Antibiotic impasse: Resistant to progress

Brad Spellberg, MD, felt helpless when a patient was dying of Klebsiella pneumonia this summer. There wasn't much the infectious diseases specialist could do as the hospital-acquired gram-negative bacterium K. pneumoniae spread through the woman's body.

The bacterium was resistant to all available antibiotics, including colistin, a drug shelved in the 1960s because of its high level of toxicity. Forty-eight hours after the patient was placed on a mechanical ventilator, she died of sepsis.

It wasn't Dr. Spellberg's first encounter with total antibiotic resistance.

"I've seen patients die of treatable infections. I've told their family, 'I have no medicine to use,' " said Dr. Spellberg, an associate professor of medicine at the Harbor-UCLA Medical Center in Torrance, Calif. "This is a catastrophic public health crisis. I don't know how else to put it. Antibiotic development is dying ... and the incidence and frequency with which [bacteria] are resistant is dramatically rising."

During the past three decades, the number of new antibacterial drugs approved by the Food and Drug Administration has declined steadily. Twenty-nine such drugs were licensed between 1980 and 1989, according to the FDA. The number fell to 23 in the 1990s and dropped to nine between 2000 and 2009.

Infectious diseases experts say only three of this decade's new antibiotics are considered novel. They are the types of drugs needed to overcome resistance, because they have a new target of action and no cross-resistance with other antibiotics. But studies show that resistance is beginning to develop against some of these drugs as well.

Even more troubling to experts is the limited number of potentially new antibiotics in research and development.

In 2009, about 16 potential antibiotics were undergoing clinical development, but most were in the early phases of the process, said Dr. Spellberg, a member of the Infectious Diseases Society of America. A new antibiotic takes an average of eight years to progress through the three phases of clinical trials to FDA approval. He said 80% to 90% of drugs fail between phase I and II.

"The [research and development] pipeline is basically dry," Dr. Spellberg said.

One reason for the slowdown is that many manufacturers have focused on other drugs, in part, because antibiotic research is too risky of an investment, said William Schaffner, MD, an infectious diseases specialist and chair of the Dept. of Preventive Medicine at Vanderbilt University School of Medicine in Nashville, Tenn.

He said it makes financial sense for companies to develop drugs for chronic diseases, because patients probably will use the medication throughout their lives. Antibiotics, on the other hand, are prescribed sparingly to try to prolong their use, and they lose effectiveness over time as bacteria mutate and become resistant to the drug.

Complicating matters is the growing resistance of bacteria to antibiotics. Some strains of bacteria, hospital- and community-acquired, have developed resistance to multiple antibiotics. Other strains, such as gram-negative bacteria, can be resistant to all available drugs.

Contributing to this resistance are years of antibiotic misuse due partially to pressure from patients to prescribe the drugs when they are not needed, said J. Fred Ralston Jr., MD, president of the American College of Physicians.

Antibiotics also are added to livestock feed to prevent infections and increase animal growth rates, infectious diseases experts say. Using the drugs in such a way can transfer antibiotic-resistant bacteria from animals to consumers when they eat the meat products.

The antibiotic shortage, coupled with growing resistance, has led physicians to rely increasingly on old and often toxic drugs. As resistance begins developing to these medications, doctors' last resort typically is to combine antibiotics in hopes of creating a cocktail that can fight the infection.

When that doesn't work, there is little physicians can do.

"It's very clear with how resistance is developing around the world that if we continue to use [antibiotics] recklessly, we're not going to have them," said Robert S. Daum, MD, section chief of pediatric infectious diseases at the University of Chicago Medical Center. "In the pre-antibiotic era, if you had a serious infection, the chances of you dying were very high. No one wants to return to that."

Antibiotic challenges

Hospital-acquired infections kill about 90,000 people in the U.S. each year, according to the National Institute of Allergy and Infectious Diseases. That figure is up from about 13,300 deaths in 1992. More than 70% of the bacteria that cause these infections are resistant to at least one of the antibiotics typically used to treat them.

One such bacterium that experts are monitoring is Clostridium difficile, which causes about 500,000 infections a year, resulting in nearly 30,000 deaths, according to the Centers for Disease Control and Prevention.

Physician practices also are struggling to treat a rising number of community-acquired methicillin-resistant Staphylococcus aureus infections in otherwise healthy children, said Meg Fisher, MD, a pediatric infectious diseases specialist and medical director of the Children's Hospital at Monmouth Medical Center in New Jersey.

She estimated that pediatricians see the skin infection several times a week. It is susceptible to a few antibiotics, but she said none of the drugs works well.

"We would like to have a medicine, like penicillin or amoxicillin, that tastes good, is easy to take and would be effective," said Dr. Fisher, chair of the American Academy of Pediatrics' Section on Infectious Diseases.

Dr. Daum said that to develop such drugs, scientists have to identify new ways to effectively kill bacteria now that old techniques no longer work.

To preserve the remaining effective antibiotics, hospitals across the country have developed antimicrobial stewardship programs focusing on teaching doctors to prescribe antibiotics sensibly.

Dr. Daum is the head of one such program at the University of Chicago Medical Center. There, physicians must call an infectious diseases expert for permission to prescribe most antibiotics. Among the exceptions are common drugs, such as amoxicillin. If an antibiotic is warranted, the physician's request is granted immediately.

The goal is not to obstruct medicine but to convince physicians that antibiotics are precious resources and that doctors need a good reason to use them.

"Antibiotics have been taken for granted for a long time," Dr. Daum said. "In a large number of medical [visits], particularly in outpatient [settings], antibiotics are perceived as nontoxic drugs that are useful for a fever."

Prescribing antibiotics for upper respiratory tract infections is among the most common misuses of the drugs. In most cases, these infections are viral and will clear on their own without antibiotics. The same is true for most ear infections, coughs, bronchitis and influenza.

Among the key reasons physicians misuse antibiotics are unfamiliarity with certain older drugs and pressure from patients who request antibiotics when they are not needed, said Belinda Ostrowsky, MD, MPH, director of the antimicrobial stewardship program at Montefiore Medical Center and Albert Einstein College of Medicine in New York.

Dr. Ostrowsky suggested that physicians become more familiar with available antibiotics (new and old) and their toxicity levels. She said doctors should be aware of the types of antibiotic resistance in their hospitals or communities, and they should be comfortable with how to dose these medications. For example, older patients with kidney function problems may require a lower antibiotic dose, while obese patients often need a higher dose.

Before writing a prescription, Dr. Fisher, of the AAP, said a doctor should be able to name the bacteria afflicting the patient. "If you're not sure what you're treating, then you probably shouldn't be giving an antibiotic," she said.

Medical organizations and public health agencies are working to educate physicians and patients on the proper use of the drugs and create incentive programs to boost development of antibiotics.

For example, the Dept. of Health and Human Services in August awarded a contract to a San Francisco biopharmaceutical company to develop a broad-spectrum antibiotic that will treat plague and tularemia infections, which are possible bioterrorism agents. The new drug also is expected to treat some common antibiotic-resistant infections.

In June, the American Medical Association outlined a multifaceted approach to help combat antibiotic resistance to the U.S. House Committee on Energy and Commerce Subcommittee on Health.

The AMA proposes incentivizing research and development programs to create novel antibiotics for clinical use and developing and implementing alternative interventions to reduce dependence on antibiotics, among other things.

This year, the Infectious Diseases Society of America called on manufacturers to develop 10 new, safe and effective antibiotics by 2020. At the same time, the FDA is updating guidance for drugmakers on how to get new antibiotics approved.

A remedy to the antibiotic problem is possible if the nation's leaders make it a priority, Dr. Spellberg said. But he worries that the few promising compounds in clinical development will never become a reality.

If they don't, physicians would be left to treat bacterial infections as they did in the pre-antibiotic era -- largely empty-handed.