Announcement

**Ronan Kelly** · January 7, 2012, 06:35 AM

Re: Mumbai: Drug resistant TB strain detected at Hinduja hospital

Totally Drug-Resistant Tuberculosis in India
Zarir F. Udwadia, Rohit A. Amale, Kanchan K. Ajbani, and Camilla Rodrigues
+ Author Affiliations

P. D. Hinduja National Hospital and Medical Research Centre, Mumbai, India
Correspondence: Zarir F. Udwadia, MD, FRCP, P. D. Hinduja National Hospital and Medical Research Centre, Veer Savarkar Marg, Mahim, Mumbai 400 016, India (zarirfudwadia@gmail.com).
TO THE EDITOR?Three years after extensively drug-resistant (XDR) tuberculosis was first described in 2006, Velayati et al [1] drew attention to the emergence of totally drug-resistant (TDR) tuberculosis in a cohort of 15 patients from Iran, resistant to all first- and second-line drugs. Since the first cases of XDR tuberculosis in India were reported from the P. D. Hinduja National Hospital and Medical Research Centre [2], physicians here have grappled with increasingly resistant strains of tuberculosis. We describe the first patients from India with TDR tuberculosis. Drug susceptibility testing (DST) was ?

http://cid.oxfordjournals.org/content/early/2011/11/24/cid.cir889.extract

**Gert van der Hoek** · January 8, 2012, 07:42 AM

Re: Mumbai: Drug resistant TB strain detected at Hinduja hospital

TDR-TB: no choice left

As if Multi-drug resistant (MDR-TB), extensively-drug resistant (XDR-TB) were not scary enough, now TB has a deadlier edge known as Totally Drug-Resistant TB (TDR-TB). As the name says it all, the physicians are literally left with no choice to treat, as all known TB combination drugs do not work on the patient, owing to the TB bacilli’s ability to mutate and get resistant to the drugs. The clinicians have little to offer these patients with TDR-TB except for drastic surgeries and some relief medications.

TDR-TB cases were first reported in Iran in 2009 and India stands as the second country to report this scary form of TB and 12 TDR-TB cases have been reported in the last 3 months at Hinduja Hospitals in Mumbai.

Of the 12 cases reported in Mumbai 83.3% of them were from the Mumbai city. Moreover, it is worrisome to note that the average age of the 12 patients is just about 32 years.

The TDR-TB strains from the reported 12 patients were found to be resistant to all the first line drugs namely, streptomycin, isoniazid, rifampicin, ethambutol and pyrazinamide and second line drugs namely, ofloxacin, moxifloxacin, kanamycin, amikacin, capreomycin, para-aminosalicylic acid and ethionamide.

In the report published in the December 2011 issue of Clinical Infectious Diseases journal, the authors declare that the emergence of TDR-TB is the failure of overall health system.

Only 1% of patients with drug resistant TB have access to second-line drugs provided by the government sector and the private sector has clinicians who do not follow appropriate guidelines for management of TB patients.

According to an earlier study on the prescription pattern of clinicians in a particular area, less than 5% of clinicians prescribed the right drugs for drug-resistant patients.

MicroBiologyBlog

Thanks to Crof

**Gert van der Hoek** · January 11, 2012, 04:32 AM

Re: Mumbai: Totally Drug resistant TB strain detected at Hinduja hospital

Maryn McKenna has some more details in her blog :

India Reports Completely Drug-Resistant TB

By Maryn McKenna January 9, 2012

- snip -

The first cases, as it turns out, were not these Indian ones, but an equally under-reported cluster of 15 patients in Iran in 2009. They were embedded in a larger outbreak of 146 cases of MDR-TB, and what most worried the physicians who saw them was that the drug resistance was occurring in immigrants and cross-border migrants as well as Iranians: Half of the patients were Iranian, and the rest Afghan, Azerbaijani and Iraqi. The Iranian team raised the possibility at the time that rates of TDR were higher than they knew, especially in border areas where there would be little diagnostic capacity or even basic medical care.

The Indian cases disclosed before Christmas demonstrate what happens when TB patients don?t get good medical care. The letter to CID describes the course of four of the 12 patients; all four saw two to four doctors during their illness, and at least three got multiple, partial courses of the wrong antibiotics. The authors say this is not unusual:

The vast majority of these unfortunate patients seek care from private physicians in a desperate attempt to find a cure for their tuberculosis. This sector of private-sector physicians in India is among the largest in the world and these physicians are unregulated both in terms of prescribing practice and qualifications. A study that we conducted in Mumbai showed that only 5 of 106 private practitioners practicing in a crowded area called Dharavi could prescribe a correct prescription for a hypothetical patient with MDR tuberculosis. The majority of prescriptions were inappropriate and would only have served to further amplify resistance, converting MDR tuberculosis to XDR tuberculosis and TDR tuberculosis.

As their comment suggests, the other TB challenge is diagnosis, especially of resistant strains, and here again the news is not good. The WHO said last spring that only two-thirds of countries with resistant TB epidemics have the lab capacity to detect the resistant strains. As a result, only one MDR patient out of every 10 even gets into treatment, and when they do, cure rates range from 82 percent down to 25 percent. That?s for MDR. None of the TDR patients have been recorded cured, and at least one of the known Indian patients has died.

Meanwhile, health authorities estimate that one patient with active TB can infect up to 15 others. And thus resistant TB spreads: XDR-TB was first identified just in 2006, and it has since been found in 69 countries around the world.

read more

**Shiloh** · January 11, 2012, 07:19 AM

Re: Emergence of Totally Drug resistant TB strain

Source: http://www.dnaindia.com/bangalore/re...-loose_1636131

It?s deadly A TDR-TB patient on the loose
Published: Wednesday, Jan 11, 2012, 10:24 IST
By Deepthi MR | Place: Bangalore | Agency: DNA

Even as two cases of Totally Drug-Resistant Tuberculosis (TDR-TB) have been detected in Bangalore, one of the patients is missing. This poses a grave threat of rapidly spreading the deadliest strain of the Mycobacterium tuberculosis, the bacterium that causes the disease.

A 56-year-old man has been missing for two weeks as he has not turned up at Rajiv Gandhi Institute for Chest Diseases (RGICD) for treatment and may be a cause of concern in the city. ?TB can spread fast. A person with TB, if not treated, can spread it to 10 other people around him, on average,? said Shashidhar Buggi, director of SDS...

**Gert van der Hoek** · January 13, 2012, 04:41 AM

Re: Emergence of Totally Drug resistant TB strain

ECDC review on "Totally Drug Resistant" Tuberculosis.

New drug resistant form of tuberculosis reported in India

12 Jan 2012

In a recent scientific article (Udwadia, F et al. Clin. Infect. Dis. 2011, Dec 21, Eprint) four cases of so-called total drug resistant tuberculosis (TB) were reported from India. According to the article, these patients have shown resistance to all the first line TB drugs (isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin) and to seven second line anti-TB drugs (ofloxacin, moxifloxacin, kanamycin, amikacin, capreomycin, para-aminosalcyclic acid and ethionamide).

ECDC comment (12 January 2012):
Drug-resistant tuberculosis is manmade and results from inadequate treatment management of TB cases like irregular treatment regimen prescription, poor compliance to treatment plans or sub-optimal dosing due to biological variations in drug uptake. The key to preventing the development of drug resistance, multi-drug resistance or extensively drug resistance is to provide patients with the correct multi-drug TB treatment regimen for the entire treatment time.

Total drug resistant TB is a relative notion and depends on the local drugs available and tested on. This term/expression should either be avoided or should be defined worldwide. The World Health Organization (WHO) has internationally-endorsed treatment recommendations for the treatment of drug-susceptible, MDR-TB and XDR-TB.

Successful treatment of TB is possible but requires full support from the health care system by offering optimal diagnostic services, high-quality drugs for the full time of treatment and support to the patient in fulfilling the treatment. To make this happen, strong TB diagnostic services and processes that ensure the rational use of TB drugs (1,2,3) are essential in order to be able to test all suspected TB cases for drug-resistance and to identify resistance as soon as possible to enable appropriate therapy. Furthermore, ensuring treatment outcome monitoring of all cases is vital.

In 2009, 1.450 MDR-TB cases were reported in the EU/EEA (5.3% of all TB cases) and 66 XDR-TB case were reported by 15 EU/EEA countries. Cases resistant to almost all anti-TB drugs have been reported in the EU, albeit not many. In 2007, two cases resistant to all the second-line TB drugs in Italy were also described in the literature (4). Both cases had acquired resistance to these multiple drugs as a result of mismanagement of treatment (this included erratic treatment prescription and poor treatment adherence).

Yet, the full extent of the XDR-TB burden in the EU/EEA is not known as to date not all countries report these results, and much less for TB forms resistant to almost all anti-TB drugs. However, MDR-TB and XDR-TB are clearly present in the EU/EEA and it is important to maintain and strengthen TB control programmes to assure all TB patients are rapidly identified, tested for drug-resistance, receive appropriate treatment and are supported to ensure full completion of treatment. It is every individual patient’s right to receive the best of care and in a public health view, this is essential to prevent the further spread/transmission of TB in the population.
To prevent further spread of TB, drug-resistant TB, MDR-TB, XDR-TB in the population, it is essential that appropriate infection control measures are in place.(5)

In response to the findings of a survey on MDR-TB case management in the EU (6,7), ECDC and the European Respiratory Society (ERS) jointly developed European Union Standards for Tuberculosis Care (ESTC)(8). These aim at providing EU-tailored standards for the diagnosis, treatment and prevention of tuberculosis (TB)(9). Effective TB, MDR-TB and XDR-TB prevention and control in the EU can only be achieved when all the three components function optimally. These ESTC have been developed on the basis of the existing International Standards for TB Care, to ensure conformity and comparability with the global standards.

To further support EU Member States in improving and maintaining strong TB control programmes, ECDC is coordinating the European Reference Laboratory Network for TB (ERLN-TB) with the aim to strengthen TB diagnosis, surveillance, drug susceptibility testing, and international coordination in the EU/EEA. Also, ECDC has been developing molecular surveillance of MDR-TB in the EU (through an open contract), aiming at developing molecular typing in EU Member States to enable the mapping of MDR-TB in the EU/EEA. In 2012, ECDC will be incorporating molecular typing in the ERLN-TB as well as introducing the Molecular Surveillance System for which MDR-TB reporting will be provided. This will be essential to further monitor MDR-TB in the EU and identify strengths and challenges.

References:
1. Langendam MW, van der Werf MJ, Huitric E, Manissero D. Prevalence of inappropriate tuberculosis treatment regimens: A systematic review. ERJ. 2011 Oct 17; Epub ahead of print.
2. van der Werf MJ, Langendam MW, Huitric E, Manissero D. Knowledge of tuberculosis treatment prescription of health workers: A systematic review. ERJ. 2011 Dec 19; Epub ahead of print
3. van der Werf MJ, Langendam MW, Huitric E, Manissero D. Multidrug resistance after inappropriate tuberculosis treatment: A meta-analysis. ERJ. 2011 Oct 20; Epub ahead of print]
4. Migliori et al. First tuberculosis cases in Italy resistant to all tested drugs. Eurosurveillance, volume 12(20)
5. Sotgiu, G et al. TB and M/XDR-TB infection control in European TB reference centres: the Achille’s heel? Eur Respir J. 2011 Nov;38(5):1221-3.
6. Migliori*, G.B., G. Sotgiu* et al. TB and MDR/XDR-TB in the EU and EEA countries: managed or mismanaged? Eur Respir J. accepted for publication (2012)
7. Sotgiu G, et al. Development of a standardised tool to survey MDR-/XDR-TB case management in Europe. Eur Respir J. 2010 Jul;36(1):208-11.
8. http://ecdc.europa.eu/en/press/news/...2FLists%2FNews
9. Migliori, G.B., et al. Towards the development of EU Standards for TB Care (ESTC). Eur Respir J. 2011 Sep;38(3):493-5.

**Gert van der Hoek** · January 13, 2012, 05:39 AM

Re: Emergence of Totally Drug resistant TB strain

Totally Resistant TB: Earliest Cases in Italy

By Maryn McKenna January 12, 2012 |

A follow-up to Monday’s post on the recognition in India of totally drug-resistant tuberculosis, TDR-TB: The fantastic early-warning list ProMED points out that the earliest recorded cases of TDR were not the current 12 known cases in Mumbai or the 15 cases in Iran in 2009, but rather two women from Italy who died in 2003 after being sick for several years.

It’s a sad story that was briefly recounted in 2007 in the journal EuroSurveillance, published by the European Centre for Disease Prevention and Control (ECDC).

The last thing to say is that, even if TDR-TB emerges from poor treatment, there is no reason to think that it will not spread from person to person — just as drug-susceptible TB does, and MDR-TB and XDR-TB have been demonstrated to do. In other words, the suffering, and spending, contained in the stories above could become much more common, if TDR-TB begins to spread.

Read more - Nature

thanks to Crof

**Gert van der Hoek** · January 16, 2012, 05:59 AM

Re: Emergence of Totally Drug Resistant TB-strain

From WHO

Tuberculosis that is ?resistant to all drugs?

Frequently asked questions

January 2012

What is ?totally drug resistant? tuberculosis (?TDR-TB?)?
In 2006, the first reports of extensively drug-resistant tuberculosis (XDR-TB), an even more severe form of drug resistant TB than multidrug-resistant TB (MDR-TB), began to appear. [1,2] MDR-TB is defined as resistance to isoniazid and rifampicin, with or without resistance to other first-line drugs (FLD). XDR-TB is defined as resistance to at least isoniazid and rifampicin, and to any fluoroquinolone, and to any of the three second-line injectables (amikacin, capreomycin, and kanamycin). Within a year of the first reports of XDR-TB, isolated cases were reported in Europe that had resistance to all first-line anti-TB drugs (FLD) and second-line anti-TB drugs (SLD) that were tested.[3,4,5] In 2009, a cohort of 15 patients in Iran was reported which were resistant to all anti-TB drugs tested.[6]

The terms ?extremely drug resistant? (?XXDR-TB?) and ?totally drug-resistant TB? (?TDR-TB?) were given by the respective authors reporting this group of patients. Recently, a further 4 patients from India with ?totally drug resistant? tuberculosis (?TDR-TB?) were described [7], with subsequent media reports of a further 8 cases.[8]

Is the term ?totally drug resistant? clearly defined? Is it recognised by the WHO?

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.[9] Data on the reproducibility and reliability of DST for the remaining SLDs 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.[10]

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.

How easily do MDR or XDR-TB or ?TDR-TB? spread?
TB bacilli with different levels of resistance spread in the same way and with the same risk of infection as fully drug susceptible strains. For more information please click here.

What does the WHO recommend should be done to address MDR or XDR-TB?
The discovery of patients with MDR or XDR-TB emphasizes the importance of ensuring that all care for tuberculosis, whether in the public or private sector, must conform to international standards[11] in order to prevent the emergence of drug resistance. Almost all countries must, in addition, ensure appropriate diagnosis and treatment of cases of MDR-TB.[11,12] National regulations for the quality and dispensing of anti-TB drugs, particularly of the second-line drugs, need to be strictly enforced.

To achieve this, most countries require simultaneous scale-up of the diagnostic and treatment services for drug-resistant TB, and the provision of adequate and continuous supplies of quality assured SLDs for both MDR- and XDR-TB to meet the increased demand.

MDR and XDR-TB raise many difficult issues concerning the management of patients, for example, whether to isolate patients, the need for institutional, palliative or end-of-life care, and the compassionate use of new drugs. The reader is referred to the WHO?s Guidelines for the programmatic management of drug-resistant tuberculosis.[10]

Are there any treatment options for patients with XDR-TB?
XDR-TB severely reduces the options for treatment, but, yes, there are still options available, although they have not been studied in large cohorts. For such cases additional drugs will need to be procured from among the group of agents that are known to have some action against tuberculosis but are not routinely recommended for treatment of MDR-TB.[10] These include clofazimine, linezolid, amoxicillin/clavulanate, thioacetazone, imipenem/cilastatin, clarithromycin and high-dose isoniazid. Efficacy is not assured, however, and both toxicity and cost for some of these compounds are high. Potential purchasers should be aware that international availability of some of these agents is limited at present.

Will the new drugs in development soon be available for treatment of XDR-TB?
Several new drugs belonging to new classes of anti-mycobacterial agents are under development, but until they are shown to be effective in properly conducted clinical trials, WHO cannot recommend their routine use. In particular WHO advises strongly against simply adding a single new drug to a failing regimen. The use of experimental drugs outside clinical trials (compassionate use) has been addressed by the WHO.[10]

What strategies underlie WHO?s recommendations for dealing with drug resistance?
The WHO-recommended Stop TB Strategy provides the framework for the effective large-scale treatment and control of both drug-susceptible and drug-resistant disease.[13] The Global Plan to Stop TB, 2011 ? 2015, developed by the Stop TB Partnership, including WHO, estimates funding needs for implementation levels needed to achieve global targets.[14] Critical weaknesses in many countries? current capacity and approaches to the treatment and control of MDR-TB and XDR-TB have been identified and the policy approaches necessary to address them have been described.[15]

Are countries aware of the need to respond to drug resistant TB? How are they doing?
In 2009, the Beijing Call for Action[17] and the approval of the World Health Assembly Resolution 62.15 [17], with 193 Member States present, signalled a step forward in countries? commitment to, and planning for, the treatment and control of MDR-TB. Planning, funding, and implementation have, however, fallen behind the milestones that were set. In 2010, only 20 out of 36 countries with a high burden of TB or MDR-TB had at least one laboratory capable of performing TB culture and DST per 5 million people. Much of Africa and the Indian subcontinent remain poorly served. Globally in 2010, only 4% of new and 6% of previously treated TB patients were reportedly tested for susceptibility to isoniazid and rifampicin, while the Global Plan targets are 20% or more, and 100%, respectively. The number of reported cases of MDR-TB was only 18% of the estimated number of cases among TB patients notified in 2010. And only around one quarter of them were treated in accordance with recommended international guidelines. Data (unpublished) collected by WHO show that just over a half of MDR-TB patients in recent cohorts completed their treatment successfully, and among patients with XDR-TB, death is more common than successful treatment; default and treatment failure rates are also high.

Are sufficient financial resources available in countries to address MDR-TB?
According to the 2011 WHO Global TB report, funding for MDR-TB in 2011 was US$0.7 billion, US$ 0.2 billion less than the need estimated in the Global Plan to Stop TB.[18] Of the reported funding, US$ 0.5 billion (71%) was accounted for by three upper-middle income countries: Kazakhstan, the Russian Federation and South Africa. The funding required for MDR-TB to reach the 2015 target of universal access to care rises from US$ 0.9 billion in 2011 to US$ 2 billion in 2015; most of this funding is needed in middle-income countries. Thus, much more funding needs to be mobilized in high MDR-TB burden countries to ensure proper diagnosis and treatment.

What measures will be taken by the WHO at the global level, to address ?TDR-TB? specifically?
To facilitate discussion and to make surveillance consistent, an initial step is for WHO and partners to develop a consensus on whether a new definition is needed, and if so what the term and definition should be for such patients, taking into account the technological limitations of DST that still exist in 2011. If ?totally drug-resistant? TB defines a subset of XDR-TB with different characteristics to other XDR-TB cases, particularly with respect to the outcome of such cases, then an internationally recognised definition may be needed. This should be seen as a call for national TB programmes and research groups to make data available on the outcomes of all highly resistant cases.

WHO is organising an Expert Group Meeting in March, 2012 to assess additional data on DST accuracy obtained since 2008. This meeting will be expanded to include a consultation on possible definitions for ?totally drug-resistant? TB. WHO is also convening another Expert Group Meeting in March to assess the latest evidence behind a new molecular line probe assay for detecting XDR-TB.

For more information, please contact:
Monica Dias
Stop TB Department
WHO/Geneva
Email: diash@who.int

**Shiloh** · January 31, 2012, 01:04 PM

Re: Emergence of Totally Drug Resistant TB-strain

Source: http://www.huffingtonpost.ca/2012/01...n_1242847.html

Extreme Tuberculosis Raises Alarms In Canada
Tuberculosis
First Posted: 01/30/2012 4:55 pm Updated: 01/31/2012 6:34 am

Canadian doctors say that offering more support to physicians in India who are struggling to treat patients with a serious strain of turberculosis could help protect people here.

"The rich countries should help the resource-poor countries to increase TB control," said Dr. Monica Avendano, a TB specialist at West Park Health Care Centre in Toronto.Avendano. "It's just a plane ride [away]."

Unless TB is dealt with in Southeast Asia and the former Soviet republics, "we will continue to have this emergency worldwide," she added.

The physicians in Mumbai reported 12 TB patients with a strain that was resistant to a dozen drugs. Three of the patients have since died.

"In TB, we often use this phrase that TB anywhere is TB everywhere given how connected the world is," said Dr. Madhukar Pai of McGill University in Montreal, who has been studying the Indian TB control program...

**Gert van der Hoek** · January 7, 2013, 10:34 AM

Re: Emergence of Totally Drug Resistant TB-strain

A year on, 8 more cases of TDR-TB at Hinduja

Priyanka Vora, Hindustan Times

Mumbai, January 06, 2013

A year after PD Hinduja Hospital announced the detection of 12 cases of totally drug-resistant (TDR) tuberculosis, the hospital has reported eight more cases of the strain.

As the Brihanmumbai Municipal Corporation (BMC) does not classify cases as TDR, preferring to list all severe drug resistant cases under the wider term Extra Extensively Drug Resistant Tuberculosis (XXDR), the new cases at Hinduja Hospital show that the city continues to see more cases of the severe form of tuberculosis.

While XXDR tuberculosis is classified as a form resistant to at least two of the 12 prescribed anti-TB drugs, TDR, the severest form, is resistant to all 12 drugs.

From January 2012, Hinduja Hospital has reported 20 patients, including the 12 new cases, who are resistant to all known 12 anti-TB drugs.

Of these 20 patients, six have succumbed to the disease. Following the Mahim hospital?s announcement, the central government team had visited the city and classified these cases as XXDR and not TDR.

Announcement

Emergence of Totally Drug Resistant TB-strain

Emergence of Totally Drug Resistant TB-strain

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