Fight Resistance

In the middle of what should have been the dry season, the skies opened up and pelted Uganda with rain. Towns and fields flooded, mud-walled homes crumbled, food and other necessities ran out, and the area's already high rates of malaria, diarrheal diseases, and acute respiratory infections spiked.

Days later, nurse Jacky Tumusiime traveled to a remote village near the Tanzanian border to tend to the sick. When she arrived at 11:00 a.m., 100 people were lined up waiting for her; some had been there since the night before. Poverty is a good predictor of disease, and this was a poor town—infectious diseases run rampant here. After a full day, Tumusiime looked up to discover that the line of patients was longer than when she first arrived.

Cubist Pharmaceutical's Barry Eisenstein, MD, says that specialty companies are missing the "international machinery" and are not geared to be able to distribute antibiotics to the developing world.

Tumusiime brings supplies that are mostly donated by the good-hearted from her native New Zealand. There are never enough to go around. Still, during the floods, she's better stocked than the local clinics, which quickly run out of supplies. Of course, most people buy their drugs on the street and in local shops, not clinics. And mostly, they buy antibiotics.

"These doctors dish out antibiotics like sweets," says Tumusiime. "In fact, it's rare to leave a doctor's office without at least two types of antibiotics. They are prescribed for everything from broken bones to a lump on the head from falling off a bike." Many patients, she says, skip doctors' visits and just get antibiotics. After all, it's all they've ever known.

The pattern Tumusiime describes—massive overprescribing and misprescribing of antibiotics—is duplicated throughout the world. Globally, says Anibal Sosa, MD, director of international programs for the Alliance for the Prudent Use of Antibiotics (APUA), studies show that between 40 and 90 percent of antibiotic prescriptions are unnecessary.

Misuse of antibiotics, of course, has a cost: antimicrobial resistance (AMR), which in recent years has become an increasingly worrisome problem the world over. In the last year alone, the news media have reported on two frightening situations in the United States, an outbreak of methicillin-resistant Staphylococcus aureus (MRSA) and a suspected case of extensively drug-resistant tuberculosis (XDR-TB). But those reports are just the tip of the iceberg. In 2005 (year of the most recent available data), 94,000 patients were infected with serious MRSA infections and almost 19,000 people died—more than from AIDS. But it's not only the human cost that's staggering: Some experts suggest that resistant pathogens in the hospital cost the country nearly $6.7 billion. Other estimates put the cost of hospital-acquired infections in the developed world—largely due to resistance—at $32.5 billion, more than current global sales of antibiotics.

But as alarming as these figures are, there's reason to think drug resistance is much more extensive—and much faster growing—in the developing world. Overall figures are difficult or impossible to come by. But consider the following:

• In South Asia, multidrug-resistant strains of S. typhi, the organism that causes typhoid fever, have emerged: In a 1994 study, typhoid fatality rates approached 10 percent—close to the 12.8 percent recorded pre-antibiotics. And the situation is worsening: Another study showed 56 percent of isolates in South Asia were reported to be methicillin-resistant. In Vietnam, penicillin is no longer effective in 60 to 70 percent of the population affected with Streptococcus pneumoniae—a top killer—and resistance to third-generation cephalosporins is also increasing. When it comes to treating typhoid in Vietnam, there is almost total resistance to all first- and second-line antibiotics.
• During the Rwandan genocide, shigellosis ripped through the refugee camps in Zaire, killing 20,000 in the first month alone. Previously, cheap antibiotics were effective against the disease. Now, throughout much of Africa, Shigella bacteria have grown resistant to four first-line antibiotics—ampicillin, tetracycline, cotrimoxazole, and chloramphenicol—and resistance to ciproflaxacin is increasing.
• Many sexually transmitted diseases in Asia have become a death sentence with the rapid rise of resistance to fluoroquinolones. In Hong Kong, for example, the rate of resistance to ciprofloxacin has grown from 18 percent of gonorrhea patients in 1997 to 73 percent in 2003. During that same time period, fluoroquinolone resistance in Africa increased from 17 percent to 38 percent.
• In KwaZulu-Natal, South Africa, one outbreak of XDR-TB killed 74 patients within a matter of weeks, sparking fears that XDR-TB could spread rapidly—and lethally.

"There are a lot of questions about, How did that happen?" says Margaret Riley, professor of biology at the University of Massachusetts, Amherst. "The easy answer is, 'We abused and overused antibiotics.' And that, of course, is true. We have used too much per patient, too much per year, too much per country—too much in just about any measure, and we're using it in agriculture and things of the sort."

Already, 20 million people in developing countries die each year from infections and parasitic diseases, according to the World Health Organization (WHO). That number will only grow as a high rate of AMR combines with a high rate of infections in warm, unhygienic living conditions to create a medical nightmare of infections with no cure.

There's a name for that nightmare: the "post-antibiotic age," an idea that has been kicked around for several decades. In the developed world, the concept has galvanized physicians, who are slowly changing their indiscriminate prescribing of antimicrobial drugs, says William Schaffner, MD, Vanderbilt University's chairman of preventive medicine.

Total Approved Antibacterials: US

But in the developing world, the post-antibiotic age may already be here.

The Never-Ending Story: Man vs. Bacteria

Throughout much of history, humans have been at the mercy of bacteria-borne illnesses. In the Middle Ages, plague and leprosy killed millions. Penicillin, discovered in 1928 and first used successfully in patients in 1941, was startlingly effective against infection. But if the public in the 1950s hoped that the battle against bacteria was over, they were wrong.

The explanation was Darwinian survival of the fittest. Bacteria multiply quickly. Under optimal conditions, a single bacterium can produce a billion offspring in a day. And they mutate rapidly; recent research suggests bacteria undergo genetic changes a thousand times more frequently than anyone had suspected. So while penicillin could kill off many of the bacteria involved in a given infection, it often would leave behind other strains—strains resistant to penicillin—that eventually proliferated and spread through the population.

Over the years, a pattern emerged. Bacteria developed resistance to a given antibiotic. Companies developed new antibiotics that selected for new resistant phenotypes. The length of time an antibiotic could be viable depended on the drug and the extent of patients' abuse—the resistance problem was exacerbated when they took their drugs for too short a time or at too low a dose, increasing the likelihood that microbes would adapt and spread, rather than be killed. (See Intervals to Resistance chart.)

Antibiotics used to be big business. By the 1980s, the market for third- and fourth-generation cephalosporins was growing nearly 30 percent a year. But the glut of competition—and the ability to use vancomycin, the "drug of last resort," for tricky infections—ultimately made the market seem unattractive for companies, even saturated. The industry began to focus on more profitable chronic conditions.

The decoding of the Haemophilus influenzae genome in 1995 engendered a concentrated but brief interest in bacteriology. The pharma industry saw new opportunity in target-based approaches to antibiotic discovery, and companies plunged into high-throughput screening campaigns of candidate genes. GlaxoSmithKline, for example, invested $70 million in this approach—but walked away with no leads. A literature review found that 34 other companies also came up empty-handed. Even today, nearly 15 years after the emergence of bacterial genomics, there are no promising antibiotic pipeline candidates derived from this strategy.

"The target-based approach was and has been a complete and absolute failure—there's no other way to state it," says Thomas Evans, head of infectious diseases at the Novartis Institutes for BioMedical Research. "It's clear that approach, which almost every big company took and some are still taking, makes perfect sense and should have worked—but it's not going to."

With fewer Big Pharma companies investing in antibiotics, there's been fewer antimicrobial drugs. This documented decrease has brought the problem of antimicrobial resistance to a head, given that we once again face infectious diseases with no cure.

Dr. Anthony Fauci, director of NIAID, says antimicrobial resistance is a big problem, but many developing countries have more pressing concerns, and resistance is "a luxury to deal with."

Despite the seriousness of AMR, it hasn't topped officials' agendas. "My perception is that resistance is the least of their worries," says Anthony Fauci, MD, director of the National Institute for Allergy and Infectious Diseases, part of the National Institutes of Health. "The developing world has so many other big challenges that resistance is a luxury to deal with. You know, they'll take any antibiotics that are available—even if they have to deal with resistance—because right now that can't be at the forefront."

The problem with that reasoning is that Africa and Asia—and other parts of the developing world that are highly prone to infectious diseases—can't afford the steep slide into resistance. AMR can deliver what amounts to a crushing blow to societies that are already disproportionately suffering. The agents most affected are inexpensive, older antimicrobials, which in many cases are all that are available or affordable. But new therapies—for example, the treatment for MDR-TB—can be a hundred times more expensive than standard therapies. And that's just for one disease. "The estimated monetary cost of antimicrobials required to treat a resistant N. gonorrheae infection is 2 to 7 times greater than a nonresistant infection," APUA's Sosa writes. "This multiple is 10 to 11 times for shigellosis in adults and as much as 11 to 90 times for resistant Streptococcus pneumoniae."

What's more, AMR is hurting current treatment efforts and helping to destroy precious infrastructure in the developing world. For example, a recent study in the Lancet reported that 70 percent of pathogens found in hospital nurseries in developing countries are resistant to the antibiotics ampicillin and gentamicin. However, those are precisely the drugs WHO recommends to treat children for this purpose.

One has to look only as far as the protocol for TB in the less-developed world to see how resistance can affect outcomes. "If a TB patient fails on antibiotics, they'll just repeat the course," says Kari Stoever, director of the Albert B. Sabin Vaccine Institute and executive secretary of the Global Network for Neglected Tropical Disease Control. "And if they don't have the drugs due to pricing, distribution, whatever the reason, then after two trials of a standard antibiotic, that patient will just be turned away."

Systems Failing

There are two broad approaches to managing antimicrobial resistance: managing behavior to maintain drugs' effectiveness and ensuring a robust pipeline of new antimicrobial treatments. On both these fronts, it's fair to say that the systems-based approaches to stop resistance have been given a lot of lip service, but have largely failed.

Managing behavior Antimicrobial resistance shouldn't have gotten this far. Back in 2001, WHO issued its Global Strategy for Containment of Antimicrobial Resistance. Through a set of 67 recommendations, it called for a massive overhaul of the way public health systems respond to AMR. In particular, it recommended the implementation of national programs to promote rational use of medicines—programs that generally don't exist in most developing nations.

The intervals between Antibiotic discovery and the development of resistance

The plan made sense, but countries failed to implement it. WHO tried again with resolution WHA58.27, which recommended speeding implementation of the 2001 working plan, and then again in May 2007 with resolution WHA60.16, which once again recommended creating national bodies to run rational drug-use programs. This initiative lies at the heart of empowering local governments to maintain their supply of effective antibiotics to fight infection. The price tag for the program? Just $30 million over six years. A bargain—if only someone were willing to support it.

Drug development Meanwhile, regulators and government officials can't seem to coordinate the range of issues to align public health guidelines with market incentives and inspire drug development.

Experts in infectious-disease control have tried to combat AMR by coaching physicians to prescribe fewer antibiotics, and to "save" newer therapies for patients who have failed on others. This can slow the time before resistance develops—but it also depresses sales when an innovative antibiotic is on patent, undercutting profitability and giving companies minimal incentive to develop additional products.

"It's somewhat of a self-limiting occurrence," says John Lebbos, MD, an analyst for Decision Resources. "The more innovative you are, the more limited market you get."

Antibiotic Pipeline: The late-stage antibiotic pipeline shows a glut of treatments for particular conditions, but a lack of drugs appropriate for the developing world

Other industry insiders say the real problem is the changing regulatory environment for antibiotics. "The success rates of approvals went down," says Robert Reynolds, MD, director of drug discovery technology for the nonprofit Southern Research Institute. "The perception was that FDA had much more stringent requirements, which changed the net-present-value calculations on developing new antibiotics."

After safety issues were spotted with Pfizer's Trovan and GSK's Raxar in 1999, the standards for antibiotics changed. The following year, Sanofi-Aventis submitted its ketolide antibiotic drug Ketek for FDA review. But with a higher safety bar, FDA wanted more testing. The company spent an additional three years—and $518 million, according to Paul Rubin, an economics professor for Emory University—conducting Phase III trials with a whopping 24,000 patients (on top of the initial 7,000 patients it had already tested).

Part of the problem with Ketek was that Sanofi-Aventis had used the noninferiority trial design at a time when the agency began to question its value. Noninferiority trials were previously considered the gold standard, testing a drug's rough equivalence to treatments already on the market. FDA decided to approve the drug anyway—a decision that would come under attack in 2006, when the drug was linked to liver damage and failure.

Since then, FDA has encouraged superiority trials for antibiotics. The result is predictable: more studies, bigger trials, and a number of new antibiotics shelved or delayed. Recently, FDA required additional testing from Replidyne and Forest's antibiotic candidate faropenem and Pfizer's dalbavancin, developed to fight the deadly MRSA infection, although neither of these drugs showed safety issues.

"The policy and execution of the policy by regulatory authorities really matter in terms of how drugs are developed and even what drugs we attempt to develop in the first place," says Steve Projan, vice president of biological technologies, Wyeth Research. "The regulatory authorities have become very gun-shy, and their response is larger trials to assess the safety of drugs. But there are only a certain number of 20,000-patient trials we can run until we run out of money."

Projan says new trial-design requirements for antibiotics dangerously limit the number of potential players. He is calling for provisional FDA approval of antibiotics based on Phase II data, followed by rigorous Phase IV monitoring. "That way, we get the large safety datasets that we need to assess the safety of drugs, but we do it in a manner in which we don't have to sell the farm and mortgage the house to pay for the large trials that are currently demanded," he says.

Others say the need for new antibiotics is too important for FDA to pursue its current course for long. "As the medical need, such as MRSA, becomes even more self-evident, then the regulatory environment will become more balanced," says Susan Froshauer, CEO of Rib-X Pharmaceuticals, a start-up focused on next-generation antibiotics.

Today's Market: No "International Machinery"

Augmentin. Zithromax. Cipro. These are just some of the blockbuster brands that have reached the end of their patent life in recent years. By the time J&J's juggernaut drug Levaquin goes off patent in 2011, Big Pharma will have effectively exited the business of broad-spectrum antibiotics for community-acquired infections.

At first glance, these massive patent expirations may seem to be a good thing for the developing world. "When Cipro went off patent, the cost went down to nominal unit prices, and Asia-based companies began shipping Cipro out by the crateload," says Jonathan Angell, an infectious-diseases analyst at Datamonitor. "And with more patent expiries en route, like Avelox, Zyvox, and Levaquin, there will be another generation of generic drugs that are available."

In the face of massive genericization of broad-spectrum antibiotics, pharma has turned its attention to the high-value hospital market. (Meanwhile, generic arms of companies like Sandoz and Greenstone remain profitable in this area.) These hospital-administered therapies serve niche indications, but they can cost "an arm and a leg," says Datamonitor's Angell. Among the drugs anticipated are Pfizer's Zeven, Theravance's telavancin, Cerexa's ceftaroline, and J&J's ceftobiprole. (See "Antibiotic Pipeline," .) Additional specialization is likely to occur. By 2016, newly launched drugs will account for only 1 percent of the volume of antibiotics sold in the seven major markets and 23 percent (or $2 billion) of the value, according to Datamonitor.

These late-stage antibiotics will mostly compete with already established products. There is also likely to be a glut of new drugs targeted at specific infections, namely complicated skin and soft-tissue infections and pneumonias. That means the antibiotic market will be characterized by both intense competition and massive unmet medical need—particularly to manage infections caused by strains of pseudomonas or acinetobacter (now seen in soldiers returning from Iraq), or other new strains of bacteria that may arise.

"The development of all drugs takes 10 years—and it's difficult to predict what the big outbreaks are going to be and what drug resistance is going to be," says Barry Eisenstein, MD, senior vice president, scientific affairs, for Cubist Pharmaceuticals. The company markets Cubicin, a once-daily IV bactericidal antibiotic that treats vancomycin-resistant enterococci and MRSA. "That's nature and evolution. We can make some reasonable predictions, but it's not like knowing that diabetes is still going to be problem five years from now."

Hospital antibiotics remain an attractive niche for specialty and biotech companies, which can remain profitable by charging high prices and keeping small sales forces. IMS reports, for example, that with $250 million in sales from January through November 2007, Cubicin was the fifth-highest-grossing antibiotic in the United States. But small companies can't gain the global reach and supply chain savvy to distribute drugs outside developed or—at best—emerging nations.

"I've talked to all the companies with antibiotics in Phase III, and none of them plan to introduce those second-line antibiotics into Africa," says University of Massachusett's Margaret Riley.

That being said, there's at least one forecast that can be made with confidence: As therapies become more advanced and expensive, the developing world is likely to fall further behind. "The costs for some of the very sophisticated antibiotics that work against multidrug-resistant infections are problematic," says Rib-X's Froshauer. "The armamentarium available to hospitals in developing countries is very different."

Small companies also don't have the ability to establish support projects, like Lilly's technology-transfer program to teach local and generic companies how to manufacture MDR-TB therapies, or even GSK's Alexander Project, a decade-long global AMR-surveillance study. And if their drugs are not marketed in the developing world, these companies will be less likely to pursue counterfeiters—as Pfizer has done.

"It's difficult to get therapies to the developing world," says Eisenstein of Cubist Pharmaceuticals. "Larger companies, like Lilly, have a policy and process to get antibiotics to catastrophes. But [Cubist] just became profitable a year ago—we don't have that kind of international machinery."

However, at least early-stage biotechs are trying new approaches to combat AMR. "It's important that there are a lot of irons in the fire, that a lot of people are trying to reach the destination," says Novartis' Thomas Evans. "That's important because we don't yet know the right road."

Some new promising approaches include peptide deformylase inhibitors and novel inhibitors of fatty acid biosynthesis, which are entering clinical development. Still, by any measure, investment in research is weak—GSK estimates that a fourfold increase is needed to generate a new antibiotic by 2012.

"If we block the ability of the microbe in one way, it will naturally select for ways around the therapy that we use," says Thomas Parr, Targanta's chief scientific officer. "So it is a race—but not one that we're likely to win outright. It's going to be a chronic struggle for all of us."

Greasing the Wheels of R&D

So when it comes to creating new antibiotics, what is the way forward? It's likely to include a variety of approaches.

On the legislative front, the passage of the FDA Revitalization Act offered a small victory. The bill includes a provision geared toward incentivizing neglected-disease R&D by offering a priority-review voucher. This voucher will be given to companies that develop drugs for neglected diseases, which they can use to "jump the queue" for FDA review of another product. Biotechs, if they wish, might sell the voucher to gain cash. "The voucher can get a product to market more than a year ahead of schedule," says Jeffrey Moe, adjunct associate professor and senior director of business development for Duke University's Fuqua School of Business. Moe proposed the voucher idea and said it can help companies secure the highly coveted first-in-market position. These products can also qualify for orphan status.

Admittedly, bacterial resistance presents a much different profile than traditional "neglected" diseases (take dengue fever, for example, which occurs primarily in parts of the world where there are no profits to be had from developing a new drug). And they're not true orphan drugs, because so many people are affected by resistant bacteria. However, given the importance of antibiotics to safeguard the well-being of the population, the provision was accepted.

Another promising piece of legislation is the Strategies to Address Antimicrobial Resistance, or STAAR, Act. Introduced in November 2007, STAAR delineates a multipronged approach to coordinate and fund federal activities related to antibiotic resistance, such as surveillance and control efforts—including monitoring antibiotics in food.

But the solution is not just more funding—it's smarter funding. In this regard, says Margaret Riley, NIAID traditionally has been too conservative about funding risky research. For instance, she says the current theory of the development of AMR needs fine-tuning. Riley points to a study that found bacteria like E. coli and Klebsiella have the same rates of resistance in the outback of Australia as in high-traffic clinical settings. What's more, patients in India, Turkey, and Poland had MRSA before they had methicillin.

"The problem with just coming up with the next gold standard is that all of that genetic variation that allows bacteria to fortuitously evade an antibiotic is already in their population somewhere," says Riley.

Riley's own research (funded, admittedly, by NIAID) looks at bacteriocins, which are highly targeted proteins produced by bacteria that can kill or inhibit other bacteria. Some people consider bacteriocins narrow-spectrum antibiotics—and because of that targeting, says Riley, resistant strains would take longer to evolve and spread.

Other scientific theories are also gaining steam, says Cubist's Eisenstein, who has sat on NIAID review committees. He ticks off a series of scientific ideas, including decreasing bacteria's mutation rates, altering quorum sensing—the process through which bacteria communicate with one another—or inhibiting bacterial efflux pumps, which are thought to play a role in AMR. But they are still a long way off from becoming a drug. "Quite frankly, none of them will turn into drugs in the next decade," says Eisenstein.

What Industry Can Do

Clearly, one is still left to wonder who will help the developing world when its antibiotics no longer work.

Certainly, this is an area where public/private partnerships can help. For example, the nonprofit Institute for One World Health worked with a range of entities to bring an injectable version of paromycin to India to cure visceral leishmaniasis—better known as "black fever." Other partnerships include the Alliance for the Prudent Use of Antibiotics, which focuses on antimicrobial stewardship, and the United States Pharmacopeia's Drug Quality and Information program, which focuses on counterfeiting.

Another way in for industry might be through vaccines. "A person might say, 'What are you talking about, vaccines? We're talking about resistance to drugs,'" says NIAID's Fauci. "Well, if you prevent infections, then you don't have to treat them. The less treatment, the less exposure to the selective pressure of antimicrobials that pushes microbes to resistance."

Wyeth's pneumococcal vaccine Prevanar, which prevents infections caused by S. pneumoniae, offers an example. Wyeth turned Prevanar into a blockbuster drug by proving its health value in developed markets, but also by talking to governments in the developing world about the overall economic productivity this vaccine can confer on a nation. "Demonstrating that the pneumococcal conjugate vaccine is successful stimulated competition," says Projan, "but it also stimulated other companies to think that, yes, you can not only do good for society but also do well commercially with an effective and safe vaccine."

But back in a village in Uganda, Jacky Tumusiime doesn't count Prevanar among the emergency supplies she carries to tend to the sick. Instead, she talks about counterfeit antibiotics from India, about wishing Augmentin and other drugs were available, about giving children drugs that just don't work. To the developed world, this may sound like merely a story of unfortunate circumstances happening to somebody else. But what's important to remember is that bacteria know no boundaries, no borders. And while researchers worry about the pathogens developing on their turf, in this era of rapid travel and globalized commerce, it's important to remember that the developing world's problems—and its bacteria—are only a plane ride away.