Superbugs are scary. And new antibiotics are hard to come by. There are reports of incurable strains of gonorrhea, typhoid, malaria, and hospital-acquired infections such as Candida auris (a fungus). To this long criminal lineup, we need to add drug-resistant tuberculosis (DR-TB).
TB is an airborne infection caused by Mycobacterium tuberculosis. When streptomycin was first discovered in the 1940s, there was tremendous hope that TB could be defeated. But TB bacteria quickly became resistant to streptomycin when it was given alone. We quickly learnt that TB requires a combination of drugs to fend off drug-resistance.
Today, drug-sensitive TB treatment requires 4 drugs (isoniazid, rifampicin, pyrazinamid and ethambutol) during the first two months, followed by two antibiotics (isoniazid and rifampicin) for an additional 4 months. DR-TB treatment requires prolonged therapy (often, 24 months) with several, toxic medicines, including those that cause deafness and psychosis.
Drug-resistant TB affects over half a million people each year, and kills nearly 230,000 people. While only about a quarter of people with DR-TB are diagnosed and placed on treatment, outcomes are poor, even among those who get second-line therapy. Only 1 in 2 patients with multidrug-resistant TB survive. With extensively drug-resistant TB, only 1 in 3 patients survive. When TB strains are resistant to all available anti-TB medicines, then they are called ‘totally drug-resistant.’ Such totally drug-resistant strains have been reported in countries such as India and South Africa.
While new antibiotics such as bedaquiline, delamanid and pretomanid have been discovered, DR-TB continues to be very hard to manage. There is a desperate need for new and alternative therapies. One such alternative might be killing TB bacteria with viruses that destroy bacteria (i.e. bacteriophages).
A new book called The Perfect Predator provides a terrific overview of the field of phage therapy and its potential for addressing superbugs. Thomas Patterson, a UCSD professor, was dying of a super-resistant strain of Acinetobacter baumanii infection. Totally out of all options, Steffanie Strathdee, his wife and a UCSD global health researcher, working with Robert Schooley, a UCSD professor of medicine, tried out bacteriophages to kill the acinetobacter infection.
As I read the book (see my book review), I wondered if phages could work for drug-resistant TB, especially in patients with extensively drug-resistant infection? Sadly, there are no human trials of mycobacteriophages for DR-TB. However, this week, Nature Medicine published a fascinating case report, documenting the first therapeutic use of phages for a human mycobacterial infection. Not DR-TB, but something close.
A 15-year old patient with cystic fibrosis was referred for lung transplantation. This patient was infected for many years with a non-tuberculous mycobacterium called M. abscessus, commonly found in the environment (soil, water, etc). Healthcare-associated infections due to this bacterium are usually of the skin and the soft tissues under the skin. It is also a cause of serious lung infections in persons with various chronic lung diseases, including cystic fibrosis.
Although not as virulent at M. tuberculosis, infection of the lung with M. abscessus is the most difficult non-tuberculous mycobacterial infection to treat. Very few antibiotics work against M. abscessus and thus, it closely resembles DR-TB.
Although the patient with cystic fibrosis had a successful, bilateral lung transplant, because of her immune-suppressed state, her pre-existing M. abscessus infection became disseminated and worse, affecting the lungs, skin nodules, and the chest surgical wound infection. The treating team at the Greater Ormond Street Hospital in London decided to try out mycobacteriophages, with the help of phage experts at the University of Pittsburgh, and UCSD.
The research team had to first screen collections of phages to identify those that could infect and kill M. abscessus. In addition, they used genome engineering to improve the killing or lytic ability of some phages. In the end, they put together a cocktail of 3 different phages (image below) and delivered them intravenously. Intravenous phage treatment was well tolerated and associated with objective clinical improvement, including chest wound closure, improved liver function, and substantial clearing of infected skin nodules. There was evidence of phage replication in the body, indicating that phages successfully infected the mycobacteria.
I spoke to Professor Graham Hatfull, a leading phage scientist and one of the senior authors of the paper. He confirmed that the patient is alive but still on phage therapy (for about 11 months now), along with conventional antibiotics. While the phages have not completely cured the patient of the M. abscessus infection, Hatfull believes the phages might have helped clear her lungs. I asked him whether 11 months of phage therapy has resulted in any resistance to the phages. “We have seen no evidence of resistance to any of the 3 phages,” he replied.
In the absence of a control group, Hatfull and his co-authors are cautious about making any causal claims. They also note that it was not easy to identify sufficient phages to effectively kill M. abscessus, and the three-phage cocktail they used in their patient might not be a generalizable treatment for all patients with M. abscessus because of variability in strains.
“Not only do all these phages not infect M. abscessus, but in fact the phages that infected this one particular strain in this one particular patient we treated, they don’t infect or control other clinical isolates of M. abscessus. The strain variation is really great, and this is not a universal solution to all non-tuberculous mycobacterial infections. But that puts in front of us a major research problem. What can we do to try and understand that variation, and can we expand the bank of phages so that we can get a collection of phages that do infect various strains?” Hatfull remarked.
Case reports are not sufficient for clinical use, but Graham Hatfull, Helen Spencer and their team have proven the concept that mycobacteriophages might have some role in treating M. abscessus in humans, and, by analogy, drug-resistant TB. They have opened the door for similar work in patients with XDR-TB who are out of therapeutic options.
In general, the field of phage therapy has to evolve from a series of case reports of compassionate use among desperately ill patients, to an evidence-base that demonstrates that phage therapy is safe, effective, and can become a part of routine clinical practice. Thankfully, such randomized trials are emerging. More are needed, and need to be funded.
In practical terms, challenges include the need to screen phage collections to identify those that work for a particular patient’s micro-organism, and the need to produce them in sufficient quantity and quality (i.e. purified) for clinical use. In other words, phage therapy is bespoke, made-to-order for each patient and their specific strain of superbug. The cost of all this is probably high, unless it is done at scale. Scalability and costs are particularly critical for DR-TB, a disease that is concentrated in low and middle-income countries.
Although there are biological and practical hurdles, I hope the TB field will explore the role of phages in the treatment of drug-resistant TB. Given the paucity of new antibiotics and the growing DR-TB threat, we must keep an open mind to novel therapeutic options, even if means injecting people with viruses.
Note: I have no financial or industry conflicts to disclose