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South Africa Warns of Emergence of “Totally” Drug-Resistant Tuberculosis

South Africa Warns of Emergence of “Totally” Drug-Resistant Tuberculosis After spending 5 months volunteering at a small hospital in South Africa in 2007, physical therapist Natalie Skipper returned to her hometown of Paris, Tenn—and to a diagnosis of extensively drug-resistant tuberculosis (XDR-TB) that took 2 years to treat, including 90 days in isolation. Skipper was “lucky,” relatively speaking, because despite the difficulty in treating XDR-TB, she was ultimately cured. Now, however, newly identified strains of TB have emerged in South Africa and elsewhere that some experts say might make treating TB nearly impossible, especially for vulnerable populations. (Photo credit: CAMR/A. Barry Dowsett/www.sciencesource.com) Newly identified strains of Mycobacterium tuberculosis have emerged in South Africa and elsewhere that some experts say might make treating tuberculosis nearly impossible. In February, researchers at Stellenbosch University in Tygerberg, South Africa, identified a TB strain they described as “totally” drug resistant (TDR-TB) that was resistant to 4 first-line and 6 second-line drugs. In a molecular analysis of 309 drug-susceptible and 342 multidrug-resistant TB (MDR-TB) isolates collected from 2008 to 2009 from Eastern Cape Province, the researchers found that 92% of 236 MDR-TB strains belonged to an atypical Beijing genotype that was resistant to 10 anti-TB drugs (Klopper M et al. Emerg Infec Dis. doi: 10.3201/eid.1903.120246). South Africa, which has the fourth-largest prevalence of MDR-TB in the world (after China, India, and the Russian Federation), is now the fourth country to report the emergence of a virtually untreatable strain of TB. India, Iran, and Italy have also published reports of TDR. And experts warn it's just a matter of time before the TDR-TB spreads around the world. “Any place there is currently MDR or XDR, there will be TDR,” warned Paul van Helden, PhD, professor of molecular and cellular biology, Stellenbosch University, and one of the study's authors. Both MDR-TB, defined by resistance to both first-line drugs isoniazid and rifampin, and XDR-TB, which in addition to the first-line drug resistance seen in MDR, is resistant to any fluoroquinolone and at least 1 second-line injectable drug, are already widespread around the world. Globally, 3.7% of new TB cases—there were an estimated 8.7 million new cases of TB in 2011—and 20% of previously treated TB cases are MDR-TB, according to the World Health Organization (WHO). XDR-TB has been identified in 84 countries. In the United States, MDR-TB accounted for 1.3% of the 10 528 cases of TB in 2011—a slight increase from previous years—and there were 6 cases of XDR-TB, according to the US Centers for Disease Control and Prevention (CDC). The WHO estimates treatment success as 48% for MDR and 33% for XDR, with 26% of patients with XDR dying. Tdr-tb not recognized by who Although the emergence of TDR has alarmed TB experts, the WHO has stopped short of recognizing an “untreatable strain” of TB. Drug-susceptibility testing for TB is not accurate or comprehensive enough to declare that all drugs are ineffective, according to the agency. Nor is there enough evidence to link test results to patient outcomes. “Everyone agrees that there are very severe forms of drug-resistant TB out there,” said Eric Nuermberger, MD, associate professor of medicine and international health, Johns Hopkins University. “But we can't confidently say that these patients will have a worse outcome than those with XDR-TB.” Bedaquiline, the first new anti-TB drug in 40 years, was approved by the US Food and Drug Administration in December for drug-resistant TB, and drugs such as linezolid (approved for drug-resistant skin infections and methicillin-resistant Staphylococcus aureus) and the leprosy drug clofazimine are being studied as treatments for drug-resistant TB. “It may be that these new drugs are decent regimens,” says Nuermberger. But for countries that don't have access to second-line anti-TB drugs, the disease may be virtually untreatable for those patients. “Some countries don't have the funds or the ambition to buy the TB drugs they need,” said Lucica Ditiu, MD, executive secretary of the Stop TB Partnership, an international organization housed by the WHO. “Predicting the amount of second-line TB drugs, which have a short shelf life, is a major problem for countries that struggle to find and diagnose individuals with MDR and XDR,” she said. In the United States, there have been temporary shortages of second-line and even first-line anti-TB drugs. “It's not a huge threat in the United States, but the drug shortages are indicative of the systematic ills that make TB control so difficult,” said Nuermberger. People with hiv/aids vulnerable Countries like South Africa that have huge populations of individuals with HIV/AIDS are particularly vulnerable to a TDR epidemic. During the early days of the HIV/AIDS epidemic in the United States, outbreaks of MDR-TB killed patients and health care workers alike. “But since the advent of highly effective antiretroviral therapy, we’ve seen a reduction in the number of people with HIV/AIDS who develop TB in the United States,” said Kenneth Castro, MD, director of the Tuberculosis Elimination Program at the CDC. Populations in the United States most at risk of TB are foreign-born individuals, homeless people, substance abusers, and individuals with compromised immune systems (such as people infected with HIV) or patients receiving immunosuppressant medications. Health care workers who work abroad in certain settings may also face an increased threat. “Clinician friends of mine have developed TB in settings where there was inadequate infection control,” said Castro. He also noted researchers studying resistance to second-line drugs among patients with MDR-TB from 8 countries in Africa, Asia, Europe, and Latin America identified a number of risk factors for second-line drug resistance (Dalton T et al. Lancet. 2012;380[9851]:1406-1417). For example, risk of XDR-TB was higher in patients previously treated for TB, particularly with second-line drugs. They also found that resistance to second-line injectable drugs was associated with social factors across countries, including unemployment, alcohol abuse, smoking, and imprisonment. Drug-susceptibility testing is crucial to treating TB appropriately and to limiting the spread of drug-resistant forms of the disease. Yet worldwide, only 4% of people with a new case of TB and 6% of those who have previously been treated for TB undergo susceptibility testing, according to WHO estimates. “This is a disaster,” said Ditiu. Setup costs are a barrier for implementing rapid molecular assays to detect TB drug resistance. Even in countries where such assays are available, the tests aren't comprehensive enough to determine optimal treatment regimens. South Africa, for example, is rolling out country-wide GeneXpert, which identifies resistance to only 1 drug (followed by another assay that identifies resistance to 4 other antibiotics); the CDC's assay detects the presence of mutations that confer resistance to 7 anti-TB drugs. “The mutations and resistance mechanism against many TB drugs aren't known,” said Tommie Victor, PhD, professor, molecular and cellular biology, Stellenbosch University. “We need large investments in research to understand these mutations so we can develop an assay that will detect them.” Some TB experts also believe that only specialists should treat the disease, citing statistics that only 10% of new cases of MDR-TB receive appropriate treatment globally. “The worst thing you can do is to add another drug to a failing regimen, since the organism will become resistant to that drug as well,” said Ditiu. Many US clinicians have little experience treating the disease because rates of TB are low in the United States, added Castro. He urged physicians to “have a higher index of suspicion for TB when treating patients with respiratory symptoms, especially at-risk individuals.” Once TB is suspected or diagnosed, physicians should contact their state TB Control Program (TB is a reportable disease) for assistance in contact investigation and other help (http://www.cdc.gov/tb/links/tboffices.htm). Physicians can also contact the CDC-funded TB Regional Training and Medical Consultation Centers (http://www.cdc.gov/tb/education/rtmc/default.htm) at no cost to talk with experts who can help oversee the patient's treatment and manage drug toxicity. “And if drug- resistant TB is present, it's even more important to get that expertise,” Castro said. There is also optimism that several new anti-TB drugs now in clinical trials may effectively combat drug-resistant TB. “There are 3 drugs in phase 2 and phase 3 trials that are looking very promising,” said van Helden. And new drugs aside, countries can make major strides in reducing the threat of drug-resistant TB by marshalling public health efforts to prevent and control the disease, provided they have the funds to do so. For countries worried about having run out of treatment options to offer TB patients, the low incidence of TB overall in the United States is also “incredibly encouraging,” said van Helden. The number of new TB cases has declined annually for nearly 2 decades, after public health agencies intensified efforts toward prevention and control of the disease. “If your TB numbers overall come crashing down, then your numbers of XDR and TDR must also come down,” he said. But continued public health vigilance is needed to keep the disease in check, and funds for TB control are dwindling in the United States, noted Nuermberger. “A number of people who run TB programs in the US feel like they are on the cusp of losing control again, like they did in the late ’80s and early ’90s, when we had very costly and damaging outbreaks of MDR-TB,” he said. “At the moment we have adequate resources in the US, but funding has dwindled in the last few years.” http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

South Africa Warns of Emergence of “Totally” Drug-Resistant Tuberculosis

JAMA , Volume 309 (11) – Mar 20, 2013

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American Medical Association
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Copyright © 2013 American Medical Association. All Rights Reserved.
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0098-7484
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1538-3598
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10.1001/jama.2013.1802
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Abstract

After spending 5 months volunteering at a small hospital in South Africa in 2007, physical therapist Natalie Skipper returned to her hometown of Paris, Tenn—and to a diagnosis of extensively drug-resistant tuberculosis (XDR-TB) that took 2 years to treat, including 90 days in isolation. Skipper was “lucky,” relatively speaking, because despite the difficulty in treating XDR-TB, she was ultimately cured. Now, however, newly identified strains of TB have emerged in South Africa and elsewhere that some experts say might make treating TB nearly impossible, especially for vulnerable populations. (Photo credit: CAMR/A. Barry Dowsett/www.sciencesource.com) Newly identified strains of Mycobacterium tuberculosis have emerged in South Africa and elsewhere that some experts say might make treating tuberculosis nearly impossible. In February, researchers at Stellenbosch University in Tygerberg, South Africa, identified a TB strain they described as “totally” drug resistant (TDR-TB) that was resistant to 4 first-line and 6 second-line drugs. In a molecular analysis of 309 drug-susceptible and 342 multidrug-resistant TB (MDR-TB) isolates collected from 2008 to 2009 from Eastern Cape Province, the researchers found that 92% of 236 MDR-TB strains belonged to an atypical Beijing genotype that was resistant to 10 anti-TB drugs (Klopper M et al. Emerg Infec Dis. doi: 10.3201/eid.1903.120246). South Africa, which has the fourth-largest prevalence of MDR-TB in the world (after China, India, and the Russian Federation), is now the fourth country to report the emergence of a virtually untreatable strain of TB. India, Iran, and Italy have also published reports of TDR. And experts warn it's just a matter of time before the TDR-TB spreads around the world. “Any place there is currently MDR or XDR, there will be TDR,” warned Paul van Helden, PhD, professor of molecular and cellular biology, Stellenbosch University, and one of the study's authors. Both MDR-TB, defined by resistance to both first-line drugs isoniazid and rifampin, and XDR-TB, which in addition to the first-line drug resistance seen in MDR, is resistant to any fluoroquinolone and at least 1 second-line injectable drug, are already widespread around the world. Globally, 3.7% of new TB cases—there were an estimated 8.7 million new cases of TB in 2011—and 20% of previously treated TB cases are MDR-TB, according to the World Health Organization (WHO). XDR-TB has been identified in 84 countries. In the United States, MDR-TB accounted for 1.3% of the 10 528 cases of TB in 2011—a slight increase from previous years—and there were 6 cases of XDR-TB, according to the US Centers for Disease Control and Prevention (CDC). The WHO estimates treatment success as 48% for MDR and 33% for XDR, with 26% of patients with XDR dying. Tdr-tb not recognized by who Although the emergence of TDR has alarmed TB experts, the WHO has stopped short of recognizing an “untreatable strain” of TB. Drug-susceptibility testing for TB is not accurate or comprehensive enough to declare that all drugs are ineffective, according to the agency. Nor is there enough evidence to link test results to patient outcomes. “Everyone agrees that there are very severe forms of drug-resistant TB out there,” said Eric Nuermberger, MD, associate professor of medicine and international health, Johns Hopkins University. “But we can't confidently say that these patients will have a worse outcome than those with XDR-TB.” Bedaquiline, the first new anti-TB drug in 40 years, was approved by the US Food and Drug Administration in December for drug-resistant TB, and drugs such as linezolid (approved for drug-resistant skin infections and methicillin-resistant Staphylococcus aureus) and the leprosy drug clofazimine are being studied as treatments for drug-resistant TB. “It may be that these new drugs are decent regimens,” says Nuermberger. But for countries that don't have access to second-line anti-TB drugs, the disease may be virtually untreatable for those patients. “Some countries don't have the funds or the ambition to buy the TB drugs they need,” said Lucica Ditiu, MD, executive secretary of the Stop TB Partnership, an international organization housed by the WHO. “Predicting the amount of second-line TB drugs, which have a short shelf life, is a major problem for countries that struggle to find and diagnose individuals with MDR and XDR,” she said. In the United States, there have been temporary shortages of second-line and even first-line anti-TB drugs. “It's not a huge threat in the United States, but the drug shortages are indicative of the systematic ills that make TB control so difficult,” said Nuermberger. People with hiv/aids vulnerable Countries like South Africa that have huge populations of individuals with HIV/AIDS are particularly vulnerable to a TDR epidemic. During the early days of the HIV/AIDS epidemic in the United States, outbreaks of MDR-TB killed patients and health care workers alike. “But since the advent of highly effective antiretroviral therapy, we’ve seen a reduction in the number of people with HIV/AIDS who develop TB in the United States,” said Kenneth Castro, MD, director of the Tuberculosis Elimination Program at the CDC. Populations in the United States most at risk of TB are foreign-born individuals, homeless people, substance abusers, and individuals with compromised immune systems (such as people infected with HIV) or patients receiving immunosuppressant medications. Health care workers who work abroad in certain settings may also face an increased threat. “Clinician friends of mine have developed TB in settings where there was inadequate infection control,” said Castro. He also noted researchers studying resistance to second-line drugs among patients with MDR-TB from 8 countries in Africa, Asia, Europe, and Latin America identified a number of risk factors for second-line drug resistance (Dalton T et al. Lancet. 2012;380[9851]:1406-1417). For example, risk of XDR-TB was higher in patients previously treated for TB, particularly with second-line drugs. They also found that resistance to second-line injectable drugs was associated with social factors across countries, including unemployment, alcohol abuse, smoking, and imprisonment. Drug-susceptibility testing is crucial to treating TB appropriately and to limiting the spread of drug-resistant forms of the disease. Yet worldwide, only 4% of people with a new case of TB and 6% of those who have previously been treated for TB undergo susceptibility testing, according to WHO estimates. “This is a disaster,” said Ditiu. Setup costs are a barrier for implementing rapid molecular assays to detect TB drug resistance. Even in countries where such assays are available, the tests aren't comprehensive enough to determine optimal treatment regimens. South Africa, for example, is rolling out country-wide GeneXpert, which identifies resistance to only 1 drug (followed by another assay that identifies resistance to 4 other antibiotics); the CDC's assay detects the presence of mutations that confer resistance to 7 anti-TB drugs. “The mutations and resistance mechanism against many TB drugs aren't known,” said Tommie Victor, PhD, professor, molecular and cellular biology, Stellenbosch University. “We need large investments in research to understand these mutations so we can develop an assay that will detect them.” Some TB experts also believe that only specialists should treat the disease, citing statistics that only 10% of new cases of MDR-TB receive appropriate treatment globally. “The worst thing you can do is to add another drug to a failing regimen, since the organism will become resistant to that drug as well,” said Ditiu. Many US clinicians have little experience treating the disease because rates of TB are low in the United States, added Castro. He urged physicians to “have a higher index of suspicion for TB when treating patients with respiratory symptoms, especially at-risk individuals.” Once TB is suspected or diagnosed, physicians should contact their state TB Control Program (TB is a reportable disease) for assistance in contact investigation and other help (http://www.cdc.gov/tb/links/tboffices.htm). Physicians can also contact the CDC-funded TB Regional Training and Medical Consultation Centers (http://www.cdc.gov/tb/education/rtmc/default.htm) at no cost to talk with experts who can help oversee the patient's treatment and manage drug toxicity. “And if drug- resistant TB is present, it's even more important to get that expertise,” Castro said. There is also optimism that several new anti-TB drugs now in clinical trials may effectively combat drug-resistant TB. “There are 3 drugs in phase 2 and phase 3 trials that are looking very promising,” said van Helden. And new drugs aside, countries can make major strides in reducing the threat of drug-resistant TB by marshalling public health efforts to prevent and control the disease, provided they have the funds to do so. For countries worried about having run out of treatment options to offer TB patients, the low incidence of TB overall in the United States is also “incredibly encouraging,” said van Helden. The number of new TB cases has declined annually for nearly 2 decades, after public health agencies intensified efforts toward prevention and control of the disease. “If your TB numbers overall come crashing down, then your numbers of XDR and TDR must also come down,” he said. But continued public health vigilance is needed to keep the disease in check, and funds for TB control are dwindling in the United States, noted Nuermberger. “A number of people who run TB programs in the US feel like they are on the cusp of losing control again, like they did in the late ’80s and early ’90s, when we had very costly and damaging outbreaks of MDR-TB,” he said. “At the moment we have adequate resources in the US, but funding has dwindled in the last few years.”

Journal

JAMAAmerican Medical Association

Published: Mar 20, 2013

Keywords: south africa,tuberculosis

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