1. DIAGNOSIS & MANAGEMENT
OF TB IN RNTCP
DR. RAJESH N.SOLANKI
MD, FNCCP
PROFESSOR,
DEPARTMENT OF TB & CHEST DISEASES,
B.J.MEDICAL COLLEGE & CIVIL HOSPITAL,
AHMEDABAD.
NODAL OFFICER-STATE DOTS PLUS COMMITTEE, GUJARAT
Member, National DOTS Plus Committee, GOI
Member, National Air Borne Infection Control Committee, GOI
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.
4. BACTERIOLOGICAL DIAGNOSIS
1) SMEAR - Examination
2) FNAC – from Lymph nodes, Abscesses
3) Biopsy - Incisional or Excisional biopsy
Biopsy is more reliable.
5. 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.
6. Extra pulmonary TB
TB of organs other than lungs
confirmed by bacteriological
Or
Histopathological confirmation
Or
Radiological evidence
Or
Strong clinical evidence
7. How to Diagnose EPTB
•
•
•
•
•
•
Clinical Evaluation
Radiological
Histo-pathological
Bacteriological
Serological
Biochemical Markers
8. 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. DIAGNOSTIC METHODS
(LABORATORY ASPECTS)
•
SOLID CULTURE: L J MEDIA, “Gold Standard” for Culture
•
LIQUID CULTURE: BACTEC, “Gold Standard” for DST
•
MOLECULAR TECHNIQUE: PCR BASED
•
MICROSCOPIC OBSEVATION OF DRUG SUSCEPTIBILITY
(MODS)
•
ADDITIONAL MODELITIES
-SEROLOGICAL MARKERS
-GAMMA INTERFERRON
-PIEZO ELECTRIC SENSOR
-HRCT AND CECT
10. 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).
11. 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
12. 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.
13. 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
14. 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. MOLECULAR DIAGNOSIS
• REAL TIME PCR
• MULTIPLEX PCR WITH ADDED
ADVANTAGE (LPA- HAIN’S TEST)
• TRANSCRIPTION MEDIATED
AMPLIFICATION
• DETECTION BY SEQUENCING
16. 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.
18. 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
19. 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
20. 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.
21. 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
23. 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
24. 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,
25. 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.
26. 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)
27. 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.
28. 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.
29. 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
30. 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
31. 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.
32. The Revised National Tuberculosis
Program or RNTCP, is an
application of the principles of
DOTS to the Indian context
33. The 5 components of DOTS
Political
& admin.
commitment
Diagnosis
by
microscopy
Adequate supply of
the right drugs
Directly
observed
treatment
Accountability
TB Register
34. Science of DOTS
Diagnosis of TB primarily based on
sputum microscopy
Domiciliary treatment
Short course chemotherapy
Intermittent chemotherapy
Directly observed treatment
35. 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
36. 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
37. 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”.
38. 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.
39. 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
40. 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)
41. 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”
43. 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
44. 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
46. 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
47. 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
49. 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
•
50. 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)
51. 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
52. 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
53. 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
54. 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
55. 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
56. 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);
57. 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
59. 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
61. 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
62. 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
•
•
•
•
63. 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. R Prasad Lucknow
CULTURE SENSITIVITY OF Miss. SABAH, 13 yrs. F
LAB-A
LAB-B
LAB-C
LAB-D
STM.
S
R
MS
R
RIF.
S
R
R
INT
INH.
R
R
R
S
ETM.
S
S
S
S
PZA.
R
R
R
AWT
THIA.
S
R
-S
PAS.
S
S
MS
S
KANA.
--MS
-CYCLO.
S
-S
-ETHIO.
-R
R
S
CIPRO.
---S
SPAR
-S
S
S
CLOFA.
-R
S
--
65. 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
66. 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
67. 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
Notes de l'éditeur
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