October 1, 2007

XDR TB: Where it Came From, Where We’re Going

Where have extensively drug-resistant strains of tuberculosis (XDR TB) come from?  How can they be treated? Are there new drugs in the pipeline to fight them? These were the key questions on the agenda at a symposium on XDR TB during IDSA 2007 in San Diego.

Neel GandhiLast November, a study in The Lancet (2006; 368:1575-1580) brought to light an outbreak of highly virulent XDR TB in KwaZulu Natal, South Africa. At the symposium, lead author Neel Gandhi, MD, of the Albert Einstein College of Medicine, said TB treatment facilities had been overwhelmed by rising TB rates driven by the growing HIV epidemic. Treatment completion rates suffered, Dr. Gandhi said, and, “One could postulate that low TB treatment completion rates gave rise to a large number of cases of MDR TB.”

But that was just the first step, he added. XDR TB may have arisen, in part, because all MDR TB patients must travel to a single hospital in the nearest major city—a difficult and expensive journey for those living in far-flung rural areas. Many patients likely ended up discontinuing their treatment. “As a result,” Dr. Gandhi said, “patients with incompletely treated MDR TB may have amplified resistance to second-line drugs, resulting in XDR TB.” 

However, incomplete treatment alone does not explain how XDR TB spread to so many patients, he said. Dr. Gandhi presented genetic evidence suggesting that patients being treated for susceptible TB were likely re-infected with new, resistant strains while in the hospital. “Since we believe that primary transmission is the principal driver,” he said, “creating effective infection control programs is the first critical step” to controlling the epidemic. 

The other key step is to diagnose patients earlier so that infection control can be applied quickly and the right treatment can begin promptly. According to Dr. Gandhi’s modeling estimates, combining these two steps can cut future XDR TB cases in half.

Treatment prospects for patients with XDR TB are by definition slim, commented Neil W. Schluger, MD, of Columbia University. Quinolones, especially moxifloxacin, are believed to be very active against many cases of drug-resistant TB (although XDR TB is, by definition, resistant to at least one fluoroquinolone); however, he noted, “One of the very worrisome things about quinolones and the treatment of TB is how available quinolones are in the world generally. This raises the question of whether TB has already become resistant to fluoroquinolones because of their widespread use.”

Linezolid has been used with some success in a very small number of MDR and XDR TB cases. But the drug is very expensive and serious adverse events were common.

Surgery has a fairly high success rate, from 75 to 98 percent in published studies. However, Dr. Schluger said, any surgical procedure to remove part of the lung “is a big operation and has considerable mortality associated with it.”

Furthermore, surgery may not help patients with the most resistant strains, Dr. Schluger added. “If you operate on a patient but you don’t have any drugs to give that patient after surgery, that patient is probably not going to do well,” he said.

There is a glimmer of hope for new drugs to treat MDR and XDR TB, according to the Global Alliance for TB Drug Development’s Ann M. Ginsberg, MD, PhD. Two new fluoroquinolones—moxifloxacin and gatifloxacin—are in phase III clinical trials. Three other drugs with novel modes of action are in phase II: Tibotec’s diarylquinoline compound TMC207, and two nitroimidazole compounds: OPC-67683, by Otsuka Pharmaceutical Co., Ltd., and the Global Alliance for TB Drug Development’s PA-824. Trials for the first two drugs are enrolling MDR TB patients specifically.

Two other compounds are in phase I clinical trials. “We’re a lot further along than we were in 2000. Having seven compounds in the clinic is reason for hope,” Dr. Ginsberg said.

Slides from this session and many others from IDSA 2007 are available online.  

Audio files of individual sessions or a full-conference CD-ROM are available for purchase from Sound Images.

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Congratulations to the 2007 Society Award Recipients
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IDSA Announces New Board Members
Welcome, New IDSA Members!
Electronic Tools for Infectious Diseases Practitioners
From the President
Public Reporting of HAIs May Have Unintended Consequences
Treatment Options for C. difficile
XDR TB: Where it Came From, Where We’re Going
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