Deadliest Enemy: Our War Against Killer Germs

by Mark Olshaker

At the end of the experiment, none of the volunteers in the mosquito-free section of the clean house or the sorry souls who had occupied Fomite House had come down with any serious illness. But many of the volunteers in...

Since its publication, Silent Spring has been an endless source of discussion and controversy, and it is not our aim to argue its accuracy or even its legacy, one way or the other. It should be noted, however, that the extensive agricultural use of DDT, rather than the extremely limited public health use, is what drove the environmental effects and the resulting movement against it. But by 1970, several years into the Silent Spring/DDT-banning era, the public health community declared victory over Ae. aegypti and moved on to other priorities.

By the time the connection showing that Zika caused GBS and microcephaly was confirmed less than a year after its arrival in the Americas, the virus had taken on the persona of a twenty-first-century thalidomide tragedy; thalidomide was the German sedative and morning sickness antidote of the late 1950s and early 1960s that led to babies born with missing, short, or flipper-like limbs, vision and hearing problems, and deformed hearts and other organs. For decades, the mere mention of thalidomide struck fear into the hearts of pregnant women. Now the same was happening with Zika. The difference was that with thalidomide, you had to actively take a pill to risk these birth defects. With Zika, you just had to passively be bitten by an Aedes mosquito. And mosquitoes were all around.

The origin story of antibiotics is well-known, almost mythic: Returning to his lab at St. Mary’s Hospital in London in 1928 after a holiday, Dr. Alexander Fleming noticed that a fungus had corrupted one of his staphylococci culture petri dishes and that the staph colonies surrounding the fungus had been destroyed. This was every bit the equal of the observation that English milkmaids didn’t get smallpox.

Fleming grew this fungal mold in a pure culture and found that the result killed a range of disease-causing bacteria. The mold was from the Penicillium genus, so he called it penicillin. It was left to Drs. Howard Florey and Ernst Chain to figure out penicillin’s structure and transform it into a lifesaving medical agent. The three pioneers shared the Nobel Prize in Physiology or Medicine in 1945.

At around the same time that Florey and Chain were working in England, a team at a division of IG Farben in Germany (later to become Bayer) led by Dr. Gerhard Domagk was exploring the properties of red chemical dyes called sulfonamides: substances derived from coal tar that did not kill bacteria but inhibited their growth. They became the basis for a group of medicines known as sulfa drugs, the first of which was marketed as prontosil. In 1933, one of Domagk’s colleagues treated a ten-month-old baby boy with an almo...

Today, heart disease and cancer are, by far, the leading causes of death in the United States. In 1900, they were relatively insignificant. This is not because our forebears pursued a healthier lifestyle, didn’t smoke, or followed a more prudent diet. It’s because back then infectious diseases didn’t give our two modern killers a chance to move in; they got to people earlier and more often than heart disease and cancer ever could. Antibiotics, along with the other basic public health measures we have described, have had a dramatic impact on the quality and longevity of our modern life. When ordinary people called penicillin and sulfa drugs miraculous, they were not exaggerating. The discoveries of Domagk, Fleming, Florey, and Chain ushered in the age of antibiotics, and medical science assumed a lifesaving capability previously unknown.

Note that we use the word “discoveries” rather than “inventions.” Antibiotics were around many millions of years before we were. Since the beginning of time, microbes have been competing with other microbes for nutrients and a place to call home. Under this evolutionary stress, beneficial mutations occurred in the “lucky” and successful ones that resulted in the production of chemicals—antibiotics—to inhibit other species of microbes from thriving and reproducing, while not compromising their own survival. Antibiotics are, in fact, a natural resource—or perhaps more accurately, a natural phenomenon—that can be cherished or squandered like any other gift of nature, such as clean and adequate supplies of water and air.

In his book Missing Microbes, Dr. Martin Blaser explains how our use of antibiotics over the past eighty years is greatly altering the three-billion-year-old microbiome that resides in our bodies. He lays out with clarity and vision why what I call “supermicrobial evolution in our modern world” poses a real and new danger for our future encounters with infectious diseases. What we are dealing with, to put it plainly, is a slow-motion worldwide pandemic. With each passing year, we lose a percentage of our antibiotic firepower. In a very real sense, we confront the possibility of revisiting the dark age where many infections we now consider routine could cause severe illness, when pneumonia or a stomach bug could be a death sentence, when a leading cause of mortality in the United States was tuberculosis.

After studying the issues for more than two years, O’Neill and his highly talented team of researchers determined that, left unchecked, in the next thirty-five years antimicrobial resistance could kill 300 million people worldwide and stunt global economic output by $100 trillion. There are no other diseases we currently know of except pandemic influenza that could make that claim. In fact, if the current trend is not altered, antimicrobial resistance could become the world’s single greatest killer, surpassing heart disease or cancer.

the economic incentives for pharmaceutical companies to develop new antibiotics are not much brighter than those for developing new vaccines. Like vaccines, they are used only occasionally, not every day; they have to compete with older, extremely cheap generic versions manufactured overseas; and to remain effective, their use has to be restricted rather than promoted.

Without effective and nontoxic antibiotics to control infection, any surgery becomes inherently dangerous, so all but the most critical, lifesaving procedures would be complex risk-benefit decisions. You’d have a hard time doing open-heart surgery, organ transplants, or joint replacements, and there would be no more in vitro fertilization. Caesarian delivery would be far more risky. Cancer chemotherapy would take a giant step backward, as would neonatal and regular intensive care. For that matter, no one would go into a hospital unless they absolutely had to because of all the germs on floors and other surfaces and floating around in the air. Rheumatic fever would have lifelong consequences. TB sanitaria could be back in business. You could just about do a postapocalyptic sci-fi movie on the subject.

First described by Garrett Hardin in Science magazine in 1968, the “Tragedy of the Commons” applies to scenarios where an individual acts to significantly benefit [himself], and as a consequence accepts as a tradeoff a small amount of overall harm to society at large. If only one person is so acting, the total harm to society is small. But when everyone in society undertakes the same action, the collective harm to everyone becomes enormous.

Several surveys show that while the majority of people understand that antibiotics are overprescribed and therefore subject to mounting resistance, they think the resistance applies to them, rather than the microbes. They believe that if they take too many antibiotics—whatever that unknown number might be—they will become resistant to the agents, so if they are promoting a risk factor, it is only for themselves rather than for the entire community.

Why do doctors overprescribe? Is it about covering their backsides in this litigious society? Is it a lack of awareness of the problem? According to Spellberg, “The majority of the problem really revolves around fear. It’s not any more complicated than that. It’s brain-stem-level, sub-telencephalic, not-conscious-thought fear of being wrong. Because we don’t know what our patients have when they’re first in front of us. We really cannot distinguish viral from bacterial infections. We just can’t.

“You can say on a population basis that 95 percent of patients who present with these signs and symptoms have a virus. But when I have an individual in front of me and I’m going to see 10,000 of these individuals in my career, I’m going to be wrong sometimes. And if I’m wrong, the consequences could be really bad. That’s what drives most of it. And patients suffer from the same fear. They come, they don’t feel well, they want something. They don’t want to get into a philosophical debate. They want something that’s going to make them feel better. That’s why they ask for the prescription.”

Spellberg asked what the patient’s symptoms were and was told there weren’t any. “So the question is: How do we treat asymptomatic bacteriuria [bacteria in the urine]? And the answer is: We don’t. This is cognitive dissonance staring us in the face. If this resident had this question on a board exam, he’d get it correct. But that’s a piece of paper and this is a patient staring him in the face, and he’s afraid. And we have not tackled the fear. We’ve got to figure out psychological ways of getting around the fear.”

The BRIC countries are all at about the same level of development. Their combined population is around 3,938,300,000, or about 54 percent of the world’s total. Then there is the rest of the planet; approximately 2,494,400,000 people, making up the remaining 34 percent. As much difficulty as we’re having controlling antibiotic resistance in “our” 12 percent of the population, for the remaining 88 percent, we believe the situation to be a whole lot worse.

In many of these countries, antibiotics are sold right over the counter just like aspirin and nasal spray; you don’t even need a doctor’s prescription. While over-the-counter sales of antibiotics without prescriptions are illegal in numerous places around the world, lax enforcement results in extensive sales in many low- and middle-income countries.

While we in the public health community would certainly like to see a complete cessation of antibiotic use without a doctor’s prescription, how do we tell sick people in developing countries that they first have to see a doctor, when there may be no more than one or two physicians for thousands of individuals, and even if they could find one, they couldn’t afford the visit in the first place? Taking an action...

But all of the world’s use of antibiotics for humans is a relatively small percentage of total use. The United States, Canada, and Europe use about 30 percent of our antibiotics on humans. The rest we use on animals—specifically, animals we kill for food or companion animals.

There are four applications for antibiotic use in raising food animals, all of which, to one extent or another, result from the way we go about protein-food production in the modern world. We produce our food animals in very large numbers and raise them densely packed together, whether we’re talking about chicken and turkey operations, cattle and swine feedlots, or industrial fish farms. While these animals are less likely to catch infectious diseases when large production operations use high levels of biosecurity—the practice of limiting the ways that disease-causing germs can contact the animals—when these germs do get introduced, their spread is rapid and extensive. So we use antibiotics to treat the resulting infections. But we also use them to prevent infections in the first place, or to control them by dosing healthy animals so they don’t catch anything from the sick ones. And then we use them to enhance growth.

In the late 1940s, fishermen near Lederle Laboratories in New York State noted that trout seemed to be larger than before. When Dr. Thomas Jukes, a prominent biochemist, investigated the apparent phenomenon with his colleague Dr. Robert Stokstad, they found that the antibiotic Aureomycin in the runoff from Lederle’s plant was the cause. After experimentation with livestock and poultry produced similar results, the serendipitous discovery was hailed as an agricultural breakthrough.

“The combination of colistin and ciprofloxacin is just stupidity on a scale that defies all imagination,” commented Dr. Timothy Walsh, professor of medical microbiology at Cardiff University in Wales.

What are the implications of all of this? The end result could very well be untreatable bacterial infections going directly into the world food supply. This would be the ultimate Frankenstein scenario.

Other preventative measures are as simple as frequent handwashing. More than 160 years since Dr. Ignaz Semmelweis demonstrated to his Austrian medical colleagues that washing their hands before touching patients prevented hospital deaths, many medical personnel have yet to learn the lesson. According to most statistics, doctors are worse offenders than nurses.

Up-front costs and the time it takes to get through clinical trials and approval are key discouraging factors, as is opportunity cost. It is much more profitable for a big pharmaceutical concern to devote its financial and development resources to a drug that people are going to take every day than to one that is used only rarely and that will be rationed in order to preserve its effectiveness.

Another approach is treating some infections passively. For those bacteria that do their damage by releasing a toxin, such as staphylococcus or diphtheria, if you can neutralize the toxin, that’s as good as killing the pathogen. One form of this method actually hearkens back to preantibiotic days: Serum therapy, invented by German doctor Emil von Behring in the 1890s as a treatment for diphtheria, involves injecting blood serum from someone who has already had the same infection into the patient.

Another passive strategy is to deprive the offending bacteria of nutrients it needs to divide and grow, such as iron. The bacterium cannot manufacture iron, so it must steal it from the host. If we can find ways to “hide” our iron from them, we might not have to attack the biochemical pathways in the bacteria, which is what allows the bugs to build up resistance. This is one area in which we might expect significant scientific breakthroughs in the coming decades.

Pigs are especially important to infecting humans with avian influenza viruses. The cells lining their lungs have receptors that match up with both bird and human viruses, so those lungs turn out to be perfect places for influenza strains to “meet each other” and mix. It is even possible to have a triple reassortment, where strains of all three species—humans, birds, and pigs—mix to form a completely unpredictable new influenza virus. When that happens, it’s a spin of the genetic roulette wheel whether the new strain is more or less serious than the strains from which it emerged. In 1918, that spin resulted in the virulence jackpot.

It is the range of possible results from the changeability and mixing of influenza strains that makes it the king of infectious microbial beasts. While it can be almost as mild as a common cold, it can also be just as fearsome and deadly as smallpox, and even easier to catch. That is why this particular beast terrifies epidemiologists.

When we attempt to assess the risk of another 1918-type influenza pandemic, keep in mind the points we made earlier: that we live in a globally interdependent world, with widespread rapid travel and many concentrations of people, pigs, and birds living in close proximity. Thus, that world has become a hypermixing vessel—one with about three times the human population of 1918.

A pessimist sees the difficulty in every opportunity; an optimist sees the opportunity in every difficulty. —SIR WINSTON CHURCHILL

flu vaccine is one of the poorest-performing vaccines in our medical armamentarium. Is it better than nothing? Generally so, but in some years by no more than 10 to 40 percent.

the actual protection offered has been significantly lower than the medical community and the public believed. This has been particularly true for individuals over sixty-five years of age—the cohort of the population most vulnerable to seasonal influenza. We have too few good studies to determine the effectiveness in older people, but we found, on average, the vaccine works about 59 percent of the time in protecting younger adults. In some years it’s much less effective than that. For example, for the H3N2 strain, the 2014–15 vaccine actually provided 0 percent protection.

Tony Fauci is adamant about what we have to do in this regard. “We need to realize right now that we do not have an adequate vaccine for influenza,” he told us. “And we need to figure it out in the same way that we’re putting an incredible amount of money into trying to figure out if we can get a vaccine against HIV. I think we were lulled into some kind of complacency, because we had an influenza vaccine that we essentially used every year, that we modified a little bit to account for drift and shift. And we never said, ‘Wait a minute; we’ve got to do better than this!’”

Priority 1: Create a Manhattan Project–like program to secure a game-changing influenza vaccine and vaccinate the world.

The single most consequential action that we can take to limit, and possibly even prevent, a catastrophic global influenza pandemic is to develop a game-changing influenza vaccine and vaccinate the world’s population.

Our best guess is that we would need to invest $1 billion per year for seven to ten years to make this happen.

Priority 2: Establish an international organization to urgently address all aspects of antimicrobial resistance.

Priority 3: Support and substantially expand the mission and scope of the Coalition for Epidemic Preparedness and Innovations (CEPI) to fast-track comprehensive public-private vaccine research, development, manufacturing, and distribution for diseases of current or potential critical regional importance.

Priority 4: Launch the Global Alliance for Control of Aedes-Transmitted Diseases (GAAD) and coordinate with the Bill & Melinda Gates Foundation’s malaria strategy, “Accelerate to Zero.”

Priority 5: Fully implement the recommendations of the bipartisan report of the Blue Ribbon Study Panel on Biodefense.

Priority 6: Establish an international organization similar to the National Scientific Advisory Board for Biosecurity (NSABB) to minimize the use of DURC and GOFRC to transmit pathogens of pandemic potential.

Further, an international NSABB-like organization needs to be set up to manage a mutually agreed-upon approach for where and how DURC and GOFRC work should be done globally. This international organization should draw upon the guidance of experts in this area, not simply from the United States, but from around the world. We are under no illusions that such an approach would stop all intentional or unintentional misuse of newly emerging technologies. But to not try to stop it is irresponsible.

Priority 7: Recognize that TB, HIV/AIDS, malaria, and other life-threatening infectious diseases remain major global health problems.

Priority 8: Anticipate climate-change effects.

Priority 9: Adopt a One Health approach to human and animal diseases throughout the world.

One of the premises of our Crisis Agenda is that the United States will have to bear both the primary leadership responsibilities and the bulk of the financial burden. The G20 should provide substantial support, but given the relative lack of international support for global public health programs, this is unlikely to happen. Most of the G20 countries have provided only limited financial support for the WHO, have been largely absent in responding to critical regional outbreaks, and have undertaken minimal efforts in new vaccine and antimicrobial drug research and development.

The Bill & Melinda Gates Foundation and the US government together account for 23 percent of the WHO’s budget, so that gives some idea of how influential the Gates Foundation is on the international public health stage.