Totally drug-resistant tuberculosis in India

Totally drug-resistant tuberculosis TB at large in India

17:45 12 January 2012 by Andy Coghlan

A strain of tuberculosis that is resistant to all existing TB drugs has emerged in Mumbai, India.

“We currently have 12 confirmed cases, of which three are dead,” says Zarir Udwadia of the Hinduja National Hospital and Medical Research Centre in Mumbai, and head of the team whose diagnoses of four cases has just been published. The emergence of the disease in such a densely populated city is a major concern as it could spread so easily. “We know one patient transmitted it to her daughter,” Udwadia told New Scientist. “It’s estimated that on average, a tuberculosis patient infects 10 to 20 contacts in a year, and there’s no reason to suspect that this strain is any less transmissible,” he warns.

For patients, the outlook is grim. “Short of quarantining them in hospitals with isolation facilities till they become non-infectious – which is not practical or possible – there is nothing else one can do to prevent transmission,” says Udwadia. The worry is that if it continues spreading, TB will become incurable again and patients will have to rely on their immune system, rather than medical intervention, to overcome the illness – a scenario last seen a century ago.

Wake-up call
The World Health Organization is urgently organising a meeting to review the evidence and decide what steps to take next. “This is a problem that was predicted,” says Paul Nunn, coordinator of the STOP TB department of the WHO in Geneva. “It’s a wake-up call for countries to accelerate provision of proper care, particularly for multidrug-resistant patients,” says Nunn.

“It’s very worrying, but kind of inevitable, given the gradual emergence of resistance,” says Ruth McNerney, a TB researcher at the London School of Hygiene and Tropical Medicine. “It’s like watching a slow-motion horror movie unfold.” Multidrug-resistant (MDR) TB, which is resistant to the mainline treatments isoniazid and rifampin, emerged in the early 1990s. In 2006, extensively drug-resistant (XDR) strains emerged, defying all the expensive second-line treatments too. Now, the focus may switch to totally drug-resistant (TDR) tuberculosis. The first two cases of TDR were reported in Italy in 2007. Then, 15 patients with TDR were reported in Iran in 2009.

The Indian report is the first since then. Udwadia blames the emergence of totally untreatable TB on poor management of the MDR strain. “Years of mismanagement of MDR-TB at government and private care levels resulted in amplification of the level of resistance till we finally ended up with this untreatable strain,” he says.

Expensive drugs
He adds that while India has made huge strides in controlling conventional TB through its national programme, it has failed to provide the same level of support and treatment for patients with MDR-TB – not least because the drugs can cost between $2000 and $12,000 per patient. Treating conventional TB costs just $20 per patient.

Patients with MDR-TB – of which there were 110,000 in India in 2006 – must turn to private practitioners for help. They seldom receive proper treatment, though. Udwadia surveyed 106 private practitioners in a Mumbai suburb and found that only five of them would prescribe the correct prescription if approached by a MDR-TB patient. Nunn agrees that this is a major problem in many countries, calling on governments to accelerate and boost programmes to diagnose and treat MDR-TB, despite the cost.

He thinks it is possible that drugs such as clofazimine and thioacetazone might yet be able to treat the new form of TB, but they have serious side effects. Thioacetazone strips the skin off patients with HIV, for instance. So the best response is for countries to step up surveillance and treatment for MDR-TB. “We must wake up the politicians,” says McNerney. “Do we wait until it starts to come to the UK and the US on airplanes, or do we act now?”

Journal reference: Clinical Infectious Diseases, DOI: 10.1093/cid/cir889

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ProMED Digest
Date: Fri, 13 Jan 2012

TUBERCULOSIS, TDR – INDIA (02): (KARNATAKA), REQUEST FOR INFORMATION
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A ProMED-mail post <http://www.promedmail.org&gt; ProMED-mail is a program of the International Society for Infectious Diseases <http://www.isid.org&gt;

[1]
Date: Wed 11 Jan 2012
Source: DNAIndia.com [edited]
<http://www.dnaindia.com/bangalore/report_tb-in-its-new-avatar-arrives-in-bangalore_1636125&gt;

Following the discovery of 4 cases of totally drug resistant tuberculosis (TDR-TB) in a Mumbai hospital 3 days ago, 2 confirmed cases with the deadly new strain of TB have been detected at the Rajiv Gandhi Institute of Chest Diseases (RGICD) in Bangalore. But the scarier scenario is this: one among them, a 56-year-old man (the hospital has not disclosed his name), has gone absconding, raising the threat perception many levels higher, considering that he could infect others with the deadly strain.

Shockingly, the RGICD has not informed the state health department. Dr Shashidhar Buggi, director, RGICD, said: “If they ask us, we will let them know. We are a national institute; if the state government asks us for the report, we will definitely give it to them.” This spells another concern. While one of the confirmed TDR-TB patients has gone missing, state health department officials remain in the dark.

TDR-TB is a strain of tuberculosis which cannot be treated by any available drug. This means that a person afflicted by this strain faces a 100 percent mortality rate and, until death, can infect many others.

Both the TDR-TB cases in Bangalore were confirmed after the RGICD sent their sputum (phlegm) samples to Chennai’s Intermediate Reference Laboratory, where the samples tested positive for the deadly TDR-TB strain. The other patient suffering from the TDR-TB is a 29-year-old woman (name undisclosed).

“These patients were being treated for over 2.5 years. After 8 months, when they were not responding to medication, we sent their sputum samples to the Intermediate Reference Laboratory in Chennai. It was then found that they had both become extremely resistant to the drug‚ a condition named extreme drug resistance (XDR). When this condition continued for more than a year, it was confirmed that they had multi drug resistance (MDR). Now, it has been 2 years since they have been getting treatment, and the tests have confirmed that they have TDR,” said Dr Buggi.

Over 498 cases of MDR alone have been registered with the RGICD since 2005, of which 230 have been treated and discharged. “In 2009, we had 114 cases; in 2010, there were 74 fresh cases. The number came down to 50 MDR cases in 2011,” he said. “We have sent samples of 8 suspected TDR-TB patients to Chennai and are awaiting the results. The tests identify micro-organisms causing infections in the lower respiratory tract like TB,” he said.

When DNA [DNAIndia.com] tried contacting senior health officials, none of them were available.

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[2]
Date: Wed 11 Jan 2012
Source: DNAIndia.com [edited]
<http://www.dnaindia.com/bangalore/report_its-deadly-a-tdr-tb-patient-on-the-loose_1636131&gt;

Even as 2 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 _Mycobacterium tuberculosis_, the bacterium that causes the disease.

A 56-year-old man has been missing for 2 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 Tuberculosis and Chest Diseases Hospital and RGICD.

Now, this patient is like a ticking time-bomb. And nobody is coming forward to inform the authorities about his whereabouts, or whether he has died. “We don’t know why he stopped coming to the hospital. But we have not seen him in 2 weeks. We are now considering operating [on] the other patient (a 29-year-old woman) depending on her condition. But for now, we have no news of the other patient,” he said.

The absconding patient is said to have been taking treatment for TB at the RGICD for 2 years. “We had 2 cases of TB for which we had been giving treatment for more than 8 months. We sent their phlegm for testing in Chennai, where it was confirmed that both have developed extreme drug resistance. After another 6-8 months of treatment, it was found that they were suffering from multi-drug resistance (MDR),” Buggi said.

It has been 2 years since the 2 patients started treatment for MDR. Buggi said the RGICD had recently sent samples of phlegm for testing at Chennai’s Intermediate Reference Lab; out of the 10 samples, 2 were confirmed to have TDR.

[Byline: Deepthi MR]

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[3]
Date: Thu 12 Jan 2012
Source: DNAIndia.com [edited]
<http://www.dnaindia.com/bangalore/report_tdr-tb-threat-ramdas-says-rgicd-is-guessing_1636519&gt;

The revelation of 2 confirmed totally drug resistant-tuberculosis (TDR-TB) cases at Rajiv Gandhi Institute of Chest Diseases (RGICD) has shaken the health ministry and officials who had instantly gone into a denial mode, even as they blame the RGICD for not bringing the cases to their notice.

However, minister for medical education, health and family welfare, SA Ramdas, following a DNA report on Wednesday [11 Jan 2012], has decided to constitute a 3-man committee to submit a detailed report on the status of tuberculosis in the state to the government. He also conducted a “surprise visit” to RGICD and declared that he is not convinced that the 2 were TDR-TB cases because “the 2 cases were only confirmed by clinical tests, and biological tests have not been done while confirming them.”

He alleged that RGICD has only conducted a clinical analysis of the 2 patients wherein sputum (phlegm) culturing was not conducted. He blamed RGICD for guessing that, since the patients have not responded to the medication for 2 years, it must be TDR. Biological tests (also called culture and sensitivity tests) include culture of the sputum being subjected to multiple tests during which the DNA strands are isolated.

The tests involve allowing the bacteria “_Mycobacterium tuberculosis_” to grow, and various drugs are used on it to indicate whether the samples are TDR-TB-positive or not. These tests are conducted only in Chennai and at New Delhi’s National Institute of Tuberculosis.

Ramesh, joint director, Lady Willingdon State Tuberculosis Centre’s Revised National Tuberculosis Control Programme, which is a state government-administered organisation, said: “We have not received TDR cases so far, and if Rajiv Gandhi Institute for Chest Diseases has them, then they should have informed us.” Despite that, RGICD authorities stand by their version that 2 patients are indeed confirmed as TDR-TB cases, one of which‚ a 56-year-old man, is missing. Ramdas, however, does admit that there are 56 cases of major multi drug resistant tuberculosis (MDR-TB), and 6 cases of extreme drug resistant tuberculosis (XDR-TB).

“We have sent 4.8 lakh [a lakh is a unit in the South Asian numbering system equal to 100 000] sputum samples from the state to Chennai’s Intermediate Reference Lab and received 68 000 TB-positive cases, of which 56 are MDR positive and 6 have extreme drug resistance [XDR]. If there are other cases, we will trace the patients and give them appropriate treatment,” he said.

There is no denying that the state ministry is concerned despite its initial reaction, hence the constitution of the 3-member committee, which in all likelihood comprises Dr Suryakanth, officer in-charge at Lady Willingdon State Tuberculosis Centre’s Revised National Tuberculosis Control Programme; Dr Sathya Prakash, senior scientist, National Tuberculosis Institute; and Dr Raghupathi, resident medical officer, state health department.

[Byline: Deepthi MR]

– —

Communicated by:
ProMED-mail
<promed@promedmail.org>

The situation concerning the presence of so-called “totally drug resistant” tuberculosis (TDR-TB) in the Indian state of Karnataka is quite confusing. According to the news report posted one day ago by ProMED-mail (Tuberculosis, TDR – India: (MH, KA) 20120110.1005663), Rajiv Gandhi Institute of Chest Diseases (RGICD), which is a government-run institute specializing in treating tuberculosis, stated that there were no cases of TDR-TB in the state of Karnataka, of which Bangalore is the capital. However, the 1st 2 news reports above state that 2 confirmed cases with TDR-TB have been detected at the Rajiv Gandhi Institute of Chest Diseases (RGICD) in Bangalore. Nevertheless, the 3rd news report above raises questions about the validity of the TDR-TB diagnosis in these patients, stating that these diagnoses were based on lack of clinical response to drug therapy, not on drug susceptibility testing. We await further information to make sense of the situation.

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ProMED Digest
Date: Tue, 10 Jan 2012

TUBERCULOSIS, TDR – INDIA: (MAHARASHTRA, KARNATAKA)
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A ProMED-mail post <http://www.promedmail.org&gt; ProMED-mail is a program of the International Society for Infectious Diseases <http://www.isid.org&gt;

[1]
Date: Sat 7 Jan 2012
Source: Indianexpress.com [edited]
<http://www.indianexpress.com/news/mumbai-hospital-reports-1st-set-of-total-drug…/896826/&gt;

Almost 3 years after the 1st set of patients were diagnosed with Totally Drug-Resistant Tuberculosis (TDR-TB) in Iran, researchers at the P D Hinduja National Hospital and Medical Research Centre here said today [7 Jan 2012] they have detected India’s 1st set of TDR-TB patients, 12 over the past 2 months.

In a paper published in the international journal Clinical Infection Diseases, Zarir Udwadia and his team have described how they detected the 1st 4 TDR-TB patients [Udwadia ZF, Amale RA, Ajbani KK, Rodrigues C. Totally Drug-Resistant Tuberculosis in India. Clin Infect Dis. 1st published online 21 Dec 2011 doi:10.1093/cid/cir889].

“Prior to TDR, XDR or extensively drug-resistant TB was the furthest stage patients had been diagnosed with in India. After drug susceptibility testing was performed on 4 TB patients present at the hospital, it was seen that all 4 patients were resistant to both 1st line as well as 2nd line treatment,” said Udwadia, adding that there was no treatment for them.

According to Udwadia, the drug-resistant nature of the TB-causing _Mycobacterium tuberculosis_ increases with mutations of the strain often catalysed by incorrect and erratic administration of 2nd-line drugs. “An audit of the patients’ prescriptions showed that 3 of the 1st 4 patients received unsupervised 2nd-line drugs often in incorrect dosages by private practitioners in an attempt to treat their multi-drug resistant TB (MDR-TB). By the time they were referred to us, they had moved from the MDR stage and the XDR stage to TDR-TB,” he said.

[Byline: Ananya Banerjee]

– —

Communicated by:
Mark Liao
MSI
UC Davis School of Medicine
<markliaohk@gmail.com>

[Similar news releases were also submitted by Ryan McGinnis <digicana@gmail.com> and ProMED-mail Rapporteur Mary Marshall. – Mod.ML]

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[2]
Date: Sun 8 Jan 2011
Source: IBNLive South [edited]
<http://ibnlive.in.com/news/no-cases-of-tdr-tuberculosis-in-karnataka/218853-60-115.html&gt;

Following the reports of deaths of some patients from Totally Drug Resistant Tuberculosis, (TDR TB), which is far more dangerous than Multi-Drug Resistant (MDR) and Extreme Drug Resistant (XDR) forms, in Mumbai, experts say that improper treatment regimens followed by private practitioners and non-compliance to the whole course of proper treatment make tuberculosis patients vulnerable to this deadly infection.

According to the Rajiv Gandhi Institute of Chest Diseases (RGICD), which is a government-run institute specializing in treating tuberculosis, there were no cases of TDR in the State [Karnataka]. A total number of 450 MDR cases were treated since 2005, of which only 219 patients could complete the treatment. The institute had also detected 2 patients with XDR in the years 2010-11.

Speaking to Express [Express News Service], Dr Shashidhar Buggi, Director, Rajiv Gandhi Institute of Chest Diseases (RGICD), said: “Had these patients not completed the treatment, it could have infected several others. The MDR treatment is long and costly. However, at RGICD, we are providing free treatment to such patients with the help of the state government.” He also maintained that for MDR patients, thoracic surgery is important, but there is a shortage of surgeons in our country.

Dr VM Katoch, Director General, Indian Council of Medical Research (ICMR), said that private practitioners do not follow the proper course of treatment. Sometimes, patients visit multiple doctors, which leads to non-compliance of the treatment.

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[3]
Date: Mon 9 Jan 2012
Source: Wired.com [edited]
<http://www.wired.com/wiredscience/2012/01/invincible-tb-india/#more-91763&gt;

Over the past 48 hours, news has broken in India of the existence of at least 12 patients infected with tuberculosis that has become resistant to all the drugs used against the disease. Physicians in Mumbai are calling the strain TDR, for Totally Drug-Resistant. In other words, it is untreatable as far as they know.

News of some of the cases was published on 21 Dec 2011 in an ahead-of-print letter to the journal Clinical Infectious Diseases. That letter describes the discovery and treatment of 4 cases of TDR-TB since last October [2011]. On Saturday [7 Jan 2012], the Times of India disclosed that there are actually 12 known cases just in one hospital, the P. D. Hinduja National Hospital and Medical Research Centre; in the article, Hinduja’s Dr. Amita Athawale states: “The cases we clinically isolate are just the tip of the iceberg.” And, as a follow up, the Hindustan Times reported yesterday [8 Jan 2012] that most hospitals in the city — by extension, most Indian cities — don’t have the facilities to identify the TDR strain, making it more likely that unrecognized cases can go on to infect others.

TB is already one of the world’s worst killers, up there with malaria and HIV/AIDS, accounting for 9.4 million cases and 1.7 million deaths in 2009, according to the WHO. At the best of times, TB treatment is difficult, requiring at least 6 months of pill combinations that have unpleasant side effects and must be taken long after the patient begins to feel well.

Because of the mismatch between treatment and symptoms, people often don’t take their full course of drugs, and from that and some other factors, we get multi-drug resistant and extensively drug-resistant MDR and XDR TB.

MDR is resistant to the 1st-choice drugs, requiring that patients instead be treated with a larger cocktail of “2nd-line” agents, which are less effective, have more side effects, and take much longer to effect a cure, sometimes 2 years or more. XDR is resistant to the 3 1st-line drugs and several of the 9 or so drugs usually recognized as being 2nd choice.

As of last spring [2011] according to the WHO, there were about 440000 cases of MDR-TB per year, accounting for 150000 deaths, and 25000 cases of XDR. At the time, the WHO predicted there would be 2 million MDR or XDR cases in the word by 2012. That was before TDR-TB.

The 1st 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 4 of the 12 patients; all 4 saw 2 to 4 doctors during their illnesses, and at least 3 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 [2011] that only 2/3rds 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 1st identified just in 2006, and it has since been found in 69 countries around the world.

[Byline: Maryn McKenna]

– —
Communicated by:
Michael J. Buman, RN
<bustedmedic@yahoo.com>

[Multidrug-resistant TB or MDR-TB refers to tuberculosis that is caused by a strain of _Mycobacterium tuberculosis_ resistant to 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).

In 2003, 2 middle-class, HIV-negative Italian women died of tuberculosis that was caused by strains resistant to every anti-tuberculosis drug (Migliori GB et al. 1st tuberculosis cases in Italy resistant to all tested drugs. Eurosurveillance Weekly Release 12: 5, 2007). The authors of the report attributed the development of drug resistance in these patients to medical mismanagement and inappropriate use of anti-tuberculosis therapy. WHO referred to these cases as extremely drug-resistant tuberculosis or XXDR-TB, which was defined as TB due to strains resistant to all 1st and 2nd line anti-TB drugs (<http://euro.who.int/tuberculosis/publications/20071204_5&gt; and <http://www.aidsmap.com/en/news/CBA086E0-D64C-43A4-B9A5-D21C57B35E8D.asp&gt;).

In 2009, 15 “Totally Drug Resistant” or TDR isolates (10.3 percent) of 146 MDR-TB strains were reported from Iran (Velayati, AA, Masjedi MR, Farnia P, et al. Emergence of new forms of totally drug-resistant tuberculosis bacilli: Super extensively drug-resistant tuberculosis or totally drug-resistant strains in Iran. Chest 2009; 136: 420-425). These TDR strains were resistant to all 1st- and 2nd-line drugs tested and thus seemingly similar to XXDR-TB strains.

In December 2011, the 1st 4 of the 12 patients from Mumbai, India were reported with what was labeled TDR tuberculosis [Udwadia ZF, Amale RA, Ajbani KK, Rodrigues C. Totally Drug-Resistant Tuberculosis in India. Clin Infect Dis. 1st published online 21 Dec 2011 doi:10.1093/cid/cir889, available at <http://cid.oxfordjournals.org/content/early/2011/11/24/cid.cir889.full.pdf%20html?sid>%5D. The drug susceptibility testing was performed at the Hinduja Hospital,

Mumbai’s busiest referral laboratory and a Revised National Tuberculosis Control Programme (RNTCP) accredited laboratory for Mumbai. The isolates from each of the 4 patients in this report were resistant to all 1st-line (isoniazid, rifampicin, ethambutol, pyrazinamide, and streptomycin) and some 2nd-line (ofloxacin, moxifloxacin, kanamycin, amikacin, capreomycin, para-aminosalicylic acid, and ethionamide) drugs tested; thus, this TDR designation is again seemingly similar to XXDR-TB strains and does not include what are called 3rd-line anti-TB drugs, such as the macrolides (e.g., clarithromycin), clofazimine, amoxicillin/clavulanic acid, linezolid, imipenem, high-dose isoniazid, and several new investigational drugs (<http://www.medscape.com/viewarticle/706826_6&gt;).

The latest WHO global resistance report estimated 110-132 cases of MDR tuberculosis from India in 2006, which accounts for 20 percent of the world’s MDR tuberculosis load (<http://cid.oxfordjournals.org/content/early/2011/11/24/cid.cir889.full.pdf%20html?sid&gt;). Indian patients with MDR tuberculosis currently are not covered by India’s RNTCP, with most MDR patients seeking care from private physicians. According to Udwadia et al
(<http://cid.oxfordjournals.org/content/early/2011/11/24/cid.cir889.full.pdf%20html?sid&gt;), an audit of the Indian patients’ prescriptions revealed that 3 patients had received erratic, unsupervised 2nd-line drugs, added individually and often in incorrect doses, from multiple private practitioners, which undoubtedly contributed to the emergence of drug resistance.

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