EPILOGUE
Many of the institutions at the forefront of research on infectious disease are as prominent today as they were during the years of the antibiotic revolution, and even before. While the Lister Institute of Preventive Medicine is now a charity employing fewer than half a dozen full-time staff members, it continues to fund research and disburse prize fellowships, some of them very substantial. The Robert Koch Institute is an agency of the Federal Republic of Germany, still performing significant research, though with more emphasis on epidemiology than pharmacology or biochemistry. The Institut Pasteur remains one of the world’s preeminent research institutions, with more than a hundred labs and a thousand scientists working throughout the world on basic biochemistry, virology, and a huge number of other subjects.
Oxford’s Sir William Dunn School of Pathology continues to occupy the cutting edge of research into human health and disease, publishing papers on everything from T-cell activation to intercellular signaling to—yes—bacterial pathogenesis. And St. Mary’s Hospital still runs a Centre for Infection Prevention and Management (and is custodian for Alexander Fleming’s laboratory, now a museum).
Peoria’s Northern Lab—renamed the National Center for Agricultural Utilization Research in 1990, but still known to almost everyone as the Northern Lab—remains committed to producing more and better agricultural produce, while also maintaining the Agricultural Research Service’s Microbial Culture Collection, nearly a hundred thousand strains of actinomycetes, yeasts, and molds that are made available to research institutions throughout the world. In 1965, the Rockefeller Institute for Medical Research became Rockefeller University, but didn’t miss a step in any other sense; twelve Nobel Prizes in Physiology or Medicine were awarded to its researchers over the next fifty years.
The laboratories built by Abbott, Squibb, Merck, Eli Lilly, and others in the 1930s continue as factories of innovation, though the drug industry has experienced a vertigo-inducing series of corporate makeovers since the beginning of the antibiotic revolution. Some of the original companies recruited by A. N. Richards and the OSRD in 1943 are still recognizable, though each is enormously larger. Merck, which merged in 1953 with the Philadelphia-based Sharp & Dohme and subsequently acquired half a dozen other competitors, including Schering-Plough, now produces revenue in excess of $40 billion annually. Pfizer is even bigger, a company with sales of more than $50 billion. Eli Lilly is a $23-billion company. The combination of Bristol-Myers and Squibb, which merged in 1989, weighs in at nearly $20 billion as does Abbott Laboratories.
Others are no longer going concerns, run onto the rocks by waves of the “creative destruction” that the Austrian economist Joseph Schumpeter called the defining characteristic of capitalism. In 1988, Eastman Kodak acquired Winthrop (or Sterling Winthrop), a member of the original penicillin project and the discoverer of the first quinolone antibiotics. It was then broken apart and sold, in pieces: to the French pharmaceutical company Sanofi, to the British firm SmithKline Beecham (a successor to the original Beecham’s Pills, now known as GlaxoSmithKline), and to the revived German giant, Bayer, which, as a result, finally reacquired the rights to the name “Bayer Aspirin.” Earlier, in 1974, Bayer had acquired Cutter Laboratories. Parke-Davis, America’s biggest pharmaceutical company through the 1950s, never achieved that status again; in 1976, it was acquired by Warner-Lambert. When Pfizer acquired Warner-Lambert in 1976, though, the most valuable asset in the transaction was a discovery made in Parke-Davis’s labs: the cholesterol-reducer atorvastatin, which, as Lipitor, became the most profitable drug of all time. Hoechst AG, where Emil Behring and Paul Ehrlich made history, was reconstituted after the Second World War. In 1999, it merged with Rhône-Poulenc (the onetime employer of German pharmacology’s nemesis, Ernest Fourneau). In 2004, the combined company—briefly Aventis—was acquired by Sanofi.
It is difficult to calculate, with all those acquisitions and divestitures, just how large the enterprises borne out of the original penicillin project became. A reasonable guess is that they deliver to their shareholders somewhere north of $40 billion in operating income annually. What they don’t deliver much of is antibiotics. Though Pfizer still makes four antibacterial compounds, in 2011 the company closed its dedicated-to-antibiotics Connecticut research lab. Roche, Bristol-Myers Squibb, and Eli Lilly—all charter members of the penicillin project—no longer make any antibiotics at all. Neither does Johnson & Johnson, the largest pharmaceutical company in the world.
The primary reason is that it’s extraordinarily difficult to find new antibiotics. After sixty years, almost every antibiotic that remains on pharmacy shelves still uses one of a very limited number of methods for attacking pathogens—disrupting bacterial DNA, weakening bacterial cell walls, inhibiting the enzymes used by bacteria to synthesize proteins—that were used by the original beta-lactams, macrolides, and tetracyclines. The successors to penicillin and erythromycin are more effective and less toxic than the versions that started the antibiotic revolution in the 1940s, but they’re refined versions of a seventy-year-old biochemical technology. Molecules aimed at new targets, such as drugs that disrupt bacterial DNA synthesis (by, for example, inhibiting the enzyme that allows DNA to unwind without breaking), are regularly tested. A few have made it all the way into clinical trials.
In addition, almost all of the newly discovered molecules that show some antibacterial potential have the tyrothricin problem: They’re just as toxic to humans as they are to pathogens, which places something of a ceiling on their appeal. It’s because antibiotic-resistant infections have become so dangerous, and so ubiquitous, that drugs like colistin, first isolated in 1949 but so toxic to kidneys and the nervous system that it never came into wide use, is now a last-resort drug for resistant Gram-negative infections. When a patient is at risk of death from an infection that is resistant to safer antibiotics, the risk of kidney failure appears less daunting.
The genomic revolution, by identifying which genes were the blueprints for essential proteins, could, in theory, have empowered medicinal chemists with the ability to target only the genes necessary for bacterial survival and leave the ones for mammals untouched. It’s easy to see why this seemed so promising; knowing every aspect of a particular bacterium’s genetic makeup—what it eats, how it reproduces—would surely produce true “magic bullets.”
The promise of genomic antibacterials remains unfulfilled. The first bacterial genome was sequenced in 1995—Haemophilus influenzae, the likely killer of George Washington in 1799—and thousands of genes were identified shortly thereafter as potential antibacterial targets, because they produced proteins essential to bacterial survival. Dozens of pharmaceutical companies evaluated them, exposing the genes to literally hundreds of thousands of molecular compounds (GlaxoSmithKline, between 1995 and 2001, assayed nearly half a million alone). Seven years, and more than $100 million later, fewer than half a dozen even qualified as “hits”: potential “lead molecules.” Given historical rates of attrition, the number that might even make it to the next step—as a “development candidate”—is statistically indistinguishable from zero.
Even if weren’t so difficult to find new antibiotics, their very nature makes them a suboptimal long-term investment given the need to allocate limited resources among a wide range of alternatives. Antibiotics were, in a sense, victims of their own dramatic effectiveness. A drug that does its job in ten days can’t possibly compete for institutional resources with one that will be taken every day for a lifetime. The managers and shareholders of companies like Merck, Pfizer, and Eli Lilly didn’t require very sophisticated arithmetic to see a greater potential return from drugs that treated chronic ailments rather than acute infections. And they invested their research and validation assets accordingly. From 1962, when George Lesher of Sterling Winthrop* discovered the first of the quinolone antibiotics, until 2000 not a single new class of antibacterial drugs appeared. Between 2011 and 2013, the FDA approved only three new molecular compounds that might combat bacterial pathogens. The cost of developing a new antibiotic is higher, in relative terms, than the price for a new drug to treat depression, or cancer, or hypertension.
What are those costs? The most widely cited method for calculating the cost of drug development estimated, in 2003, that the average out-of-pocket cost for a drug at the moment it received marketing approval from the FDA was more than $400 million. Another calculation, made in 2011, and no less controversial, came up with a median R & D cost of $43.4 million.
There are two primary reasons for the huge difference between the estimates, each of which is regularly used as a bludgeon in the never-ending debate over drug prices. The lower number fails to account for any costs incurred prior to the submission of the drug for the first stage of FDA approval; this “phase 0” stage, in which thousands of potential molecules are screened for evidence of antibacterial activity, and hundreds extracted in quantities sufficient for testing, can take more than five years, and is responsible for fully 30 percent of the $400 million figure. The lowball calculation only estimates the R & D costs directly attributable to the new and approved drug. Since most of the R & D budget of a large pharmaceutical firm is spent on drugs that never make it to market, failing to account for those dollars somewhere is a fairly significant bit of financial sleight of hand. A number that estimates total R & D costs without any basic research costs because—as the author of the original paper wrote—“there is no reasonable estimate available,” doesn’t encourage much faith in the number’s precision.
This doesn’t mean that the figures provided by drug companies themselves are disinterested and therefore reliably accurate. The big pharmaceutical corporations are regularly accused of profiteering; of overcharging for lifesaving medications; of financing favorable research and suppressing negative results; of producing drugs to treat conditions that are virtually nonexistent or new and expensive versions of drugs that are no better than the ones already on offer. Companies with those sort of image problems have every reason to magnify the size of their research budgets, if only to slow their descent in public esteem.
However, the commitment of pharmaceutical companies to research isn’t just a PR strategy. Pfizer’s audited spending on research and development exceeds $11 billion a year. If it really cost less than $50 million to bring a new drug to market—if the much-cited $43.4 million figure were accurate—this would suggest that Pfizer alone should be launching 250 new drugs annually.
In 2012, the best year for new drug approvals since 1996, the FDA approved a total of thirty-seven “new molecular entities” for the entire pharmaceutical industry.
None of them were antibiotics.
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If you leave the Smithsonian Museum of American History, the custodian of Anne Miller’s world-historic medical chart, and walk two blocks east along Constitution Avenue until you reach Fifteenth Street, then turn right and proceed for half a mile until you reach Pennsylvania Avenue, you’ll find yourself facing the White House. There, on July 9, 2012, seventy years after penicillin pulled Mrs. Miller back from the brink of death, President Barack Obama signed into law Senate Bill 1387: the Food and Drug Administration Safety and Innovation Act. The new law, yet another amendment to the original 1938 Food, Drug, and Cosmetic Act, included dozens of provisions regarding everything from a new protocol for the approval of medical devices, to the authorization of fees for users of generic and prescription pharmaceuticals, to protection of the global supply chain for finished drugs.
Less well publicized, but almost certainly as important, it incorporated into the legislation a series of provisions known collectively by the acronym GAIN: Generating Antibiotic Incentives Now. Intended to increase the likelihood that pharmaceutical companies would invest in the development of antibiotics that treat serious or life-threatening conditions, GAIN offered fast-track approval for compounds that promised to combat infections, and a five-year extension of their exclusive term of patent.
The reason for GAIN and other similar proposals was simple and terrifying. In the United States alone, antibiotic-resistant bacteria now infect two million people annually. More than twenty thousand of them die. Alexander Fleming’s observation in his 1945 Nobel Lecture—“It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them”—had been an understatement of massive proportions. Infectious disease specialists today look back at the early days of antibiotic resistance with a kind of nostalgic fondness. How much easier to deal with bacteria that produce a single enzyme that inactivates penicillin*than with a hospital full of patients infected with MRSA (for methicillin-resistant S. aureus), which doesn’t just laugh at penicillin, but cephalosporin, ampicillin, and every other beta-lactam antibiotic? Or XDR TB (extensively drug-resistant tuberculosis), a bacillus that is unaffected by either isoniazid or rifampin, the more recent agents called fluoroquinolones, and at least one of these second-line drugs: capreomycin, kanamycin, or amikacin.
The human microbiome—the microorganisms in a particular environment—is largely composed of harmless or beneficial microbes, but it is also a perfect reservoir for spreading the genes for every imaginable form of antibiotic resistance.
There are any number of reasons for the explosive growth in the number and virulence of antibiotic-resistant bacteria—as late as the 1990s, fewer than 15 percent of hospital-acquired infections were resistant to antibiotic treatment; acute-care hospitals today routinely report rates of 60 percent or more. The widespread use of subtherapeutic antibiotic treatment on livestock is unquestionably one of them. Overuse of antibiotics in animal feed leads to the creation and spread of antibiotic-resistant bacteria in poultry and meat consumed by the public.
Another driver of resistance is directly attributable to seven decades of overenthusiastic writing of prescriptions. Despite attempts to convince physicians to restrict the overuse of antibiotics from 1946 forward, the fact that antibiotics are so safe for any individual patient has persuaded hundreds of thousands of doctors to prescribe them for conditions for which they are almost always useless. A 1956 survey of doctors in North Carolina found that two-thirds of them, when presented with acute bronchitis—almost certainly a viral disease—prescribed antibiotics “indiscriminately to all patients. . . .” More than fifty years later, in 2010, 70 percent of emergency room doctors and 80 percent of primary care doctors were still prescribing antibiotic treatment for the disease. Patients bear some responsibility, too. Antibiotic prescriptions typically call for ten days of treatment in order to improve the odds that all the pathogenic bacteria causing the infection have been killed; since many antibiotics work by disrupting bacterial cell walls during cell division, and not all bacteria are dividing at the same time, it’s critical to maintain a concentration of antibiotics until the entire pathogenic population has been exposed to them. In industrialized countries, though, up to 40 percent of patients fail to comply with the instructions they’re given along with antibiotics; feeling better after a few days, they stop taking their medicine, thereby sparing the strongest and most resistant bacteria.
Part of the solution to antibiotic resistance is behavioral change. The Centers for Disease Control and Prevention have established “stewardship” programs intended to promote more judicious use of antibiotics, especially in hospitals, where 20 to 50 percent of prescriptions remain either inappropriate or unnecessary. Better and faster diagnostic tests can make it easier to distinguish the bacterial diseases that require antibiotics from the viral infections that don’t.
Just as clearly, though, is the need for improving the incentives for developing new antibiotics, which is the logic behind GAIN. They’ve been a long time coming. In the thirty years after Proloprim appeared in 1969, not a single new class of antibiotics was licensed; every weapon against infectious disease was a derivative of an earlier one. And even since 2000, only two new classes have been approved for treatment: the oxazolidinones like Linezolid, which works by disrupting bacterial RNA translation, and Daptomycin, a cyclic lipopeptide that turns bacterial walls into Swiss cheese by literally changing their geometry.
It’s not only that pharmaceutical companies aren’t discovering new antibiotics. The old ones are disappearing, too. From 1938 to 2013, only 155 antibacterial compounds received FDA approval. Because of resistance, toxicity, and replacement by a newer-generation derivative, only 96 antibiotics remain available today. The decline isn’t helped by the eagerness with which pharmaceutical firms are exiting the field. In 1988, thirty-two independent companies were actively researching antibiotics; during the 1990s, the number of companies that had received FDA approval for an antibiotic declined almost every year. It now stands at eleven, the lowest number since 1961. Some of this is the result of mergers, but not all. Though twenty-eight companies remain of the thirty-two operating in 1988, seventeen have left the field of antibacterial development altogether. Antibiotics built virtually every modern pharmaceutical company, but are now barely a rounding error in the industry’s balance sheet.
If the current trend lines in the battle against infectious disease—every day, more resistance; every year, fewer new antibiotics—continue unchanged, the future takes on a distinctly scary cast: a world in which every puncture wound, or skin rash, or cough carries the risk of death from an unkillable, unstoppable bacterial pathogen. It wouldn’t be precisely like the one that greeted George Washington on the last day of his life. It would be worse. Victims of bacterial infections in a completely antibiotic-resistant world would know precisely what was killing them. And would be utterly impotent to do anything about it.
Fortunately, those trend lines aren’t set in stone. The Harvard-wide Program on Antibiotic Resistance (HWPAR) is developing novel methods for fighting bacterial pathogens, ones that don’t actually kill bacteria, or even halt their reproduction, but degrade the structures that make the bacterium dangerous. A compound that attacks the toxins produced as part of the bacterial infection is the anti-infective warfare equivalent of defusing the enemy’s artillery shells, rather than bombing the cannon themselves. Other researchers are developing ways to attack the source of antibiotic resistance: inhibiting the formation of the enzymes that penicillin-resistant bacteria use to disrupt the beta-lactam ring, for example. Michael Fischbach, at the University of California, San Francisco health campus, has discovered more than three thousand molecules within the human microbiome—the trillions of microorganisms that peacefully coexist inside our own bodies—that show antibiotic potential. Even better: Instead of relying on patience to await microbial innovation, Dr. Fischbach wrote a software program that could teach itself to recognize the patterns of successful antibiotic production in hundreds of existing microbial gene clusters.
And then there’s GAIN. The tweaks it incorporates into the economics of antibiotic development—reducing the time, and therefore the costs, of bringing a drug to market; extending the patent life of drugs—are already bearing fruit. During a single four-month period in 2014—an even better year than 2012, with forty-four new drugs accepted—the FDA approved three distinct antibiotics as “qualified infectious disease products” specifically for the treatment of acute skin infections caused by MRSA: Dalvance, from the Chicago-based Durata Therapeutics; Sivextro, from Cubist Pharmaceuticals; and Orbactiv, developed by the Medicines Company of Parsippany, New Jersey. None of the new drugs represent a revolutionary advance, but a new protocol for antibiotic resistance, one that attracts the attention of the pharmaceutical industry, is one of the most hopeful signs imaginable in the battle against infectious disease.
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The story of antibiotics, and the more general fight against disease, has alternated between unbridled optimism and dark foreboding. Every triumphal discovery—from Paul Ehrlich’s arsenicals to Gerhard Domagk’s sulfanilamides to penicillin, streptomycin, and the broad-spectrum antibiotics—has been followed, sometimes in a matter of months, by a reminder that the enemy in this particular war may lose individual battles, but that the war against it is essentially eternal. Back in 1962, Ernst Chain bemoaned the adaptability of his old enemy, the staph bacterium, which “had again emerged as a dangerous disease against which he had no effective chemotherapeutic weapon.” Bacterial pathogens, it seemed to him, were so adaptable that humanity’s struggle against them was inevitably a losing game. The only plausible response to Chain’s depressing conclusion came from his friend, the MIT chemist John Sheehan—the first person to chemically synthesize penicillin—who reminded him that, while the war against infectious disease was almost certain to go on forever, humanity wasn’t any more easily defeated than the pathogens. “How about an expression of faith,” Sheehan asked, “in the adaptability of the chemist?”