brief presentation on multi drug resistant tb 2016 who guidelines and newer anti tb drugs.

1. MULTIDRUG RESISTANT
TB AND NEWER ANTI TB
DRUGS
PRESENTER – DR.MANJUSH HALBHAVI
MODERATOR – DR.H.B.GADIYAR

2. TUBERCULOSIS – AN
OVERVIEW
TB: Oldest recognized disease of mankind
India – Rigveda and Atharvaveda (3500-1800 BC)
and Samhita’s of Charaka and Shushruta (1000 and
600 BC) : “YAKSHMA”
TB also recognized in Egyptian mummies – confirmd
by PCR

3. TUBERCULOSIS – AN
OVERVIEW
Robert Koch :
Discovered
Mycobacterium
tuberculosis in 1882

4. DRUG RESISTANCE
WHO DEFINITION: Drug resistance is when a
micro organism changes in ways that render
medications that used to cure the infections they
cause ineffective.
The presence of drug resistant strains result from
simple Darwinian pressures brought out by the
presence of antibiotics.
Multiple drug resistance results from stepwise
accumulation of individual elements.
Hence MDR – TB is a man made catastrophe.

5. DRUG RESISTANCE –
TYPES
When drug resistance is demonstrated in a
patient who has never received anti-TB
treatment previously, it is termed primary
(Initial) resistance, i.e. TB patient’s initial M.TB
population resistant to drugs
Secondary (Acquired) resistance is that which
occurs as a result of specific previous
treatment, i.e. Drug-resistant M. TB in initial
population, selected by inappropriate drug use
(inadequate treatment or non-adherence)

6. DRUG RESISTANCE –
TYPES
• Drug resistant TB
 Mono resistance
 Poly resistance
 Multi Drug Resistant TB(MDR - TB)
 Extensive Drug Resistant TB (XDR - TB)
 Total Drug Resistance (TDR – TB)

7. DRUG RESISTANCE
Mono Drug Resistance
(Resistance to single first line ATT)
Poly Drug Resistance
(Resistance to two or more first line ATT
except MDR-TB)

8. MDR – TB – strains with resistance to both first
line drugs i.e, Rifampicin and Isoniazid. (a
laboratory diagnosis)
XDR – TB – strains with MDR + resistance to any
fluoroquinolone + resistance to at least one 2nd-
line injectable drug (amikacin, kanamycin, or
capreomycin)

9. TDR – TB –
Resistance to all first-
line anti-TB drugs
(FLD) and second-line
anti-TB drugs (SLD)
that were tested.

11. EPIDEMIOLOGY
Globally in 2014, there were an estimated 3.3%
of new cases and 20% of previously treated
cases with MDR-TB.
Extensively drug-resistant TB (XDR-TB) has
been reported by 105 countries in 2014. On
average, an estimated 9.7% of people with MDR-
TB have XDR

12. EPIDEMIOLOGY

13. BURDEN OF MDR – TB IN
INDIA
Each year about 2.2 million people develop TB in
India and an estimated 220,000 die from the
disease
In 2015 the RNTCP covered a population of 1.28
billion. A total of 9,132,306 cases of suspected
TB were examined by sputum smear microscopy
and 1,423,181 people were diagnosed and
registered for TB treatment

14. BURDEN OF MDR – TB IN
INDIA
The notification of TB cases is estimated to be
only 58%. Over one third of cases are not
diagnosed, or they are diagnosed but not treated,
or they are diagnosed and treated but not notified
to the RNTCP.
The emergence of MDR – TB in India is mainly
due to non compliance of patients in taking the
drugs completing the regimen, hence giving rise
to the need for DOTS, which includes
supervising people taking their drugs to prevent
the emergence of resistance.

15. EMERGENCE OF MDR TB
Resistance is a man-made amplification of a natural
phenomenon. i.e. Selection & proliferation of pre
existing mutants due to man made factors leads to
drug resistance.
Inadequate drug delivery is main cause of secondary
drug resistance.
Secondary drug resistance is the main cause of
primary drug resistance due to transmission of
resistant strains.
MDR due to spontaneous mutations is not possible
as the genes encoding resistance for anti TB are
unlinked.

16. MECHANISM OF DRUG
RESISTANCE

17. FACTORS RESPONSIBLE FOR
DEVELOPMENT OF DRUG
RESISTANCE
CLINICAL / OPERATIONAL FACTORS
Unreliable treatment regimen by doctors
Lesser number of drugs
Inadequate dosage / duration
Addition of a single drug in failing regimen
Easy availability of drugs in private sector
Poor drug supply
Poor quality of drugs : poor bioavailability

19. FACTORS RESPONSIBLE FOR
DEVELOPMENT OF DRUG
RESISTANCE
BIOLOGICAL FACTORS :
Initial bacillary population
Local factors in host favorable for multiplication of
bacilli
Presence of drug in insufficient concentration

20. FACTORS RESPONSIBLE FOR
DEVELOPMENT OF DRUG
RESISTANCE
SOCIOLOGICAL FACTORS :
Irregular intake
inadequate duration
Neglect of disease
Ignorance

21. DRUG RESISTANCE : MOLECULAR
BASIS
DRUG RESISTANT ISOLATES SHOW
MUTATION IN GENES
INH : kat g, inhA
RIFAMPICIN : rpoB
STREPTOMYCIN : rpsL
ETHIONAMIDE : inhA
FLUOROQUINOLONES : gyrA, gyrB
DNA probes using genetic information have
been devised

22. MANAGEMENT
PRINCIPLES
SUSPICION
DIAGNOSIS
TREATMENT

23. SUSPICION
A close contact of Drug Resistant TB case.
Treatment failures.
All retreatment cases.
No sputum conversion after initial 2 months of
ATT.
Extensive disease at start of treatment.
All HIV patients with TB.
Extrapulmonary TB not responding to
standard ATT regime

24. RNTCP CRITERIA – MDR TB
Following are the criteria to label a patient as MDR-TB
suspect –
A new smear (+) pt. remaining smear (+) at end of 5th
month
A new smear (-) pt. becoming smear (+) at the end of 5th
month
A pt. treated with regimen for previously treated
remaining (+) at fourth month
Smear-positive contacts of an established / confirmed
MDR-TB case

25. LABORATORY
DIAGNOSIS
Mantoux test
Erythema of more than 20 mm at 72 hours –
Positive
Negative test, in general, rules out the disease
Guinea pig Inoculation
Pus/ aspirate is inoculated intraperitoneally .
Positive cases reveal tubercle after 5-8 weeks
One of the most reliable proof of Tuberculous
pathology

26. LABORATORY
DIAGNOSIS
Sputum smears stained by Z – N staining
• Three morning successive mucopurulent sputum samples are needed
to diagnose pulmonary TB.
Advantage: - cheap – rapid
- Easy to perform
- High predictive value > 90%
- Specificity of 98%
Disadvantages:
- sputum ( need to contain 5000-10000 AFB/ ml.)
- Young children, elderly & HIV infected persons may not produce cavities &
sputum containing AFB.

27. LABORATORY
DIAGNOSIS
Detecting AFB by fluorochrome stain using
fluorescence microscopy
The smear may be stained by aura mine-O dye. In this method the TB bacilli are stained
yellow against dark background & easily visualized using florescent microscope.
Advantages:
- More sensitive
- Rapid
Disadvantages:
- Hazards of dye toxicity
- more expensive
- must be confirmed by Z-N stain

28. LABORATORY
DIAGNOSIS
Tuberculin Test
Interpretation:
* A positive test indicates previous exposure and carriage of T.B.
* A negative tuberculin test excludes infection in suspected persons
* Tuberculin positive persons may develop reactivation type of T.B.
* Tuberculin negative persons are at risk of gaining new infection
* False positive reactions are mainly due to:
- Infection with nontuberculous mycobacteria
* False negative reactions may be due to:
- Sever tuberculosis infection (Miliary T.B.) - Hodgkin’s disease
- Corticosteroid therapy - Malnutrition - AIDS
* Children below 5 years of age with no exposure history:
- Positive test must be regarded suspicious

29. LABORATORY
DIAGNOSIS
BACTEC 460
specimens are cultured in a
liquid medium (Middle brook7H9
broth base )containing C14 –
labeled palmitic acid & PANTA
antibiotic mixture.
Growing mycobacteria utilize
the acid, releasing radioactive CO2
which is measured as growth index
(GI) in the BACTEC instrument.
The daily increase in GI output
is directly proportional to the rate
& amount of growth in the
medium.

30. LABORATORY
DIAGNOSIS
Polymerase Chain Reaction (PCR) & Gene probe
Nucleic acid probes & nucleic acid amplification tests
in which polymerase enzymes are used to amplify (
make many copies of specific DNA or RNA sequences
extracted from mycobacterial cells.)

31. DRUG SUSCEPTIBILITY TESTING
DEFINITION : Drug-susceptibility testing
(DST) refers to in vitro testing using either
phenotypic methods to determine susceptibility
or molecular techniques to detect resistance-
conferring mutations to a particular medicine.
Types:
Culture – LJ medium/ Middle Brook medium/ Sula
medium
Molecular DST – Beacon assays/ Line probe
assays

32. CULTURES
LOWENSTEIN – JENSEN MEDIUM – SOLID
MEDIUM
Lowenstein –Jensen medium is an egg based
media with addition of salts, 5 % glycerol,
Malachite green & penicillin.
M.tuberculosis appear dry, rough raised
irregular colonies
Appear wrinkled and creamy white which
become yellowish later.

33. LOWENSTEIN – JENSEN
MEDIUM

34. CULTURES
MGIT - MYCOBACTERIUM GROWTH INDICATOR TUBE
– LIQUID MEDIUM
The MGIT Mycobacteria Growth Indicator Tube contains 7
mL of modified Middlebrook 7H9 Broth base. The complete
medium, with OADC enrichment and
PANTA antibiotic mixture, is one of the most commonly
used liquid media for the cultivation of mycobacteria.

35. BACTEC MGIT 960

36. COMPARISON – MGIT VS LJ
MEDIUM
National Health Laboratory Services tuberculosis
(TB) laboratory, South Africa did a study to To
compare Mycobacterium Growth Indicator Tube
(MGIT) with Löwenstein-Jensen (LJ) medium
with regard to Mycobacterium tuberculosis yield,
time to positive culture and contamination, and to
assess MGIT cost-effectiveness. The study
concluded that MGIT gives higher yield and
faster results at relatively high cost.

37. MOLECULAR DST –
BEACON ASSAYS
Beacon assays detect M. tuberculosis complex
and associated rifampicin resistance directly from
sputum samples using ultra sensitive PCR.
The GeneXpert TB assay is an automated real
time based system that has a number of
advantages including the fact that it is a closed
tube system.
The WHO is encouraging the use of the
GeneXpert TB test, but it has a number of
disadvantages including cost.

38. GeneXpert

39. MOLECULAR DST – LINE
PROBE ASSAYS
The WHO Expert Group concluded that there was
sufficient generalisable evidence to justify a
recommendation on the use of line probe assays for
rapid detection of MDR-TB, at country level, and with
further operational research to address country-specific
implementation needs.
Line probe assays are tests that use PCR and reverse
hybridization methods for the rapid detection of
mutations associated with drug resistance.
One of the disadvantages with these assays is that
they have an open-tube format, which can lead to cross
contamination and an increased risk of false positive
results

40. LINE PROBE ASSAYS

41. LABORATORY
DIAGNOSIS

42. TREATMENT –
PRINCIPLES
1. Use at least 4 reliable drugs .
2. Do not use drugs with cross resistance .
3. Eliminate drugs that are not safe for the patient.
4. Include drugs from Groups A-D in a hierarchical
order.
5. Monitor and manage adverse effects of drugs.
6. Never add a single drug to failing regime.

43. ANTI TB DRUGS

44. REGIMEN UNDER DOTS PLUS
PROGRAMME IN INDIA (PMDT)
INITIAL INTENSIVE PHASE : 6- 9 months
Inj. Kanamycin
Tab Ethionamide
Tab Ofloxacin
Tab. Pyrazinamide
Tab. Ethambutol
Cap Cycloserine
CONTINUATION PHASE : 18 months
Tab Ethionamide
Tab Ofloxacin
Tab Ethambutol
Cap Cycloserine

45. REGIMEN UNDER DOTS PLUS
PROGRAMME IN INDIA (PMDT)

46. A second-line TB medicine (drug or agent) is
used to treat drug-resistant TB. For the treatment
of RR-TB and MDR-TB, streptomycin is included
as a substitute for second-line injectable agents
when aminoglycosides or capreomycin cannot be
used and susceptibility is highly likely. core
second-line TB medicines (or agents) refer to
those in Groups A, B or C.

47. WHO GUIDELINES FOR DR – TB (2016
UPDATE) – SECOND LINE ANTI TB
DRUGS

48. WHO GUIDELINES FOR DR – TB (2016
UPDATE)

49. WHO GUIDELINES FOR DR – TB
(2016 UPDATE)

50. CHANGES IN 2016
The main changes in the 2016 recommendations are as follows:
A shorter MDR-TB treatment regimen is recommended under
specific conditions
Medicines used in the design of longer MDR-TB treatment regimens
are now regrouped differently based upon current evidence on their
effectiveness and safety
Clofazimine and linezolid are now recommended as core second-
line medicines in the MDR-TB regimen while p-aminosalicylic acid is
an add-on agent.
MDR-TB treatment is recommended for all patients with RR-TB,
regardless of confirmation of isoniazid resistance.
Specific recommendations are made on the treatment of children
with RR-TB or MDR-TB.
Clarithromycin and other macrolides are no longer included among
the medicines to be used for the treatment of MDR/RR-TB.
Evidence-informed recommendations on the role of surgery are now
included.

51. WHO – CURRENT
RECOMMENDATIONS 2016
SHORTER MDR TB REGIMEN: In patients with RR-TB or
MDR-TB who were not previously treated with second-line
drugs and in whom resistance to fluoroquinolones and
second-line injectable agents was excluded or is
considered highly unlikely, a shorter MDR-TB regimen of
9–12 months may be used instead of the longer regimens
(conditional recommendation, very low certainty in the
evidence).
Intensive phase of four months (extended up to a
maximum of six months in case of lack of sputum smear
conversion) with gatifloxacin (or moxifloxacin), kanamycin,
prothionamide, clofazimine, high-dose isoniazid,
pyrazinamide and ethambutol

52. WHO – CURRENT
RECOMMENDATIONS 2016
LONGER MDR TB REGIMEN: are treatments for RR-
TB or MDR-TB which last 18 months or more and
which may be standardized or individualized.In
patients with RR-TB or MDR-TB, a regimen with at
least five effective TB medicines during the intensive
phase is recommended, including pyrazinamide and
four core second-line TB medicines – one chosen from
Group A, one from Group B, and at least two from
Group C.
If the minimum number of effective TB medicines
cannot be composed as given above, an agent from
Group D2 and other agents from Group D3 may be
added to bring the total to five.
In patients with RR-TB or MDR-TB, it is recommended
that the regimen be further strengthened with high-
dose isoniazid and/or ethambutol.

53. WHO – CURRENT
RECOMMENDATIONS 2016
SURGICAL
INTERVENTION IN
MDR TB:
In patients with RR-
TB or MDR-TB
patients, elective
partial lung resection
(lobectomy or wedge
resection) may be
used alongside a
recommended MDR-
TB regimen

54. END TB STRATEGY
The END TB Strategy, approved by the 67th World
Health Assembly in 2014, is designed to achieve a
health-related target under the United Nations
SDG 3 that calls for ending the TB epidemic by
2035
PRINCIPLES:
Government stewardship and accountability, with
monitoring and evaluation
Strong coalition with civil society organizations and
communities
Protection and promotion of human rights, ethics
and equity
Adaptation of the strategy and targets at country
level, with global collaboration

55. END TB STRATEGY

56. NEWER ANTI TB DRUGS
GROUP A – FLUOROQUINOLONES
ciprofloxacin, levofloxacin, gatifloxacin, and
moxifloxacin inhibit strains of M tuberculosis
Moxifloxacin is the most active against M
tuberculosis by weight
the drug must be used in combination with two or
more other active agents-to prevent resistance
standard dosage of ciprofloxacin is 750 mg orally
twice a day, levofloxacin is 500–750 mg once a
day, moxifloxacin is 400 mg once a day.

57. NEWER ANTI TB DRUGS
MECHANISM OF ACTION:
Quinolones and
fluoroquinolones inhibit bacterial
replication by blocking their DNA
replication pathway.
In gram-positive bacteria, the
main target for fluoroquinolones
is DNA gyrase (topoisomerase
II), an enzyme responsible for
supercoiling of bacterial DNA
during DNA replication; in gram-
negative bacteria, the primary
target is topoisomerase IV, an
enzyme responsible for
relaxation of supercoiled circular
DNA and separation of the inter-
linked daughter chromosomes

58. NEWER ANTI TB DRUGS
GROUP B – SECOND LINE
INJECTABLE DRUGS –
AMINOGLYCOSIDES
Amikacin, Kanamycin.
aminoglycosides primarily
act by binding to the
aminoacyl site of 16S
ribosomal RNA within the
30S ribosomal subunit,
leading to misreading of the
genetic code and inhibition
of translocation.
Most MDR strains are amikacin
sensitive
Amikacin is also active against
atypical mycobacteria

59. NEWER ANTI TB DRUGS
GROUP C : OTHER CORE SECOND LINE
AGENTS
Ethionamide/Prothionamide
Cycloserine/ Terizidone
Linezolid
Clofazimine

60. NEWER ANTI TB DRUGS
Ethionamide/Prothionamide:
nicotinic acid derivative related to isoniazid. It is
thought that they undergo intracellular modification and
act in a similar fashion to isoniazid i.e competitive
inhibition of Inh A resulting in inhibition of synthesis of
mycolic acids.
Dose:
500mg – 1g/day per oral – adult dose
10 to 20 mg/kg orally in 2 or 3 divided doses per day
or 15 mg/kg orally once per day after meals –
Paediatric dose
Adverse effects:
Intense gastric irritation , neurologic symptoms
Hepatotoxic.
Neurologic symptoms may be alleviated by pyridoxine.

61. NEWER ANTI TB DRUGS
Cycloserine/ Terizidone:
Terizidone is a derivative of Cycloserine.
Cycloserine is an inhibitor of cell wall synthesis.
ADVERSE EFFECTS:
peripheral neuropathy and central nervous system
dysfunction
depression and psychotic reactions
Pyridoxine 150 mg/d should be given with cycloserine to
ameliorates neurologic toxicity
CONTRAINDICATIONS: Epilepsy; depression; severe
anxiety or psychosis; severe renal insufficiency;
excessive concurrent use of alcohol

62. NEWER ANTI TB DRUGS
Linezolid:
Prevents the formation of a functional 70S initiation complex,
which is essential to the bacterial translation process.
It achieves good intracellular concentrations.
Linezolid has been used in combination with other second- and
third-line drugs to treat patients with tuberculosis caused by
multidrug-resistant strains
ADVERSE EFFECTS:
bone marrow suppression
irreversible peripheral and optic neuropathy
600-mg (adult) dose administered once a day
it should be considered a drug of last resort for infection caused
by multidrug-resistant strains

63. NEWER ANTI TB DRUGS
Clofazimine:
Clofazimine exerts a slow bactericidal effect
Clofazimine inhibits mycobacterial growth and binds
preferentially to mycobacterial DNA
Appears to preferentially bind to mycobacterial DNA leading to
disruption of the cell cycle and eventually kills the bacterium.
It may also bind to bacterial potassium transporters, thereby
inhibiting their function.
Lysophospholipids have been found to mediate the activity of
this drug.
ADVERSE EFFECTS:
Splenic infarction,
bowel obstruction, and
gastrointestinal bleeding

64. NEWER ANTI TB DRUGS
Bedaquiline:
Bedaquiline works by blocking an enzyme inside the
Mycobacterium tuberculosis bacteria called ATP
synthase.
The recommended dose is 400 mg a day for two
weeks and then 200 mg taken three times a week
(with at least 48 hours between doses).
ADVERSE EFFECTS:
The most common side effects are headache,
dizziness, malaise, joint pain, QT prolongation and
increases in liver enzymes

65. NEWER ANTI TB DRUGS
Delamanid:
Delamanid is a dihydro-nitroimidazooxazole
derivative. It acts by inhibiting the synthesis of
mycobacterial cell wall components, methoxy mycolic
acid and ketomycolic acid.
Dose: 100 mg/day
ADVERSE EFFECTS:
The most common side effects are nausea, vomiting
and dizziness.
Anxiety, pins & needles, and shaking are other
important side effects
QT prolongation

66. Ann Thorac Med. 2016 Oct-Dec; 11(4): 233–236.
Multi-drug resistant tuberculous spondylitis: A review of the
literature
Quratulain Fatima Kizilbash1,2,3 and Barbara Joyce Seaworth1,2,3
While tuberculous vertebral osteomyelitis is an ancient scourge, multi-
drug resistant-tuberculosis (MDR-TB) is a modern major public health
concern. The objective of this study was to review and summarize the
data available on MDR-TB spondylitis. An extensive search of the
PubMed database was conducted for articles in English relevant to
MDR-TB spondylitis by December 2015. Tuberculous spondylitis
accounts for 0.5–1% of all TB cases, and it is estimated that there are
probably 5000 MDR-TB spondylitis cases each year worldwide. The
diagnosis of MDR-TB spondylitis requires a high index of suspicion
based on epidemiologic, clinical, and radiologic features. Cultures and
susceptibility testing remain the gold standard for the diagnosis of
MDR-TB, but this can take several weeks to obtain. Medical treatment
is the mainstay of therapy, and ideally, it should be based on drug
susceptibility testing. If empiric treatment is necessary, it should be
based on drug exposure history, contact history, epidemiology, and
local drug resistance data, if available. The total duration of treatment
should not be <18–24 months. Clinical, radiographic, and if possible,
bacteriologic improvement should be used to assess the treatment
success. Surgery should be reserved for neurologic deterioration,

67. REFERENCES
TUBERCULOSIS OF SKELETAL SYSTEM – SM TULI,
5TH EDITION
RNTCP GUIDELINES 2016
IMPLEMENTING THE END TB STRATEGY: THE
ESSENTIALS – WHO
WHO TREATMENT GUIDELINES FOR DRUG
RESISTANT TUBERCULOSIS – 2016 UPDATE
KD TRIPATHI TEXT BOOK OF PHARMACOLOGY, 7TH
EDITION
PARKS TEXTBOOK OF P AND SM , 23RD EDITION
ANNALS OF THORACIC MEDICINE, 2016 Oct-Dec;
11(4): 233–236.

68. THANK YOU