June 28, 2012

WHO Guidelines for Drug-Resistant Tuberculosis

WHO Guidelines for Drug-Resistant Tuberculosis - 2011 Update

New guidelines from the World Health Organization (WHO) on the management of drug-resistant tuberculosis (TB) offer the latest approaches for better control of the disease that claims millions of lives each year.

The guidelines, published online August 4, 2011 in the European Respiratory Journal, update recommendations from previous guidelines published in 2008 and are intended to help inform practitioners, particularly those in lower-income settings, of the very latest and most cost-effective standards of care for achieving optimal patient outcomes.

"The updated WHO program guidelines on [multidrug-resistant]-TB are an essential resource for healthcare professionals with a responsibility for TB patient care," stated Mario Raviglione, MD, director of the WHO Stop TB Department in a press release.

"WHO has produced this latest version to reflect important developments in TB, developments that will have a beneficial impact on clinical and operational outcomes."

The guidelines reflect the recommendations of a multidisciplinary panel of TB practitioners, public health professionals, representatives of professional societies, national TB control program staff, guideline methodologists, and other professionals.

Although there are no radical changes from the 2008 guidelines, the new guidelines include some important adjustments and provide the most updated information on issues such as diagnosis, treatment, and monitoring.

The guidelines feature 11 key recommendations for caregivers, including the following:
  1. Wider use of rapid drug susceptibility testing for isoniazid and rifampicin or rifampicin alone over conventional testing upon patient diagnosis with TB and before treatment initiation to allow for earlier identification of patients with drug-resistant TB. The approach is considered the most cost-effective, and administration of appropriate treatment as quickly as possible is recommended to avoid unnecessary deaths.
  2. Monitoring patients with sputum smear microscopy and culture, rather than sputum smear microscopy alone, for multidrug-resistant TB (MDR-TB) to detect failure as early as possible during treatment. Users are advised to be aware of differences in the quality of the culture performance because a false-positive result could lead to an unnecessary continuation or modification of treatment and increased risk for toxicity.
  3. The use of fluoroquinolones and ethionamide, with later-generation fluoroquinolone, rather than earlier-generation forms of the drug recommended for patients with MDR-TB.
  4. A focus on cost-effective ambulatory models of care that treat patients outside of the hospital rather than hospitalizing them. In addition to reducing the risk for re-infection, the ambulatory care model reduces travel and social isolation for patients.
  5. For patients with MDR-TB, the minimum duration of treatment has been extended by 2 months from previous guidelines to reflect research showing improved treatment success with the longer duration. Intensive treatment should therefore last at least 8 months, and for those who have not been treated with second-line drugs for TB in the past, treatment should extend to 20 months. The duration may be adjusted for some patients according to their clinical and bacteriologic response.
  6. Early use of antiretroviral agents for HIV-infected patients with TB who are receiving second-line drug regimens, irrespective of CD4 cell-count, as early as possible (within the first 8 weeks) after initiation of anti-TB treatment.
Tuberculosis claimed as many as 1.7 million lives in 2009, not including those who died from the disease while affected by AIDS. An estimated 3% of new TB cases around the world are MDR-TB — major shortcomings in healthcare systems have led to increasing resistances to anti-TB drugs.

Evidence is said to be particularly lacking in pediatric MDR-TB, the best drug regimens for treatment with isoniazid resistance, extremely drug-resistant TB or non-MDR-TB polydrug resistance, and therapy for symptomatic relief from adverse reactions linked to second-line anti-TB drugs.

The guidelines therefore place a heavy emphasis on the need for more research, while striving to help improve understanding of critical issues, such as duration, composition, and management of treatment, particularly for patients with MDR-TB.

"The new evidence-based WHO guidelines are a milestone clinicians and public health specialists were waiting anxiously to guide their interventions," said Professor G.B. Migliori, head of the Respiratory Infections Assembly at the European Respiratory Society.

"They resulted from an unprecedented collaboration among the top global experts and national program managers who accepted to share data to inform the guidelines."

Rapid drug susceptibility testing of isoniazid and rifampicin or of rifampicin alone is recommended vs conventional testing or no testing at the time of diagnosis of TB, subject to available resources (conditional recommendation; very low-quality evidence).

This strategy was the best for not only averting deaths and preventing MDR-TB, but was also the most cost-effective.

The use of the sputum smear microscopic test and culture vs sputum smear microscopic test alone is recommended for monitoring patients with MDR-TB during treatment (conditional recommendation; very low-quality evidence).

Performing monthly smear microscopic testing and culture was the best strategy to indentify failures earlier.
Recommendations for second-line anti-TB regimens include the following:
  • In the treatment of patients with MDR-TB, a fluoroquinolone should be used (strong recommendation; very low-quality evidence); specifically, a later-generation fluoroquinolone vs an earlier-generation fluoroquinolone should be used (conditional recommendation; very low-quality evidence).
  • In the treatment of patients with MDR-TB, ethionamide (or prothionamide) should be used (strong recommendation; very low-quality evidence).
  • In the treatment of patients with MDR-TB, 4 second-line anti-TB drugs likely to be effective (including a parenteral agent), as well as pyrazinamide, should be included in the intensive phase 3 (conditional recommendation; very low-quality evidence).
  • In the treatment of patients with MDR-TB, regimens should include at least pyrazinamide, a fluoroquinolone, a parenteral agent, ethionamide (or prothionamide), and either cycloserine or PAS (p-aminosalicylic acid) if cycloserine cannot be used (conditional recommendation; very low-quality evidence).
  • In the treatment of patients with MDR-TB, an intensive phase of at least 8 months' duration is recommended, and a total treatment duration of at least 20 months is recommended in patients without any previous treatment of MDR-TB (conditional recommendation; very low-quality evidence).
Antiretroviral therapy is recommended for all patients with HIV and drug-resistant TB requiring second-line anti-TB drugs, irrespective of CD4 cell count, as early as possible (within the first 8 weeks) after initiation of anti-TB treatment (strong recommendation; very low-quality evidence).

Patients with MDR-TB should be treated with mainly ambulatory care rather than models of care based principally on hospitalization (conditional recommendation; very low-quality evidence).

Clinical Implications
The second-line treatment regimen for patients with MDR-TB should include pyrazinamide, a fluoroquinolone, a parenteral agent, ethionamide (prothionamide), and cycloserine. If cycloserine cannot be used, PAS should be prescribed.

In the treatment of patients with MDR-TB, an intensive phase of at least 8 months' duration is recommended, along with a total treatment duration of at least 20 months.

Funding for the meetings and reviews involved in the updating of the guidelines came entirely from the US Agency for International Development (USAID). Four authors had performed work for Otsuka Pharmaceutical Co Ltd. and abstained from discussions relating to the recommendations on drug regimens.

  1. Falzon D., Jaramillo E., Sch√ľnemann H. J., Arentz M., Bauer M., et al: WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update. Eur Respir J. August 2, 2011, doi: 10.1183/09031936.00073611. Available online at: http://erj.ersjournals.com/content/early/2011/08/04/09031936.00073611.abstract?sid=9f90036a-ad94-4e0b-a122-50e707024d3c
  2. Melville N A, Nghiem H T: WHO Updates Guidelines for Drug-Resistant Tuberculosis. Medscape Education. Aug 10, 2011. Available online: http://www.medscape.org/viewarticle/747803

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