|Year : 2007 | Volume
| Issue : 2 | Page : 54-57
Multidrug resistant tuberculosis: Role of previous treatment with second line therapy on treatment outcome
R Singh, D Gothi, JM Joshi
Department of Respiratory Medicine, B.Y. L. Nair Ch Hospital, Mumbai-8., India
J M Joshi
Department of Respiratory Medicine, B.Y. L. Nair Ch Hospital & TN Medical College, Mumbai-8.
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Setting: The tuberculosis referral center of a tertiary care hospital. Objective: To determine human immunodeficiency virus (HIV) seropositivity, diabetes mellitus (DM), treatment outcome, cost, and adverse drug reaction in patients with multidrug resistance (MDR) pulmonary tuberculosis. Design: 56 cases of MDR tuberculosis from April 2001 to April 2003 were included. Fasting blood sugar and three-step rapid immunoassay test for HIV was performed in all cases. 45/56 patients were able to arrange for second line drugs with the help of Medical Social Worker.
Results: 1/56(1.8%) and 7/56 (12.5 %) cases were positive for HIV and DM respectively. Of the 45 cases started on second line drugs, 5 (11.1%) defaulted, 9 (20%) patients died, 31 patients (68.8%) completed treatment of which 19 (61%) were cured and 9 (39%) failed therapy. 17/19 (89%) who were cured had never received any second line drug previously (P=0.004 i.e. less than 0.5). The cost of therapy was $1000-2000. Adverse drug effects were seen in 13/45 patients (28.8%). Conclusions: Successful outcome of therapy was associated with absence of previous treatment with one or more second line drugs. Treatment with second line drugs was expensive and toxic
Keywords: Multi drug resistant Tuberculosis, Treatment
|How to cite this article:|
Singh R, Gothi D, Joshi J M. Multidrug resistant tuberculosis: Role of previous treatment with second line therapy on treatment outcome. Lung India 2007;24:54-7
|How to cite this URL:|
Singh R, Gothi D, Joshi J M. Multidrug resistant tuberculosis: Role of previous treatment with second line therapy on treatment outcome. Lung India [serial online] 2007 [cited 2015 May 5];24:54-7. Available from: http://www.lungindia.com/text.asp?2007/24/2/54/44211
| Introduction|| |
Multidrug resistant (MDR) tuberculosis is defined as resistance to both isoniazid and rifampicin alone or in combination with other drugs and has been reported from different regions of the world since the 1990s. It is the most severe form of bacterial resistance today and an important cause for concern in tuberculosis control  . The World Health Organization (WHO) in April 1993 declared tuberculosis a "Global Emergency"  . A recent report of the WHO/ International Union Against Tuberculosis and Lung Diseases (IUATLD) Global Project on drug-resistant TB between 1999 and 2002 confirmed that multidrugresistant TB is found in all regions of the world  . MDR tuberculosis has reached epidemic proportions in some parts of the world. In a WHO survey of 1995, in Delhi (India) where 2240 patients were enrolled, the overall resistance was found to be 32.4%, polyresistance (resistance to any 2 drugs) was 21.5% and multi-drug resistance (resistance to isoniazid and rifampicin) was 13.3%. 
Misdiagnosis due to laboratory related errors has been reported recently and is likely to be a serious problem encountered in the management of MDR tuberculosis  . Isoniazid and rifampicin resistance can be measured reliably but resistance to pyrazinamide, ethambutol, streptomycin and second line drugs is more difficult to measure in a consistently reliable manner  . Diagnosis of MDR tuberculosis requires demonstration of resistance to at least isoniazid and rifampicin, hence specific attention should be focused on measurement of resistance to these drugs using standardized laboratory techniques, which specify innoculum size and are calibrated between laboratories. Treatment of MDR tuberculosis with second line drugs is expensive and less effective  hence susceptibility results alone should not dictate treatment and careful clinical correlation is necessary in making the diagnosis of MDR tuberculosis , . Most studies ,, on treatment of MDR tuberculosis including two recent studies are based on culture sensitivity results alone ,,,, . WHO has recommended that multidrug resistant tuberculosis should be considered after failure of fully supervised category II retreatment regimen  . We therefore evaluated cases of MDR pulmonary tuberculosis diagnosed on the basis of WHO recommended criteria i.e. failure of supervised category II retreatment and sputum culture sensitivity results showing resistance to isoniazid and rifampicin. Our objective was to detect human immunodeficiency virus (HIV) seropositivity and diabetes mellitus in patients suffering from MDR pulmonary tuberculosis and to analyze the outcome of the treatment, cost, and adverse drug reaction with second line therapy.
| Material and Methods|| |
A study of MDR pulmonary tuberculosis was undertaken from April 2001 to April 2003 in our out patient department of tertiary health care center. The institute ethics committee approved the study and informed consent was obtained from all the patients. MDR-tuberculosis was diagnosed on the basis of failure of WHO Category II directly observed re-treatment regimen and resistance to isoniazid and rifampicin on culture sensitivity testing. Sputum culture and sensitivity for Mycobacterium tuberculosis (M. Tuberculosis) was done from a referral laboratory by Bactec radiometric medium (Becton Dickinson, Towson, Md.). Multi drug resistance was reported if growth on drug containing mediums (0.2 ugm of isoniazid/ ml and 1.0 ugm of rifampicin/ml) was more than 1% of the colonies that grew on a drug free (control) medium.
A detailed history of earlier treatment with first and second line drugs was obtained. All the patients had history of multiple courses of first line drugs in past. Some of these patients had a history of receiving second line drugs, where the drugs were given in either inadequate dosage or duration or one drug was added to a failing first line regimen. Other investigations performed included a chest radiograph, total and differential blood counts, liver and renal function tests, fasting blood sugar and three step rapid immunoassay test for HIV after pre-test counseling.
The second line drugs consisted of three to five new drugs (one injectable and the remaining oral) and with no cross-resistance to any of the drugs used in the recent past [Table 1]. Arrangement of the required second line drugs for the entire duration of the therapy was made prior to starting treatment in order to prevent interruption in treatment. Drugs were arranged with the help of medical social worker (MSW), major contribution being from private charities and a nominal contribution by the patient depending on his economic status as judged by the MSW. Patients who could not arrange for second line drugs were referred to tuberculosis hospitals for further management. Treatment was started in all cases after extensive counseling. Delay or failure to collect the drugs was countered by home visits. Nutrition supplements were provided at each visit.
While on second line therapy, patients were assessed on outpatient basis at the end of 2 months and then at monthly intervals till sputum smear became negative. Once sputum smear and culture turned negative, the injectable drug was stopped and the oral drugs were continued for at least 12 months thereafter, up to a maximum of 1824 months. After confirming sputum smear and culture negativity on completion of therapy, the patient was declared cured. If sputum smear and culture remained positive after 1 year of therapy, the patient was declared failed on second line treatment. If serious adverse effects developed during the treatment, the offending drug was withdrawn and other drugs were continued for the prescribed duration. Association of previous second line drugs and outcome of therapy was analyzed using the chi-square test. A p value of less than 0.05 was considered to indicate statistical significance.
| Results|| |
56 cases of MDR pulmonary tuberculosis, age range 13-68 years mean age 30.34 years with a male to female ratio of 3:1 were included in the study. Only 1/56 (1.8%) case was HIV seropositive, while 7/56 (12.5%) cases were found to have associated diabetes mellitus. 45 patients were started on second line treatment and 11 patients were referred to tuberculosis hospitals for further management. Of the 45 patients started on therapy, 39 patients (86.66%) were given a 4-drug regimen, 5 patients (11.1%) were started on a 3-drug regimen, while only 1 patient (2.22%) received a 5-drug regimen. 5/45 (11.1%) defaulted and 9/45 (20%) died while on treatment. 31/45 (68.8%) completed treatment. 19 of the 31 who completed treatment (61%) were cured and 12 (39%) failed. Of the 19 cases cured, 17 (89%) had never received any second line drug in the past as against 2 (10.5%) cases that had received one or more second line drug previously [Table 2]. Chi square was used to test significance of difference between the proportion of patients cured, among those receiving second line therapy for the first time and among those who had received one or more second line drugs in the past. The difference was statistically significant (P=0.004). The time for bacteriological conversion in the cured patients was 3 to 9 months. 6 patients (31.5%) converted in 3 months, and 12 (63%) in next 3 months. 94.7% patients had bacteriological conversion in 6 months. Cost of various treatment regimens ranged from $ 1000 to $ 2000, excluding the cost of management of adverse drug reaction and disease related complication.
Serious adverse drug effects [Table 3] were seen in 13 out of the 45 patients (28.8%). Five patients had psychosis, 3 had ototoxicity while 2 patients had both psychosis and ototoxicity. Peripheral neuropathy and nephrotoxicity were seen in one patient each. Peripheral neuropathy and ototoxicity both were seen in 1 patient. The 7 patients with cycloserine-induced psychosis were referred to psychiatrist where they were started on sedatives and anti-depressants and the offending drug was discontinued. 6 patients with ototoxicity were referred to the otolaryngology department where a pure tone audiometry (PTA) was done to determine the severity of hearing loss and the aminoglycoside was discontinued. Peripheral neuropathy was seen in 2 patients both had diabetes mellitus. In the patient with nephrotoxicity, aminoglycoside was stopped and patient was referred to nephrologist for treatment of renal failure. Among the less serious adverse events, one patient had acne and all cases had gastric intolerance but none required discontinuation of drugs for the same.
| Discussion|| |
Although there have been several well-documented outbreaks of MDR tuberculosis in institutional settings, little evidence indicates that HIV is associated with MDR tuberculosis among the general population.  In our study HIV and MDR co-infection was seen in only one case. Patients of HIV and MDR tuberculosis co-infection have now been reported to respond well to appropriate chemotherapy  . The only patient with HIV and MDR tuberculosis in our study defaulted; hence outcome of therapy could not be assessed. An early referral, confirmation of drug resistance by culture sensitivity and prompt treatment can reduce morbidity and mortality of such cases.
Recently, Bashar M et al  showed that MDR tuberculosis was significantly higher in patients with coexisting diabetes mellitus. The authors have explained that it could be due to some degree of impaired gastointestinal drug absorption even in the absence of clinical gastroparesis. Also, the hyperglycemic state may additionally interfere with achieving adequate tissue levels of the medications, or interfere with alveolar macrophage or CD4+ cell function.
Treatment of MDR tuberculosis should be given using at least 3 new drugs, which the patient has not taken before and which have no cross-resistance to the drugs taken in the past. In our study additional first line drugs were not given while treating MDR tuberculosis because after failure of fully supervised first line therapy, there is little point in giving any of these drugs even if culture sensitivity reports suggest sensitivity to these  . Drugs should be selected from the second line drugs i.e. kanamycin, amikacin, capreomycin, ethionamide, cycloserine, and para amino salicylic acid (PAS)  . Quinolones (ciprofloxacin or ofloxacin) can only be used as additional fourth drug as their efficacy is uncertain  . All quinolones have complete cross-resistance to each other; hence after failure of one quinolone, use of another is not justified. Amikacin has cross-complete resistance to streptomycin and kanamycin and hence cannot be used after failure of these drugs. Drugs other than these drugs including macrolides (roxithromycin, azithromycin), clofazimine are not recommended for treatment of MDR tuberculosis , .
Different treatment regimens and strategies have been used in the five studies ,,,, with varying outcomes. Park et al, Geerligs et al and Tahaoglu et al have used 4-7 drugs on an average and hospitalized patients to ensure compliance. Singla et al  had given outpatient based treatment and did not make any special efforts to supply second line drugs or to ensure compliance, resulting in a high default rate of 46%. In our study despite ensuring regular supply of drugs from MSW and use of compliance enhancing measures the default rate was still a high of 11.1%. Cost of outpatient-based treatment in our study was up to $ 2000 whereas in the study by Geerling et al  hospital based treatment was a prohibitive $ 60,000. A possible pragmatic solution would be to increase the incentives to compliance, free drugs with practical help: food, housing, social support for disadvantaged groups such as the homeless and refugees, and to strengthen or at least define clearly if and when compulsory detention and treatment should be used for cases when the collaborative approach has failed ,.
Failure rate in our study was higher in those who had received one or more second line drug in the past as compared to those who were freshly treated with second line drugs. Thus, poor outcome of therapy in this study was related to erratic use of one or more second line drugs in past. Addition of a single drug to a failing regimen (addition syndrome)  is known to result in development of resistance to the drugs used. This explains the poor outcome of second line therapy in those patients who had received one or more of second line drugs added to their first line therapy. Tahaoglu et al  have reported similar finding, where a poor outcome was associated with previous treatment with ofloxacin. Hence, unrestricted availability and use of second line drugs must be viewed with serious concern.
13 patients (28%) in this study, developed serious adverse effects to second line drugs, which is comparable to previous reports  . Psychosis and ototoxicity were the two most commonly seen adverse effects and were attributed to the use of cycloserine and aminoglycosides. Peripheral neuropathy and nephrotoxicity was seen only in patients with diabetes mellitus.
Due to the alarming worldwide threat imposed by MDR tuberculosis it has been suggested that the WHO recommended tuberculosis control programme using directly observed treatment short course (DOTS) should have additional intervention for treatment of MDR tuberculosis (DOTS plus)  . Evidence from Peru suggests that use of standardized regimens at country level may be feasible and cost effective  . WHO has listed second line drugs for tuberculosis under the essential drugs list and these drugs can be accessed at special prices with quality assurance through the Green Light Committee (GLC)  . Treatment of MDR-tuberculosis is complicated, expensive and requires quality-controlled laboratory and centers specialized in handling such cases. In addition it would be irrational for any country to divert resources to regimens with second line drugs where new infectious cases remain untreated or ineffectively treated with first line drugs.
| Conclusion|| |
Poor outcome of treatment was associated with use of erratic second line drugs in past. Thus, unrestricted availability of second line drugs probably has a worse impact on the outcome of MDR tuberculosis. Also, treatment with second line drug is expensive and toxic; as the top priority remains prevention, not treatment of MDR tuberculosis
Acknowledgement: Dr Abnair Daniel Elkan, Senior Resident, Department of Preventive and Social Medicine, T N Medical College & B Y L Nair Hospital. Mr. Dattaji Shankarrao Patankar, Medical Social Worker, Department of Medical Social Worker, T N Medical College & B Y L Nair Hospital.[Figure 1]
| References|| |
|1.||Crofton j. Multi-drug resistance: danger for the Third World. In: Porter JDH, McAdam, KDNJ. Editors: "Tuberculosis back to the future', ' Chichester, John Wiley and Sons Ltd., 1994;231-233. |
|2.||World Health Organization. Tuberculosis notification update, July 1992, WHO/ TB/ 1992, 169. |
|3.||Anti-tuberculosis drug resistance in the world. WHO/IUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance Executive Summary Third Global Report. WHO/HTM/ TB/2004.303. |
|4.||Cohn DL, Bustreo F, Raviglione MC. Drug resistant tuberculosis: Review of the worldwide situation and the WHO/ IUATLD Global Surveillance Project. International Union Against Tuberculosis and Lung Disease. CIin Infect Dis 1997,24 Suppl l:S121-30. |
|5.||Nitta AT, Davidson PT, de Koning ML, Kilman RJ. Misdiagnosis of multidrug resistant tuberculosis possibly due to laboratory- related errors. JAMA 1996; 276: 1980-83. [PUBMED] |
|6.||Vareldzis BP, Grosset j, de Kantor I, Crofton j, Laszlo A, Felten M et al. Drug resistant tuberculosis: laboratory issues, World Health Organization recommendations. Tuber Lung Dis 1994; 75 (1): 1-7. |
|7.||Drobniewski F. Is death inevitable with multi-resistant TB plus HIV infection? Lancet 1997:349;71-2. |
|8.||Singla R, Myneedu VP, Jaiswal A, et al: Ethionamide, Cycloserine, Isoniazid, Sodium PAS and Kanamycin in retreatment of drug failure pulmonary tuberculosis patients. Indian Journal of Tuberculosis 1995; 42: 23-26. |
|9.||Geerligs WA, van Altena R, van der Werf TS. Antituberculosis Drug Resistance Correspondence. N Eng J Med 1998;339;1079-80. |
|10.||Park SK, Kim CT, Song SD. Outcome of chemotherapy in 107 patients with pulmonary tuberculosis resistant to isoniazid and rifampicin. Int J Tuberc Lung Dis 1998: 2: 877-84. |
|11.||Tahaoglu K, Torun T, Sevim T, et al. The treatment of multidrugresistant tuberculosis in Turkey. N Engl J Med 2001;345:170-4. |
|12.||Chan ED, Laurel V, Strand Mj, Atac G, Kir A, Karasulu L, Ozmen I, Kapakli N. et al. Treatment and Outcome Analysis of 205 Patients with Multidrug-Resistant Tuberculosis. Am J Respir Crit Care Med. 2004;169:1103-9. |
|13.||TB/HIV research priorities in resource-limited settings. An expert consultation WHO, Geneva, Switzerland 14-15 February 2005 WHO/HTM/TB/2005.355. WHO/HIV/2005.03. Available at: Accessed on 7 th February, 2006. |
|14.||Bashar M, Alcabes P, Rom WN. and Condos R. Increased incidence of Multidrug-resistance tuberculosis in diabetic patients on the Bellevue chest services, 1987 to 1997. Chest 2001;120:1514-1519. |
|15.||Crofton j, Chaulet P, Maher D. Guidelines for the management of drug resistant tuberculosis. WHO/ TB/ 96.210 Rev (1). |
|16.||Davidson PT, Le HQ. Drug treatment of tuberculosis. Drugs 1992; 43;651-73. |
|17.||Veen j. Drug resistant tuberculosis: back to sanatoria, surgery and cod-liver oil? Eur Respir J 1995; 8: 1073-1975. [PUBMED] [FULLTEXT]|
|18.||Ormerod P. More carrot or more stick or both? Thorax Editorial 1999; 54: 95-97. |
|19.||WHO Global tuberculosis: WHO Report 1998. Geneva, WHO / TB / 98. 237. |
|20.||Suarez PG, Floyd K, Portocarrero j, et al. Feasibility and cost effectiveness of standardized second line drug treatment for chronic tuberculosis patients: a national cohort study in Peru. Lancet 2002; 359: 1980-1989. |
|21.||Treatment of tuberculosis. Guidelines for National Programmes, Third Edition. WHO/CD5/TB 2003.313. |
[Table 1], [Table 2]
|This article has been cited by|
||Clinical characteristics, drug resistance, and treatment outcomes among tuberculosis patients with diabetes in Peru
| ||M.J. Magee,E. Bloss,S.S. Shin,C. Contreras,H. Arbanil Huaman,J. Calderon Ticona,J. Bayona,C. Bonilla,M. Yagui,O. Jave,J.P. Cegielski |
| ||International Journal of Infectious Diseases. 2013; 17(6): e404 |
||Effect of diabetes on treatment outcome of smear positive pulmonary tuberculosis – A report from South India
| ||Vijay Viswanathan,A. Vigneswari,K. Selvan,K. Satyavani,R. Rajeswari,Anil Kapur |
| ||Journal of Diabetes and its Complications. 2013; |