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Published Date: 2012-05-01 22:13:55
Subject: PRO> Tuberculosis, TDR - India (05): (MH) fatal
Archive Number: 20120501.1119816

TUBERCULOSIS, TDR - (INDIA) (05): (MAHARASHTRA) FATAL
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Date: Mon 30 Apr 2012
Source: The Asian Age [edited]
http://www.asianage.com/mumbai/nti-confirms-hinduja-s-tb-cases-fully-drug-resistant-696

The National Tuberculosis Institute (NTI), Bangalore has validated Hinduja Hospital's study that confirms drugs resistance to all the known TB drugs (1st and 2nd line) in 8 patients whose samples were re-tested.

On 6 Jan 2012, Hinduja Hospital had announced that they had detected 12 totally drug resistant (TDR) TB cases, a terminology that was not accepted by the World Health Organisation (WHO). Drugs resistance is developed because of mismanagement of multi-drug resistant tuberculosis (MDR-TB). They had published the study in the scientific publication Clinical Infectious Diseases Advance Access on 21 Dec 2011.

However, after the Central Tuberculosis Division (CTD), with their team of experts including NTI, arrived in Mumbai to take stock of the situation, they said that the patients suffered from XXDR-TB, which in medical literature is extremely drug-resistant tuberculosis. Of the 12 cases, 8 samples were then sent for re-testing to NTI.

"Of the 8 samples sent, 2 patients died early this year. The other 6 patients live in Mumbai, one of who is a 15-year-old. 5 of these patients are undergoing treatment with the Revised National Tuberculosis Control Programme (RNTCP) for extensively drugs resistant (XDR) TB, while one is being treated at the Hinduja Hospital," said Dr Minni Khetarpal, city TB officer, Brihanmumbai Municipal Corporation.

"The NTI has confirmed the Hinduja report. We will place this report on record before the Directly Observed Treatment Shortcourse (DOTS) committee and figure out the future line of treatment that could be offered to these patients now," said Dr P.Y. Gaikwad, state TB officer.

However, Dr Gaikwad added that 2 of these patients are sensitive to one 2nd-line drug. "All the other patients are doing well. It shows that immunity of the host (patient) also matters, not just the drug sensitivity to the bacteria. Many of these patients are working for a living," said Dr Gaikwad.

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[Multidrug-resistant TB or MDR-TB refers to tuberculosis that is caused by a strain of _Mycobacterium tuberculosis_ resistant to at least 2 of the most effective drugs used to treat TB, isoniazid (INH) and rifampin. Extensively drug-resistant TB or XDR-TB refers to a subgroup of MDR-TB strains that are additionally resistant to any of the fluoroquinolone class of drugs (e.g., levofloxacin. moxifloxacin, or gatifloxacin) and any of the 3 injectable drugs used to treat tuberculosis (capreomycin, kanamycin and amikacin). Extremely drug-resistant (XXDR) has been used to refer to a subgroup of XDR-TB that are resistant to all 1st and 2nd line anti-TB drugs (http://euro.who.int/tuberculosis/publications/20071204_5 and http://www.aidsmap.com/en/news/CBA086E0-D64C-43A4-B9A5-D21C57B35E8D.asp).

1st line anti-TB drugs are: INH, rifampin, pyrazinamide, ethambutol and streptomycin; and 2nd line drugs are: amikacin, kanamycin, capreomycin, viomycin, fluoroquinolones, ethionamide, cycloserine, and para-aminosalicylic acid (http://www.ncbi.nlm.nih.gov/pubmed/15971391). 3rd-line drugs include the macrolides (such as clarithromycin), clofazimine, amoxicillin/clavulanic acid, linezolid, imipenem, high-dose isoniazid, and several new investigational drugs.

The TDR-TB strains from India were reported resistant to all 1st-line (isoniazid, rifampin, ethambutol, pyrazinamide, and streptomycin) and the 2nd-line (ofloxacin, moxifloxacin, kanamycin, amikacin, capreomycin, para-aminosalicylic acid, and ethionamide) drugs tested. No mention was made of the activity of so-called 3rd-line anti-TB drugs. The in vitro drug susceptibility testing, however, for some anti-TB drugs remains problematic.

According to a January 2012 WHO document (http://www.who.int/tb/challenges/mdr/tdrfaqs/en/index.html):
"The term "totally drug resistant" has not been clearly defined for tuberculosis. While the concept of "total drug resistance" is easily understood in general terms, in practice, in vitro drug susceptibility testing (DST) is technically challenging and limitations on the use of results remain: conventional DST for the drugs that define MDR and XDR-TB has been thoroughly studied and consensus reached on appropriate methods, critical drug concentrations that define resistance, and reliability and reproducibility of testing. Data on the reproducibility and reliability of DST for the remaining SLDs [2nd-line drugs] are either much more limited or have not been established, or the methodology for testing does not exist.

Most importantly, correlation of DST results with clinical response to treatment has not yet been adequately established. Thus, a strain of TB with in vitro DST results showing resistance could in fact, in the patient, be susceptible to these drugs. The prognostic relevance of in vitro resistance to drugs without an internationally accepted and standardised drug susceptibility test therefore remains unclear and current WHO recommendations advise against the use of these results to guide treatment.

"Lastly, new drugs are under development, and their effectiveness against these "totally drug resistant" strains has not yet been reported.

"For these reasons, the term "totally drug resistant" tuberculosis is not yet recognised by the WHO. For now these cases are defined as extensively drug resistant tuberculosis (XDR-TB), according to WHO definitions."

A statement from the Indian Revised National Tuberculosis Control Programme (RNTCP) (January 2012) (http://www.tbcindia.nic.in/pdfs/RNTCP%20Response%20DR%20TB%20in%20India%20-%20Jan%202012%20update.pdf), in response to challenges of drug resistant TB in India, essentially agrees with that of the WHO:
"Recently, a letter to Clinical Infectious Disease Journal in December 2011 described 4 patients from Mumbai, India with "totally drug resistant" tuberculosis (coined "TDR-TB" from earlier reports) i.e., resistant to all 1st- line and 2nd-line drugs tested. Such cases have been reported sporadically in Europe and 15 cases in Iran in 2009. Subsequent media reports have added reports of further cases in Mumbai and in Bangalore.

"A careful audit of their prescriptions revealed that these 3 patients had received erratic, unsupervised 2nd-line drugs, added individually and often in incorrect doses, from multiple private practitioners (on average from 4 physicians during a 18-month period) in an attempt to cure their multi-drug resistant (MDR) tuberculosis. The author urged that patients with MDR tuberculosis only be treated within the confines of government sanctioned MDR TB treatment programs to prevent the emergence and spread of this untreatable form of tuberculosis.

"The patients in question represent MDR TB patients, who may also have XDR TB. The term TDR TB "totally drug resistant" is non-standardized, and in any case testing for resistance beyond XDR TB is not reliable, and correlation of DST results with clinical response to treatment has not yet been established, and some treatments might have some efficacy. Current WHO recommendations advise against the use of these DST results beyond those used to identify XDR-TB to guide treatment. Furthermore, new drugs to treat MDR TB are under final stages of development, hence the notion of "total drug resistance" may be fleeting. For these reasons, the term "totally drug resistant" tuberculosis is not yet recognized by the WHO. For now these cases are defined as extensively drug resistant tuberculosis (XDR-TB), according to WHO definitions, and accordingly can be managed by national XDR TB treatment guidelines."

Hinduja Hospital is a leading multispecialty health care hospital and medical research center in Mumbai, India (http://www.hindujahospital.com/). Mumbai, formerly known as Bombay, is the capital of the Indian state of Maharashtra. A map of the states of India can be accessed at http://www.globalsecurity.org/military/world/india/images/IndiaMap_tourism.gif. The HealthMap/ProMED-mail interactive map of India can be accessed at http://healthmap.org/r/2gZV. - Mod.ML]

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