On Wednesday, the Food and Drug Administration approved a new antibiotic that, in combination with two existing antibiotics, can tackle the most ugly and deadly forms of tuberculosis. The trio of drugs cure drug-resistant tuberculosis (XDR-TB), along with cases of multidrug-resistant tuberculosis (MDR-TB), which have been shown to be unresponsive to other treatments.
Tuberculosis is the only leading infectious killer in the world, infecting about 10 million people in 2017 and killing 1.6 million of them. XDR-TB and MDR-TB are even more severe forms of the disease caused by the bacterium Mycobacterium tuberculosisDrug-resistant strains of tuberculosis kill approximately 60% and 40% of their victims, respectively.
MDR-TB strains can withstand at least two of the most potent anti-TB drugs, isoniazid and rifampin. One strain enters the XDR territory when they also become resistant to any fluoroquinolone drug, such as ciprofloxacin or levofloxacin, plus at least one of the three second line injection drugs, which are amikacin, kanamycin and capreomycin. The drug-resistant strains of tuberculosis infected about 558,000 people in 2017.
Existing treatments for MDR- and XDR-TB cases are long, complex and often unsuccessful. Treatment regimens may include up to eight antibiotics taken for 18 months or more. In the latest Global Tuberculosis Report, the World Health Organization found that MDR-TB treatment was successful in only 55% of cases, while treatment for XDR-TB was successful in 34%.
The new three-drug regimen with the new FDA-approved antibiotic beats those numbers comfortably, according to data from a small Phase III clinical trial. The regimen eliminates the infection in 95 of 109 patients with XDR-TB or MDR-TB unresponsive within six months. This is an 87% success rate for six months of treatment. (Two patients not included in 95 extended their treatment to nine months).
A triumphant trio
The three drugs in the range include two existing antibiotics: linezolid, which is used in drug-resistant infections, and a drug specifically developed for MDR-TB called bedadquilin. The newcomer is pretomanide, or PA-824.
Pretomanid was developed by the nonprofit TB Alliance, which acquired the rights in 2002 from Chiron Corporation (which was later acquired by the pharmaceutical giant Novartis). According to Reuters, TB Alliance this year granted Mylan a license to manufacture and sell pretomanid as part of certain regimes in high-income countries, as well as a non-exclusive license to sell in low-income and middle-income countries most affected by TB.
Pretomanide is a new medicine that works specifically against M. tuberculosis and appears to be able to kill both actively replicating cells and hidden ones in a dream state. Molecular studies show that pretomanide has a complex killing method that potentially destroys the bacterial cell walls while poisoning the germs by removing nitric oxide.
Unfortunately, the drug only has these devastating effects on Mycobacteriumand not other types of bacteria. M. tuberculosis and his loved ones are a little band with weird balls. They have a unique external structure that makes them difficult to characterize and difficult to kill.
Most bacteria can be easily divided into one of the two main groups based on the structure of their cell walls, which in turn can be determined by how the cells absorb certain dyes. Typically, bacteria are sorted using a basic dye test designed by the Danish doctor Hans Christian Gram in 1884, called Gram staining.
When stained, bacteria with a thick homogeneous cell wall made predominantly of the polymeric peptidoglycan will appear purple or "gram positive". This thick layer of peptidoglycan helps keep it in a purple dye called crystal violet. In contrast, cells with more complex cell walls, consisting of a relatively thin layer of peptidoglycan plus an outer membrane, are also not held in crystal violet. Instead, they can be contrastingly colored to be a contrasting pink – Gram negative.
The simple test sorts out ordinary bacteria, E. coli is gram-negative, for example, while Staphylococcus aureus. aureus is gram-positive. The cell wall structure suggested by Gram staining may also be helpful in determining which types of drugs will act against a bacterium. After all, in order to kill a germ, the drug generally has to push it past the protective cell.
But none of this applies to MycobacteriumThe genus cannot be Gram stained. Instead of a cell wall structure identified as gram negative or positive, M. tuberculosis and his loved ones have a unique thick, waxy cell wall rich in mycolic acid.
A small victory in a huge war
Pretomanid appears to be mistaken for mycolic acid synthesis, according to a gene activity study M. tuberculosis was in the midst of death. At the same time, the new antibiotic also appears to act as a "suicide bomb", releasing nitric oxide, which poisons the cell's breathing. These activities appear to have the overall effect of destroying the cell and making its interior toxic – a combination that would lead to death. And even if the bacteria are in a cover mode where it doesn't reproduce or work on its wall – something M. tuberculosis sometimes in the human lung – studies have found that nitric oxide poisoning is enough to take out those annoying sleepers.
Overall, this is good news for the treatment of tuberculosis. In a press release, President and CEO of TB Alliance, Dr. Mel Spiegelman, called FDA approval this week "a victory for people suffering from these highly drug-resistant forms of the world's most lethal infectious disease. The new regime will hopefully provide shorter, more manageable and highly effective treatment for those in need. "
With its inherent shipping specifics M. tuberculosis, pretomanide has no effect on other bacteria, whether gram-positive or gram-negative. It would certainly be helpful if he did. Drug resistance among bacterial pathogens is not limited to tuberculosis – it also reaches a critical level for many ulcers. WHO considers antibiotic resistance in general to be "one of the biggest threats to health globally." In the US alone, at least 2 million people receive antibiotic-resistant infection each year, killing at least 23,000, according to the Centers for Disease Control and Prevention. So far, drug-resistant tuberculosis is rare in the United States.
Meanwhile, the development of antibiotics is stagnant. Inventing new and effective antibiotics is challenging work and is not liked by many pharmaceutical companies because of the lack of profit. Antibiotics are relatively inexpensive medicines taken for short periods. They simply do not give the revenue seen from long-term chronic condition medicines, such as blood pressure medications. And with the ongoing threat of resistance, a new antibiotic that has been needed for decades may have a limited life span in clinical use.
To help stimulate the creation of new antibiotics, last year the FDA created a program called the Restricted Population Pathway for Antibacterial and Antifungal Medicines, or LPAD. The purpose of the program is to accelerate the development and approval of new antibiotics. For the time being, pretomanide is the second medicine approved this way.
FDA Deputy Commissioner Amy Abernathy said in a statement that "We hope to continue to see more development of antibacterial drugs for the treatment of serious or life-threatening infections."