When using a virus to fight a superbug is the best approach

ALTERNATIVE METHOD Certified for human treatment in a few European countries, phage therapy pivots on naturally occurring viruses to attack antibiotic-resistant bacteria

In the summer of 2016 as Delhi sweltered, Pranav Johri was feeling the chills. The 33-year-old businessman had felt a pulling pain in his groin region a few weeks ago that only grew worse, coupled with a low fever and persistent aches. He was soon diagnosed with Chronic Bacterial Prostatitis along with Chronic Epididymitis – an inflammation of the prostate gland and the epididymis, caused by a bacterial infection. He was prescribed a 10-day course of antibiotics, and, when it didn’t show visible results, a four-week course of a second antibiotic.

Nothing worked. A second doctor and urine culture later in August, he was put on a different antibiotic regime but with little result. “Every summer, my wife and I would go mountaineering. Now, I couldn’t even move normally without assistance,” he said.

As October rolled around, Johri was running out of options – the pelvic pains had worsened, so had the chills and shivers. His doctor suggested the bacterial infection was antibiotic-resistant and his best bet would be to manage symptoms. “It was like a wave hitting me, my doctor admitting that we had run out of options. I started to consult and read up on antibiotic resistance. It is then that I read about phage therapy,” he said.

OLD MEDICINE, NEW BOTTLE

What Johri had stumbled on was no new frontier in medical science but a 100-yearold system that pivots on naturally occurring viruses, or phages, to attack and destroy bacteria. Phage therapy is certified for human treatment only in a few European countries, primarily Georgia.

On November 14, 2016, he flew to Georgia to admit himself at the George Eliava Institute of Bacteriophage, Microbiology and Virology in Tbilisi. Johri admits he wasn’t completely convinced as most doctors dismissed phage therapy as fringe. “But it was my only shot,” Johri said.

In Tbilisi, doctors found four major bacterial strains in his samples and administered a phage cocktail – since each virus attacks a specific strain of bacteria, a cocktail of medicines is needed to treat a complex infection. The application was oral, rectal and topical. By the fourth day, the pain had started easing. “It felt like a miracle,” Johri said.

But the fourth strain – Streptococcus Mitis – was still proving resistant, and, so doctors proposed a ‘custom phage’ engineered by isolating the bacterial strain and growing a phage accordingly. In two months, it worked. “We are not generally concerned of side effects, the phage itself is very safe. We were able to achieve very good results with Pranav,” said Dr Naomi Hoyle of Eliava Phage Therapy Center.

Johri flew back to Tblisi in March 2017 and then again in November. By the New Year, the strength was back in his limbs. He is spending the winter in a ski resort.

Bacteriophages (Latin for ‘bacteriaeater’) are naturally occurring viruses, available in the order of trillions in the environment. A phage resembles the structure of a spaceship, explained BL Sarkar, emeritus scientist, Vibriophage Reference Laboratory at the Kolkatabased Icmr-national Institute of Cholera and Enteric Diseases, with spidery tail fibres to recognise and attach to the target’s surface.

The phages inject their DNA material into the bacteria, replicate rapidly and rupture the cell walls in a process called lysis. They are the opposite of broad-spectrum antibiotics, which work against a large variety of bacteria. “The phages are specific to their target bacterial host cell but are unresponsive to human or eukaryotic cell whereas antibiotics target both pathogenic microorganisms and normal microflora,” Sarkar explained.

This makes phage therapy both challenging and unique. Because of its targeted nature, there is little commercial incentive in scaling up production because its use will never be as generic as, say, penicillin. But precisely of this character, it is a boon in a world with rising resistance to wide-spectrum antibiotics, said Tushar Suvra Bhowmick at the Center for Phage Technology at Texas A&M University. “Phages are very safe to apply in the human body as it doesn’t affect normal microflora of the gut system. There is very little side effect,” she said.

WHY PHAGES?

Reckless overuse of antibiotics has led to several disease-causing bacteria – like Mycobacterium tuberculosis that causes TB – developing resistance to medicines. A 2011 study published in the Indian Journal of Medical Research called for rationalising antibiotics use, saying, “Antibiotics are often prescribed in irrational or inappropriate ways in India; that is, the drugs are prescribed at an incorrect dose, frequency, or duration, are redundant, or have the potential for adverse interactions with other drugs.”

The American Centre for Disease Control estimates two million Americans get antibiotic-resistant infection annually and 23,000 die. There are no official corroborating figures for India but a study this year in the Proceedings of the National Academy of Sciences noted antibiotics use more than doubled in India between 2000 and 2015, fuelling resistance that made common infections such as E-coli, strep throat, pneumonia and TB more difficult to treat.

“In the US, a lot of companies and pharmaceutical firms are working against antibiotic resistance. In India, there is a big problem with antibiotic resistance. There is a lot of potential for phages because we are producing superbugs,” said Bhowmick.

A 2018 paper by Frank Oechslin at the University of Lausanne showed bacteria developed resistance to phages in 80% of studies targeting “the intestinal milieu”. But the paper said developing phage resistance came at a fitness cost for the bacteria, and, in some cases, decreased infectivity.

“It remains unclear whether the widespread use of phages to treat infections might lead to a problematic increase in phage-resistant bacterial pathogens in an analogous way that resistance developed to antibiotics,” the paper said, adding, the main question was whether phages would be used in as generic a manner as antibiotics.

Phage scientists are united in their answer: There is no foreseeable future where phages will be used generically, and its use will largely be restricted to superbugs. “Phage therapy may be an alternative and potential weapon against infectious diseases as it has been experimentally proved that bacteriophages are therapeutically superior to antibiotic therapy,” said Sarkar.

In 2016, Steffanie Strathdee, director of University of California San Diego’s

PHAGES INJECT THEIR DNA MATERIAL INTO THE BACTERIA, REPLICATE RAPIDLY AND RUPTURE THE CELL WALLS

IN A PROCESS CALLED LYSIS

Global Health Institute, launched an international effort including in India, to find phages to save her husband, who was infected with an Iraqi superbug. Her husband recovered after months of seesawing treatment, including a tumultuous period where the infection developed resistance to phages. Others have not been as successful. A European trial, Phagoburn that focused on treating burns with phages, has suffered a series of setbacks – only 27 patients in the final trial as against an initial projection of over 200 — and been all but derailed.

MEDICAL USE

In 1992, there was a turning point in cholera phage therapy in India, explained Sarkar, when a new strain, known as O139 Bengal, emerged.

“This study indicated that in case of cholera, oral administration of a suitably designed phage cocktail could provide a method of treatment alternative to antibiotic therapy.”

Phage therapy is not approved for human use in most countries, including India, and this presents a major challenge, said Gopal Nath, professor, Microbiology at Banaras Hindu University.

Nath’s team used animal models for phages in burn wounds and septicaemia infections, especially in immune-compromised cases. In a 2016 paper published in Indian Journal of Medical Research, Nath and co-authors found significant success in using bacteriophages to fight Methicillin resistant Staphylococcus aureus, which causes osteomyelitis, in rabbits. “We also found phages are very effective for topical (surface) use in burn wounds,” he said. Phages are also used to produce recombinant monoclonal antibodies antibodies, made by identical immune cells that are clones, at Vallabhbhai Patel Chest Institute in Delhi, in an effort to fight infections such as flu.

Urmi Bajpai, associate professor of biomedical science at Delhi University, said: “We need to have a large bank of diverse and well-characterised virulent bacteriophages [the kind that can cause lysis of bacteria] that can kill drug-resistant bacteria and purify them for therapeutic standards and do clinical trials. Phagederived enzymes are also being developed as antimicrobials.”

OTHER USES

Other focus areas include veterinary, agriculture and pollution treatment. Scientists at the National Environmental Engineering Research Institute, for example, are working on using bacteriophage for controlling foaming and bulking in wastewater treatment plants.

Some breakthroughs have come from a private company based in Bengaluru called Gangagen, which has discovered P-128, a phage-derived protein, in early clinical development, that rapidly and specifically kills Staphylococcus bacteria, including drug resistant strains. At its facility in Bengaluru, a combination of microbiologists, biochemists, biotechnologists and molecular biologists work to isolate phages from the environment and study their ability to infect and kill superbugs.

“Phage genetics and molecular biology approaches are then applied to unravel the functions of the different products encoded by the phage DNA and those products having the potential to be developed as antimicrobial agents are characterised and prioritised,” said TS Balganesh, the firm’s president.

LOOKING AHEAD

But by when will phage therapy be ready for human trials? Sarkar thinks scientists can get there in two to three years, subject to government approval. The UCSD has announced the launch of a new clinical centre with a three-year, $1.2 million grant for clinical trials in collaboration with pharma companies, reported Science. Johri who had to shell out over ₹8 lakh, is hopeful the costs will come down with more options and research.

He has now started ‘Vitalis Phage Therapy’ to facilitate distance treatment for Indian patients by the Eliava Institute. “I hope more and more people are able to take advantage of phage therapy. They gave me my life back,” he said.