NEW DELHI — Pranav Johri completed five rounds of antibiotics to treat a persistent prostate problem in his early 30s, but his case flummoxed doctors because the medicine seemed to make him worse.
"My entire life had become so limited," says the 35-year-old workaholic from India's capital city, recalling how he couldn't summon strength for much more than a small meal in between long naps.
The athletic man Apurva Virmani Johri had married just a few years prior was confined to their bedroom, surrounded by photos of the couple hiking around the world — a constant reminder of their former life.
"I think the hardest part was just not seeing him smile," she says. "This is a person who would smile at the drop of a hat."
Pranav's breaking point came when his doctor told him to prepare for a lifetime of symptom management, rather than a cure for his prostatitis, a swelling of the walnut-sized gland below a man's bladder.
The frustrated patient scoured the internet for answers to his mysterious predicament. He contacted a specialist to conduct more in-depth testing and learned the bacteria causing his prostatitis was resistant to all five antibiotics he'd taken.
He stumbled upon stories of others in similar circumstances who turned to a long-retired cure for their illnesses: phage therapy.
Desperate, Pranav travelled to an Eastern European institute specializing in the treatment, which involves a cocktail of natural bacteria eaters. He paid thousands of dollars for the last ditch-effort to rid his body of the infection.
Western doctors mostly shelved phage therapy as a treatment after the advent of antibiotics.
But the drugs, once considered a medical marvel, no longer work against a growing number of bacterial infections. Rampant misuse and overuse helped spur the growth of antibiotic-resistant bacteria, resulting in superbugs that now kill an estimated 1.5 million people each year.
While superbugs proliferate, antibiotic discovery has stalled. For pharmaceutical companies, there is little profit incentive to invest in drugs that quickly cure patients; medicine for chronic conditions presents a more tempting return on investment.
"I think the hardest part was just not seeing him smile,"Pranav Johri's wife Apurva Virmani Johri
That leaves patients like Pranav, whose infections don't respond to antibiotics and whose doctors run out of new medicines to prescribe, turning to the century-old practice.
However, experts warn phage therapy is an unlikely magic bullet: the treatment is not widely available, backed mostly by anecdotal evidence, and requires bespoke solutions for most patients.
Some medical experts instead hang their hope on lengthening the lifespan of existing drugs. Catching infections sooner and treating patients properly could help slow down resistance. But, like antibiotic discovery, diagnostics research lacks the necessary funding for big advances.
Without more investment and progress in drug discovery and diagnostics, experts fear the world will enter a post-antibiotic era, in which millions are expected to die each year from infections once easily treated.
"It's not a problem for the future. It's a problem that exists right now," says Bob Hancock, a microbiology professor at the University of British Columbia whose lab focuses on designing new therapies for infections.
"It's kind of the global climate change of health."
More than 100 years ago, French-Canadian Felix d'Herelle discovered phage therapy to treat bacterial infections, starting with dysentery in humans.
Phages, put simply, are natural bacteria eaters. They can be found in the environment — on land, in water, and even in sewage — and work by injecting themselves into a bacterial cell and forcing it to self-destruct.
Phages do not attack the good bacteria in a human body, resulting in fewer side effects than long courses of antibiotics, such as the digestive issues and joint pain Pranav endured during his antibiotic treatment.
Graphic: THE CANADIAN PRESS/Sean Vokey
"Today, I feel I got off lucky," he says, adding he's read horror stories of others with lifelong side effects.
However, data is limited as to whether phage therapy is safe for humans. The treatment raises safety concerns, including whether it's effective and the possibility of serious infections in immunocompromised patients. Other commonly cited risks include lack of clarity about side effects and possible septic shock.
The advent of antibiotics in the 1940s led most Western practitioners to prescribe pills over phages. Physicians in what was then the Soviet Union and parts of Eastern Europe, however, continued administering phage therapy.
In 1923, D'Herelle co-established The Eliava Institute in what is now Tbilisi, Georgia. The institute treated patients with phages so often it created a modern offshoot, the Eliava Phage Therapy Center, to expand on the institute's growing practice.
Pranav paid roughly C$6,000 plus travel expenses for his three visits to Tbilisi to treat his antibiotic-resistant infections.
A few days after his first treatment at the institute, Pranav says his fever disappeared and the thermometer showed a normal temperature for the first time in months. He and his wife went out to celebrate and Pranav managed to sightsee, and eat lunch and dinner — an impossibility just days prior.
Before discovering phage therapy, Pranav felt he had run out of options. Antibiotics made him sicker and doctors offered no alternatives.
"How have we been so irresponsible with a cure?"Pranav Johri
"I've never forgotten the hopelessness that I felt when I was going through the worst of this problem," he says, angry to be collateral damage of such a man-made problem.
People managed to fly a man to the moon, develop handheld devices that pack all the power computers once did, and create tiny microchips, says Pranav, his voice growing more animated as he rattles of a list of humanity's achievements.
"How have we been so irresponsible with a cure?"
Antibiotics experienced a heyday in the 1950s. Alexander Fleming discovered penicillin, the world's first true antibiotic, in 1928 and doctors started prescribing it widely in the mid-1940s. Over the next decades, a slew of antibiotics entered the market. But discoveries stalled in the 1980s and researchers haven't discovered any new classes of antibiotics in decades. Many experts discount the 1997 discovery of bedaquiline, says UBC's Hancock, as it is a narrow-spectrum antibiotic.
Meanwhile, drug-resistant bacteria started cropping up. Only a few years after doctors regularly started prescribing penicillin, Fleming started to warn the public about resistance. Now once curable infections, like gonorrhea, are more difficult — if not impossible — to treat.
Hover over a bar on the chart for detailed information.
Types of antibiotics:
Source: Nature reviews
It doesn't help the profit imperative that antibiotic-resistant diseases, like drug-resistant tuberculosis, overwhelmingly impact poorer people in developing nations, who can't afford expensive therapies, says Florian Von Groote-Bidlingmaier, the director of TASK Applied Science, who is responsible for multi-drug-resistant tuberculosis trials at Brooklyn Chest Hospital in Cape Town, South Africa.
Still, some new drugs aimed at drug-resistant TB have emerged in recent years, including bedaquiline and delamanid, and others are in the pipeline. Researchers have also created shorter regimens of new combinations of drugs to decrease side effects and increase compliance.
However, new drugs will likely meet the same fate as their predecessors; bacteria will eventually develop resistance. Already, doctors report seeing patients with strains resistant to bedaquiline.
"There will never be a total cessation, in my opinion, of generating drug resistance," says Mel Spigelman, CEO of TB Alliance, a New York-based NGO working to discover and develop new TB drugs.
The goal, he says, is to ensure new discoveries fend off resistance for 50 years instead of five.
"There will never be a total cessation, in my opinion, of generating drug resistance."CEO of TB Alliance Mel Spigelman
He believes the development of treatments with fewer side effects that cause patients to stop the drug regimen — a major problem with current TB medicine — would markedly reduce resistance.
At least one Western medical researcher joins patients in reconsidering phage therapy — but it took a first-hand brush with death to open her eyes.
Steffanie Strathdee, an infectious disease epidemiologist, remembers visiting her husband Tom Patterson in a U.S. hospital, where he slipped in and out of consciousness while fighting a deadly multi-drug resistant infection.
Tom, now 71 years old, fell ill on the last night of their trip to Egypt in November 2015. By the time he was moved to a hospital in the couple's hometown of San Diego, doctors told them he would likely die.
Steffanie begged him for a sign that he wanted to live.
In his hallucinatory state, Tom envisioned himself as a snake. He could hear her, but could not find his hand.
"Finally, I was able to wrap, to coil myself around her hand and squeeze," he recalls.
Faced with the task of saving her own husband, Steffanie stumbled upon phage therapy, a treatment the Canadian-American first learned about during a virology class at the University of Toronto.
"We were really desperate," she says of any hope that injecting her husband with phages would cure him.
The U.S. Food and Drug Administration, after all, only approves phage therapy as a last resort — or as Steffanie puts it, when a patient is at death's door.
"One of the doctors described it as a Hail Mary pass where the quarterback is blindfolded," she says.
Over several days, Tom received two phage cocktails created by two different groups of researchers over several days. One went into his abdomen and another was injected through an IV. He's believed to be one of a handful of patients, if not the first person to undergo phage therapy through an IV for multi-drug resistant bacteria in the United States.
He woke up days later. He had to relearn basic tasks, like how to swallow and speak, but that day marked the beginning of a full recovery.
Tom, who is co-writing a book with his wife about the experience, hopes his story will help advance the field and help save millions of lives.
"One of the doctors described it as a Hail Mary pass where the quarterback is blindfolded."Steffanie Strathdee
"It's worth the pain and agony and time that I went through, if it moves everything forward," he says.
The University of California San Diego school of medicine, whose physicians and scientists first helped treat Tom and several other patients since, announced last week it would open the Center for Innovative Phage Applications and Therapeutics.
IPATH will be the first phage therapy centre in North America and Steffanie, who works at the medical school, will be one of the centre's two directors. IPATH will conduct rigorous clinical trials to help validate phage therapy as a treatment for multi-drug-resistant infections.
While phage therapy appears promising, it lacks rigorous scientific research— one of the major reasons experts don't expect phages to replace antibiotics anytime soon.
Health Canada has not granted market authorization for drugs classified as phage therapy, meaning physicians wanting to try it for patients with an antibiotic-resistant infection must submit a clinical trial application to Health Canada. The department has not received any to date.
Patients in search of the treatment instead find clinics abroad.
About 130 foreign patients have visited the phage therapy centre in Georgia since January, says Mzia Kutateladze, the institute's director. Most foreign patients are European, she says, but the centre has also treated some Canadians.
Even if the treatment was more accessible, phages are complicated to mass produce like standardized antibiotic pills. They each only respond to one or a few specific bacterial strains and must often be tailored to individual patients.
At the Eliava centre, physicians have access to several commercial phages that Kutateladze says work for most local patients and some foreigners. But when those fail to match, researchers must develop a custom phage. It's a difficult process that can take one to two months, she says, and costs an extra C$2,100.
Growing so-called phage libraries at hospitals and research institutions could help speed up the process, explains Steffanie.
"Think of it as a walk-in cooler, with all these different phages that have already been identified, characterized, purified and ready to go."
For now, stories like Pranav's and Tom's compose the bulk of evidence of successful phage treatment, and it's unclear how long it will take to conduct clinical trials and grow robust phage libraries to increase access to people whose lives are at risk.
In the meantime, one of the most important efforts is to increase the lifespan of the medicine still available and working.
With better diagnostic tools, doctors can identify patients' illnesses faster and determine the bacteria's resistance profile. They can then prescribe the correct medication rather than treat patients with medicine that won't work while test results are pending. That practice can further exacerbate resistance growth and result in unnecessary side effects.
"I think diagnostics are at the centre of many of the challenges and many of the solutions," says Heidi Albert, head of the Foundation for Innovative New Diagnostics (FIND) in South Africa, an NGO that works to help deliver new diagnostic tools.
FIND helped develop a drug-resistant TB test for a device called GeneXpert that allows doctors to test for tuberculosis and whether it's resistant to one of the four front-line TB drugs in a matter of hours, as opposed to weeks.
"In TB, that is one of the real success stories," she says. It also facilitates easier testing of children and people living with HIV, notoriously difficult demographics to diagnose, and offers an accurate indicator for whether a patient's strain is multi-drug resistant. GeneXpert requires much less sophisticated infrastructure than the alternative testing method.
But, it's not perfect, she admits. The test requires an uninterrupted power source and some temperature-controlled areas for testing and storage. Those requirements may be too much to ask in low-income countries, including India, where FIND's office in New Delhi experiences intermittent power outages.
FIND is working to make the testing device smaller and less dependent on infrastructure, something like a pregnancy test, but more research and development funding is needed.
Investing now in preventative measures could help the government stave off future losses, says Hancock, the microbiology professor at the University of British Columbia.
He recently co-founded the Canadian Anti-infective Innovation Network to leverage homegrown efforts to tackle antibiotic resistance. He is asking the government to invest $100 million to $200 million, but has yet to see any government funding for the network.
But the Public Health Agency of Canada insists Canada wants to be a leader on the issue.
Research and innovation is one of four pillars of the pan-Canadian framework for action on drug resistance released last year, notes Jacqueline Arthur, manager of strategic issues for antimicrobial resistance.
"No one country or one group of academics or researchers is going to figure it out all on their own."Deputy chief public health officer of Canada Dr. Howard Njoo
The country is a small- to medium-player in new drug discovery, she says, but also has expertise in other areas of the drug pipeline.
"So, we have to really work together to establish where is Canada best placed to be a leader, not only for Canada but internationally," she says.
Dr. Howard Njoo, deputy chief public health officer of Canada, also believes the country must be strategic about how it can use its strengths to add to global efforts.
"No one country or one group of academics or researchers is going to figure it out all on their own."
But Hancock says funding to his 80-member group spanning academia, government and industry would at least be a definitive step after years of talk without any government-led change.
"That's very slow action if this is the largest threat to human health."