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The case for stronger antibiotic regulation
Nathan Nelson

Department of Physics, The Ohio State University, Columbus, OH 43210

ABSTRACT. Because the use of antibiotics actually promotes the spread of bacterial resistance, the use of antibiotics must be more heavily regulated. Bacteria gain resistance through three mechanisms, each requiring only minor biochemical modifications. The genes coding for each mechanism are readily passed among bacteria through several methods, allowing rapid transfer of resistance. Antibiotics are misused in the treatment of disease in humans and as growth enhancers in the food animal industry. With restricted antibiotic use, the proportion of resistant bacteria decreases. Trials of antibiotic regulation in Greece have been highly successful; polls among physicians suggest that similar regulations would be supported in the United States as well.

Because the use of antibiotics promotes the spread of bacterial resistance, their use in both humans and food animals must be more heavily regulated. The improper use of antibiotics acts as a natural selection pressure that favors the survival and reproduction of resistant bacteria. Therefore, the use of antibiotics increases the proportion of resistant bacteria in a population. Over 100 antibiotics are available for use in infected patients today.5 However, without stricter regulations, many of these will become ineffective in the next few years.

Penicillin serves as an example of the overuse of antibiotics. When penicillin was introduced to the public in 1944, it was hailed as a miracle drug, a "silver bullet" that killed bacteria but left the body unharmed. However, Alexander Fleming, the man who discovered penicillin, isolated bacteria in his laboratory that developed resistance to the antibiotic. Within two years of its introduction, 14% of all bacteria isolated from sick patients in London were resistant to penicillin. Because it was the only antibiotic available, penicillin was heavily used during the late 40's. By 1949, 59% of bacteria in sick patients were resistant to penicillin. Clearly, a method to resist the antibiotic had spread in the bacterial population.

Bacteria resist antibiotics by three mechanisms, each requiring only minor changes in biochemistry. First, bacteria may possess enzymes that degrade antibiotics. Originally, only Streptomyces sp. had genes for penicillinase, the enzyme that degrades penicillin, but now, even common bacteria like Escherichia coli, an intestinal bacterium, have these genes.6 Second, bacteria may replace or alter the method through which the antibiotic enters the cell. Within a few years of its introduction, bacteria had developed and rapidly spread several genes that encoded a molecular pump that bound tetracycline and actively transported it outside of the cell. Finally, bacteria may alter the cellular target site of the antibiotic. Erythromycin inactivates ribosomes, areas of the cell that construct proteins. Bacteria eventually evolved with slightly modified ribosomes to which erythromycin could not bind. Again, as with the other two methods, this method of resistance requires relatively simple biochemical modifications, even allowing other species of bacteria to easily incorporate them into their genome.

Several methods of genetic transfer allow bacteria to pass these mechanisms of resistance. Bacteria have special DNA elements called R plasmids that contain resistance genes and are easily passed to other bacteria. Bacteria may also take up random sequences of DNA encountered in their environment. If this DNA contains resistance genes, the bacteria could become resistant. Viruses can also serve as a means of DNA transfer. Occasionally, when viruses are made in an infected bacterial cell, DNA with resistance genes may accidently be encapsulated into a daughter virus particle. When this daughter virus infects another bacteria, DNA for antibiotic resistance is spread to that cell.6 Finally, since bacteria reproduce as rapidly as once every 15 minutes, if a cell contains resistance genes, all daughter cells will also have these genes. The large amount of transfer methods demonstrates the ease and speed at which an antibiotic resistance mechanism, once developed, can be passed to other bacteria. When antibiotics are present, the large number of transfer methods guarantees that resistance genes can be passed to other cells.

In humans, antibiotics are often used when unnecessary, and when they are necessary, often the wrong antibiotic is prescribed, selecting for bacteria that have developed or received a resistance mechanism. Antibiotics are necessary when an infection can not be eliminated through the bodies natural defenses; they are unnecessary when incorrectly prescribed for a viral infection like the "common cold." According to a study done by the Center for Disease Control, of the 150 million outpatient prescriptions each year in the United States, 50 million were estimated to be unnecessary.5 In other surveys, 80% of physicians in the United States admitted to writing outpatient prescriptions for antibiotics when they thought it unnecessary because their patients adamantly demanded antibiotics. Other studies have shown misuse in inpatient hospital care. During hospital stays, patients are often prescribed broad spectrum antibiotics which kill all types of bacteria, rather than targeting a specific population. In 70% of hospital cases, no tests were run to determine the type of bacteria present.2 Since broad spectrum antibiotics affect all bacteria, they select for resistance in harmless bacteria, giving them the potential to become pathogenic. For instance, five years ago Acinetobacter sp. and Xanthomonas sp. were harmless bacteria, but today cause pathogenic infections.5

Antibiotics are also misused as growth enhancing supplements in food animals. In any year, domestic food animals outnumber humans in the United States by five to one. Many of these animals are given antibiotics. In fact, 40% of all antibiotics made in the U.S. are used as growth enhancing supplements for animals. Antibiotics apparently reduce inflammation in the intestine and allow more efficient uptake of nutrients, enhancing growth. Approximately 25 mg of antibiotic per 2 kilograms of food saves 900 million kilograms of food each year because of more efficient growth of food animals.1 However, this large scale use acts as a tremendous selection pressure encouraging the spread of resistance genes.

Moreover, antibiotic resistant bacteria in food animals are able to pass their resistance to bacteria resident in humans and other species. A fascinating experiment was performed in the mid-1970s that proved this point. In this study, a group of 150 chickens was fed with food containing low levels of antibiotics, about 200 grams of tetracycline per ton of food. The other 150 chickens were the control group, and were given no antibiotics. Within 24 hours of the initial dose of oxytetracycline, resistant Escherichia coli had appeared in the intestine of the first group of chickens. Within five months, the Escherichia coli in the intestines of a family living 100 meters away from the chickens became resistant to the oxytetracycline, even though the family had not been eating the chickens. The resistance had been transferred merely through casual contact with bacteria in fecal matter while attending to the chickens.5

Interestingly, multiple resistance in bacteria often arises from overuse of just one antibiotic. This was found to be the case in the farm study just mentioned. In the chickens that were fed the oxytetracycline, within three months some of the Escherichia coli in their intestines were resistant to multiple antibiotics. The bacteria were resistant to tetracycline, ampicillin, streptomycin, and sulfonamides, even though the chickens had never received any of these drugs.5 This trend was also found in the human Escherichia coli three months later. R plasmids often carry genes for more than one antibiotic resistance. The Escherichia coli in this study eventually received an R plasmid that had oxytetracycline resistance as well as resistance to these other drugs. As the R plasmid was transferred, the Escherichia coli transferred resistance to all the drugs.

This overuse of antibiotics in humans and animals leaves a bleak picture of resistant organisms today. For many years vancomycin was regarded as one of the most powerful antibiotics. In 1991, vancomycin only failed to cure infections 0.3% of the time. By 1999, vancomycin failed at a rate of 7.9%, a 26 fold increase.6 Such an increase in ineffectiveness is correlated with frequency of use. Figure 1 demonstrates this point. Some of the most powerful antibiotics like tetracycline and ampicillin are no longer effective because of heavy use; the ineffectiveness increases almost linearly with the amount of use.

Figure 1. The relationship between resistant fecal strains and antibiotic use. The fecal strains were isolated from patients with diarrheal disease caused by bacterial infection. Clearly, the use of antibiotics correlates with the percentage of bacteria resistant to that antibiotic. Antibiotics and resistant fecas strains

When antibiotics are not present, bacteria with resistance genes are at a slight selective disadvantage compared to those without resistance mechanisms.4 As mentioned earlier, resistance mechanisms often require the production of extra proteins, as with penicillinase, or alterations to cellular components, like ribosomes, that may make them slightly less efficient. These resistance mechanisms require that bacteria synthesize additional nucleic acids or proteins, requiring energy that could be used for reproduction.

Because they are at a selective disadvantage, the incidence of antibiotic resistant bacteria decreases when antibiotics are not present. Therefore, regulation of antibiotics would slow and even reverse the increase in antibiotic resistant bacterial populations. Many studies have confirmed this theory. In the 1980's, Hungary heavily used penicillin to cure ear and sinus infections in children. This heavy use selected for resistant bacteria, specifically Streptococcus pneumoniae, the pathogen behind most of these infections. In the late 1980's, nearly 50% of all members of this species were not killed by penicillin. However, from 1983 to 1992, the use of penicillin in Hungary was cut in half by recommendations by the Hungarian National Institute of Public Health and as physicians realized the inefficacy of the drug. The levels of resistant Streptococcus pneumoniae dropped from 50% to 34% during this time period.

Regulation of antibiotics would take two forms. First, elimination of antibiotics as growth enhancers for food animals would greatly alleviate the resistance problem. Unfortunately, with lower growth efficiency, farmers would have to spend more money on food for the animals. However, with decreased antibiotic use, money would be saved that could be used as government subsidies to compensate the farmers for the loss. For instance, welfare programs would not have to pay for more expensive antibiotics if the older, currently ineffective, antibiotics again become useful.

Second, the use of antibiotics in human medicine must be regulated, and evidence exists that this regulation would be successful. In 1990, the Laiko General Hospital in Athens, Greece implemented a new policy for antibiotics. Several of the most popular antibiotics, such as cephalosporins and vancomycin, could be ordered from the pharmacy only after a physician filled out an order form outlining the antibiotic request. The request was reviewed by infectious diseases physicians before approval. Along with this restriction in policy, other programs were effected. Improved rules for hand washing were enforced, and educational programs for physicians on antibiotic misuse were created. As a result, the use of antibiotics in the hospital was reduced by 80%, with no deaths attributable to the policy. Within the span of a few years, the resistance of Pseudomonas aeruginosa to ceftazidime was reduced from 45% to 8% within the hospital. Before that time, 55% of infectious bacteria in the hosptial were resistant to amikacin, and 85% were resistant to gentamicin. After implementation of the policy, resistance to these antibiotics dropped to 12% and 19% respectively.3

Similar actions would be supported by a majority of physicians in the United States. In 1989, the Infectious Diseases Society of America sent out a questionnaire regarding antibiotic regulation to 881 physicians. Only 4.6% of the responses were against any interference in the use of antibiotics. 85.4% wanted increased education efforts for both physicians and the public and 87.3% actually favored controls of antibiotic use.3 These doctors realized that antibiotic use is often unnecessary and that increased regulation does not necessarily have to interfere with proper prescriptions.

Antibiotic use in animals and humans must be regulated for two main reasons. First, with overuse of antibiotics, more bacteria become antibiotic resistant. This has become of greater concern in the last few decades as bacteria gain resistance to even the most powerful antibiotics. Second, with restricted antibiotic use, bacteria actually lose their resistance to antibiotics, rather than maintaining a high level of antibiotic resistance in the population. Implementation of antibiotic restriction policies in Greece have been highly successful, and current feedback from physicians suggests that such restrictions would be both supported and successful in the United States.

References

1. J. A. Fisher, The Plague Makers. (Simon and Schuster, New York, 1994).

2. R. Gaynes and D. Monnet, in Antibiotic Resistance: Origins, Evolution, Selection and Spread, edited by D. Chadwick and J. Goode (John Wiley and Sons, Chichester, 1997), pp. 47-56.

3. H. Giamarellou and A. Antoniadou, in Antibiotic Resistance: Origins, Evolution, Selection and Spread, edited by D. Chadwick and J. Goode (John Wiley and Sons, Chichester, 1997), pp. 76-86.

4. R. E. Lenski, in Antibiotic Resistance: Origins, Evolution, Selection and Spread, edited by D. Chadwick and J. Goode (John Wiley and Sons, Chichester, 1997), pp. 131-141.

5. S. B. Levy, The Antibiotic Paradox. (Plenum Press, New York, 1992).

6. S. B. Levy, Scientific American, March 1998.