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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 22  |  Issue : 1  |  Page : 28-34

Primary drug resistance in pulmonary tuberculosis cases by standard proportion method and BACTEC radiometric method


1 Department of Clinical Microbiology and Pathology, Northern Railway Central Hospital, New Delhi, India
2 Department of Clinical Microbiology, Maulana Azad Medical College, New Delhi, India

Date of Submission30-Jan-2020
Date of Decision06-May-2020
Date of Acceptance18-Jun-2020
Date of Web Publication13-Aug-2020

Correspondence Address:
Dr. Deepa Pandey
Department of Clinical Microbiology and Pathology, Northern Railway Central Hospital, Connaught Place, New Delhi - 110 001
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jacm.jacm_3_20

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  Abstract 


OBJECTIVE: The objective was to study anti-tubercular drug susceptibility level among 'newly diagnosed' pulmonary tuberculosis (TB) cases by two methods of drug sensitivity testing i.e., standard proportion method (SPM) and BACTEC radiometric method.
MATERIALS AND METHODS: Sputum samples from fifty new cases of pulmonary TB were cultured and subjected to antitubercular drug susceptibility testing by using conventional SPM and radiometric method (BACTEC 460 TB system) and compared.
RESULTS: Monoresistance was found to be 2%, 8%, 0% and 2% for Streptomycin (S), Isoniazid (H), Rifampicin® and Ethambutol (E), respectively. Any resistance (with or without resistance to other drugs) was 4%, 28%, 10% and 16% for S, H, R and E, respectively. Primary multidrug resistance was 10% (5/50) namely H + R, 6% (3/50); H + R + E, 2% (1/50); H + R + S, 0% (0/50) and H + R + E + S, 2% (1/50). H + E resistance was found in 10% (5/50) of isolates.
CONCLUSION: Comparing with other studies, the levels of H, R and multi drug resistance (MDR) were within the expected levels in our study. However, more number of similar studies on drug resistance need to be undertaken regularly to assess the changing trends.

Keywords: Ethambutol, Isoniazid, primary drug resistance, Pyrazinamide, Rifampicin, Streptomycin


How to cite this article:
Pandey D, Baveja C P. Primary drug resistance in pulmonary tuberculosis cases by standard proportion method and BACTEC radiometric method. J Acad Clin Microbiol 2020;22:28-34

How to cite this URL:
Pandey D, Baveja C P. Primary drug resistance in pulmonary tuberculosis cases by standard proportion method and BACTEC radiometric method. J Acad Clin Microbiol [serial online] 2020 [cited 2020 Sep 30];22:28-34. Available from: http://www.jacmjournal.org/text.asp?2020/22/1/28/291929




  Introduction Top


Documenting the current status of drug resistance and the effect of directly observed treatment short (DOTS) on the level of drug resistance is crucial. To assess the amount of resistant bacilli transmission in the community, a useful epidemiological indicator is level of antitubercular drug resistance.[1] Continuous and/or periodic study of drug resistance is required to decide therapy to be used for treatment, which acts as a useful parameter in the evaluation of current and past chemotherapy programmes.[2],[3] It has an impact on the design of therapeutic regimens and policy decisions.[4] Drug resistance in tuberculosis (TB) may be primary resistance or acquired resistance. Primary resistance is the presence of drug resistance in a TB patient who has never received prior treatment with anti-TB drugs.[1] It is attributed as an infection due to the spread of drug-resistant organisms. An indicator of TB control efforts in past is primary drug resistance. A patient with primary drug resistance can be resistant to one or more drug. Resistance to a single antitubercular drug is defined as 'monoresistance', and resistance to more than one antitubercular drugs is defined as 'polyresistant'.[5] Resistant to both Isoniazid (H) and Rifampicin®, with or without resistance to other drugs, is defined as multiple drug resistance (MDR). A patient with resistance to both Isoniazid (H) and Rifampicin ® is primary MDR. This study was conducted to assess the pattern of primary drug resistance.


  Materials and Methods Top


Fifty new cases of pulmonary TB presenting with any of the complaints of persisting cough for 3 or more weeks, continuous fever, weight loss and haemoptysis were included. All the cases were confirmed by Ziehl–Neelsen (ZN) staining, fluorescent staining,[6],[7] culture on Lowenstein–Jensen (LJ) medium,[8] and radiometric method (BACTEC 460 TB system) (Headquarters Franklin Lakes, New Jersey, U.S).[9] Exclusion criteria included patients who were on antitubercular treatment, defaulter, failure and relapse cases of pulmonary TB and those with extrapulmonary TB. The positive cultures were processed for drug sensitivity testing for Streptomycin (S), Isoniazid (H), Rifampicin ® and Ethambutol (E) by using standard proportion method (SPM) and radiometric method.[8],[9],[10]


  Results Top


This study included fifty cases (n = 50) of pulmonary TB (clinically diagnosed). Out of the fifty patients included in the study, males were 44% and females were 56%. Positive culture on LJ medium was obtained in 88% of cases. Twelve percent of the samples were contaminated on LJ medium. These contaminated samples were subcultured from the corresponding BACTEC vials to LJ medium, and positive growth was obtained in all the 6 samples. Mycobacterial culture on BACTEC 460 TB system (radiometric method) showed positive results in 100% of the samples [Table 1].
Table 1: Correlation of culture on Lowenstein.Jensen medium and culture by BACTEC (n=50)

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Drug susceptibility patterns

By SPM (n = 50), 96% of the isolates were sensitive to Streptomycin, 74% of the isolates were sensitive to Isoniazid, 94% of the isolates were sensitive to Rifampicin and 90% of the isolates were sensitive to Ethambutol [Table 2].
Table 2: Drug susceptibility pattern of antitubercular drugs by standard proportion method and BACTEC radiometric method

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Using BACTEC radiometric method (n = 50), 96% of the isolates were sensitive to Streptomycin, 72% of the isolates were sensitive to Isoniazid, 90% of the isolates were sensitive to Rifampicin and 84% of the isolates were sensitive to Ethambutol in this study [Table 2].

Considering SPM as gold standard for DST, Streptomycin sensitivity and specificity was 100% and positive predictive value (PPV) and negative predictive value (NPV) was 100%. Sensitivity was 97.29%, specificity was 100%, PPV was 100% and NPV was 92.85% for Isoniazid. Rifampicin sensitivity was 95.74%, specificity was 100%, PPV was 100% and NPV was 60%. Ethambutol sensitivity was 93.33%, specificity was 100%, PPV was 100% and NPV was 62.5% by BACTEC radiometric method. Of the fifty samples, the resistance to any drug was 30% by SPM and 32% by BACTEC radiometric method [Table 3].
Table 3: Drug susceptibility by standard proportion method and BACTEC radiometric method

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The resistance level to all primary drugs for any resistance ranged from 4% to 26% by SPM and 4% to 28% by BACTEC radiometric method [Table 3]. Drug susceptibility patterns were analysed for the four antitubercular drugs namely Streptomycin (S), Isoniazid (H), Rifampicin ® and Ethambutol (E). Any resistance was assessed as isolates with or without resistant to other drugs. Any resistance to Streptomycin was seen in 2 cases (4%) by SPM and as well as BACTEC radiometric method. Isolates resistant to Isoniazid with or without resistant to other drugs were 13 (26%) by SPM and 14 (28%) by BACTEC radiometric method. Thirteen isolates resistant to Isoniazid by SPM were also resistant by BACTEC radiometric method. One isolate which was sensitive by SPM was however resistant by BACTEC radiometric method. Any resistance to Rifampicin was observed in 3 isolates (6%) by SPM and 5 isolates (10%) by BACTEC radiometric method. Three isolates which were resistant to Rifampicin by SPM were also resistant to Rifampicin by BACTEC radiometric method. Two isolates (4%) which were sensitive to Rifampicin by SPM were however resistant to Rifampicin by BACTEC radiometric method. By SPM, Ethambutol resistance was seen in 5 isolates (10%) with or without resistant to other drugs, whereas 8 isolates (16%) were resistant by BACTEC radiometric method. Five isolates were resistant by SPM were also resistant by BACTEC radiometric method. Three isolates which were sensitive to Ethambutol by SPM was however resistant to this drug by BACTEC radiometric method.

One isolate showed monoresistance to Streptomycin by SPM as well as by BACTEC radiometric method. Five isolates (10%) showed monoresistance to Isoniazid by SPM, but only 4 isolates (8%) showed this type of resistance by BACTEC radiometric method. Three isolates which were monoresistant to Isoniazid by SPM were also resistant by BACTEC radiometric method. No isolate was resistant only to Rifampicin by either of the two methods of drug susceptibility testing (DST). In case of Ethambutol, only one isolate was resistant by BACTEC radiometric method. However, this isolate was sensitive to Ethambutol by SPM.

Multidrug resistance (MDR) was seen in 3 isolates (6%) by SPM and 5 isolates (10%) by BACTEC radiometric method. Resistance to both Isoniazid and Rifampicin was found in 2 isolates (4%) by SPM and about 3 isolates (6%) by BACTEC radiometric method. One isolate (2%) which showed combined resistance to Isoniazid, Rifampicin and Ethambutol by SPM was also resistant by BACTEC radiometric method. One isolate was resistant to all the four drugs (H, R, E and S) by BACTEC radiometric method. However, it was sensitive to Streptomycin and Isoniazid by SPM.

Other patterns which were obtained included combined Isoniazid and Ethambutol resistance seen in 4 isolates (8%) by SPM and 5 isolates (10%) by BACTEC radiometric method. Four isolates which were resistant to both Isoniazid and Ethambutol by SPM also showed resistance by BACTEC radiometric method. One isolate (2%) showed resistant pattern of Isoniazid and Streptomycin by BACTEC radiometric method. No isolate in our study showed other resistant patterns such as Isoniazid, Ethambutol and Streptomycin (H + E + S), Rifampicin and Ethambutol (R + E), Rifampicin and Streptomycin (R + S), Rifampicin, Ethambutol and Streptomycin (R + E + S) and Ethambutol and Streptomycin (E + S).


  Discussion Top


Despite the availability of effective antitubercular chemotherapy for over 50 years, TB remains a major global [11] and public [12] health problem. Over the years, drug-resistant strains have also emerged. Primary infection with such strains and its further spread is a concerning issue as it will demand modification of the drugs used in the treatment. Data on trends of primary drug resistance globally [13],[14],[15],[16],[17],[18] [Table 4] and in Indian studies [19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36] [Table 5] are tabulated.
Table 4: Global patterns of primary drug resistance

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Table 5: Primary drug resistance in India

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In this study, 72% of the isolates were sensitive to all drugs by SPM, whereas 28% were resistant to any drug by SPM. However, radiometric method showed that 68% of the isolates were sensitive to all drugs and 32% of the isolates were resistant to any drug.

In our study, primary drug resistance in fifty new pulmonary TB cases was evaluated. Streptomycin resistance in the present study was 4% by both DST methods, and monoresistance to this drug was found in 2% of isolates. Primary drug resistance by the ICMR, in a nationwide study during 1965–1967 in 9 urban areas of the country which included pulmonary TB patients who had denied any history of previous treatment, showed Streptomycin resistance ranging from 8% to 20%.[19],[20] Namaei et al. reported a high prevalence of Streptomycin resistance in Iran [18] (23.75%). The author attributes this to the usage of this drug for many years for the treatment of many infectious diseases including brucellosis and TB. A review of surveys carried out during 1985–1994 on drug resistance revealed the rates of primary drug resistance to Streptomycin to be from 0.1% to 23.5%.[14] High resistance rates to Streptomycin (S) were reported in Zaire, Brazil, and Pakistan, whereas low levels of resistance were reported from China, Bosnia– Herzegovina and Ethiopia. WHO/IUATLD global project on drug resistance surveillance spread over 35 countries in 5 continents carried out during 1994–1997 had a prevalence of Streptomycin resistance as 6.5% (0.3%–28%).[15] Other WHO/IUATLD global projects on drug resistance surveillance in 1996–1999 and 1999–2002 showed the prevalence of Streptomycin resistance to be 5.2% (0.3%–32.4%)[16] and 6.3% (0%–51.5%),[17] respectively. Streptomycin resistance in the present study was within the range seen in various studies. Although this study had lower level of drug resistance, it can be the result of low exposure due to absence of Streptomycin from DOTS regimen for Category I patients to which our study group belongs. Isoniazid resistance was 26% by SPM and 28% by BACTEC radiometric method in this study. A nationwide study on primary resistance during 1965–1967 in urban areas showed Isoniazid resistance from 11% to 20%.[20] During the 1980s, studies have shown that Isoniazid initial drug resistance ranged from 10.8% to 32.9%.[22] In a study, 32.9% of resistance was found in a rural population of Kolar.[24] Contrary to this in a Korean study,[2] easy access to the antitubercular drugs led to much higher level of initial resistance. In 1985–1986, another study at State TB Centre, Bengaluru,[24] found 17.35% as initial drug resistance to Isoniazid. A retrospective study in the early 1990s, at New Delhi,[26] showed 18.5% Isoniazid primary resistance. According to Indian studies, primary Isoniazid resistance in various studies ranged from 2.24% to 32.87%.[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36] In this study, the level of resistance was slightly towards higher side (26%). As this drug forms the backbone of antitubercular therapy and is in use since the past 30–40 years, unsupervised, undisclosed therapy and improper compliance may have led to the emergence of resistant strains, which is likely. In addition, larger sample size should be included to assess the level of resistance.

A review of surveys of drug-resistant TB carried out during 1985–1994 revealed the global existence of the problem [14] with higher Isoniazid primary resistance from India, Haiti and Kenya, whereas lower from Argentina, Melbourne and South Eastern England. Cohn et al. reviewed and found the primary initial Isoniazid resistance in the order of 0%–16.9%.[14] Namaei et al. reported very low level of Isoniazid resistance in Iran [18] and contributed this to be due to strict implementation of DOTS, good patient compliance and non-availability of anti-TB drugs for prescription by private physician. Mahadev et al. reported 10.3% of Isoniazid resistance in Hooghly district of West Bengal and 2.5% in Mayurbhanj district of Odisha.[34] In a study by Malhotra et al., primary Isoniazid resistance was estimated to be 13.6% (6/44).[37]

In the present study, any resistance to Rifampicin was observed in 3 isolates (6%) by SPM and 5 isolates (10%) by BACTEC radiometric method. Two isolates which were sensitive to Rifampicin by SPM was however resistant to Rifampicin by BACTEC radiometric method. However, monoresistant to Rifampicin was not found by either of the two methods of DST.

In the Indian scenario during the 1980s, primary drug resistance to Rifampicin resistance started appearing. It was found in Bengaluru, Jaipur, North Arcot and Puducherry, but not in Gujarat [22],[23],[24],[25],[27] This was attributed to the introduction of short-course chemotherapy regimens including Rifampicin. Lower Rifampicin resistance (0.6%) was reported in a retrospective study done in the early 1990s,[2] whereas a study conducted by Malhotra et al. reported 6.8% primary resistance to Rifampicin.[37]

Surveys reviewed from 1985 to 1994 globally,[14] showed primary resistance to Rifampicin as a single agent was unusual (0%–3%). WHO/IUATLD global projects of drug resistance surveillance reported primary Rifampicin resistance prevalence of 1.8% (0%–16.8%),[15] 1.2% (0%–15.8%)[16] and 1.4% (0%–15.6%)[17] in 1994–1997, 1996–1999 and 1999–2002, respectively. Resistance was found in 5 isolates (10%) by SPM, whereas 8 isolates (16%) were resistant by BACTEC radiometric method. Among these, three isolates which were sensitive to Ethambutol by SPM were however resistant by BACTEC radiometric method. Only one isolate (2%) which was found resistant only to Ethambutol by BACTEC radiometric method was sensitive to it by SPM. Furthermore, Ethambutol susceptibility was not performed in most of the Indian surveys.[1]

Cohn et al. reviewed 63 surveys and found the primary Ethambutol resistance in the order of 0%–4.2%.[14] WHO/IUATLD global projects on drug resistance surveillance from 1994 to 1997, 1996 to 1999 and 1999 to 2002 reported 1% (0%–9.9%),[15] 0.6% (0%–11.1%)[16] and 0.8% (0%–24.8%), respectively.[17]

Primary MDR

Our study showed 6% multidrug resistance by SPM and about 10% by BACTEC radiometric method. In a study conducted by Malhotra et al., 2 strains (4.5%) were multidrug resistant.[37] The median prevalence of primary MDR by WHO/IUATLD global project on drug resistance surveillance during 1994–1997 was 1.4% (0–14.4%),[15] 1996–1999 was 1% (0%–14%)[16] and 1999–2002 was 1.1% (0%–14.2%).[17] In addition, the median prevalence of primary resistance to at least one drug during 1996–1999 and 1999–2002 was 10.7% (2%–36%)[16] and 10.2% (0%–57.1%),[17] respectively. Our study was in agreement with a study in ten provinces of China on MDR-TB among new cases, which showed levels of 5.4% (range 2.1%–10.4%).[38]

In our study, DST was done on fifty isolates. All the cases were followed up to correlate the drug-resistant patterns with the clinical outcome. Sputum smear were examined by ZN staining after completion of treatment. The cases in which strain was sensitive became sputum smear negative after the completion of treatment. One isolate was resistant to all the four drugs by BACTEC radiometric method but was sensitive to Rifampicin and Ethambutol by radiometric method, and the patient was cured with the DOTS treatment. RNTCP treatment regimen for Category I was followed which included Pyrazinamide (Z) also. In vitro susceptibility of Pyrazinamide (Z) was not done as it is not done routinely. Besides other drugs, Pyrazinamide (Z) may also have contributed in the cure of such patients. This scenario is witnessed by clinicians where patient responds to the antitubercular therapy despite having a resistant profile. This can be due to the fact that patient is given, under supervision, more than one drug for treatment as advised by DOTS course. In addition,in vitro drug susceptibility patterns may be different from in vivo clinical effectiveness of drugs. In this study, 96% of the cases showed clinical cure after completion of treatment and only 4% of the cases defaulted from the treatment. This can be due to better patient supervision at the DOTS centres, effective drug quality, patient compliance and better programme management.


  Conclusion Top


Comparing with other studies, the levels of H, R and MDR were within the expected levels in our study. However, more number of similar studies on drug resistance need to be undertaken regularly to assess the changing trends. Further studies are required on a larger number of cases to explore the correlation of in vitro drug-resistant Mycobacterium tuberculosis strains and clinical response to antitubercular drugs.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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