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Year : 2007  |  Volume : 24  |  Issue : 2  |  Page : 51-53 Table of Contents   

Pattern of initial drug resistance and its impact on short course chemotherapy of pulmonary tuberculosis

Department of Respiratory Medicine and Pathology Military Hospital Namkum, Ranchi., India

Correspondence Address:
S P Rai
Senior Adviser (Medicine & Respiratory Medicine) Military Hospital (CTC) Pune 40.
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0970-2113.44210

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Objectives : To find the pattern of initial drug resistance in fresh sputum culture positive cases of pulmonary tuberculosis and its impact on maintenance phase of short course chemotherapy (SCC) and treatment outcome.
Methods : Case records of all patients of initial drug resistance treated by us be­tween Jan 2001 to May 2004 were analyzed retrospectively. Pattern of drug resis­tance leading to modification of maintenance phase of anti-tubercular treatment (ATT) and treatment out-come in these patients were analyzed. After treatment all cases were followed up for a minimum of six months duration, for relapse.
Results : Out of 769 cases of culture positive pulmonary tuberculosis , drug resis­tance was seen in 138 patients. Out of total 203 individual drug resistance, resis­tance was present to isoniazid in 22, rifampicin in 27, ethambutol in 23, streptomy­cin in 16, pyrazinamide in 36 and ciprofloxacin in 79 cases. Among them 5 drugs resistance was seen in 4 patients, 4 drugs resistance in 3 patients, 3 drugs resistance in 9 patients, 2 drugs resistance in 22 patients and single drug resistance in 100 patients, Multi drug resistance (MDR) was observed in 12 patients. One patient died of hemoptysis after 4 months of ATT. Four patients continued to be sputum positive even after one year of second line ATT. They were subsequently lost to follow up. All the remaining patients achieved cure and had no relapse at the end of six months follow up.
Conclusion: This study highlights the importance of initial drug resistance in modifying maintenance phase of short course chemotherapy, thereby improving success rates and helps in preventing multidrug resistance tuberculosis.

Keywords: Pulmonary Tuberculosis, Initial drug resistance, Short course chemotherapy.

How to cite this article:
Rai S P, Bhattacharyya D, Kashyap M. Pattern of initial drug resistance and its impact on short course chemotherapy of pulmonary tuberculosis. Lung India 2007;24:51-3

How to cite this URL:
Rai S P, Bhattacharyya D, Kashyap M. Pattern of initial drug resistance and its impact on short course chemotherapy of pulmonary tuberculosis. Lung India [serial online] 2007 [cited 2020 Aug 6];24:51-3. Available from: http://www.lungindia.com/text.asp?2007/24/2/51/44210

   Introduction Top

Drug resistant pulmonary tuberculosis is a serious problem throughout the world, especially in those parts where the disease prevalence is high. Since the introduction of modern tuberculosis chemotherapy, there has been steady increase in the emergence of drug resistance [1],[2] . Various biological factors contribute to the development of drug resistance but most important ones are poor compliance, improper dosing and inadequate duration of chemotherapy [3],[4] . As resistant organisms retain their virulence and infectivity, the resistant strains have been gradually increasing in the community [5] . Management of drug resistant tuberculosis is more difficult, complicated, challenging and costlier. All efforts should be made to prevent the resistance by early diagnosis, using standard regimen in adequate dosage and achieving excellent compliance. During maintenance phase of SCC, if the initial strain is already resistant to either isoniazid or rifampicin, then practically patients are getting monotherapy, with increased likelihood of the emergence of MDR strains. Reports of drug resistance pattern and response to antitubercular drugs are few in this county [6],[8] , Initial drug resistance as high as 33.8 %has been reported from some regions. In this study, we have retrospectively analyzed drug resistance pattern and response to therapy among hospitalized cases in a tuberculosis center of Armed Forces.

   Material and Methods Top

The study population consisted of serving personnel suffering from pulmonary tuberculosis who were referred from different part of country for SCC, which is administered daily under direct supervision. All fresh cases of pulmonary tuberculosis with less than 4 weeks of antitubercular treatment (ATT) were included in this study. All patients with relapse, treatment failure and those who had received more than 4 weeks of ATT were excluded from the study. Three sputum specimens for direct Acid Fast Bacilli (AFB) and Mycobacterium Tuberculosis (MTB) culture were carried out in addition to chest x-ray, blood for HIV serology, routine blood count and biochemical parameters. Sputum cultures were placed on Lowenstein Jensen medium and identification was done as per standard guidelines of National Tuberculosis Institute Laboratory [9] . Standardized inoculums were placed in medium containing required concentration of drugs. A control strain of H-37 RV was set up with each batch of drug sensitivity testing. Resistance was defined as growth of more than 20 colonies in minimum inhibitory concentration of 5 mcg/ml for Isoniazid (H), a resistance ration > 16 for Streptomycin (S), 64 mcg/ml for Rifampicin (R), 8 mcg/ml for Ethambutol (E), 100 mcg/ml for Pyrazinamide (Z) and 16 mcg/ml for Ciprofloxacin (C).

All cases received initially intensive phase with first line anti-tubercular drugs 2 EHRZ or 2 SHRZ followed by HR, provided the sputum became negative at the end of 2 months of therapy. In those whose sputum remained positive for AFB, intensive phase was continued till the availability of MTB culture sensitivity report. Patients with single drug resistance to ethambutol, pyrazinamide or streptomycin were treated with first line drugs for 6­9 months while rifampicin or isoniazid resistance cases were treated with remaining first line ATT for 12 months. Patients with 2 or more drug resistance (other than MDR) were treated with 3 additional new drugs besides drug sensitive first line drugs for 9-12 months after sputum conversion, where as MDR patients were treated for 18 months after culture negativity.

All cases with 2 or more drug resistance received additional new drugs besides drug sensitive first line drugs for 6-12 months after sputum conversion. Cases with single drug resistance excluding Rifampicin received first line ATT for 6-9 months while Rifampicin resistant cases received first line ATT for 12 months. Additional drugs were continued in the maintenance phase if resistance to H or R was found, to prevent the emergence of MDR strain.

   Results Top

Between Jan 2001 to May 2004, initial MTB cultures were positive in 769 patients of pulmonary tuberculosis. Highest resistance was seen to ciprofloxacin in 79 (10.27%) cases. If single drug resistance to ciprofloxacin is not taken into consideration, overall resistance to primary line ATT was seen in 91 patients (11.83%). MDR was seen in 12 patients (1.56 %). Among the primary anti-tubercular drugs, highest resistance was seen to pyrazinamide - 36 patients (4.68%) followed by rifampicin 27 patients (3.51%), isoniazid 22 patients (2.86 %), ethambutol 23 patients (3%) and streptomycin 16 patients (2.08 %). Pattern of drug resistance to individual drugs and multiple drugs are shown in [Table 1]and [Table 2].

During the maintenance phase 16 patients having resistance to rifampicin and 10 patients having resistance to isoniazid would have received monotherapy in absence of culture reports. Four patients continued to be sputum positive even after one year second line ATT and were lost to follow up. One patient of far advanced pulmonary tuberculosis with three drug resistance (EHR) died of massive hemoptysis. All the remaining patients achieved cure and had no relapse at the end of six months follow­-up.

   Discussion Top

Tubercle bacilli have spontaneous, predictable rates of chromosomally borne mutation that confer resistance to antimicrobial agents. These mutations are unlinked; hence resistance to a drug is generally not associated with resistance to an unrelated drug, so the development of spontaneous, dual resistance is highly improbable. The problem of resistance results from treatment, that is inadequate often because of an irregular drug supply, inappropriate regimen, or poor compliance [10] . These patients with so­called secondary drug resistance occasionally transmit drug resistant organisms to their contacts, in whom "primary" drug resistant tuberculosis then develops [10] .

Our study represents the drug resistance pattern of pulmonary tuberculosis among serving soldiers belonging to various ethnic and geographic groups of India. In this study, the overall incidence of initial drug resistance is 17-94%. Among the primary antitubercular drugs highest resistance was seen to pyrazinamide-4.68 %, followed by rifampicin - 3.51%, isoniazid - 2.86 % ethambutol - 3 % and streptomycin - 2.08 %. Highest resistance was seen to ciprofloxacin -10.27 %. MDR was observed in 12 patients (1.56%). The level of actual primary drug resistance is difficult because of undisclosed therapy in some patients.

High incidence of resistance to ciprofloxacin is expected due to its common misuse in the treatment of common infections. In view of cross-resistance between quinolones, this valuable second line group of drug is increasingly being in-effective. Higher resistance to pyrazinamide and rifampicin observed in this study reflects a dangerous trend which is likely to have adverse impact on treatment outcome and the suggestions that pyrazinamide should be used invariably in second line therapy may not be correct.

With increase in single drug resistance to H and R, during maintenance phase, strains are practically being exposed to monotherapy leading to the development of MDR [8],[11] . Hence intensive phase should be extended in patients with delayed sputum conversion or inadequate clinical and radiological improvement, till sensitivity reports are available. Alternatively at least three drugs should be used in such case to prevent MDR. In our study low incidence of MDR is seen because we have excluded patients of relapse, and those who have received more than 04 weeks of ATT. These patients had primary drug resistance who acquired infection from patients having drug resistance. The treatment outcome of drug resistant cases with the use of modified regimens was excellent.

Key to success in the treatment of drug resistant tuberculosis lies with supervised therapy with appropriate modification of regimen depending on sensitivity patterns. This study stresses the importance of initial drug resistance in modifying maintenance phase of short course chemotherapy, thereby improving success rates and helps in preventing multidrug resistance tuberculosis.

   References Top

1.Paramasivan CN. An overview on drug resistant tuberculosis in India. Lung India 1998; 16:21-8.  Back to cited text no. 1    
2.Jain NK. Drug resistance in India, A tragedy in making. Ind J Tub 1992; 39:145-8.  Back to cited text no. 2    
3.Jacobs R F. Multiple drug resistant tuberculosis. Clini Infect. Dis 1994; 19:1-10.  Back to cited text no. 3    
4.Malin A S, M Adarm KPWJ, Escalating threat fzom tuberculosis the third epidemic. Thorax 1995 ;50:537-42.  Back to cited text no. 4    
5.Chandrasekaran S, Jagota P, Chaudhuri K. Initial drug resistance to anti-tuberculosis drugs in urban and rural district tuberculosis programme. Ind J Tub 1992; 39:171-5.  Back to cited text no. 5    
6.Jena j, Panda BN, Nema BK, Ohri VC, Pahwa RS.Drug resistance pattern of Mycobacterium tuberculosis in chest diseases hospital of Armed Forces. Lung India 1995,13 . 56-9.  Back to cited text no. 6    
7.Kailash Chand, Tiwary S C, Varghese Sj. Prevalence of drug resistance tuberculosis in armed forces - a study fzom tertiary referral chest diseases hospital at Pune. MJAFI 2000 ; 56:130  Back to cited text no. 7    
8.Rosha, Kataria V K. Impact of initial drug resistance pattern on the maintenance phase of short course chemotherapy with reference to the emergence of multi drug resistance. Ind J Tub 2001; 48:205  Back to cited text no. 8    
9.National consensus on MDR-TB-Tuberculosis Research Forum. Lung India 1999; 17: 57-64.  Back to cited text no. 9    
10.Goble M, Iseman MD, Madsen L, Wait D, Ackerson L, Horsburgh CR (Jr). Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampicin. N Engl J Med 1993; 328:527-32.  Back to cited text no. 10    
11.Iseman MD. Treatment of multi-drug resistant tuberculosis. New Eng J Med 1993; 329:784-91.  Back to cited text no. 11    


  [Table 1], [Table 2]


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