1. Why should you care about antibiotic resistance?

The effect of antibiotic usage impacts not only the individual, but also society. These drugs are the only therapeutic agents that are truly societal drugs, because the treatment of individuals can affect the family, the community and society at large. When treating an individual, we are not just targeting disease-causing organisms. We are also affecting the entire normal bacterial flora which are subsequently shed into the environment.

2. How transmissible is antibiotic resistance?

Resistance genes can easily spread. Some years ago, data from various laboratories suggested the increase of resistance genes to and from enterococci and the major gram-positive bacterial species to and from Escherichia coli and the gram-negative species.  It was also noted that mycobacteria have picked up tetracycline resistance genes originally disseminated among enterococci and staphylococci. The frequency of use of nucleotides in the DNA of the tetracycline resistance gene is so different from the mycobacterial host DNA that results suggest the event occurred within recent history, and emerged in this decade. Not only do bacteria exchange genes, but they also move via people, animals and plants.

3. Are your patients at risk of developing an antibiotic resistant infection?

Patients who frequently require diagnostic and surgical procedures are at high risk of infections related to them. Common patient-related factors for postoperative infection include age, nutritional status, underlying disease states (e.g., diabetes mellitus), presence of remote infection, uremia, hepatic disease, kidney disease and chronic lung disease, use of steroids, and cytotoxic and radiation therapy.

4. Is antibiotic resistance inevitable?

Resistance problems emerge when the numbers of resistant bacterial infectious agents reach a high proportion. The development of resistance as a clinical problem is not inevitable. It is the steady use of the antibiotic and the continous selection that propels the rare resistant mutants to prominence in an environment. A resistance problemhas arrived when you see that your patient has a resistant bacterial infection. The chance of finding a multiresistant pneumococcal infection in a child is probably millions of times greater now than it was 10 or 15 years ago.

The acquisition of resistance may be a rare event; an integration event may occur only once in 10 million bacteria. But once it has occurred, it can be selected and propagated. The reverse situation, loss of resistance gene(s), is not selectable. Moreover, when the new gene inserts into the chromosome or plasmid, it may cause changes which prevent it from coming out by the same way it went in. Therefore, the forward movement, the creation, development and selection of resistance which determines multidrug resistance, is a persistent problem precisely because its selection is so powerful, whereas its reversal is not. Moreover, loss will not emerge while continued antibiotic selection is present.

5. Where are antibiotics used and misused?

Antibiotics are used extensively in humans at home, and at hospitals, in animals, and in agriculture. In the United States, 48% of antibiotics are still being given to animals, and 90% of that is for growthpromotant use. Antibiotics are sprayed on fruit trees. Recently the American Society for Microbiology wrote a letter opposing a petition to the US Environmental Protection Agency to permit spraying gentamicin on apple trees to treat infection. This use of antibiotics delivers wide geographical selection; and residues could enter consumers. It came as a surprise that the application was even being considered. Treatment in any environment results in the selection of resistant bacteria and the continued exchange of transposons, integrons and plasmids. What was once a susceptible flora now becomes a resistant one. And the resistant bacteria can move to associate with other members of the environment - people and animals as well as plants.

6. What is the societal cost of the misuse of antibiotics?

The economic aspect of antimicrobial resistance may be the more compelling force to restore more prudent use of antibiotics. It was once estimated that for the United States alone, antibiotic resistance costs between $100 million and $30 billion annually. Another study concluded that at a minimum, resistant infections were twice as costly, in time and dollars, as a susceptible infection. As health care costs continue to rise, the economics of the problem will necessitate a change in how we use antibiotics.

7. Is antibiotic use the only factor influencing the increase of antibiotic resistance?

The antibiotic and the resistance determinant are the two major factors related to antibiotic resistance. Their interaction is compounded by the spread of bacteria and resistance genes. If antibiotic usage is limited, many antibiotic resistance determinants will not be selected. In Europe there is a big difference between the resistance frequencies in Northern Europe and the Mediterranean region. We can ascribe that to antibiotic use, but it could also be due to differences in infection control. There are too few data to explain the difference. Resistance originates as a local problem, so we all need to be vigilant and maintain good infection control measures combined with prudent use of antibiotics to circumvent escalating resistance.

8. Why do hospitals and nursing homes have high rates of antibiotic resistance?

In a study of nosocomial infections, it was found that infections correlated directly with the amount of direct contact of patients by physicians and nurses. Others have shown that in nursing homes and hospitals more than 50% of the antibiotic-resistant transmission was by cross-contamination. In health care facilities we have high levels of antibiotic use and high levels of person to person contact - both are important contributors to nosocomial infection. As you treat with an antibiotic, the numbers of resistant organisms increase. Spread from hospital personnel to patients is well documented. A closed environment such as the ICU is a breeding ground for resistant strains. There is a second compounding problem. When you stop using the antibiotic, the resistant strains do not decrease readily. They stay there since there is only a small difference in the growth rate between resistant and susceptible strains in the same bacteria. Eventually, however, with time, if you do not administer the antibiotic, the susceptible strains will come back.

9. What is the association between antibiotic use and the emergence of resistance?

To date, our understanding of the relationship between antibiotic use and the emergence of resistance is based on several lines of evidence.  First is the observed, correlated increase in antibiotic use and resistance development, coupled with our basic science understanding of resistance genes and their selection.  More direct evidence comes from a study which examined the effect of low doses of antibiotics used as growth promotants in animals.  Chickens raised from eggs were fed sub-therapeutic amounts of tetracycline in their feed.  Within 24-36 hours the chickens were excreting tetracycline-resistant E.coli.  As the number of weeks on tetracycline increased, other resistances in addition to that of tetracycline appeared in the E. coli strains.  This finding paralleled results reported previously in which chronic use of ampicillin for urinary tract infections of British women was associated with a multi-drug resistant fecal flora.  More recently, a Danish study correlated the amount of erythromcin used in different hospitals with the frequency of erythromycin resistance among staphylococci.  Likewise, a study of mupirocin, a relatively new treatment for Staphylococcus aureus colonization of the nose and skin, demonstrated that as the amount of mupirocin use increased, there was a dramatic increase in resistance to mupirocin among methicillin-resistant staphylococci.  While evidence is mounting, more research is needed to better understand the relationship between antibiotic use and the emergence of resistance.

10. Why do different resistance patterns occur in different areas of a country or the world?

The answer lies in the differences in usage. For example, large differences in total antibiotic use were reported from nine different hospitals in Sweden. Why? With such a homogeneous population and geography, one would have expected similar use, but this was not observed. Resistance is a local problem which is clearly linked to the amounts of antibiotics used in that hospital and to the attention given to infection control. In Denmark, MRSA has been greatly diminished by cohorting patients. In Denmark, Holland, Australia, and other countries, patients are screened as they enter the hospital. If they are found to have methicillin-resistant Staphylococcus aureus they are moved to other wards of the hospital for separate treatment. In Perth, Western Australia, hospitals aimed to keep MRSA out of the area while it was endemic on the eastern coast. They did this by triage, as in Denmark and Holland. Any patient with MRSA was put in a separate section of the hospital. This procedure worked. While the incidence of MRSA in the rest of Australia ranged between 11% and 25%, in Perth it was 0.4%. In hospitals in the US, we have an analogous system where patients with VRE or MRSA are kept in separate rooms with cross-contamination precautions.

11. Where do the resistant bacteria come from?

Resistant bacteria are acquired from the environment. One obvious source is in food. We cultured fresh fruits and vegetables looking for resistant bacteria. Among gram-negative lactose-fermenting bacteria, more than half found on many vegetables tested were resistant to multiple antibiotics. As a result of this study and others like it, uncooked fruits and vegetables were removed from the diets of immunocompromised patients or those receiving cancer chemotherapy at our hospital. A study of fecal flora among baboons in Amboselli National Park in Kenya compared the kinds of bacteria harboured by animals eating the refuse from the tourist camp with those of animals eating the roots of trees and other vegetation in the wild. Significantly greater numbers of resistant organisms were found among the animals foraging around the camp than among the animals eating a more natural diet. In a study of the effect of diet on drug-resistant intestinal flora, Corpet demonstrated a 1000-fold drop in tetracycline-resistant bacteria in six volunteers when he substituted a normal diet with one which was sterilized. These studies demonstrate that our fecal flora is dictated to a large extent by what we eat.

12. How can we reverse the drug resistance problem?

We must control the environmental densities of two major factors: the antibiotic and the resistance genes. Reduction of either component will lessen the generaton of antibiotic resistant bacteria.  In this effort, we can evaluate shorter or rotating courses of use. Education of the consumer as well as the prescriber is critically important. We need to find new drugs which can circumvent the resistance mechanisms or which have new targets. We also have to consider how to use the new drugs once we have them. It appears that the most effective approach will be that which restores the susceptible microbial flora.

There is a need for a global surveillance system to monitor where the organisms are, where they are being transported, and what new ones appear. These data will greatly assist in our understanding of the spread of resistance. Increased understanding of the science of resistance, the approach to clinical problems, and how we can deal with resistance in line with the ecological considerations, will lead to a return of the susceptible strains, which will help us diminish and curtail the drug resistance problem.

13. How can a health care institution improve usage?

Develop institutional ownership of the issues through the strategic planning process. Interlink resource allocation to the overall hospital strategic plan. Encourage physician buy-in through participation. Assess existing processes and identify opportunites for improvement. Establish a multi-disciplinary culture.

14. Who is at highest risk for developing an antibiotic resistant infection?

The numbers of patients who have compromised host defenses, such as organ transplant recipients, oncology patients and HIV-infected patients are increasing. These patients frequently require diagnostic and surgical procedures and they are at high risk for infections related to these procedures. These patients have intercurrent infections as well, resulting in the exposure of their skin, gastrointestinal and genito-urinary flora to repeated courses of broad spectrum antibiotics, which is a recipe for the development of resistance. The patient population is also getting older and surgical procedures are now performed on elderly patients who are at high risk for infection.

The patient-related factors for postoperative infection cited in most textbooks of surgery include age, nutritional status, underlying disease states such as diabetes mellitus, the presence of remote infection, uremia, hepatic disease, kidney disease and chronic lung disease. All of these are risk factors for postoperative infection even though they may or may not relate directly to the need for surgery. Steroids, cytotoxic and radiation therapy also place patients at risk and re-operation is always associated with an increase in respiratory infection.

15. What are some prevention strategies for surgical practice?

• Preventing the development of antimicrobial resistance will require the concerted efforts of both medical and surgical practitioners.
• Prescribing practices should be modified for example to eliminate, excessive antibiotic prophylaxis before surgery and to select the appropriate agent, route of administration, dose and duration of therapy.
• Adherence to infection control guidelines is important both in the operating room and in the postoperative recovery room.
• The use of antimicrobials as antipyretic should be discouraged.
• A strong institutional infection control presence is part of a good management strategy to limit risk in the surgical setting. Universal precautions should be taken and aseptic technique scrupulously followed. There should be a high staff-to-patient ratio wherever possible. Good housekeeping practices help to control the cleanliness of the surgical theatre, and the rational and limited use of antimicrobials should be encouraged.
• Adherence to the principals of good surgical technique becomes more important when the margin of safety provided by effective antimicrobials is threatened. In particular:
• We should aim to minimize the pre-hospital stay.
• Clipping hair should replace shaving whenever practical; shaving, if it must be done, should be done immediately before the procedure and avoided whenever possible.
• Tissues should be handled as gently as possible.
• The use of cautery should be minimized.
• Procedures should be selected based on consideration of the patient's general condition, using the narrowest spectrum agent possible for prophylaxis.
• Ensure that the timing of chemoprophylaxis is appropriate and accurate.
• The length of the procedure is an independent variable for postoperative infection and merits careful monitoring to decrease unnecessary intradepartmental variation.
• Opportunities for intraoperative contamination of the surgical site should be limited.
• For those patients at highest risk, non-surgical approaches should be considered when resistant pathogen risk is elevated.
• Whenever possible, devices and lines should be removed, immune suppression discontinued, and prosthetic materials avoided.
• Patients demands for antimicrobials should not be indulged; instead the rationale for the use or non-use of antibiotics in a given setting should be clearly explained.
• Finally, although technology has helped in many ways, it is advisable to maintain a healthy scepticism for any new technology and wait to see, as we do with pharmacological agents, that new devices or procedures are safe, efficacious, and cost effective. Newer is not always better.

Source: Royal Society of Medicine. 1997. Resistant Organisms: Global Impact on Continuum of Care edited by DK Henderson and SB Levy. International Congress and Symposium Series #220. New York, NY: RSM with support from 3M Healthcare