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1 MRMS Journal of Health Sciences 2016;4(3) pssn: , essn: Original Article Drug Sensitivity Pattern among Category Relapse Cases of Pulmonary Tuberculosis and ts Correlation with Pre- treatment Sputum and Radiological Status. Narendra Kumar Narahari 1, Sudhir Kumar Vujhini 2 1 Assistant Professor, Department of Respiratory Medicine, 2 Associate Professor, Department of Transfusion Medicine, Nizam s nstitute of Medical Sciences, Hyderabad, Telangana, ndia. Corresponding Author: Dr. Narendra Kumar Narahari Received: drnarendrajipmer@gmail.com Accepted: Abstract: Background: An increased incidence of drug resistance is seen even after active implementation of directly observed treatment short course (DOTS). Early diagnosis of such cases can be improved by performing DST (drug sensitivity test) in all relapse cases. Objective: To know the drug sensitivity pattern and emergence of drug resistance among the category relapse cases of pulmonary tuberculosis by culture of sputum & drug sensitivity. Material and methods: n this prospective analysis, we have studied the pattern of drug resistance met with in Mycobaclerium tuberculosis isolates obtained from 102 relapse cases who have completed category- treatment under DOTS. Results: A very high prevalence of MDR-TB (35.29%) is seen among the category relapse cases. An increased drug resistance among relapse cases correlated well with extensive disease with cavitation radiologically and heavy sputum bacillary load in their pre treatment status. Conclusions: We conclude that all relapse cases should be evaluated for sputum culture and drug sensitivity at the earliest to know about the sensitivity pattern before putting them on category 2. DOTS therapy needs to consider some individualization of treatment based on case specific circumstances, not routinely but atleast for those patients with very extensive disease with cavitation and heavy bacillary load in the sputum. Key words: Pulmonary Tuberculosis, treatment, sputum NTRODUCTON: Tuberculosis remains a major public health problem in ndia. ndia accounts for 1/4 th of the global incidence of tuberculosis and tops the list of 22 high tuberculosis burden countries. [1] Though multi drug therapy in tuberculosis in a well established and executed programme proved to be a major success, very often relapses occur in some of the treated cases in the programme. [2] Relapses are usually due to incomplete sterilization of tuberculosis lesions, [3] initial drug resistance patterns, irregularity of the treatment, inadequate treatment regimens and duration. [4] t was considered that relapse was caused by the drug sensitive organisms based on the bacteriological evaluation, but with the emergence of multidrug resistant strains and the changing trends of global resurgence of tuberculosis, a change in drug sensitive pattern within the relapses has been observed. [2] nadequate drug therapy, inadequate doses and lack of properly organized system to ensure effective treatment are the common causes for the development of drug resistance in the community and it reflects failure of National Tuberculosis Programmes. [4] The Global data showed that 32% of the relapse cases are actually MDR TB (multidrug-resistant tuberculosis). [5] With the alarming threat of XDR-TB (extremely drug resistant tuberculosis) and TDR-TB (totally drug resistant tuberculosis), and the increase in HV population the mortality rate is destined to increase, unless some urgent measures are taken up. Therefore, reduction in relapses cases who received revised national tuberculosis control programme (RNTCP) category treatment may also reduce the total number of MDR cases in MRMS Journal of Health Sciences, Vol. 4, No. 3, July-September 2016 Page 166 [6] ndia. n a country like ndia with high initial NH resistance, most experts and literature [4,6,7] recommend supervised daily regimen during intensive phase over thrice weekly treatment to reduce the risk of relapse and drug resistance. This approach should be highly individualized at least in patients with extensive disease with cavitation and heavy bacillary load as the evidence suggests. [8] MATERAL AND METHODS All patients coming to pulmonary medicine OP and pulmonary medicine ward in Government general hospital, Kurnool, who complain of cough for three weeks or more, with or without other symptoms suggestive of tuberculosis (viz. breathlessness, fever, chest pain, hemoptysis, and wheeze) after RNTCP treatment during the period January 2006 to December 2008 were evaluated. All these patients

2 had earlier received fully supervised short course chemotherapy under DOTS (Cat-).Among them 102 patients who fit into down cited selection criteria (Table 1) were taken for the study. Table: 1 showing Selection Criteria nclusion criteria Adult patients with pulmonary tuberculosis who have completed supervised short course chemotherapy under RNTCP (DOTS) for 6 months and presenting with Positive sputum smear samples and Clinical deterioration and /or Radiological worsening Exclusion criteria Pediatric patients Extra pulmonary tuberculosis patients Adult patients with pulmonary tuberculosis who took daily regimen of antitubercular drugs. Co-morbid conditions (corpulmonale, cardiac, renal diseases, liver cirrhosis Diabetes) HV Defaulters, treatment failures The relapse cases were evaluated clinically, radiologically and bacteriologically. The diagnosis of sputum positive pulmonary tuberculosis was done as per RNTCP diagnostic algorithm. Sputum specimens were also collected from these patients and transported to State Tuberculous Center, and/ or ravatham clinical laboratories, Hyderabad, for culture and sensitivity for mycobacterium tuberculosis, through a courier system. Complete Blood Picture, urinalysis, blood sugar, urea, creatinine, uric acid, and liver function tests were done in all cases. Culture of mycobacterium tuberculosis usually takes 6-8 weeks to become positive. Drug susceptibility testing of the first line antituberculous drugs (ATT) was done by absolute concentration method (MC, minimum inhibitory concentration) following the TRC protocol. Meanwhile patients were referred to District tuberculosis center (DTC) for continuation of DOTS under category- till their culture and sensitivity reports were obtained. Once the sensitivity reports were available, patients were treated with drug regimen decided on the basis of the drug susceptibility profile in the reports. Polyresistance was defined as resistance to two or more anti-tuberculosis drugs. Resistance to RF (Rifampicin) and NH (isoniazid), with or without resistance to any other drug was labelled as multidrug resistance or MDR-TB. RESULTS & DSCUSSON Table 2: Distribution of cases according to type, culture and drug sensitivity (NH: isoniazid, RF: rifampicin) Out of 102 relapse cases in our study, 75(73.52%) cases belong to the age group below 45 years who are in the economically productive age group and are the bread earners of the family. Mean age of the study group was Drug sensitivity pattern No. of cases Percentage of the total ( N = 102) Sputum smear % positive and culture negative Culture positive (Sputum smear positive) % NH + RF % (sensitive) Drug resistant % (Resistance) years. Mean age among male and female patients was and years respectively. 71 (69.60%) cases were males and 31 (30.39%) were female patients. Male to female ratio is 2:1. The most common clinical presentation was cough, fever and dyspnea, followed by loss of weight and appetite. Extensive disease with cavitation in the chest radiographs was found in 76 (74.50%) cases. Most of the relapses (87%) occurred within one year of stopping chemotherapy. 76 cases (74.50%) were culture positive and sputum smear positive and 26 (25.49%) were sputum smear positive and culture negative. Out of the 76 culture positive cases, 23 (22.54%) were both NH and RF sensitive. 53 (51.96%) out of 76 culture positive cases were drug resistant cases.(table 2). Among them, 37 (36.27%) are poly resistant and 36 (35.29%) patients are both NH and RF resistant. These were MDR TB cases. Single drug resistance was seen in 15.68% of the cases and mono resistance to NH and RF was seen in 2 (0.01%) and 14 (13.72%) of the cases. Resistance to each drug NH is 38.23%, and rifampicin is 35.29%, and that due to ethambutol and streptomycin is 15.68% and 10.78% (Table 3) Out of the 53 drug resistant cases, most of them 52(98.11%) had extensive disease with cavitation on their pre-treatment chest radiographs (i.e at the time of initiation of cat ). This pattern shows the distribution of resistance cases according to the severity of disease on their pre-treatment chest radiographs.(table 4) MRMS Journal of Health Sciences, Vol. 4, No. 3, July-September 2016 Page 167

3 Table 3: Distribution of drug resistant cases Drug sensitivity pattern No. of Percentag cases e of the total ( N = 102) Poly drug resistance % MDR TB ( NH % RF resistant) Single drug resistance % a NH ( soniazid) % b RF (Rifampicin) % Resistance to any V drug a Resistance to any H % b Resistance to any R % c Resistance to any E % d Resistance to any S % Table 4: Distribution of resistance cases according to the severity of disease on their pre-treatment chest X-rays X ray findings (at the time of initiation of cat ) Minimal disease without cavitation Extensive disease with cavitation No. of Percentage resistance of the total cases among ( N = 53) cat relapses % % MDR- TB: multi drug resistant tuberculosis, NH: isoniazid, RF: rifampicin, H: isoniazid, R: rifampicin, E: ethambutol, S: streptomycin Out of the 53 drug resistant cases, most of them 49(92.45%) had heavy bacillary load in the pre-treatment sputum smears. This pattern shows the distribution of resistance cases according to bacillary content in the pre-treatment sputum smears.(table 5) DSCUSSON: The present study gives information about the bacteriological status and prevalence of drug resistance among relapse cases who received DOTS category treatment. Relapse is defined as a TB patient who was declared cured or treatment completed by a physician, but who reports back to the health service and is now found to be sputum smear positive. The definition of relapse used in this study is from RNTCP. However relapse also refers to the circumference in which a patient becomes and remains culture negative while receiving therapy, but at some point after completion of therapy either becomes culture positive again or has clinical or radiological deterioration that is consistent with active tuberculosis including an appropriate response to re-treatment. [8] Rigorous efforts should be made to establish a diagnosis and to obtain microbiological confirmation of the relapse to enable testing for drug resistance. [8] Table 5: Distribution of resistance cases according to bacillary load in the sputum Pretreatment Sputum status (at the time of initiation of cat ) Heavy bacillary load Less bacillary load No. of resistance cases among cat relapses Percentage the total ( N = 53) % % Relapses in the present study occurred mainly in the cavitatory, far advanced disease and in those having delayed sputum conversion indicating a much higher mycobacterial population where naturally drug resistant strains are more likely. The relapse is usually due to quiescent bacterial population, which did not proliferate during the initial treatment. Selection of spontaneous resistant mutant bacilli among these dormant bacterial populations was not a possibility and for this reason it was theoretically accepted that relapse exhibits the same pattern of drug sensitivity as that of patients with initial tuberculosis. f the relapse occurred several years after the initial treatment, it was concluded that re-infection is more likely to cause the disease. However due to changing trends in the pattern of drug resistance during recent years, microbiological confirmation of relapse should be pursued vigorously by drug susceptibility tests. nadequate treatment and treatment duration which causes incomplete sterilization of tuberculous lesions [3] are the main causes for true relapse, along with host factors, disease and treatment related factors which add up to the menace. [8] There are indications that the initial bacterial content, the extent of disease at diagnosis (presence of cavitation, extent of disease in the chest X-ray) initially, the speed of sputum conversion, early response to therapy, amount of therapy administered (number of doses, duration of therapy, intermittency of therapy) influence the relapse. [8] n a study by panda etal, [2] more than threefold rise of poly resistance was seen in relapse cases, with MDR- TB seen in 13.7% of the relapse cases. Single drug resistance among the relapse cases was around 17%. The resistance to different primary drugs was Streptomycin (20.7%), soniazid (17.0%) and Rifampicin (28.3%) respectively. Similar to our observation 36% of MDR- TB is seen in cat relapse cases in a study by shahzad et al. [9] WHO-UALTD Global Project on Antituberculosis Drug Resistance Surveillance ( ) in ndia showed that MDR among new TB cases was 2.3% and in previously MRMS Journal of Health Sciences, Vol. 4, No. 3, July-September 2016 Page 168 of

4 treated patients was 17.2%. [10] Rajendra Prasad et al [11] in his review stated that acquired drug resistance in ndia varied from 6 to 100%. The data of acquired drug resistance in ndia of the various studies along with the present study is represented down below. (Table 6) Table 6: Acquired drug resistance in ndia. Study Any H% Any S% Any R% H+R% WHO- UATLD ( ) [10] Deivanayag am (2002) [12] Paramasivan et al (2002) [13] North Arcot (South) Raichur (South) Prasad et al (2003) [14] Paramasivan et al (2010) [15] Prasad et al (2012) [16] Present 38.23% 10.78% 35.29% 35.29% study The alarming rise of MDR-TB is a growing concern and its emergence can be prevented by effective treatment of all TB cases. [11] The aims of chemotherapy are not only to cure but also to reduce relapse rate and the duration of infectivity there by stopping the spread of infection to others. Based on a study by Chang et al [8] it was mentioned that standard thrice weekly intermittent regimens with fewer administered doses might still be cost effective in the absence of cavitation on initial chest x ray. However among the patients with positive pretreatment cultures and cavitation, meaningful reduction of relapse rate could be achieved by daily regimen and the risk be further reduced by prolonging the treatment. Furthermore, in my study drug resistance is seen in patients with extensive disease or cavitation in the initial chest X-rays in 98.11% (52 out of 53drug resistant cases). n patients with heavy bacillary load in the pre-treatment sputum smear, 92.45% showed drug resistance. (49 out of 53 drug resistant cases). t should be understood that in case of minimal disease without cavitation and less bacillary load, intermittent therapy may be effective. But in cases of extensive disease with cavitation and heavy bacillary load, their efficacy is still debatable. ntermittent therapy with fewer administered doses results in insufficient sterilization of persisters leading to high relapse rate in cases of extensive disease. [8] The most successful method of eliminating drug resistance is to prevent its emergence by ensuring that drug sensitive tuberculosis is treated aptly. Certain factors like extent of disease and initial bacillary content, presence of residual cavitation at the end of chemotherapy plays an important role and in evaluating the pattern of resistance among relapses. [8] t was recommended to administer daily regimen in intensive phase to achieve early sputum conversion and to reduce the emergence of drug resistant mutants in patients with heavy bacillary load as faster sterilization is expected when actively dividing bacilli are killed daily. Thereafter, to continue thrice weekly regimen to ensure sterilization of the lesions by eliminating slowly or intermittently growing bacilli which helps in assuring complete cure and prevention of relapses and drug resistance. [8] CONCLUSON: t is high time to review all the relapse cases by sputum culture and drug susceptibility tests to know about sensitivity pattern before putting them on Category 2. DOTS therapy needs to consider some individualization of treatment based on case specific circumstances, not routinely but atleast for those patients with very extensive disease with cavitation and heavy bacillary load in the sputum. [8] By revising the management strategies and establishment of laboratory services for adequate and timely diagnosis, one can prevent the spread of MDR-TB and its associated morbidity and mortality by choosing the correct regimen on the basis of DST results performed in the beginning. [11] REFERENCES: 1. RNTCP status report. TB ndia 2007 Chapter 1 Page 10-13, 22 WHO report Geneva Global tuberculosis control surveillance, planning and financing. 2. Panda BN, Jena J, Rai SP, Chatterji RS. Supervised chemotherapy in pulmonary tuberculosis and emergence of drug resistance in case of relapse. nd. J. Tub 2000; 47: Tripathy SP. Relapse in tuberculosis. nd.j.tub 1980; 28: Azhar GS. DOTS for TB relapse in ndia: A systematic review. Lung ndia 2012; 29: World health organization. Treatment of tuberculosis guidelines. 4 th ed. WHO/HTM/TB/ Availablefrom: hqlibdoc.who.int/publications/2010/ _eng.pdfSimilar, accessed on May27, De S. High relapse rate in RNTCP: An increasing concern and time to intervene. Lung ndia 2013; 30: Chang KC, Leung CC, Grosset J, Yew WW. Treatment of tuberculosis and optimal dosing schedules. Thorax 2011; 66: Chang KC, Leung CC, Yew WW, Ho SC, Tam CM. A nested case-control study on treatment - related risk factors for early relapse of tuberculosis. Am J Respir Crit Care Med 2004; 170: Shahzad M, Ayyaz S, Humayun GM, Kamran MH, Dogar LA, Shaheen MA etal. A comparision of drug resistance pattern in category- failure versus category- relapse pulmonary TB patients MRMS Journal of Health Sciences, Vol. 4, No. 3, July-September 2016 Page 169

5 attending a tertiary care hospital in south punjab, Pakistan. s WHO category ATT regimen appropriate? Pakistan journal of chest medicine 19.1(2015). 10. WHO-UALTD Global Project on Antituberculosis Drug Resistance Surveillance ( ). Fourth Global Report. 2008, updated Prasad R, Gupta N, Singh M. Multidrug resistant tuberculosis: trends and control. ndian J Chest Dis Allied Sci Oct-Dec; 56(4): Review. 12. Deivanayagam CN, Rajasekaran S, Venkatesan R,Mahilmaran A, Ahmed PR, Annadurai S, et al. Prevalence of acquired MDR-TB and HV coinfection. ndian J Chest Dis Allied Sci 2002;44: Paramasivan CN, Venkataraman P, Chandrashekhran V, Bhatt S, Narayanan PR. Surveillance of drug resistant in tuberculosis in two districts of south ndia. nt J Tuberc Lung Dis Source of Support: Nil. Conflict of nterest: None ;6: Prasad R, Suryakant, Mukerji PK, Gupta AK, Garg R, Rizvi DM, et al. Acquired drug resistance in patients of pulmonary tuberculosis attending a tertiary care center. nt J Tuberc Lung Dis 2003;11 (Suppl.):S3O Paramasivan CN, Rehman F, Wares F, Sundar Mohan N, Sundar S, Devi S, et al. First- and second-line drug resistance patterns among previously treated tuberculosis patients in ndia. nt J Tuberc Lung Dis 2010; 14: Prasad R, Verma SK, Garg R, Jain A, Anand SC, Hosmane GB, et al. Drug susceptibility pattern of Mycobacterium tuberculosis isolates from patients of Category- failure of pulmonary tuberculosis under directly observed treatment short-course from North ndia. Biosci Trends 2012; 6: Cite this article as: Narendra Kumar Narahari, Sudhir Kumar Vujhini. Drug Sensitivity Pattern Among Category Relapse Cases of Pulmonary Tuberculosis and ts Correlation With Pre- treatment Sputum And Radiological Status. MRMS J Health Sciences 2016;4(3): MRMS Journal of Health Sciences, Vol. 4, No. 3, July-September 2016 Page 170