India: MSF Calls For `Rational’ Antibiotic Use In Treating TB

MSF Briefing Report

 

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Tomorrow (March 24th) is World TB Day, and the focus this year is on multidrug-resistant tuberculosis (MDR TB) (see ECDC/WHO: World TB Day - Focus On MDR & XDR Treatment Outcomes), a growing concern around the world, but no more so than in India where more than 25% of all new TB cases reported in 2012 are to be found.

 

On Friday, Médecins Sans Frontières (MSF) released a sharply worded statement admonishing the Indian government for failing to regulate the sale and use of antibiotics for the treatment of Tuberculosis.

 

They warned that the inappropriate prescribing of antibiotics risks fueling the expansion of drug-resistant TB in that nation. The following excerpts come from a press release from MSF.

 

Patients in India suffer the consequences of poor regulation of TB drugs

March 21, 2014

The Ministry of Health must act to stop drug resistance from spiralling

New Delhi/Mumbai, March 21, 2014: Immediate action from the Indian government is needed to prevent the unregulated sale and inappropriate prescription of tuberculosis (TB) drugs in the private healthcare sector, a practice that has had a significant role in the emergence of drug-resistant TB in the country, warned the international medical humanitarian organisation Doctors Without Borders/Médecins Sans Frontières (MSF) in a statement released today in advance of World TB Day.

“It is the patients who suffer the consequences of poor regulation of TB drug formulations in India. An increasing number of our patients are being diagnosed with drug resistant TB (DR-TB). We encounter a spectrum of resistance patterns which range from mono-drug-resistant TB all the way through to extensively drug-resistant TB (XDR-TB),” said Dr Simon Janes, medical coordinator with MSF in India. “This makes it even more difficult for treatment providers like MSF and the government’s TB Control Programme to accurately diagnose and treat the different forms of drug-resistant tuberculosis.”

Read the briefing report

DR-TB infections are on the rise in India. The rising incidence has made the disease more difficult and considerably more expensive to treat. The conditions for emergence of drug resistance are increasingly being linked to poor drug regulation in India.

India has the largest private TB drug market, with rampant proliferation of first-line TB drugs in a wide variety of dosages and combinations.

Lack of oversight from the drug regulatory authority - the Drug Controller General of India (DCGI) - has made even basic treatment of drug-sensitive TB difficult to monitor. In the face of so many different formulations available in pharmacies across the country, ensuring the correct prescription of first-line TB drugs in the private sector is almost an impossible task for the Central TB Division (CTD).

As a result, poor compliance to World Health Organization (WHO) treatment guidelines is common among private doctors. TB patients being treated by private doctors in India might be facing a grave risk of developing drug-resistant TB due to irrational prescribing practices or indiscriminate use of non-WHO-recommended drug regimens.

“In our experience of working in India since 1999, we have seen prescriptions from private health providers that were completely inappropriate. For example we have seen many prescriptions that prescribe three out of the four first-line TB drugs in combination with a quinalone (antibiotic)”, said Dr Homa Mansoor, the TB Medical Referent for MSF India. “The alarm on drug resistance has been sounded, and the Health Ministry must act now to address this public health crisis."

(Continue . . . )

 

This coming week will no doubt bring many more reports on the challenges, and the progress being made, in the battle against TB.  For more on World Tuberculosis Day, the WHO has released the following brochure:

Reach the 3 million: Find. Treat. Cure TB

Authors:
WHO. Stop TB Partnership. The Global Fund to Fight AIDS, TB and Malaria

Publication details

Number of pages: 17
Publication date: March 2014
Languages: English

Downloads

Brochure: Reach the 3 million
pdf, 1.72Mb

 

While currently the biggest antibiotic-resistance crisis in India, TB is far from being the only concern.

 

Three and a half years ago The Lancet published a study (see NDM-1: A New Acronym To Memorize)  by Walsh, Toleman, Livermore, et al. that sounded the alarm on the emergence and growing prevalence of the NDM-1 enzyme on the Indian sub-continent.

 

Of particular concern, this NDM enzyme is carried by a plasmid – a snippet of portable DNA  - that can be easily transferred to other types of bacteria (see Study: Adaptation Of Plasmids To New Bacterial Species).

 

Six months after the first Lancet article - in April, 2011 - the same researchers published another study that found the NDM-1 enzyme in 4% of New Delhi’s sampled drinking water sources, and 30 per cent of the sewage tested. Most alarmingly, the researchers also identified 11 new species of bacteria carrying the NDM-1 gene, including strains which cause cholera and dysentery.

 

The rise of antibiotic resistance - including these emerging NDM enzymes - has long been linked to the overuse and misuse of antibiotics. A practice that is still widespread in many parts of the world, but has been particularly rampant on the Indian sub-continent.

 

After years of delay and debate, India this month finally placed restrictions on the sale of antibiotics without a prescription (see Times of India report 46 drugs under strict prescription norm), although pharmacists are already chaffing under the rules (see Pharmacists oppose sales record rule), and it remains to be seen just how effective these new rules will end up being.

 

Short of seeing an extremely high mortality influenza pandemic, it is hard to envision a looming medical crisis more dire than the growing threat of antimicrobial resistance. The World Health Organization, the ECDC, and the CDC all consider the spread of antibiotic resistant organisms to be a major public health concern.

 

For a more complete look at the complex issues of antibiotic resistance, and the dearth of new drugs on the horizon, I can think of no resource better than Maryn McKenna’s superb book (and recent winner of the 2013 June Roth Memorial Book Award, American Society of Journalists and Authors)  Superbug: The Fatal Menace of MRSA.

And while I dabble in the issues of antibiotic resistance, undoubtedly the best coverage can be found on Maryn’s Superbug blog.

ECDC/WHO: World TB Day - Focus On MDR & XDR Treatment Outcomes

 

Map Credit - Tuberculosis surveillance and monitoring in Europe 2014

 

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Next Monday (March 24th) is World TB Day, and so for the next couple of weeks we can expect to see a flurry of reports and assessments released on the global battle against this insidious disease.  The ECDC describes this year’s campaign:

 

2014 theme: MDR TB and MDR TB treatment outcomes

For World TB Day 2014, ECDC is focusing on multidrug-resistant tuberculosis (MDR TB), particularly on MDR TB treatment and treatment outcomes.

In the EU/EEA, the treatment success rates of MDR TB patients have remained stable but at a very low level: only one in every three (34%) patients in the reporting EU/EEA countries finishes MDR TB treatment successfully. More than half die, fail treatment or default (stop taking treatment).

MDR and XDR TB patients face much longer treatment, take more drugs, suffer from more side effects and treatment costs are five times higher compared to drug-susceptible TB. Only complete and successful tuberculosis treatment helps to prevent disease transmission and development of resistant strains that lead to the development of extensively drug-resistant TB (XDR TB), which is almost impossible to treat.

Merely 7 of the 21 countries reporting have maintained a mean five-year decline in MDR notification rates and the overall MDR TB treatment success rate remains far below the 70% target defined by the Framework Action Plan to Fight Tuberculosis in the European Union.

Why is MDR TB still a public health concern?

• TB is slowly declining but MDR and XDR TB pose a serious challenge in the attempt to eliminate TB across Europe, even though the number of reported MDR TB cases seem to decline slowly.
  
• In EU, only 1 in every 3 MDR TB patients has a successful treatment outcome; more than half either die, fail treatment or default (stop taking treatment). XDR TB has even worse treatment outcomes: only 1 in 4 patients finishes treatment successfully
  
• By not diagnosing and not treating patients with MDR TB early and successfully, we put their live at risk and pave the way for XDR TB
  
• Only complete and successful tuberculosis treatment helps to prevent disease transmission and development of resistant strains

 

Today the ECDC and the World Health Organization released an extensive (15mb, 218 pg) PDF report on the TB situation in Europe entitled:

 

Tuberculosis surveillance and monitoring in Europe 2014

18 Mar 2014

Available as PDF in the following languages

ENGLISH

Abstract

​The sixth report launched jointly by the European Centre for Disease Prevention and Control (ECDC) and the WHO Regional Office for Europe (WHO/Europe) indicates that, despite notable progress in the past decade, tuberculosis (TB) is still a public health concern in many countries across Europe. Of particular concern are the high rates of multidrug resistant (MDR) TB outside the European Union (EU)/European Economic Area (EEA). Meanwhile EU/EEA countries themselves have a significant number of TB cases among vulnerable population groups, such as people of foreign origin and prisoners.

An assessment of progress towards TB elimination for the four epidemiological indicators and eight core indicators defined in the report ‘Progressing towards TB elimination: A follow-up to the Framework Action Plan to Fight Tuberculosis in the European Union’ showed that none of the core indicators was achieved at EU/EEA level.

 

While progress has been made in reducing the overall incidence of Tuberculosis in Europe over the past decade, as the following press release indicates, the rise in MDR and XDR TB – and their dismal treatment outcomes -  has tempered any celebrations:

 

Tuberculosis cases down by 6% but only 1 in 3 MDR TB patients finishes treatment successfully

18 Mar 2014

​In 2012, 68 423 cases of tuberculosis (TB)  were reported in 29 EU/EEA countries according to new data published by the European Centre for Disease Prevention and Control and the WHO Regional Office for Europe ahead of World Tuberculosis Day. This results in a notification rate of 13.5 per 100 000 population and constitutes a 6% decrease compared to 2011 (72 000 cases reported), confirming the average annual decline of 5% since 2008.

The surveillance data show that the majority of EU/EEA countries report sustained low levels of TB, which means fewer than 20 TB cases per 100 000 population. In 19 of them, the number of tuberculosis patients decreased. Rates were below 10 per 100 000 population in 18 countries and below 20 in 23 countries.

Overall, the EU/EEA countries have been – and still are – successful in the fight against TB and met the target of an average five-year decline. However, they have not yet met the set targets for successful treatment of the multidrug-resistant form of tuberculosis, MDR TB.

(Continue . . . )

WHO: Global Tuberculosis Report – 2013

 

Credit WHO

 

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Nearly twenty years ago the World Health Organization declared tuberculosis a public health emergency, and that organization (along with many others) has been working towards a goal of reducing the number of TB related deaths in half by 2014.

 

Today, WHO has today release their 18th global report on tuberculosis,  which outlines the progress to date, and the challenges ahead in the global battle.  Using their @WHO twitter account, WHO began tweeting details early this morning.

 

A few excepts from the Executive Summary, and then links to and excerpts from the press release follow:

COUNTDOWN TO 2015: key findings

On track:

• The rate of new TB cases has been falling worldwide for about a decade, achieving the MDG global target. TB incidence rates are also falling in all six WHO regions. The rate of decline (2% per year) remains slow.
• Globally by 2012, the TB mortality rate had been reduced by 45% since 1990. The target to reduce deaths by 50% by 2015 is within reach.
• Two WHO regions have already achieved the 2015 targets for reduced incidence, prevalence and mortality: the Region of the Americas and the Western Pacific Region.
  
• Of the 22 high TB burden countries (HBCs) that account for about 80% of the world’s TB cases, seven have met all 2015 targets for reductions in TB incidence, prevalence and mortality. Four more HBCs are on track to do so by 2015.

Off track:

• By 2012, the level of active TB disease in the community (prevalence) had fallen by 37% globally since 1990. The target of a 50% reduction by 2015 is not expected to be achieved.
• The African and European regions are currently not on track to achieve the mortality and prevalence targets.
• Among the 22 HBCs, 11 are not on track to reduce incidence, prevalence and mortality in line with targets. Reasons include resource constraints, conflict and instability, and generalized HIV epidemics.
• Progress towards targets for diagnosis and treatment of multidrug-resistant TB (MDR-TB) is far off-track. Worldwide and in most countries with a high burden of MDR-TB, less than 25% of the people estimated to have MDR-TB were detected in 2012.
• Many countries have made considerable progress to address the TB/HIV co-epidemic. However, global-level targets for HIV testing among TB patients and provision of antiretroviral therapy (ART) to those who are HIV-positive have not been reached.

 

And the press release:

 

Gains in tuberculosis control at risk due to 3 million missed patients and drug resistance

Progress in TB control can be substantially accelerated by addressing these challenges

News release

23 October 2013 | LONDON/GENEVA - Tuberculosis (TB) treatment has saved the lives of more than 22 million people, according to the WHO "Global tuberculosis report 2013" published today. The report also reveals that the number of people ill with TB fell in 2012 to 8.6 million, with global TB deaths also decreasing to 1.3 million.

The new data confirm that the world is on track to meet the 2015 UN Millennium Development Goals (MDGs) target of reversing TB incidence, along with the target of a 50% reduction in the mortality rate by 2015 (compared to 1990). A special "Countdown to 2015" supplement to this year’s report provides full information on the progress to the international TB targets. It details if the world and countries with a high burden of TB are “on-track” or “off-track” and what can be done rapidly to accelerate impact as the 2015 deadline approaches.

(Continue . . . )

You can download the 2013 report (either in sections, or in its entirety) at the following link:

Global tuberculosis report 2013

This is the eighteenth global report on tuberculosis (TB) published by WHO in a series that started in 1997. It provides a comprehensive and up-to-date assessment of the TB epidemic and progress in implementing and financing TB prevention, care and control at global, regional and country levels using data reported by 197 countries and territories that account for over 99% of the world’s TB cases.

ECDC: Live #TBChat On Twitter Friday March 22nd

 

Tuberculosis surveillance and monitoring report - ECDC

 

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I’ve mentioned a couple of times this week that next Sunday is World TB Day (see WHO/ECDC: 1 In 5 TB Patients With Extrapulmonary TB & Dr. Chan: Sitting On MDR-TB `Powder Keg’). 

 

Tomorrow – March 22nd, 2013 - the ECDC will use Twitter to get the word out via a #TBChat they will hold between 10.00–11.00 UTC/GMT (11:00–12:00 CET).

 

Note: 07:00-08:00  EDT in the U.S.

 

 

For those who would like to join in, I’ve included the details from today’s ECDC announcement.

 

#TBchat: Join us live on Twitter

21 Mar 2013

ECDC

Experts from the European Centre for Disease Prevention and Control (ECDC) and WHO/Europe will answer questions on tuberculosis (TB) during a live Twitter chat on Friday, 22 March 2013, 10.00–11.00 UTC/GMT (11:00–12:00 CET). The chat, using the hashtag #TBchat, is part of ECDC’s activities for World TB Day, marked annually on 24 March.

Topics

• Latest findings from the Tuberculosis Surveillance and Monitoring in Europe 2013 report
• Extrapulmonary TB
• Multidrug- and extensively drug-resistant tuberculosis (M/XDR-TB)
• Research to find and develop new testing methods, TB drugs and vaccines

How to send questions to #TBchat

Send your questions as tweets to @ECDC_EU or @WHO_Europe using the hashtag #TBchat. If you are unable to join the live chat, leave your questions on the ECDC Facebook page.

After the chat, a summary of the discussion will be available on Storify.

WHO/ECDC: 1 In 5 TB Patients With Extrapulmonary TB

Credit ECDC

 

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While many are unaware of it, tuberculosis infections can spread far beyond the lungs. When that happens it most often involves the lymph nodes (Tuberculous lymphadenitis), or  pleural, and skeletal/joint areas, although any organ can be involved.

When the TB bacillus infects areas outside of the lungs it is considered an extrapulmonary infection. Diagnosis of extrapulmonary TB can be difficult, and is easily missed.

 

Today, in advance of next Sunday’s World TB Day, the ECDC and the World Health Organization have released a joint report on the treatment of TB. While reductions in pulmonary TB were reported in EU/EEA countries in 2011, the same cannot be said for extrapulmonary TB infections.

 

New ECDC/WHO Euro report: One in five TB patients has extrapulmonary tuberculosis

19 Mar 2013

Every day, around 200 people fall sick with tuberculosis (TB) across the EU/EEA, signalling that there is no room for complacency when it comes to TB prevention and control even in times of financial austerity. To mark World TB Day on the 24 March, ECDC and the WHO Regional Office for Europe release new surveillance data today.

 

The data show that the EU/EEA countries reported over 72 000 cases of TB in 2011, which is a 4% decrease compared to 2010. The average notification rate - 14.2 per 100 000 population - also represents a decline of pulmonary TB notifications. Notification rates vary significantly across Europe, from 2.8 in Iceland to 89.7 in Romania.

 

ECDC contributes to TB control by raising awareness and supporting  EU countries, as director Marc Sprenger points out: “Our primary aim is to further reduce TB transmission by timely diagnosis and adequate treatment of pulmonary TB. This is essential for TB elimination. But we should not forget about the patients with extrapulmonary TB: this group is often neglected in TB control strategies. In 2011, 22% of all notified patients in the EU/EEA had extrapulmonary TB, which can affect any organ of the body making the diagnosis particularly difficult for both physicians and patients”.

Extrapulmonary TB: a challenging diagnosis

A case with TB outside the lungs is considered an extrapulmonary TB case. Symptoms may be diffuse and mimic other pathologies, delaying the diagnosis or making it particularly difficult. In 2011, globally 6.2 million TB cases were notified, 0.8 million with extrapulmonary TB. In the European Union, one in five tuberculosis patients has extrapulmonary TB and unlike pulmonary TB, this form of the disease does not show a downward trend. Extrapulmonary TB is rarely infectious but contributes significantly to TB-related morbidity and can cause complications, lifelong sequelae and disabilities.

 

For World TB Day 2013, ECDC is launching a video documentary that focuses on extrapulmonary tuberculosis (TB). Two patient stories illustrate how difficult the diagnosis of extrapulmonary TB can be before proper treatment and care can start:

Winnie, 39 years old, living in Stockholm (Sweden)

After the first symptoms of abdominal pain started, Winnie visited her family doctor. With increasing swelling of the abdomen, the 39 year-old mother of two was later referred to Stockholm’s Karolinska Hospital gynaecological clinic. The suspected diagnosis of ovarian cancer made Winnie fear for her life and the future of her family.
Seven months after the first symptoms, Winnie was finally told she had extrapulmonary tuberculosis. Treatment started almost immediately: it was just the beginning of Winnie’s battle against the disease.

Italian patient, 54 years old, living in Brescia (Italy)

Nothing indicated that it could be tuberculosis causing the painful swelling in the chest of one Italian patient. For months, her family doctor and several speciality doctors struggled to find a diagnosis that matched her elusive symptoms.
Only after a full clinical investigation did the 54 year-old housewife learn that she had tuberculosis, not in her lungs, but in her chest. For her, the word “tuberculosis” still carries stigma and discrimination. That’s why she decided to share her story but not her identity.

TB treatment

Adequate treatment is essential to prevent the development of the drug-resistant forms of the disease, the multidrug-resistant TB (MDR TB) and the extensively drug-resistant TB (XDR TB). In 2011, cases of MDR TB have decreased but continue to be prevalent especially in the Baltic countries.

 

The ECDC/WHO surveillance report highlights that for the patients with known treatment outcome, only 74% were treated successfully. For 17%, treatment outcome is unknown. This is especially serious given that one untreated TB or MDR TB patient can infect 10-15 other individuals per year.

Press Release “Adequate treatment essential to stop TB across Europe - ECDC/WHO new report”

Watch

Extrapulmonary Tuberculosis: a challenging diagnosis - video documentary

Download

ECDC/WHO TB Surveillance and Monitoring Report 2013
ECDC/WHO TB Surveillance and Monitoring Report 2013 Slide presentation - main findings

Join
Joint twitter chat on Tuberculosis - 22 March 11:00 CET
Use #TBchat
Follow us on @ECDC_EU

 

A few recent blogs on the spread of TB, and particularly the threat posed by MDR-TB, you may wish to revisit:

 

Study: Substandard & Falsified TB Drugs

Lancet: TB Vaccine Trial Disappoints

EID Journal: The Emergence Of `Totally Resistant TB’

EID Journal: XDR-TB/HIV Treatment Outcomes

Lancet: TB Vaccine Trial Disappoints

WHO Fact Sheet on TB

 

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The World Health Organization estimates that roughly 2 billion people – nearly 1 in 3 – are infected with the TB bacilli, and of those, 1 in 10 will develop active TB during his or her lifetime.

 

The incidence of Tuberculosis varies greatly around the world, with North America, Europe and Australia/New Zealand seeing the lowest rates, and with the highest rates found in Africa, India, and Asia.

 

(From Global TB Control Report 2010)

 

With growing instances of MDR-TB (multi-drug resistant tuberculosis), and XDR-TB (extensively drug resistant Tuberculosis) and perhaps even  The Emergence Of `Totally Resistant TB’ the need has never been greater to find a way to prevent infection.

 

A vaccine against TB called BCG (Bacillus Calmette-Guérin) was developed in the 1920s, but only gained wide usage after World War II. While deployed in many countries (but never routinely in the United States), its efficacy is limited.

The World Health Organization released a position paper on the use of BCG in 2004, where they discuss its use and limitations against Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB).

 

The bacille Calmette–Guérin (BCG) vaccine has existed for 80 years and is one of the most widely used of all current vaccines, reaching >80% of neonates and infants in countries where it is part of the national childhood immunization programme.

BCG vaccine has a documented protective effect against meningitis and disseminated TB in children.

It does not prevent primary infection and, more importantly, does not prevent reactivation of latent pulmonary infection, the principal source of bacillary spread in the community.

 

The impact of BCG vaccination on transmission of Mtb is therefore limited.

 

 

In short, the protective effects of the BCG vaccine are variable, decline with time, and offer no protection against the most common form of TB infection.

 

The hunt for a better TB vaccine is ongoing, and while there are perhaps a dozen different vaccines under development, human trials are expensive, time consuming, and difficult to mount ethically.

 

Today, The Lancet has published the fast-tracked results of a phase 2B trial (human safety and efficacy) of a booster vaccine called MVA85A, meant to be given to infants after they have already received the BCG vaccine in order to improve its protection. 

 

This is literally the first new TB vaccine to undergo human trials in 90 years.

 

Unfortunately, while the experimental vaccine proved well-tolerated, it did not produce a significantly enhanced level of protection among the infants in the trial (1399 received MVA85A & 1398 received placebo).

In a 3 year follow-up there were 32 cases of TB among the children who received the MVA85A Booster, compared to 39 cases among those receiving the placebo.

 

The vaccine's efficacy rating of 17% was far below expectations.

 

In addition to the The Lancet study (below), you’ll find a comment (A major event for new tuberculosis vaccines) that states that these results “do not carry a terminal prognosis for MVA85A, or for any of the other TB vaccines under development”, along with an informative  Podcast.

 

Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial

Dr Michele D Tameris MBChB , Mark Hatherill FCP, Bernard S Landry MPH, Thomas J Scriba PhD , Margaret Ann Snowden MPH , Stephen Lockhart DM , Jacqueline E Shea PhD , J Bruce McClain MD , Prof Gregory D Hussey FFCH , Prof Willem A Hanekom FCP , Hassan Mahomed MMed , Prof Helen McShane FRCP , the MVA85A 020 Trial Study Team

Interpretation

MVA85A was well tolerated and induced modest cell-mediated immune responses. Reasons for the absence of MVA85A efficacy against tuberculosis or M tuberculosis infection in infants need exploration.

 

 

While the results announced today are disappointing, it is important to note that this study was conducted on infants. Unknown yet is how well this vaccine (or others in the works) might work as a booster for adolescents or adults with HIV.

 

For more background on the spread of TB, and efforts to combat it, you may wish to revisit these blogs.

 

EID Journal: Challenges To Defining TDR-TB

World TB Day Roundup

WHO: Blood Tests To Detect Active TB Unreliable

EID Journal: Challenges To Defining TDR-TB

 

(From the 2011 TB Progress Report)

 

# 6600

 

In January of this year reports began to emerge out of India regarding what was being called Totally Drug Resistant (TDR) tuberculosis (see Crof’s report India: New TB strain is "totally drug-resistant" (updated)).

 

While not an officially recognized term, TDR-TB was portrayed by the media as a frightening escalation of the existing classifications of Multi-drug resistant (MDR-TB) and Extensively-drug resistant (XDR-TB).

 

Resistant forms of Tuberculosis have come about primarily as the result of incomplete, irregular, or inappropriate treatment and management of infected patients.

 

A few days later (January 14th), the World Health Organization updated their Drug-resistant tuberculosis FAQ where they take exception to the term TDR-TB.

 

Why are these terms not yet recognised by WHO?

Terms such as “totally drug resistant” have 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

Around the same time we saw an ECDC Comment On Drug Resistant TB In India. One of the points being made in the comments section (excerpted below) is that the term TDR-TB is as yet not well defined, and may be misleading.

 

 

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.

 

In March, as part of my World TB Day Roundup, the World Health Organization released this statement on the supposed TDR-TB, cautioning:

 

More evidence and better diagnostics needed before redefining severe forms of drug-resistant TB says WHO

Note for the media

23 March 2012 | Geneva - Reports of tuberculosis (TB) cases with severe patterns of drug resistance are increasing, said experts who attended a WHO meeting in Geneva on 21-22 March. Participants stressed that the emergence of drug resistance should be a wake-up call for Ministries of Health. The group urged the global TB community to make greater efforts to prevent drug resistance and scale up provision of appropriate care and management to avoid a scenario where TB becomes incurable.

Insufficient evidence

The meeting concluded that there is currently insufficient evidence to adopt new case definitions for drug-resistant TB. Drug susceptibility testing (DST), which is key to defining new levels of drug resistance, lacks accuracy for several of the drugs that are used to treat multi drug-resistant (MDR) and extensively drug resistant (XDR)-TB. Secondly, there is insufficient correlation of DST results with clinical response to treatment for several drugs currently used to treat XDR-TB. Thirdly, new drugs are currently undergoing clinical trials, and could prove effective against drug resistant strains. The meeting urged diagnostics companies and TB laboratories to develop better diagnostic tests and also agreed that WHO and technical partners should develop more detailed guidance on XDR-TB treatment.

(Continue . . . )

 

 

All of which brings us to a new article appearing ahead of print in the CDC’s EID Journal that looks at the:

 

Challenges and Controversies in Defining Totally Drug-Resistant Tuberculosis

Peter Cegielski , Paul Nunn, Ekaterina V. Kurbatova, Karin Weyer, Tracy L. Dalton, Douglas F. Wares, Michael F. Iademarco, Kenneth G. Castro, and Mario Raviglione

Abstract

In March 2012, in response to reports of tuberculosis (TB) resistant to all anti-TB drugs, the World Health Organization convened an expert consultation that identified issues to be resolved before defining a new category of highly drug-resistant TB.

 

Proposed definitions are ambiguous, and extensive drug resistance is encompassed by the already defined extensively drug-resistant (XDR) TB. There is no evidence that proposed totally resistant TB differs from strains encompassed by XDR TB.

 

Susceptibility tests for several drugs are poorly reproducible. Few laboratories can test all drugs, and there is no consensus list of all anti-TB drugs. Many drugs are used off-label for highly drug resistant TB, and new drugs formulated to combat resistant strains would render the proposed category obsolete. Labeling TB strains as totally drug resistant might lead providers to think infected patients are untreatable. These challenges must be addressed before defining a new category for highly drug-resistant TB.

(Continue . . . )

 

Given the complexities of evaluating for total drug resistance, attaching the label TDR-TB to these strains may well be both premature and inaccurate.

  

But the sobering fact remains, if you are infected with one of these XDR-TB strains - and no drug is available to you that can treat it – for you, it may as well be totally resistant.

 

Of course, this disparity of available medical treatment exists for a great many diseases around the world, and is not just limited to TB.

 

 

The authors of the EID study conclude with this warning:

 

As countries increase treatment of MDR and XDR TB, it is inevitable that resistance to second-line drugs will increase. New drugs and better diagnostic tools are needed urgently for patients with highly drug-resistant TB.

 

For more on the global spread of TB, you may wish to revisit:

 

WHO-ECDC: Joint Report On Tuberculosis In Europe

Resistant TB: The Limits Of Surveillance & Reporting

WHO: Blood Tests To Detect Active TB Unreliable

WHO-ECDC: Joint Report On Tuberculosis In Europe

 

 

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World TB day is March 24nd, and the ECDC, the World Health Organization, the CDC, along with many other partners (including the National TB Controllers Assoc., Stop TB USA, and the global Stop TB Partnership) have joined together around the globe to raise awareness and promote strategies to reduce TB around the world.

 

 

Today, the ECDC and WHO released a 172 page Tuberculosis Surveillance And Monitoring In Europe report for 2012, that finds some encouraging signs, but also cautions on the increased incidence of extensively drug resistant (XDR) TB in parts of the EU.

 

Here is the announcement from the ECDC.

 

New ECDC-WHO report: tuberculosis on the retreat in Europe but concerns about drug-resistant TB and treatment failure remain

19 Mar 2012

ECDC

In 2010, the EU/EEA countries reported nearly 74 000 tuberculosis cases – around 7% less than 2009. While the notifications for multidrug- and extensively drug-resistant tuberculosis (M/XDR TB) have been stable over the past 5 years, the proportion of extensively drug-resistant patients among this group rose from 8.2% in 2009 to 13.2% in 2010 in the EU/EEA, possibly due to increased reporting.

These rising numbers pose a serious threat in the attempt to eliminate TB, highlighting the importance of early detection and adequate treatment of tuberculosis patients in the region.

 

ECDC Director Marc Sprenger, stresses that “Countries with low incidence of TB – which means less than 20 patients per 100 000 population – face a particular challenge in taking the final step towards elimination of the disease as TB often concentrates in big cities. In this setting, key populations like people who inject drugs, homeless people and migrants are disproportionally affected by TB. That is why we have to exchange best practices from across Europe: if TB services are not tailored towards the needs of urban risk groups there is a continuing risk of higher rates of TB in general and drug-resistant TB in particular.”

On the occasion of World TB Day 2012, ECDC supports simultaneous Urban TB Control events in Barcelona, Milan, London and Rotterdam on 22 and 23 March.

 

Join us on Tuesday, 20 March, when ECDC and WHO/Euro host a joint Twitter chat on the current TB situation in Europe. Use the hashtag #TBchat.

Read more:

Read the full press release

 

The full ECDC-WHO report Tuberculosis surveillance and monitoring in Europe 2012

ECDC report Towards TB elimination A follow-up to the Framework Action Plan to fight TB in the EU

ECDC Spotlight Tackling Tuberculosis in Children 2011

NPR Science Friday: McKenna On Resistant TB

 

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Later today (Friday, January 13th) Maryn McKenna will be a guest during the first hour (2 –3 pm EST) on NPR’s Science Friday to discuss the recent detection of a dozen cases of tuberculosis in India said to be `totally resistant’ to current antibiotic treatment.

 

 

 

Friday, January 13th, 2012

New Tuberculosis Strain Thwarts All Antibiotics

Physicians in India have discovered a strain of tuberculosis they call ‘TDR’ for ‘Totally Drug-Resistant’--meaning there is no antibiotic available to fight it. Maryn McKenna, author of Superbug , discusses the possible origins of the strain, and what options--if any--doctors have to treat it.

Guests

Maryn McKenna
Author, "Superbug: The Fatal Menace of MRSA," (Free Press, 2010)
Blogger, Wired
Atlanta, Georgia

 

 

Maryn, who is Flublogia’s resident expert on everything drug resistant, has written twice this week about this new development in her Superbug Blog, links to which you’ll find below:

 

 

Totally Resistant TB: Earliest Cases in Italy

• By Maryn McKenna
• January 12, 2012

India Reports Completely Drug-Resistant TB

• By Maryn McKenna 
• January 9, 2012  | 

ECDC Comment On Drug Resistant TB In India

 

 

 

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While more than a little discomfiting, in recent years we’ve grown accustomed to hearing about MDR-TB (multi-drug resistant tuberculosis), and XDR-TB (extensively drug resistant Tuberculosis). 

 

These varyingly resistant forms of Tuberculosis have come about primarily as the result of incomplete, irregular, or inappropriate treatment and management of infected patients. Patient compliance for long-term treatment has long been a major obstacle.

 

Until now – as difficult as treatment might have been - there has always been some combination of antibiotics that could be used to treat even the most resistant of TB cases.

 

All that appeared to change a few weeks ago when it was announced in an ahead-of-print letter to the journal Clinical Infectious Diseases that a four cases of TDR (totally drug resistant) tuberculosis had been identified in India. A follow up news report indicated that there are now at least 12 known cases in one hospital alone.

 

For more background on this announcement, I would invite you to read Maryn McKenna’s recent blog entry called India Reports Completely Drug-Resistant TB.

 

Today the ECDC has published their own comments on this development, along with links to other TB-related documents, on their website.

One of the points being made in the comments section (excerpted below) is that the term TDR-TB is as yet not well defined, and may be misleading.

 

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.

 

Follow the link below to read the entire comment.

 

 

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 and to seven second line anti-TB drugs.

With the existing forms of multi-drug and extensively drug resistant TB (M/XDR-TB) this so-called total drug resistant TB would indicate that none of the known TB combination regimens would be effective for such patients.

Read more:

Read the ECDC comment on this in our full

Public Health Development “New drug resistant form of tuberculosis reported in India”

 

ECDC Tuberculosis Programme

Tuberculosis, a global challenge: discover the ECDC Spotlight

Get the facts: read the ECDC special report “Progressing towards TB elimination”

Download the report “Tuberculosis surveillance in Europe 2009”

Discover the Spotlight “Tackling tuberculosis in children: towards a TB-free generation

Keep in touch with ECDC on facebook

Read the ECDC/WHO co-authored article “Tackling the spread of drug-resistant tuberculosis in Europe”

 

 

 

This story is just beginning to unfold, and I’m sure we’ll hear a lot more about it – and whether or not this new form of tuberculosis is indeed, as the study authors dubbed it - `totally resistant’ – in the coming months.

WHO: Blood Tests To Detect Active TB Unreliable

 

 

 

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Although following story was telegraphed earlier in the week by comments to the press by Mario Ravigli - the director of WHO's Stop TB Department – today we have the official announcement from the World Health Organization’s media centre, along with a detailed Policy Statement.

 

 

 

For the first time, the WHO has issued a “negative" policy recommendation against a well established practice used in Tuberculosis care. 

 

The World Health organization is calling for countries to immediately ban the use of blood tests designed to detect active TB, and rely instead upon microbiological or molecular tests for the diagnosis of Tuberculosis.

 

The two main measures of the accuracy of a diagnostic test are sensitivity and specificity.

 

• Sensitivity is defined as the ability of a test to correctly identify individuals who have a given disease or condition.

 

• Specificity is defined as the ability of a test to exclude someone from having a disease or illness.

 

And based on a year-long review by the WHO and global experts – which examined 94 existing studies – researchers found overwhelming evidence that these serological diagnostic tests produced an `unacceptable level of wrong results’  (compared to WHO sanctioned tests).

They found both `low sensitivity’, where the test failed to identify TB in patients (which can lead to patients not receiving the appropriate treatment).

 

And `low specificity’, where the test indicated TB when the patient was not infected (which could lead to unwarranted treatment and no treatment for the true cause of their illness).

 

First, some excerpts from the WHO’s media centre press release, followed by a link to the Policy Statement, and the strongly worded conclusion from its executive summary.

 

 

WHO warns against the use of inaccurate blood tests for active tuberculosis

A substandard test with unreliable results

News release

20 July 2011 | GENEVA - The use of currently available commercial blood (serological) tests to diagnose active tuberculosis (TB) often leads to misdiagnosis, mistreatment and potential harm to public health, says WHO in a policy recommendation issued today. WHO is urging countries to ban the inaccurate and unapproved blood tests and instead rely on accurate microbiological or molecular tests, as recommended by WHO.

TB can be wrongly diagnosed

Testing for active TB disease through antibodies or antigens found in the blood is extremely difficult. Patients can have different antibody responses suggesting that they have active TB even when they do not. Antibodies may also develop against other organisms which again could wrongly indicate they have active TB. In addition, different organisms share the same antigens, making tests results unreliable. These factors can result in TB disease not being identified or wrongly diagnosed.

A blood test for diagnosing active TB disease is bad practice

"In the best interests of patients and caregivers in the private and public health sectors, WHO is calling for an end to the use of these serological tests to diagnose tuberculosis," said Dr Mario Raviglione, Director of WHO Stop TB Department. "A blood test for diagnosing active TB disease is bad practice. Test results are inconsistent, imprecise and put patients' lives in danger."

 

Today's policy recommendation applies to blood tests for active TB. Blood tests for inactive TB infection (also known as dormant or latent TB) are currently under review by WHO.

(Continue . . . )

 

 

 

Commercial Serodiagnostic Tests for Diagnosis of Tuberculosis - Policy Statement pdf, 809kb

 

EXECUTIVE SUMMARY

Conclusions:  Commercial serological tests provide inconsistent and imprecise findings resulting in highly variable values for sensitivity and specificity.

 

There is no evidence that existing commercial serological assays improve patient-important outcomes, and high proportions of false-positive and false-negative results adversely impact patient safety.

 

Overall data quality was graded as very low and it is strongly recommended that these tests not be used for the diagnosis of pulmonary and extra-pulmonary TB. 

 

For some background on Tuberculosis, which kills 1.7 million people each year,  last March I wrote a blog titled World TB Day: March 24th. 

 

Some of the resources I cited that day may be of interest.

 

(From the 2011 TB Progress Report)

 

The World Health Organization  released a new report and a factsheet on MDR-TB & XDR-TB in advance of this yearly event on the the status of Tuberculosis around the world and the progress being made in its control.

WHO progress report 2011

Towards universal access to diagnosis and treatment of MDR and XDR-TB by 2015

Lancet Study: TB Screening

 

 

 

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The World Health Organization estimates that roughly 2 billion people – nearly 1 in 3 – are infected with the TB bacilli, and of those, 1 in 10 will develop active TB during his or her lifetime.

 

The incidence of Tuberculosis varies greatly around the world, with North America, Europe and Australia/New Zealand seeing the lowest rates, and with the highest rates found in Africa, India, and Asia.

 

(From Global TB Control Report 2010)

 

For details on declining TB rates in the United States you may wish to revisit MMWR: Tuberculosis Trends In The United States.  For a more global view, I wrote about the WHO: Global Tuberculosis Control Report 2010 last November.

 

Last year, you may recall, I highlighted the increasing rates of TB in the UK on a couple of occasions. 

 

Last July, in UK: TB Rising we looked at a report on the incidence of Tuberculosis in London, England. This from the Journal of Public Health.

Recent trends in tuberculosis in children in London

J.E.T. Ruwende, E. Sanchez-Padilla, H. Maguire,
J. Carless, S. Mandal, D. Shingadia

Abstract

Background Childhood tuberculosis (TB) represents a sentinel event of recent transmission and is an indication of the effectiveness of prevention and control interventions. We analysed the trends in the epidemiology of TB in children in London aged 0–14 years between 1999 and 2006.

 

<SNIP>

 

Conclusions Ethnicity, country of birth and age are important risk factors for development of. With an overall TB incidence in London exceeding 40/100 000, universal BCG immunization of all neonates should be considered across all London boroughs.

 

 

In October, in UK: TB `Rife’ in Birmingham, we looked at press reports out of England’s second most populous city proclaiming  UK: "Third World" rate of TB in Birmingham.

 

While nowhere near the problem that it is in many developing nations, the rate of Tuberculosis has been rising in England steadily for the past decade.

 

Part of this increase has been due to Immigrants arriving from countries where TB is more prevalent. Although new arrivals are required to have chest X-rays to screen them for TB, that only catches active TB.

 

TSKs (Tuberculin Skin Tests), are also recommended for certain age groups immigrating from specific countries. These, however, will show positive for those who have received the TB vaccine, or who have been previously exposed (but not necessarily infected), limiting their usefulness.

 

This from the BBC

20 April 2011 Last updated at 21:32 ET

TB screening 'missing most cases'

Current screening for TB in immigrants arriving in the UK is missing the majority of cases, say researchers.

 

The genesis of this media report is the following study which appears in The Lancet (free registration req.), that argues that the adoption of blood tests (interferon-γ release-assay (IGRA)) to screen specific cohorts of immigrants for latent TB is both cost effective and will result in earlier treatment for many who unknowingly are infected. 

 

 

Screening for latent tuberculosis

Current UK policy requires that all immigrants from countries with a tuberculosis incidence higher than 40 per 100,000 have a chest X-ray on arrival to check for active tuberculosis. However, very few immigrants have active tuberculosis on arrival, and many are carriers of latent tuberculosis, which often progresses to infectious active tuberculosis within a few years of arrival in the UK. An Article, by Pareek and colleagues, estimates the yields from, and cost-effectiveness of, screening for latent infection at different thresholds in relation to incidence of tuberculosis in immigrants’ countries of origin.

 

The entire (very detailed) research article is called:

The Lancet Infectious Diseases, Early Online Publication, 21 April 2011

doi:10.1016/S1473-3099(11)70069-X

Screening of immigrants in the UK for imported latent tuberculosis: a multicentre cohort study and cost-effectiveness analysis

 

The blood test in question (IGRA) are whole-blood tests that can often diagnose Mycobacterium tuberculosis infection, in both its  latent form (LTBI) and active tuberculosis (TB) disease.

 

Unlike the TST (Tuberculin Skin Test), the IGRA (aka. IGT) doesn’t give a false positive in those with prior BCG (bacille Calmette-Guérin) vaccination.

 

The CDC maintains the following FAQ sheet on the IGRA tests.  

 

In June of 2010 the CDC published via the MMWR Updated Guidelines for Using Interferon Gamma Release Assays to Detect Mycobacterium tuberculosis Infection --- United States, 2010.

 

It should be noted that the NHS’s  NICE (National Institute of Health and Clinical Excellence) updated their 2006 guidance on screening for TB in March of this year, including the use of the IGRA blood tests.

 

 

These guidelines are recommendations, and it is up to local NHS agencies to decide whether to adopt them.

 

They now have the  combined weight of this new guidance, along with the Lancet study, to consider.

MMWR: Tuberculosis Trends In The United States

 

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Today’s MMWR from the CDC, released on this World TB Day, contains two reports on the incidence of Tuberculosis in the United States.

 

I’ve pulled some excerpts from each report (and reformatted for readability), but follow the links to read them in their entirety.

 

The first takes a closer look at an unexpected drop in TB cases in two states – Georgia and Pennsylvania – in 2009, and concludes that these reductions were real, and not the result of surveillance artifacts, health-care provider under diagnoses, or underreporting.

 

Assessment of Declines in Reported Tuberculosis Cases --- Georgia and Pennsylvania, 2009

Weekly

March 25, 2011 / 60(11);338-342

What is already known on this topic?

In 2009, tuberculosis (TB) incidence in the United States decreased to 3.8 cases per 100,000 population, the lowest recorded rate since national TB surveillance began in 1953. The 11.4% decrease from 2008 was the greatest single-year decrease ever recorded.

What is added by this report?

Findings from systematic investigations in Georgia and Pennsylvania, two states that experienced unexpectedly large decreases in TB incidence in 2009, indicate that the decline in new TB disease in those states appeared actual and not attributable to surveillance artifact, health-care provider underdiagnosis, or underreporting.

What are the implications for public health practice?

The TB surveillance systems in Georgia and Pennsylvania appear to be functioning appropriately. Current efforts to diagnose, treat, and report TB cases should be vigorously maintained as the United States moves closer to the goal of TB elimination.

 

 

The second report looks at the trends in Tuberculosis in the United States, and finds that while significant reductions in TB have been made, the stated goal back in 1989 of reaching an incidence rate of < 0.1 per 100,000 population by 2010 has not been met.

 

Trends in Tuberculosis --- United States, 2010

Weekly

March 25, 2011 / 60(11);333-337

In 2010, a total of 11,181 tuberculosis (TB) cases were reported in the United States, for a rate of 3.6 cases per 100,000 population, which was a decline of 3.9% from 2009 and the lowest rate recorded since national reporting began in 1953 (1). This report summarizes provisional 2010 data from the National TB Surveillance System and describes trends since 1993.

 

Despite an average decline in TB rates of 3.8% per year during 2000--2008, a record decline of 11.4% in 2009 (2), and the 2010 decline of 3.9%, the national goal of TB elimination (defined as <0.1 case per 100,000 population) by 2010 was not met (3).

 

Although TB cases and rates decreased among foreign-born and U.S.-born persons, foreign-born persons and racial/ethnic minorities were affected disproportionately by TB in the United States. In 2010, the TB rate among foreign-born persons in the United States was 11 times greater than among U.S.-born persons.

 

TB rates among Hispanics, non-Hispanic blacks, and Asians were seven, eight, and 25 times greater, respectively, than among non-Hispanic whites. Among U.S.-born racial and ethnic groups, the greatest racial disparity in TB rates was for non-Hispanic blacks, whose rate was seven times greater than the rate for non-Hispanic whites.

 

Progress toward TB elimination in the United States will require ongoing surveillance and improved TB control and prevention activities to address persistent disparities between U.S.-born and foreign-born persons and between whites and minorities.

FIGURE 1. Rate* of tuberculosis (TB) cases, by state/area --- United States, 2010†

Source: National TB Surveillance System.

* Per 100,000 population.

† Provisional data as of February 26, 2011.

§ 20 states had TB case rates <2.0 (range: 0.61--1.88) per 100,000

What is already known on the topic?

In 1989, the Strategic Plan for Elimination of Tuberculosis in the United States set a target date of 2010 to achieve its goal, defined as an annual tuberculosis (TB) case rate of <0.1 per 100,000 population.

 

What is added by this report?

For 2010, preliminary data show a national TB case rate of 3.6 per 100,000 population, a decrease of 3.9% from 2009, but the goal of eliminating TB in the United States by 2010 was not achieved, and foreign-born persons and racial/ethnic minorities continued to be affected disproportionately.

 

What are the implications for public health practice?

Ongoing surveillance and improved TB control and prevention activities, especially among disproportionately affected populations, are needed to eliminate TB in the United States.