XDR-TB Succumbs to Multi-Drug Regimen

By John Gever
BOSTON, 08 aug 2008--Most patients in one large-scale program were cured of extensively drug-resistant tuberculosis (XDR-TB) with individualized outpatient regimens of second-line antibiotics, researchers here said. Among 48 HIV-negative patients with XDR-TB in Lima, Peru, 29 achieved cure with regimens involving cycloserine, a fluoroquinolone drug, and at least one other drug including an injectable agent, for a cure rate of 60.4%, reported Carole Mitnick, Sc.D., and colleagues in the Aug. 7 issue of the New England Journal of Medicine. The patients were among 810 with drug-resistant TB who were referred for therapy from 1999 through 2002 under a program organized by the Peruvian government, Dr. Mitnick said in an interview.
Drug susceptibility testing was conducted in 651 patients, with 48 deemed to have extensive drug resistance. The remaining 603 cases were classed as multi-drug resistant (MDR).
The cure rate for the MDR-TB patients was 66.3%, the researchers said.
Before entering the program, those with XDR-TB had received a mean of 4.2 earlier treatment regimens with a mean total duration of treatment of 34.7 months.
In the program, drug-susceptibility testing was performed for each patient in a U.S. lab to guide treatment. The goal was to find at least five drugs likely to be effective. While susceptibility results were pending, patients received empirical therapy.
Oral drug treatment lasted at least 18 months and injectables were given for at least eight months after sputum cultures became negative.
If it was impossible to identify five drugs likely to be effective, a smaller number were given for longer periods. All regimens included a fluoroquinolone and an injectable agent.
The same approach was used for XDR- and MDR-TB.
A total of 18 drugs were available in the program. They included oral agents such as ethambutol and pyrazamide, first- or second-line injectables, first- or later-generation fluoroquinolones, and a variety of other drugs.
The XDR-TB patients received a mean of 5.3 anti-TB drugs for which susceptibility had been shown or that patients had not received for more than a month.
Median time for sputum culture conversion from positive to negative was 90 days in the XDR-TB patients, significantly longer than the median 61 days for MDR-TB cases.
But the median time to cure was nearly the same: 26.0 months (95% CI 24.6 to 27.8) for XDR-TB compared with 24.8 months (95% CI 24.5 to 25.2) in the MDR-TB cases.
Fewer than 10% of patients in both groups failed to comply with therapy, reflecting daily supervision of the outpatient therapy by program workers.
A few patients in each category showed positive bacteriological results following cure or completion of therapy (two patients with XDR-TB and 15 with MDR-TB). Dr. Mitnick and colleagues had no information on the results of follow-up treatment in those patients.
Dr. Mitnick said the findings were simultaneously encouraging and discouraging.
"The good news is that community-based treatment was able to cure more than 60% of patients with XDR-TB in a resource-poor setting in South America," she said. "The bad news is that this program was able to cure only 60% of those patients."
She said the previous, extensive therapy failures that preceded the patients' treatment in the program were a significant problem in both groups.
The XDR-TB patients were resistant to a mean of 8.4 drugs according to the susceptibility testing, while the MDR-TB isolates resisted a mean of 5.3 drugs, Dr. Mitnick said.
On the plus side, she said, the 60% cure was achieved with outpatient treatment, whereas earlier programs elsewhere had confined XDR-TB patients in "prison-like" conditions with much poorer results.
In an accompanying editorial, Mario C. Raviglione, M.D., of the World Health Organization's Stop TB department, agreed that such efforts to treat XDR-TB had largely failed.
The report from the Peruvian program, he wrote, "reveals a new and brighter perspective: even in developing countries, extensively drug-resistant tuberculosis may be cured in the majority of cases when management is aggressive and appropriate."
He said the program's outpatient basis may have contributed to its success. "It was community-based in the majority of patients, thus avoiding the additional stress of prolonged hospitalizations [and] it included psychological support for people taking potentially toxic drugs," he noted.
"If every national program put this strategy in place with equal vigor and assertiveness, as in the metropolitan Lima project, drug resistance would be minimized and, when already present, effectively managed," he added.
The study was funded by the Bill and Melinda Gates Foundation, Thomas J. White, Partners in Health, the Peruvian Ministry of Health, the David Rockefeller Center for Latin American Studies at Harvard University, the Francis Family Foundation, the Pittsfield Anti-tuberculosis Association, the Eli Lilly Foundation, and the Hatch Family Foundation, and by career development awards from the National Institute of Allergy and Infectious Diseases and the National Heart, Lung, and Blood Institute.
Study authors and Dr. Raviglione reported no potential conflicts of interest.
Additional source: New England Journal of MedicineSource reference: Mitnick C, et al "Comprehensive treatment of extensively drug-resistant tuberculosis" N Engl J Med 2008; 359: 563-74. Additional source: New England Journal of MedicineSource reference: Raviglione M, et al "Facing extensively drug-resistant tuberculosis -- a hope and a challenge" N Engl J Med 2008; 359: 636-37.

WHO strategy to stop drug-resistant TB

By MARIA CHENG, AP Medical WriterThu Jun 21, 6:56 PM ET
More than 130,000 lives could be saved if the world implements a two-year strategy to stop the growing problem of drug-resistant tuberculosis, the World Health Organization and partners said Thursday.
Officials are concerned that the current epidemic of curable TB might evolve into a drug-resistant variety immune to existing medicines.
"It would be very scary if that happened," said Dr. Ruth McNerney, an infectious diseases expert at London's School of Hygiene and Tropical Medicine. "Tuberculosis would then turn into what it was centuries ago when it was Europe's biggest killer and wiped out generations of people."
The new plan from WHO and the Stop TB Partnership outlines actions they say are needed to slow the spread of multi-drug resistant TB and extensively drug-resistant TB, or XDR-TB.
Drug-resistant TB is primarily a problem in Asia, Africa and eastern Europe, despite the recent trans-Atlantic health scare sparked by Andrew Speaker, an American with XDR-TB who flew to several countries despite being infected.
WHO estimates that $2.15 billion is needed over the next two years to help poor countries tackle issues including disease surveillance, diagnosis and treatment. So far, the health agency says it has about $640 million.
"We're extremely concerned about multi-drug resistant tuberculosis because we've already got more than 400,000 cases occurring every year," said Dr. Paul Nunn, WHO's tuberculosis, HIV and drug-resistance coordinator.
It is also much more expensive to treat resistant TB. Treating regular tuberculosis costs as little as $16 for six months per patient. But it costs up to $15,000 to treat one XDR-TB case for several years — with no guarantee of a cure.
Though experts say WHO's strategy is a good start, they are unsure how much of a difference it will ultimately make.
"We can try to control the damage that we see today from drug-resistant TB," said Dr. Eric Goemaere, head of Medecins Sans Frontieres in South Africa. "But we are only seeing the tip of the iceberg."

CDC Reviews Evaluation of People Who May Have Been Exposed to the Recent XDR-TB Case

June 20, 2007 — In a teleconference June 19, the US Centers for Disease Control and Prevention (CDC) presented guidelines reviewing the evaluation of people who might have been exposed to the recent case of extensively drug-resistant pulmonary tuberculosis (XDR-TB). The new guidelines, which are summarized in algorithms on the CDC website, address the management of people with a positive QuantiFERON-TB Gold (QFT-G) or tuberculin skin test (TST).
In May 2007, a person with recently diagnosed, culture-confirmed XDR-TB traveled on the following 2 extended flights, each lasting more than 8 hours: Air France #385/Delta #8517 on May 12 from Atlanta, Georgia, to Paris, France; and Czech Air #0104 on May 24 from Prague, Czech Republic, to Montreal, Quebec. Since May 25, this person has been hospitalized in airborne isolation.
For the purpose of this XDR-TB contact investigation, all US residents and citizens who were on these flights are considered to be contacts of the XDR-TB patient. For people identifying themselves as passengers on one of these flights, the CDC requests that the physicians they contact perform TB evaluation and testing or refer the passenger to the appropriate state or local TB control office for TB testing, evaluation, and follow-up.
Theresa Harrington, MD, a medical officer with the United States Public Health Service and medical epidemiologist with the CDC's Division of TB Elimination Outbreak Investigation Team, noted that the purpose of the teleconference was not to discuss the specifics of this XDR-TB case or subsequent investigation, but rather to address guidelines for the clinical evaluation and management of individuals exposed or potentially exposed to XDR-TB.
She also pointed out that it is the physician's responsibility to determine whether or not the patient is truly a contact of the index case, and not just a member of the worried well who might be unduly concerned about casual or distant contact not likely to constitute true exposure. Passengers on the same plane, healthcare workers who examined or treated the patient, and household or family contacts of the index patient are considered to be actual contacts.
"Among persons who are infected with Mycobacterium tuberculosis (i.e., latent tuberculosis infection), it can take 8 to 10 weeks [after] exposure [before] the TST result or QFT-G [test] becomes positive," Dr. Harrington said. "A first-round TST or QFT-G [test], not both, should be performed as soon as possible following exposure to the XDR-TB patient. If the first round of symptom screening and TST or QFT-G result is negative, a second TB evaluation and TST or QFT-G [test should be] performed 8 to 10 weeks [after] the last known exposure to the XDR-TB patient (i.e., round 2 testing)."
Dr. Harrington noted that the second round of TB evaluation and testing is required because a negative TST or QFT-G result obtained less than 8 weeks after exposure can be unreliable in excluding latent tuberculosis infection (LTBI).
For the purpose of a contact investigation, a positive TST result is defined as an induration of 5 mm or more for any contact. Although people with a previous documented positive TST or QFT-G result or with previously diagnosed TB disease do not need to be retested, these people should still undergo TB evaluation, which should include a complete history, signs and symptoms screening, and chest X-ray.
Past medical-history evaluation should document any illness that increases the risk of latent TB progressing to TB, such as HIV infection, cancer, immunocompromised state, renal failure, or even uncontrolled diabetes mellitus. If patients at high risk for HIV infection are not aware of their HIV status, HIV counseling and testing should be offered. Other important points to cover in the medical history are any previous treatment for TB, having been part of a TB investigation, past TST results, immigration from a TB-endemic area, or having received a Bacille Calmette-Guérin (BCG) vaccination. Social or behavioral risk factors for LTBI include incarceration and illicit drug use.
Symptoms suggestive of active TB include fever, chills, night sweats, productive cough, and unexplained weight loss. Signs of active TB that should arouse suspicion on physical examination include cachectic habitus, chronically ill appearance, cough, and pulmonary findings.
If the medical evaluation suggests active TB, a chest X-ray should be performed immediately, with airborne isolation for the patient if the X-ray is positive, as well as sputum smear for acid-fast staining and sputum culture and evaluation by a TB expert.
"Consultation with a TB expert, especially one with experience managing [multidrug-resistant] or XDR-TB, is strongly recommended," Dr. Harrington said. "This is recommended especially for any contact suspected of having active TB disease who has a positive TST or QFT-G result or who is immunocompromised, regardless of TST or QFT-G result."
If there is no evidence of active TB and the initial TB test is negative, the TB test should be repeated 8 to 10 weeks later. No further evaluation is necessary if the second test is negative and the patient is not immunocompromised. However, if the second round TB test is positive, this should be considered a new conversion.
Physicians administering a TST or QFT-G test should document the date, the spot where the test is placed, the lot number, the expiration date, and the antigen used. The test should be read 48 hours later and size (in mm) of the induration should be recorded for TST; if positive, a chest X-ray should be performed. If there are signs and symptoms of active TB, chest X-ray and sputum for smear and culture are warranted.
A TST or QFT-G test can be used in people who have a history of BCG vaccination; in these people, a TST result of 5 mm induration or more is considered to be positive, warranting further TB evaluation and testing.
A nonimmunocompromised patient with a positive TB test, either TST or QFT-G, can be considered to have been infected, either in the past or recently. If not previously treated, these patients should receive standard LTBI treatment with 5 months of isoniazid. If the TB test is positive but there is no other evidence suggesting infection, a TB expert should be consulted. Follow-up symptom screening and chest X-ray should be performed at 3, 6, 12, 18, and 24 months, because the risk of developing active TB from LTBI is highest during the first 2 years.
"The risk of progressing to TB disease from LTBI is approximately 10% over a lifetime in a person with a normal immune system, or 5% within the first 2 years following infection, and that's why we want to follow them particularly closely with symptom screening and chest radiograph for those first 2 years," Dr. Harrington said.
Contacts who are immunocompromised, for example because of HIV infection, AIDS, use of corticosteroids, or tumor necrosis factor-alpha treatment, should have a medical evaluation and chest X-ray immediately. However, these patients do not always have infiltrates on chest X-ray. If there is no evidence suggesting active TB, and the initial TST or QFT-G test is negative, the test should be repeated 8 to 10 weeks after the last exposure to the index patient. If the test is still negative after the second round, follow-up symptom screening and chest X-ray should be performed at 3, 6, 12, 18, and 24 months. If the initial or second-round test is positive, further management is warranted.
For immunocompromised contacts with a positive TST or QFT-G test, past medical history should be reviewed for other risk factors, such as previous TB exposure, birth in a country with a high TB burden, previous TB or LTBI, and/or previous exposure to a TB contact. If any of these risk factors are present, a positive TST or QFT-G test probably suggests TB infection in the past, not from the index patient. Isoniazid treatment for 9 months can be considered for LTBI if the patient was not previously treated.
If it is unclear whether or not the positive test result in the above scenario resulted from exposure to the XDR-TB index case, a TB expert should be consulted. Standard therapy suffices if the patient was exposed to someone infected with a normal-resistance TB organism. However, the lack of available agents to treat XDR-TB mandates consultation with a TB expert for those thought to be infected from exposure to the XDR-TB index case.
"At least at this point, we're not expecting that there has been a lot of transmission from this case," Dr. Harrington said. "If you do find a person that you really think became infected from the XDR-TB patient, there is no standard therapy. We do not yet have enough world experience with XDR-TB, and there are very few medications that can be offered to somebody for treatment of disease, which is separate from treatment for latent TB infection."
Lauren Lambert, MD, a CDC expert on hospital transmission of TB, briefly addressed the evaluation of healthcare workers with possible exposure to an index case.
"Many of the guidelines [in place to protect] healthcare workers from infection resulting from exposure to TB are not evidence-based, but are based on expert opinion because there are a lack of available data," Dr. Lambert said. "So, for example, although the guidelines state that healthcare workers should be tested periodically, there is no real evidence to suggest what 'periodically' really means. It's a very gray area."