TUBERCULOSIS (TB) deserves its bad reputation as a global scourge. It is a wily infection that is continually seeking to outmanoeuvre scientists’ valiant attempts to target and destroy it effectively.
It kills as many as 2- million people a year — more people than any other disease caused by a single infectious agent, say experts.
The World Health Organisation designates TB as a “disease of poverty, affecting mostly young adults in their most productive years”. TB is the leading cause of death among people infected with HIV/AIDS (the two are said to go “hand in hand”.)
That doesn’t mean the rich are immune. Far from it. TB is airborne, and “as long as we breathe, we are all at risk”, says Dr Zi Chapanduka, medical, regulatory and corporate affairs director at Eli Lilly SA. Estimates are that one in three humans already carries the bacterium mycobacterium tuberculosis that causes TB. That translates to 2-billion people.
Although it remains latent in most cases, TB is highly infectious. Like the common cold, it spreads quickly and easily through the air. When immune systems are compromised, which can happen from excessive stress, illness, medication or bad lifestyle habits, the risk of people showing symptoms of the disease after breathing in the bacterium rises significantly.
Fifty years ago, there were no medicines to cure TB. These days, it can be cured with correct treatment using antibiotic drugs.
A major problem continues to be compliance. Deadly drug-resistant strains of TB develop when patients do not complete the full period of treatment, says Dr Refiloe Matji, Southern Africa regional director of the University Research Company’s Centre for Human Services, on the centre’s website (www.urc-chs.com).
That has led to multidrug- resistant TB (MDR-TB), and the even more virulent extensive drug-resistant TB (XDR-TB). The WHO defines MDR-TB as strains that are resistant to at least the two main first-line TB drugs; and XDR-TB as MDR-TB that is also resistant to three or more of the six classes of second-line drugs.
But it isn’t just patients missing a dose or not completing the full treatment that has caused the new strains. Inappropriate treatment prescribed by doctors is also a factor, say specialists.
Treatment is typically a combination of antibiotics, and in non- drug-resistant cases should last six months. As resistance develops, that period can more than double, even quadruple, or in a worst-case scenario of XDR-TB, make the disease untreatable.
The introduction of new medicines to existing regimens makes it difficult for scientists to identify which, if any, of the drugs are working at the current dosage levels. struggled to identify optimum dosages as well as exactly where in the body these drugs work to combat the bacterium.
Now US scientists say the typical dose of a medication considered pivotal in treating TB effectively is much too low to account for modern-day physiques.
The finding, online and in a recent print edition of Antimicrobial Agents and Chemotherapy, is “particularly important for those living in societies plagued by obesity”, says Dr Tawanda Gumbo, associate professor of internal medicine at the University of Texas Southwestern and the study’s lead author.
The research is US-based, but relevant for SA, where obesity and TB rates are high.
“What really drives the variability of this particular drug is patient weight and gender, so in our simulations we took that into account,” Gumbo says. “What we found is that we’re really using doses for very skinny people — 48kg to 50kg . I haven’t met many adults who are at that weight.”
The model developed at the university uses cultured cells to gauge the effectiveness and proper dosage of anti-tuberculosis drugs. It allow scientists to test molecules directly that have the potential to shorten therapy, and come up with doses that you would use in patients, Gumbo says.
“If you have a molecule that could cure TB in a month in this model, there’s a good chance it would do the same in patients.”
For this study, the researchers used pyrazinamide — an older drug generally used in combination with other drugs — daily for one month. They used the data collected to calculate how much bacteria the drug killed before resistance emerged.
They opted to focus on pyrazinamide because doctors once used it alone to treat the disease, so there are studies documenting precisely how the drug behaves in patients — something that is unclear for some newer drugs.
When the researchers began testing pyrazinamide in the laboratory, they found that concentration of the drug declined at a rate matching that in patients.
“In patients, unlike in test tubes, it’s not a constant concentration. A patient given multiple drugs degrades each of them at different rates,” Gumbo says.
“Using this model, we can copy this concentration profile of the drugs to human-like exposures.”
His team’s finding suggests that different doses are probably needed in different countries.
“Most of the patients we see here (in the US) are not 50kg, unless they have some other severe disease,” he says.
The next step, Gumbo says, is to continue researching drug combinations to devise optimum treatment regimens for TB patients.
“We’ve rationally and scientifically come up with a dose that depends not just on the kinetics or the concentration time profile of patients, but also how the bug itself responds to that particular drug,” he says.
“Instead of using the average or a mean patient, we can now project how a drug combination will fare in actual patients. Researchers can use these simulations to determine the duration of therapy, which could shorten from years to months.”
In related research, Australian scientists used epidemiological and molecular data from TB strains isolated from Cuba, Estonia and Venezuela to estimate the rate of evolution of drug resistance ,and compare the relative “reproductive fitness” of resistant and drug-sensitive strains.
“The overall fitness of drug- resistant strains was comparable to drug-sensitive strains,” says Dr Mark Tanaka of the Evolution and Ecology Research Centre at the University of New South Wales. This was especially so in Cuba and Estonia, that have a high prevalence of drug-resistant cases.
The finding may reflect inconsistency in drug treatment programmes 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 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, says Tanaka.
The study also reveals that the contribution of transmission to the spread of drug resistance is very high — up to 99% — compared with acquired resistance due to treatment failure.
“Drug-resistant strains of TB are likely to become highly prevalent in the next few decades,” says Dr Fabio Luciani, the study’s lead author. “Limiting further transmission might be an effective approach to reducing the impact of drug resistance.” Marika Sboros and Science Daily