|Year : 2013 | Volume
| Issue : 1 | Page : 40-46
Changing patterns and trends of multidrug-resistant tuberculosis at referral centre in Northern India: A 4-year experience
AK Maurya1, AK Singh2, M Kumar2, J Umrao2, S Kant3, VL Nag2, RAS Kushwaha3, TN Dhole2
1 Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences; Department of Pulmonary Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India
2 Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
3 Department of Pulmonary Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India
|Date of Submission||03-Jul-2012|
|Date of Acceptance||12-Oct-2012|
|Date of Web Publication||15-Mar-2013|
T N Dhole
Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh
Source of Support: Extramural ICMR Project Sanction No. 5/8/5/4/2007-ECD-I was funded by Indian Council of Medical Research, New Delhi., Conflict of Interest: None
Purpose: India has a high burden of drug-resistant tuberculosis (TB), although there is little data on multidrug-resistant tuberculosis (MDR-TB). Although MDR-TB has existed for long time in India, very few diagnostic laboratories are well-equipped to test drug sensitivity. The objectives of this study were to determine the prevalence of MDR-TB, first-line drug resistance patterns and its changing trends in northern India in the 4 years. Materials and Methods: This was a prospective study from July 2007 to December 2010. Microscopy, culture by Bactec460 and p-nitro-α-acetylamino-β-hydroxypropiophenone (NAP) test was performed to isolate and identify Mycobacterium tuberculosis (M. tb) complex (MTBC). Drug sensitivity testing (DST) was performed by 1% proportional method (Bactec460) for four drugs: Rifampicin, isoniazid, ethambutol and streptomycin. Various clinical and demographical profiles were evaluated to analyse risk factors for development of drug resistance. Results: We found the overall prevalence rate of MDR-TB to be 38.8%, increasing from 36.4% in 2007 to 40.8% in 2010. we found that the prevalence of MDR-TB in new and previously treated cases was 29.1% and 43.3% ( P < 0.05; CI 95%). The increasing trend of MDR-TB was more likely in pulmonary TB when compared with extra-pulmonary TB ( P < 0.05; CI 95%). Conclusions: we found a high prevalence (38.8%) of MDR-TB both in new cases (29.1%) and previously treated cases (43.3%).This study strongly highlights the need to make strategies for testing, surveillance, monitoring and management of such drug-resistant cases.
Keywords: Anti-tubercular therapy, multidrug-resistance tuberculosis, Mycobacterium tuberculosis complex, tuberculosis
|How to cite this article:|
Maurya A K, Singh A K, Kumar M, Umrao J, Kant S, Nag V L, Kushwaha R, Dhole T N. Changing patterns and trends of multidrug-resistant tuberculosis at referral centre in Northern India: A 4-year experience. Indian J Med Microbiol 2013;31:40-6
|How to cite this URL:|
Maurya A K, Singh A K, Kumar M, Umrao J, Kant S, Nag V L, Kushwaha R, Dhole T N. Changing patterns and trends of multidrug-resistant tuberculosis at referral centre in Northern India: A 4-year experience. Indian J Med Microbiol [serial online] 2013 [cited 2019 Jul 17];31:40-6. Available from: http://www.ijmm.org/text.asp?2013/31/1/40/108720
| ~ Introduction|| |
Inspite of hard efforts taken to control tuberculosis (TB),  this disease continues to be one of the major public health problems worldwide, particularly in developing countries.  Currently, India records an annual incidence of 1.9 million new TB cases accounting for one-fifths of the world's new TB cases and two-thirds of the TB cases in the South-East Asia Region.  Multidrug-resistant TB (MDR-TB) is defined as the resistance of Mycobacterium tuberculosis (M.tb) to isoniazid and rifampicin combination with or without resistance to any other drugs.  The emergence and spread of MDR-TB is an increasing public problem in India, with an estimated number of 1, 10, 000 cases spread across the country.  World Health Organization (WHO) has estimated that the number of incident cases (including new and re-treatment cases) occurring worldwide in 2003 alone was to the extent of 4,58,000 (95% CI, 3, 21, 000-16,89,000) with a projected figure of prevalent cases 2-3 times higher.  WHO has accepted that MDR-TB has become wide spread and as per most recent data in 2008, among all incident TB cases, 3.6% were estimated to have MDR-TB worldwide. Almost half of the global MDR-TB cases were reported to be from China and India.  In India, drug resistance tuberculosis (DR-TB) and MDR-TB have been continuously identified and treated, despite the effort of Revised National Tuberculosis Control Programme (RNTCP) which is based on the directly observed treatment strategy (DOTS) and DOTS Plus. As per recently published reports from India, MDR-TB has been found in 3% of new cases and in 12% of treated patients.  WHO and the International Union Against Tuberculosis and Lung Diseases (IUATLD) have estimated that 50 million people worldwide are infected with DR M.tb strains  which are resistant to at least one of the first-line anti-TB drugs.  This surveillance programme of M.tb drug resistance using drug susceptibility testing (DST) may guide decision makers in defining standardised protocols for chemotherapy and enable routine assessment of the quality of the programme.  Direct transmission of new cases of DR-TB has gradually increased to MDR-TB as previously treated cases (defaulters, failures and re-treatment) are already high and widely spread in the society. The trend of DR-TB is continuously changing and appearance of new forms of resistant TB bacilli has become a significant obstacle to effective global TB control. Information on anti-TB drug resistance patterns, particularly among new and previously treated cases, is crucial for planning an effective TB control programme. The objectives of this study were to determine prevalence of MDR-TB, first-line anti-tuberculosis drug resistance patterns and its changing pattern in cases of tuberculosis cases at a tertiary care referral centre in northern India over a period of 4 years.
| ~ Materials and Methods|| |
Prospective observational study.
Clinical specimens and data collection
All patients visiting indoor patient department (IPD) and outdoor patient department (OPD) and various wards from January 2007 to December 2010 at two tertiary care centres in Lucknow. Approximately 2-10 ml of non-repeat specimens from suspected cases of both pulmonary tuberculosis (PTB) and extra-pulmonary tuberculosis (EPTB) were collected from respiratory specimens [sputum and broncho-alveolar lavage (BAL) fluid] and non-respiratory specimens [lymph node aspirate, cold abscesses, pleural fluid, cerebrospinal fluid (CSF), synovial fluid, ascitic fluid, urine, gastric aspirate, pus, bone marrow, wound and pus swab]. Patients of all ages were considered for the study and included both male and female population from urban and rural settings. The study was approved by the Institutional Ethical Committee and a written informed consent was obtained from all subjects before enrolment into the study. The clinical history regarding present and past history of anti-tubercular treatment (ATT), family history of TB and any other associated disease(s) was taken in the prescribed proforma.
Criteria for inclusion
Patients included in the study were new or previously treated PTB and EPTB patients from any age group, in whom TB was confirmed by culture and DST against Mycobacterium tuberculosis (M. tb) complex (MTBC) strain was performed. All non-consenting patients, those infected with Mycobacteria other than tuberculosis (MOTT) and unknown bacteriological profile were not included in this study.
Smear examination and culture
All the clinical specimens were subjected to direct smear microscopy by Ziehl-Neelsen (ZN) staining method.  Specimens that contained normal commensal bacterial flora, were decontaminated by standard N-acetyl-L-cysteine-NaOH method.  Specimens from sterile sites were centrifuged and the sediment was inoculated into the Bactec12B vial supplemented with the antimicrobial mixture PANTA (Becton Dickinson, Sparks, MD, USA). All the inoculated media were incubated at 37 ± 1°C and tested twice a week for the first 3 weeks and then once a week for the remaining 3 weeks. Positive Bactec12B vials were subjected to smear microscopy for acid-fast bacilli (AFB). No growth after 8 weeks of incubation was treated as negative for mycobacteria. Growth of MTBC was typed by niacin production, catalase activity at 68°C and pH 7, and susceptibility to p-nitrobenzoic acid. 
Final identification of MTBC by the Bactec p-nitro-α-acetylamino-β-hydroxypropiophenone (NAP) test (Becton Dickinson, Sparks, MD, USA) was carried out.  Standard strain M.tb, H37Rv ATCC™ No. 27294 was used as a positive control.
Drug sensitivity testing
Drug sensitivity testing (DST) for four primary first-line anti-TB drugs was performed by standard 1% proportional method using Bactec460 TB system.  The first-line drugs were provided in a drug kit (Becton Dickinson, Sparks, MD, USA). Following final concentrations were used-isoniazid (H) 0.1 mcg/mL, rifampicin (R) 2.0 mcg/mL, streptomycin (S) 6.0 mcg/mL and ethambutol (E) 7.5 mcg/mL. 0.1 ml of the appropriate drug solution was injected into labeled Bactec 12B vials which resulted in the desired concentration of a drug in the medium. This was followed by inoculation of 0.1 mL of bacterial suspension from a positive Bactec12B vial with a growth index (GI) range of 500-800. For the control, the same bacterial inoculum was diluted 1:100 before inoculation. The inoculated Bactec12B vials were incubated and read daily in the instrument till the GI of the control vial reached more than 30. The reference strain of M.tb H37Rv was used as a quality control on a weekly basis.
Definitions of resistance type
Resistance in new cases was defined as the presence of a resistant strain of MTBC in patients who had never received anti-tuberculosis drugs or who had been treated for <1 month. Resistance in previously treated (chronic) cases was determined in failure, relapse and re-treatment. MDR-TB was defined as MTBC strains that were resistant to atleast isoniazid and rifampicin.
After obtaining informed consent from the patients, HIV status was determined as per the Joint recommendation of the United Nations Program on HIV/AIDS/WHO. 
Data was analysed using SPSS 15.0 (Statistical Package for the Social Sciences, Chicago, IL, USA) for Windows. Standard χ2 tests were used to assess statistical relationships between the prevalence of MDR-TB in PTB and EPTB, HIV status and MDR-TB. P < 0.05 was considered statistically significant.
| ~ Results|| |
7450 clinical specimens from different enrolled patients from both OPD and IPD of different wards of tertiary care centres in Lucknow, India and from referred patients of other health care centres suspected to have drug-resistant TB were received. Among 7450 clinical specimens, 6234 (83.7%) were PTB and 1216 (16.3%) were EPTB. Of these 7450 samples, only 1408 (19.46%) were AFB positive in ZN microscopy and 817/7450 (10.9%) samples showed growth of Mycobacterium. Overall, MTBC was isolated in 755/817 (92.4%) specimens, whereas MOTTs were isolated in 62/817 (7.6%) specimens by NAP differentiation test. Among these 755 MTBC strains, 705 (93.4%) were from respiratory specimens and 50 (6.6%) strains were from extra-pulmonary specimens. DST was performed over only 250 MTBC strains 'clinically suspected'of DR-TB strains. Among 250 total MTBC strains, 79 (31.6%) patients were newly diagnosed and 171 (68.4%) were previously treated TB. We found 97 (38.8%) MDR-TB strains from 250 MTBC isolates tested for first-line anti-tubercular drugs. Out of these 97 MDR-TB strains, 80 (82.5%) were PTB and 17 (17.5%) were EPTB cases (P < 0.05; CI 95%).
Demographical characterisation of MDR-TB patients
Of these 97 MDR-TB patients, 81 (83.5%) were male and 16 (16.5%) were female. The mean age of all patients was 31.2 ± 13.2 (77-14) years. Patients belonging to 21-40 years of age accounted for 64.9% of the total MDR-TB burden. Microscopy positivity for AFB was observed in 77 (79.4%) MDR-TB patients. The mean time to culture positivity was 2.6 weeks ± 4 days. Among all MDR-TB patients, 23 (22.7%) and 74 (77.3%) were newly diagnosed and previously treated patients, respectively (P < 0.05; CI 95%). The history of contact with TB patients was determined in 43 (44.2%) MDR-TB patients. We found that among MDR-TB patients, 28 (28.8%) were diabetic, 45 (46.4%) were non-diabetic and status of diabetes for remaining 24 (24.8%) was unknown. Regarding the outcome of MDR-TB patients, 54 (55.6%) recovered, 5 (5.2%) died and 17 (17.5%) patients were still on ATT, and 22 (22.6%) patient's outcome was unknown [Table 1].
|Table 1: Demographical characterisation of multidrug-resistant tuberculosis (MDR-TB) cases (n = 97)|
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Resistance patterns in new cases
Out of 79 new cases, 58 (73.4%) were DR-TB strains and 21 (26.6%) strains were fully susceptible (SS). Single drug resistance (resistance to any single drug) was observed only in 10 (12.6%), any-two drug resistance in 24 (30.3%), any-three drug resistance in 16 (20.2%) and all-four drug resistance in 8 (10.1%) strains; among these a total of 23 (29.1%) strains were identified as MDR-TB. We found different patterns of MDR-TB, in which maximum resistance was observed with HR+S (12.6%) when compared with other combinations of drugs tested. Individual drug resistance to H was observed in 41 (51.8%) when compared with other drugs tested [Table 2]. Among 79 new cases, 23 (29.1%) MDR-TB, 39 (49.4%) non-MDR-TB and 17 (21.9%) were SS. The maximum number of MDR-TB was observed in age groups of ≥20-40 years (69.6%) when compared with other age groups in new cases.
|Table 2: Drug resistance patterns of fi rst line anti-tubercular drugs in new and previously treated cases (n = 250)|
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Resistance patterns in previously treated cases
Out of 171 previously treated cases,105 strains (61.5%) were DR-TB and 66 (38.5%) strains were SS. Single drug resistance (mono-resistance to any drug) was observed only in 17 (9.9%), any-two drug resistance in 30 (17.5%), any-three drug resistance in 29 (16.9%) and all-four drug resistance was observed in 29 (16.9%) strains; among these a total of 74 (43.3%) strains were identified as MDR-TB. We found different patterns of MDR-TB, among which maximum resistance was observed with HR+ES in 27 (15.7%) when compared with other combination of drugs tested. Among individual drugs, maximum resistance was observed with H in a total of 91 (53.2%) strains [Table 2]. In a total of 171 previously treated cases, 74 (63.3%) MDR-TB, 30 (25.6%) non-MDR-TB and 67 (57.3%) cases were SS. Among previously treated cases maximum number of MDR-TB was observed in age groups ≥20-40 years (63.6%) when compared with other age groups [Table 3].
|Table 3: Age group distribution of multidrug-resistant tuberculosis (MDR-TB), non-MDR-TB and susceptible (SS) both in new and previously treated cases (n = 250)|
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Resistance among HIV patients
Among 97 MDR-TB patients, only 71 patients accepted HIV testing, in which 16/71 (22.5%) patients were HIV-positive co-infected with MDR-TB. Out of these,16 MDR-TB with HIV-positive, 4 (25%) were HIV-positive in new patients ( P > 0.05; CI 95%) and remaining 12 (75%) were previously treated patients (P < 0.05 CI 95%). All HIV patients co-infected with MDR-TB were on treatment with anti-retroviral therapy and ATT as per standard recommendation.
Trends of MDR-TB from 2007 to 2010
In the present study, a continuous increasing trend of MDR-TB and non-MDR-TB was observed from 2007 to 2010. A total cases of 16 (36.4%), 18 (36.7%), 25 (39.1%) and 38 (40.8%) were identified as MDR-TB cases in 2007, 2008, 2009 and 2010, respectively [Figure 1]. Overall MDR-TB gradually increased from 2007 to 2010 in both new and previously treated cases.
|Figure 1: Year-wise distribution of multidrug-resistant tuberculosis (MDR-TB), non-MDR-T B and susceptible (SS) from 2007 to 2010|
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| ~ Discussion|| |
The annual incidence of 1.9 million new TB cases account for one-fifths of the world's new TB cases in India and two-thirds of the TB cases in the South-East Asia Region.  The emergence of resistance to drugs that were used to treat DR-TB and especially MDR-TB has become a significant public health problem in a number of countries and an obstacle to effective TB control. The available information from the several drug resistance surveillance studies conducted in the past suggest that the rate of MDR-TB is relatively low in India.  However, this translates into a large absolute number of DR-TB cases and as yet the management of patients with MDR-TB is inadequate. Specific measures are being taken within the RNTCP to address the MDR-TB problem through appropriate management of patients and strategies to prevent the propagation and dissemination of MDR-TB strains.  As per WHO 2010, there were 29,423 MDR-TB cases reported throughout the world in 127 countries in 2008. These cases only represent about 7% of the total MDR-TB cases that were estimated to have emerged during 2008.  This reflects in part the limited use or availability of DST in countries due to lack of laboratory capacity in the developing countries. Among 27 high MDR-TB burdened countries, only 1% of new TB cases and 3% of previously treated TB cases underwent DST  although, data is insufficient to indicate whether the prevalence of MDR-TB is rising or falling globally. However, only 7% of the estimated 4,40,000 (95%; CI 3,90,000-5, 10, 000) cases of MDR-TB disease worldwide were reported to WHO in 2008 and of these, only a fifth (12% of the total) were treated according to WHO recommended standards.  As per the report of TB India 2009, the emergence and spread of MDR-TB is an increasing public problem in India, with an estimated number of 1, 10, 000 cases spread across the country.  Our study showed that the prevalence of MDR-TB seemed to be very high, i.e., 38.8% among 'clinically suspected' DR-TB cases. Prevalence of MDR-TB has been shown to vary widely over different geographical regions, with higher rates reported from Nepal (48%), Gujarat, India (34%), New York, USA (30%), Brolivia (15%) and South Korea (15%).  However, one previous study from northern India reported that the prevalence of MDR-TB was 19.8%.  We found that 97 (38.8%) were MDR-TB cases; such high prevalence may be because most of these cases were 'clinically suspected' considered for DST and taken ATT during previous treatment or referred cases from others health centres of northern India. A study from Burkina Faso reported that prevalence of MDR-TB in new cases and previously treated cases were 3.4% and 50.5%, respectively.  The high frequency of chronic cases (relapse, failure, re-treatment) may explain the high MDR-TB rate in previously treated cases (43.2%) versus new cases (29.1%). Such high MDR-TB prevalence in previously treated cases was well-established due to partial/incomplete treatment that led to the emergence of DR-TB mutant strain selection, and in new cases it may be explained by the fact that, in this geographical area, DR-TB strains are circulating in the community.
We found high rates of TB-HIV co-infection (22.5%) in MDR-TB patients when compared with co-infection (7.5%) in non-MDR-TB with HIV. This corroborates the result of a study carried out by Gandhi et al.  and the WHO/IUATLD 2002-2007 (31.6%).  The therapeutic response to TB is usually similar in patients with and without HIV, except that HIV patients have a greater risk of drug toxicity and mortality during treatment.  However, as in other studies, HIV sero-prevalence among TB patients is quite high, indicating the importance of encouraging TB patients to be tested for HIV. 
We found different patterns of MDR-TB strains in new cases were HR, HRE, HRS and HRES with 6.3%, 3.7%, 12.6% and 6.3%, respectively, and overall total MDR-TB prevalence was 29.1%. Among previously treated cases, we found HR, HRE, HRS and HRES to be 12.2%, 7.6%, 7.6% and 15.7%, respectively, and overall total MDR-TB prevalence was 43.3%. But a previous study by Sangaré et al.  reported different resistance patterns to HR, HRE, HRS and HRES in new cases were 0.9%, 0.3%, 0.0% and 2.2%, respectively, and overall total resistance was 3.4%; HR, HRE, HRS and HRES among previously treated cases were 8.6%, 5.4%, 1.1% and 35.5%, respectively, and total overall resistance was 50.5%.We found H and R individual drug resistance to be 51.8% and 48.8% in new cases and 53.2% and 47.3% in previously treated cases. Such high rate of resistance to H and R was because these drugs were used in the intensive phase of treatment and in re-treatment of failure cases; mono-resistance to each drug might have caused additional resistance. Some authors believe that such a regimen is equivalent to treatment with one drug (monotherapy) in MDR-TB patients on re-treatment.  In our study a continuous increasing trend of MDR-TB was observed, i.e., 36.4%, 36.7%, 39.1% and 40.8% in 2007, 2008, 2009 and 2010, respectively. Such finding is accordance with a study where in MDR-TB trend rose from 34.44% to 38.82% from 2005 to 2007.  Previous studies showed that an increasing trend of DR-TB and susceptibility of the human population to TB was observed due to co-infection with HIV. Co-infection of DR-TB with HIV is driving the worldwide TB pandemic and may be responsible for overwhelming situation, especially in the poor countries. ,, On the basis of previous studies, it has become clear that DR-TB is multifaceted and that different mutations may lead to different levels of resistance. This may be the reason why for more than one-third of cases of MDR-TB, standard short-course therapy has been found to be an effective treatment. ,,
Further strategies must focus in diagnosing DR-TB and initiating second-line treatment in DR-TB cases to prevent further spread of such strains. A low-cost, rapid point-of-care test that should be sensitive in general patients and can be used at the peripheral health care centre is urgently needed to combat the problem of DR-TB. Our study has several limitations. First prevalence of MDR-TB cannot be extrapolated to the general population, because this study population with 'clinically suspected'cases of all DR-TB. Second our study population does not contain full clinical or treatment details; thus we are unable to provide details about the timing of DST result and second-line TB therapy for every patient. Third clinical outcomes of DR-TB cases are not available because of the scattered distribution of the study population. Further molecular epidemiological tools are needed which particular clone/cluster strains are spreading in that particular community and to explain why the prevalence of MDR-TB strains are increasing in new cases of TB.
| ~ Conclusion|| |
We are reporting a high prevalence (38.8%) of MDR-TB at a tertiary care referral centre both in new cases (29.1%) and previously treated cases (43.3%). The prevalence was more in the PTB (32%) cases when compared with EPTB (6.8%) cases. Transmission of MDR-TB strains within a community is a serious problem, and it has to be tackled seriously, so that we can reduce prevalence of MDR-TB. Culture and DST for patients with 'clinically suspected' DR-TB cases must not be overlooked, so there is need for surveillance of emerging and increasing trend of MDR-TB and to optimise patient management accordingly. The use of rapid, sensitive and specific methods for detecting MDR-TB must be recommended to combat the problem of DR-TB. This strongly highlights the need to make useful strategies for testing, surveillance and effective clinical management of MDR-TB cases in India.
| ~ Acknowledgment|| |
Authors would like to thank the Technical Member of Mycobacteriology Laboratory, Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Science, Lucknow, India for their technical support during research work.
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[Table 1], [Table 2], [Table 3]
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