Brief presentation on recent guidelines for treating skeletal TB

1. Management of Osteoarticular
tuberculosis
Presenter : Dr Savan (JR)
Moderator : Dr Syed Ifthekar (Asst. Prof)

2. Strategic Framework to END TB in India
• PILLAR 1: B U I L D, S T R E N G T H E N A N D S U S T A I N A N
E N A B L I N G E N V I R O N M E N T F O R T B E L I M I N A T I O N
Build, strengthen and sustain enabling policies, empowered institutions,
multi-sectoral collaborations, engaged communities, and human
resources with enhanced capacities to create a supportive ecosystem
which accelerates PREVENT – DETECT – TREAT

3. PILLAR 2: P R E V E N T
Prevent the emergence of TB in susceptible populations using a combination of
biomedical, behavioural, social and structural interventions.
S T R A T E G I C A R E A
Access to shorter and effective TB Preventive Treatment (TPT) and
Programmatic management of LTBI
Scale up TB - infection control (TB-IC) measures at home, community, and
health care facilities

4. PILLAR 3 : D E T E C T A L L
Early identification of presumptive TB, at the first point of contact be it private or
public sectors, and prompt diagnosis using high sensitivity diagnostic tests to
provide universal access to quality TB diagnosis including drug resistant TB in the
country.
S T R A T E G I C A R E A
Scale-up free, high sensitivity TB diagnostic tests and algorithms
Intensify TB case finding efforts amongst all programmes within the
MOHFW and other ministries

5. PILLAR 4 : TREAT ALL
S T R A T E G I C A R E A
Strengthen treatment of DSTB
Expand treatment and management of DRTB
Address TB in priority populations
Strengthen and expand coverage of patient support systems

6. Objectives of NTEP
• To achieve 90% notification rate for all cases.
• To achieve 90% success rate for all NEW and 85% success rate for retreatment cases.
• Improve outcome of treatment for DR-TB cases.
• To achieve decreased morbidity and mortality for HIV associated TB cases.
• To improve outcome of TB care in private sector.

7. TERMINOLOGIES
1.) New Case –
never taken treatment before or taken treatment for <1 month duration.
2.) Previously Treated Case –
patients who have received 1 month or more of TB treatment in past.
3.) Recurrent TB –
completed course of treatment/declared cured & now presenting as
microbiologically confirmed case.

8. TERMINOLOGIES (cont…)
4.) Treatment after failure –
treated for TB & treatment failed at end of most recent course of
treatment.
5.) Treatment after loss to follow up –
treated >1month on ATT & registered as loss to follow up & now
presenting as microbiologically confirmed case of TB
6.) Transferred IN –
received in TB unit after having registered in another TB unit for
treatment.

9. TERMINOLOGIES (newer ones in NTEP)
1.) Presumptive TB case in place of TB suspect –
*person with cough >2 weeks duration
*individual having fever or night sweats for >2 weeks
*contacts of smear positive TB patients having cough for any duration
*suspected / confirmed extra pulmonary TB having cough of any
duration
2.) Bacteriologically Confirmed Case in place of sputum positive TB
3.) Clinically Diagnosed TB Case
diagnosed with active TB by a clinician & decided to be given full course
of TB treatment, NOT bacteriologically confirmed.

10. Diagnosis and Investigations
1.) Roentgenogram
AP & lateral views & X-ray of the chest are mandatory.
Localized osteoporosis – 1st radiological sign of active disease
Articular margins & bony cortices become hazy

11. Thickened synovium, capsule & pericapsular tissues cause a soft tissue swelling.
Involvement of articular cartilage - joint space seen on X-rays.
Collapse of bone, subluxation/ dislocation, migration & deformity of joint.

12. 2.) Blood
A relative lymphocytosis, low hemoglobin, & raised ESR rate in active stage of disease.
3.) Mantoux (Heaf) Test
4.) Biopsy
5.) Smear and Culture
6.) Isotope Scintigraphy
7.) Modern Technologies – CT scan/MRI

13. DETECTION of TB
(Recent Advances in Detection of TB)
1.) CBNAAT (aka Gene Xpert) – DNA based technology
offered to any person with cough for >2 weeks
duration at baseline to rule out rifampicin resistance.
(Earlier CBNAAT was offered only to PLHIV/paediatric
contact cases/contacts of DRTB/recurrent TB cases)
False Positive results – contamination or error in testing process/cross reactivity with non TB
mycobacteria
False Negative results – low bacterial load below LOD (130 CFU/ml)/technical errors while
testing

14. On completion of a test run, the Cartridge-based Nucleic Acid Amplification Test (CBNAAT) gives the
following results:
1.MTB DETECTED; Rif Resistance DETECTED
2.MTB DETECTED; Rif Resistance NOT DETECTED
3.MTB DETECTED; Rif Resistance INDETERMINATE
4.MTB NOT DETECTED
5.Error
6.Invalid
7.No result
Conclusive results include:
MTB NOT DETECTED, MTB DETECTED
with Rif Resistance/ without Rif
Resistance.
Non-conclusive results include:
MTB Detected, Rif Resistance
Indeterminate, Errors, Invalid and No
Result - the test has to be repeated in
these cases.

15. The Cartridge-based Nucleic Acid Amplification Test (CBNAAT) test has some limitations such as:
1. load below LOD ~ 130 CFU/ml result in false-negative result.
2. on anti-TB regimen can have positive results due to killed bacilli in specimen.
3. positive test result does not indicate presence of viable organisms.

16. 4. result affected by anti-TB medication, therapeutic success or failure cannot be
assessed by test.
5. Mutations or polymorphisms in primer or probe binding regions may affect the
detection of new or unknown MDR or Rif-resistant strains, resulting in a false-
negative result.
6. modification in sample processing - alter performance of test.

17. Results of CBNAAT
Xpert MTB/RIF cartridge includes reagents for detection of MTB complex & RIF resistance as
well as a sample processing control (SPC).
SPC controls adequate processing of the target bacteria & monitors presence of inhibitor(s) in
the PCR reaction.
Probe Check Control (PCC) verifies:
reagent rehydration
PCR tube filling in cartridge
probe integrity
dye stability

18. SPC should be positive in a negative sample & can be negative or positive in a positive sample.
Test result will be "Invalid" if the SPC is not detected in a negative test.
Before start of PCR reaction, the GeneXpert Dx System measures the fluorescence signal from
the probes to monitor bead rehydration, reaction-tube filling, probe integrity and dye stability.
PCC passes if fluorescence signal from the probes meets assigned acceptance criteria.
Results are interpreted by the GeneXpert Dx System from measured fluorescence signals &
embedded calculation algorithms & are displayed in the View Results window.

19. MTB Detected:
MTB target DNA is detected.
Both controls, SPC and PCC, meet the assigned acceptance criteria.
Lower Ct values represent a higher starting concentration of DNA template.
Higher Ct values represent a lower concentration of DNA template.
In MTB DETECTED results "RIF Resistance DETECTED" ,"RIF Resistance NOT DETECTED" or "RIF
Resistance INDETERMINATE" will display on a separate line.

20. MTB detected
Rif Resistance not detected
MTB detected
Rif Resistance detected

21. MTB Not Detected:
MTB target DNA is not detected.
Both controls, SPC and PCC, meet the assigned acceptance criteria

22. Invalid:
Presence or absence of MTB cannot be determined:
SPC does not meet acceptance criteria, i.e. the sample was not properly processed, or PCR
was inhibited. Note:
repeat test with extra specimen.

23. Error:
One or more of the PCC results failed (FAIL).
Both MTB and SPC display NO RESULT.
repeat test with extra specimen.
If PCC passed (PASS), the error is caused by a system component failure.

24. 2.) Line Probe Assay (LPA)
offered at baseline to all previously treated TB patients to rule out both
rifampicin and isoniazid resistance.
FL-LPA : to r/o isoniazid resistance
SL-LPA : to r/o rifampicin resistance

25. Mycobacteria Growth Indicator Tube (MGIT)
• Intended for the detection and recovery of mycobacteria.
• Contains 7 mL of modified Middlebrook 7H9 Broth base.
• One of the most commonly used liquid media for the cultivation of mycobacteria.
• All types of clinical specimens, pulmonary as well as extra-pulmonary
(except blood and urine), can be processed.

26. Interferon-Gamma Release Assays (IGRAs)
• whole-blood tests that can aid in diagnosing Mycobacterium tuberculosis infection.
• do not differentiate latent tuberculosis infection (LTBI) from tuberculosis disease.
• Two types of IGRAs that have been approved are QuantiFERON-TB Gold In-Tube test (QFT-GIT) and T-
SPOT.
• IGRAs measure a person’s immune reactivity to M. tuberculosis.
• White blood cells from most persons that have been infected with M. tuberculosis will release
interferon-gamma (IFN-g) when mixed with antigens derived from MTB.
• To conduct the tests, fresh blood samples are mixed with antigens and controls.

28. Advantages of IGRAs
require single patient visit to conduct test,
results available within 24 hours,
do not boost responses measured by subsequent tests,
prior BCG vaccination does not cause a false-positive IGRA test result.

29. Disadvantages & limitations of IGRAs
blood samples must be processed within 8-30 hours after collection while white blood
cells are still viable,
errors in collecting or transporting blood specimens or in running and interpreting the
assay can decrease accuracy of IGRAs,
limited data on use of IGRAs to predict who will progress to TB disease in future,
limited data on use of IGRAs for children younger than 5 years of age.

30. Classification Based on Resistance
1.) Mono resistant – resistant to one 1st line anti TB drug.
2.) Poly Drug Resistant – resistant to more than one 1st line anti TB drug
except Rifampicin.
3.) Rifampicin Resistant – resistance to rifampicin with or without resistance
to other drugs.
Patients with rifampicin resistance have to managed as MDR TB case.

31. 4.) MDR TB – resistance to both isoniazid and rifampicin.
5.) XDR TB – resistance to
* isoniazid + rifampicin
* any one fluoroquinolone
* any one 2nd line injectable
(kanamycin/amikacin/capreomycin)
NEW classification of XDR TB as per NSP 2020-25
MDR/RR TB + any one fluoroquinolone + atleast one Group A drug
Group A drugs – levo/moxifloxacin, bedaquilline, linezolid
Group B drugs – cycloserine/terizidone, clofazimine
Group C drugs – ethambutol, pyrazinamide, ethionamide, amikacin, delamanid, etc

32. 6.) Presumptive MDR
*currently on ATT, but poor response (no clinical improvement or sputum positive on 3rd or 5th
month of follow up)
*any contact of MDR case
7.) Recurrent Case
*cured after ATT but now microbiologically confirmed case of TB
*Relapse of TB is no longer a used terminology.

33. Types of the Skeletal TB
1. Caseous exudative :
more destruction, more exudation & abscess formation.
onset is less insidious,
constitutional symptoms & local signs of inflammation & swelling are more marked,
abscess & sinus formation common
2. Granular type :
less destructive,
insidious onset & course,
abscess formation is rare.
Its classical example is that of caries sicca of shoulder.

34. CATEGORIES for TB Management
1.) Category I – New & previously treated cases.
2.) Category IV – MDR TB
3.) Category V – XDR TB

35. TREATMENT OF TB
FIRST LINE
1. Isoniazid (H)
2. Rifampicin (R)
3. Pyrazinamide (Z)
4. Ethambutol (E)
5. Streptomycin (S)
SECOND LINE
1. Fluoroquinolones – ofloxacin, levofloxacin,
moxifloxacin, ciprofloxacin
2. Oral Drugs –
ethionamide, prothionamide, cycloserine,
PAS, rifabutin, thiacetazone, terizidone
3. Injectable drugs –
kanamycin, amikacin, capreomycin

36. NEWER DRUGS
1.) BEDAQUILINE :
i) MOA – inhibits mycobacterial ATP synthase.
ii) Food increases absorption of Bedaquiline
iii) Shows cross resistance with clofazimine.
iv) Used in treatment of XDR-TB
v) S/E – GI toxicity, hyperuricemia, hepatotoxicity, QT prolongation

37. NEWER DRUGS (cont…)
2. DELAMANID & PRETOMANID
> act by inhibiting mycolic acid
> S/E – QT prolongation
> Pretomanid is a prodrug that requires activation by bacteria.
3. TEDUZOLID & SUTEZOLID – derivatives of Linezolid

38. ATT for Osteoarticular TB
2 months of intensive phase with 4 drugs to be taken daily – 2(HRZE)
10 months of continuation phase with 3 drugs to be taken daily – 10(HRE)
Total duration of 12 months, which can be maximally extended upto 18 months.
No extension of Intensive Phase as per new guidelnes.

39. Dosage
• Isoniazid : 3-8 mg/kg/day
• Rifampicin : 10 mg/kg/day
• Pyrizinamide : 35 mg/kg/day
• Ethambutol : 2.5 mg/kg/day in IP followed by 15 mg/kg/day in CP
In chidren, Ethambutol is replaced by Streptomycin as the former causes Optic
Neuritis.

40. Ceiling dose of Isoniazid
varies depending on condition being treated the patient’s weight.
treatment of latent tuberculosis infection in adults weighing more than 30 kg - 300 mg taken
orally once a day for 9 months.
treatment of active tuberculosis disease - 5 mg/kg taken orally or intramuscularly once a day
(not to exceed 300 mg per day).
Alternatively - 15 mg/kg, not to exceed 900 mg, can be taken orally or intramuscularly one to
three times per week.

41. REGIMEN CLASS INTENSIVE PHASE CONTINUATION PHASE
Drug sensitive TB (2) HRZE, FDC daily (4) HRE, FDC daily
Isoniazid Resistant (6) ZERO -
Shorter MDR regimen (4-6) CHOBZEE
Clofazimine, high dose isoniazid,
moxifloxacin, bedaquiline,
pyrazinamide, ethambutol,
ethionamide
(5) COZE
Clofazimine, moxifloxacin,
pyrazinamide, ethambutol
Conventional MDR regimen (6-9) levofloxacin, cycloserine,
kanamycin, ethionamide,
ethambutol, pyrazinamide
(18) levofloxacin, ethionamide,
cycloserine
DRUG REGIMEN

42. FIXED DOSE COMBINATION
Adults : Children :
1 FDC contains - 1 FDC contains -
H : 75mg H : 50mg
R : 150mg R : 75mg
Z : 400mg Z : 150mg
E : 275mg E is given separately
as per age of the child
In Intensive Phase - (2) HRZE, i.e 56 FDC tablets in total
In Continuation phase – (4) HRE, i.e 112 FDC tablets in total

43. Summary of Regimens
1.) Category 1 : 2HRZE + 4HRE
2.) Shorter MDR Regimen : (4-6) Mfx, Km, Eto, Cfz, Z, Hh, E
(5) Mfx, Cfz, Z, E
3.) Conventional MDR Regimen : (6-9) Lfx, Km, Eto, Cs, Z, E
(18) Lfx, Eto, Cs

44. 4.) INH Resistance – (6) Z, E, R, O
5.) Conventional XDR Regimen – (6-12) Cs, PAS, Mfx, H, Cfz, Lzd, Amx/Clv
(18) PAS, Mfx, H, Cfz, Lzd, Amx/Clv
6.) New XDR Regimen – BPaL : Bedaquilline, Pretomanid, Linezolid
Post Treatment follow-up screening at 6, 12, 18, 24 months
Summary of Regimens (cont…)

45. Dosage in BPaL Regimen
Pretomanid : 200mg once daily for 26 weeks
Bedaquilline : 400mg once daily for first 2 weeks f/b 200mg thrice a week for 24 weeks
Linezolid : 1200mg once daily for 24 weeks
(after 1 month, dose & duration modification for linezolid is permissible – with an option to
extend treatment to 39 weeks if patient was culture positive at week 1)

46. Inclusion Criteria for Bedaquilline/Delamanid
1. Aged > 6 years with MDR/RR/XDR TB
2. Non pregnant females
3. Well controlled arrhythmia & no cardiac disease
Exclusion criteria for Bedaquilline/Delamanid
1. Conduction abnormality
2. Prolonged QT
3. Heart failure, hypokalemia, family h/o long QT syndrome

47. ATT IN LIVER DISEASE

53. Chemoprophylaxis
Infants & children staying in contact with infected mother or attendants.
Isoniazid - 5 mg/kg/wt daily, for 6 months OR
Isoniazid & ethambutol for 4 to 6 months OR
Rifampicin & Isoniazid for 3 to 6 months

54. Prophylactic chemotherapy for:
• Close-contacts TB patient
• Positive tuberculin test with abnormal chest X-ray
• Tuberculin skin test converters at any age
• Tuberculin skin test reactors younger than 35 years

55. NEW INITIATIVES IN NTEP (NSP 2020-25)
1.) Nikshay Poshan Yojna :
*nutritional incentive of Rs 500/month for notified TB patients.
*In tribal areas Rs 750/month.
2.) Incentive for DOTS providers – on successful completion of treatment
i) New & previously treated TB patient : Rs 1000/-
ii) MDR & XDR TB : Rs 5000/- (2000/- on IP & 3000/- on CP)
3.) Incentive given to private paractitioners on notification of a case of TB is
Rs 500/-
Incentive given to private practitioner on completion of treatment is Rs
500/-

56. NEW INITIATIVES IN NTEP (NSP 2020-25)
(cont…)
4.) Number of days within which private practitioner has to notify a case of TB is 30 days.
If failed to do so , punishable under IPC 269/270.
5.) Daily DOTS regimen dispensed in form of fixed dose combination (FDC).
Depending on weight of the patient, he/she is adviced to take number of medications
per day.
6.) CBNAAT
7.) Line Probe Assay (LPA)

57. Middle Path Regimen for TB Spine
1. Rest in hard beds
2. Use of anti TB drugs
3. Radiographs & ESR at 3-6 months interval. Measurement of kyphosis & CT/MRI scan for
cervicodorsal, cervicovertebral, LS & SI joint assessment at 6 month interval for 2 years.
4. Gradual mobilization –
a) In absence of neural deficit with help of brace.
b) 3-9 weeks post-treatment patient is put on back extension exercises for 5 to 10 minutes for
3-4 times a day.
c) Braces used for 18 to 24 months.

58. 5. Abscesses
a) Aspirated near the surface.
b)1 gm of streptomycin +/- isoniazid instilled at each aspiration.
c) I&D if aspiration fails.
d)All radiologically visible abscess is not drained.
6. Sinus
a) Majority heal within 6-12 weeks of treatment.
b)In few cases, treatment should be prolonged or sinus tract excised.

59. 7. Neural Complications
a) Surgical decompression unnecessary for progressive improvement.
b) Decompression done for:
i) Failure to respond to conservative treatment
ii) New appearance of neurological complications
iii)Worsening of neurological symptoms
iv)Recurrence of neurological complications
8. Excisional surgery done for posterior spinal disease associated with sinus or abscess
formation if no improvement seen after 3-4 weeks of therapy.
9. Posterior spinal arthrodesis – for symptomatic unstable spinal lesions

60. 10. Operative Debridement
a) Failure to improve after 3-6 months of chemotherapeutic treatment
b) Recurrence of disease
11. Postoperative
a) Nursed in hard bed
b) Mobilization after 3-5 months – in absence of paraplegia

61. Indications for Surgery in Spinal TB
1. Neurological deficit
2. Rapidly worsening deficits
3. New onset or deteriorating deficits during chemotherapy
4. No improvement after 6-8 weeks of chemotherapy
5. Spinal Instability
6. Panvertebral disease
7. > 3 contiguous vertebrae involved

62. 8. Children with initial kyphosis > 30 deg
9. Posterior neural arch with pedicular destruction
10. Clinical instability
11. Late deformity
12. Severe kyphosis with late onset neurological deficits
13. Disease recurrence despite chemotherapy
14. Primary drug resistance