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  1. Tuberculosis
  2. MICROBIOLOGY Tuberculosis (TB) is caused by organisms of the Mycobacterium tuberculosis complex, which includes M. tuberculosis, the most common and important agent of human mycobacterial disease, and M. bovis, which (like several other mycobacterial species) is acquired via ingestion of unpasteurized milk. M. tuberculosis is a thin aerobic bacillus that is neutral on Gram’s staining but that, once stained, is acidfast; i.e., it cannot be decolorized by acid alcohol because of the cell wall’s high content of mycolic acids and other lipids.
  3. EPIDEMIOLOGY • An estimated 10.4 million new cases of TB occurred worldwide in 2016, with ∼1.7 million TBrelated deaths—almost entirely in lowincome countries. Globally, TB rates are stable or falling • Isolates of M. tuberculosis MDR and XDR are increasing in frequency • Disease from a pt with pulmonary TB is spread by droplet nuclei that are aerosolized by coughing, sneezing, or speaking. • Droplets <5–10 µm in diameter may be suspended in air for several hours. Transmission is determined by the intimacy and duration of contact with a pt with TB, the degree of infectiousness of the pt, and the shared environment. • Pts with cavitary or laryngeal disease are most infectious, with as many as 105–107 acidfast bacilli (AFB)/mL of sputum. • Risk factors for development of active disease after M. tuberculosis infection include recent acquisition (i.e., within the preceding 18 months), comorbidity (e.g., HIV disease, diabetes, silicosis, immunosuppression, gastrectomy), malnutrition, tobacco smoking, and presence of fibrotic lesions.
  4. PATHOGENESIS • AFB that reach alveoli are ingested by macrophages. The bacilli impair phagosome maturation, multiply, lyse the macrophages, and spread to regional lymph nodes, from which they may disseminate throughout the body. • These initial stages of infection are generally asymptomatic and induce cellular and humoral immunity. • About 2–4 weeks after infection, a tissuedamaging response resulting from delayedtype hypersensitivity (the basis for tuberculin skin testing [TST]) destroys nonactivated macrophages that contain multiplying bacilli, and a macrophageactivating response activates cells capable of killing AFB. A granuloma forms at the site of the primary lesion and at sites of dissemination. The lesions can then either heal by fibrosis or undergo further evolution. Despite “healing,” viable bacilli can remain dormant within macrophages or in necrotic material for years. • Cellmediated immunity confers partial protection against TB. Cytokines secreted by alveolar macrophages contribute to disease manifestations, granuloma formation, and mycobacterial killing.
  5. CLINICAL MANIFESTATIONS TB is classified as pulmonary, extrapulmonary, or both. Extrapulmonary TB may occur in 10–40% of patients, with even higher rates among HIVinfected patients. Pulmonary TB • •:Primary disease may cause no or mild signs and symptoms (fever and occasional pleuritic chest pain) in contrast to the prolonged disease course that is common in post primary or adulttype disease. • Primary disease is frequently located in the middle and lower lobes. The primary lesion usually heals spontaneously, and a calcified nodule (Ghon focus) remains. • Transient hilar and paratracheal lymphadenopathy is common. • In immunosuppressed patients and children, primary disease may progress rapidly to significant clinical disease, with cavitation, pleural effusions, and hematogenous dissemination (miliary disease). • •Postprimary (AdultType) Disease : Also referred to as reactivation or secondary TB(primary infection or reinfection). • It is usually localized to the apical and posterior segments of the upper lobes, where the substantially higher mean oxygen tension favors mycobacterial growth. • The extent of lung parenchymal involvement varies greatly, from small infiltrates to extensive cavitary disease. With cavity formation, liquefied necrotic contents are ultimately discharged into the airways and may undergo bronchogenic spread, resulting in satellite lesions within the lungs that may in turn undergo cavitation • Adulttype disease presents initially with nonspecific and insidious signs and symptoms, such as diurnal fever, night sweats, weight loss, anorexia, malaise, and weakness. • As the disease progresses, patients develop cough and purulent sputum production, often with blood streaking. Extensive cavitation may develop, with occasional massive hemoptysis following erosion of a vessel located in the wall of a cavity. • Extensive disease may produce dyspnea and sometimes ARDS. Physical findings are of limited use in pulmonary TB. Some pts might have detectable rales in the involved areas during inspiration, especially after coughing. Rhonchi due to partial bronchial obstruction and classic amphoric breath sounds in areas with large cavities may be heard. Systemic features include fever and wasting. In some recurrent cases and among people with low Karnofsky score, finger clubbing has been reported. • The most common hematologic findings are mild anemia, leukocytosis, and thrombocytosis with a slightly elevated ESR or CRP. Hyponatremia due to the syndrome of inappropriate secretion of antidiuretic hormone has also been reported.
  6. • Extrapulmonary TB • Any site in the body can be involved, but the most commonly affected sites are the lymph nodes, pleura, genitourinary tract, bones and joints, meninges, peritoneum, and pericardium. Up to two-thirds of HIV-infected patients with TB have extrapulmonary disease. • • Lymph node TB: Presents as painless swelling of the lymph nodes, most commonly at posterior cervical and supraclavicular sites (a condition historically referred to as scrofula). • – Lymph nodes are usually discrete in early disease but develop into a matted nontender mass over time; a fistulous tract draining caseous material may result. • – Fine-needle aspiration or surgical-excision biopsy of the node is required for diagnosis. Cultures are positive in 70–80% of cases. • –D/D includes neoplastic diseases such as lymphomas or metastatic carcinomas, and rare disorders like Kikuchi’s disease (necrotizing histiocytic lymphadenitis), Kimura’s disease, and Castleman’s disease. • • •Pleural TB: ∼20% of extrapulmonary cases. Isolated pleural effusion usually reflects recent primary infection, and the collection of fluid in the pleural space represents a hypersensitivity response to mycobacterial antigens. • Pleural disease may also result from contiguous parenchymal spread, as in many cases of pleurisy accompanying postprimary disease. Depending on the extent of reactivity, the effusion may be small, remain unnoticed, and resolve spontaneously or may be sufficiently large to cause symptoms such as fever, pleuritic chest pain, and dyspnea. • Physical findings are those of pleural effusion: dullness to percussion and absence of breath sounds. CXR reveals the effusion and can also show a parenchymal lesion. • Thoracentesis is required to ascertain the nature of the effusion. The fluid is straw-colored and at times hemorrhagic; it is an exudate with a protein concentration >50% of that in serum (usually ∼4–6 g/dL), a normal to low glucose concentration, a pH of ∼7.3 , and detectable WBC(usually 500–6000/μL). Neutrophils predominance in the early stage, lymphocyte predominates in later stage. Cultures often may be falsely negative for M.TB. Lysozyme is also present in the pleural effusion. Measurement of IFN-γ, can be diagnostically helpful. • Needle biopsy of the pleura is recommended over pleural fluid analysis; it reveals granulomas and/or yields a positive culture in up to 80% of cases. • This form of pleural TB responds rapidly to chemotherapy and may resolve spontaneously. glucocorticoid may reduce the duration of fever and/or chest pain but is not of proven benefit. • Tuberculous empyema is complication of pulmonary TB. It is result of the rupture of a cavity, with spillage of a large number of organisms into the pleural space. This process may create a bronchopleural fistula with evident air in the pleural space. CXR shows hydropneumothorax with an air-fluid level. The pleural fluid is purulent and thick and contains large numbers of lymphocytes. Acid-fast smears and mycobacterial cultures are often positive. Surgical drainage is usually required as an adjunct to chemotherapy. Tuberculous empyema may result in severe pleural fibrosis and restrictive lung disease. Removal of the thickened visceral pleura (decortication) is occasionally necessary to improve lung function.
  7. • TB of the Upper Airways : Always a complication of advanced cavitary pulmonary TB, TB of the upper airways may involve the larynx, pharynx, and epiglottis. Symptoms include hoarseness, dysphonia, and dysphagia in addition to chronic productive cough. Findings depend on the site of involvement, and ulcerations may be seen on laryngoscopy. Acid-fast smear of the sputum is often positive. Carcinoma of the larynx may have similar features but is usually painless. • • Genitourinary TB local symptoms predominate (e.g., urinary frequency, dysuria, hematuria, abdominal or flank pain), and up to 75% of patients have a CXR demonstrating previous or concomitant pulmonary disease. Disease is occasionally identified only after severe destructive lesions of the kidneys have developed. • In 90% of cases, urinalysis shows pyuria and hematuria with negative bacterial cultures. Culture of three morning urine specimens yields a definitive diagnosis in nearly 90% of cases. Mycobacterial culture of three morning urine specimens is diagnostic in 90% of cases. • In female patients, it affects the fallopian tubes and the endometrium and may cause infertility, pelvic pain, and menstrual abnormalities. In male patients, genital TB affects the epididymis, producing a tender mass that drain externally through a fistulous tract; orchitis and prostatitis may also develop. • In half of cases of genitourinary TB, UTI is also present Diagnosis requires biopsy or culture of specimens obtained by dilation and curettage.. Genitourinary TB responds well to chemotherapy.
  8. • •Skeletal TB: TB of the bones and joints is responsible for ∼10% of extrapulmonary cases. • Pathogenesis is related to reactivation of hematogenous foci or to spread from adjacent paravertebral lymph nodes. Weightbearing joints (spine in 40% cases,hips in 13%, knees in 10%) affected. • Skeletal TB responds to chemotherapy, but severe cases may require surgery • Spinal TB (Pott’s disease or tuberculous spondylitis) involves two or more adjacent vertebral bodies, the lower thoracic and upper lumbar vertebrae are usually affected in adults. With advanced disease, collapse of vertebral bodies results in kyphosis (gibbus). A paravertebral “cold” abscess may also form. In the upper spine, this abscess may track to and penetrate the chest wall, presenting as a soft tissue mass; in the lower spine, it may reach the inguinal ligaments or present as a psoas abscess. CT or MRI reveals the characteristic lesion and suggests its etiology. Aspiration of the abscess or bone biopsy confirms the tuberculous etiology, as cultures are usually positive and histologic findings highly typical. Complication of Pott’s disease is paraplegia,due to abscess or a lesion compressing the spinal cord. Paraparesis requires rapid drainage. • TB of the hip joints, usually involving the head of the femur, causes pain; TB of the knee produces pain and swelling. If the disease goes unrecognized, the joints may be destroyed. Diagnosis requires examination of the synovial fluid, which is thick in appearance, with a high protein concentration and a variable cell count
  9. • Tuberculous Meningitis and Tuberculoma :TB ofCNS is ∼5% of extrapulmonary cases. It is seen most often in young children but also develops in adults, especially those infected with HIV. • Tuberculous meningitis results from the hematogenous spread of primary or postprimary pulmonary TB or from the rupture of a subependymal tubercle into the subarachnoid space. • A miliary pattern is found on CXR. The disease often presents subtly as headache and slight mental changes after a prodrome of weeks of low-grade fever, malaise, anorexia, and irritability. If not recognized, tuberculous meningitis may evolve acutely with severe headache, confusion, lethargy, altered sensorium, and neck rigidity • Paresis of cranial nerves (ocular nerves in particular) is a frequent finding, and the involvement of cerebral arteries may produce focal ischemia. The ultimate evolution is toward coma, with hydrocephalus and intracranial hypertension. • Lumbar puncture is used for diagnosis. In general, examination of CSF reveals a high LC(up to 1000/μL), usually with a predominance of lymphocytes but sometimes with a predominance of neutrophils in the early stage; a protein content of 100–800 mg/dL; and a low glucose concentration. • Culture of CSF is diagnostic in up to 80% of cases and remains the gold standard. Real-time automated nucleic acid amplification (the Xpert MTB/RIF assay) has a sensitivity of up to 80% and is the preferred. Imaging studies (CT and MRI) may show hydrocephalus and abnormal enhancement of basal cisterns or ependyma. • If unrecognized, tuberculous meningitis is uniformly fatal. This disease responds to chemotherapy. Trials have demonstrated that patients given adjunctive glucocorticoids may experience faster resolution of CSF abnormalities and elevated CSF pressure, resulting in lower rates of death or severe disability and relapse. WHO now recommends that adjuvant glucocorticoid therapy with either dexamethasone or prednisolone, tapered over 6–8 weeks, should be used in CNS TB. • Tuberculoma, an uncommon manifestation of TB of the CNS, presents as one or more space- occupying lesions and usually causes seizures and focal signs.
  10. • Gastrointestinal TB: disease can affect any portion of the GI tract (with the terminal ileum and cecum most commonly involved), causing abdominal pain, obstruction, hematochezia, and often a palpable mass. TB peritonitis can follow spread of the organism from ruptured lymph nodes and intraabdominal organs; peritoneal biopsy is usually required for diagnosis. • Pericardial TB (Tuberculous Pericarditis) is characterized by an acute or subacute onset of fever, dull retrosternal pain, and sometimes a friction rub. Effusion is common. Chronic constrictive pericarditis is a potentially fatal complication, even in treated patients. Adjunctive glucocorticoids remain controversial; no conclusive data demonstrate a benefit. Mostly it is diagnosed post mortem. • Miliary or Disseminated TB: Miliary disease arises from hematogenous spread of M. tuberculosis throughout the body. Symptoms are nonspecific, and small (1- to 2-mm) granulomas may develop in many organs. Hepatomegaly, splenomegaly, lymphadenopathy, and choroidal tubercles of the eye may occur. Pancytopenia is seen which is rapidly fatal.
  11. • Less Common Extrapulmonary Forms TB may cause chorioretinitis, uveitis, panophthalmitis, and painful hypersensitivityrelated phlyctenular conjunctivitis. Tuberculous otitis is rare and presents as hearing loss, otorrhea, and tympanic membrane perforation. In the nasopharynx, TB may simulate granulomatosis with polyangiitis. Cutaneous manifestations of TB include primary infection due to direct inoculation, abscesses and chronic ulcers, scrofuloderma, lupus vulgaris , miliary lesions, and erythema nodosum. Tuberculous mastitis results from retrograde lymphatic spread, often from the axillary lymph nodes. Adrenal TB is a manifestation of disseminated disease presenting rarely as adrenal insufficiency. Finally, congenital TB results from transplacental spread of tubercle bacilli to the fetus or from ingestion of contaminated amniotic fluid. This rare disease affects the liver, spleen, lymph nodes, and various other organs. • HIV-Associated TB: TB is most common diseases among HIV-infected persons worldwide. TB is likely the main cause of death in this population. The manifestations of TB vary with the stage of HIV infection. When cell-mediated immunity is only partly compromised, pulmonary TB presents as typical upper- lobe cavitary disease. In late HIV infection, a primary TB-like pattern may be evident, with diffuse interstitial or miliary infiltrates, little or no cavitation, and intrathoracic lymphadenopathy. • –Extrapulmonary disease occurs frequently in pts of HIV; common forms include lymphadenitis, meningitis, pleuritis, pericarditis, mycobacteremia, and disseminated disease. • – Immune reconstitution inflammatory syndrome (IRIS), which may occur 1–3 months after initiation of antiretroviral therapy, may exacerbate the signs and symptoms of TB.
  12. DIAGNOSIS • Diagnosis is first evaluated when the CXR of a patient with respiratory symptoms is abnormal. If the patient has no complicating medical conditions that cause immunosuppression, the chest radiograph may show typical upper-lobe infiltrates with cavitation • Immunosuppressed patients, including those with HIV co-infection, may have “atypical” findings on CXR—e.g., lower-zone infiltrates without cavity formation—or interstitial disease only. • Diagnosis at primary level through traditional AFB microscopy, Diagnosis at a secondary level through realtime automated nucleic acid amplification technology (e.g., the Xpert MTB/RIF assay, which also allows detection of drug resistance), At a tertiary level molecular tests, rapid culture, and DST. • AFB microscopy of diagnostic specimens—can provide a presumptive diagnosis. In suspected pulmonary TB, two or three sputum samples should be examined. • Definitive diagnosis requires growth of M. tuberculosis in culture or identification of the organism’s DNA in clinical samples. – Liquid media and speciation by molecular methods have decreased the time required for diagnostic confirmation to 2–3 weeks (from 4 to 8 weeks). • Nucleic acid amplification is useful not only for rapid confirmation of TB in AFB-positive specimens but also for diagnosis of AFB-negative pulmonary and extrapulmonary TB. • Drug susceptibility can be assessed via indirect testing on solid media (which takes ≥8 weeks), direct testing in liquid media (which takes ∼3 weeks), or PCR (which can provide results within hours). • TST is the most widely used screening test for latent TB infection. • Interferon γ release assays (IGRAs) measure the release of interferon γ by T cells after stimulation with TB-specific antigens and are more specific for M. tuberculosis than is TST
  13. • NUCLEIC ACID AMPLIFICATION TECHNOLOGY: Several test systems based on amplification of mycobacterial nucleic acid are now the preferred first- line diagnostic tests. • Xpert MTB/RIF can simultaneously detect TB and rifampin resistance in less than 2hrs. WHO recommends its use worldwide as the first-line diagnostic test in all adults with signs or symptoms of active TB. • The newer Xpert MTB/RIF Ultra assay (Ultra), uses the same GeneXpert diagnostic platform (i.e., the “noise” produced by detection of DNA from nonviable bacilli) as positive with the greatest increases among smearnegative, culture-positive cases and among HIV-infected persons. • In the diagnosis of extrapulmonary TB, Xpert MTB/RIF and Ultra should be the initial test applied to CSF from patients in whom TB meningitis is suspected. • Truenat MTB and MTC Plus are two newly introduced rapid molecular tests. Truenat MTB-Rif Dx detects rifampin resistance with a sensitivity of 93% and a specificity of 95%. • New high-throughput automated platforms for TB diagnosis and drug- resistant variants are becoming available (Abbott RealTime MTB and RIF/INH, FluoroType MTBDR, BD Max MDR-TB). • The TB-LAMP assay: Another available molecular test for detection of M. tuberculosis is based on the loop-mediated isothermal amplification (LAMP) temperature-independent technology that amplifies DNA, is relatively simple to use, and is interpreted through a visual display
  14. • AFB MICROSCOPY: presumptive diagnosis is still commonly based on the finding of AFB on microscopic examination of a diagnostic specimen smear of sputum or tissue. • In this method light microscopy of specimens stained with Ziehl- Neelsen basic fuchsin dyes—is satisfactory, it is time consuming and operator dependent. The use of AFB microscopy in examining urine or gastric lavage fluid is limited by the low numbers of organisms, which can cause false-negative results, or the presence of commensal mycobacteria, which can cause falsepositive results. • MYCOBACTERIAL CULTURE: Definitive diagnosis depends on the isolation and identification of M. tuberculosis from a clinical specimen. Commercial liquid-culture systems such as the Mycobacterial Growth Indicator Tube (MGIT) system are recommended by the WHO as the reference standard for culture. MGIT cultures usually become positive after a period ranging from 10 days to 2–3 weeks. . A low-cost, rapid immunochromatographic lateral-flow assay based on detection of MTP64 antigen may also be used for species identification of the M. tuberculosis complex in culture isolates
  15. • DRUG SUSCEPTIBILITY TESTING: Universal DST is considered by the WHO as the current standard of care for all TB patients and should consist of DST to at least rifampin for all initial isolates of M. tuberculosis, as rifampin resistance is an excellent proxy for MDR-TB diagnosis. In addition, expanded and rapid susceptibility testing for isoniazid and key second-line anti-TB drugs (especially the fluoroquinolones and the injectable drugs) is mandatory when RR-TB is found. • Susceptibility testing may be conducted directly by molecular techniques (with the clinical specimen) or indirectly (with mycobacterial cultures) on solid or liquid medium. Results are obtained with reporting time of 3 weeks. • Apart from the Xpert MTB/RIF, Xpert MTB/RIF Ultra, and Truenat MTB-Rif Dx assays, which, as mentioned above, effectively detect rifampin resistance, the most widely used tests are molecular line probe assays (LPAs) for all regimens of TB treatment. • LPAs are a family of DNA stripbased tests capable of detecting bacterial DNA and identifying drug resistance-associated mutations. After extraction of DNA from M. tuberculosis isolates or from clinical specimens, the resistance gene regions are amplified by polymerase chain reaction (PCR), and labeled and probe-hybridized PCR products are detected by colorimetric development. This assay reveals the presence of M. tuberculosis as well as mutations in target resistance-gene regions.
  16. • RADIOGRAPHIC PROCEDURES: CXR is a rapid imaging technique used as a primary tool to detect pulmonary TB. CXR has high sensitivity but poor specificity. Suspicion of pulmonary TB is often based on abnormal CXR findings in a patient undergoing triage for respiratory symptoms. “classic” picture is that of upper-lobe disease with infiltrates and cavities, • CT is useful in interpreting questionable findings on plain CXR and in diagnosing some forms of extrapulmonary TB (e.g., intrabdominal disease, Pott’s disease). • MRI is useful in the diagnosis of bone lesions and intracranial TB. • DIAGNOSIS OF M. TUBERCULOSIS INFECTION: Two tests currently exist for identification of individuals with TB infection: the TST and IGRA, both of which measure host immunological response to TB antigens • Tuberculin Skin Testing : Components of M. tuberculosis in a concentrated liquid-culture medium(known as tuberculin purified protein derivative PPD) are capable of eliciting a skin reaction when injected subcutaneously into patients with TB. The skin test with tuberculin PPD (TST) is most widely used in screening for TB infection. It measures the response to antigenic stimulation by T cells that reside in the skin rather than the response of recirculating memory T cells. • IFN-γ Release Assays : These tests mainly measure the response of recirculating memory CD4+ T cells—normally part of a reservoir in the spleen, bone marrow, and lymph nodes—to persisting bacilliproducing antigenic signals.
  17. TREATMENT First-Line Agents • Rifampin: Rifampin is the most important and potent antituberculous agent. The standard dosage in adults is 600 mg/d. – The drug distributes well throughout body tissues, including inflamed meninges. It turns body fluids (e.g., urine, saliva, tears) red-orange and is excreted through bile and the enterohepatic circulation • Isoniazid: Isoniazid is a critical drug for active and latent TB disease. The usual adult dosage is 300 mg/d or 900 mg twice per week. Isoniazid is distributed well throughout the body and infected tissues, including CSF and body cavities. The most important toxicities are hepatotoxicity and peripheral neuropathy. Because peripheral neuropathy can result from interference with pyridoxine metabolism, pyridoxine (25–50 mg/d) should be given to patients with other risk factors for neuropathy, such as diabetes, alcohol abuse, or malnutrition. • Ethambutol: The least potent first-line agent, ethambutol is synergistic with the other drugs in the standard first-line regimen given at a dosage of 15 mg/kg daily. This agent can cause dose-dependent optic neuritis, producing central scotoma and impairing both visual acuity and the ability to see green. • Pyrazinamide: The usual dosage is 15–30 mg/kg daily (maximum, 2 g/d). In side effects: Hyperuricemia that can be managed conservatively is common. Second-Line Agents • Fluoroquinolones: Levofloxacin, gatifloxacin and moxifloxacin have solid, broad antimycobacterial activity. • Other agents (e.g., capreomycin, clofazimine, linezolid, carbapenems, bedaquiline) are used uncommonly but may be needed in disease caused by resistant strains of M. tuberculosis. Other Effective Agents • • Streptomycin: The usual adult dose is 0.75–1.0 g IM daily or 5 times per week. Streptomycin causes ototoxicity but is less nephrotoxic than other aminoglycosides. • • Rifabutin: Rifabutin has fewer drug interactions than rifampicin and is recommended in place of rifampicin for HIV-infected patients who are taking protease inhibitors or non-nucleoside reverse transcriptase inhibitors. Rifabutin reaches tissue concentrations 5–10 times higher than those in plasma and has a much longer half-life than rifampin. Adverse effects are gastrointestinal. • • Rifapentine: Rifapentine is similar to rifampin but can be given once or twice weekly. This drug is not approved for treatment in HIV-infected patients because of elevated rates of relapse.
  18. • Under NTEP initiation and sustaining all TB patients on appropriate anti-TB treatment wherever they seek care, with patient friendly system and social support. Provision of free TB drugs in the form of daily fixed dose combinations (FDCs) for all TB cases is advised with the support of directly observed treatment (DOT). • (DOT is a specific strategy, to improve adherence by any person observing the patient taking medications in real time. Screening of all patients for rifampicin resistance (and for additional drugs wherever indicated) is done. • For drug sensitive TB and For new TB cases, the treatment in intensive phase (IP) consists of eight weeks of Isoniazid (INH), Rifampicin, Pyrazinamide and Ethambutol (HRZE) in daily doses as per four weight band categories and in continuation phase three drug FDCs- Rifampicin, Isoniazid, and Ethambutol (HRE) are continued for 16 weeks. • For previously treated cases of TB: the Intensive Phase is of 12 weeks, where injection streptomycin is given for 8 weeks along with four drugs (INH, Rifampicin, Pyrazinamide and Ethambutol) and after 8 weeks the four drugs (INH, Rifampicin, Pyrazinamide and Ethambutol) in daily doses as per weight bands are continued for another four weeks. In continuation phase Rifampicin, INH, and Ethambutol are continued for another 20 weeks as daily doses. • The continuation phase in both new and previously treated cases may be extended by 12-24 weeks in certain forms of TB like skeletal, disseminated TB based on clinical decision. • Patients eligible for retreatment should be referred for a rapid molecular test or drug susceptibility testing to determine at least rifampicin resistance, and preferably also isoniazid resistance status. On the basis of the drug susceptibility profile, a standard first-line treatment regimen (2HRZE/4HR) can be repeated if no resistance is documented; and if rifampicin resistance is present, shorter regimen for MDR-TB (multi drug resistant TB) regimen should be prescribed according to WHO’s recent drug resistant TB treatment guidelines.
  19. • MDR/RR-TB TREATMENT Shorter oral Bedaquiline-containing MDR/RR-TB regimen • This regimen is recommended for those MDR/ RR-TB patients in whom resistance to the component drugs has been excluded or those who have not been previously treated for more than one month with second-line drugs used in shorter oral Bedaquiline-containing MDR/RR-TB regimen. • Total duration of shorter oral Bedaquiline-containing MDR/RR-TB regimen is for 9-11 months, depending on IP duration. • IP should be given for at least 4 months. After 4th month of treatment, if the result of sputum microscopy is negative then CP should be initiated with Bdq continued for another 2 months. • If sputum smear microscopy does not become negative by the 4th month of treatment, subject the patient to FL-LPA and SL-LPA and culture & DST and the IP should be extended. IP can be extended to 5th or 6th month based on smear results at the end of 4th and 5th month of treatment. This will be done for a maximum of 2 months (i.e., total duration of IP is not more than 6 months). • If any additional resistant to Z/Cfz on C&DST of the baseline sample is detected or to FQ/InhA & KatG mutation of the 4th month sample is detected, the patient needs to be reassessed at N/DDR-TBC for stopping shorter oral Bedaquiline-containing MDR/RR-TB regimen and initiation of longer oral M/XDR-TB regimen, immediately on receiving the report. • Duration of CP is fixed for 5 months.
  20. Longer oral Bedaquiline-containing MDR/RR-TB regimen • Longer oral M/XDR-TB regimen is recommended for MDR/RR-TB patients with H resistance detected with both KatG and InhA mutation; and MDR/RR-TB patients with FQ resistance detected in shorter oral Bedaquiline-containing MDR/RR-TB regimen. • This regimen is used also for XDR-TB patients. • Longer oral M/XDR-TB regimen is of 18-20 months with no separate IP or CP. • Once a patient is placed on a longer oral M/XDR-TB regimen for at least 4 weeks, normally that patient can no longer be switched to the shorter oral Bedaquiline-containing MDR/RRTB regimen because this 4-weeks treatment would represent an exposure to second-line medicines. • NTEP guidelines are to start with all 5 drugs of Group A and B and continue with 4 drugs in the latter part of the regimen (beyond 6-8 months) if the patient can tolerate the drugs. • GROUP A DRUGS: Levofloxacin, Moxifloxacin, Bedaquiline, Linezolid. • Group B drugs: Clofazimine and Cycloserine or terizidone.
  21. H mono/poly DR-TB regimen • H mono/poly DR-TB regimen (R resistance not detected & H resistance detected) • Under NTEP: H mono/poly DR-TB regimen is of 6 or 9 months with no separate IP/CP.
  22. TB preventive treatment(TPT)