TB

Another Outbreak of TB Linked to Contaminated Bone Grafts

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Urgent need to improve donor screening and product testing, CDC says

A photo of bone allograft material held in tweezers over a beaker.

Contaminated bone allograft material from a single manufacturer led to five diagnosed cases of tuberculosis (TB) and two deaths so far, according to CDC data.

In July, clinicians in two different states rapidly diagnosed and reported two cases of TB in patients who previously underwent spinal surgical procedures that used bone allografts, Jonathan Wortham, MD, from the CDC in Atlanta, and colleagues wrote in the Morbidity and Mortality Weekly Report (MMWR)opens in a new tab or window.

Both clinicians alerted the CDC because the cases looked similar to an outbreak in 2021opens in a new tab or window, involving the same manufacturer. The manufacturer issued a voluntary recallopens in a new tab or window on July 13, 2023. The 2021 outbreak involved 113 patients in 18 states who received contaminated bone allografts.

The bone allografts in this most recent outbreak were from a single deceased donor and were used in 36 recipients. Whole genome sequencing in infected recipients and positive cultures from unused product confirmed that the bone allograft material was the source of the bacteria.

As of December 20, 2023, five recipients had tested positive for TB. An additional 10 had signs or symptoms consistent with TB and 79% had positive interferon-gamma release assay results.

Eight hospitals and five dental offices in seven states received the bone allograft product in question, but the product was rapidly removed from further distribution, the authors wrote, preventing as many as 53 additional procedures with the TB-contaminated material.

The CDC also informed the affected healthcare facilities to quarantine any unused product and implement TB prevention and control measures with affected patients. Patients who received the material were started on multidrug treatment for TB.

The donors from both the 2021 and 2023 outbreaks had evidence of sepsis, which should have made them ineligible for tissue donation, Wortham and investigators commented in the study. The donor from this year’s outbreak also had pneumonia and radiographic changes consistent with a TB diagnosis. Neither donor was tested for TB.

“This second outbreak of bone allograft-related TB in recent years underscores the urgent need to implement improved donor screening and culture-based testing to prevent tissue-derived Mycobacterium tuberculosis transmission,” the authors wrote. Frozen live-cell tissue allografts have expiration dates of months to years after manufacturing, allowing for ample time for both culture-based testing and additional scrutiny of donor medical records, they noted.

The manufacturer involved in both outbreaks did test for M. tuberculosis using nucleic acid amplification before distribution, but this method did not detect the organism, possibly due to low levels of the bacteria. Although nucleic acid amplification tests give more rapid results than culture-based testing, they are less sensitive. Culture-based testing, however, can also yield false-negative results and can take as long as 2 months. In this instance, liquid cultures did not grow M. tuberculosis until 40 days after inoculation, although cultures will usually deliver a positive result in 14 to 21 days, the authors said.

More than half of patients with TB had no symptoms before testing positive

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Researchers found high rates of tuberculosis among high-risk patients who sought care at primary health care clinics, many of whom had no preceding symptoms suggesting a high rate of subclinical TB.

“WHO estimates that each year, more than 4 million out of the 10 million people with active TB are not diagnosed or started on treatment. Identifying and treating this group is central to the global End TB strategy,” Rebecca H. Berhanu, MD, infectious diseases physician and clinical researcher at the Vanderbilt Institute for Global Health, told Healio.

IDN0123Berhanu_Graphic_01_WEB
Berhanu RH, et al. Clin Infect Dis. 2022;doi:10.1093/cid/ciac965.

“The objective of this study was to see if we could find people who were asymptomatic or did not have overt symptoms of TB by testing all high-risk people attending primary health care clinics, including people with HIV, those with a close household contact with TB and people with a prior history of treated TB,” she said.

Berhanu added that she and colleagues called this strategy “Targeted Universal Testing for TB.”

The researchers assessed clinic attendees in primary health care facilities in South Africa who were classified as high risk for TB due to HIV-positive status, contact with a patient with TB in the past year or having TB themselves and having undergone sputum testing for pulmonary TB in the previous 2 years.

According to the study, a single sample was collected for Xpert Ultra and culture and the results were analyzed.

Overall, 30,513 patients had a TB test result available for analysis. Of these, 21,734 (71%) were HIV positive, 12,492 (41%) reported close contact with a person with TB and 1,573 (5%) reported a prior TB diagnosis. In total, 8.3% of these patients were positive for Mycobacterium tuberculosis by culture and/or Xpert, compared with 6% with trace-positive results excluded.

Additionally, and also with trace-positives excluded, the study showed a yield of 6.7% for asymptomatic patients and 10.1% for symptomatic patients, whereas only 10% of trace-positive results were culture positive.

Berhanu added that more than half (55%) of patients with a positive test did not report any preceding TB symptoms, which she said suggests a high rate of subclinical TB among people attending primary health care clinics.

“Universal testing of individuals at high risk for TB in primary health care clinics may be a good way of identifying subclinical TB cases sooner. However, we have to be cautious of the interpretation of Xpert Ultra test results, especially Xpert Ultra-trace positive results, in this population,” Berhanu concluded.

Study recommends cut in TB treatment time for children

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https://www.nature.com/articles/d44148-022-00043-6?utm_source=facebook&utm_medium=social&utm_campaign=Nature-africa-2022Q2&fbclid=IwAR1djQX7EJvNG65dS_TNucOvVt3NNSsK2AVDeED_Xo7DYIYzwEe9VYJsc3w

Providers should ‘think TB’ as data show possibility of underdiagnosis

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There was a 20% decline in reported cases of tuberculosis in the United States in 2020 compared with previous years, which was not a result of underreporting but did raise concerns that TB was underdiagnosed, researchers said.

Kathryn Winglee

“This drop was dramatically different from the average yearly decrease of 2% to 3% observed over the past 10 years,” Kathryn Winglee, PhD, a statistician in the CDC’s Division of Tuberculosis Elimination, told Healio. “CDC explored whether this decrease could have been caused by underreporting due to strains on the public health system from the COVID-19 pandemic.”

Source: Adobe Stock.
TB may be underdiagnosed in the U.S.

Winglee and colleagues compared trends of prescriptions for TB medications with reported TB cases to determine if the number of patients who were likely treated for TB differed from the number of cases reported by public health departments.

Overall, the data showed large declines in 2020 “strongly correlating” with national TB surveillance case counts, which researchers said helped rule out underreporting as a cause. According to the study, NTSS case counts decreased every year except 2007 and 2014, with 2009 seeing the largest decrease before 2020. They said the 2020 decrease is larger than previously reported because the treatment start date is missing for 2.8% of cases counted in 2019 and 5.2% of cases counted in 2020.

Similarly, the researchers found that the isoniazid IQVIA projected patient counts generally decreased each year, with 2020 seeing the largest decrease (28.6%). However, the pyrazinamide IQVIA patient counts revealed 4 years during which more cases occurred than the previous year 2014, 2015, 2017 and 2019. Azithromycin IQVIA data also showed multiple years with more projected patients than the previous year but a large drop in 2020 of 25.9%.

Researchers then analyzed whether the large declines in 2020 were within the error of what was expected based on previous trends. Overall, they found that most of the data within the 95% prediction interval with the April to December 2020 NTSS monthly case counts and IQVIA isoniazid projected patient counts were all below the lower bound of the 95% prediction interval. In contrast, however, the IQVIA projected patient counts for pyrazinamide, were only lower than the 95% prediction interval in April.

“This analysis has helped to rule out underreporting of TB cases as a cause of the 2020 decline, since the trends in TB prescriptions are similar to the trends in reported TB cases,” Winglee said. “However, concerns remain about missed or delayed diagnoses of TB disease.”

Because of this, she sais health care providers “should think TB,” especially for patients with risk factors and symptoms of TB disease.

“Timely diagnoses of TB disease save lives and prevent further spread in our communities,” she said.

A CenturiesOld Chinese Herbal Medicine Could Help Us to Fight TB

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As science struggles to find new chemicals to address old afflictions, one more time an ancient — and wholly natural — remedy may be the answer, in this case with fighting tuberculosis (TB), according to Science Alert. It turns out that a compound called arteminsinin, which comes from a form of wormwood, not only treats malaria, but antibiotic-resistant TB bacteria.

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While the research is ongoing, it adds to the growing body of evidence that Mother Nature more often than not has the solution to common illnesses. Antibiotics are a foundational component of modern medicine, without which many of our current treatment modalities and medical procedures become exceedingly dangerous. But overuse of antibiotics has made them increasingly ineffective against serious infections.

This antibiotic-resistance has turned into a worldwide health threat of massive proportions that kills tens of thousands every year. One infection, Methicillin resistant Staphylococcus aureus (MRSA), kills more Americans each year than the combined total of emphysema, HIV/AIDS, Parkinson’s disease, and homicide. Solutions for this include improved infection prevention, more responsible use of antibiotics in human medicine, limiting use of antibiotics in agriculture, and finding innovative approaches to treat infections.

But in the wake of this crisis, a good thing has emerged: the re-discovery of natural infection-fighting methods. From garlic to cinnamon to probiotics and fermented foods, to sunlight and Manuka honey, there are positive things in nature that are turning out to be good combatants for fighting infections.

Manuka honey has even been shown to be more effective than antibiotics in the treatment of more than 250 clinical strains of bacteria as well as serious, hard-to-heal, antibiotic-resistant skin infections, including MRSA.

A Radical New Paradigm for TB?

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Correspondence in the July 16th issue ofThe New England Journal of Medicine (NEJM) 1,2 suggests significant progress in the development of 2 drugs to fight extremely, or extensively, drug-resistant tuberculosis (XDR-TB). These scientific advances may be just the tip of the iceberg in an innovative global effort to eradicate all forms of TB—including multidrug-resistant TB (MDR-TB), which is resistant to isoniazid and rifampin, and XDR-TB, which is also resistant to any fluoroquinolone and at least 1 of 3 injectable second-line drugs (capreomycin, kanamycin, and amikacin).3

NEJM Updates and Commentary

The NEJM letters provide updates on linezolid, an agent currently approved in the U.S. for treatment of certain bacterial infections, and delamanid, a drug conditionally approved by the European Medicines Agency for MDR-TB. Following up on their previously published 4-month study results,4 Lee and colleagues reported that at 1 year, 71% (27 of 38) of patients who had linezolid added to their background regimen were cured of XDR-TB infection.4

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In another letter, Gupta and researchers reported a post-hoc analysis of cases of XDR-TB culled from 3 trials that tested delamanid for MDR-TB. In their analysis, 65% (11 of 17) of patients with delamanid added to their background treatment regimen for 6 months or more were cured.2

What impact will these reports have on the management of XDR-TB?

Commenting on behalf of the World Health Organization (WHO), Karin Weyer, MD, coordinator of WHO’s Global TB Programme Unit for Laboratories, Diagnostics, & Drug Resistance, says, “The paper on linezolid suggests potential in using a lower dose of the drug to reduce its well-described serious adverse effects; however, given the limited data (as acknowledged by the authors), the findings are not sufficient to indicate a change in clinical practice, and more controlled trials are necessary.” She points out that delamanid is one of the drugs that the WHO recommends for MDR-TB, giving the clinician more options to design an effective treatment regimen.

Building a Global Armamentarium

Another expert in this field, C. Robert Horsburgh, Jr., MD, Professor of Epidemiology, Biostatistics, and Infectious Diseases at Boston University, also stresses the need for drugs. He says, however, that, “The advantage for patients with XDR-TB is that it’s unlikely that they would have encountered these drugs before, so resistant isolates are unlikely.”

Dr. Horsburgh adds that Lee and colleagues reported that cases of linezolid resistance developed in patients treated with linezolid.4

Albert A. Rizzo, MD, Senior Medical Advisor, American Lung Association, and Chief, Pulmonary and Critical Care Medicine Section, Christiana Care Health System, in Newark, Delaware, says, “The updates on linezolid and delamanid are encouraging in supporting the efficacy of these drugs when used in combination with WHO-recommended background regimens of medications for treating MDR- and XDR-TB. These 2 drugs have the ability to increase the sputum conversion rate more quickly, which can be an indication of more likely cure. This is particularly important in the MDR and XDR strains.”

But even if large-scale prospective clinical trials support the efficacy of these drugs against XDR-TB, they don’t solve the global problem. The 3 experts cited above referred to the potentially game-changing work of the TB Alliance, an organization charged with creating global solutions to TB drug development.

A Completely New Strategy

Mel Spigelman, MD, President and Chief Executive Officer of the TB Alliance, compared the research described above with the approach of the Alliance: “The work coming out now is excellent science and will lay the groundwork for things down the road. The challenge is, we need treatments for drug-resistant TB that can be translated into dramatic effects around the world. In most parts of the world, current treatment regimens are too expensive, take too long, and require too much sophisticated medical supervision. Adding a drug to the current MDR- or XDR-TB therapy will just make the regimen more expensive, complex, and less feasible in different parts of the world.”

But these very same drugs, and others currently under investigation, can be used in a new way that may radically alter TB treatment.

“One of our Phase 2 clinical trials, Nix-TB,5 uses new drugs in a different way,” Dr. Spigelman says. “The 3-drug regimen we’re testing—linezolid, bedaquiline, and pretomanid—is designed to be administered orally once a day. In the mouse model it cured TB in 3 to 4 months. If it works in man, it could reduce the cost of treatment for drug-resistant TB by 95% or more.”

All TB treatment—for TB, MDR-TB, and XDR-TB—here and in developing countries will shift dramatically if a well-tolerated, simple, short “universal regimen” is developed. “Our goal is to provide a new regimen, like the one above, to which no one is resistant,” says Dr. Spigelman. To lessen the likelihood of resistance to the new regimen, the Alliance will seek to develop a fixed-dose combination.

Problem solved?

Dr. Weyer is very encouraged by the progress so far. “The novel drug regimen being developed by the TB Alliance could be one of the few game-changers in TB treatment, should the trials prove its efficacy and safety, and feasibility is later confirmed in the field.”

But implementation of the universal regimen is at least 10 years off, predicts Dr. Horsburgh. In the meantime, he stresses the importance of susceptibility testing to identify the right regimen, and patient support to ensure compliance with it.

For now, says Dr. Rizzo, “The best advice is to use the most effective agents and have them administered in a correct, compliant manner for the needed duration to achieve cure.”

Published: 08/20/2015

References:

  1. Lee M, Cho SN, Barry CE III, et al. Linezolid for XDR-TB—final study outcomes. N Engl J Med. 2015;373:290-291.
  2. Gupta R, Geiter LJ, Wells CD, et al. Delamanid for extensively drug-resistant tuberculosis. N Engl J Med. 2015;373:291-292
  3. TB Alliance. MDR-TB/XDR-TB.
  4. Lee M, Lee J, Carroll MW, et al. Linezolid for treatment of chronic extensively drug-resistant tuberculosis.N Engl J Med. 2012;367:1508-1518.
  5. TB Alliance. TB Alliance launches “Nix-TB” clinical trial to test new XDR-TB treatment.

Four-Month Moxifloxacin Regimens Less Effective for TB Treatment .

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In a randomized, controlled trial, two 4-month moxifloxacin regimens were both inferior to the standard 6-month regimen.

The need to treat tuberculosis (TB) patients with 6-month drug regimens creates problems with adherence, adverse effects, and cost of care. The finding that moxifloxacin has antimycobacterial activity has raised the possibility that use of this agent might shorten treatment duration.

In a recent multinational, randomized, placebo-controlled, noninferiority trial involving 1931 adults with newly diagnosed, previously untreated, drug-sensitive TB, researchers compared the standard 6-month regimen (8 weeks of ethambutol/isoniazid/rifampin/pyrazinamide, followed by 18 weeks of isoniazid/rifampin) with two 4-month moxifloxacin-based regimens — one isoniazid-based (8 weeks of moxifloxacin/isoniazid/rifampin/pyrazinamide followed by 9 weeks of moxifloxacin/isoniazid/rifampin and 9 weeks of placebo) and the other ethambutol-based (8 weeks of moxifloxacin/ethambutol/rifampin/pyrazinamide followed by 9 weeks of moxifloxacin/rifampin and 9 weeks of placebo). The predefined definition of noninferiority was a <6% between-group difference in favorable treatment outcomes within 18 months after the end of treatment.

Conversion to culture-negative status occurred more quickly with the moxifloxacin regimens than with the standard one. However, per-protocol analysis showed that both moxifloxacin regimens were inferior to the standard regimen: Favorable outcome rates were 85% with isoniazid-based moxifloxacin, 80% with ethambutol-based moxifloxacin, and 92% with the standard regimen. The most common reason for an unfavorable outcome was relapse after conversion to culture-negative status. Comparable results were found in a modified intention-to-treat analysis.

COMMENT

Although one could imagine other 4-month moxifloxacin regimens that might be investigated, the present results discourage studying them at this time. A key finding of this trial is that the shorter time to culture conversion seen with the moxifloxacin regimens did not accurately predict long-term outcomes. A better understanding of why this occurred is needed.

– See more at: http://www.jwatch.org/na35640/2014/09/09/four-month-moxifloxacin-regimens-less-effective-tb?query=etoc_jwid#sthash.2C8anDmi.dpuf