New Drug Speeds Response in multidrug-resistant TB

Patients with multidrug-resistant TB (MDR-TB) given a new anti-TB drug -- TMC207 -- combined with a background regimen, responded almost twice as fast as those on placebo with the background regimen, a researcher reported here.

Final results from the first part of a stage IIb trial among 47 patients, found the median time to culture conversion was 11 weeks for those treated for eight weeks with TMC207 and the five-drug MBR-TB background regimen, according to Andreas Diacon, MD, of the University of Stellenbosch in South Africa.

In contrast, the median time for patients assigned to placebo combined with the five-drug background regimen was 18 weeks, Diacon reported here at the Interscience Conference on Antimicrobial Agents and Chemotherapy.

"Importantly," Diacon said, "these patients were only treated with TMC207 for eight weeks and still there is a significant reduction in the median time to culture conversion compared with placebo."

The drug has been closely followed (See ICAAC-IDSA: Novel Drug Shows Power in MDR-TB) but Diacon presented the final results of the first stage of the trial, which involved eight weeks of therapy with TMC207 and two years of the background regimen alone.

A second stage of the trial, with a different and larger cohort of patients treated for 24 weeks, is currently under way, he added.

TMC207 interferes with synthesis of adenosine triphosphate in Mycobacterium tuberculosis cells, but not in other cells, even those of closely related bacteria. Inhibiting the compound reduces the energy available for the TB bacteria to combat other drugs or to reproduce.

The researchers were looking at the safety and tolerability of the drug, as well as efficacy, in 47 patients with multidrug-resistant TB, defined as a strain resistant to the first-line drugs isoniazid (Nydrazid) and rifampin (Rifadin).

They were treated with a five-drug background regimen, which varied from patient to patient but usually included ethionamide (Trecator), pyrazinamide, kanamycin (Kantrex), and ofloxacin (Floxin). TMC207 was given daily at 400 milligrams for two weeks, followed by 200 milligrams three times weekly for six weeks.

At the end of the first stage of the trial, Diacon said, 81% of those treated with TMC207 were considered cured, defined as two consecutive negative cultures at least 28 days apart and no recurrence of the disease.

In contrast, 57% of those getting the background regimen alone were considered cured, a difference that was significant at P=0.03, he said.

The drug was generally well tolerated, Diacon said. No patients stopped the drug because of adverse events, and the proportions of patients with grade 3 and 4 adverse events were similar between the arms -- 26% for TMC207 and 21% for placebo.

The results are exciting, according to Patrick Charles, MD, PhD, of Austin Health in Heidelberg, Australia, who moderated the session at which the study was presented but who was not involved in the research.

"It's really the first new drug to treat these extremely resistant cases," he told MedPage Today.

For patients with multidrug-resistant TB, he said, treatment options are "very limited and very expensive, so to have a new drug is very exciting."

According to the abstract, preliminary results from the second stage of this trial, involving 161 MDR-TB patients with TMC207 administered for six months, are expected soon.

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New drug-resistant TB strains could become widespread says new study

The emergence of new forms of tuberculosis could swell the proportion of drug-resistant cases globally, a new study has found. The finding raises concern that although TB incidence is falling in many regions, the emergence of antibiotic resistance could see virtually untreatable strains of the disease become widespread.

Australian researchers from the University of New South Wales and the University of Western Sydney have published the new finding in the latest issue of the Proceedings of the National Academy of Sciences.

Laboratory-based studies have suggested that antibiotic-resistant TB strains cause longer-lasting infections but with a lower transmission rate. Therefore, scientists have questioned whether drug-resistant TB strains are more likely than drug-sensitive strains to persist and spread – an important question for predicting the future impact of the disease.

One in three humans already carries the TB bacterium. Although it remains latent in most cases, the World Health Organisation (WHO) has estimated there were 9.27 million new cases of TB in 2007. There were 1.6 million TB-related deaths in 2005. Drug-resistant TB is caused by inconsistent or partial treatment, when patients do not take all their medicines regularly for the required period or because the drug supply is unreliable.

A research team led by UNSW's Dr Mark Tanaka used epidemiological and molecular data from Mycobacterium tuberculosis strains isolated from Cuba, Estonia and Venezuela to estimate the rate of evolution of drug resistance and to compare the relative "reproductive fitness" of resistant and drug-sensitive strains.

"We found that the overall fitness of drug-resistant strains is comparable to drug-sensitive strains," says Dr Tanaka of the Evolution and Ecology Research Centre. "This was especially so in Cuba and Estonia, where the there is a high prevalence of drug-resistant cases."

The finding may reflect an inconsistency in drug treatment programs in these countries. Indeed, Estonia now has one of the highest rates of multi-drug resistance in the world. The intermittent presence of drugs and the resulting transmission of resistant strains would have let drug-resistant strains collectively spend more time within untreated hosts, allowing them to evolve ways to become more infectious and out-compete the drug-sensitive strains.

The study also reveals that the contribution of transmission to the spread of drug resistance is very high – up to 99 per cent – compared with acquired resistance due to treatment failure. "Our results imply that drug resistant strains of TB are likely to become highly prevalent in the next few decades," says UNSW's Dr Fabio Luciani, the study's lead author. "They also suggest that limiting further transmission of TB might be an effective approach to reducing the impact of drug resistance."

"Mathematical and statistical methods can add a lot of value to empirical data by allowing us to account for the processes behind them," says research co-author, Dr Andrew Francis from the University of Western Sydney. "In this case, we use samples of TB genotypes, together with information about drug resistance, to make inferences and predictions that wouldn't have been possible just a few years ago."

Source : www.eurekalert.org

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Parkinson's medications may help treat extreme drug-resistant TB

Two drugs that are commonly used to treat Parkinson's disease have been found to be effective in treating extreme drug-resistant tuberculosis, say researchers at the University of California, San Diego.

They have discovered that the two commercially available drugs, entacapone and tolcapone, have the potential to treat multi-drug resistant and extensively drug resistant tuberculosis.

"We have computational, and experimental data to support this repositioning," said Dr Philip E. Bourne, professor of pharmacology at UCSD's Skaggs School of Pharmacy and Pharmaceutical Sciences and the principle investigator on the project.

"What is exciting about this finding is that the TB target, enzyme InhA, is already well known. But existing drugs are highly toxic and of completely different chemical structure than entacapone and tolcapone.

"Here we have drugs that are known to be safe and with suitable binding properties which can be further optimized to treat a completely different condition," he added.

While working with the TB bacterium itself, they found that the active component in Comtan tablets (entacapone) is effective at inhibiting M.tuberculosis in concentrations well below a level that is toxic to cells.

"Although we have demonstrated in the lab that Comtan is active against M.tuberculosis, additional studies are required in order to transform it into an anti-tubercular therapeutic," said Sarah L. Kinnings, a graduate student and lead author on the study.

"Given the continuing emergence of M.tuberculosis strains that are resistant to all existing, affordable drug treatments, the development of novel, effective and inexpensive drugs is an urgent priority," she added.

The study appears in PLoS Computional Biology.

Source : www.newkerala.com

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