当前位置：搜档网 › nejmra0908076_2

nejmra0908076_2

T h e ne w engl a nd jour na l o f medicine

n engl j med 363;11 https://www.sodocs.net/doc/2511691491.html, september 9, 2010

1050

current concepts

MDR Tuberculosis — Critical Steps

for Prevention and Control

Eva Nathanson, M.Sc., Paul Nunn, F.R.C.P., Mukund Uplekar, M.D.,

Katherine Floyd, Ph.D., Ernesto Jaramillo, M.D., Ph.D., Knut L?nnroth, M.D., Ph.D.,

Diana Weil, M.Sc., and Mario Raviglione, M.D.

From the Stop TB Department, World Health Organization, Geneva. Address reprint requests to Dr. Jaramillo at the Stop TB Dept., World Health Organiza-tion, CH-1211 Geneva, Switzerland, or at jaramilloe@who.int.

N Engl J Med 2010;363:1050-8.

ultidrug-resistant (MDR) tuberculosis is defined as disease caused by strains of Mycobacterium tuberculosis that are at least resistant to treatment with isoniazid and rifampicin; extensively drug-resistant (XDR)

tuberculosis refers to disease caused by multidrug-resistant strains that are also resistant to treatment with any fluoroquinolone and any of the injectable drugs used in treatment with second-line anti-tuberculosis drugs (amikacin, capreomycin, and kanamycin). MDR tuberculosis and XDR tuberculosis are serious threats to the progress that has been made in the control of tuberculosis worldwide over the past decade.1,2

In 2008, an estimated 440,000 cases of MDR tuberculosis emerged globally.1 India and China carry the greatest estimated burden of MDR tuberculosis, together accounting for almost 50% of the world’s total cases. More than three quarters of the estimated cases of MDR tuberculosis occur in previously untreated patients. The proportion of MDR cases among new cases and previously treated cases of tuberculosis reported globally from 1994 through 2009 ranged from 0 to 28.3% and from 0 to 61.6%, respectively (Fig. 1). The highest proportions of MDR cases, and the most severe drug-resistance patterns, appear in the countries of the former Soviet Union. By 2009, a total of 58 countries had reported at least one case of XDR tuberculosis. In eight countries, reported cases of XDR tuberculosis account for more than 10% of all cases of MDR tuberculosis, and six of these countries were part of the former Soviet Union. By far the largest number of cases of XDR tuberculosis has been reported from South Africa (10.5% of all cases of MDR tuber-culosis in that country), owing to rapid spread among people infected with the human immunodeficiency virus (HIV).

National programs are failing to diagnose and treat MDR tuberculosis. Globally, just under 30,000 cases of MDR tuberculosis were reported to the World Health Organization (WHO) in 2008 (7% of the estimated total), of which less than one fifth were managed according to international guidelines. The vast majority of the remaining cases probably are not diagnosed or, if diagnosed, are mismanaged. This problem remains despite the evidence that management of MDR tuberculosis is cost-effective 3 and that treatment of MDR tuberculosis, and even treatment of XDR tuberculosis, is feasible in persons who are not infected with HIV.4,5

In some countries, the incidence of tuberculosis is rising, and the incidence of MDR tuberculosis appears to be rising even faster (e.g., in Botswana and South Korea).6 However, in Estonia, Hong Kong, the United States, and Orel and Tomsk Oblasts (in the Russian Federation), the incidence of tuberculosis is falling, and the incidence of MDR tuberculosis appears to be falling even faster.1,6 This trend is

The New England Journal of Medicine

Downloaded from https://www.sodocs.net/doc/2511691491.html, by Waroot Chamnanya on September 30, 2010. For personal use only. No other uses without permission.

current concepts

n engl j med 363;11 https://www.sodocs.net/doc/2511691491.html, september 9, 2010

1051

the result of high-quality care and control prac-tices that result in high rates of case detection and cure, drug-susceptibility testing for all pa-tients, and the provision of appropriate treat-ment for all patients carrying drug-resistant strains. In short, preventing initial infection with MDR tuberculosis and managing the treat-ment of existing cases appropriately are the keys to containing the spread of this disease.

The WHO-recommended Stop TB Strategy 7provides the framework for treating and caring for those who are sick and controlling the epi-demic of drug-susceptible and drug-resistant dis-ease. The DOTS approach, which underpins the Stop TB Strategy, calls for political commitment to national programs designed to control disease by means of early diagnosis with the use of bacteriologic testing, standardized treatment with supervision and patient support, and provision and management of the drugs used in treatment; the approach also includes the monitoring of treatment and evaluation of its effectiveness. Be-tween 1995 and 2008, a total of 36 million people were treated successfully with the use of the DOTS approach, and 6 million lives were saved.8Specific guidelines for controlling drug-suscep-tible and drug-resistant disease already exist,9,10and the Global Plan to Stop TB, 2006 through 2015, developed by the Stop TB Partnership, specifies the scale at which these interventions need to be funded and implemented to achieve global targets.11 However, to date, planning, funding, and implementation are falling far be-hind the milestones that have been set.

Prompted by concern that political support for the management of MDR tuberculosis is insuf-ficient, WHO, the Bill and Melinda Gates Foun-dation, and the Chinese Ministry of Health orga-nized a ministerial conference in Beijing in April 2009.12 The report from the conference in Beijing and the subsequent resolution (number 62.15) approved by the World Health Assembly in May 2009 state that significant changes in several components of the health care system must be made if MDR tuberculosis is to be eliminated.13,14This review assesses the critical factors imped-ing control and discusses the solutions required to address them.

0 to <3%3 to <6%6 to <12%12 to <18%≥18%

No data available

Figure 1. Distribution of the Proportion of Cases of MDR Tuberculosis among New Cases of Tuberculosis, 1994–2009.

The following 27 countries are responsible for 85% of the world’s estimated cases of MDR tuberculosis and are classified as countries with a high burden of MDR tuberculosis: China, India, Russia, Pakistan, Bangladesh, South Africa, Ukraine, Indonesia, Philippines, Nige-ria, Uzbekistan, Democratic Republic of Congo, Kazakhstan, Vietnam, Ethiopia, Myanmar, Tajikistan, Azerbaijan, Moldova, Kyrgyzstan, Belarus, Georgia, Bulgaria, Lithuania, Armenia, Latvia, and Estonia. Adapted from the 2010 report on MDR and XDR tuberculosis from the WHO.1

The New England Journal of Medicine

Downloaded from https://www.sodocs.net/doc/2511691491.html, by Waroot Chamnanya on September 30, 2010. For personal use only. No other uses without permission.

T h e ne w engl a nd jour na l o f medicine

n engl j med 363;11 https://www.sodocs.net/doc/2511691491.html, september 9, 2010

1052

Cr itical Weaknesses and How

to Addr ess Them Prevention is better than cure. Thus, the top pri-ority for the control and, ultimately, elimination of MDR tuberculosis is prevention of its emer-gence.15 Once MDR tuberculosis has emerged, however, urgent measures are required to curb its effects on efforts to control the disease. The major obstacles and approaches to controlling MDR tuberculosis are described below and sum-marized in Table 1. Three topics of great impor-tance — the global shortage of health care work-ers,16 the need for improvements in surveillance systems,1 and the urgent need for intensified re-search on new diagnostic tests, drugs, and vac-cines 17 — have been well described elsewhere and are beyond the scope of this article.

Financing Control and Care

To achieve the goal of universal access to diagno-sis and treatment described in the Global Plan to Stop TB, 1.3 million cases of MDR tuberculosis in the 27 countries with the highest burden of MDR disease will need to be treated between 2010 and 2015.1 The total estimated cost of such treatment is several billion U.S. dollars, an amount far in excess of the existing level of funding. The national strategic plans in these countries must incorporate the preparation of ambitious budgets for the prevention and control of MDR tuberculo-sis. These plans must be consistent with poli-cies on health care financing, including social-protection schemes (the delivery of commodities to reduce the social vulnerability of poor popu-lations), and with broader planning and financ-ing frameworks. These countries — especially the middle-income countries among them — must mobilize their domestic resources. In 2001, the WHO Commission on Macroeconomics and Health indicated that these middle-income coun-tries could finance all, or almost all, of their health care needs.18 While maximizing the use of domestic resources, they should also target re-sources available from international financing organizations, such as the Global Fund to Fight AIDS (Acquired Immunodeficiency Syndrome), Tuberculosis, and Malaria and UNITAID, an or-ganization that provides grants allowing coun-tries to purchase diagnostic tests and drugs used in the treatment of HIV–AIDS, malaria, and tu-berculosis. The failure to adequately fund a re-sponse to MDR tuberculosis would have cata-strophic consequences in terms of both human lives and tuberculosis control in general.

Abolishing Financial Barriers

Health expenditures that account for more than 40% of household income (after deducting the cost of basic subsistence) have been defined as catastrophic.19 In virtually all countries with a high burden of MDR tuberculosis, treatment costs (per course of treatment) for one person are more than 100% of the gross national income per cap-ita (the cost of second-line anti-tuberculosis drugs alone is typically $2,000 to $4,000 per patient).1 Collective financing mechanisms are therefore required to guarantee universal access to health care. The main source of funding should be do-mestic resources, such as contributions from tax-es, payroll deductions, or mandatory insurance premiums.20,21 Most countries in Africa, Asia, and the Middle East have not attained universal health coverage,22 although there are exceptions. Lessons need to be drawn from universal health-financing schemes applied in such diverse set-tings as Mexico, Rwanda, and Thailand, where access to care may facilitate early detection and treatment of all tuberculosis cases.

Even before universal health coverage is achieved, immediate steps can be taken to reduce catastrophic health expenditures for patients with tuberculosis and their households.23 These steps include decentralization of services to reduce the indirect costs that patients seeking care incur, provision of patient incentives and social support to promote adherence to treatment, and subsidi-zation of care provided in the private sector that is in line with guidelines from national tubercu-losis programs.

Engaging All Care Providers

A substantial proportion of patients with tuber-culosis or MDR tuberculosis seek care with pro-viders who are not linked to national tuberculo-sis programs.24,25 In five countries with a high burden of MDR tuberculosis, more than half of all sales of first-line anti-tuberculosis drugs oc-cur in the private sector, and the proportion is even higher for sales of second-line drugs.26 Many physicians in the private sector and some in the public sector do not follow internationally recommended treatment regimens for tuberculo-sis, use medicines of questionable quality, and ne-

The New England Journal of Medicine

Downloaded from https://www.sodocs.net/doc/2511691491.html, by Waroot Chamnanya on September 30, 2010. For personal use only. No other uses without permission.

current concepts

n engl j med 363;11 https://www.sodocs.net/doc/2511691491.html, september 9, 2010

1053

* T h e i n t e r n a t i o n a l g r o u p k n o w n a s U N I T A I D p u r c h a s e s a n d d i s t r i b u t e s d i a g n o s t i c t e s t s a n d d r u g s u s e d i n t h e t r e a t m e n t o f H I V –A I D S , m a l a r i a , a n d t u b e r c u l o s i s . A I D S d e n o t e s a c q u i r e d i m m u n o d e f i c i e n c y s y n d r o m e , M D R -T B m u l t i d r u g -r e s i s t a n t t u b e r c u l o s i s , T B t u b e r c u l o s i s , W H O W o r l d H e a l t h O r g a n i z a t i o n , a n d X D R -T B e x t e n s i v e l y d r u g -r e s i s t a n t t u b e r c u l o s i s .

The New England Journal of Medicine

Downloaded from https://www.sodocs.net/doc/2511691491.html, by Waroot Chamnanya on September 30, 2010. For personal use only. No other uses without permission.

T h e ne w engl a nd jour na l o f medicine

n engl j med 363;11 https://www.sodocs.net/doc/2511691491.html, september 9, 2010

1054

glect essential principles of case management.27,28 Such practices lead to the development, amplifi-cation, and spread of drug resistance. In addi-tion, collaboration with public and private hospi-tals warrants special attention.29

Guidance on implementing a mix of public and private approaches to tuberculosis care is available,30 and many national tuberculosis pro-grams have begun to incorporate diverse sources of care, including public, voluntary, private, and corporate providers. Nonetheless, only a fraction of the tuberculosis cases diagnosed by practitioners outside the public sector are registered with or referred to national tuberculosis programs.31,32 These approaches should therefore be scaled up and applied to the prevention and management of MDR tuberculosis as well. National tubercu-losis programs need to play a stewardship role and provide guidelines, training, technical and finan-cial support, and the supervision needed to align the practices of private providers with the Inter-national Standards for TB Care.33 Effective en-gagement of diverse care providers will require national tuberculosis programs to both augment their own capacities and strengthen private pro-vider networks to enable them to shoulder their responsibility for managing tuberculosis and MDR tuberculosis. Professional associations need to act as intermediaries between national tuberculosis programs and private providers. Nongovernmen-tal organizations have introduced successful pro-grams for the management of MDR tuberculosis in a number of countries and are key players in scaling up diagnosis and treatment.34,35

But collaborative approaches and appropriate incentives alone may not enlist the support of all relevant care providers — some regulation may be necessary. In some countries with a high bur-den of tuberculosis, providers are not required to notify the government when a new case of tuber-culosis has been diagnosed. And even in coun-tries where notification is required, systems have not been established to ensure that the require-ment is met. Case notification for both tubercu-losis and MDR tuberculosis must be made man-datory; providers who follow best practices should be certified and accredited and should be offered access to free supplies of quality-assured anti-tuberculosis drugs for their patients.30 Sustain-able engagement of all care providers will require national tuberculosis programs to work in close

partnership with health professionals, represen-tatives of the pharmaceutical industry, pharma-cists, and drug regulatory authorities, in addition to consumer and patient associations.

Optimizing Disease Management and Care

Transmission of drug-resistant tuberculosis oc-curs in the community,36 as indicated by the high frequencies of MDR tuberculosis among previ-ously untreated patients in some countries. In most countries with limited resources, patients with MDR or XDR tuberculosis must complete two unsuccessful courses of treatment with first-line anti-tuberculosis drugs before being eligible for treatment with second-line drugs.37 Moreover, in many countries, treatment of MDR tuberculo-sis is started only after the diagnosis has been confirmed, a process that takes months when conventional methods are used. As a result, per-sons with infectious MDR or XDR tuberculosis remain in the community for long periods of time. Prompt diagnosis and treatment of tuber-culosis and MDR tuberculosis can keep the case reproduction number of MDR strains below their replacement rate — and perhaps even below that of non-MDR strains.6

Outbreaks of MDR tuberculosis have occurred in hospitals, and patients with tuberculosis who are hospitalized have a higher risk of acquiring MDR tuberculosis than do those who are treated as outpatients.38,39 Treating MDR tuberculosis in a hospital is more expensive than doing so on an ambulatory basis. Hospital treatment is also more socially and economically disruptive for most patients.40 In addition, the number of hospital beds may become insufficient as countries ex-pand treatment for MDR tuberculosis. Despite the complexities involved in caring for patients with MDR tuberculosis, including lengthy ther-apy with poorly tolerated drugs, clinic-based or community-based care has proved to be feasible and effective in several countries, including Ne-pal 41 and Peru.42 However, the effectiveness of outpatient care depends on the availability of pri-mary care facilities, qualified health care work-ers, and social support networks to promote ad-herence to treatment. Countries need to select the model of care that is right for them, taking into account the personal rights and needs of patients and communities,43 the numbers of pa-tients who have both MDR tuberculosis and

The New England Journal of Medicine

Downloaded from https://www.sodocs.net/doc/2511691491.html, by Waroot Chamnanya on September 30, 2010. For personal use only. No other uses without permission.

current concepts

n engl j med 363;11 https://www.sodocs.net/doc/2511691491.html, september 9, 2010

1055

HIV–AIDS, the social circumstances of patients,44 the health care infrastructure, and the ability of the country to mobilize resources.Responding to the Laboratory Crisis Weak laboratory capacity remains a serious im-pediment to prompt diagnosis and better control of MDR tuberculosis.1 The goal of universal ac-cess to drug-susceptibility testing has not yet been achieved. In 2008, drug-susceptibility testing was performed in only 1% of new tuberculosis cases and 3% of previously treated cases in the 27 countries with the highest burden of MDR tuber-culosis.Today, rapid molecular tests for MDR tubercu-losis are available.45 For instance, one new auto-mated rapid test for rifampicin resistance holds promise for easier detection of MDR tuberculosis even in community settings.46 The implementa-tion of this and other rapid tests, especially in countries with a high prevalence of concurrent HIV infection and MDR tuberculosis, can prevent fatal delays in detection.47 The establishment of quality-assured diagnostic capacity, including rapid diagnostic technologies to identify MDR tubercu-losis, is feasible in resource-limited settings.48 Use of the new molecular technologies offers one of the best avenues for improving overall diagnostic capacity in the laboratory.49 At present, however, the adoption of the new rapid tests will not elimi-nate the need for conventional drug-susceptibility testing with the use of solid or liquid culture. Con-ventional susceptibility testing is required to de-termine susceptibility to drugs other than rifam-picin and isoniazid.9 While countries expand

laboratory capacity and introduce the new rapid tests, targeted drug-susceptibility testing should be performed in specific groups of patients at risk for drug resistance. Expansion of diagnostic capacity for MDR tuberculosis must be coupled with ac-cess to second-line anti-tuberculosis drugs. Efforts to shorten the time required for diagnosis must occur in tandem with measures that minimize or-ganizational delay to ensure prompt initiation of treatment.Ensuring Access to Quality-Assured Drugs In 2007, only 15% of reported new cases of tuber-culosis were treated with fixed-dose combina-tions of anti-tuberculosis drugs,50 despite their logistic advantages and potential to reduce the risk of the development of drug resistance.51 The use of counterfeit and poor-quality anti-tubercu-losis drugs, which can lead to the development

and amplification of drug resistance, is well doc-umented, but there is no accurate estimate of the scale of the problem.52,53 International quality standards have been developed but are often ig-nored, and an insufficient number of manufac-turers have been approved under the WHO Pre-qualification Programme.54To effectively prevent and manage MDR tu-berculosis, countries need to secure affordable, quality-assured, anti-tuberculosis drugs through national procurement mechanisms. Affordable and quality-assured, second-line anti-tuberculo-sis drugs can also be accessed through the WHO Green Light Committee, which ensures manage-ment of MDR tuberculosis that is in line with international quality standards in 70 countries.1 However, of particular concern for efforts to in-crease the scale of MDR tuberculosis manage-ment is the insufficient supply of quality-assured, second-line anti-tuberculosis drugs.13 As of April 2010, only two manufacturers that produce three of the seven second-line anti-tuberculosis drugs on the WHO Model List of Essential Medicines had been approved by the WHO Prequalification Programme.54 Building up a reliable market of second-line anti-tuberculosis drugs, with manu-facturers investing in increased volumes and im-proved quality, requires more accurate forecast-ing of demand. In addition, national authorities need to expedite the enrollment of many more patients under proper management conditions.Restricting Drug Availability

Anti-tuberculosis drugs are widely available over the counter in retail pharmacies in many coun-tries.55 This encourages self-treatment and the purchase of inadequate quantities and combina-tions of medicines. Even when the drugs are pre-scribed, those prescribing the drugs outside na-tional tuberculosis programs may not abide by recommended regimens, and some patients may purchase only part of the prescription because of

financial constraints.56 Prescription and dispens-ing of medicines in general, and of antibiotics in particular, are poorly monitored and regulated in most countries.57 Even when regulations exist, their enforcement is often insufficient.An essential step toward improved prevention

The New England Journal of Medicine

Downloaded from https://www.sodocs.net/doc/2511691491.html, by Waroot Chamnanya on September 30, 2010. For personal use only. No other uses without permission.

T h e ne w engl a nd jour na l o f medicine

n engl j med 363;11 https://www.sodocs.net/doc/2511691491.html, september 9, 2010

1056

of MDR tuberculosis is to encourage the engage-ment of private and public providers with nation-al tuberculosis programs on a voluntary basis.30 A more forceful approach would be to restrict the right to prescribe and dispense the drugs to the national tuberculosis program itself or to pro-viders that have been accredited by the program. Either approach would require a combination of new government policy and dialogue with care providers, including pharmacists, and the phar-maceutical industry. Such measures undertaken by national tuberculosis programs to optimize drug management and supply have been success-ful in some countries, including Brazil, Ghana, Syria, and Tanzania. Consumers also need to be aware of the risks of poor prescribing prac-tices and, as discussed above, the clinical and public health threats posed by substandard medi-cines.52,57 Demand-driven efforts to push for more accountability and enforcement of regulations by national authorities may be highly effective. Further advances in social responsibility and im-proved marketing practices on the part of drug manufacturers are also essential, along with supportive government measures.

Prioritizing Control of Tuberculosis Infection

As a result of inadequate measures of infection control, there is ongoing transmission of MDR tuberculosis and XDR tuberculosis in health care facilities and congregate settings (e.g., prisons).38 To date, virtually no country with a high burden of tuberculosis has implemented systematic mea-sures to reduce the risk of tuberculosis transmis-sion in health facilities.1 Health care workers, especially those working in tuberculosis hospi-tals and in resource-limited settings, are at sub-stantially higher risk of contracting tuberculosis and MDR tuberculosis than the general popula-tion.58,59

All health care facilities that admit patients with tuberculosis or patients suspected of having tuberculosis should implement tuberculosis-con-trol measures that complement general measures of infection control, especially those which tar-get other airborne infections.60 Home-based and community treatment of MDR tuberculosis should be promoted. To curb the increased risk of noso-comial tuberculosis and MDR tuberculosis among health care workers, some countries have added

tuberculosis to the list of recognized occupa-tional hazards.59 Infection control requires en-gagement with a wide range of stakeholders across the health care system, including hospital administrators, architects, engineers, doctors, nurses, and laboratory staff. On the policy level, infection control requires collaborative action among those concerned with infections with airborne potential, such as influenza.

The Urgent Need for Action Critical weaknesses in current approaches to the treatment and control of MDR tuberculosis and XDR tuberculosis have been identified and are being addressed at the global level. In 2009, the Beijing Call for Action 13 and the passage of World Health Assembly Resolution 62.1514 signaled a major step forward in coordinated planning for the treatment and control of MDR tuberculosis and in the commitment to achieve universal ac-cess to diagnosis and treatment by 2015 for pa-tients who have the disease. Resolutions, however, are useful only insofar as they stimulate the ap-propriate policymakers in governments to act on them. By October 2009, 20 of the 27 countries with the highest burden of MDR tuberculosis were updating their national tuberculosis-control plans to include a component addressing MDR tuber-culosis, in compliance with the World Health As-sembly resolution. Furthermore, for the countries that have received grants from the Global Fund in its ninth round of grants, funding requested for the management of MDR tuberculosis was by far the largest requested for all aspects of tuber-culosis control: more than $500 million (in U.S. dollars) was requested for the management of MDR tuberculosis in 28 countries over a period of 5 years.

Every one of the recommendations in this ar-ticle for improving the treatment and control of MDR tuberculosis requires action beyond national tuberculosis control programs, sometimes in the political environment outside the health care sys-tem. This is a highly ambitious but necessary agenda for health authorities in the affected countries and for the global health community. The steps involved in controlling MDR tubercu-losis are also important steps toward strengthen-ing health care systems, including progress in achieving universal health care coverage. If this

The New England Journal of Medicine

Downloaded from https://www.sodocs.net/doc/2511691491.html, by Waroot Chamnanya on September 30, 2010. For personal use only. No other uses without permission.

current concepts

n engl j med 363;11 https://www.sodocs.net/doc/2511691491.html, september 9, 2010

1057

References

World Health Organization. Multi-

1. drug and extensively drug-resistant TB (M/XDR-TB): 2010 global report on sur-veillance and response. 2010. (Accessed August 16, 2010, at http://whqlibdoc.who .int/publications/2010/9789241599191_eng .pdf.)

Raviglione MC, Smith IM. XDR tuber-2. culosis — implications for global public health. N Engl J Med 2007;356:656-9.

Tupasi TE, Gupta R, Quelapio MI, et al. 3. Feasibility and cost-effectiveness of treat-ing multidrug-resistant tuberculosis: a co-hort study in the Philippines. PLoS Med 2006;3(9):e352.

Orenstein EW, Basu S, Shah NS, et al. 4. Treatment outcomes among patients with multidrug-resistant tuberculosis: system-atic review and meta-analysis. Lancet In-fect Dis 2009;9:153-61.

Sotgiu G, Ferrara G, Matteelli A, et al. 5. Epidemiology and clinical management of XDR-TB: a systematic review by TBNET. Eur Respir J 2009;33:871-81.

Dye C. Doomsday postponed? Prevent-6. ing and reversing epidemics of drug resis-tant tuberculosis. Nat Rev Microbiol 2009; 7:81-7.

Raviglione MC, Uplekar MW. WHO’s 7. new Stop TB Strategy. Lancet 2006;367: 952-5.

L?nnroth K, Castro KG, Chakaya JM, 8. et al. Tuberculosis control and elimina-tion 2010-50: cure, care, and social devel-opment. Lancet 2010;375:1814-29.

World Health Organization. Treat-9. ment of tuberculosis: guidelines. 4th ed. 2009 (WHO/HTM/TB/2009.420). Geneva, 2010.

World Health Organization. Guide-10. lines for the programmatic management of drug-resistant tuberculosis: emergency update 2008. (Accessed August 16, 2010, at http://whqlibdoc.who.int/publications/ 2008/9789241547581_eng.pdf.)

Stop TB. Partnership: global plan to 11. stop TB, 2006-2015. (Accessed August 16, 2010, at https://www.sodocs.net/doc/2511691491.html,/global/plan/default.asp.)

Cheng MH. Ministerial meeting agrees 12. plan for tuberculosis control. Lancet 2009; 373:1328.

World Health Organization. Global tu-13. berculosis control and patient care: a min-isterial meeting of high M/XDR-TB burden countries. (Accessed August 16, 2010, at

http://www.who.int/tb_beijingmeeting/en/ index.html.)

Idem.14. Prevention and control of multi-drug-resistant tuberculosis and extensive-ly drug-resistant tuberculosis. World Health Assembly resolution 62.15. May 2009. (Accessed August 16, 2010, at http://apps.who.int/gb/ebwha/pdf_files/A62/A62_R15-en.pdf.)

Reichman LB. Unsexy tuberculosis. 15. Lancet 2009;373:28.

The world health report 2006: work-16. ing together for health. Geneva: World Health Organization, 2006. (Accessed Au-gust 16, 2010, at http://www.who.int/whr/ 2006/whr06_en.pdf.)

Fauci AS. Opinion: fighting TB should 17. be priority. New York: https://www.sodocs.net/doc/2511691491.html,, 2009. (Accessed August 16, 2010, at http://www https://www.sodocs.net/doc/2511691491.html,/id/33890464/ns/ health-infectious_diseases/.)

Macroeconomics and health: investing 18. in health for economic development. Re-port of the Commission on Macroeco-nomics and Health. Geneva: World Health Organization, 2001. (Accessed August 16, 2010, at http://whqlibdoc.who.int/publications/2001/924154550X.pdf.)

Xu K, Evans DB, Kawabata K, Zeram-19. dini R, Klavus J, Murray CJL. Household catastrophic health expenditure: a multi-country analysis. Lancet 2003;362:111-7.Social health protection: an ILO strat-20. egy towards universal access to health care. Social security policy briefings. Paper 1. Geneva: International Labour Organiza-tion, 2008. (Accessed August 16, 2010, at https://www.sodocs.net/doc/2511691491.html,/public/english/ protection/secsoc/downloads/policy/ policy1e.pdf.)

World Health Organization. Social 21. health insurance: sustainable health fi-nancing, universal coverage and social health insurance. April 2005. (Accessed August 16, 2010, at http://apps.who.int/gb/ebwha/pdf_files/WHA58/A58_20-en.pdf.)Garrett L, Chowdhury AM, Pablos-22. Méndez A. All for universal health cover-age. Lancet 2009;374:1294-9.

Hanson C, Floyd K, Weil D. Tubercu-23. losis in the poverty alleviation agenda. In: Raviglione M, ed. TB: a comprehensive international approach. New York: Infor-ma Healthcare, 2006:1097-114.

Pantoja A, Floyd K, Unnikrishnan KP, 24. et al. Economic evaluation of public-pri-vate mix for tuberculosis care and con-trol, India. I. Socio-economic profile and costs among tuberculosis patients. Int J Tuberc Lung Dis 2009;13:698-704.

L?nnroth K, Aung T, Maung W, Kluge 25. H, Uplekar M. Social franchising of TB care through private GPs in Myanmar: an assessment of treatment results, access, equity and financial protection. Health Policy Plan 2007;22:156-66.

Pathway to patients: charting the dy-26. namics of the global TB drug market. New York: TB Alliance, 2007. (Accessed August 16, 2010, at http://www.tballiance .org/downloads/publications/Pathway_to_Patients_Compendium_FINAL.pdf.)

Loveday M, Thomson L, Chopra M, 27. Ndlela Z. A health systems assessment of the KwaZulu-Natal tuberculosis pro-gramme in the context of increasing drug resistance. Int J Tuberc Lung Dis 2008; 12:1042-7.

Uplekar M, Pathania V, Raviglione M. 28. Private practitioners and public health: weak links in tuberculosis control. Lancet 2001;358:912-6.

Uplekar M. Stopping tuberculosis: 29. time to turn urgent attention to hospitals. Int J Tuberc Lung Dis 2008;12:986.

World Health Organization. Engaging 30. all health care providers in TB control: guidance on implementing public-private mix approaches. 2006. (Accessed August 16, 2010, at http://whqlibdoc.who.int/hq/ 2006/WHO_HTM_TB_2006.360_eng.pdf.)L?nnroth K, Uplekar M, Blanc L. Hard 31. gains through soft contracts: productive engagement of private providers in tuber-culosis control. Bull World Health Organ 2006;84:876-83.

Irawati SR, Basri C, Arias MS, et al. 32. Hospital DOTS linkage in Indonesia: a model for DOTS expansion into govern-ment and private hospitals. Int J Tuberc Lung Dis 2007;11:33-9.

Hopewell PC, Pai M, Maher D, Uplekar 33. M, Raviglione MC. International stan-dards for tuberculosis care. Lancet Infect Dis 2006;6:710-25.

Van Deun A, Maug AK, Salim MA, et 34. al. Short, highly effective and inexpensive standardized treatment of multidrug-resis-tant tuberculosis. Am J Respir Crit Care Med 2010 May 4 (Epub ahead of print).Cox HS, Kalon S, Allamuratova S, et al. 35. Multidrug-resistant tuberculosis treatment

policy agenda is not pursued with urgency, the human and financial costs to societies will be profound.

Supported by a grant from the Bill and Melinda Gates Foun-dation.No potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at https://www.sodocs.net/doc/2511691491.html,.

We thank Karin Bergstr?m, Léopold Blanc, Robert Matiru, Andrea Pantoja, Fabio Scano, Karin Weyer, and Matteo Zignol

for their support in developing the background documents for the ministerial meeting in Beijing in April 2009 and for review-ing earlier versions of the manuscript.The New England Journal of Medicine

Downloaded from https://www.sodocs.net/doc/2511691491.html, by Waroot Chamnanya on September 30, 2010. For personal use only. No other uses without permission.

n engl j med 363;11 https://www.sodocs.net/doc/2511691491.html, september 9, 2010

1058

current concepts

outcomes in Karakalpakstan, Uzbekistan: treatment complexity and XDR-TB among treatment failures. PLoS ONE 2007;2(11): e1126.

Marais BJ, Victor TC, Hesseling AC, 36. et al. Beijing and Haarlem genotypes are overrepresented among children with drug-resistant tuberculosis in the Western Cape Province of South Africa. J Clin Microbiol 2006;44:3539-43.

Basu S, Friedland GH, Medlock J, et al. 37. Averting epidemics of extensively drug-resistant tuberculosis. Proc Natl Acad Sci U S A 2009;106:7672-7.

Nodieva A, Jansone I, Broka L, Pole I, 38. Skenders G, Baumanis V. Recent nosoco-mial transmission and genotypes of multi-drug-resistant Mycobacterium tuberculo-sis. Int J Tuberc Lung Dis 2010;14:427-33.Gelmanova IY, Keshavjee S, Golub-39. chikova VT, et al. Barriers to successful tuberculosis treatment in Tomsk, Russian Federation: non-adherence, default and the acquisition of multidrug resistance. Bull World Health Organ 2007;85:703-11.

Heller T, Lessells RJ, Wallrauch CG, 40. et al. Community-based treatment for multidrug-resistant tuberculosis in rural KwaZulu-Natal, South Africa. Int J Tuberc Lung Dis 2010;14:420-6.

Malla P, Kanitz EE, Akhtar M, et al. 41. Ambulatory-based standardized therapy for multi-drug resistant tuberculosis: ex-perience from Nepal, 2005-2006. PLoS ONE 2009;4:e8313.

Shin S, Furin J, Bayona J, Mate K, Kim 42. JY, Farmer P. Community-based treatment of multidrug-resistant tuberculosis in Lima, Peru: 7 years of experience. Soc Sci Med 2004;59:1529-39.

Singh JA, Upshur R, Padayatchi N. 43. XDR-TB in South Africa: no time for de-nial or complacency. PLoS Med 2007;4(1): e50.

Floyd K, Hutubessy R, Samyshkin Y, 44. et al. Health-systems efficiency in the Russian Federation: tuberculosis control. Bull World Health Organ 2006;84:43-51.World Health Organization. Molecu-45. lar line probe assays for rapid screening of patients at risk of multidrug-resistant tuberculosis (MDR-TB). Policy statement. June 27, 2008. (Accessed August 16, 2010, at http://www.who.int/tb/dots/laboratory/lpa_policy.pdf.)

Boehme CC, Nabeta P, Hillemann D, 46. et al. Rapid molecular detection of tuber-culosis and rifampin resistance. N Engl J Med 2010;363:1005-15.

Gandhi NR, Shah NS, Andrews JR, 47. et al. HIV coinfection in multidrug- and extensively drug-resistant tuberculosis re-sults in high early mortality. Am J Respir Crit Care Med 2009;181:80-6.

Paramasivan CN, Lee E, Kao K, et al. 48. Experience establishing tuberculosis lab-oratory capacity in a developing country setting. Int J Tuberc Lung Dis 2010;14:59-64.

Birx D, de Souza M, Nkengasong JN. 49. Laboratory challenges in the scaling up of HIV, TB, and malaria programs: the inter-action of health and laboratory systems, clinical research, and service delivery. Am J Clin Pathol 2009;131:849-51.

Global tuberculosis control: epidemi-50. ology, strategy, financing. WHO report 2009. Geneva: World Health Organization, 2009. (WHO/HTM/TB/2009.411.) (Accessed August 16, 2010, at http://www.who.int/tb/publications/global_report/en/index.html.)Blomberg B, Fourie B. Fixed-dose com-51. bination drugs for tuberculosis: applica-tion in standardised treatment regimens. Drugs 2003;63:535-53.

Caudron JM, Ford N, Henkens M,

52. Macé C, Kiddle-Monroe R, Pinel J. Sub-standard medicines in resource-poor set-tings: a problem that can no longer be ignored. Trop Med Int Health 2008;13: 1062-72.

Newton PN, Green MD, Fernández 53. FM, Day NP, White NJ. Counterfeit anti-infective drugs. Lancet Infect Dis 2006;6: 602-13.

World Health Organization. Prequali-54. fication programme. (Accessed August 16, 2010, at http://apps.who.int/prequal/.)Kobaidze K, Salakaia A, Blumberg 55. HM. Over the counter availability of anti-tuberculosis drugs in Tbilisi, Georgia, in the setting of a high prevalence of MDR-TB. Interdiscip Perspect Infect Dis 2009; 2009:513-609.

Uplekar M, Juvekar S, Morankar S, 56. Rangan S, Nunn P. Tuberculosis patients and practitioners in private clinics in In-dia. Int J Tuberc Lung Dis 1998;2:324-9.Cars O, H?gberg LD, Murray M, et al. 57. Meeting the challenge of antibiotic resis-tance. BMJ 2008;337:a1438.

Skodric-Trifunovic V, Markovic-Denic 58. L, Nagorni-Obradovic L, Vlajinac H, Woeltje KF. The risk of occupational tuberculosis in Serbian health care workers. Int J Tu-berc Lung Dis 2009;13:640-4.

Naidoo S, Jinabhai CC. TB in health 59. care workers in KwaZulu-Natal, South Af-rica. Int J Tuberc Lung Dis 2006;10:676-82.

WHO policy on TB infection control 60. in health-care facilities, congregate set-tings and households. Geneva: World Health Organization, 2009. (Accessed August 16, 2010, at http://whqlibdoc.who .int/publications/2009/9789241598323_eng .pdf.)

The New England Journal of Medicine

Downloaded from https://www.sodocs.net/doc/2511691491.html, by Waroot Chamnanya on September 30, 2010. For personal use only. No other uses without permission.

nejmra0908076_2

相关文档

最新文档