Antimicrobial Resistance: Dentistry's Role
Daniel A. Haas, DDS, PhD, FRCD(C)
The resistance of bacteria, fungi and viruses to antimicrobials is increasing rapidly, with deleterious consequences. Dentistry's role in this development is unclear, because the necessary information has not yet been collected. Nevertheless, dentists should recognize that it is essential to use antimicrobials in an appropriate and responsible manner, both to treat infection effectively, and to minimize the likelihood that the bacteria in the general population will develop resistance to antimicrobials. The purpose of this article is to make dentists aware of the concerns raised by antimicrobial resistance, and how it can be avoided.
Antibiotics are invaluable drugs in the management of infectious disease. Unfortunately, their value is being jeopardized by the presence of microorganisms resistant to their effects.1-19 This resistance was first observed in the 1940s, when it was discovered that penicillin was no longer always effective against Staphylococcus aureus. Since then, a succession of new antibiotics has been required to cope with the ongoing emergence of new strains of resistant bacteria, which have rendered even newly-formed drugs ineffective. The competition between new drug development and the emergence of new resistant organisms continues today. Currently, the most serious concern is that the bacteria are winning the race.
The emergence of resistant organisms has potentially serious consequences for society. Infection by resistant microorganisms can be fatal to susceptible individuals, such as the immunocompromised, the elderly, and the debilitated. In May 1997, this concern led Health Canada and the Canadian Infectious Disease Society to organize a national conference entitled "Controlling antimicrobial resistance: an integrated action plan for Canadians," which was held in Montreal. The goal of the conference, at which the authors of this article represented the Canadian Dental Association, was to develop a plan to limit the development and transmission of antimicrobial resistance in Canada.
A number of recommendations aimed at reducing the threat of antimicrobial resistance were formulated during the conference. As a result of these recommendations, a Canadian coordinating committee on antimicrobial resistance will be convened, and a surveillance system will be established that, in part, will help to identify the scope of antimicrobial resistance and antimicrobial usage in long-term care facilities. Another goal espoused by the conference is to achieve a 25 per cent overall reduction in the number of prescriptions for antimicrobials within three years, which could be achieved by focusing on community acquired respiratory infection. In addition, the perceptions of both the public and physicians about the risks and benefits of antimicrobial therapy will need to be improved.
Antimicrobial resistance is an issue that affects all Canadians, including dentists. The purpose of this article is to raise dentists' awareness of antimicrobial resistance by reviewing the current status of the problem, and considering ways in which dentists can minimize our potential contribution to it.
The issue of antimicrobial resistance is no longer a topic of discussion for scientists and health professionals alone. There is an increased public awareness of the importance of antimicrobial resistance, stemming largely from reports in the media, including several published on the front pages of national newspapers.20,21
This exposure has made our patients much more knowledgeable on the subject of antimicrobial resistance, and we should be prepared to answer their questions. To help facilitate these discussions, Table I provides a brief glossary of the current terms.
Antimicrobials include antibacterial, antifungal and antiviral drugs. Although the term antibiotic strictly refers to the chemical substances produced by microorganisms, the common usage is to include synthetic compounds as well. Antibiotic use is very widespread. In 1996 in Canada, physicians wrote over 26 million prescriptions for antimicrobials, with amoxicillin being the one most commonly prescribed.29 The number of antimicrobial prescriptions written by dentists is not known at present. In the United States, more antibiotics are sold than over-the-counter medications. Currently, one prescription for antibiotics is written for every six physician visits.14 In a day-care centre of more than 25 children, at least one child will be on an antimicrobial agent each day. Antibiotics are often prescribed for infections that are viral in origin, even though antibiotics are ineffective in these cases. This inappropriate prescribing may be attributed to pressure being put on the physician by the patient or parent to do something active, as opposed to letting an ear infection or respiratory infection resolve on its own. However, inappropriate prescribing leads to the selection of resistant microorganisms, and to an increased transfer of the genes responsible for this resistance from the resistant organisms. The increased use of broader-spectrum antibiotics and the widespread use of antimicrobials for immunocompromised patients have also contributed to the selection of multi-drug resistant organisms that cause nosocomial (hospital acquired) infections.30
Which organisms are involved? Whereas penicillin was once very effective against Staphylococcus aureus, today over 95 per cent of all Staphylococcus aureus are resistant to penicillin. Other examples of resistant bacteria include penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus (VRSA), vancomycin-resistant e nterococcus (VRE), Candida albicans resistant to fluconazole, herpes simplex virus resistant to acyclovir, 31 multi-drug resistant tuberculosis, and human immunodeficiency virus (HIV) resistance to zidovudine.32 Infection by any of these organisms may require treatment options that are currently limited or unavailable, and all of these organisms or agents can kill susceptible individuals.
It is worth noting that approximately 50 per cent of all the antibiotics produced today are used in agriculture, including fish farming.15In spite of the extensive use of antibiotics in agriculture, their impact on the development of antimicrobial resistance has not been fully investigated. Approximately 60 per cent of the antibiotics used in food animals are administered for disease prevention, 25 per cent to promote growth, and only 12 per cent to treat a specific identifiable disease. Nevertheless, the antibiotics employed in food production could result in human exposure to resistant organisms.
Infectious organisms may develop resistance to antibiotics and antimicrobials by a number of mechanisms, as summarized in Table II. Microorganisms can produce enzymes that destroy the administered drug. For example, Staphylococci produce the enzyme beta-lactamase, which destroys penicillin and cepha-losporins. In some cases, microorganisms can change their permeability and not allow the prescribed drug to invade them. Tetracycline resistance is an example of this mechanism. In other cases, the receptor site for the drug may be altered, which is the mechanism underlying erythromycin and vancomycin resistance. Metabolic pathways may also be altered, as is found with sulfonamide resistance. Other mechanisms are known as well, and bacteria continue to develop new means of resisting the effects of antibiotics. The mechanisms of resistance to the antibiotics used in dentistry are listed in Table III.
Patients may develop a drug-resistant infection either by contracting a resistant microorganism or by having the resistance arise once antibiotic treatment has begun. A spontaneous mutation may occur, or resistance can be transferred from one species to another through DNA strands or plasmids. Even unrelated bacteria may share genetic information, an ability that was unanticipated during the first two decades of antibiotic use. In addition, because some of the antibiotic resistance genes are acquired as a group, the microorganisms that receive one of these genes frequently become resistant to other unrelated antibiotics. Once a microorganism becomes resistant, there is selective pressure favoring its growth as other, nonresistant organisms are eliminated by the antimicrobial drug.
Most antibiotics originate either directly from a microbe, or are chemically-modified versions of products produced by microbes.43 Does every new antibiotic require bacteria in order for new mechanisms of resistance to develop? The simple answer is no. Bacteria represent an extremely diversified branch of living organisms, which have been living with each other for millions of years in places such as the sea, hot springs and soil. Bacteria have developed a variety of resources that make them capable of resisting environmental pressures. 2,5-7,9,10 Their short generation times facilitate their ability to deal with the drugs aimed at harming them. Bacteria have an extremely long history of successfully dealing with each other's stratagems, including antibiotics.
Particular antibiotics provide the kind of environmental pressures that promote the development of bacterial resistance not only to themselves, but also to other unrelated antibiotics. Researchers have recently looked at collections of bacterial strains that pre-date the introduction of antibiotics into clinical use, and have found bacteria that were resistant to tetracycline or erythromycin.44
Oral bacteria make substances called bacteriocins that interfere with each other.45-47 Mammalian mucosal cells and white blood cells make a wide array of peptide antibiotics that are now termed defensins. Oral bacteria have evolved in the presence of mucosal defensins48,49 and, like all other bacteria, have a long history of responding successfully to antimicrobial challenge.
Dentistry's impact on the development of antimicrobial resistance is not known at present, but researchers are beginning to look at this question. Our contribution is difficult to determine, as there are currently no accurate data available in Canada on the number of prescriptions for antibiotics being written by dentists. Whatever the statistics on dental prescribing show eventually, it is already recognized that dentists must use antibiotics appropriately.1,12,13,18,19
Antibiotics should be used only for the management of active infectious disease or to prevent the potential systemic spread of infection in a patient known to be at risk.12,18 The guidelines for prophylaxis against bacterial endocarditis, as well as the recommendations for more limited antibiotic use in patients with total joint replacement, have recently been updated.50,51 It is important to follow these revised recommendations, and to only use prophylactic antibiotics when there is a clear indication to do so. The new recommendations were developed, in part, in response to the recognized problem of microbial resistance to antibiotics.
Orofacial infections must be treated with local drainage whenever possible. Antibiotics should be considered as adjuncts to treatment when there are signs of systemic involvement, such as extraoral, neck or intraoral airway swelling, or fever. Antimicrobials are not the primary treatment for dental infections, except in the case of primary spreading cellulitis. Antibiotics should be used very selectively in periodontal treatment, and ideally only in selected patients where a laboratory has identified the presence of specific target organisms.
The routine use of antibiotics before or after extractions or endodontics has not been shown to be effective.1,52 Therefore, routine prescribing for every extraction or endodontic procedure must be discouraged. Before prescribing antibiotics, we should weigh the risks of resistance and allergy against any potential benefit. Our decisions on antibiotic use should be supported by the current literature, which is continually being updated as bacteria develop new "tricks" to cope with antibiotics.
Recommendations on the use of antibiotics are evolving.1,18,53 General principles for prescribing antimicrobials that are consistent with these recommendations are summarized in Table IV. The approach of using long durations of antibiotic therapy is now being challenged. It has been suggested that antibiotics should instead be used in sufficiently high doses for short durations. Clinical judgment must be applied, but most acute odontogenic or periodontal infections will resolve in three to seven days. Prescribing beyond that duration should only be done selectively. When using antibiotics orally, loading doses should be considered to achieve therapeutic levels more rapidly. There must be a clear indication to prescribe. In addition to the risk of promoting resistance, practitioners prescribing antibiotics must consider the potential for drug allergy, gastrointestinal side effects, and the risk of secondary infections such as Candida. In the case of superficial infections, topical antiseptics (e.g. chlorhexidine) or antifungals should be considered instead of systemic antimicrobial agents.
The administration of any drug carries with it risks that must be considered against the potential benefits. Only if we determine that the benefits of a drug outweigh the risks involved for a particular patient should we proceed with its use. We should reconsider routine or automatic prescribing that does not involve adequate clinical investigation or the pursuit of alternative therapies. The exposure of the general population to antibiotics must be reduced to avoid pressuring bacteria into taking evasive measures that will make otherwise useful antibiotics ineffective. We all have to live with the ability of bacteria to adapt to antibiotics. The inappropriate use of antibiotics may affect not only the patients who receive them, but the entire population, including each of us and every member of our own families.
The authors represented the Canadian Dental Association at the conference entitled, "Controlling antimicrobial resistance: an integrated action plan for Canadians," which was organized by Health Canada and the Canadian Infectious Disease Society, and held in Montreal in May, 1997.
Dr. Haas is an associate professor in the faculty of dentistry and department of pharmacology in the faculty of medicine at the University of Toronto, as well as with the department of dentistry, Sunnybrook Health Science Centre.
Dr. Epstein is head of dentistry at the Vancouver Hospital and Health Sciences Centre; on the medical-dental staff of the B.C. Cancer Agency; professor and head of hospital dentistry at the University of British Columbia; and research associate professor at the University of Washington.
Dr. Eggert is a professor with the department of oral health sciences, faculty of medicine and oral health sciences, University of Alberta, and chair of the CDA committee for consumer products recognition.
Reprint requests to: Dr. D. Haas, Faculty of Dentistry, University of Toronto, 124 Edward St., Toronto, ON, M5G 1G6.