Diagnosis & management of tb in RNTCP


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  • DOTS is a systematic strategy for tuberculosis control. The five components of DOTS are political and administrative commitment, diagnosis primarily by microscopy of patients attending health facilities, regular supply of good quality anti-TB drugs, direct observation of treatment, and systematic monitoring and evaluation.
    Source: WHO. Framework for effective tuberculosis control. WHO/TB/94.179.
  • Directly observed treatment must be done by a person who is accessible and acceptable to the patient and who is accountable to the health system. Treatment observation is a service to patients and providers. Direct observation is recommended for all patients because many patients – at least a third – do not take medications regularly, even if excellent health education is done. Furthermore, it is not possible to predict which patients will take medicines. Non-adherence to treatment is common in all age, sex, race, educational, social, and religious groups. A patient’s extent of knowledge about his or her disease has minimal impact on drug-taking behaviour. This is demonstrated by the high proportion of health professionals who do not complete recommended treatment with even short courses of antibiotics.
    Source: See World Health Organization. Treatment of tuberculosis. Guidelines for national programmes. (Second Edition.) WHO/TB/97.220,1997.; also Fox W. The problem of self-administration of drugs: with particular reference to pulmonary tuberculosis. Tubercle 1958;39:269-274.; Fox W. Self-administration of medicaments. A review of published work and a study of the problems. Bull Int Union Tuberc 1961;31:307-331.; Sbarbaro JA. The patient-physician relationship: Compliance revisited. Annals of Allergy 1990;64:326-332; Iseman MD, Cohn DL, Sbarbaro JA. Directly observed treatment of tuberculosis---we can’t afford not to try it. N Engl J Med 1993;338:576-578.; CDC. Initial therapy for tuberculosis in the era of multidrug resistance. Recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR 1993;42(RR7):1-8.; Haynes RB, McKibbon KA, Kanai R. Systematic review of randomized trials of interventions to assist patients to follow prescriptions for medications. Lancet 1996;348:383‑386
  • Diagnosis & management of tb in RNTCP

    2. 2. DIAGNOSTIC APPROACH • Constitutional or generalized symptoms due to tuberculous toxemia: Low grade evening rise fever, anorexia, weight loss (slow & progressive), digestive disturbances, night sweats, fatiguability, weakness etc. • Pulmonary : Cough w or w/o Expectoration, shortness of breath, hemoptysis, chest pain. • Extra-pulmonary : Symptoms and signs as per affected system. CARDINAL SYMPTOM: Cough for 2 weeks or more
    3. 3. BACTERIOLOGICAL DIAGNOSIS 1) SMEAR - Examination 2) FNAC – from Lymph nodes, Abscesses 3) Biopsy - Incisional or Excisional biopsy Biopsy is more reliable.
    4. 4. Radiological Diagnosis • Difficult to interpret active or inactive lesions • Atypical presentation of HIV-TB co-infection • Inter and intra observer variation • Co-morbid respiratory illness • Expert radiologists always demand for clinical, bacteriological and serological correlation.
    5. 5. Extra pulmonary TB TB of organs other than lungs confirmed by bacteriological Or Histopathological confirmation Or Radiological evidence Or Strong clinical evidence
    6. 6. How to Diagnose EPTB • • • • • • Clinical Evaluation Radiological Histo-pathological Bacteriological Serological Biochemical Markers
    7. 7. Diagnosis of Paediatric TB • TB suspected if, the child has – Fever and/or cough for more than three weeks – With or without weight loss or no weight gain – History of contact with a suspected or diagnosed case of active TB in the last two years
    9. 9. RAPID DIAGNOSIS • A number of rapid assays have been developed where rifampicin resistance is used for presumptive diagnosis for MDR-TB. The rapid tests have decreased the time for diagnosing MDR-TB - L-J culture : 3-4 months - MGIT {currently the gold-standard for (DST)} : 3 to 4 weeks - FAST Plaque-Response : 2 days - Nucleic acid amplification technology : 8 hours or less - GenoType® MDRTB plus - INNO-LIPA Rif. TB • Three tests have proven efficacy and are commercially available, 1. INNO-LIPA Rif.TB kit (Innogenetics, Zwijndrecht, Belgium), 2. Geno Type® MDRTB plus assay (Hain’s Life science, GMBH, Germany). 3. FAST Plaque-Response test (Biotec Ltd, UK).
    10. 10. Reducing diagnostic delay in RNTCP DOTS-Plus Projected time to DST results by assay Specimen collection/delivery (7d) Molecular DST Processing (1d) MODS direct DST Initial culture MGIT culture/DST DST Return results (3d) LJ culture/DST 0 20 40 Days 60 80
    11. 11. RAPID DIAGNOSIS The new rapid assays have proven efficacy under controlled laboratory conditions, but available information about effectiveness under programmatic settings is on going at various places Information from the programmatic implementation of the test is required to -confirm the performance of the test in these settings, -Indicate how the test may be best applied and confirm the benefits (including financial) from implementation, -Identify constraints on implementation.
    12. 12. Projects in Pipeline – FIND (India) Product Sites Evaluation 1. Cellestis St. John’s Research Institute, Bangalore 2. Cepheid & Capilia TB Hinduja Hospital, Mumbai 3. Eiken LAMP assay JALMA Institute, Agra Demonstration 1. MGIT DST & MTB Speciation by Capilia LRS Institute, Delhi; STDC Ahmedabad; STDC Hyderabad 2. HAIN’S TEST- MTBDR plus STDC Ahmedabad; STDC Hyderabad; SMS Medical College, Jaipur; GHTM Thambaram; AIIMS; TRC Chennai 3. LED Fluorescence microscope CMC Vellore; other sites to be identified
    13. 13. Liquid culture (approved by WHO 2007) • M.tb grows rapidly in liquid culture – 15 days to obtain growth in liquid • Inhibitors need to be added to reduce growth of commensals • Liquid culture is more sensitive than solid culture • BSL level III and it requires Negative pressure system MGIT 960 uses fluorochrome tubes, which glow on depletion of oxygen, whereas MB/BacT detects CO2 production MGIT 960 approved by US FDA for culture & DST
    15. 15. MTBDR plus assay (Line Probe Assay) • Multiplex PCR DNA strip assay. • It is designed to detect mutant conferring H and R resistance. • Result within 8 hours. • rpo B, kat G and inh A. • For effectiveness and utility (EP), Confirmation of accuracy (DP) required.
    16. 16. Master-Mix (Pre PCR) room DNA EXTRACTION Amplification Hybridization
    17. 17. High tech in low tech settings: XpertTM MTB GeneXpert Automated Sample Prep, Amplification and Detection <120 minutes 2008 Development Evaluation in 5 trial sites 2010 2009 Demonstration in 15 microscopy centers STAG Access A technology platform:  TB & Rif Resistance  Potential for HIV viral load  Potential for … Challenges downstream: Meeting the target price
    18. 18. Integrated automated NAAT: Cepheid MTB / Rif-resistance test Major advantages in workflow • fully automated with 1-step external sample prep. • time-to-result 1 1/2 h (walk away test) • throughput: up to 16 tests / module / run • no bio-safety cabinet • closed system (no contamination risk) Performance • specific for MTB • sensitivity similar to culture • detection of rif-resistance via rpoB gene cartridge MTB
    19. 19. TRANSCRIPTION MEDIATED AMPLIFICATION • • • • It is based on RNA amplification. Very rapid Highly sensitive Further studies required for smear negative cases & Extra Pulmonary TB • Not recommended for the non-respiratory specimens.
    20. 20. Results of Different Methods –P D Hinduja National Hospital and Medical Research Centre, Mumbai Methods (N=139) Respiratory Sp. (N=94) Non-Resp. SP (N=45) Positive 64 (68%) 28 (62%) Negative 30 (32%) 17 (38%) Positive 74 (79%) 29 (64%) Negative 20 (21%) 16 (36%) Positive 75 (80%) 27 (60%) Negative 19 (20%) 18 (40%) Phage Assay (n=84) Resp. Sp. (44) Non-Resp. Sp. (40) Positive 32 (73%) 25 (63%) Negative 12 (27%) 15 (37%) L J method TB-BACTEC TMA
    21. 21. SERO DIAGNOSIS SEROLOGY  Antibody detection ( IgG, IgM, IgA )  Antigen detection  Immune complex Assays METHODS  Radioimmunoassay  Enzyme link Immuno Sorbant Assay.  Agglutination Test  Immunodiffusion Test.  Monoclonal Antibodies
    22. 22. SEROLOGY: TB • • • • • • IDEAL:INFECTION Vs DISEASE SENSITIVITY: Variable (30% to 65%) SPECIFICITY : Variable (20% to 48%) Can not asses Diseases Severity No values in MONITORING & PROGNOSIS CLINICAL INTERPRETATION: PUO with sero-positive value ?? • No proper study suggestive of cut of value –pos/neg • Only supportive value in Initial Diagnosis in NSN or EP TB
    23. 23. BIOCHEMICAL MARKERS • Fluid/Pus Analysis :- pleural, pericardial, ascitic, CSF, Synovial, Abscess - Protein level - Glucose level - TC and DC - ADA - LDH - Fluid smear for AFB and Culture • TUBERCULINE TEST: up to 40% adults are infected with TB infection,
    24. 24. GAMMA INTERFERON • LTBI – It detects accurately latent Tuberculosis infection with high sensitivity and specificity. • The Tb specific antigens, early secretary antigenic target 6(ESAT6) and culture filtrate protein 10 (CFP10), encoded by genes located within the region of difference segment of the M. tuberculosis genome are specific to TB.
    25. 25. GAMMA INTERFERON • It detects CMI response to TB infection. • TB specific antigen stimulates T-cells within a patient's whole blood sample • If previously exposed to M.Tuberculosis T-cells will secrete the cytokine interferon-gamma into the plasma • Measured by ELISA to indicate the likelihood of TB infection. ( Value > 0.35 IU/ml)
    26. 26. GAMMA INTERFERON • Useful in HIV infected individuals, childhood TB and Extra Pulmonary TB. LIMITATIONS • Storage time : < 16 hours and temperature 220c +/- 50c • M. kansasii, M. marinum and M.szulgai infections may show positivity.
    27. 27. MODS ASSAY FOR DIAGONOSIS OF TB • Microscopic Observation Drug Susceptibility (MODS) culture for the diagnosis and direct detection of MDR-TB. • It is faster and more sensitive than gold standard techniques. • It is inexpensive and more appropriate for the countries with limited resources. • A disadvantage is that requirement of inverted microscope which is not routinely available.
    28. 28. PIEZOELECTRIC IMMUNOSENSOR • A piezoelectric immunosensor was developed for detecting M.tuberculosis. • It is based on modified protein A and its specific binding with the antibodies. • It is rapid, sensitive, specific and inexpensive and can be easily set up in every publichealth laboratory. • This sensor was stable and reusable. • The study for immunosensor was carried out at Hunan university, Changhsa; results were good. Fengjiao He et al. ;2002:China
    29. 29. FIND deliverables for 3 levels of the health system Time to response LJ - 40d MGIT 15d MTBDR+ 1d Sensitivity Smear - 60% LED +10% LAMP+25% Xpert +40% Point of care Symptoms AG/AB Molecular Enose
    30. 30. Management of Tuberculosis Before 1940s Sanatorium based treatment and surgery ( collapse therapy ) 1940-60s Anti-TB drugs like SM, INH, PAS and TZN 1960-70s Conventional/Standard Chemotherapy up to 2 years 1972 – 92 Short course chemotherapy (6-9 months) 1993-2005 RNTCP Based on DOTS Strategy 2006 STOP TB STRATEGY and ISTC based on on DOTS & DOTS-Plus.
    31. 31. The Revised National Tuberculosis Program or RNTCP, is an application of the principles of DOTS to the Indian context
    32. 32. The 5 components of DOTS Political & admin. commitment Diagnosis by microscopy Adequate supply of the right drugs Directly observed treatment Accountability TB Register
    33. 33. Science of DOTS  Diagnosis of TB primarily based on sputum microscopy  Domiciliary treatment  Short course chemotherapy  Intermittent chemotherapy  Directly observed treatment
    34. 34. Drug action on TB bacillary population RIF INH RIF Extra-cellular rapidly multiplying ≥108 SM Extra-cellular slowly multiplying <105 EMB PAS Dormant No drugs No drug PZA Intra- and extracellular, acidic environment <105
    35. 35. Scientific basis of intermittent chemotherapy  Organism multiplication time (TB) is 18 hrs  24 hours maintenance of MIC not necessary.  Achievement of serum peak levels of all drugs simultaneously is essential.  Lag period exhibited by mycobacteria
    36. 36. Suitability and Science for Intermittent use • In vitro experiments have shown that when tubercle bacilli are exposed to a drug for a short-time (6-24 hrs.) and after careful removal of the drug, are transferred to a drugfree medium, the surviving bacilli may grow again after an interval of several days. • This interval is called “Lag period”.
    37. 37. Growth of M TB during & after exposure to H Log Viable Units of M TB INH added Lag phase INH washed References: Days • Dickinson JM, Mitchison DA. In vitro studies on the choice of drugs for intermittent chemotherapy of tuberculosis. Tubercle, 1966, 47: 370–380. • Canetti G, Grumbach F, Grosset J. Long-term, two-stage chemotherapy of advanced experimental murine tuberculosis with intermittent regimes during the second stage. Tubercle,1963, 44:236–240.
    38. 38. Lag in growth of M. Tuberculosis after temporary exposure to drugs * Depending on the pH of the medium (6.2 - 5.5) Ref. : K.T. Toman, WHO 1997
    39. 39. Why not once or twice a week? The risk of adverse effects increases with the length of the interval of intermittency. Thus, if treatment is taken only once a week, toxicity is high. - Toman’s Tuberculosis (WHO, 2002)
    40. 40. Treatment Regimens Cat I New smear–positive; 2(HRZE)3/ seriously ill smear negative; 4(HR)3 seriously ill extra-pulmonary Cat II Previously treated smear– positive (relapse, failure, treatment after default) Cat III New smear–negative and extra-pulmonary, not seriously ill 2(HRZES)3/ 1(HRZE)3/ 5(HRE)3 2(HRZ)3/ 4(HR)3 “Extension of CAT I or CAT II in CP can be decided by Concerned Specialists”
    41. 41. Drug Dosages of Anti TB Drugs DRUGS DOSAGES FORMULATION Inj. SM. 750 mg 1 vial Tab. INH 600 mg 300 mg*2 tablet Cap. RMP. 450 mg 1 Capsule Tab. EMB. 1200 mg 600 mg*2 tablet Tab. PZA. 1500 mg 750 mg*2 tablet
    42. 42. Paediatric Patient Wise Boxes 6 – 10 kg would require PC 13 11 – 17 kg would require PC 14 18 – 25 kg would require PC 13 + PC 14 26 – 30 kg would require PC 14 + PC 14
    43. 43. Drug Dosages of Anti TB Drugs: Paediatric Drugs PC 13 PC 14 No. of Tablets Pyrazinamide Tablet 250 mg 500 mg 1 Tablet Ethambutol Tablet 200 mg 400 mg 1 Tablet Isoniazid Tablet 75 mg 150 mg 1 Tablet Rifampicin Tablet 75 mg 150 mg 1 Tablet
    44. 44. Directly Observed Treatment Treatment observer must be accessible and acceptable to the patient and accountable to the health system
    45. 45. Directly Observed Treatment (DOT) vs DOTS  Directly observed treatment (DOT) is one element of the DOTS strategy  An observer watches and helps the patient swallow the tablets  Direct observation ensures treatment for the entire course  with the right drugs  in the right doses  at the right intervals
    46. 46. During the intensive phase of treatment each and every dose of medicine is to be taken under direct observation of the PHW or community volunteer; During Continuation phase, one of the three weekly doses should be directly observed
    47. 47. Management of MDR TB in RNTCP
    48. 48. MDR-TB: DIAGNOSTIC APPROACH • MDR-TB is a lab diagnosis, NOT a clinical one • Quality assured laboratory facility for culture and DST must be available • In Clinical practise, patient is failing to respond after optimum duration of first line ATT, Always the possibility of MDR TB Suspect rather than a MDR TB case Not all CAT II “failures” are MDR-TB cases i.e. a ”chronic” case is not always MDR-TB •
    49. 49. When To Suspect DR TB? • CLINICALLY : If patient has taken first line ATT for more than 5 month and shows no improvement or worsening of clinical signs and symptoms It should be investigated completely to rule out other etiology And if a case of Treatment Failure, by doing Culture & DST (Pus/Fluid or Tissue Specimens) one can know that patient is Mono, Poly, MDR TB or XDR TB (Laboratory Diagnosis)
    50. 50. DRUG RESISTANT TB • MDR-TB suspects – Category II cases who remain smear positive after 4 months of treatment or later – Failures of Cat I,II and III • • – Contacts of MDR-TB who found as smear positive TB in diagnosis MDR-TB is defined as resistance to isoniazid and rifampicin, with or without resistance to other anti-TB drugs. XDR-TB is defined as resistance to at least Isoniazid and Rifampicin (i.e. MDR-TB) plus resistance to any of the fluoroquinolones and any one of the second-line injectable drugs (amikacin, kanamycin, or capreomycin). •51
    51. 51. Patient flow under DOTS Plus MDR TB Suspect identified and sample sent to laboratory for diagnosis MDR Suspect Patient diagnosed as MDR TB Patient referred to DOTS PLUS Site for evaluation and initiation of treatment •Cat I and III failures •Cat II who remain smear + at 4 months or later • Smear + contacts of MDR cases Patient discharged to home district for daily ambulatory DOT Follow up Protocol • Smear and Culture monthly during IP and Quarterly during CP • Physical evaluation monthly during IP and Quarterly during CP • KFT and other investigations at regular intervals
    52. 52. MDR-TB and DOTS-Plus – – – – – – Rational treatment design (evidence-based) Standardized Treatment regimens (STR) Treatment regimen – • Include at least 4 drugs • Include an injectable in IP • Include at least 3 most active drugs in CP • have an IP of at least 6-9 and CP of 18 months Daily regimens - Directly observed therapy (DOT) ensuring long-term adherence Initial hospitalization for Pre-treatment Evaluation & initiation of Treatment Monitoring and Management of adverse reactions Adequate human resources
    53. 53. DOTS Plus Site – Gujarat DOTS Plus Site •Tertiary care Centre •Dedicated inpatient facility •Trained Staff available •Facilities for pre-Rx assessment & management of adverse reactions •1 per 10 million population
    54. 54. Treatment Strategies Standardized treatment No DST done (or DST only done to confirm MDR-TB). All patients in a patient group or category get the same regimen. Empiric treatment No DST done (or DST only done to confirm MDR-TB). Each regimen is individually designed based on patient history. Individualized treatment Regimen is designed based on patient history and DST. Standardized treatment Initially all patients in a certain group get the same regimen and it is then adjusted when DST results become available. Each regimen is individually designed based on patient history and then adjusted when DST results become available. followed by individualized treatment Empiric treatment followed by individualized treatment However, one treatment strategy does not fit for all
    55. 55. Grouping of Anti TB Agents Grouping Drugs Group 1: First-line oral anti-TB agents Isoniazid (H); Rifampicin (R); Ethambutol (E); Pirazinamide (Z) Group 2: Injectable anti-TB agents Streptomycin (S); Kanamycin (Km); Amikacin (Am); Capreomycin (Cm); Viomycin (Vm). Group 3: Flouroquinolones Ciprofloxacin (Cfx); Ofloxacin (Ofx); Levofloxacin (Lvx); Moxifloxacin (Mfx); Gatifloxacin (Gfx) Group 4: Oral second-line anti-TB agents Ethionamide (Eto); Prothionamide (Pto); Cycloserine (Cs); Terizadone (Trd); para-aminosalycilic acid (PAS); Group 5: Agents with Unclear role in Treatment of DR TB Clofazimine(cfz); Clarithromycin(Clr) Amoxacillin/Clavulanate(amx/clv); Thioacetazone(Thz); High Dose INH; Imipenem/Cilastatin(Ipm/Cln); Linezolide(lzd);
    56. 56. MDR TB:RNTCP Category IV Regimen RNTCP is using a Standardised Treatment Regimen (STR) for the treatment of MDR-TB cases under the programme by daily DOT. REGIMEN: 6 (9) Km Ofx Eto Cs Z E / 18 Ofx Eto Cs E Na PAS is a substitute drug for any one Bactericidal (Km, Oflo, Ethio, PZA) or Two bacteriostatic drugs (Cys, EMB) in case of ADRs
    57. 57. Drug Dosages and Formulation CAT IV Drugs Kanamycin Ofloxacin Ethionamide Ethambutol Pyrazinamide Cycloserine Na PAS 16-25 Kgs 26-45 Kgs >45 Kgs 500 mg 400 mg 375 mg 400 mg 500 mg 250 mg 5gm 500 mg 600 mg 500 mg 800 mg 1250 mg 500 mg 10 gm 750 mg 800 mg 750 mg 1000 mg 1500 mg 750 mg 12 gm
    58. 58. Treatment regimen • Standardized regimen- Cat IV – Intensive phase (6-9 months) • Km, Ofx*, Cs, Eto, Z, E – Continuation phase (18 months) • Ofx*, Cs, Eto, E – PAS is used a substitute drug – Three weight bands – • 3 monthly drug box 16-25 Kg ; 26-45 Kg and >45 Kg • Patients who remain culture + after 6 months of Rx are subjected to SLDST (Km and Ofx) – If found to be XDR will be started on Cat V regimen – Cm, Mx, Lzd, Amoxy-clav, Clofazimine, High H, PAS, Clarithromycin & Thiacetazone
    59. 59. XDR TB: Drug Dosages & Formulation CAT V Drugs Capreomycin INH Moxifloxacin PAS Linezolide Co- AmoxyClav Clofazamine ≤45 Kgs 750 mg 600 mg 400 mg 10 gm 600 mg 1250 mg BID 200 mg >45 Kgs 1000 mg 900 mg 400 mg 12 gm 600 mg 1250 mg BID 200 mg Clarithromycin Thiacetazone 500 mg BID 150 mg 500 mg BID 150 mg
    60. 60. CASE REPORT • A female patient 28 year, residing at Navsari, Gujarat, after her marriage on Immigration, she went to New Zealand. • She became chest symptomatic in January 2007 and her induced sputum was smear negative. • After all investigation, RUL infiltrate on CXR, in early March induced sputum showed culture positive TB and she was diagnosed as XDR-TB
    61. 61. MYCOBACTERIAL INVESTIGATIONS SPECIMEN / SITE: Induced Sputum STAINED FILM : No acid fast bacilli seen. CULTURE (1) Growth of Mycobacterium tuberculosis ** This isolate of M. tuberculosis complex is resistant to INH at a concentration of 0.1 and 0.4 mcg/ml. • (1) (1) Streptomycin R Isoniazid R Rifampicin R Ethambutol R Pyrazinamide S Ciprofloxacin R Clofazimine R Rifabutin S Capreomycin R Prothionamide S Amikacin R Cycloserine S P-aminosalicylic acid R Moxifloxacin R • • R = Resistant S = Sensitive I = Intermediate (1) Growth of Mycobacterium tuberculosis** • Mycobacterium tuberculosis causes a NOTIFIABLE DISEASE please notify the Medical Officer of Health by telephone (09) 623-4600 OR Fax (09) 630-7431 For notifications outside the Auckland region, please contact your local Medical Officer of Health. COMMENT Moxifloxacin MIC >0.2mg/L Signed out by : SANDIE NEWTON on 3 Apr 07 9:16 • • • •
    62. 62. CASE REPORT CONT. • She was put on Cys, Pth, Rifabutin and PZA at Auckland hospital. • After 4 months, she came to India and DTO and my self got reference from concerned authority. • Feed back was given by us and she was on Pth, PZA and Rifabutin as she developed Cys toxicity. • Letter on Dr. Cathy gave us reports after reconfirmation on five subculture turned out to be only H resistance and not a XDR-TB.
    64. 64. Treatment Challenges……. • Long duration, Toxic, expensive treatment – 2000 $ per patient course (1.5 Lacs rupees) • Daily ambulatory DOT – 6-9 months of injectables • Availability of DOTS Plus sites (1 per 10 million population) • Extensive training, supervision and monitoring needed at all levels • Ensuring treatment adherence • Ensuring timely follow up
    65. 65. Global Policy: MDR-TB and XDR-TB 1. 2. 3. 4. 5. 6. 7. 8. Strengthen basic TB and HIV/AIDS control, to avoid creation of MDR-TB and XDR-TB Scale-up programmatic management of MDRTB and XDR-TB Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB Expand MDR-TB and XDR-TB surveillance Introduce infection control, especially in high HIV prevalence settings Strengthen advocacy, communication and social mobilization (e.g., Response Plan) Pursue resource mobilization at global, regional and country levels Promote research and development into new diagnostics, drugs and vaccines
    66. 66. Is DOTS Essential?  DOTS is not the final answer There will be a better way! BUT  DOTS is the BEST strategy for controlling TB that we have BUT  The most contentious part of DOTS is DO