|Year : 2017 | Volume
| Issue : 1 | Page : 41-45
Treatment outcomes of drug-resistant pulmonary tuberculosis under programmatic management of multidrug-resistant tuberculosis, at tertiary care center in Mumbai
Manoj Ashok Waghmare, Ketaki Utpat, Jyotsna M Joshi
Department of Pulmonary Medicine, T. N. Medical College, B. Y. L. Nair Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||9-Jan-2017|
Dr. Jyotsna M Joshi
Department of Pulmonary Medicine, T. N. Medical College, B. Y. L. Nair Hospital, Mumbai - 400 008, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: This study was undertaken to analyze the clinical profile and treatment outcome in pulmonary drug-resistant tuberculosis (TB) patients under programmatic management of multidrug-resistant tuberculosis (PMDT) at a tertiary care center in Mumbai. Methodology: A retrospective study was conducted at PMDT site of a tertiary care hospital. The data of 194 pulmonary multidrug-resistant (MDR) TB patients diagnosed at our hospital or prediagnosed patients referred to our hospital were meticulously reviewed to study demography, baseline drug susceptibility to first- and second-line drugs, treatment outcomes, comorbidities, and adverse drug reactions (ADRs). Results: Out of 194 patients, 48.4% (68 cured + 26 treatment completed) were successfully treated, 22 (11.3%) failed on therapy, 39 (20.15%) patients died, 23 (11.8%) defaulted, 26 (13.4%) completed treatment with outcomes unknown, 13 (6.7%) were transferred out and in 3 patients (1.5%) treatment was stopped due to ADRs. Most common ADRs were gastrointestinal 32 (16.4%) and psychiatric 37 (19%). However, there was no statistical significance between the prevalence of ADRs and unfavorable outcomes. Most common comorbidities were GERD 27 (40.2%) and diabetes mellitus 22 (32.8%). Conclusion: Baseline drug susceptibility testing (DST) with rapid diagnostic tests, performing DST for second-line drugs, i.e., fluoroquinolones and aminoglycoside and modification of treatment regimen based on the same at start of MDR treatment has prime importance. Early detection of ADR's and comorbidities and their prompt treatment are also equally important.
Keywords: Drug resistant tuberculosis, pulmonary multidrug-resistant tuberculosis, treatment outcomes
|How to cite this article:|
Waghmare MA, Utpat K, Joshi JM. Treatment outcomes of drug-resistant pulmonary tuberculosis under programmatic management of multidrug-resistant tuberculosis, at tertiary care center in Mumbai. Med J DY Patil Univ 2017;10:41-5
|How to cite this URL:|
Waghmare MA, Utpat K, Joshi JM. Treatment outcomes of drug-resistant pulmonary tuberculosis under programmatic management of multidrug-resistant tuberculosis, at tertiary care center in Mumbai. Med J DY Patil Univ [serial online] 2017 [cited 2019 Jan 23];10:41-5. Available from: http://www.mjdrdypu.org/text.asp?2017/10/1/41/197892
| Introduction|| |
Tuberculosis (TB) is one of the most rampant infectious diseases that continues to challenge the clinicians by its high incidence and variable presentations. The problem is exemplified many fold with the advent of drug resistance in TB. Multidrug-resistant (MDR) TB is defined as disease caused by strains of Mycobacterium tuberculosis that are resistant to treatment with at least isoniazid (H) and rifampicin (R). Pre-extensively drug-resistant (pre-XDR) TB refers to disease caused by MDR strains that harbor additional resistance to either any fluoroquinolone (FQ) or any of the injectable second-line aminoglycosides (AM). While XDR-TB refers to MDR-TB with additional resistance to both FQ and AM. MDR-TB has microbial, clinical, and programmatic causes. From a microbiological perspective, the resistance is caused by a genetic mutation that makes a drug ineffective against the mutant bacilli. However, it should be stressed that MDR-TB is essentially a man-made phenomenon. Lack of awareness among treating physicians, improper treatment regimes, poor adherence, and drug toxicities are the prime culprits contributing to its occurrence.,, The treatment of MDR-TB is challenging owing to its delayed diagnosis, prolonged duration of therapy and significant drug toxicities. The disease thus contributes to significant morbidity and mortality which to a great extent is preventable by rapid diagnosis, prompt institution of therapy, assuring adherence to guidelines and management of adverse drug reactions (ADRs). MDR-TB treatment is standardized under programmatic guidelines for management of drug-resistant tuberculosis (PMDT). However, there are limited data available on the clinical profiles and treatment outcomes of patients enrolled under this program. Hence, we conducted this study to analyze the treatment outcomes and the influencing factors for the same in a cohort of pulmonary MDR-TB patients presenting at our PMDT site with an intention of attaining a better understanding of this multifaceted disease.
| Methodology|| |
A retrospective study was conducted at the PMDT site of Tertiary Care Hospital in Mumbai after approval from Ethics Committee for Academic Research Projects, Postgraduate Academic Committee, T. N. Medical College and B. Y. L. Nair Hospital, Mumbai. The data of 194 pulmonary MDR-TB patients either diagnosed at our hospital or prediagnosed patients referred to our hospital since August 2012 to December 2013 were reviewed. A detailed history regarding previous exposures to all first- and second-line drugs was obtained. Diagnosis of MDR-TB was made on basis of microbiological laboratory tests such as nucleic acid amplification tests (Gene Xpert), line probe assay, and conventional drug susceptibility testing (DST) from a Revised National TB Control Programme (RNTCP) accredited laboratory. All patients also underwent second-line DST to diagnose additional resistance to FQ or AM or both at baseline itself. Patients were extensively counseled about the nature of the disease and treatment regimen, associated ADRs and hazards of noncompliance to therapy. After a thorough pretreatment evaluation including testing for human immunodeficiency virus (HIV), patients were initiated on standard category four regime comprising kanamycin, ethionamide, cycloserine, levofloxacin, ethambutol, and pyrazinamide as per PMDT guidelines. Therapy was modified in cases of pre-XDR or XDR TB. Levofloxacin was substituted with para-aminosalicylic acid (PAS) and moxifloxacin while kanamycin was substituted with capreomycin wherever the particular drug was proven to be resistant. Drugs provided under PMDT were used. Follow-up sputum acid-fast bacilli smear and cultures were done according to PMDT guidelines at 3, 4, 5, 6, 9, 12, 15, 18, 24 months. Furthermore, DST was done at the time of diagnosis, when 6 months sputum smear remained positive and also in continuation phase at sputum reversion. A complete follow-up data pertaining to the clinical improvement, microbiological conversion, ADRs on therapy, and treatment outcomes were available for all patients.
All data obtained were meticulously reviewed to study epidemiology, drug sensitivity pattern on the basis of sputum examinations, frequency of MDR, pre-XDR, XDR TB, treatment outcome with respect to died, default, cured, and failure, ADRs, and comorbidities. Definitions of outcomes used in this study are based on PMDT guideline.
| Results|| |
Totally 194 cases of pulmonary MDR-TB were enrolled. Majority of the cases were from young age group with mean age of 29 years. Male to female ratio was 1:1.17. In terms of the baseline drug susceptibility tests, 59 (30.4%) were MDR-TB, 124 (64%) patients were MDR TB with additional FQ resistance (pre-XDR [FQ]) and 11 (5.6%) patients were MDR TB with additional AM resistance (pre-XDR [AM]). FQ resistance was more common as compared to AM resistance. Ten (5.1%) cases were XDR TB [Figure 1]. Among the 133 subjects for whom there was sufficient data to evaluate outcome, 125 (93.99%) converted their sputum cultures to negative (“initial favorable response”) while 8 (6.01%) had failed to convert to negative (“microbiologic failure”). Mean sputum conversion was noted at 3 months in 92 patients (69%), while at 4, 5, 6–11 months sputum conversion was found in 18 (13.5%), 8 (6%), and 6 patients (4.5%), respectively.
|Figure 1: Drug resistance pattern at initiation of antituberculous treatment at PMDT site of tertiary care center in Mumbai from August 2012 to December 2013|
Click here to view
Among 115 MDR-TB patients 38 (43.47%) were cured, 7 (10.1%) completed treatment, 9 (13.04%) died, 1 (1.4%) failed, 11 (15.4%) defaulted, 3 (4.3%) stopped treatment due to ADR's and 8 (11.5%) transferred. Among pre-XDR patients 38 (33.04%) cured, 19 (16.5%) completed treatment, 26 (22.6%) died, 17 (14.75) failed, 11 (9.5%) defaulted, and 4 (3.4%) transferred. Whereas among 10 XDR patients there was no cure or treatment completed, 5 (50%) died, 4 (40%) failed, and 1 (10%) defaulted. Overall 94 (48.4%) patients out of 194 were successfully treated (cured 68 [35%] + treatment completed 26 [13.4%]). Thirty-nine (20%) died, 22 (11%) failed, 23 (11%) defaulted, and 13 (6.7%) were transferred out to other sites and 3 (1.5%) patient's treatment was discontinued due to ADR's, [Figure 2]. Out of 194 patients 105 patients had ADRs in the course of treatment, most common of which were psychiatric and gastrointestinal. Various ADRs were gastrointestinal 32 (30%), psychiatric 37 (35.2%), ototoxicity 18 (17%), joint pain 14 (13%), hypothyroidism 7 (6.6%), hepatitis 3 (2.8%), ocular toxicity 4 (3.8%), acne 3 (2.8%), stomatitis 6 (5.7%), peripheral neuropathy 4 (3.8%), gynecomastia 2 (1.9%) and alopecia, pellagra, esophagitis, periostitis, epistaxis, renal toxicity, 1 (0.9%) each [Table 1]. We applied simple Chi-square test to analyze the relationship between ADRs and unfavorable outcomes, but there was no statistical significance between the two with P value being 0.3539 (>0.05)
|Figure 2: Treatment outcome at the end of 24–27 months of antituberculous treatment at PMDT site of tertiary care center in Mumbai from August 2012 to December 2013|
Click here to view
|Table 1: Adverse drug reactions to various drugs developed during treatment course, at PMDT site of tertiary care center in Mumbai from August 2012 to December 2013|
Click here to view
Totally 67 patients out of 194 had associated comorbidities most common of which was GERD 27 (40%) and diabetes mellitus (DM) 22 (32%). Other comorbidities were systemic hypertension 3 (4.4%), anemia 9 (13.5%), HIV 6 (8.9%), thromboembolism 3 (4.4%), seizure disorder 5 (7.4%), and Down's syndrome 1 (1.4%) [Table 2].
|Table 2: Comorbidities associated with pulmonary drug resistant tuberculosis patients, at PMDT tuberculosis site of tertiary care center in Mumbai from August 2012 to December 2013|
Click here to view
| Discussion|| |
The emergence of drug resistance is a worrisome problem which poses a formidable challenge to physicians across the world and hinders effective TB control. Treatment of MDR-TB is complex due to the prolonged regimens, expensive drugs, and high incidence of drug toxicities. This is, in turn, contributes to poor treatment adherence and further exponential magnification of drug resistance which can have devastating consequences. In India, MDR-TB has been persistently identified despite the successful implementation of RNTCP. As per recently published reports from India, MDR-TB has been found in 3% of new cases and 12% of treated patients. Formulation and implementation of PMDT guidelines are milestone achievement to combat this challenging problem.
We report an analysis of a cohort of drug-resistant (DR) TB patients managed at our PMDT site. The majority of patients in this study were from young population, with mean age of 29 years which corresponds to the previous studies. Furthermore, we observed female preponderance in contrast to recent studies where male preponderance was observed , which may be due to nutritional deficiencies in Indian females that take a toll on their immunity. More than 80% of patients were previously treated for TB reiterating the fact that errors in treatment of drug-sensitive TB at various levels are the most important contributing factors for the creation of drug resistance.
FQs are broad spectrum antibiotics extensively and often indiscriminately used in India to treat bacterial infections leading to a high prevalence of resistance to it. Same is true in case of AMs. Undetected resistance to these drugs is a major contributing factor to poor bacteriological conversions in MDR-TB patients. This study revealed higher rate of baseline resistance to FQs, which is 64% as compared to a study done in Gujrat by Ramachandran et al. in 2005 where it was 24% and in a study done by Agrawal et al. in 2004 where it was 35%. This high rate of resistance was expected in this study as our hospital is tertiary care center where many of the patients were referred from periphery after exposure to these drugs leading to a referral bias. 5.1% of patients were XDR-TB patients. Various studies from India reported the prevalence of XDR-TB among MDR TB patients ranging from 0.89% to 33%. In a study conducted by Rajasekharan et al. between 2004 and 2007, the prevalence of XDR-TB among MDR TB was 4.6% which is similar to our study. In another study conducted by Myneedu et al. between 2007 and 2009, the prevalence of XDR-TB among MDR TB was 20.2%. Sharma et al. demonstrated a prevalence of XDR-TB to be 2.4% in Delhi from 1997 to 2003. Availability of baseline second line DST for FQ and AM was a very significant element of our study which facilitated pertinent treatment modification at the commencement of therapy. This had major positive impact on the treatment outcomes.
Mean sputum culture conversion in our study observed was at 60–90 days which is similar to other studies from India., Rapid initial sputum conversion is crucial factor deciding the disease course. It is also of epidemiological significance as it helps to curb the chain of transmission thereby preventing further amplification of drug resistance. Delay in sputum conversion suggests probable noncompliant therapy or resistance to second-line drugs. Factors negatively associated with culture conversion at 2 months can be easily identified and addressed with dedicated patient follow-ups. This helps in better care of individual patients by identifying the lacunae early and treating them vigorously.
Favorable outcome in our study was high 48.4% as compared to other studies conducted in India by Kapadia et al. in 2013 where it was 39.13% and in study done by Rajasekaran et al. in 2014 where it was 44%. We attribute this favorable outcome to (1) use of the World Health Organization-accredited rapid tests for diagnosis, (2) strict adherence to treatment guidelines, (3) aggressive patient counseling, and (4) modification of treatment regimen at start of therapy itself based on the second line DST for FQ and AM. The default rate in this study was 11.8% which is very low as compared to other studies done in India., We achieved this low rate of default because of our aggressive counseling strategy, and meticulous follow-ups. Whereas failure rate, death rate, transfer out rate were similar to these studies.
A variety of ADRs were observed but due to early identification and their prompt treatment only few of these warranted discontinuation of therapy. Most common ADR observed in our study was psychiatric, culprit drugs being cycloserine, FQs, and ethionamide. However, even major psychoses were managed with antipsychotic drugs without discontinuation of MDR therapy. The second most common ADR's were gastrointestinal nausea and vomiting contributory drugs being ethionamide, PAS, pyrazinamide, and ethambutol. These cases were managed with proton pump inhibitors and spacing of drugs at intervals throughout the day. Patient's prior awareness about possible ADRs also played an important role in reducing default rate due to ADRs in our study.
Various comorbidities were observed, of which DM and HIV need special mention as these lead to an immunocompromised state. It is believed that seropositivity increases chances of having MDR-TB infection. However, according to recent PMDT guidelines the presentation of MDR-TB in the HIV-infected patient does not differ from that of drug-sensitive TB in the HIV-infected patients. In our study, only 3% of patients were seropositive out of 194, similar to result was obtained in a study done by Deivanagayam. However, in a study conducted by Balaji et al. between 2002 and 2007 27.9% patients were HIV infected. In another study conducted by Rajasekharan et al. between 2004 and 2007 it was 13.9%. In this study, 11.34% of patients had DM as comorbidity. This is similar to the prevalence of DM in general population as detected in national survey data from western India. Fisher-Hoch conducted a study from 1997 to 2002 and 31.6% patients with MDR TB had type 2 DM. In addition, in a study done by Mi et al. the prevalence of DM was 16.6%, but there was no significant difference in the prevalence of drug sensitive or DR-TB among diabetic patients. All of our patients were treated on outpatient basis excluding the initial hospitalization for pretreatment evaluation. This highlights the fact that MDR-TB therapy can be administered on an ambulatory basis with just a few exceptional cases requiring hospitalization.
We hereby emphasize certain facts. Baseline first- and second-line DST with rapid diagnostic tests, performing DST for FQ and AM and modification of treatment regimen based on the same at start of MDR treatment has prime importance. Aggressive counseling of patients, strict adherence to guidelines by clinicians, early detection of ADRs and their prompt treatment are also equally important.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
World Health Organization. World Health Organization multidrug and extensively drug-resistant TB (M/XDR-TB): Global report on surveillance and response. World Health Organization, Geneva, Switzerland: 2010.
Sharma SK, Kumar S, Saha PK, George N, Arora SK, Gupta D, et al.
Prevalence of multidrug-resistant tuberculosis among category II pulmonary tuberculosis patients. Indian J Med Res 2011;133:312-5.
Behera D. Drug resistant tuberculosis in India – Is it a matter of concern? Indian J Tuberc 2007;54:105-9.
Nathanson E, Gupta R, Huamani P, Leimane V, Pasechnikov AD, Tupasi TE, et al.
Adverse events in the treatment of multidrug-resistant tuberculosis: Results from the DOTS-plus initiative. Int J Tuberc Lung Dis 2004;8:1382-4.
Drobniewski F, Eltringham I, Graham C, Magee JG, Smith EG, Watt B. A national study of clinical and laboratory factors affecting the survival of patients with multiple drug resistant tuberculosis in the UK. Thorax 2002;57:810-6.
Arora VK, Sarin R, Singla R, Khalid UK, Mathuria K, Singla N, et al
. DOTS-plus for patients with multidrug-resistant tuberculosis in India: Early results after three years. Indian J Chest Dis Allied Sci 2007;49:75.
Samper S, Iglesias MJ, Rabanaque MJ, Gómez LI, Lafoz MC, Jiménez MS, et al.
Systematic molecular characterization of multidrug-resistant Mycobacterium tuberculosis
complex isolates from Spain. J Clin Microbiol 2005;43:1220-7.
Yew WW, Chan CK, Chau CH, Tam CM, Leung CC, Wong PC, et al.
Outcomes of patients with multidrug-resistant pulmonary tuberculosis treated with ofloxacin/levofloxacin-containing regimens. Chest 2000;117:744-51.
Telzak EE, Sepkowitz K, Alpert P, Mannheimer S, Medard F, el-Sadr W, et al.
Multidrug-resistant tuberculosis in patients without HIV infection. N Engl J Med 1995;333:907-11.
Quesada SP, Paschoal JA, Reyes FG. Considerations on the aquaculture development and on the use of veterinary drugs: Special issue for fluoroquinolones – A review. J Food Sci 2013;78:R1321-33.
Dhingra VK, Rajpal S, Mittal A, Hanif M. Outcome of multi-drug resistant tuberculosis cases treated by individualized regimens at a tertiary level clinic. Indian J Tuberc 2008;55:15-21.
Ramachandran R, Nalini S, Chandrasekar V, Dave PV, Sanghvi AS, Wares F, et al.
Surveillance of drug-resistant tuberculosis in the state of Gujarat, India. Int J Tuberc Lung Dis 2009;13:1154-60.
Agrawal D, Udwadia ZF, Rodriguez C, Mehta A. Increasing incidence of fluoroquinolone-resistant Mycobacterium tuberculosis
in Mumbai, India. Int J Tuberc Lung Dis 2009;13:79-83.
Rajasekaran S, Chandrasekar C, Mahilmaran A, Kanakaraj K, Karthikeyan DS, Suriakumar J. HIV coinfection among multidrug resistant and extensively drug resistant tuberculosis patients – A trend. J Indian Med Assoc 2009;107:281-2, 284-6.
Myneedu VP, Visalakshi P, Verma AK, Behera D, Bhalla M. Prevalence of XDR TB cases – a retrospective study from a tertiary care TB hospital. Indian J Tuberc 2011;58:54-9.
Kapadia VK, Tripathi SB. Analysis of 63 patients of MDR TB on DOTS plus regimen: An LG hospital, TB unit, Ahmedabad experience. Gujarat Med J 2013;68:2.
Jain K, Desai M, Solanki R, Dikshit RK. Treatment outcome of standardized regimen in patients with multidrug resistant tuberculosis. J Pharmacol Pharmacother 2014;5:145-9.
Basit A, Ahmad N, Khan AH, Javaid A, Syed Sulaiman SA, Afridi AK, et al.
Predictors of two months culture conversion in multidrug-resistant tuberculosis: Findings from a retrospective cohort study. PLoS One 2014;9:e93206.
Dholakia YN, Shah DP. Clinical profile and treatment outcomes of drug-resistant tuberculosis before directly observed treatment strategy plus: Lessons for the program. Lung India 2013;30:316-20.
Falzon D, Jaramillo E, Schünemann HJ, Arentz M, Bauer M, Bayona J, et al.
WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update. Eur Respir J 2011;38:516-28.
Deivanayagam CN, Rajasekaran S, Venkatesan R, Mahilmaran A, Ahmed PR, Annadurai S, et al.
Prevalence of acquired MDR-TB and HIV co-infection. Indian J Chest Dis Allied Sci 2002;44:237-42.
Balaji V, Daley P, Anand AA, Sudarsanam T, Michael JS, Sahni RD, et al.
Risk factors for MDR and XDR-TB in a tertiary referral hospital in India. PLoS One 2010;5:e9527.
Ramachandran A, Snehalatha C, Kapur A, Vijay V, Mohan V, Das AK, et al.
High prevalence of diabetes and impaired glucose tolerance in India: National urban diabetes survey. Diabetologia 2001;44:1094-101.
Fisher-Hoch SP, Whitney E, McCormick JB, Crespo G, Smith B, Rahbar MH, et al.
Type 2 diabetes and multidrug-resistant tuberculosis. Scand J Infect Dis 2008;40:888-93.
Mi F, Jiang G, Du J, Li L, Yue W, Harries AD, et al.
Is resistance to anti-tuberculosis drugs associated with type 2 diabetes mellitus? A register review in Beijing, China. Glob Health Action 2014;7:24022.
[Figure 1], [Figure 2]
[Table 1], [Table 2]