Tuberculosis

Two-drug Combination Shows Effectiveness against Drug-resistant Tuberculosis in a Laboratory Study

Tuberculosis (TB) is an opportunistic infection in people with HIV. The Centers for Disease Control and Prevention (CDC) considers HIV-TB coinfection as an AIDS diagnosis, regardless of the stage of HIV infection. HIV-TB coinfected patients with resistance to currently available anti-TB drugs are difficult to treat successfully.

The National Institute of Allergy and Infectious Diseases (NIAID) reported last week that new laboratory study findings may eventually help individuals resistant to TB medications, regardless of their HIV status. Following is the text of a NIAID press announcement that reviews an article about the study, which appears in the February 27, 2009 issue of the journal Science.

Lab Tests Show Two-Drug Combination Effective Against Drug-Resistant TB Bacteria

In a finding that could soon help people infected with untreatable, highly drug-resistant tuberculosis (TB), scientists have shown that two FDA-approved drugs work in tandem to kill laboratory-grown strains of Mycobacterium tuberculosis (Mtb), the bacterium that causes TB. The drugs -- meropenem and clavulanate --are already used to treat other bacterial diseases, but their effectiveness against TB bacteria had not been studied systematically until now.

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is planning a clinical trial [in 2009] to test the combination in people who have extensively drug-resistant TB (XDR TB).

XDR TB is a rare but dangerous form of multidrug-resistant TB that is causing concern among public health officials. In 2006, of an estimated 490,000 cases of multidrug-resistant tuberculosis that occurred worldwide, approximately 40,000 were XDR TB. These numbers are widely considered to be conservative estimates. Death rates associated with XDR TB are high in most settings.

USE NIAID scientist Clifton E. Barry, III, PhD, collaborated with NIAID grantee John S. Blanchard, PhD, of Albert Einstein College of Medicine in the new research. The scientists conducted a detailed investigation of the activity of the Mtb enzyme ß-lactamase. This enzyme shields TB bacteria from a class of antibiotics called ß-lactams. Penicillin is a ß-lactam, as is meropenem, the antibiotic used in this study. The drug clavulanate is a ß-lactamase inhibitor.

In a series of laboratory experiments, the researchers determined the balance of clavulanate and meropenem needed to inhibit the growth of Mtb strains. In addition to killing drug-susceptible strains of Mtb, the combination also worked on strains of XDR TB.

Dr. Barry is now working with colleagues at South Korea's National Masan Tuberculosis Hospital and with the manufacturers of meropenem and clavulanate to launch a clinical trial of the drug combination in individuals who have multidrug-resistant or XDR TB.

XDR TB is a rare but dangerous form of multidrug-resistant TB that is causing concern among public health officials. In 2006, of an estimated 490,000 cases of multidrug-resistant tuberculosis that occurred worldwide, approximately 40,000 were XDR TB. These numbers are widely considered to be conservative estimates. Death rates associated with XDR TB are high in most settings.

USE NIAID scientist Clifton E. Barry, III, PhD, collaborated with NIAID grantee John S. Blanchard, PhD, of Albert Einstein College of Medicine in the new research. The scientists conducted a detailed investigation of the activity of the Mtb enzyme ß-lactamase. This enzyme shields TB bacteria from a class of antibiotics called ß-lactams. Penicillin is a ß-lactam, as is meropenem, the antibiotic used in this study. The drug clavulanate is a ß-lactamase inhibitor.

In a series of laboratory experiments, the researchers determined the balance of clavulanate and meropenem needed to inhibit the growth of Mtb strains. In addition to killing drug-susceptible strains of Mtb, the combination also worked on strains of XDR TB.

Dr. Barry is now working with colleagues at South Korea's National Masan Tuberculosis Hospital and with the manufacturers of meropenem and clavulanate to launch a clinical trial of the drug combination in individuals who have multidrug-resistant or XDR TB.

3/03/09

Sources

NIAID News. Lab Tests Show Two-Drug Combination Effective Against Drug-Resistant TB Bacteria. Press release. February 26, 2009.

JE Hugonnet, LW Tremblay, HI Boshoff, and others. Meropenem-clavulanate is effective against extensively drug-resistant Mycobacterium tuberculosis. Science 323(5918): 1215-1218. February 29, 2009 (DOI: 10.1126/Science.1167498).