When the drugs don't work, could bacteriophages?
Many would agree that the theme of our research very often appears to us as the most pertinent problem in the world, however, it does not always happen that your chosen subject coincidentally takes centre stage in a real-life situation. A few months ago it did for me when my sister’s father-in-law, a poet, and whom she and her daughter lovingly call ‘DaduBhai,’ was admitted to the ICU of a hospital in Mumbai, India.
DaduBhai was admitted to the hospital for asthma-related lung issues, but was otherwise cheerful. To him and us family members, it was expected to be a short-term hospital visit. However, during a visit a couple of weeks after admission, I learnt that he contracted the multiple drug-resistant bacteria, Klebsiella pneumonia and Acinetobacter baumanii, acquired during his extended stay and attributed to being on a ventilator in the ICU. Since he wasn’t responding to most of the antibiotics, broad-spectrum drugs known for their adverse side effects were administered to him, which caused damage to multiple organs. Such progressive deterioration in DaduBhai’s condition due to a hospital-acquired infection was extremely disturbing.
Infectious diseases, which were considered conquered in the wake of the discovery of antibiotics in the 1940s, are once again becoming a serious medical emergency across the globe and drug discovery programs have not able to keep pace with the growing threat of antimicrobial resistance.
Bacteriophages are small viruses that are natural killers that target specific bacteria. Unlike antibiotics, they are found in abundance in nature, such as in our body, soil, rivers, ponds and oceans, and in sewage.
Lately, though, I have become fascinated with the translational health benefits of bacteriophage therapy or phage therapy. In fact, prior to antibiotics, phage therapy was given to patients and wounded soldiers and the treatment is still being used in several countries such as Poland, Georgia and Russia with high success. Bacteriophages were first discovered in the Ganga River in India more than a century ago, but regrettably, phage therapy is not even known to most of the medical community.
What are bacteriophages and how do they work?
Bacteriophages are small viruses that are natural killers that target specific bacteria. Unlike antibiotics, they are found in abundance in nature, such as in our body, soil, rivers, ponds and oceans, and in sewage. Being an inexpensive natural resource and safe for humans, as evident by their numerous and benign presence in the environment, phages offer immense potential as an alternative when antibiotics are rendered ineffective due to bacterial resistance. They can be easily isolated by using simple microbiological techniques. It typically takes one to two days of incubation for phages to appear (seen as clear zones on the bacterial lawn of the petri dishes) if the collected sample has phages present in them. The isolated phages are then grown to high numbers in a lab and any impurities are removed. They can be stored under refrigerated conditions and for long-term use, under sub-zero temperatures. Phage preparations are given to patients after testing their ability, in a procedure similar to how antibiotics are routinely tested in clinical laboratories, to kill a specific bacteria present.
A phage enthusiast
Why this therapy is not being considered globally, at least when antibiotics fail to deliver, was intriguing to me. Knowing this, I didn’t want to give up on DaduBhai, so I explained phage therapy to my brother-in law and to the doctors to consider as an option, but no one in the hospital had heard of bacteriophages as therapeutics, nor were they inclined to adopt the treatment as they had never heard of it, were unsure of the procedure and seemed unenthusiastic about trying it.
Few control studies and clinical trials have been carried out on phage therapies that meet the stringent regulatory criterion as adopted by the US and Europe. There is more faith placed in well characterised drug molecules, than in complex biological entities (with their own protein and DNA) that once administered in a patient are not well understood and are perceived to cause potential harm to the host, at worst by evoking an immune response. Their pharmacodynamic and pharmacokinetic properties are still to be understood, but they have potential to become a mainstream treatment with more validation.
Being a phage enthusiast, however, and having studied them for around 3-4 years, I did some more case study research.
Around the same time as DaduBhai was ill, a case study was published by a team of scientists and doctors in San Diego, USA. The team was treating Tom, a patient suffering from a multidrug-resistant strain of Acinetobacter baumanii. Doctor Schooley, who was attending Tom, decided to try bacteriophages as emergency investigational new drugs (eIDs), approved by the Food and Drug Administration (FDA). Tom who had been in a coma for about two months woke up after three days of intravenous phage therapy and eventually recovered completely.
On reading this study, my family members went from being rather tentative about the treatment, to gaining more confidence in it. Time was running short for DaduBhai and we were really hoping that he would be able to survive while we looked into options.
While Tom’s was a unique case, where the attending doctor, together with scientists working on phages, tried an alternative therapy as a last resort, I had also read a lot about the Eliava Phage Therapy Centre in Tiblisi, Georgia which has found success treating patients from across the world for decades. We got in touch with the centre and while discussing the procedures, I was given the details for Pranav, a resident of New Delhi who had recently undertaken phage therapy for prostatitis in their centre. Pranav had multiple infections with drug-resistant bacteria and could not be treated with the given antibiotic regimen. Everything I had read and watched online was becoming a reality. Getting to know the first-hand experience of someone from my own town was encouraging and so comforting in those tense moments. Finally, my family saw a ray of hope!
Sadly, just when we were preparing travel and visa formalities, DaduBhai succumbed to his infections. His life came to an abrupt end without being able to complete his unfinished poems and say any goodbyes to the family.
We know DaduBhai is not an isolated case. The WHO’s predictions on the impending antibiotic resistance threat are real. Is it really time to submit to the situation, or should we be looking towards alternative options?
What will it take for a wider acceptance of phage therapy?
In order for phage therapy to be used widely, we as a research community need to:
Understand the challenges of phage therapy through research and clinical trials
Create awareness about the potential of phage therapy amongst the medical practitioners, regulatory authorities and the public
Generate funding to build libraries/repositories of bacteriophages suitable for therapeutic use
Regularly use them when necessary as emergency drugs when all the available antibiotics fail (after successful clinical trials are completed)
Create policies that include these therapies as alternatives/complementary to antibiotics.
Potentially we could also have more phage therapy centres to treat patients who are terminally ill or are infected with multidrug and total drug-resistant strains of disease-causing bacteria.
More lives could be saved and successful stories such as those of Tom and Pranav could be more common than the loss my family faced. The loss of our DaduBhai.
Dr Urmi Bajpai is associate professor in the Department of Biomedical Science at Acharya Narendra Dev College in the University of Delhi. Her research efforts are towards finding new inhibitors for Mycobacterium tuberculosis, a bacterium that causes TB, and studying the potential of bacteriophage-derived enzymes as antibacterial agents. You can follow her on Twitter here.