Tuberculosis other mycobacterial infections II Prof Meral Snmezolu

Tuberculosis & other mycobacterial infections II Prof Meral Sönmezoğlu Division of Infectious Diseases Yeditepe University Hospital

Tuberculosis • Important new findings at the global level are: • The absolute number of TB cases has been falling since 2006 (rather than rising slowly as indicated in previous global reports); • TB incidence rates have been falling since 2002 (two years earlier than previously suggested); • Estimates of the number of deaths from TB each year have been revised downwards; • In 2009 there were almost 10 million children who were orphans as a result of parental deaths caused by TB.

Tuberculosis 2010 • In 2010, there were 8. 8 million (range, 8. 5– 9. 2 million) incident cases of TB, • 1. 1 million (range, 0. 9– 1. 2 million) deaths from TB among HIV-negative people and • an additional 0. 35 million (range, 0. 32– 0. 39 million) deaths from HIV-associated TB.

2012 • Incident case 8. 6 million • 1. 3 milion died from tb • 170. 000 MDR

2015 • There were an estimated 10. 4 million new (incident) TB cases worldwide, • of which 5. 9 million were men, • 3. 5 million were women and • 1 million were children. • People living with HIV accounted for 11% of the total • 1. 8 million people died from TB*, including 0. 4 million among people with HIV • 480. 000 MDR

Tuberculosis: current problems • About 3. 8 million cases per year; 90% (and 98% of the 3 million deaths) are in developing countries • Multidrug resistance (“MDR-TB”) • AIDS: atypical presentations and distribution • Nosocomial spread • Foreign-born

Millennium Development Goals set for 2015 Goal : Combat HIV/AIDS, malaria and other diseases Target: Halt and begin to reverse the incidence of malaria and other major diseases Indicator: Incidence, prevalence and death rates associated with TB Indicator: Proportion of TB cases detected and cured under DOTS Stop TB Partnership targets set for 2015 and 2050 By 2015: Reduce prevalence and death rates by 50%, compared with their levels in 1990 By 2050: Reduce the global incidence of active TB cases to <1 case per 1 million population per year

History of TB Scientific Discoveries in 1800 s • Until mid-1800 s, many believed TB was hereditary • 1865 Jean Antoine. Villemin proved TB was contagious • 1882 Robert Koch discovered M. tuberculosis, the bacterium that causes TB Mycobacterium tuberculosis

Robert Koch (March 24, 1882)

• on March 24, 1882, when he presented his findings at a monthly meeting of the Physiological Society of Berlin, he did so with clarity and elegant logic. The medical men present were dumbstruck by Koch’s address. So spellbound and conscious of the fact that they were witnesses to scientific history, the audience could not even applaud, let alone engage in the traditional scientific attack on another colleague’s work. • In the room that night was a 28 -year-old dermatologist named Paul Ehrlich, who ultimately achieved great fame as the discoverer of Salvarsan 606, the first “magic bullet” against syphilis. Ehrlich later recalled the evening as “the most gripping experience” of his scientific life, and as soon as the lecture was completed he rushed home to his makeshift laboratory, where he spent the night developing a novel staining technique for the tubercle bacillus (Ehrlich-Ziehl. Neelsen (EZN))

STOP TB World TB Day 24 th March 1882 when Dr Robert Koch astounded the scientific community by announcing that he had discovered the cause of tuberculosis, the TB bacillus Robert Koch, discoverer of the tubercle bacillus, concluded his Nobel Lecture on December 12, 1905

Prevalence of MDR Tuberculosis among New Cases of Tuberculosis, 2007, and Countries with at Least One Reported Case of XDR Tuberculosis as of December 2008 Donald P and van Helden P. N Engl J Med 2009; 360: 2393 -2395

TB & HIV CO-INFECTION • TB is the most common opportunistic infection in HIV and the first cause of mortality in HIV infected patients (1030%) • 10 million patients co-infected in the world. • Immunosuppression induced by HIV modifies the clinical presentation of TB : 1. Subnormal clinical and roentgen presentation 2. High rate of MDR/XDR 3. High rate of treatment failure and relapse (5% vs < 1% in HIV)

Key Components

Treatment 22 million lives were saved through the Stop TB Strategy, 1995 -2012. MDR-TB cases 450 000 people developed multidrugresistant tuberculosis (MDR-TB) in the world in 2012. Funding 2 billion US dollars per year needed to fill resource gap for implementing existing TB interventions.

TURKEY

Tuberculosis

Tuberculosis 2015 yılında 12. 772’ye düştü

Tuberculosis

Tuberculosis

• DSÖ Küresel Tüberküloz 2015 Raporu verilerine göre • Türkiye’nin 2014 yılı Tb insidans hızı yüz binde 18, prevalans hızı yüz binde 22 ve mortalite hızı yüz binde 0, 62’dir. • Ülkemizde tüberküloz hasta sayısı ve olgu hızı her yıl yaklaşık %6 -7 oranında azalmakta olup 2014 yılı toplam tüberküloz olgu hızı yüz binde 17, 2’dir.

• Toplam 13. 378 hastanın 7. 728’i (%58) erkek, 5. 650’si (% 42) kadındır. • Hastaların % 6’sı (809 kişi) yabancı ülke doğumlu hastadır. • Hastaların 8. 632’sinde (% 65) akciğer tüberkülozu varken, 4. 746’sında (%35) akciğer dışındaki organlar (lenf bezleri, plevra, kemik, böbrek, beyin vb. ) tutulmuştur.

Tuberculosis

Mycobacterium tuberculosis • MTB is a bacterium belonging to the Mycobacterium genus • Its identification is based on the following characteristics: shape of the colonies, growth rate, and biochemical reactivity. • subdivided in two main groups based on their growth rates (fast vs. slow)

Mycobacterium tuberculosis

Mycobacterium tuberculosis • Thick lipid coat of “Mycolic fatty acids” • Grows very slowly • Resists killing by macrophages and grows in them

Mycobacterium tuberculosis • The rapidly growing Mycobacterium species (Mycobacterium abscessus, M. fortuitum, M. porcinum), whereas the majority are nonpathogenic • Majority of the slowly growing Mycobacterium species are pathogenic for humans and/or animals (e. g. , all the species of the MTB complex [MTBC], M. leprae, M. ulcerans, M. avium), and only a few of them are nonpathogenic (e. g. , M. terrae, M. gordonae). • MTB complex: MTB (Koch, 1882), M. bovis (Karlsen and Lessel, 1970), M. africanum [25], M. microti (Reed, 1957), “M. canettii’

Mycobacterium tuberculosis • rod-shaped bacteria (0. 2– 0. 6 m wide, 1– 10 m long), nonmotile, nonencapsulated, Grampositive, • aerobes (growing most successfully in tissues with a high oxygen content such as lungs), or facultative anaerobes. • They are facultative intracellular pathogens, usually infecting mononuclear phagocytes (e. g. , macrophages).

Mycobacterium tuberculosis • An obligate aerobe: prefers P 02 of 130 torr • Replicates every 20 hours • Natural resistance to one drug is one in every 105 to 107 cells • Natural resistance to two or more drugs is 1 in every 109 to 1012 cells

Tuberculosis: the basics • The Mycobacterium tuberculosis complex: M. tuberculosis, M. bovis, M. africanum • Transmitted primarily by airborne droplet nuclei • Persons with positive AFB sputum smears are especially effective transmitters • Between 5% and 15% of infected persons will develop active disease (involving any organ) within two years

TB Transmission and Pathogenesis No infection (70%) Adequate Exposure Non-specific immunity Inadequate Infection (30%) Not everyone who is exposed to TB will become infected

Tuberculosis: the basics (2) • Populations at increased risk of infection: medically-underserved, low-income groups; immigrants; residents of long-term care or correctional facilities • Infected persons with increased risk of active disease: close contacts of cases; children < 5 years old; persons with chronic diseases (renal failure; silicosis; diabetes); immunosuppressed; HIV-positive persons

Immunology of tuberculosis • Tubercle bacillus + macrophages --> processed antigen • Antigen recognition by lymphocytes --> activated lymphocytes --> lymphokines • Lymphokines--> attraction, stimulation, and retention of macrophages at antigen site • Activated macrophages--> lytic enzymes with mycobactericidal but also tissue-necrosing capacity

Mycobacterium tuberculosis (MTB) enters the host within inhaled droplets.

Immunology of tuberculosis (2) • Interferon-gamma probably stimulates macrophages to produce interferon-alfa and 1, 25 -dihydroxyvitamin D, both of which are mycobacterial inhibitors • Cytokines secreted by alveolar macrophages: interleukin 1 (fever); interleukin 6 (hyperglobulinemia), and tumor necrosis factor alpha (killing of organisms, granuloma formation, fever and weight loss)

Primary tuberculous infection • Inhalation leads to infection at periphery of middle lung zone • Pneumonia 2 to 6 weeks after infection followed by lymphohematogenous dissemination • Cell-mediated immunity (manifested by positive PPD) usually contains the infection • Some organisms remain viable

Pathogenesis of tuberculosis

Reactivation of tuberculosis • Occurs most often in persons > 50 years of age; more common in men • Higher risk in elderly persons and in those with malnutrition, diabetes mellitus, post-gastrectomy, immunocompromise, alcoholism, HIV infection, or corticosteroid therapy

TB Transmission and Pathogenesis (2) No infection (70%) Adequate Exposure Non-specific immunity Inadequate Infection (30%) Early progression (5%) Inadequate Immunologic defenses Adequate Containment (95%)

Residua of primary infection • Ghon complex (after Anton Ghon, German bacteriologist): calcified peripheral focus of tuberculous infection with calcified regional (hilar) lymph node (also called Ranke complex) • Simon focus (after Georg Simon, German pediatrician): focus at apex of lung, containing viable organisms and manifested on x-ray as “fibrous cap”

TB Pathogenesis (1) Pathogenesis is defined as how an infection or disease develops in the body.

TB Pathogenesis (2) Latent TB Infection (LTBI) • Occurs when tubercle bacilli are in the body, but the immune system is keeping them under control • Detected by the Mantoux tuberculin skin test (TST) or by blood tests such as interferon-gamma release assays (IGRAs) which include: – Quanti. FERON®-TB Gold test (QFT-G) – Quanti. FERON®-TB Gold In-Tube (QFT-GIT) – T-Spot®. TB test (T-SPOT)

TB Pathogenesis (3) TB Disease • Develops when immune system cannot keep tubercle bacilli under control – May develop very soon after infection or many years after infection • About 10% of all people with normal immune systems who have LTBI will develop TB disease at some point in their lives • People with TB disease are often infectious

TB Transmission and Pathogenesis (3) No infection (70%) Adequate Exposure Non-immunologic defense Early progression (5%) Inadequate Infection (30%) Immunologic defenses Adequate Containment (95%) Late progression(5%) Inadequate Immunologic defenses Adequate Continued containment (90%)

TB Pathogenesis (4) Droplet nuclei containing tubercle bacilli are inhaled, enter the lungs, and travel to small air sacs (alveoli)

TB Pathogenesis (5) 2 Tubercle bacilli multiply in alveoli, where infection begins

TB Pathogenesis (6) A small number of tubercle bacilli enter bloodstream and spread throughout body

TB Pathogenesis (7) LTBI 4 • 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)

TB Pathogenesis (8) TB Disease 5 • 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

LTBI vs. TB Disease Latent TB Infection (LTBI) TB Disease (in the lungs) Inactive, contained tubercle bacilli Active, multiplying tubercle bacilli in the body 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 infectious Often infectious before treatment Not a case of TB A case of TB

Axioms on Simon foci • “If humans did not have apices to their lungs, the tubercle bacillus would not have survived as a human pathogen. ” • “Once a Simon focus has formed, one will eventually die of tuberculosis if something else doesn’t cause death first. ”

Caseous necrosis of tuberculosis • This walled-off, friable, cheesy nodule in the subapical region (a Simon focus) develops from organisms spread hematogenously from the initial focus of infection in the lower half of the lung. Reactivation of this lesion would probably destroy the capsule, and the caseous material would be expectorated leaving a cavity.

Tuberculous pleuritis non-necrotizing granulomas the Langhans' giant cells, the epithelioid cells, and the lymphocytes.

Progression to active tuberculosis • One year after infection: approximately 5% • Thereafter: approximately 5% (lifetime) • It now seems that many people eventually outlive their tubercle bacilli and are consequently vulnerable to reinfection (Stead, studies in Arkansas, early 1980 s) • Tuberculin-positive persons with HIV infection: risk is 7% to 10% per year

Insights from genotyping of M. tuberculosis isolates (N Engl J Med 2003; 349: 1149 -1155) • Previously, it was thought that 90% of TB cases in industrialized nations resulted from reactivation of infection acquired in remote past. • It now seems that recent transmission causes 40% to 50% of TB cases in urban areas.

The cavity (1) • Formation of the cavity is the pivotal event in the evolution of pulmonary tuberculosis. • Mortality of cavitary pulmonary tuberculosis without treatment approaches 90%. • All therapies prior to 1948 were aimed at closing cavities.

The cavity (2) • Even healed, cavities are unstable. • The walls of cavities contain extensive sheets of bacilli (up to 1011 bacilli/gram). • The cavity is thinnest at the point of penetration of bronchi. • Open cavities may persist for years, constantly draining bacilli into the rest of the bronchial tree.

Complications of pulmonary tuberculosis • Cough, fever, night sweats, weight loss, anemia • Massive hemoptysis (erosion of a vessel in the wall of a cavity; a dilated vessel in a cavity (Rasmussen’s aneurysm; or an aspergilloma) • Progressive pulmonary disease, rarely ARDS • Hyponatremia due to syndrome of inappropriate secretion of antidiuretic hormone (SIADH)

Major syndromes of extrapulmonary tuberculosis • Disseminated (miliary) tuberculosis • “Serosal” tuberculosis (anatomic spaces or cavities): pleurisy, pericarditis, meningitis, peritonitis, arthritis • Tuberculosis of solid organs: renal (genitourinary), osteomyelitis, adrenal glands (Addison’s disease), lymph nodes

Miliary tuberculosis: diagnostic aids • Repeat physical examination: choroidal tubercles, palpable lymph nodes • Repeat CXR and tuberculin test • Cultures: sputum (up to 63% positive), urine, bone marrow, CSF, gastric aspirate, pleural fluid • Biopsy: palpable nodes, marrow, liver • Therapeutic trial

“Cryptic miliary tuberculosis” • An occult illness with gradual decline in general health • Often no significant fever • Non-reactive tuberculin skin test • Normal chest x-ray

Frequency order of extrapulmonary sites 1. Lymph node 2. Pleura 3. Genitourinary tract 4. Bone and joints 5. Meninges 6. Peritoneum

Tuberculous pleurisy • Subpleural focus ruptures into the pleural space • Usually younger adults, 3 to 7 months after primary tuberculous infection • Abrupt or insidious onset. DDx: pneumonia, pulmonary infarct, tumor, others • Natural history untreated: 65% of 141 patients developed active tbc (Roper & Waring)

Tuberculous meningitis • Rupture of subependymal tubercle into subarachnoid space (“Rich focus”; Rich and Mc. Cormack, 1933) • The intrathecal tuberculin reaction (instillation of PPD material into CSF of PPD-positive volunteers) • Usually occurs within first 6 months of infection; now seen in older adults

Tuberculous pericarditis • Rupture of a tuberculous mediastinal lymph node into the pericardial sac • Mortality 80% to 90% without treatment. Major problems even with appropriate Rx • Diagnosis is difficult to make short of total pericardiectomy • Constrictive pericarditis • Can extend into myocardium --> fiber atrophy

Tuberculous peritonitis • Onset is usually insidious. Mortality 45% to 55% untreated but as low as 0% to 4% with treatment • Polar types: plastic or adhesive type (“doughy abdomen”) and exudative or serous peritonitis with ascites • Presentations: debilitating FUO; chronic abdominal pain; ascites of unknown origin

Tuberculous arthritis • Tuberculous focus in bone ruptures into joint space; trauma predisposes • Adults: spine 50%, hips 15% • Children: Knees 15% • Insidious joint pain and swelling, most often involving large weight-bearing joints • Absence of proteolytic enzymes explains preservation of joint space

Genitourinary tuberculosis • Tubercle of the glomerulus ruptures into the calyceal system • May progress to involve the entire kidney (“autonephrectomy”) and/or may spread throughout the GU tract (prostatitis, epididymitis, salpingitis) • Insidious onset

Tuberculous osteomyelitis § Subchondral osteoporosis with surrounding ring of sclerosis § Spine: anterior involvement of vertebral bodies with disk collapse (Pott’s disease) § Suspect: Monoarticular arthritis of insidious onset; paraspinous mass; back pain

Tuberculosis of the adrenal glands (Addison’s disease) • Tuberculosis formerly the major cause of the disease as described by Thomas Addison (now rare; most common cause is idiopathic [autoimmune]) • Wasting, hyperpigmentation, low blood pressure, hyponatremia, hyperkalemia

Tuberculosis in HIV-positive patients • Present in 5% to 35% of patients diagnosed with AIDS • Precedes diagnosis of AIDS in 67% of patients • Although most of these cases result from reactivation, CXR often resembles progressive primary tuberculosis • Multiple drug resistance a major problem

Diagnosis of TB Disease Medical Evaluation Bacteriologic Examination 109

Tuberculosis • Primary – Lung tubercles, caseous, tuberculin skin reaction • Secondary (reactivation) – Consumption: Coughing and chronic weight loss • Dissemination – Extrapulmonary TB (lymph nodes, kidneys, bones, genital tract, brain, meninges)

AFB smears • Three morning specimens • Fluorescent methods are more sensitive than traditional Kinyoun or Ziehl-Neelsen method • Predictive value of a positive test decreases strikingly as prevalence of the disease decreases (Bayes’ s theorem)

TB Skin Test

Tuberculin skin test guidelines • 5 mm for close contacts; for persons with compatible chest x-rays; and for HIV-infected persons • 10 mm for recently-infected persons, persons with high-risk medical conditions, and high-risk patients under 35 years of age • 15 mm for low-risk persons under age 35

Tubercule formation A tubercle in the lung is a “granuloma” consisting of a central core of TB bacteria inside an enlarged macrophage, and an outer wall of fibroblasts, lymphocytes, and neutrophils

Rapid laboratory confirmation • Fluorochrome smear on concentrated specimens • Rapid methods of detection: Bactec system; polymerase chain reaction • Rapid mechanisms of identification: DNA probes; HPLC • Rapid methods of susceptibility testing • Handle reports as critical laboratory values

Nontuberculous mycobacteria (NTM) • Synonyms: atypical mycobacteria, mycobacteria other than tuberculosis (MOTT), nontuberculous mycobacteria (NTM) • Numerous species; widespread • Can be difficult to treat • “MAC” = M. avium-intracelluare complex

Non tuberculos mycobacteria • M. avium Complex (MAC) • M. gordonae • M. haemophilum • M. immunogenum • M. malmoense • M. marinum • M. mucogenicum • M. chelonae • M. nonchromogenicum • M. scrofulaceum • M. fortuitum • M. simiae • M. smegmatis • M. szulgai • M. terrae complex • M. ulcerans • M. xenopi • M. kansasii • M. abscessus • M. genavense

Pulmonary disease due to NTM in immunocompetent persons • Isolation of organism from sputum does not necessarily imply disease • M. avium-intracelluare (especially in the Southeast) and M. kansasii (especially in the west) cause disease resembling tuberculosis (clinically milder but more difficult-to-treat)

Mycobacterium avium-intracelluare (“MAC”) in HIV disease • Disseminated “MAC” infection with or without pulmonary involvement • Prolonged fever, weight loss, hepatosplenomegaly, diarrhea, abdominal pain • Positive blood cultures; AFB also found in bone marrow, liver, and often stool

Lymphadenitis due to NTM • Usually due to M. scrofulaceum or M. avium-intracelluare • “Scrofula”: cervical lymphadenitis, usually in children • Usual treatment of choice: surgical excision without chemotherapy

Swimming pool and fish-tank granuloma • Caused by Mycobacterium marinum • Small violet nodule or pustule at the site of minor trauma may evolve into crusted ulcer or abscess • Multiple lesions can resemble lymphocutaneous sporotrichosis

Infections related to injections or surgery • “M. fortuitum complex”: Mycobacterium fortuitum, M. chelonae, M. abscessus (all “rapidly-growing mycobacteria”) • Opportunistic pathogens causing wound infections (which can be epidemic) and skin infections

Tuberculosis Elimination requires long antibiotic treatment with “cocktail” of antibiotics because of the resistance that develops.

What’s New? (1) • Provider/program responsibility for successful treatment, not the patient • Patient-centered case management with emphasis on directly observed therapy (DOT) • Evidence-based ratings of treatment options • Role of two-month sputum cultures to identify patients at increased relapse risk

What’s New? (2) • Extend treatment for patients with drugsusceptible pulmonary TB at increased risk for relapse • Role of new drugs (rifabutin, rifapentine, and fluoroquinolones) • Practical aspects of therapy: drug administration, fixed-dose combinations, adverse effects monitoring and management, and drug interactions

What’s New? (3) • Treatment completion defined primarily by number of doses ingested within specified time • Description of special treatment situations: – HIV/AIDS – Children – Extrapulmonary TB – Culture-negative TB – Pregnancy and breast feeding – Hepatic and renal disease

What’s New? (4) • Updated guidelines for management of drugresistant TB • Recommendations compared with those of the World Health Organization (WHO) and the International Union Against TB and Lung Disease (IUATLD); WHO DOTS strategy described • Current research status to improve treatment

Antituberculosis Drugs First-Line Drugs Second-Line Drugs • Isoniazid • Streptomycin • Rifampin • Cycloserine • Pyrazinamide • p-Aminosalicylic acid • Ethambutol • Ethionamide • Rifabutin* • Amikacin or kanamycin* • Rifapentine • Capreomycin • Levofloxacin* • Moxifloxacin* • Gatifloxacin* * Not approved by the U. S. Food and Drug Administration for use in the treatment of TB

Drug Abbreviations Ethambutol EMB Isoniazid INH Pyrazinamide PZA Rifampin RIF Rifapentine RPT Streptomycin SM

Role of New Drugs (1) • Rifabutin: For patients receiving medications having unacceptable interactions with rifampin (e. g. , persons with HIV/AIDS) • Rifapentine: Used in once-weekly continuation phase for HIV-negative adults with drug-susceptible noncavitary TB and negative AFB smears at completion of initial phase of treatment

Role of New Drugs (2) • Fluoroquinolones (Levofloxacin, Moxifloxacin, Gatifloxacin): Used when -first-line drugs not tolerated; -strains resistant to RIF, INH, or EMB; or -evidence of other resistance patterns with fluoroquinolone susceptibility

Factors Guiding Treatment Initiation • Epidemiologic information • Clinical, pathological, chest x-ray findings • Microscopic examination of acid-fast bacilli (AFB) in sputum smears • Nucleic acid amplification test (when performed)

When to Consider Treatment Initiation • Positive AFB smear • Treatment should not be delayed because of negative AFB smears if high clinical suspicion: – History of cough and weight loss – Characteristic findings on chest x-ray – Emmigration from a high-incidence country

Baseline Diagnostic Examinations for TB • Chest x-ray • Sputum specimens (= 3 obtained 8 -24 hours apart) for AFB microscopy and mycobacterial cultures • Routine drug-susceptibility testing for INH, RIF, and EMB on initial positive culture

Other Examinations to Conduct When TB Treatment Is Initiated (1) • Counseling and testing for HIV infection • CD 4+ T-lymphocyte count for HIV-positive persons • Hepatitis B and C serologic tests, if risks present

Other Examinations to Conduct When TB Treatment Is Initiated (2) • Measurements of aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, alkaline phosphatase, serum creatinine, and platelet count • Visual acuity and color vision tests (when EMB used)

Treatment Regimens • Four regimens recommended for treatment of culture-positive TB, with different options for dosing intervals in continuation phase • Initial phase: standard four drug regimens (INH, RIF, PZA, EMB), for 2 months, (except one regimen that excludes PZA) • Continuation phase: additional 4 months or (7 months for some patients)

Why Extend Continuation-Phase Treatment for 3 Months? • Cavitary disease and positive sputum culture at 2 months associated with increased relapse in clinical trials • Extended continuation phase decreased relapses in silicotuberculosis (from 20% to 3%)

When to Extend Continuation-Phase Treatment for 3 Months? • Cavitary pulmonary disease and positive sputum cultures at completion of initial phase • Initial phase excluded PZA • Once-weekly INH and rifapentine started in continuation phase and sputum specimen collected at the end of initial phase is culture positive • HIV-infected with positive 2 -month sputum culture

Algorithm to Guide Duration of Continuation. Phase Treatment for Culture-Positive TB Patients High clinical suspicion for active TB Place patient on initial-phase regimen: INH, RIF, EMB, PZA for 2 months NO Give continuationphase treatment of INH/RIF daily or twice weekly for 4 months Is specimen collected at end of initial phase (2 months) culture positive? YES

Algorithm to Guide Duration of Continuation. Phase Treatment for Culture-Positive TB Patients (Continued) NO NO Is the patient HIV positive? Give continuationphase treatment of INH/RIF daily or twice weekly for 4 months Was there cavitation on initial CXR? YES Give continuation-phase treatment of INH/RIF daily or twice weekly for 7 months Give continuationphase treatment of INH/RIF daily for 7 months

Treatment of Culture-Positive TB (1) (Rated: AI in HIV-negative, AII in HIV-positive patients) Initial Phase 2 months - INH, RIF, PZA, EMB daily (56 doses, within 8 weeks) Continuation Phase Options: 1) 4 months - INH, RIF daily (126 doses, within 18 weeks) 2) 4 months - INH, RIF twice / week (36 doses, within 18 weeks) 3) 7 months - INH, RIF daily (217 doses, within 31 weeks)* 4) 7 months - INH, RIF twice / week (62 doses, within 31 weeks)* * Continuation phase increased to 7 months if initial chest x-ray shows cavitation and specimen collected at end of initial phase (2 months) is culture positive

Common Adverse Reactions to Drug Treatment (1) Caused by Any drug Adverse Reaction Signs and Symptoms Allergy Skin rash Ethambutol Eye damage Isoniazid, Hepatitis Pyrazinamide, or Rifampin Blurred or changed vision Changed color vision Abdominal pain Abnormal liver function test results Fatigue Lack of appetite Nausea Vomiting Yellowish skin or eyes Dark urine

Common Adverse Reactions to Drug Treatment (2) Caused by Isoniazid Adverse Reaction Peripheral neuropathy Pyrazinamide Gastrointestinal intolerance Streptomycin Signs and Symptoms Tingling sensation in hands and feet Upset stomach, vomiting, lack of appetite Arthralgia Joint aches Arthritis Ear damage Gout (rare) Balance problems Hearing loss Ringing in the ears Kidney damage Abnormal kidney function test results

Common Adverse Reactions to Drug Treatment (3) Caused by Rifamycins Adverse Reaction Signs and Symptoms Thrombocytopenia Easy bruising • Rifabutin Slow blood clotting • Rifapentine Gastrointestinal intolerance • Rifampin Drug interactions Upset stomach Interferes with certain medications, such as birth control pills, birth control implants, and methadone treatment

Drug Interactions • Relatively few drug interactions substantially change concentrations of antituberculosis drugs • Antituberculosis drugs sometimes change concentrations of other drugs -Rifamycins can decrease serum concentrations of many drugs, (e. g. , most of the HIV-1 protease inhibitors), to subtherapeutic levels -Isoniazid increases concentrations of some drugs (e. g. , phenytoin) to toxic levels

TUS 2012 • Çocukluk döneminde akciğer dışı tüberkülozun en sık görülen şekli aşağıdakilerden hangisidir? • A) Tüberküloz menenjit B) Renal tüberküloz C) Tüberküloz lenfadenit D) Tüberküloz peritonit E) Tüberküloz perikardit

TUS 2012 • Tüberküloz enterit, bağırsakta en sık aşağıdaki lokalizasyonların hangisinde görülür? • A) Duodenum B) Proksimal-orta jejunum C) Sigmoid kolon ve rektum D) Transvers kolon E) Distal ileum ve çekum

TUS 2012 • Antitüberküloz tedavi alan bir hastada gelişen hepatotoksisiteden sorumlu olma ihtimali en az olan ilaç aşağıdakilerden hangisidir? • A) Rifampisin • B) İzoniazid • C) Etambutol • D) Pirazinamid • E) Rifabutin

TUS 2012 • Aşağıdaki hastalıklardan hangisinde kapalı plevral biyopsinin tanı değeri en yüksektir? • A) Tüberküloz plörezisi B) Romatoid artrite bağlı plörezi C) Şilotoraks D) Parapnömonik efüzyon E) Asbest’e ikincil efüzyon

TUS 2013 • Aşağıdaki tüberküloz ilaçlarından hangisinin kullanımı sırasında konvülsiyon gelişebilir? • A) Rifampin B) Pirazinamid C) Streptomisin D) İzoniazid E) Etambutol

• Among the traditional forms of first-line antituberculosis therapy, isoniazid is most often associated with nervous system effects, most prominently peripheral neuropathy, psychosis and seizures. • Adverse events are reported with other antituberculosis therapies, the most prominent being optic neuropathy with ethambutol and ototoxicity and neuromuscular blockade with aminoglycosides. • The second-line agent with the most adverse effects is cycloserine, with psychosis and seizures, the psychosis in particular limiting its usage. Fluoroquinolones are rare causes of seizures and delirium.