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No. 4, 2012

LABORATORY BRANCH UPDATES

LB Expands Molecular Detection of Drug Resistance Service

The ability to rapidly and accurately detect drug resistance in Mycobacterium tuberculosis complex (MTBC) is critical for the effective treatment of patients suffering from TB and relevant interventions of TB control programs. Efforts to treat patients and control the spread of TB can be hindered by the emergence of MTBC resistant to both first and second line anti-TB drugs. Additionally, the slow growth rate of MTBC and inherent difficulties associated with conventional drug susceptibility testing methods often serve as impediments to obtaining timely results.

Since September 2009, the Laboratory Branch of CDC’s Division of Tuberculosis Elimination has offered a service for molecular detection of drug resistance (MDDR) using conventional DNA sequencing for the identification of drug resistance associated mutations in isolates of MTBC. In June 2012, the service was expanded by incorporating pyrosequencing (PSQ) into the testing algorithm and by accepting nucleic acid amplification-positive (NAAT+) sputum sediments for testing to provide the ability for local providers and programs to potentially further reduce delayed diagnosis of multidrug-resistant (MDR) TB. The service allows rapid identification of MDR TB through the detection of genetic mutations associated with rifampin (RMP) and isoniazid (INH) resistance. In addition, when resistance to RMP is already known or detected in the MDDR service, genetic loci associated with resistance to ethambutol (EMB), pyrazinamide (PZA), and the most effective second-line drugs (i.e., fluoroquinolones [FQ] and the injectables amikacin [AMK], kanamycin [KAN], and capreomycin [CAP]), are examined. In addition, all isolates of MTBC will undergo conventional drug susceptibility testing since the absence of a mutation is not confirmation of drug susceptibility.  Testing and reporting is CLIA compliant.

For more information, please go to http://www.cdc.gov/tb/topic/laboratory/default.htm.

—Submitted by Beverly Metchock, DrPH, D(ABMM)
Reference Laboratory Team Lead, DTBE/LB

 

A Revitalized Focus on Pyrazinamide Is Essential for Tuberculosis Elimination

Pyrazinamide (PZA) is still a unique and essential agent for tuberculosis therapy in combination with both current and new drugs. Early data from studies show the importance of PZA for any regimen that might use a new anti-tuberculosis drug. A series of national meetings have drawn attention to this issue.

In May 2011, the National Institutes of Health (NIH) hosted a workshop, “Essentiality of PZA.” The gathering laid the groundwork for exploring the subject further in-depth. Richard Hafner of NIH’s Division of Acquired Immunodeficiency Syndromes (DAIS) concluded that “PZA has potent sterilizing activity and is a highly important drug in current anti-tuberculosis combination therapy. Unfortunately, while PZA-resistant TB has been increasing worldwide, rapid and reliable diagnostic tools for the detection of PZA-resistant TB are still unavailable. This presents a major barrier for treatment, especially for multidrug-resistant and extensively drug-resistant disease. PZA is the least understood anti-TB drug due to its complex mechanisms of action and obstacles in establishing animal models for PZA testing.”

In December 2011 in Atlanta, CDC hosted a meeting to review in detail our research activities related to PZA in order to enhance alignment with NIH and Food and Drug Administration (FDA) goals and priorities. The Global Alliance for TB Drug Development was also in attendance. CDC presented information on the surveillance of PZA resistance, experience in providing clinical microbiologic service, and preliminary results on approaches to improve drug susceptibility testing for PZA. A series of concrete actions steps were laid out for the various federal agencies to strengthen internal U.S. government interaction. The goal was to facilitate ongoing partner planning and efforts to advance PZA drug susceptibility testing in both the short‐term and long‐term. Assistant Surgeon General Kenneth G. Castro, USPHS and co-chair of the Federal TB Task Force remarked on the importance of ongoing inter-agency discussion tied to concrete tracking of action.

In September 2012 in Baltimore, in follow-up, NIH and Johns Hopkins University hosted a broader, partner workshop: “Demystifying PZA—Challenges and Opportunities.” Topics included mechanisms of action; drug resistance and associated testing; combination therapy; and toxicity. In-depth presentations in these four areas led to lively and stimulating discussion, capitalizing on previous meetings and contributing significantly to the growing momentum needed to tackle the issues. The next step was announcement of a NIH-sponsored “TB Diagnostics Research Forum,” designed to facilitate future dialog and collaboration; this will be the subject of a future report to TB Notes.

Fortunately, all three meetings are well documented on the World Wide Web on the site of the Stop TB Partnership’s Working Group on New TB Drugs, including slides and film of the presentations. We encourage you to visit and become part of the effort to improve the understanding and place of PZA in TB elimination.

—Reported by Michael Iademarco and Jamie Posey
Div of TB Elimination

References

  1. http://www.newtbdrugs.org/meetings/pza-workshop.php
  2. http://www.newtbdrugs.org/downloads/resource-docs/2011-12-25-Summary-PZA-Day-at-CDC.pdf
  3. http://newtbdrugs.org/meetings/pza-workshop-2012.php

 

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