12/16/2007 - 22:00

The scourge of antibiotic-resistant bacteria

Laura H. Kahn

Laura H. Kahn

A general internist who began her career in health care as a registered nurse, Kahn works on the research staff of Princeton University's ...

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Ever since Alexander Fleming accidentally discovered penicillin in 1928, antibiotics have kept simple cuts, scratches, and abrasions from becoming severely infected and prevented diseases such as pneumonia, scarlet fever, and tuberculosis from becoming a death sentence. However, antibiotics contain a serious downside: Their overuse and misuse has contributed to an increase in antibiotic-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococcus (VRE), and extreme drug-resistant tuberculosis (XDR-Tb).

This year, the Journal of the American Medical Association published an estimation of the magnitude of invasive MRSA infections in the United States. After conducting active surveillance in nine U.S. communities in 2005, the authors of the study found almost 9,000 MRSA cases, with an estimated rate of 31.8 cases per 100,000 people. Further, they estimated that in 2005, there were more than 18,000 deaths due to invasive MRSA in the United States. An accompanying editorial pointed out that if the estimates prove to be correct, the number of people who died from invasive MRSA infections in 2005 would exceed the number of people who died from HIV.

The JAMA articles prompted a New York Times editorial, which highlighted how a Brooklyn middle school student died from MRSA and recommended more judicious use of antibiotics in medicine and agriculture and better infectious disease surveillance in hospitals.

In practicing medicine, using one antibiotic to treat an individual with a serious infection can lead to a secondary super-infection that requires an additional, stronger antibiotic. Unfortunately, these antibiotics typically kill some good bacteria found in the gut (such as Enterococcus faecium), which can lead to severe diarrhea. If the diarrhea is due to Clostridium difficile, a dangerous gastrointestinal pathogen, it must be treated with the antibiotic metronidazole--and, if necessary, vancomycin. But Enterococcus faecium develops a resistance to vancomycin over time, which can lead to vancomycin-resistant enterococcus (VRE). VRE was first reported in 1986, and almost all of its forms are resistant to even high levels of the antibiotic ampicillin. Those most at risk from VRE infections are the immunosuppressed.

Once, tuberculosis was a highly treatable disease. But because of poorly managed tuberculosis care, which includes incorrectly prescribing antibiotics, patient noncompliance, and poor drug quality or supply, mycobacterial strains resistant to the first-line drugs and many second-line drugs have developed. The AIDS pandemic worsened this situation by, in essence, creating a population highly susceptible to developing and spreading tuberculosis. XDR-Tb has been found throughout the world, but it occurs most frequently in Asia, the former Soviet Union, and South Africa.

Antibiotic-resistant bacteria in animals

Animals often receive antibiotics for growth promotion in their feed, which is a major contributing factor to the development of resistant strains--in both animals and humans. For example, farm animals, particularly pigs, are believed to be able to infect people with MRSA. (See "Drug Resistant Infections: Riding Piggyback.") In 1951, the FDA approved the use of antibiotics in animal feed without a veterinary medical prescription; Europe quickly followed suit.

As the spread of drug-resistant bacteria became a concern, countries began questioning the practice. In 1969, Britain issued the Swann report, which recommended that human therapeutic antibiotics be banned from being used as growth promoters in agriculture. The report was largely ignored. Nearly 30 years later, the World Health Organization concluded that antibiotics as growth promoters in animal feeds should be prohibited. And in 1998, European Union health ministers voted to ban four antibiotics widely used to promote animal growth. Regulation banning the use of antibiotics in European feed, with the exception of two antibiotics in poultry feeds, became effective in 2006. (See "History of the Use of Antibiotic as Growth Promoters in European Poultry Feeds.")

With good animal husbandry and hygiene, there shouldn't be adverse effects, health-wise or production-wise, from not using antibiotics in animal feed. In Scandinavia, there's evidence that the ban has led to a lower prevalence of antimicrobial resistance in animal bacterial populations. (See "Antimicrobial Resistance in Scandinavia After Ban of Antimicrobial Growth Promoters.") Meanwhile, in the poultry industry, the ban hasn't had a deleterious effect. Economic performance in poultry production wasn't adversely affected either.

In the United States, antibiotic use in animal feeds remains controversial. The FDA first called for restrictions in 1977, which generated many studies and reports on the issue. In 1980, the Institute of Medicine reviewed the subject and recommended that more studies be conducted. In 1999, the General Accounting Office (GAO) also concluded that the evidence was inconclusive. A follow-up 2004 GAO study found that evidence existed of antibiotic-resistant bacteria being transferred from animals to humans. But since federal agencies don't collect data on antibiotic use in animals, conclusions on the potential impact on human health couldn't be made.

Therefore, antibiotics are still used in U.S. animal feed--along with evidence of other worrisome ingredients. (See "What Do We Feed to Food-Production Animals? A Review of Animal Feed Ingredients and Their Potential Impacts on Human Health" and "Antibiotic Resistance in Bacteria Associated with Food Animals: A United States Perspective of Livestock Production.") Growing U.S. consumer concern about using antibiotics in animal feed has led to a niche market of "antibiotic-free" animal products, but this small market is unlikely to change entrenched industry-wide practices. (See "Health Management with Reduced Antibiotic Use: The U.S. Experience.")

Antibiotic-resistant bacteria in hospitals

Once resistant bacteria get into a hospital, it can be extremely difficult to get rid of them. For example, the New Bolton Center's George D. Widener Hospital for Large Animals (the hospital that treated the shattered leg of the famed racehorse Barbaro) experienced an outbreak of multidrug resistant Salmonella Newport (MDR S. Newport) in January 2004. It tried to locate the outbreak's source and disinfect treatment areas and barns. But new infections continued to occur, and tests showed that the outbreak was more widespread than originally thought. In April, the hospital decided to limit new admissions and only do elective procedures. The hospital closed in May for an intensive cleaning that included sandblasting, painting, scrubbing, disinfecting, reinstalling plumbing fixtures, and replacing equipment and supplies. The entire process took almost two months. In August, the hospital reopened to a limited patient load; it now conducts close bacterial surveillance of all patients and the hospital environment. (See "The Great Scrub at New Bolton Center".)

While this example involved animals, it's important to note that the bacteria can infect humans. MDR S. Newport emerged in the United States in 1998 and has spread to Canada. It can become endemic on dairy farms and has been identified in horses; it causes fever and diarrhea and can kill those with compromised immune systems. Infants and the elderly are at considerable risk. People can come in contact with the bacteria if they handle or eat improperly cooked meat or unpasteurized dairy products. Direct spread from animals to people can also occur. And MDR S. Newport is resistant to at least nine of the standard seventeen drugs used to treat it.

As opposed to the New Bolton Center, hospitals for humans typically do not close for a top-to-bottom disinfection and scrubbing. They might close wards or treatment areas, but it's too expensive to close the entire hospital.

From 1995 to 1997, the New Jersey Department of Health and Senior Services conducted a study of antibiotic-resistant bacteria rates in the state's hospitals. It found a fivefold increase in VRE and penicillin-resistant Streptococcus pneumonia after monitoring began in 1992. However, conducting surveillance and doing something about the problem are two different things.

In 2006, the Centers for Disease Control and Prevention issued guidelines for health-care facilities to decrease the burden of antibiotic-resistant bacteria. They don't recommend hospital closure and disinfection; instead, they recommend the usual strategies--staff education, hand washing, surveillance.

While these measures are important, if antibiotic-resistant bacteria are found to be widespread, then hospitals should consider following the New Bolton Center's example--closure with intensive disinfection, cleaning, and painting, followed by strict infection-control measures and intensive surveillance. In addition, rather than just conducting surveillance of these infections, state health officials should be given the power to close facilities when the rates of antibiotic-resistant hospital infections become unacceptably high, as the threat of closure might make hospitals take the issue more seriously.

Antibiotic-resistant bacteria, Congress, and the pharmaceutical industry

According to the Infectious Diseases Society of America (IDSA), 2 million people get bacterial infections each year. Of these, 90,000 die. Approximately 70 percent of these infections are due to organisms that are resistant to at least one drug.

How has the pharmaceutical industry responded to this crisis? Unfortunately, the industry hasn't been developing new drugs because they're not considered profitable; instead, it prefers to invest in blockbuster drugs for chronic diseases such as hypertension and hypercholesterolemia. In Britain, scientists are developing new strategies to control antibiotic-resistant bacteria, and a biotech company has been established to commercialize the technology. But without major pharmaceutical investment, getting these new technologies to market might be a challenge. (See "Genes Targeted in Breakthrough Against Drug-Resistant Superbugs.")

While drugs for chronic diseases are important, they don't address the growing antibiotic-resistant bacteria crisis. Therefore, Congress should develop incentives for the pharmaceutical industry to develop new therapies against antibiotic-resistant bacteria. The IDSA has made a list of policy priorities that Congress should implement, including getting the FDA and National Institutes of Allergy and Infectious Diseases more involved in new drug development.

But it's important to note that new antibiotics wouldn't be the final answer. Bacteria would eventually become resistant to those antibiotics, too. After all, resistance is a cycle of microbial evolution. In the long term, we need new strategies for countering bacterial infections such as targeting host-specific (rather than pathogen-specific) biochemical pathways. (See "Intracellular Bacterial Growth is Controlled by a Kinase Network Around PKB/AKT1.")

Sadly, the call to action has been unheeded for a long time. Almost a decade ago, Surgeon General David Satcher testified before Congress on the need for action against antimicrobial-resistant bacteria. Indeed, translating talk into action is the greatest hurdle we face in addressing this issue. We cannot "win the war" against microbes, but we could be much smarter in learning how to live with them.