Return to PJ Online Home Page
Hospital Pharmacist Vol 7 No 7 p183-187
July 2000 Special Features

Antibiotic resistance

Restrictive antibiotic policies - how effective are they?

By D. Binyon MSc, MRPharmS and R. P. D. Cooke, FRCP, FRCPath

In the second part of our special feature, the authors consider how effective programmes which discourage indiscriminate antibiotic use have been
The first part of the feature covers hospital acquired infection

The overuse of antibiotics has led to increasing concerns about bacterial resistance which led to a House of Lords Select Committee1 and the Department of Health2 issuing reports which proposed a course of action for the NHS. The four key elements identified were strategy, surveillance, prudent antibiotic use and infection control. The problem of antibiotic overuse is an international one and alarm had been expressed in the United States for several years.3 Although there is no absolute proof that antibiotics cause resistance, most authorities believe that a link is almost certain.4

Extent of antibiotic overuse The two major areas of concern are in the agriculture industry, where low levels of antibiotics are added to animal foodstuffs to reduce illness (such as the glycopeptide antibiotic avoparcin, now banned within the European community) and the prophylaxis and treatment of human illness. Twenty per cent of antibiotic prescriptions relate to hospitalised patients, while the rest occur in the community. It has been estimated that between 20 to 50 per cent of this use is unnecessary.5 Spending on antimicrobial drugs in UK hospitals represents almost 20 per cent of total hospital drug expenditure and between 25 to 50 per cent of all patients admitted to hospital will receive an antimicrobial agent at some stage during their stay.6 Unfortunately, doctors often prescribe antibiotics excessively and inappropriately, for various reasons (see Panel 1).7 In addition, staff compliance with basic infection control practices, such as handwashing, is often inadequate. Furthermore, shortage of health care staff and isolation facilities often make controlling the spread of antibiotic-resistant bacteria difficult in hospitals.

Bacterial resistance

Resistance in bacteria can be intrinsic or acquired and may occur by mutation or acquisition of DNA. Transferable resistance was first recognised in 1959 when resistance genes found in Shigella spp transferred to Escherichia coli via plasmids. Mutation is the commonest mechanism of resistance development in Mycobacterium tuberculosis.8
There are generally considered to be four main mechanisms by which bacteria can protect themselves from antibiotics:

Panel 1: Reasons doctors gave for overprescribing antibiotics

  • Insufficient training or lack of education (on the part of providers and patients) in infectious diseases and antibiotic treatment
  • Difficulty in selecting the appropriate anti-infective drugs empirically
  • Insufficient use of microbiological information
  • Need for doctors to reassure themselves that the treatment they prescribe will be effective
  • Fear of litigation which prompts the use of broad spectrum drugs
  • Patients' expectations
  1. Antibiotic modification is the best known and occurs when the sensitivity of the target within the bacteria remains the same but the antibiotic is prevented from reaching it. An example is the beta-lactamase enzyme cleaving the four-membered beta–lactam ring of penicillins and cephalosporins, rendering the antibiotic inactive.
  2. Some bacteria can prevent the antibiotic from entering the cell or are able to pump it out faster than it can flow in. Imipenem-resistant Pseudomonas aeruginosa lacks a specific D2 porin in its cell membrane, which confers resistance because imipenem cannot then penetrate the cell. Tetracycline-resistant bacteria show increased efflux of the antibiotic via an energy-dependent transport pump.
  3. Changes to the site of action may occur because of structural alterations in the molecule. Most strains of Streptococcus pneumoniae are highly susceptible to penicillins and cephalosporins, but they can acquire DNA from other bacteria (eg, enterococci) which changes the enzyme responsible for penicillin-binding proteins (PBPs) production. The altered enzyme still synthesises peptidoglycan but it now has a different structure and this results in a reduced capacity to bind penicillin.
  4. The final mechanism is the production of an alternative target (usually an enzyme) that is resistant to inhibition by the antibiotic. An example is the production of an alternative binding protein (PBP2 a) which is produced in addition to the "normal" PBPs by methicillin-resistant Staphylococcus aureus. In 1987, the appearance of vancomycin resistant enterococci (VRE) aroused interest because the genes involved could be transferred, in vitro, to Staph aureus. Resistance of Staph aureus to vancomycin in vivo has recently been reported in several countries.

Antibiotic policies

Policies are thought to be more rigorous and fixed in their suggestions whereas guidelines are more flexible and acknowledge that some patients will fall out of the recommendations. There are also legal aspects to consider: it is more difficult to justify action outside of policies than guidelines. In spite of these distinctions between policies and guidelines, however, they will be used interchangeably in this article.

Adherence Regardless of whether policies or guidelines are chosen however, one of the most important factors that will guarantee their success is the level of adherence to them. When evaluating a policy, it has been suggested that prescribers prefer and adhere more closely to policies that take an educational rather than a restrictive approach.9 Unfortunately, it has been difficult to come to a consensus on educational strategies, partly because of the complex interaction between doctors and patients or parents over antibiotic use.10
Several microbiology societies have published guidelines for optimising antibiotic use and curtailing antibiotic resistance in hospitals.7,11 These guidelines are based more on expert opinion and on the results of descriptive and analytical studies rather than on randomised, controlled trials.

Effects of policies The principal aim of an antibiotic policy is to improve the quality of prescribing. This should lead to a reduction of resistance, decreased cost and improved patient care. Before embarking upon the development, dissemination and subsequent implementation of an antibiotic policy, clinicians and key decision-makers need to be clear on how they plan to evaluate its impact. Quality indicators need to be identified. The number and complexity of these indicators will be dependent on local resources. They must be specific to the organisation, simple, measurable and meaningful. Panel 2 shows the key components of antibiotic policies.
A recent National Audit Office report suggests that hospital-acquired infections could be cut by 15 per cent through effective infection control measures and that the NHS "generally could do more to improve its strategic management" of infection, (a fifth of NHS trusts did not have an infection control programme). This must include antibiotic control.12

Presentation Antibiotic policies can be presented in a wide range of styles, from computer programmes to a single folded card, depending upon local facilities and preferences. The publication date of the policies should be included, along with a proposed review date. Trust policies tend to be targeted at junior hospital doctors while policies by health authorities should have GPs as their target audience. It makes sense to ensure that policies for both hospital and community clinicians are complementary and do not give conflicting advice. Whenever possible, policies should provide references to support their contents. For evidence-based antibiotic policy development, there are a number of reviews which could be used for guidance (for example, meningococcal treatment and prophylaxis13 and antibiotic prophylaxis for asplenic patients14).

Surveillance Surveillance on antibiotic resistance rates is essential to help doctors choose appropriate antibiotics and to detect local outbreaks. Good quality local data will also provide a basis for national and international surveillance. It is also important to know the patterns of antibiotic prescriptions so as to identify where clinical practice needs to be improved.15 To reduce antibiotic consumption, a multifaceted approach has been proposed that includes education of doctors, widely accepted recommendations for good clinical diagnosis and treatment, and a follow-up of compliance by audit. Restrictive policies, such as the requirement for written justification or automatic stop orders, are also useful inclusions to a policy in hospital settings. Such integrated strategies have reduced antibiotic use or curtailed antimicrobial resistance.16,17,18

Panel 2: Key components of antibiotic policies

  • 1. Multidisciplinary co-ordination between hospital administrators, clinicians, infectious disease specialists, infection control teams, microbiologists and hospital pharmacists
  • 2. Formulary-based local guidelines on anti-infective treatment
  • 3. Only sensitivity data to be reported for antibiotics included in the policy
  • 4. Education and regulation of prescribers by consultant specialists
  • 5. Monitoring and auditing drug use
  • 6. Surveillance and reporting of bacterial resistance patterns
  • 7. Detection of patients colonised with multi-resistant microbes
  • 8. Emphasis on basic infection control practices, especially handwashing before and after patient contact

Complementary factors In addition, improving basic infection control measures is crucial in preventing the spread of resistant bacteria. Only 40 to 50 years ago, hygienic measures were considered the most important means of preventing the spread of transmissible diseases. In hospitals, effective prevention of cross infection and the development of strict antibiotic policies should be led by the local infection control team.11

Barriers to policy implementation To achieve a more judicious prescribing of antibiotics requires an understanding of the factors that promote overuse (Panel 1), the barriers to change as well as effective strategies for changing behaviour.
Patients with lower educational levels seem to have the greatest misconceptions about antibiotic use.19,20 Doctors' prescribing behaviour is affected by real or perceived expectations of patients regarding antibiotics.10 Breaking the cycle requires educating the public that past practices are no longer acceptable and convincing doctors that a patient's satisfaction is based more on good communication than on the availability of a prescription.21
The Department of Health is striving to improve patient education by producing information leaflets describing how antibiotics are not always in the patient's best interest. This should be supported by the further development of guidelines on common conditions, such as common respiratory illnesses, where antibiotic prescriptions are often excessive.22

Educational support A recent review suggested that locally developed guidelines are more likely to be accepted and followed than those developed nationally.23 Many studies have shown that education at an individual or small group level and peer pressure are effective strategies in changing doctors' antibiotic prescribing behaviour.24,25 The effectiveness of peer education is enhanced when the message is delivered or endorsed by local opinion leaders and is made relevant to the doctor's own practice. Previous successful programmes have used clinical pharmacists.24
Providing feedback to clinicians regarding their antibiotic prescribing practices has been a successful technique for achieving behaviour change.26 Feedback can entail comparisons with peers or an accepted standard. Computer-assisted decision support can also improve antibiotic prescribing in hospitals and could be extended to community settings.27

Evidence

It is very difficult to construct well-designed, randomised, controlled trials to demonstrate how effective an antibiotic policy is at reducing antibiotic resistance. Nevertheless, the link between antibiotic use and antimicrobial resistance has been demonstrated in a number of papers. They are discussed below.

The global picture In Finland, the proportion of group A streptococcal infections resistant to macrolides was nearly halved after a successful campaign to reduce the use of macrolide antibiotics.18 A cross sectional survey in Iceland found that carriage of penicillin-resistant pneumococci was strongly associated with both individual and community-wide levels of antimicrobial use.28 Countries with a lower incidence of methicillin resistant Staph aureus (MRSA) infections tended to be those which were more restrictive in antibiotic use, applied strict infection control measures, and that had better ratios of nurses to patients in their health care institutions.29 In the United States, acquired vancomycin resistance has increased more than 20-fold among nosocomial isolates of enterococci. This rise has paralleled a massive increase in the use of vancomycin in American hospitals.30

Specialist units Much attention is currently being focused on the development of resistance in specialist units with highly immunocompromised patients. In one recent study based on a neonatal intensive care unit (NICU), the authors examined resistance rates in neonatal sepsis. They showed that by using penicillin G and tobramycin for early-onset sepsis or flucloxacillin and tobramycin for late-onset sepsis, the development of resistant bacilli only occurred in three out of 218 cases. This compared favourably with 41 out of 218 cases in the comparator NICU where amoxicillin and cefotaxime were the broad spectrum antibiotics routinely used. The study was performed over a one-year period with the units exchanging regimens after six months. The authors concluded that policies for the empirical use of antibiotics do matter in the control of antimicrobial resistance. A regimen that avoided amoxicillin and cefotaxime reduced the resistance problem.31
A paediatric study evaluated the effects of an antibiotic restriction policy on expenditures, antimicrobial resistance rates and clinical outcomes of hospitalised children two years prior to and after restricting antibiotic use in Panama. Total expenditure on antimicrobial agents decreased by 50 per cent. Susceptibility rates of many nosocomial isolates (especially staphylococci and Gram negative enteric bacilli) usually improved with restricted antibiotic usage with more than 35 per cent reduction in utilisation (notably for gentamicin, third generation cephalosporins, piperacillin and vancomycin). Major improvements in bacterial susceptibilities were observed.32

Clostridium difficile infection Another complication of the overuse of antibiotics is the risk of C difficile infection (CDI). At Eastbourne district general hospital, we have monitored the effects of our own restrictive antibiotic policy on the incidence of CDI.33 Despite the rising incidence of CDI reported nationally,34,35,36 we showed that by developing, implementing and monitoring a restrictive prescribing policy, the incidence could be maintained at a relatively low rate. The annual rate of C difficile toxin A positive stool samples fell from 12 to 8.3 per cent between 1993 and 1998 in the hospital. Our policy was based predominantly on national formulary recommendations, taking into account local resistance patterns. Restricted antibiotic usage followed the guidelines for specialist use established within the clinical directorates. We concluded that the incidence of CDI can be controlled by strict application of a restrictive antibiotic policy, provided there is close liaison with ward-based clinical pharmacists and medical microbiologists.

Policy effectiveness Not all restrictive antibiotic policies have shown success in curbing either drug expenditure or reducing resistance. Gould and Jappy described the implementation of a restrictive antibiotic policy for use in all hospitals in the Grampian region with the intention of improving the quality of prescribing and controlling escalating drug costs.37 Their policy was implemented in 1988 and was monitored by the pharmacy and microbiology departments. Unfortunately, the antibiotic expenditure increased from 11.9 to 18.7 per cent, even though hospital activity changed little. New antimicrobial agents accounted for 9 per cent of defined daily doses but represented 66 per cent of the increased costs. In discussing the effects of the policy, they suggested that any beneficial effects on controlling the levels of use were limited, as antimicrobial prescribing increased by 33 per cent. They also described a rise in the isolation of CDI by five-fold during the study. Explaining the increased prescribing of antibiotics, they implicated prolonged perioperative antibiotic prophylaxis, antibiotic prophylaxis in immunocompromised patients, and empirical broad spectrum prescribing rather than directed therapy based on microbiological data. They also recommended raising the profile of microbiologists and pharmacists in monitoring reserve list drugs in order to contain rising prescribing costs and control antibiotic usage. Some studies, however, have reported success in reducing antibiotic usage but without a corresponding reduction in resistance rates. One study, designed to link the use of vancomycin with vancomycin resistant streptococci (VRE) reviewed the appropriateness of vancomycin therapy, changes in vancomycin use, and incidence of VRE after implementation of a limited restriction policy. The policy required clinicians to obtain permission from an "Infectious Diseases Approval Service" if they wanted to continue vancomycin therapy beyond 72 hours. Pharmacy billing data and infection control data were compared before and after policy implementation. Overall, the total amount of vancomycin in grams used during the study decreased by 9 per cent. However, the incidence of VRE remained unchanged two years after policy implementation. One-third of vancomycin therapy was considered inappropriate.38

The role of pharmacists

The Guild of Healthcare Pharmacists has recently issued a policy statement on the safe use of antibiotics and antimicrobial agents. The policy offers guidance to members on their responsibilities as pharmacists. It encourages closer working relationships between pharmacists, microbiologists and other clinicians with the pharmacist taking on a linking role between the microbiologist and the prescribing clinician. Pharmacists need to be actively involved at a strategic level. Health service circular (HSC) 1999/049 defines the need for action to strengthen the prevention and control of infection, monitor and optimise antimicrobial prescribing and improve surveillance of communicable disease and infection caused by organisms resistant to antimicrobials. The circular also advises that pharmacists be included in the infection control activities of hospitals.

Audit

Under the clinical governance framework, audit is the key to promoting education and changing prescribing practices. Modifying established practice is hard and maintaining change is often considered a fantasy. This emphasises the importance of the cycle of standard setting, audit, feedback (education) and re-audit. A European group has recently been formed to assess the performance of policies across Europe in order to establish the best methods of antibiotic stewardship. Parameters that can be used to assess the comparative performance of policies will be discussed and will include antibiotic resistance rates.39

Summary

Both patients and doctors must reduce their expectations over the role of antibiotics. Patients must be educated that many common infections are viral in origin and do not require antibiotics. Antibiotics may actually be harmful to them and their families. The American Academy of Paediatrics has made a start in giving guidance to parents.40 The coming years will undoubtedly see the introduction of strict clinical guidelines on antibiotic prescribing. More firm guidance is also required on the optimum length of treatment. Surveillance of antibiotic resistance rates must be undertaken both locally and nationally.
The optimal antibiotic control measures remain to be established and will probably vary between institutions. Nevertheless, various control measures have been shown to be useful in reducing the cost of antibiotics, while maintaining the quality of patient care. More recently, interest has turned to whether antibiotic policies can reduce the spread of resistance and even reverse current high levels. Early studies indicated that this was feasible, but mathematical models and the recent discovery of the role of transposons and integrons in multi-drug resistance have both cast doubt on future success in this area. Nevertheless, there have been some major successes in recent studies, both in the community and hospitals. While cross infection is a major impediment to the control of resistance, there is little doubt that careful antibiotic prescribing combined with effective infection control can curtail the emergence and reduce the prevalence of resistance. In an attempt to contribute to the delay in the spread of bacterial resistance, it is essential that hospital pharmacists become involved in the four elements identified in the recent HSC.2 It is of great importance that policies developed should also be applicable and acceptable for use in primary care. Monitoring the usage of antibiotics in primary care is more difficult strategically but is crucial to the containment of antibiotic resistance. Liaison between the hospital microbiology department and primary care clinicians will be of paramount importance.

Mr Binyon is primary care development pharmacist for North East Fife local health care co-operative. He was formerly principal pharmacist, clinical services, at Eastbourne District General hospital, East Sussex where Dr Cooke is consultant medical microbiologist

References

1. House of Lords Select Committee on Science and Technology. Report: Resistance to antibiotics and other antimicrobial agents. London: Stationery Office. April 1998.
2. NHS Executive. HSC 1999/049: Resistance to antibiotics and other antimicrobial agents. London: NHS Executive; March, 1999.
3. American Society for Microbiology task force on antimicrobial resistance. Report. Washington DC:ASM;1994.
4. Gould IM. A review of the role of antibiotic policies in the control of antibiotic resistance. J Antimicrob Chemother 1999;43:459–65.
5. Harrison PF, Lederberg J, editors. Antimicrobial resistance: issues and options. Washington DC:National Academy Press;1998.
6. McElnay JC, Scott MG, Sidara JY, Kearney P. Audit of antibiotic usage in a medium-sized general hospital over an 11-year period. Pharm World Sci 1995;17;207–13.
7. Working Party of British Society for Antimicrobial Chemotherapy. Hospital antibiotic control measures in the UK. J Antimicrob Chemother 1994;34:21–42.
8. Musser JM. Antimicrobial agent resistance in mycobacteria: molecular genetic insights. Clin Microbiol Rev 1995;8:496–514.
9. Murray MD, Kohler RB, McCarthy MC, Main JW. Attitudes of house physicians concerning various antibiotic use programs. Am J Hosp Pharm 1988;45:584-8.
10. Macfarlane J, Holmes W, Macfarlane R, Britten N. Influence of patient's expectations on antibiotic management of acute lower respiratory tract illness in general practice: questionnaire study. BMJ 1997;315:1211–4.
11. Schlaes DM, Gerding DN, John JF, Craig WA, Bornstein DL, Duncan RA et al. Society for Health care Epidemiology of America and Infectious Diseases Society of America Joint Committee on the prevention of antimicrobial resistance: guidelines for the prevention of antimicrobial resistance in hospitals. Clin Infect Dis 1997;25:584–99.
12. National Audit Office. The management and control of hospital acquired infection in acute NHS trusts in England. London: Stationery Office;2000.
13. Public Health Laboratory Service Meningococcal Infections Working Group and Public Health Medicine Environmental Group. Control of meningococcal disease; guidance for consultants in communicable disease control. Commun Dis Rep Rev 1995;5:13.
14. Working Party of the British Committee for Standards in Haematology Clinical Haematology task force. Guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen. BMJ 1996;312:430–4.
15. Froom J, Culpepper L, Jacobs M, DeMelker RA, Green LA, van Buchem L et al. Antibacterials for acute otitis media? A review from the international primary care network. BMJ 1997;315:98–102.
16. Ekdahl K, Hansson HB, Mölstad S, Söderström M, Walder M, Persson K. Limiting the spread of penicillin-resistant Streptococcus pneumoniae: Experiences from the South Swedish Pneumococcal Intervention Project. Microb Drug Res 1998;4:99–105.
17. Kristinsson K. Effect of antimicrobial use and other risk factors on antimicrobial resistance in pneumococci. Microb Drug Res 1997;3:117–23.
18. Seppala H, Klaukka T, Vuopio-Varkila J, Muotiala A, Helenius H, Lager K et al, and the Finnish Study Group for Antimicrobial Resistance. The effects of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. N Engl J Med 1997;337:441–6.
19. Mainous AG, Zoorob RJ, Oler MJ, Haynes OM. Patient knowledge of upper respiratory infections: implications for antibiotic expectations and unnecessary utilization. J Fam Pract 1997;45:75-83.
20. Chan CS. What do patients expect from consultations for upper respiratory tract infections? Fam Pract 1996;13:229–35.
21. Belongia EA, Schwartz B. Strategies for promoting judicious use of antibiotics by doctors and patients. BMJ 1998;317:668–71.
22. Dowell SF. Principles of judicious use of antimicrobial agents for paediatric upper respiratory tract infections. Pediatrics 1998;101(Suppl 1):163–84.
23. Grimshaw JM, Russell IT. Effect of clinical guidelines on medical practice: a systematic review of rigorous evaluations. Lancet 1993;342:317–22.
24. Avorn J, Soumerai S. Improving drug therapy decisions through educational outreach. N Engl J Med 1983;308:1457–63.
25. Soumerai S, Avorn J. Principles of educational outreach to improve clinical decision making. JAMA 1990;263:549–56.
26. Schoenbaum SC. Feedback of clinical practice information. HMO Pract 1993; 7: 5-11.
27. Evans RS, Pestotnik SL, Classen DC, Clemmer TP, Weaver LK, Orme JF et al. A computer-assisted management programme for antibiotics and other anti-infective agents. N Eng J Med 1998; 338: 232–8.
28. Arason V, Kristinsson K, Sigurdsson J, Stefánsdóttir G, Mölstad S, Gudmundsson S. Do antimicrobials increase the carriage rate of penicillin-resistant pneumococci in children? Cross sectional prevalence study. BMJ 1996; 313:387-91.
29. Vandenbroucke-Grauls C. Management of methicillin resistant Staphylococcus aureus in the Netherlands. Rev Med Microbiol 1998; 9: 109-16.
30. Gold HS, Moellering RC. Antimicrobial drug resistance. N Engl J Med 1996;335:1445-53.
31. de Man P, Verhoeven BAN, Verbrugh HA, Vos MC, van den Anker JN. An antibiotic policy to prevent emergence of resistant bacilli. Lancet 2000; 355:973-8.
32. Saez-Llorens X, Castrejon de Wong MM, Castano E, De Suman O, De Moros D, De Atencio I. Impact of an antibiotic restriction policy on hospital expenditures and bacterial susceptibilities: a lesson from a paediatric institution in a developing country. Pediatr Infect Dis J 2000;19:200-6.
33. Cooke RPD, Binyon D, Goddard SV. Controlling Clostridium difficile infection by a restrictive antibiotic policy. Hosp Pharm 2000;2:52-4.
34. Djuretic T, Ryan MJ, Fleming DM, Well PG. Infectious intestinal disease in elderly people. Commun Dis Rep Rev 1996;6:R107-12.
35. Communicable Disease Surveillance Centre. Clostridium difficile in England and Wales: a quarterly report. Commun Dis Rep Wkly 1998;8:15.
36. Djuretic T, Well PG, Brazier JS. Clostridium difficile: an update on its epidemiology and role in hospital outbreaks in England and Wales. J Hosp Infect 1999;41:213-8.
37. Gould IM, Jappy B. Trends in hospital antibiotic prescribing after introduction of an antibiotic policy. J Antimicrob Chemother 1996;38:895-904.
38. Morgan AS, Brennan PJ, Fishman NO. Impact of a vancomycin restriction policy on use and cost of vancomycin and incidence of vancomycin-resistant Enterococcus. Ann Pharmacother 1997;31:970-3.
39. Gould IM. Stewardship of antibiotic use and resistance surveillance: the international scene. J Hosp Infect 1999;43 Suppl:S253-60.