Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 17  |  Issue : 2  |  Page : 81-86

Drug resistance patterns among pulmonary tuberculosis patients in a tertiary care hospital in northern Karnataka


Department of Pulmonary Medicine, J. N. Medical College, KLE University, Belgaum, Karnataka, India

Date of Web Publication5-Aug-2015

Correspondence Address:
Gajanan S Gaude
Department of Pulmonary Medicine, J. N. Medical College, KLE University, Belgaum - 590 010, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2276-7096.161510

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  Abstract 

Background: Resistance to anti-tuberculosis (anti-TB) drugs is becoming a major and alarming threat in most regions worldwide and India ranks second in the world in harboring multi-drug resistant cases (MDR)-TB. The study was carried out to evaluate the drug resistance pattern to first-line anti-TB drugs in Northern Karnataka.
Materials and Methods: A prospective study was conducted at a tertiary care hospital between January 2011 and June 2012. A total of 110 sputum samples were examined for the acid-fast bacilli (AFB) culture. A total of 48 AFB culture-positive samples were subjected for AFB drug sensitivity testing (DST). DST was done for isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), ethambutol and streptomycin (SM) after isolation by using the resistance proportion method.
Results: Of the 48 AFB culture positive specimens, 12 (25.0%) cases were sensitive to all the five drugs while 36 (75.0%) cases showed resistance to one or more drugs. Among these, the resistance to RIF was highest (91.9%), while resistance to SM, INH, PZA and ETB was observed in 72.2%, 72.2%, 63.9% and 52.8%, respectively. The resistance to all five drugs was highest (41.7%), while MDR isolates were obtained in 69.4% of the cases. Illiteracy, low socio economic status, previous history of TB and alcoholism were found to have statistically significant association for the development of MDR.
Conclusions: The proportion of drug resistance in the present study was 75.0% and MDR was present in 69.4% of cases. Therefore during initiation of new case, proper explaining and completion of the treatment is very important to avoid the development of future drug resistance in pulmonary TB patients.

Keywords: Drug resistance surveillance, drug susceptibility testing, multi-drug resistance, pulmonary tuberculosis


How to cite this article:
Gaude GS, Praveenkumar, Hattiholli J. Drug resistance patterns among pulmonary tuberculosis patients in a tertiary care hospital in northern Karnataka. J Med Trop 2015;17:81-6

How to cite this URL:
Gaude GS, Praveenkumar, Hattiholli J. Drug resistance patterns among pulmonary tuberculosis patients in a tertiary care hospital in northern Karnataka. J Med Trop [serial online] 2015 [cited 2019 Dec 8];17:81-6. Available from: http://www.jmedtropics.org/text.asp?2015/17/2/81/161510


  Introduction Top


Tuberculosis (TB) is a major public health problem in India. In 2010, there were 2-2.5 million new cases accounting for one-quarter of the total cases worldwide. [1] The impact of TB can be devastating, especially in developing countries suffering from high burdens of both TB and human immunodeficiency virus (HIV) infections. [1] There is a rising trend of drug-resistant TB in different parts of the world, India being next only to China, both contributing to more than 50% of global multi-drug resistant (MDR)-TB cases. Frequency of MDR-TB is <3% in new cases and 12-50% among retreatment cases as per the recent studies. [2] During the last decade, there has been an increase in reported incidences of drug resistance in Category II cases, particularly among those treated irregularly, with the incidence of MDR-TB varying from 12% to 17%. [3] MDR-TB, defined as resistance to at least rifampicin (RIF) and isoniazid (INH), is a compounding factor for the control of the disease, since patients harboring MDR strains need to be entered into alternative treatment regimens involving second-line drugs that are more costly, more toxic, and less effective. [4]

Hence, this study was undertaken to assess the drug resistance patterns to first-line anti-TB drugs in pulmonary TB cases and to assess the risk factors responsible for drug resistance in Northern parts of Karnataka.


  Materials and Methods Top


The study was carried out at Department of Pulmonary Medicine, KLES Dr. Prabhakar Kore Hospital and Medical Research Centre, Belgaum between January 2011 and June 2012. Patients diagnosed with sputum smear-positive pulmonary TB were included in the study.

Sampling Procedure

This was a case based study in a tertiary care hospital over a period of 18 months. A total of 110 sputum smear positive pulmonary TB patients samples were subjected for acid fast bacilli (AFB) culture by Lowenstein-Jensen (LJ) media. Among these 110 samples, 48 samples were culture positive at end of 6 weeks. Drug sensitivity testing (DST) was conducted for these 48 samples.

Method of Collection Of Data

After obtaining informed consent, a standard questionnaire containing all the relevant information was completed for each patient. A detailed history relevant to TB, including treatment duration was recorded. A patient was confirmed sputum smear positive if at least one of two sputum samples were positive for AFB by Ziehl Nelsen method. DST was carried on specimens that grew Mycobacterium tuberculosis on culture in LJ medium.

Method of Acid Fast Bacilli Culture

The AFB cultures were done in the department of Microbiology of the college on LJ medium. The sputum specimen was processed by modified Petroff's method. For each specimen, two LJ slopes were inoculated each with one 5 mm loopful of the centrifuged sediment, distributed over the surface. All cultures were incubated at 35-37°C for up to 8 weeks. The tests were done in Biosafety Class II cabinet. DST utilized the same type of LJ medium and inoculation methods. LJ medium was impregnated with INH, RIF, pyrazinamide (PZA), ethambutol (EMB) and streptomycin (SM) according to the conventional proportion method as recommended by World Health Organization (WHO)/International Union Against Tuberculosis and Lung Disease. [4] The concentrations of anti-TB drugs were 1 μg/ml for INH, 40 μg/ml for RIF, 100 μg/ml for PZA, 2 μg/ml for EMB and 4 μg/ml for SM. The growth of colonies in the drug containing plate was compared to the control plate as a proportion. The growth of an isolate from culture was scrapped with a loop and bacterial suspension was made in sterile distilled water, votexed and matched with McFarland opacity tube No. 1. Dilutions of 10 2 and 10 4 were made and inoculated on control and drug containing media and incubated at 37°C. The first reading was taken after 28 days of incubation and if the isolates were susceptible a second reading was taken on 42 nd day. Colonies were counted only on slope seeded with the inoculums that have produced exact readable counts or actual counts (up to 100 colonies on the slope). Ratio of number of colonies in drug containing slopes by that in the drug free slopes was considered as the percentage resistance (R). If the bacterial growth on the medium with the specific drug was ≥1% compared to the control, the strain was declared resistant to the specific drug; or it was defined as sensitive when the growth rate was <1% compared with the control. The ethical clearance was obtained from the Institutional Ethical Board of JNMC.

Definition of Terms

New case: Patients confirmed as having pulmonary TB for the first time and without any history of previous anti-TB (for up to 1-month) treatment. Old or treated case: Patients with previous anti-TB treatment lasting more than 1-month were considered as a treated case, and any drug resistance based on them were reported as acquired drug resistance.

Primary resistance: Drug resistance in a fresh or new case. Initial resistance: Primary resistance and undisclosed acquired resistance. MDR: Isolates being resistant to at least RIF and INH. Poly resistance: Isolates resistant to one or more drugs, but not MDR strains.

Statistical Analysis

The data obtained were coded and entered into the Microsoft Excel worksheet. The categorical data were expressed as rates, ratios and percentages. Continuous data was expressed as mean ± standard deviation. The comparison between the two groups was done by Student's t-test and association of the risk factors among two groups was analyzed using Chi-square test (with Yate's correction wherever appropriate). A P < 0.05 was considered significant.


  Results Top


A total of 110 sputum smear samples of pulmonary TB patients were included in the study. The AFB cultures on LJ medium were positive in 48 patients (43.6%). Rest of the cultures did not reveal any growth or were contaminated. The baseline characteristics of these culture positive 48 patients are given in detail in [Table 1]. About two-third patients had prior history of TB. Drug resistance was observed in 36 patients (75.0%). Twelve patients (25.0%) showed sensitivity to all the drugs tested. Among drug resistance strains, 4 patients (11.1%) had primary drug resistance, while 32 patients (88.9%) had acquired drug resistance.
Table 1: Baseline characterstics of the 48 patients, who had culture positive and sensitivity testing performed

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The resistance to RIF was highest (91.7%), while resistance to SM, INH, PZA and EMB were 72.2%, 72.2%, 63.9% and 52.8% respectively [Table 2]. The resistance to all five drugs was highest (41.7%), while it was lowest for two drugs (2.8%) [Table 3]. MDR isolates were obtained in 25 patients (69.4%).
Table 2: Resistance pattern of MTB to first line anti-TBdrugs among the 36 drug resistant strains in India

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Table 3: Resistance pattern of 36 drug resistant strains of MTB to first line anti-TB drugs

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[Table 4] shows various risk factors associated for the development of drug resistance. It was observed that illiteracy, low socio economic status, manual laborers, past history of PTB and alcoholism were found to have statistically significant association for the development of MDR.
Table 4: Factors associated with drug resistant strains in different categories of patients (n=36)

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  Discussion Top


Globally MDR-TB has increased all over the world over the past few decades. MDR-TB is a compounding factor for the control of the disease. In the present study, a total of 110 smear positive sputum samples were subjected for AFB culture, out of which only 48 (43.6%) samples had growth at the end of 8 weeks. In a study done at Sindh [4] out of 890 sputum positive PTB cases, growth was seen in 285 (32.0%) patients, while another study done at Tehran [5] revealed 548 (35.2%) culture positive cases among 1556 sputum positive PTB cases. A negative culture result with a specimen containing tubercle bacilli may be due to various causes. In patients receiving treatment, the organisms may have lost their ability to grow on culture media and be practically dead. Patients being treated with a RIF-containing regimen often become culture-negative by about the 3 rd week of treatment, [6] although they may still be sputum smear-positive: Bacilli are dead or non-viable. Sometimes negative culture can also result from the presence of a very few bacilli in the sputum sample. [6]

In the present study, DST was carried for all first line anti-tubercular drugs-INH, RIF, PZA, EMB and SM. Out of 48 M. tuberculosis isolates tested for drug sensitivity against first line drugs, 12 isolates (25%) were sensitive to all 5 drugs, while 36 isolates (75%) were found to be resistant to one or more drugs. MDR resistant strains were observed in 25 isolates (69.4%). Poly resistance was found in 5 isolates (13.9%). The prevalence of primary/initial drug resistance observed in different studies from India varies from 7.9% to 27.7%. [7],[8],[9] Similarly, the prevalence of acquired drug resistance ranges from 60% to 85%. [10],[11],[12],[13],[14],[15],[16] Thus, the message from these studies is clear that there is a high level of drug resistance seen with M. tuberculosis. In the present study, the prevalence of primary drug resistance was 11.1%, while the acquired resistance was observed in 88.9%. In the North Arcot district study of Tamil Nadu, the prevalence of acquired drug resistance was 81%. [17] The high rate of acquired drug resistance observed in these studies as well as in ours probably reflects the absence of good effective national TB control program and irregular/improper use of anti-TB drugs during recent years, which have led to accumulation and multiplication of drug resistant strains.

In this study, drug resistance to the single drug was observed to be 16.7%, while for four and five drugs it was 11.1% and 41.7% respectively. In a study done at Dhaka, resistance to single drug was found in 22.1%, to two drugs in 15.9%, to three drugs in 10.5%, and to four drugs in 4.2%. [18] The most commonly affected drugs were RIF, INH and SM. In treated cases of TB, the proportion of strains resistant to two, three or more drugs was significantly higher than among new cases. This relationship was seen globally as well as regionally and suggested amplification of resistance. [6] Resistances to two or three drugs are often difficult to treat and result in treatment failure. A total of thirteen different drug-resistant patterns were obtained after testing 36 strains of M. tuberculosis isolates. Resistance to all five first-line drugs was observed in 41.7% cases. Although higher, similar findings have been observed in other studies as well. In a study done at Bangalore [14] it was observed to be 65.2%, while another study reported it to be 56.5%. [15]

Multi-drug resistant strains were detected in 25 cases (69.4%). Among them, 23 cases (92.0%) were MDR-TB in Category II failure and 2 cases (18. 2%) were MDR-TB in Category I failure. Our MDR-TB figures differ greatly from those reported by the Revised National TB Control Programme (RNTCP) and Indian national figures in WHO global surveys. [16],[17],[18],[19] The reported prevalence of MDR-TB is 2-5% among new cases and among retreatment cases it is 12-17%. [16] The level of MDR-TB in our study is similar to the ones reported from Mumbai [20] (68%) and Varanasi [21] (67.3%). Other studies have also reported such higher prevalence of MDR strains. [22],[23],[24] A significantly higher rate of MDR-TB was found in Dehradun [25] (91.2%). A high prevalence of MDR-TB in retreatment cases is not unique to India and has been documented in Republic of Moldova (65.1%), five regions of the Russian Federation and Tajikistan (Dushanbe city and Rudaki district, 61.6%), Belarus (60.2%) and Lithuania (51.5%). [26]

In the present study, resistance rate was highest for RIF (91.7%) followed by INH (72.2%), SM (72.2%), PZA (63.9%) and EMB (52.8%) respectively. Only one study conducted at Dehradun [25] showed similar results, with 91.2% resistance for RIF and 94.1% for INH. In a study done at Mumbai, [27] the resistance rates obtained for INH, RIF, EMB and SM were 53.2%, 74.4%, 21.7% and 70.0%, respectively. This high rate of INH and RIF resistance may be due to widespread use of these drugs in first-line treatment of patients and possibly irregular and inadequate dosing of the drug. Furthermore, RIF is used in other conditions like leprosy, brucella, meningitis and as empirical therapy in the treatment of unknown pyrexia. RIF is potent bactericidal and sterilizing drug, and hence the most important in DOTS program; resistance to RIF may lead to failure of DOTS program. [28]

Risk Factors for Drug-Resistant Pulmonary Tuberculosis

Various risk factors were analyzed for development of drug resistance in TB. Among these, past history of treated pulmonary TB and previous history of irregular anti-TB therapy was found in 86.1% and 80.5% of cases, respectively. Low socio-economic status and illiteracy were observed in almost two-third of the cases. Manual laborers and alcohol consumption also contributed to the significant cases. All these risk factors contributed significantly to the development of drug resistance. Similar findings were noted in a study done at Indore. [29] In a study in Turkey however, patient's education and MDR-TB were found to be inversely related. [30] The poor compliance in TB treatment is often due to the cost of drugs when taking treatment outside DOTS program, and lack of education and/or poor socioeconomic status leads to stoppage of therapy due to financial position. A study was done in Pakistan also pointed out that MDR-TB was common in non-compliance of patients, which is due to lower education and lower socioeconomic status. [31]

The relationship between history of receiving anti-TB treatment and drug resistance has clearly been described. [32] A systematic review on 29 studies in Europe reported the pooled risk of MDR was up to 10 times higher in previously treated cases than in never treated ones. [33] Our study is consistent with the former reports that revealed the importance of previous treatment history in the development of drug resistance. The selection of resistant mutants occurs due to inadequate treatment, resulting in acquired mono-resistant TB. [34] Novel mutations in a growing population will eventually lead to MDR-TB, if the inadequate treatment continues. Insufficient duration of treatment also contributes to be a cause of drug resistance; [35] but irregular treatment is even worse. If the treatment is irregular, the number of bacterial death and bacterial growth cycles will be greater, giving more opportunities for individual mutations of different independent genes to accumulate. [36]

Alcohol abuse/dependence was associated with an eight-fold increase in drug resistance. [37] In the present study also, alcoholism also observed to be a significant factor in the development of drug resistance. This is due to the fact that alcoholism has been associated with greater treatment defaults and hence poor treatment outcome among patients with TB. Several studies have reported the association between HIV infection and MDR-TB. [38],[39] In the present study, only 2 out of the 36 patients (5.6%) tested positive for HIV. A Peruvian study also found only 1.5% of MDR-TB patients to be infected with HIV. [40] A study in sub-Saharan Africa has recorded HIV sero-prevalence rates of 50-70% in patients with TB. [41] According to current hypotheses, HIV increases the chances of transmission of MDR-TB rather than leading to an inadequate treatment. [42] However in some East European countries, MDR rates are double in patients with HIV infection. [43] Diabetes was present in 19.4% patients of our study. The overall importance of diabetes as a risk factor for drug-resistant TB is still largely unidentified.

While many patients from our study are likely to access the RNTCP for TB treatment, the seeking of care from private practitioners by many others and the constant shopping for treatment between the public and private sectors cannot be ignored. The contribution to MDR-TB levels from aberrant treatment practices in the unregulated private sector has been suspected for long and makes it likely that the levels of MDR-TB revealed by this study are an underestimate. [44]

Our study has several limitations. First, there is potential bias in estimation of drug resistance in previously treated cases. Although a detailed history was obtained from the patients, assignment of the patient to new or retreatment categories was based upon the information given by patients and may not have been accurate, therefore we cannot exclude the possibility of misclassification. Second, the population on which the study was conducted had presented to our referral center. The prevalence of PDR was 11.1%, while ADR cases constituted 88.9%. This suggests that only patients with more serious conditions may have presented to our center, and our data may not be necessarily be representative of the national population especially with regard to new cases. Third, we studied only patients with documented positive cultures, not those with negative cultures or those from whom no culture was obtained. Fourth, nonviable specimens were more likely to be resistant than viable specimen on testing by other methods. Thus, there may have been a slight selection bias against resistant isolates; the actual proportion of patients with resistant isolates may be 2-3% higher than the one reported in this investigation. Fifth, these data are based on very small numbers of patients. Hence, our observations may not be generalized to the entire country. However, the results remain important since the increasing level of drug resistance among mycobacterial isolates in our population is alarming.

 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]


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