How worried should you be about XDR TB?

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Your patients know about the man whose TB landed him in quarantine this spring. Are you up to speed on the latest developments surrounding TB?

It’s not often that a single patient’s story appears on the front page of every newspaper in the country. But on May 29, 2007, the CDC reported that a U.S. citizen had been forcibly quarantined due to concerns over extensively drug-resistant TB (XDR TB). The last time a public-health intervention of this kind occurred was 1963, and it involved a case of smallpox. Later tests of this year’s TB patient revealed less severe disease than originally thought. He eventually had a portion of diseased lung removed and continues antibiotic therapy.

The saga began when an otherwise healthy man was diagnosed with TB following sputum evaluation ordered after an incidental upper lung lesion was seen on a chest x-ray. Several weeks before the patient’s scheduled wedding in Greece, the laboratory identified the Mycobacterium tuberculosis as a rare but serious and difficult-to-treat variant. By the time the details became fully known, the individual had flown on several commercial airliners, setting off a public-health scare.

TB strains grow resistant

This recent case, while dramatic, is not isolated. The worldwide problem of drug-resistant TB has been growing since initial outbreaks in the 1980s. These cases, including the one previously described, were defined as multidrug-resistant TB (MDR TB), since these TB strains exhibited resistance to isoniazid and rifampin, the two most effective mycobacterial drugs available.

Losing these two antimicrobials handicapped effective therapy; alternate medicines were either more expensive, less well tolerated, or not available as oral formulations (see Table 1 for current TB medicines). MDR TB necessitated longer therapy (18 or even 24 months) for a much greater cost (more than $10,000 per patient). New York City was particularly hard-hit in the 1990s, with HIV infection, inadequate TB therapy, and foreign-born status as important contributing factors.

Fortunately, the newer fluoroquinolones have good in vitro activity against TB and became an important part of the newer antibiotic regimens for MDR TB. Some authorities even cite this development as the most important reason for the successful control of the domestic wave of MDR TB in the previous decade.

Using fluoroquinolones, however, does not obviate the need for multiple simultaneous antibiotics. TB’s extremely slow growth phase increases its ability to adapt and acquire new resistance mechanisms. Adding IV therapy was tedious but controlled outbreaks of MDR TB, as the IV medications would be tapered off after six to nine months, leaving one or two oral agents on board to complete the entire treatment of 18 months (usually longer if the patient was HIV-positive).

What does all this mean for the practicing primary-care clinician? Make sure you’re aware of the differences between MDR TB and XDR TB (Table 2) so that if you come across a case, you’ll know the best way to approach these difficult infections. Experts recommend that cases of resistant TB be managed by an experienced TB clinician, preferably one who is working within the public-health system, because of the complexity of the regimen and the operational challenges to prevent loss of follow-up.

Resistance grows, foiling new treatments

XDR TB is so named because the usual four-drug therapy and the more effective alternative therapies are no longer efficacious due to the extensive resistance of the organism. That is, four separate classes of antibiotics are no longer useful. In addition to the resistance seen in MDR TB, XDR TB is killed by neither fluoroquinolones nor one of the more effective injectable antibiotics. This leaves little else, as the remaining IV and oral agents are significantly limited by GI, renal, and/or neurologic toxicities.

Consequently, there are no long-term, reliably safe, and exclusively oral formulations available for treatment of XDR TB. Since second-line drugs are less effective, there is concern among infectious disease experts that XDR TB could essentially be “untreatable,” bringing back thoughts of the 19th century when “consumption” was common—and deadly.

Is the previously noted recent high-profile case unique? The CDC reported that of the 190,312 culture-confirmed TB cases in the United States with sensitivities available between 1993 and 2006, 2,927 (2%) were resistant to isoniazid and rifampin. In other words, they were MDR TB.

What is worrisome, if not alarming, is that 49 of these cases exhibited more extensive resistance that meets the definition for XDR TB. Most of these cases were found in New York City and California, and many had been previously treated for active TB. Not all the clinical data were available for analysis, but about half the patients had HIV infection.

The evolution to XDR TB was not unexpected. It is part of the natural history of resistance as MDR TB increases its ability to defend itself. Isolates have been reported across the world in the former Soviet Union, Europe, Southeast Asia, the Middle East, South Africa, and Latin America. As these reports coalesced to provide a worrisome picture of the ongoing race between TB and medical systems, some began to worry about how HIV would add to the spread of this form of TB.

At about the same time experts recognized XDR TB in the United States, other investigators discovered that XDR TB may be more common than originally thought by observing an unexpectedly high fatality rate among hospitalized patients in South Africa. In an 18-month period at one rural hospital, 221 patients were diagnosed with MDR TB. Further testing revealed that 53 of these patients had XDR TB.

HIV infection was common in this group; 44 were HIV-seropositive. Most concerning of all, 52 of the 53 patients with XDR TB died, with a median survival of 16 days from time of diagnosis. The experts appear correct: The two infections were like pouring gasoline on a fire, as the combination of XDR TB and widespread HIV was the perfect setting for a high death rate when the disorganized local public-health infrastructure was unable to cope with the rising tides of AIDS and TB.

Worries over XDR TB transmission

The general public is concerned about the transmission of XDR TB. There are no data on whether XDR TB has more or less ability to spread person-to-person than other forms of TB. Some of the most useful epidemiologic data come from school outbreaks among high school and middle-school students. In these settings, a surge of cases on occasion has been associated with bus drivers suffering from active TB, and these reports suggest that those who sit closer to the bus driver and for longer periods may have had increased risk of conversion to a positive tuberculin skin test (TST).

It is reasonable to speculate that risk of TB transmission increases when a person has active symptoms, namely cough with productive sputum. TB’s transmission is not fully understood, however, and there are reports of persons acquiring positive skin tests from other individuals with minimal symptoms. Moreover, it is likely that those with compromised immune systems, such as HIV-positive individuals, have increased susceptibility to contracting TB and progressing to active disease. In addition, children can be almost like a “canary in a coal mine” and acquire TB from adults with minimal symptoms.

Regarding plane travel, the CDC conducted an investigation in 1995-1996 after a South Korean national died in a Chicago hospital from massive hemoptysis because of active TB. The woman had flown from Seoul to Chicago, as well as on several shorter domestic flights. Passengers recalled that she had been sick en route with frequent bouts of coughing. When state public-health authorities realized she had MDR TB, they launched a comprehensive evaluation with CDC scientists. The investigation revealed that six people converted to a positive TST due to close proximity to the infected woman. Proximity was key: Further analysis revealed that sitting within two rows of the patient led to an eightfold increased risk of converting to a positive TST. Fortunately, one year follow-up revealed no new cases of active TB among these six people.

Considering the millions of daily air passengers jetting across North America, it is remarkable how uncommon the spread of TB has been via this route. Encourage your patients to use common sense, and educate them about the usual risks of international travel. (See “Keep your patients well while they travel,”.) Remind them that TB transmission has rarely occurred during air travel and that as long as they are not immunocompromised, their risk of acquisition should be very low. Caution, however, should be emphasized for those persons who are planning on extended stays lasting longer than one month in parts of the world where TB, and especially MDR TB, is endemic.

Dr. Spak is an infectious diseases staff physician at Baylor University Medical Center at Dallas.

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