Exactly five years have passed since the moment the world of medicine most feared became reality. In the spring of 2016, in Pennsylvania, a 49-year-old woman suffering from an infection was attacked by a bacterium bearing the gene scientists had feared: MCR-1. It was the first time a bacterium with this gene had been discovered in a human being. The bad news: The bacterium was resistant to the strongest antibiotic that existed, colistin. The worse news was that it could easily transmit that resistance to other bacteria.
Tom Frieden, director of the U.S. Centers for Disease Control at the time, immediately grasped the meaning of the development. “It basically shows us that the end of the road isn’t very far away for antibiotics,” he told the Washington Post.
“Antibiotic resistance is rising to dangerously high levels in all parts of the world,” the World Health Organization stated in a July 2020 position paper. The result: “A growing number of infections – such as pneumonia, tuberculosis, gonorrhea, and salmonellosis – are becoming harder to treat as the antibiotics used to treat them become less effective.” According to the WHO, by 2050, antibiotic-resistant bacteria will become the No. 1 cause of mortality. An earlier report issued by the United Nations predicted that drug-resistant diseases could cause 10 million deaths globally each year by 2050. That would be more than three times the number of deaths caused to date by COVID-19.
Indeed, this tendency is already visible, says Shlomo Maayan, director of the department of infectious diseases at Barzilai Medical Center, in Ashkelon. Resistant bacteria are proliferating, and one manifestation of this is the increase in the rate of sexually transmitted diseases. “Resistant bacteria are spreading even in the most protected places: coronavirus wards,” says Prof. Maayan. “It isn’t talked about much, but it’s happening all the time. We have to learn to accept that we are entering the post-antibiotics era.”
What will that era look like? In a world without antibiotics, any scratch that becomes infected could cause death. Basic medical treatments that are today taken for granted will no longer be effective – from those combatting infections of the urinary tract to those curing ear infections common among children. In such a world, physicians don’t know how lifesaving actions such as organ transplants or chemotherapy will be possible.
Yehuda Carmeli, director of National Center for Infection Control and Antibiotic Resistance in Israel’s Health Ministry, warns that such a scenario would mean going back 100 years in the field of medicine.
“It is impossible, after all, to achieve a working environment that is 100 percent sterile,” says Prof. Carmeli. “Chemotherapy will be impossible in a world without antibiotics because it generally lowers immune response and antibiotics are prescribed as a preventive measure against infections; other treatments for cancer will have to be found. As for simple abrasions, if a significant infection develops, nature will take its course – either the body will overcome it or it won’t.”
A world without antibiotics will be a world without transplants and chemotherapy, agrees Diana Tasher, director of the pediatric infectious disease unit at Wolfson Medical Center, Holon. “It will be impossible to perform those tasks, because in such patients it always ends with infection,” Dr. Tasher explains. “Antibiotics save their lives. Already today we are seeing strains that are resistant to every form of antibiotics – the apocalyptic scenario is already here.”
“Most people have no concept of how life was before antibiotics,” Prof. Michael Fischbach, who is researching the genetics of bacteria at Stanford University, tells Haaretz. “People – including healthy young people – would die routinely of simple infections. Just as we all know someone who has died of cancer, in a post-antibiotic world, we would all know someone who died suddenly from an infected scrape or cut.”
A somewhat less bleak view is taken by Mordechai Ravid from Tel Aviv University’s faculty of medicine. “A combination of various antibiotics is generally found that eradicates the bacterium – it’s simply becoming more difficult with time,” the professor explains. “Healthy people hardly ever die from infection alone. It happens, but it’s rare. It’s mostly people with other diseases.”
Besides the mortality issue, there are also matters of routine procedures. For example, the case of a woman of 32 who was hospitalized because of a urinary tract infection, who told Haaretz she is usually healthy and had never been hospitalized before. “The family doctor prescribed an antibiotic, but it had no effect and I felt no better. I did a test, and it turned out that the bacteria was resistant to that antibiotic. They prescribed a different antibiotic but it didn’t help either. Finally, after three weeks of pain and weakness, I was hospitalized so that I could receive a special antibiotic intravenously.”
Hearing about the case, Ravid nods. “In the past we saw bacteria like that only in hospitals,” he says, because the majority of patients there receive antibiotics as a preventive measure, which causes the spread of resistant bacteria. “But today people are arriving in the ER after being infected by resistant bacteria in their community.”
Declining efficacy
The antibiotic penicillin was discovered by the Scottish physician Alexander Fleming in 1928. He found that a natural substance secreted by the Penicillium mold destroyed the cell wall of a bacterium. Seventeen years later, penicillin became a commercial medicine. The antibiotic enabled modern medicine to make rapid progress but from the start the breakthrough had a dark side: The effectiveness of the antibiotic declines over time. Fleming himself noted in articles he published that bacteria would likely find a way to overcome penicillin as part of the natural process of evolution.
But there is a shortcut to that slow process, as seen in the 2016 case of the Pennsylvania woman. The MCR-1 gene in question is located on a plasmid, a small piece of DNA that can move from one bacterium to another, which can lead to a situation where various bacteria can become resistant to certain antibiotics. In fact, a year before the Pennsylvania case, public health experts realized how real the hazard was when the dangerous MCR-1 gene was discovered in a pig in China. Yes, even then it was an animal in China that signaled trouble for all of humanity.
Like problems related to global warming, bacteria’s race to resistance exacts a high price from animals. That’s because about 73 percent of all antibiotics sold worldwide are earmarked for animals, which has also made the drugs a tool to augment profits. Preventing disease from breaking out in unsanitary environments is only one of the reasons for administering antibiotics to farm animals: In the 1950s farmers discovered that a regular, low dosage of such substances also produced faster growth in animals. A decade and a half ago the European Union prohibited the practice of administering antibiotics regularly to livestock. Israel waited until 2018 to follow suit and ban the regular use of antibiotics for farm animals, but this regulation is not being enforced. Local veterinarians are still allowed to prescribe the drugs to combat disease, but the truth is they are often administered to speed up the animals’ growth.
Such bans will thus not solve the problem. As Dr. Tali Berman noted in a Health Ministry report, “Evidence is increasing in recent years that the extensive use of antibiotics in farm animals is responsible for the development of resistance in bacteria that affect humans.
“It’s an unsupervised realm and it’s frightening,” says veterinarian and researcher Gal Zagron, a senior official in the Ministry’s Environmental Protection Division, referring to the use of antibiotics on farm animals despite the ban.
“In Israel the threat is ignored – I’m already in the despair stage,” Dr. Zagron admits. “My worst fears about resistant bacteria that originate in animals have already come true. We are approaching the point of no return. More and more people will fall ill, and we won’t be able to treat them.”
According to her, the state of eggs sold in Israel is among the worst in the world. “In some of the coops the conditions are appallingly bad. The fowl live among their excrement, and they excrete on one another, which affects their health and also the quality of the eggs. And when the quality is low, the bacteria multiply, including those that are antibiotic-resistant.”
Together with reducing the use of antibiotics in farming, there is scope for action in human medicine as well. Israel is considered to be generous in administering antibiotics to people: that is, their per capita use in Israel is about 30 percent higher than in Holland, Germany and Scandinavia. According to the Health Ministry’s Yehuda Carmeli, Israel has set a national goal of reducing antibiotic use among people by 25 percent within five years. Surprisingly, he adds that to accomplish this, it will be necessary, among other steps, “to revise the myth that you must take an antibiotic for 10 days and use the entire dosage you received.”
But we were always told that antibiotics have to be taken until the end in order to prevent the development of resistant bacteria.
Carmeli: “That’s not true, in general. In most cases either you have a resistant bacteria or you don’t, and then even if you stop the treatment slightly before the end, either you have recovered or you haven’t. It depends on the type of infection, not the duration of treatment.”
The big problem, notes Tasher, the pediatric specialist, is that most antibiotics are not prescribed by physicians who are experts in infectious diseases, but by family doctors and pediatricians. “Until 2004, all children with middle-ear infections received antibiotics,” she notes. “Happily, that approach has changed, and today the accepted approach is to wait two or three days before receiving treatment, because the disease usually passes even without it. With throat infections, too, in the past, there was a great deal of antibiotic treatment, but today the usual thing is to wait for the results of a throat swab. We must educate both the public and the physicians to wait for the lab results.”
“Antibiotics should be viewed as a perishable resource,” suggests Prof. Carmeli. “It’s like with environmental problems. There’s a resource we all share in common that is very important to preserve for future generations. But as with global warming, the narrow, short-term interest of the individual is not consistent with the greater interest of society. The lone individual is less bothered by the phenomenon of resistance to antibiotics, so action is needed at the level of the state and of the whole world.”
Nadav Davidovitch, head of the School of Public Health at Ben-Gurion University, Be’er Sheva, remains skeptical about the effectiveness of reducing the use of antibiotics among humans in the community. “That won’t solve the problem,” Prof. Davidovitch says. “The solution has to include the meat industry – by raising animals in better conditions so they won’t become sick and require antibiotics, and by people eating less meat, milk and eggs – and until that is resolved we will remain in the same situation. In the case of antibiotics, there is no choice but to talk about cutting down on meat consumption.”
What about the development of new antibiotics? The WHO points out that there are some new ones being created, but “none of them is expected to be effective against the most dangerous forms of antibiotic-resistant bacteria.”
This inadequacy comes on top of a market failure that is slowing the pace of the development of new antibiotics. A case in point is Achaogen, a promising U.S.-based pharma company that went bankrupt two years ago. The firm’s scientists developed an antibiotic medication called plazomicin, which is capable of eradicating a violent, drug-resistant bacterium that has a fondness for the human urinary tract. The U.S. Food and Drug Administration approved the use of plazomicin, marketed under the name Zemdri, in 2018, and the future looked bright.
But very quickly the company discovered the antibiotic paradox: The surest way to preserve the effectiveness of an antibiotic is precisely to minimize its use. Every physician knows that the best new antibiotics are kept in reserve for the difficult cases. The company estimated that it would earn about $3 million in its first three months; in practice, earnings were a 10th of that.
“Why is there so much biotech/pharma research in cancer, cardiology and diabetes, and not in antibiotics?” asks Prof. Fischbach, and immediately answers: “Those are fields in which patients take medications for years, whereas antibiotics are taken for only a few days. Consequently, cancer medications are considered 10 times more profitable than antibiotics. There is a mismatch between our problem and the expected profit of those who try to solve it.”
Some countries are trying to offset this market failure by offering incentives to industry, as academic efforts continue. Indeed, this is exactly what Prof. Ada Yonath has been doing in her laboratory in the Weizmann Institute of Science, Rehovot. Yonath, a Nobel laureate in chemistry, has worked on the development of a precisely targeted antibiotic that would eradicate only pernicious bacteria.
“I am worried about the decline in the effectiveness of antibiotics due to resistance, so I am making an effort to design new antibiotics,” Yonath tells Haaretz. “About half the antibiotics in clinical use work by shutting down the activity of the ribosome [which performs protein synthesis in living cells]. That could be harmful to the good bacteria, mainly the microbiome [a human’s overall collection of microorganisms]. In contrast, we are concentrating on the structural elements that are found on the external envelope of the ribosome, in order to eradicate the violent bacterium without harming the good bacteria.”
A research study with a similar goal is underway in the laboratory of microbiologist Neta Sal-Man, at Ben-Gurion University. “The ideas we are proposing will replace classic antibiotics,” Dr. Sal-Man says. “Although they are more expensive substances, because they work on very specific mechanisms, in the future it will be either that or nothing, because the classic antibiotics are becoming less effective and come at a cost to the microbiome.”
According to Sal-Man, “bacteriological research has diminished a great deal in the past few years, but the infectious diseases are here to stay, and we need to be prepared for the next epidemic. It’s essential to give these studies attention and funding. Twenty years ago, those who studied the coronavirus (i.e., the SARS family) encountered responses along the lines of ‘What does it matter? Who cares?’ Now everyone is thankful for what they did, and for the fact that we came into this epidemic with at least the little knowledge we had.”
Anti-infection focus
The race to find a solution to the spread of resistant bacteria is progressing in several spheres. Ada Yonath and her colleagues represent one approach to improving the antibiotics mechanism. Another is the development of vaccines for common bacteria. Roi Avraham from the Weizmann Institute is moving ahead in an additional channel that is gathering momentum: instead of antibiotics, anti-infection.
“Our philosophy is to look at what happens in a condition of inflammation, to see which mechanisms the bacterium activates and try to block them, instead of blocking the whole bacterium,” says Dr. Avraham, who heads a laboratory that is working on this approach. It has a substantive advantage: If the [invading] bacteria survive without causing a disease, they do not need to develop resistant protective mechanisms in order to survive. “Anti-infection [i.e., a phenomenon in which bacteria are deactivated but not destroyed] is made possible thanks to techniques that did not exist in the past,” Avraham adds. “The potential here is tremendous.”
Another alternative to antibiotics might come from a surprising source: viruses. Phages – or, in their full name, bacteriophages – are viruses that attack bacteria. In fact, phages are a discovery from the past that was neglected when antibiotics were developed, but is now making a comeback.
Rotem Sorek, from Weizmann’s molecular genetics department, is studying the biology of phages, and has founded two companies that are developing phage-based preparations for treating human beings and for use in agriculture. “They are precision guided missiles,” the professor says. “They are aimed solely at the harmful bacteria and thereby avoid collateral damage.”
Yet the precision of phages is precisely what held back their development in the past. It’s easier to propose antibiotics that kill all the bacteria they encounter than to examine millions of phages and find the exact one needed to attack a specific bacterium. The Weizmann Institute is using advanced technology to overcome this difficulty. “Today we can find hundreds of thousands of phages that infect a particular bacterium, quickly characterize them at the molecular level, and select from them those that possess the highest effectiveness.”
If and when such medications are approved, how will they be administered to patients?
Sorek: “Like antibiotics. There will be an ointment for bacterial skin diseases and pills for bacterial intestinal diseases.”
Do you think phage-based medications will be able to replace antibiotics?
“I think that despite the spread of resistant bacteria, antibiotics will still have a place in medicine in 2050. We will need them for infections that are caused by many types of bacteria simultaneously, because phages overcome specific bacteria.”
One of the amazing things about phages is the astronomical number of different types of them that exist: 10 to the 31st power. It would seem as though they have an almost unlimited potential. Still, experience shows that discoveries like this come with a price, though for the moment it’s unknown.
For his part, Prof. Carmeli’s view on the subject is that “attempts have been made to develop the phage idea for 100 years now, and everyone is always certain that it’s going to be amazing, but in the meantime it’s not. Nothing comparable to antibiotics exists now, nor will there be anything in another decade. It might perhaps be possible, but only if immense budgets are earmarked for it. And even when there is something else, it will quickly become inefficient, because that’s the nature of things. Bacteria divide every 20 minutes, and they accumulate mutations. When there is one thing that’s effective a fighting them, the strains resistant to it will survive.”
Yonath refuses to be pessimistic. “The WHO marked 2050 as the year in which antibiotics will no longer be relevant, based on the premise that drug-resistant bacteria will continue to develop without any means to deal with them. I hope that with appropriate budgeting, scientists will find alternative antibiotics, and that at the same time alternative approaches, like those of Roi Avraham and Rotem Sorek, will come into use.”
Sorek, too, is hopeful. “Science and medicine have proved time and again that they can come up with new solutions, sometimes in record speed. That was the case with the coronavirus vaccines. I believe that the growing focus on attempts to solve the problem of bacterial resistance to antibiotics will lead to developments that we aren’t even capable of imagining.”
And Avraham sums up: “We are a moment from entering a new age. If we do things the right way, we’ll arrive there prepared.”
