Prevalence of extensively drug-resistant tuberculosis among patients with multidrug-resistant tuberculosis: a retrospective hospital-based study.
Abstract: Background & objective: Extensively drug-resistant tuberculosis (XDR-TB) is a difficult-to-treat form of multidrug-resistant tuberculosis (MDR-TB). High rates of XDR-TB have been reported from India. We sought to ascertain the prevalence of XDR-TB among patients with MDR-TB treated at a tertiary care centre in New Delhi, India.

Methods: Case records of patients treated for MDR-TB at the All India Institute of Medical Sciences hospital, New Delhi, between 1997 and 2003 were retrospectively reviewed. All patients underwent a pretreatment drug-susceptibility testing (DST) to first- as well as second-line drugs. XDR-TB was defined as TB caused by bacilli showing resistance to rifampicin and isoniazid in addition to any fluoroquinolone and to at least one of the three following injectable drugs: capreomycin, kanamycin, and amikacin.

Results: A total of 211 laboratory-confirmed cases of MDR-TB were reviewed. The mean age of the patients was 33 [+ or -] 12 yr. Fifty one (24%) patients were females. All patients were sero-negative for human immunodeficiency virus infection. Five of the 211 MDR-TB patients had XDR-TB. The prevalence of XDR-TB was 2.4 per cent among MDR-TB patients.

Interpretation & conclusion: Our results showed that XDR-TB was rare among patients with MDR-TB treated between 1997 and 2003 at our centre. Unreported selection bias might have been responsible for the high prevalence of XDR-TB reported in previous hospital-based studies from India.

Key words Drug resistance--extensively drug-resistant tuberculosis (XDR-TB)--India--multidrug-resistant tuberculosis (MDR-TB) tuberculosis
Article Type: Clinical report
Subject: Drug resistance in microorganisms (Research)
Tuberculosis (Care and treatment)
HIV infection (Care and treatment)
HIV infection (Health aspects)
Rifampin (Health aspects)
Prevalence studies (Epidemiology)
Authors: Sharma, Surendra K.
George, Ninoo
Kadhiravan, Tamilarasu
Saha, Pradip K.
Mishra, Hemant K.
Hanif, Mahmud
Pub Date: 10/01/2009
Publication: Name: Indian Journal of Medical Research Publisher: Indian Council of Medical Research Audience: Academic Format: Magazine/Journal Subject: Biological sciences; Health Copyright: COPYRIGHT 2009 Indian Council of Medical Research ISSN: 0971-5916
Issue: Date: Oct, 2009 Source Volume: 130 Source Issue: 4
Topic: Event Code: 310 Science & research
Geographic: Geographic Scope: India Geographic Code: 9INDI India
Accession Number: 229721080
Full Text: Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) have emerged as significant threats to global tuberculosis (TB) control. The magnitude of the problem is evident from the fourth global report of the World Health Organization (WHO) which reported data from 81 countries across the globe (1). Currently, MDR-TB accounts for 5.3 per cent of all TB cases in the world, with the prevalence among new and previously treated cases being 2.9 and 15.3 per cent respectively. This report also has data on XDR-TB in which second-line drug susceptibility testing (DST) was carried out on 4012 MDR-TB isolates from 35 countries; among these, 301 (7%) were found to be extensively drug-resistant (1). As of June 2008, 49 countries have reported laboratory confirmed XDR-TB cases to the WHO (2). The exact prevalence of XDR-TB in most regions of the world is currently unknown. A few earlier hospital-based studies from India have reported alarmingly high rates of XDR-TB among patients with MDR-TB (3-5). However, our personal experience in treating a large number of patients with MDR-TB is that XDR-TB would be uncommon in our setting. In order to confirm this anecdotal observation, we formally set out to ascertain the prevalence of XDR-TB among patients treated for MDR-TB at a tertiary care centre in New Delhi.

Material & Methods

The case records of patients with MDR-TB treated, during the period from 1997 through 2003, at the All India Institute of Medical Sciences (AIIMS) hospital, New Delhi were retrospectively reviewed. AIIMS is a large, tertiary level teaching hospital located in northern India. Before the initiation of treatment for MDR-TB, all patients underwent mycobacterial culture and DST at the New Delhi Tuberculosis Centre Laboratory, New Delhi. This laboratory was a supranational reference laboratory of the WHO during the study period. Cultures were done on Lowenstein-Jensen (LJ) slopes by Petroff's method (6). Niacin test, catalase test and para-nitrobenzoic acid (PNB) test were used to identify the isolated mycobacteria. DST was carried out by the proportion method for first-line drugs and resistance ratio method for second-line drugs (7). The tested drugs and their critical concentrations (in [micro]g/ml) were as follows: isoniazid--0.2, rifampicin--40, pyrazinamide--100, ethambutol--2, streptomycin--4, kanamycin--64, ciprofloxacin--8, ofloxacin--8, ethionamide --320, cycloserine--160, para-aminosalicylic acid--4, thiacetazone--4, and clarithromycin--128. MDR-TB was defined as TB caused by bacilli showing resistance to at least isoniazid and rifampicin. XDR-TB was defined as TB caused by bacilli resistant to rifampicin and isoniazid in addition to any fluoroquinolone and at least one of the three injectable second-line drugs: capreomycin, kanamycin and amikacin (8). Human immunodeficiency virus (HIV) testing was carried out routinely in all patients.

Results

Of the 211 patients with MDR-TB, 67.4 per cent came from various States outside Delhi and 32.6 per cent from within Delhi. Most (98%, n = 207) of these patients had a history of previous treatment for tuberculosis. Only four patients were naive to anti-tuberculous drugs. The mean age of the patients was 33 [+ or -] 12 yr; 51 (24%) patients were female. The mean body mass index was 17.3 [+ or -] 3.0 kg/[m.sup.2]. All patients tested negative for HIV infection. The resistance rates to various first and second-line drugs observed are shown in Table I. Of the 211 patients, 21 patients (10%) showed resistance to one of the fluoroquinolones and 14 (6.6%) showed resistance to the injectable agent, kanamycin. Five cases of XDR-TB were detected. Thus, the prevalence of XDR-TB among MDR-TB patients was 2.4 per cent. Among the five XDR-TB patients, two patients had a definite history of previous treatment with second-line drugs; the remaining three patients had multiple previous courses of anti-tuberculosis therapy which most likely included second-line agents, but no detailed records were available. Table II shows the characteristics of the patients with XDR-TB.

Discussion

We found that XDR-TB was rare among patients treated for MDR-TB at our centre. Our findings do not support the earlier reports of frequent occurrence of XDR-TB in India. The reported prevalence of XDR-TB in these hospital-based studies varied from 7.4 33.3 per cent (Table III). However, a population-based study from southern India suggested a low prevalence of XDR-TB9; notably, DST was performed at a WHO-accredited laboratory in this study. Our findings are in consonance with such an observation. The high rates of XDR-TB observed in previous hospital-based studies might be due to referral bias. Moreover, the DST was not performed at quality-assured, accredited laboratories in any of these studies. HIV infection and local failure of the control programme could have also possibly contributed to varying rates of drug-resistant TB in these studies and so is the small number of patients included in some studies.

The discrepancy in findings between the present and an earlier study (5) from the same institution can be explained by the difference in the nature of the two studies. The previous study (5) was conducted in full-blown AIDS patients and therefore, the basic study population was different from the present study. Although the present study was also hospital-based, we found that XDR-TB was rare. Notwithstanding, in our study, the DST was performed at a supranational reference laboratory. Perhaps, this might be one of the reasons for the discordant observations.

Another interesting observation was that none of the patients with MDR-TB was HIV co-infected in the present study. This finding is in agreement with previous studies on drug-resistant TB that had shown that HIV infection is not more common among drug-resistant TB patients than in the general population (10-12), although there are studies which contradict this finding (13,14). Though there are extensive data on HIV prevalence in TB as a whole, there have been only a few studies on prevalence of HIV among MDR-TB patients from India. In a study conducted in Chennai, HIV seropositivity among MDR-TB patients was 4.42 per cent (15), which is comparable to rates of HIV observed among ordinary TB patients. It is possible that HIV co-infected patients with MDR-TB succumbed to the illness before they could be diagnosed.

There are certain limitations to the present study. First, due to its retrospective nature, the study may not truly reflect the current pattern of drug resistance. It is well known that drug resistance is a dynamic phenomenon that needs to be studied in real-time. Second, being a hospital-based study, the present observations cannot be extrapolated to the community settings. Nonetheless, the low prevalence of XDR-TB in this referral population is reassuring.

The present observation, however, should not lead to a state of complacency. Large-scale representative population-based data are urgently needed to find out the true prevalence of XDR-TB in the community. Periodic drug-resistance surveillance should become a part of the national TB control programmes. It is important to improve the laboratory infrastructure and establish a nationwide network of quality-assured laboratories capable of carrying out second-line DST. Second-line drugs must be used judiciously and cautiously by physicians at all levels of medical care. Irrational use of second-line drugs, like adding fluoroquinolones to a first-line regimen or a failing regimen, should be avoided. Future large-scale population-based prospective studies should throw light on the prevalence of XDR-TB in the community.

Conflicts of interest

We declare that we have no conflict of interest.

Received February 12, 2009

References

(1.) Anti-tuberculosis drug resistance in the world. Fourth global report. The WHO/IUATLD Global Project on Anti-tuberculosis drug resistance surveillance; World Health Organization, Geneva 2008. WHO/HTM/TB/2008.394: p. 10-12.

(2.) World Health Organization. Tuberculosis: MDR-TB & XDR-TB. The 2008 Report; Geneva: WHO the Stop TB Department.

(3.) Mondal R, Jain A. Extensively drug-resistant Mycobacterium tuberculosis, India. Emerg Infect Dis 2007; 13 : 1429-31.

(4.) Jain S, Rodrigues C, Mehta A, Udwadia ZF. High prevalence of XDR-TB from a tertiary care hospital in India. Proceedings of the American Thoracic Society International Conference, May 2007, San Francisco, USA; Abstract A510.

(5.) Singh S, Sankar MM, Gopinath K. High rate of extensively drug-resistant tuberculosis in Indian AIDS patients. AIDS 2007; 21 : 2345-7.

(6.) NTI Monograph Series I. Manual for establishing and functioning of a tuberculosis culture laboratory. Bangalore: National Tuberculosis Institute; 1983. p.19.

(7.) Canetti G, Froman S, Grosset J, Hauduroy P, Langerova M, Mahler HT, et al. Mycobacteria: laboratory methods for testing drug sensitivity and resistance. Bull World Health Organ 1963; 29 : 565-78.

(8.) Centers for Disease Control and Prevention (CDC). Notice to readers: revised definition of extensively drug-resistant tuberculosis. MMWR Morb Mortal Wkly Rep 2005; 55 : 1176.

(9.) Thomas A, Ramachandran R, Rehaman F, Jaggarajamma K, Santha T, Selvakumar N, et al. Management of multidrug resistance tuberculosis in the field: Tuberculosis Research Centre experience. Indian J Tuberc 2007: 54 : 117-24.

(10.) Spellman CW, Matty KJ, Weis SE. A survey of drug-resistant Mycobacterium tuberculosis and its relationship to HIV infection. AIDS 1998; 12 : 191-5.

(11.) Asch S, Knowles L, Rai A, Jones BE, Pogoda J, Barnes PF. Relationship of isoniazid resistance to human immunodeficiency virus infection in patients with tuberculosis. Am J Respir Crit Care Med 1996; 153 : 1708-10.

(12.) Mitnick C, Shin S, Seung KJ, Rich ML, Atwood SS, Furin J, et al. Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med 2008; 359 : 563-74.

(13.) Edlin BR, Tokars JI, Grieco MH, Crawford JT, Williams

J, Sordillo EM, et al. An outbreak of multidrug-resistant tuberculosis among hospitalized patients with the acquired immunodeficiency syndrome. N Engl J Med 1992; 326 : 1514-21.

(14.) Gandhi NR, Moll A, Sturm AW, Pawinski R, Govender T, Lalloo U, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006; 368 : 1575-80.

(15.) 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.

Reprint requests: Prof. S.K. Sharma, Chief, Division of Pulmonary, Critical Care & Sleep Medicine, Head, Department of Medicine

All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110 029, India

e-mail: sksharma@aiims.ac.in, surensk@gmail.com

Surendra K. Sharma, Ninoo George, Tamilarasu Kadhiravan, Pradip K. Saha, Hemant K. Mishra & Mahmud Hanif *

Department of Medicine, All India Institute of Medical Sciences & * New Delhi Tuberculosis Centre New Delhi, India
Table I. Resistance rates to various first-line and second-line drugs
among MDR-TB patients *

First-line drug   Resistance   Second-line     Resistance
                  rate (%)     drug            rate (%)

Isoniazid         100          Kanamycin       6.6
Rifampicin        100          Ciprofloxacin   9.5
Pyrazinamide      8.1          Ofloxacin       9.0
Ethambutol        20.9         Sparfloxacin    4.8
Streptomycin      49.8         Cycloserine     4.3
                               Ethionamide     3.8
                               Clofazimine     1.9
                               PAS             2.4
                               Thiacetazone    8.7

* Note--206 patients were tested for thiacetazone, 209 patients for
cycloserine, 209 patients for clofazimine, and 208 patients for
sparfloxacin. Other drugs were tested in all 211 patients.
PAS, para-aminosalicylic acid

Table II. Characteristics of the patients with XDR-TB

S.No.  Age/Sex     Body-mass index   Previous     Previous use
                   (kg/[m.sup.2])    treatment    of second-line
                                     for TB       drugs

1      42 / Male   15.2              Yes          N.A
66     40 / Male   15.4              Yes          N.A
100    58 / Male   17.2              Yes          N.A
142    25 / Male   16                Yes          Yes
180    24 / Male   18                Yes          Yes

S.No.  Type of TB   Pattern of drug resistance

1      Pulmonary    R, H, K, Of, Cip, Thi
66     Pulmonary    R, H, S, K, Cip
100    Pulmonary    R, H, E, S, K, Cip, Of, Spar, Thi,
                    Clof, Cyc, Et, PAS
142    Pulmonary    R, H, K, Cip, Of
180    Pulmonary    R, H, S, K, Cip, Of

Cip, ciprofloxacin; Clof, clofazimine; Cyc, cycloserine; E,
ethambutol; Et, ethionamide; H, isoniazid; K, kanamycin; Of,
ofloxacin; PAS, para-aminosalicylic acid; R, rifampicin; S,
streptomycin; Spar, sparfloxacin; Thi, thiacetazone; N.A, Not
available

Table III. Published studies on the prevalence of XDR-TB in India

Study              Setting                            No. of MDR-TB
                                                      patients

Mondal et al (3)   Tertiary care centre, Lucknow           68
Jain et al (4)     Tertiary care centre, Mumbai            326
Singh et al (5)    Tertiary care centre, New Delhi         12
Thomas et al (9)   Field trial, Chennai                    66
Present study      Tertiary care centre, New Delhi         211

Study              No. of HIV-infected    Prevalence
                   patients               of XD n (%)

Mondal et al (3)   Not reported             5 (7.4)
Jain et al (4)     Not reported             36 (11)
Singh et al (5)    All HIV-infected        4 (33.3)
Thomas et al (9)   Not reported             1 (1.5)
Present study      All HIV-negative         5 (2.4)

MDR-TB, multidrug-resistant tuberculosis; XDR-TB, extensively
drug-resistant tuberculosis
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