A Microscopic Arms Race: The Battle Against Antibiotic Resistance

In 1928, bacteriologist Alexander Fleming noticed that a culture of staphylococcus bacteria had been contaminated by mold. This rather mundane event stirred Fleming’s curiosity when he noticed that the mold was dissolving the bacteria it touched. Fleming cultured the mold and found that it produced a substance that could kill several disease-causing bacteria (1), including pneumococci, streptococci, meningococci, and gonococci (2). He named the substance–the first antibiotic–penicillin, after the Penicillium mold that produced it (3). It would be the first of many antibiotics to revolutionize the field of medicine. After the discovery, Howard Florey and Ernst Chain studied penicillin’s properties and developed the first antibiotic drugs. Penicillin was in mass production by the 1940s (1). Fleming, Florey, and Chain shared the Nobel Prize in Medicine in 1945 “for the discovery of penicillin and its curative effect in various infectious diseases” (4). The development of antibiotics is widely considered to be one of the greatest public health achievements of the past century. The use of antibiotics has led to a massive improvement in the treatment of infectious bacterial diseases and has made invasive surgical procedures much safer to perform. However, the efficacy of antibiotics has encouraged overuse. Doctors would prescribe them to treat minor infections, for which antibiotics are unnecessary. Moreover, livestock breeders give antibiotics to their animals in order to protect them from disease. The overuse of antibiotics has led to the evolution of resistant strains of bacteria. Strains now exist that elude even the strongest antibacterial agents. The World Health Organization estimates that two million people in the United States are infected with antibiotic- resistant bacteria, resulting in the deaths of 14,000 each year (5). Once an indispensable weapon in the fight against disease, antibiotics have ushered in a new public health threat. A recent article in Scientific American describes a report from Colorado State University about the presence of DNA that promotes antibiotic resistance in drinking and non-drinking water. Amy Pruden, the primary author of the study, chose to look for the genes that create antibiotic resistance, rather than for antibiotics themselves since this approach provided more accurate information about the amount of antibiotic resistance in these water sources.

DNA samples were obtained from bacteria found in bodies of water in northern Colorado. The researchers looked for genes that conferred resistance to tetracycline and sulfonamide to bacterial hosts. According to the report, bodies of water in close proximity to urban areas or farming regions had levels of drug-resistance genes that were hundreds to thousands of times higher than those of isolated bodies of water. However, antibiotic resistance genes were found in every water source tested (5). The study links the increase in antibiotic resistance to the overuse of drugs in humans and animals.

According to Scientific American, “up to 95 percent of antibiotics are excreted unaltered, seeping into the environment and possibly encouraging antibiotic resistance there” (5). Microbes that are able to survive the dose of antibiotics that they encounter will be selected for survival. The presence of antibiotic resistance genes in drinking water is particularly troubling. Water filtration systems are designed to remove bacteria and toxic minerals, rather than DNA, which can pass through undetected. Pruden and her team are currently working to develop water treatment methods using ultraviolet light, peroxides, or both to clean up contaminated water (5). Others are working to prevent antibiotics from reaching water sources in the first place. A movement to end the use of antibiotics in livestock is gaining momentum.

In Europe, a January 2006 law made it illegal to give antibiotics to animals for nontherapeutic purposes. The antibiotic avoparcin, a relative of vancomycin, has been outlawed since its overuse was correlated significantly with an increase in vancomycin resistance in microbes in the human intestine (6). But antibiotic resistance threatens more than our water supplies. Hospitals have become breeding grounds for antibiotic-resistant bacteria. These strains are associated with increased lengths of stay, higher costs, and mortality (7). According to data from the Centers for Disease Control and Prevention (CDC), the proportion of infections that are resistant to antibiotics has increased (7). One such strain is known as methicillin-resistant Staphylococcus aureus (MRSA), which has become more common in recent years. In 1974, MRSA infections represented 2% of the total number of staphylococcus infections; in 1995 it was 22%; in 2004 it was about 63% (8). Ironically, it was S. aureus that was killed by penicillin in Fleming’s original culture (3). The most common sources of MRSA in hospital settings are patients who are infected with MRSA but who do not display symptoms. It is transmitted to others most commonly by healthcare workers who come into contact many patients and families each day. Individuals most susceptible to MRSA infection are those with severe disease, particularly those with compromised immune systems. Groups with the highest infection rates include: individuals recovering from surgery, individuals who have internal medical devices, such as urinary catheters, and hospitalized patients. (7). In terms of pathology, MRSA produces different symptoms in patients compared to methicillin-susceptible S. aureus (MSSA) strains. Individuals with MRSA infections are more likely to develop symptomatic infections. Higher fatality rates are also associated with MRSA infections, compared to MSSA infections.

A number of studies offer explanations for these observations. One suggested that the delayed delivery of vancomycin, which is considered the “last-hope treatment” for MRSA (6) might be responsible. The same study also mentioned the possibility that vancomycin has decreased in efficacy against the strains of MRSA in question (7).

Another study hypothesized that the particular bacteremia associated with the strains of MRSA involved in the study was particularly lethal (7). Interestingly, genetic analyses suggest that only a small proportion of the MRSA strains found in hospitals contained mutations that promote peculiar aggressiveness or persistence, which could allow them to transmit to other individuals easier. It was also found that most MRSA strains were genetically unique compared with strains prevalent in hospitals. This suggests that the MRSA strains may have been the product of MSSA strains that acquired genes for antibiotic resistance (7). The CDC has taken steps to monitor and reduce the presence of MRSA in healthcare settings. It conducts extensive surveillance of MRSA transmission rates and has published guidelines for hospitals on how to deal with MRSA infections. CDC also conducts epidemiologic and laboratory research on MRSA in hope of finding ways to actively treat infections (9). Some believe that the hospitals and public health organizations in the U.S. are not doing enough to prevent MRSA transmission. Experiments with new containment measures in European hospitals have succeeded. In Denmark and the Netherlands, hospitals isolate all incoming high-risk patients until lab results confirm that they are not infected with MRSA. Currently, less than 1% of staphylococcus infections in Dutch hospitals are MRSA, compared to 64% of staphylococcus infections in the U.S. (6). According to Scientific American, American hospitals have been hesitant to follow the European example, citing the high costs of such intense screening. However, considering that MRSA infections increase costs of care, it might be economically viable to implement an extensive screening process (6). Physicians and researchers are engaged in an arms race with bacteria, and bacterial evolution has begun to outstrip human scientific progress. At the moment, the best defense against antibiotic-resistant bacteria is prevention of transmission. Public health agencies around the world are working to find more aggressive treatments, but unless a means of stalling evolution is found, the battle with bacteria is far from over.

References
1. Alexander Fleming (1881-1955), Available at http://www.bbc.co. uk/history/historic_figures/fleming_alexander.shtml (21 February 2007).
2. S. Waksman, Penicillin (2007), Available at http://encarta.msn. com/encyclopedia_761561064/Penicillin.html (21 February 2007).
3. J. Deacon, The Microbial World: Penicillin and other antibiotics. Available at http://helios.bto.ed.ac.uk/bto/microbes/penicill.htm (21 February 2007).
4. The Nobel Prize in Physiology or Medicine 1945 (2007) Available at http://nobelprize.org/nobel_prizes/medicine/laureates/1945/ (20 February 2007).
5. C. Q. Choi, Scientific American. January 2007.
6. “Meet Resistance Head-On,” Scientific American. January 2007.
7. J. D. Siegel, E. Rhinehart, M. Jackson, L. Chiarello, Management of Multidrug-Resistant Organisms in Healthcare Settings, 2006 (2006), Available at http://www.cdc.gov/ncidod/dhqp/pdf/ar/ mdroGuideline2006.pdf (20 February 2007).
8. MRSA in Heathcare Settings (2006), Available at http://www.cdc. gov/ncidod/dhqp/ar_mrsa_spotlight_2006.html (20 February 2007)
9. What is CDC doing about MRSA? (2006) Available at http://www. cdc.gov/ncidod/dhqp/ar_mrsa_CDCactions.html (20 February 2007).