Education and debate

What can be done about resistance to antibiotics?

John Turnidge, director. 

Microbiology and Infectious Diseases, Women's and Children's Hospital, Adelaide, SA 5006, Australia

TurnidgeJ{at}wch.sa.gov.au

Antibiotic resistance is now generally accepted as a major public health issue, but it is less clear which interventions should be used and which will work. Our principal objective is to minimise antibiotic resistance and increase the likelihood that standard treatments continue to be effective, for many decades, in patients who genuinely need them. We also wish to eliminate adverse reactions and waste in health funding due to unnecessary use.

View larger version (88K): [in this window] [in a new window]   Streptococcus pyogenes

Direct evidence of the positive effects of intervention on reducing resistance is scanty. We know that it is possible to reduce antibiotic consumption in communities and countries. For instance, in the five years to 1994 per capita usage of antibiotics actually dropped in Australia, but in six other Western countries consumption has increased steadily over a decade.¹ Similar sharp drops in use of penicillin in Hungary followed the discovery of high rates of resistance in pneumococci.² In neither case is there yet direct evidence that resistance rates have dropped as a result. Recently, investigators in Finland have shown a considerable drop in the prevalence of erythromycin resistant Streptococcus pyogenes after a national campaign to reduce use of macrolides.³ Other researchers, however, have shown significant variation in the prevalence of erythromycin resistance in S pyogenes in the absence of any intervention to change macrolide use,⁴ suggesting that natural fluctuations in the spread of strains may also influence prevalence of resistance. Thus we are left largely with empirical and commonsense strategies.

Several learned groups, such as the Fogarty International Centre, a task force for the American Society for Microbiology, and the World Health Organisation, have produced recommendations about appropriate action.^5-7 International experts have also offered sound advice. ^{8 9} Each has recognised that a number of different processes must be put in place if there is any chance of success. It is generally agreed that the best way to reduce the selective pressure of antibiotics is to reduce usage. Australia and Hungary have shown that this is possible, but finding effective ways to do this is not simple. A coordinated cooperative effort between the professionals, patients, and regulators is required. The elements of this coordinated approach include education, regulatory measures, public health measures, surveillance, and further research.

Education of both professionals and the public is a key component to change. There have been many efforts over the years to improve rational use of antibiotics though education. Techniques such as the development of consensus guidelines¹⁰; promotion of rational prescribing methods, including better use of diagnostics¹¹; promotion of shorter treatment courses where these have been shown to be equally effective¹²; and the use of delayed prescribing (prescription is written but filled only if the condition worsens)¹³ have been used extensively. Additional techniquessuch as rotational usage in an individual patient or in a practice, the use of different antibiotic classes in different conditions to spread selective pressure, and a stronger emphasis on narrow spectrum agentsneed to be considered. None of these techniques will be effective, however, until the public becomes better educated about infectious diseases and the role of antibiotics, including such simple distinctions as the difference between viruses and bacteria. Ideally, this should start in secondary school as part of health education and biology courses. Patients should also be educated at the time of consultation, and the message that antibiotics are not useful in many common infections should be reinforced. Brochures and other educational material handed out at the time of consultation can help in this process, as is being tried in the United States and Australia. The risks of prescribing antibiotics when they are not needed must be emphasised, such as the side effects and potential for picking up resistant organisms and spreading them to others. This "green" message will be easier to sell now that the public is more aware of personal health and environmental issues. When antibiotics are prescribed, increased attention must be given to ensuring compliance¹⁴ and patients' understanding through such instruments as consumer product information leaflets.

View larger version (64K): [in this window] [in a new window]   Staphylococcus aureus lysed by an antibiotic (left)

There is a role for regulators. First and foremost, inclusion of microbial safety (in terms of resistance and cross resistance) in the safety evaluation of new antimicrobials would provide better focus on the full spectrum of adverse events associated with these drugs. Regulators also need to consider methods for restricting availability generally, such as controlling prescribers' access to therapeutically valuable agents (fluoroquinolones, for example), a familiar strategy in the teaching hospital environment. In countries where it is relevant, over the counter availability should be eliminated, and consideration should be given to separating prescribing from dispensing to minimise the risk of the practitioners' benefiting from prescribing broader, more expensive agents. Another technique that has recently been applied to the release of fluoroquinolones for veterinary therapeutic use in the United States has been the concept of granting a licence conditional on monitoring for the development of resistance.¹⁵ Here the regulator reserves the right to suspend marketing temporarily or permanently if resistance in potential human pathogens reaches significant levels. Unfortunately, defining these threshold levels has proved difficult so far. To balance the equation, incentives must be developed for the pharmaceutical industry to continue to develop and market antibiotics, especially ones that encourage the development or promotion of narrow spectrum agents, whose market will necessarily be smaller than that for agents with a broad spectrum.

Hospital specialists in infection control have long had a role in attempting to control cross infection with resistant bacteria, and their efforts have needed to be redoubled since vancomycin resistant enterococci have appeared.¹⁶ Nevertheless, there is room for improvement. Despite the stringent application of conventional infection control measures, there has been an inexorable increase in multiresistant Staphylococcus aureus in hospitals around the world.^17-19 Clearly, novel strategies are required if we are not to repeat this with the newly emerged vancomycin resistant strains.²⁰ Public health authorities should now consider reducing the transmission not just of infectious diseases but of antibiotic resistance. Although some of the current methods for control may be applied, novel methods will need to be developed for many organisms that are frequently commensal but increasingly resistant, such as Streptococcus pneumoniae. Critical evaluations of the role of non-human antibiotic use and transmission of resistant pathogens to humans need to be undertaken by competent public health bodies. ^{15 21} For developing countries with high resistance rates, simple public health measures such as improving levels of sanitation and access to uncontaminated water and reduction of overcrowding will help greatly.

To underpin the efforts of any interventions, reliable surveillance systems must be established. These systems provide information of prevalences of resistances and trends and, most importantly, they act as a barometer of whether interventions have been effective. They are also essential to providing guidance for empirical therapies such as those recommended in treatment guidelines.¹⁰ The American Society for Microbiology task force has carefully outlined the essential features of reliable resistance surveillance systems.⁶ In addition, surveillance of antibiotic use is vital to understanding the extent of the selective pressure and where regulatory or guideline changes may be made.¹ This component of surveillance has often been neglected in the past.

Further research is required in several areas. Improved diagnostic tests, especially those that might be applied at the bedside or at least be available within a few hours, will reduce empirical and unnecessary prescribing to an enormous extent. Understanding of the pharmacodynamics and population dynamics of antibiotic resistance is limited at present. A sharper focus on these areas will help us to determine optimum dosing schedules and durations of treatment.²² For instance, a recent study has shown an association with lower doses and longer treatment courses on the rate of carriage of penicillin insensitive Streptococcus pneumoniae.²³ Finally, it is essential that we do not run out of effective treatments for resistant organisms. There should be continued incentive to develop new antibiotics, alternative treatment modalities, and, most importantly, vaccines if we are to manage the rapidly emerging multi-resistances in the medium term.

References

1. McManus P, Hammond ML, Whicker SD, Primrose JG, Mant A, Fairall SR. Antibiotic use in the Australian community 1990-95. Med J Aust 1997; 167: 124-127[Medline].
2. Nowak R. Hungary sees an improvement in penicillin resistance. Science 1994; 264: 364[Free Full Text].
3. Seppälä H, Klaukka T, Vuopio-Varkila J, Muotiala A, Helenius H, Lager K, et al. The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. N Engl J Med 1997; 337: 441-446[Abstract/Free Full Text].
4. Stingemore N, Francis GRJ, Toohey M, McGechie DB. The emergence of erythromycin resistance in Streptococcus pyogenes in Fremantle, Western Australia. Med J Aust 1990; 150: 626-631.
5. Wallace CK, ed. Antibiotic use and antibiotic resistance worldwide. Rev Infect Dis 1987; 9(suppl 3): S231-S316.
6. American Society for Microbiology. Report of the ASM task force on antibiotic resistance. Washington, DC: ASM , 1995.
7. O'Brien TF, ed. Monitoring and management of bacterial resistance to antimicrobial agents: a World Health Organisation symposium. Clin Infect Dis 1997; 24(suppl 1): S1-176.
8. Levy SB. Confronting multidrug resistancea role for each of us. JAMA 1993; 269: 1840-1842[Medline].
9. Murray BE. Can antibiotic resistance be controlled? N Engl J Med 1994; 330: 1229-1230[Free Full Text].
10. Therapeutic guidelines: antibiotic. 10th ed. Melbourne: Therapeutic Guidelines , 1998.
11. McIsaac WJ, White D, Tannenbaum D, Low DE. A clinical score to reduce unnecessary antibiotic use in patients with sore throat. Can Med Assoc J 1998; 158: 75-83[Abstract].
12. Pichichero ME, Cohen R. Shortened courses of antibiotic therapy for otitis media, sinusitis and tonsillopharyngitis. Pediatr Infect Dis J 1997; 16: 680-695[Medline].
13. Little P, Williamson I, Warner G, Gould C, Gantley M, Kinmonth AL. Open randomised trial of prescribing strategies in managing sore throat. BMJ 1997; 314: 722-727[Abstract/Free Full Text].
14. Cockburn J, Reid AL, Bowman JA, Sanson-Fisher RW. Effects of intervention on antibiotic compliance in patients in general practice. Med J Aust 1987; 147: 324-328[Medline].
15. World Health Organisation. The medical impact of the use of antimicrobials in food animalsreport of a WHO meeting, Berlin, Germany, 13-17 October 1997. Geneva: WHO , 1997.
16. Hospital Infection Control Practices Advisory Committee. Recommendations for preventing the spread of vancomycin resistance. Infect Control Hosp Epidemiol 1995; 16: 105-113[Medline].
17. Panalilio AL. Methicillin-resistant Staphylococcus aureus in US hospitals, 1975-1991. Infect Control Hosp Epidemiol 1992; 13: 582-586[Medline].
18. Keane CT, Coleman DC, Cafferkey MT. Methicillin-resistant Staphylococcus aureusa reappraisal. J Hosp Infect 1991; 19: 147-152[Medline].
19. Turnidge J, Nimmo G, Francis G, the Australian Group on Antimicrobial Resistance. Evolution of resistance in Staphylococcus aureus in Australian teaching hospitals. Med J Aust 1996; 164: 68-71[Medline].
20. Edmond MB, Wenzel RP, Pasculle AW. Vancomycin-resistant Staphylococcus aureus: perspectives on measures needed for control. Ann Intern Med 1996; 124: 329-334[Abstract/Free Full Text].
21. Witte W. Medical consequences of antibiotic use in agriculture. Science 1998; 279: 996-997[Free Full Text].
22. Kozyrskyj AL, Hildes-Ripstein GE, Longstaffe SEA, Wincott JL, Sitar DS, Klassen TP, et al. Treatment of acute otitis media with a shortened course of antibiotics: a meta-analysis. JAMA 1998; 279: 1736-1742[Abstract/Free Full Text].
23. Guillermot D, Carbon C, Balkau B, Geslin P, Lecoeur H, Vauzelle-Kervroëden A, et al. Low dosage and long treatment duration of -lactam. Risk factors for carriage of penicillin-resistant Streptococcus pneumoniae. JAMA 1998; 279: 365-370[Abstract/Free Full Text].