progresses.

8. HIV positive patients have a higher incidence of extrapulmonary TB.
Extrapulmonary and disseminated TB may occur at sites such as the lymph nodes, genitourinary tract, pleura, bone and joints, spine, peritoneum, or meninges.
In patients with suspected pulmonary TB, three sputum specimens should be collected and submitted to the laboratory for microscopic examination for AFB smear and mycobacteriology culture.
A lack of positive acid-fast smears does not rule out probable TB, because smears may be negative.

9. Treatment
Rifampicin ( mg) + isoniazid (300 mg) + pyrazinamide (1.5-2 g) + ethambutol ( mg) daily.
Isoniazid (INH) is a bactercidal against intracellular organisms.
Rifamicin is a bactercidal against dividing organisms.
Combination is always used and selection of therapy based on resistance and patient adherence to regimen.
Pyrazinamide decreases tubular secretion of urate and causes hyperuricemia.

10. Intermittent directly observed therapy (DOT) regimens:
To be considered when non-adherence to drug therapy might be a problem.
DOT regimen: rifampicin-INH-pyrazinamide-ethambutol given daily for 2 months followed by rifampicin-INH 2-3 times weekly for 4 month.
Patients must complete 6 months or more of treatment.
HIV-positive patients should be treated for an additional 3 months and at least 6 months from the time that they convert to smear and culture negativity.
When INH and RIF cannot be used, treatment duration becomes 2 years or more, regardless of immune status.

11. Drug Resistance (MDR-TB)
If the organism is drug resistant, the aim is to introduce two or more active agents that the patient has not received previously.
With MDR-TB, no standard regimen can be proposed and second line treatment is preferred.
Patients who still have acid-fast bacilli–positive sputum smears and positive cultures after 2 months of therapy.
Patients who fail therapy or relapse after retreatment

12. Special Populations Tuberculous Meningitis and Extrapulmonary Disease
In general, INH, pyrazinamide, ethionamide, and cycloserine penetrate the cerebrospinal fluid readily.
Patients with CNS-TB are often treated for longer periods (9 to 12 months).
TB of the bone is typically treated for 9 months.
Children
TB in children may be treated with regimens similar to those used in adults and extended to 9 months.
Pediatric doses of drugs should be used.

13. Pregnant Women
The usual treatment of pregnant women is INH, RIF, and ethambutol for 9 months.
Women with TB should be cautioned against becoming pregnant, as the disease poses a risk to the fetus as well as to mother.
INH or ethambutol are relatively safe when used during pregnancy.
Supplementation with B vitamins is particularly important during pregnancy.
Renal Failure
INH and RIF do not require dose modifications in renal failure.
Pyrazinamide and ethambutol typically require a reduction in dosing frequency from daily to three times weekly

14. Patient Monitoring Symptomatic patients should be isolated.
Check sputum samples for acid-fast bacilli stains every 1 to 2 weeks until two consecutive smears are negative.
Blood urea nitrogen, serum creatinine, aspartate transaminase or alanine transaminase, and a complete blood count determined at baseline and periodically to check toxicity.
Hepatotoxicity should be suspected in patients whose transaminases exceed five times the upper limit of normal or whose total bilirubin exceeds 3 mg/dL.

15. Discontinue offending agent(s) and alternatives selected.
INH results in a temporary elevation in serum transaminases within the first 8 to 12 weeks of therapy.
INH also cause neurotoxicity, presenting as peripheral neuropathy or, in overdose, seizures, and coma.
Pyridoxine (vitamin B6) is added to combat the peripheral neuropathy caused by isoniazid.
RIF’s induction of hepatic enzymes may enhance the elimination of a number of drugs, most notably protease inhibitors.

16. Women who use oral contraceptives should be advised to use another form of contraception during therapy.
The red colorizing effects of RIF on urine, other secretions, and contact lenses should be discussed with the patient.
Retrobulbar neuritis is the major adverse effect noted in patients treated with ethambutol.
Patients usually complain of a change in visual sharpness and/or inability to see the color green.
Vision testing should be performed on all patients who must receive ethambutol for more than 2 months.

17. Ethambutol dose reduction and serum creatinine monitoring are required in patients with renal disease.
Vestibular function Impairment of eighth cranial nerve function is important adverse effect of streptomycin, but hearing may also be impaired.
Audiometric testing should be performed in patients who must receive streptomycin for more than 2 months.
Streptomycin occasionally causes nephrotoxicity.

18. TB Control
Prophylaxis: isoniazid alone for 6 months or isoniazid + rifampicin for 3 months
BCG (Bacillus Calmette-Guérin) is alive attenuated vaccine derived from M. bovis.
It prevents infection with serious TB forms.