TB Transmission

1 TUBERCULOSIS Su Lee PharmD., M.S., BCIDP, BCPS Christina Tadevosyan, PharmD Candidate 2025 [ADVENTISTHEALTH:INTERNAL] 6 TB Transmission Types of Mycobacteria M. tuberculosis • Mycobacterium tuberculosis causes most TB cases in U.S. • Slow growing (20 hrs. to double) • Nonmotile, non-spore forming, aerobic gram-positive rods that stain acid-fast due to the presence of mycolic acids in their cell wall • Mycobacteria that do not cause TB • e.g., M. avium complex (MAC), Mycobacterium leprae, etc. • TB particularly refers to only disease caused by Mycobacterium tuberculosis • People who have pulmonary cavitary lesions (infiltrates) are especially infectious • TB is a chronic, progressive infection with a period of latency following initial infections CDC 2018 [ADVENTISTHEALTH:INTERNAL] CDC 2018 TB Transmission • Transmission: Inhalation • Probability that TB will be transmitted depends on: I • Infectiousness of person with TB disease • Environment in which exposure occurred 2 • Length of exposure 3 U bacilli WE• Virulence (strength) of the tubercle • The best way to stop transmission is to: • Isolate infectious persons • Provide effective treatment to infectious persons as soon as possible [ADVENTISTHEALTH:INTERNAL] 8 Module 1 – Transmission and Pathogenesis of Tuberculosis 9 TB Pathogenesis 2 bronchiole blood vessel tubercle bacilli alveoli Tubercle bacilli multiply in alveoli, where infection begins [ADVENTISTHEALTH:INTERNAL] Module 1 – Transmission and Pathogenesis of Tuberculosis 10 TB Pathogenesis Latent TB Infection 4 special immune cells form a barrier shell (in this example, bacilli are in the lungs) • Within 2 to 8 weeks the immune system produces special immune cells called macrophages that surround the tubercle bacilli • These cells form a barrier shell that keeps the bacilli contained and under control (LTBI) [ADVENTISTHEALTH:INTERNAL] Module 1 – Transmission and Pathogenesis of Tuberculosis TB Pathogenesis : TB Disease 5 shell breaks down and tubercle bacilli escape and multiply (in this example, TB disease develops in the lungs) • If the immune system CANNOT keep tubercle bacilli under control, bacilli begin to multiply rapidly and cause TB disease • This process can occur in different places in the body [ADVENTISTHEALTH:INTERNAL] 11 Module 1 – Transmission and Pathogenesis of Tuberculosis É 12 LTBI vs. Active TB Disease Latent TB Infection (LTBI) TB Disease (in the lungs) Inactive, ~90% of exposed individuals, contained tubercle bacilli in the body Active, ~10% of exposed individuals; multiplying tubercle bacilli in the body TST or blood test results usually positive TST or blood test results usually positive Chest x-ray usually normal Chest x-ray usually abnormal Sputum smears and cultures negative Sputum smears and cultures may be positive No symptoms Symptoms such as cough, fever, weight loss Not contagious Often infectious before treatment Not a case of TB, about 10% of those with latent disease progresses to reactivation (secondary infection) A case of TB [ADVENTISTHEALTH:INTERNAL] 14 Pathophysiology of TB: 3 Phases of TB I • Primary infection • Only bacterial growth in body which are being attacked by macrophages • No s/sx and no pulmonary infiltrates on chest x-ray, Negative test • Based on patient’s immune system, it can progress to latent or active TB 2 • Latent (dormant) phase: TB Infection • Patient has a positive PPD skin test or blood test 3 • No s/sx, no positive sputum culture, no pulmonary infiltrates on chest x-ray. • Active phase: TB Disease • Contagious phase during which TB is transmitted • Presence of s/sx, positive sputum culture, positive PPD skin test, visible pulmonary infiltrates (cavitation) on chest x-ray I 2 • Disease progression is dependent upon Inoculum ( # of bacteria in body), virulence of the strain (toxicity of bacteria to body), host immune function (cell mediated immune factors) 3 [ADVENTISTHEALTH:INTERNAL] 15 Ident no Groups at High Risk for TB Infection i • Contacts of persons known or suspected to have infectious TB disease 2 US within the last 5 years from areas of the world where TB is common • Came to the 3• • 5• • 7• (for example, Asia, Africa, Eastern Europe, Latin America, and Russia) Visited areas of the world where TB is common, especially if visits are frequent or prolonged EH Live or work in 4 congregate settings whose clients are at increased risk for TB disease Health care workers who serve clients who are at increased risk for TB disease 6 such as Populations defined locally as high risk for latent TB infection or TB disease, medically underserved, low-income persons, or persons who abuse drugs or alcohol Infants, children, and adolescents exposed to adults at increased risk for infection or disease [ADVENTISTHEALTH:INTERNAL] 16 no Adeform Groups at High Risk for Developing TB Diseases In general, people at high risk for developing TB disease after infected with M. tuberculosis include: • HIV/AIDS z • Children < 5 YO 3 • Immunosuppressive therapy u • Recently infected with M. tuberculosis (within the past 2 years) g • History of untreated or inadequately treated TB disease 6 • Silicosis, diabetes, chronic renal failure, leukemia, lymphoma, or Cancer of the head, neck, or lung 7 • Gastrectomy or jejunoileal bypass 8• Weight < 90% of IBW • Cigarette smokers and persons who abuse drugs or alcohol • Populations defined locally as having an increased incidence of TB disease, possibly including medically underserved or low-income populations [ADVENTISTHEALTH:INTERNAL] https://www.cdc.gov/tb/webcourses/TB101 17 Diagnosis of TB 1. Medical history: Symptoms, PMH, Risk Factors 2. Physical examination: Signs 3. Testing for Infection skintest Positive TST or IGRA chest X-ray 4. Positive chest X-ray la Bloodtest + symptoms TB disease 5. Bacteriological examination • Specimen collection: at least 3 sputum specimens • Examination of acid-fast bacilli smears: TB or nontuberculous mycobacteria • Negative doesn’t exclude TB (Sensitivity 50%) • Direct identification of specimen (nucleic acid amplication, NAAT) to identify M. tuberculosis • Specimen culturing and identification : ALL (takes 4-8 weeks, Sensitivity 80%) • Drug susceptibility testing • MDR-TB: resistant to both isoniazid and rifampin • XDR-TB (Extensively drug-resistant) : Resistant to isoniazid, rifampin, any FQ, and at least one of 3 injectable second line drugs [ADVENTISTHEALTH:INTERNAL] 18 Clinical Presentation of active TB d • Productive cough (yellow or green •z • 3 • • • G •7 •8 • 9 sputum) Hemoptysis (coughing up blood d/t lung erosions, usually in advanced disease) Lymphadenopathy Swollenlymphnodes Unintentional weight loss Night sweats Fever Chills Chest pain Dyspnea (shortness of breath) [ADVENTISTHEALTH:INTERNAL] 20 Tuberculin Skin Test (TST) Skin test for Purified Protein Derivative (PPD) • Recommended dose : 5 tuberculin units : 0.1 mL • Mantoux Tuberculin Skin test (TST) j As • Intradermal injection of tuberculin into forearm • Measure diameter of induration (in mm) after 48-72 hours • False negative occur in 15-20 % of people infected with M. tuberculosis, primarily in those recently infected or anergic • Only 8% of people vaccinated with Bacille Calmette-Guerin (BCG) at birth will react 15 years later [ADVENTISTHEALTH:INTERNAL] 21 haethe risk fagot Ear Everyone Comorbid conditions, people from high tb rate countries or locations immunosuppressed [ADVENTISTHEALTH:INTERNAL] A 22 Role of Tuberculin skin test (TST) • A purified protein derivative (PPD)-tuberculin skin test may be done at the time of initial evaluation • Negative PPD-tuberculin skin test • does not exclude the diagnosis of active tuberculosis • A positive PPD-tuberculin skin test • supports the diagnosis of Latent TB and Culture-negative pulmonary TB w/ normal chest xray • No further PPD tuberculin skin test for people with previous positive or treatment for TB disease [ADVENTISTHEALTH:INTERNAL] 23 Interferon-Gamma Release Assays (IGRAs)/targeted blood tests • QuantiFERON®-TB Gold and T-SPOT® TB • Blood test to detects the release of interferon-gamma (IFN-γ) (cellular immune response) to M. tuberculosis infection • Less sensitivity, but greater specificity than PPD for future active infection • Can be used interchangeably with PPD • Most beneficial to verify a positive PPD in patient with BCG vaccine or for those who cannot return for a PPD reading [ADVENTISTHEALTH:INTERNAL] 24 TST vs. IGRA TST IGRA Pros • Intradermal injection – no lab needed • Requires single visit • Results within 24 hours Cons • False + in pts who received BCG vaccine or infected w/nontuberculous mycobacteria • Requires 2 visits • Results available within 48-72 hours • Cannot detect recent infection • Blood sample must be processed within 830 hrs after collection • Indeterminate results provide no useful information • Cannot detect recent infection • Limited data exist on use in children < 5YO, persons recently exposed to TB, immunocompromised persons, and those who will be tested repeated • Higher cost [ADVENTISTHEALTH:INTERNAL] 25 AFB smear vs. Culture I Acid-fast bacilllus (AFB) smear Mycobacterial culture Direct specimen Specimen inoculated onto media Staining of sample & direct microscopy Growth on selective media & biochemical or PCR identification Time to result Hours Weeks (2-8 weeks) # of organisms detected 5,000-10,000 organisms/mm3 10-100 organisms/mm3 False-positives Non-TB mycobacteria Unusual False-negatives Low disease burden Patient on anti-TB therapy Rapid screening Definitive diagnosis & susceptibility testing Sample Technique Role saw [ADVENTISTHEALTH:INTERNAL] 26 Goals of Treatment of TB • The overall goals for treatment of tuberculosis are - to cure the individual patient - to minimize the transmission of Mycobacterium tuberculosis to other persons. [ADVENTISTHEALTH:INTERNAL] needto take the pt Direct adatDoc Observationaloffice Therapy(DOT) Direct observation of therapy (DOT) involves providing the anti-TB drugs directly to the patient and watching as he/she swallows the medications. It is the preferred core management strategy for all patients with tuberculosis. CID, 2016:63:e147-195 [ADVENTISTHEALTH:INTERNAL] 27 29 PRINCIPLES OF ANTITUBERCULOSIS CHEMOTHERAPY • Combination Chemotherapy • Optimum Duration of Treatment [ADVENTISTHEALTH:INTERNAL] 31 Anti-TB drugs currently in use in the USA • First-line drugs (RIPE) • Second-line drugs • Rifampin (RIF) • Cycloserine mopiffin 2 • Rifapentine (RPT) tMysobatin 3• Rifabutin* (RBT) • Isoniazid (INH) s• Pyrazinamide (PZA) MorMyambatol 6• Ethambutol (EMB) • Levofloxacin* • Moxifloxacin* • Streptomycin (SM) y • Amikacin* • Capreomycin • Linezolid * Not approved by FDA for TB treatment [ADVENTISTHEALTH:INTERNAL] • Bedaquiline • Clofazimine if 32 Treatment of Latent TB • Latent TB : morepreferredoption • 3 mos INH + RPT qweek under DOT ( 12-dose) • 4 mos Rifampin daily (HIV negative) • 3 mos INH + Rifampin given daily (conditional recommendation) • Reduces lifetime risk of active TB from ~10 % to 1 % [ADVENTISTHEALTH:INTERNAL] MMWR 2020;69(1):1-11 34 Gold Standard Active TB treatment regimen • Drugs (RIPE) • RIF + INH + PZA + EMB • Phases of treatment • Initial phase: 8 weeks • 4 drugs used: RIF + INH + PZA + EMB daily • Continuous phase: 18 weeks (4.5 mos) • 2 drugs used: RIF + INH (daily or twice weekly) • Total duration of treatment: 26 weeks (6.5 mos) [ADVENTISTHEALTH:INTERNAL] Mechanisms of action of established and experimental drugs used for the chemotherapy of mycobacterial infections. Approved drugs for the chemotherapy of mycobacterial diseases may be grouped according to the sites of action indicated by the pictures above that expand regions of the mycobacterium: inhibitors of nucleic acid and protein synthesis; disruptors of cell wall and cell membrane synthesis; inhibitors of membrane transport. Specific antimycobacterial agents and their mechanisms of action are also listed. Rifamycin is used as a generic term for several drugs, of which rifampin is used most frequently. Clofazimine, whose mode of action is not understood, is omitted. [ADVENTISTHEALTH:INTERNAL] Citation: Chapter 60 Chemotherapy of Tuberculosis, Mycobacterium avium Complex Disease, and Leprosy, Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e; 2017. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2189§ionid=172485532 Accessed: October 30, 2021 Copyright © 2021 McGraw-Hill Education. All rights reserved 39 Isoniazid (INH) • MOA: inhibition of mycolic acid synthesis • Profound early bactericidal activity against rapidly dividing cells • Drug interactions (INH is a CYP450 inhibitor) • Metabolism: Hepatic metabolism via acetylation • 2 types of acetylators: Slow and Fast acetylators • Slow acetylators metabolize INH slows thus have increased risk of neurotoxicity due to INH accumulation [ADVENTISTHEALTH:INTERNAL] Notable Adverse Effects • Hepatotoxicity (N,V, abdominal pain, fatigue, dark urine) • Asymptomatic increase AST/ALT (10-20 %) – resolve spontaneously Normal – Clinical hepatitis (0.6% alone vs. 2.7 % in INH + RIF) – If 3 x upper normal limit (UNL) with symptom or 5 x UNL, Stop – May be used in stable hepatic disease (frequent monitoring) – Risk factor : Older age, alcoholism, pregnancy, just have baby, h/o liver diseases, other hepatotoxic drug 40 Isoniazid ADR • Peripheral neuropathy • Damage to sensory nerves of hands and feet • Symptoms include a tingling sensation or weakened sense of touch • Risk Factor : • Alcoholism • diabetes, • HIV • renal failure • pregnant and breastfeeding women • malnutrition increase risk for peripheral neuropathy • Pyridoxine(vit B-6) 25 – 50 mg/day for prevention qt [ADVENTISTHEALTH:INTERNAL] • CNS effects (irritability, seizures, dysphoria) • Lupus-like syndrome • Hypersensitivity reactions • MAO (histamine/tyramine) poisoning 41 Rifamycins • Drugs in the Class • Rifampin • Rifapentine • Rifabutin • MOA: inhibits RNA synthesis • bactericidal activity • Resistance to Rifamycins is very common therefore monotherapy is rarely recommended • EMB is used to prevent bacteria resistance to RIF [ADVENTISTHEALTH:INTERNAL] stuff stain 42 drugofchoice go Rifampin (RIF) • Recommended DOC in appropriate patients • Adverse effects • Pruritisso itching • GI sx – N/V, anorexia, abd pain • Flu-like sx • Photosensitivity • Hepatotoxicty: RIF > RPT > RBT • Orange discoloration of bodily fluids • Sputum, Urine, Sweat, Tears • Drug interaction (RIF is CYP450 inducer) • Oral contraceptives: alternative birth control • Methadone : withdrawal symptoms • Warfarin • Protease inhibitors [ADVENTISTHEALTH:INTERNAL] Rifapentine(RPT) • Rifapentine is a longer acting rifamycin • RPT can be given as a once-a-week dose during the continuation phase only in addition to the other drugs • ADRs • Same side effects as RIF • Drug interactions • 80% similar drug interactions compared to RIF 43 Rifabutin • Rifabutin is used as a substitute for RIF in the treatment of all forms of tuberculosis • It should be considered first-line drugs in special situations: Atanazadir – Patients on drugs that have drug interactions with RIF such as Protease inhibitors or oral fosomprenaviv ravin No contraceptives lextainvingse – Patients who have experienced intolerance side effects to RIF. • ADRs Lopinavir – Same as RIF but RBT has less hepatoxicity than RIF – Uveitis (an inflammatory eye condition characterized by pain, redness, and possible temporary or permanent loss of vision) • Drug interactions – Less drug interaction as compared to RIF especially with Protease inhibitors and oral contraceptives – CYP 3A substrate – Efavirenz (CYP 3A inducer) : Requires higher dose of rifabutin (450 mg or above) – Ritonavir (CYP 3A inhibitor) : Rifabutin dose should be reduced to 150 mg, daily administration recommended – Tenofovir alafenamide is a P-gp substrate, rifampin and rifabutin are P-gp inducers and contraindicated with tenofovir alafenamide, therefore replace to Tenofovir disoproxil fumarate [ADVENTISTHEALTH:INTERNAL] 45 Pyrazinamide (PZA) • MOA • PZA is believed to exert greatest activity against dormant or semidormant mycobacterium bacteria contained within macrophages • PZA also has greatest activity in acidic environment of caseous foci of the lungs • PZA is not indicated for • Severe liver disease • Gout • Pregnancy (category C) [ADVENTISTHEALTH:INTERNAL] • Adverse effects • Hepatotoxicity • GI symptoms (nausea, vomiting) • Arthralgia & Arthritis ( non-gouty forms) • Hyperuricemia (decreased uric acid excretion) • Risk increases in patients with renal insufficiency • Morbilliform rash • Dermatitis 46 Ethambutol (EMB) • Bacteriostatic • Special considerations • Initial eye exam Earsold • Not recommended for routine use in children, whose visual acuity cannot be monitored • Visual acuity and color vision should be done monthly if EMB used is > 2 months of doses or > 15-20 mg/kg • Adverse effects • Cutaneous reactions(Rash) • Eye damage (one or both eyes) • Retrobulbar neuritis and Peripheral neuritis • Decreased visual acuity or red-green color discrimination [ADVENTISTHEALTH:INTERNAL] 47 Drug interactions • Rifamycins (Inducers) • Isoniazid (Inhibitors) • RIF + INH • Inductive effect of RIF outweigh inhibitory effect of INH • Fluoroquinolones [ADVENTISTHEALTH:INTERNAL] Adverse Reactions to TB Drugs 48 Adverse Reactions to TB Drugs Caused by Adverse Reaction Signs and Symptoms Significance of Reaction* INH Peripheral neuropathy • Tingling sensation in hands and feet Serious PZA Stomach upset • • • Stomach upset Vomiting Lack of appetite Serious Increased uric acid • Abnormal uric acid level Joint aches Gout (rare) • • [ADVENTISTHEALTH:INTERNAL] Not serious unless symptomatic table sugary 49 Baseline and F/U evaluations with first line TB Meds • Everyone • TB microscopic examination and mycobacterial culture (3 specimen in 8-24 hrs apart) • Every 2-month AFB smear and culture • Susceptibility testing for INH, RIF, and EMB • AST, bilirubin, alkaline phosphatase, SCR, PLT • EMB : acuity and color vision • Serologic test : IVDA, HIV, Birth in Africa or Asia • HIV infected patients : CD4 counts [ADVENTISTHEALTH:INTERNAL] Module 5 – Infectiousness and Infection Control 51 Infectiousness Infection Control • Patients can be considered non-infectious when • Important to understand difference between respirators and surgical masks • Clinicians : Respirators(N95 mask) protect individuals from inhaling droplet nuclei • Patient : Surgical masks stop droplet nuclei from being exhaled into air by infectious TB patients or suspects they meet all of the following criteria: a • Received adequate treatment for 2 weeks or longer 2 • Symptoms have improved 3 • 3 consecutive negative sputum smears from sputum collected in 8-24 hour intervals (at least one early morning specimen) • TB AII room • Rooms to prevent spread of droplet nuclei expelled by TB patient Omsk • At negative pressure relative to other from inside to [ADVENTISTHEALTH:INTERNAL] parts of the facility, and air from the room is exhausted directly to the outdoors or passed through a filter. 52 Patient Education • Cause of TB • TB transmission • Diagnosis of TB • Treatment Plan • How to take medication • Side effects to medication • Measures to prevent the spread (Infection control) Evaluating Response to Treatment Checking to see if the patient has continued symptoms of TB 2. Conducting bacteriologic examination of patient’s sputum or other specimens. Specimens should be examined at least every month until culture results have converted from positive to negative 3. Using Chest X-rays to monitor patients’ response to treatment 1. I TST and IGRAs CANNOT be used to determine whether a patient is responding to treatment [ADVENTISTHEALTH:INTERNAL] 59 Pregnancy • INH, RIF, EMB with Pyridoxine for 9 months • PZA : category C • Recommended by WHO, but no detailed data on teratogenicity. • It is not generally recommended for pregnant women in the United States • Streptomycin(SM) or AG : category D • Fetal nephrotoxicity, congenital deafness • Breastfeeding should NOT be discouraged [ADVENTISTHEALTH:INTERNAL] • TB in children can be rapidly fatal • Recommended duration of treatment is 6 months • Preferred anti-Tb regimen for children with active TB includes: • Initial phase • INH, RIF, PZA (No EMB: could not read alphabet) • Duration is for 2 months • Continuous phase • Daily INH and RIF • Duration is for 4 months