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Antibiotic use in humans and bacterial resistance Didier Guillemot

As with any public health problem, the evolution of antibacterial resistance must be viewed from a perspective of risk, and analysed in terms of probabilities within the populations. It is necessary to be able to predict the risk of antibacterial resistance, in the future, and two main strategies have recently been developed in mathematical models that may help to evaluate these risks. It is also important to understand how antibiotics are used and how their use affects the evolution of antibacterial resistance. Understanding the epidemiology of antibacterial resistance will enable us to develop preventive strategies to limit existing resistance and to avoid the emergence of new strains of resistant bacteria.
Addresses INSERM U258, 16 avenue Paul Vaillant Couturier, 94807 Villejuif Cedex, France; e-mail: guillemot@vjf.inserm.fr Current Opinion in Microbiology 1999, 2:494498 1369-5274/99/$ see front matter 1999 Elsevier Science Ltd. All rights reserved. Abbreviations MIC minimum inhibitory concentration MRSA methicillin-resistant Staphylococcus aureus PRSP penicillin G resistant Streptococcus pneumoniae URI upper respiratory infection VRE vancomycin-resistant Enterococcus VRTI viral respiratory tract illness

populations, nor to conclude to the causality. From an epidemiological point of view, the main criteria required for the causal nature of an association are, first, the coherence with existing information (biological plausibility), second, the consistency of the association in several studies, third, the time sequence, and fourth, the specificity of the association and the strength of the association (i.e. quantitative strength, dose-response relationship and study design). In the community, there is cumulative evidence that the antibiotic exposure of populations promotes acquired antimicrobial resistance in community pathogens such as Streptococcus pyogenes, cutaneous staphylococci and propionibacteria [4]. This relation is also now well established and quantified for Streptococcus pneumoniae [5]. In the hospital setting, an increased use of antibiotics is often associated with an increase in the frequency of antibiotic resistance [6], whereas a reduced consumption of antibiotics may be followed by a reduction of resistance to specific drugs, particularly in Enterobacteriae spp. [7]. Recently the association between the use of third-generation cephalosporins and vancomycin was shown to be a risk factor for vancomycin-resistant Enterococcus (VRE) infection in surgical patients [8]. The control of methicillin-resistant Staphylococcus aureus (MRSA) is still an unresolved issue in most healthcare institutions. Strategies for the control of MRSA in hospitals focus on measures to control cross-transmission and prevent colonisation, but rarely mention specifically the control of antimicrobial use. This question of a causal relationship between MRSA and antimicrobial use has been recently reviewed by Monnet [9]. However, the main difficulty of such a work is the lack of published studies specifically designed to investigate this question. Furthermore, the relationship between antibiotic use and resistance is most evident when resistance is due to mutations selected during therapy, resulting in clinical failure. This topic was reviewed four years ago by Fish et al. [10]. In individuals receiving antibiotics, resistance tends to develop not only in the bacteria involved in the treated infection but also in the commensal bacterial flora [11]. This may explain the rapidity with which quinolone resistance has emerged in staphylococci [12,13] and in pneumococci [14]. But in most studies, it is not possible to distinguish between the risk of bacteria carried prior to treatment becoming resistant and the risk of acquiring resistant bacteria from somebody else. For S. pneumoniae, although the rate of penicillin G resistant S. pneumoniae (PRSP) increases during a -lactram therapy, the risk of a previously carried pneumococci having an increased penicillin G minimum inhibitory concentration (MIC) (i.e. becoming resistant to penicillin G) seems to be very low in comparison with carrying a new PRSP after the treatment [15].

Introduction
The evolution of antibacterial resistance in human pathogenic and commensal microorganisms is the result of the interaction between antibiotic exposure and the transmission of resistance within and between individuals. This transmission depends on the environment and the social habits of individuals [1] and, therefore, requires an epidemiological approach as with any public health problem. The evolution of antibacterial resistance must be viewed from a perspective of risk, and analysed in terms of probabilities within the human population. Risk factors must be identified and their relation with outcome quantified. The factors associated with the antibiotic use in humans must be measured and followed over time, and the reasons why changes in antibiotic prescription are difficult must be explored. The risk must be predicted and preventive strategies evaluated. In this review each of these issues is examined from an epidemiological point of view.

The relationship between antibiotic use and antibacterial resistance

The first evidence for the relationship between antibiotic use and antibacterial resistance is geographic [2] and time concordance [3]. But in such analyses, even a very strong correlation does not enable us to estimate the risk, nor to distinguish the impact of antibiotic exposure on emergence and diffusion of antimicrobial resistance in bacterial

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The application of pharmacodynamic concepts as well as epidemiological studies suggest that bacterial exposure to low and prolonged concentrations of an antibiotic may have a role in the selection of resistance [16,17].

To predict the risk

It is necessary to be able to predict the risk of antibacterial resistance in the future, taking into account the factors determining the evolution of resistance, previously measured in populations. Mathematical models in this field have recently been made in two directions. In the first one, models of within-host dynamics provide expressions for the fraction of a hosts bacteria that are resistant to antibiotics, as a function of the treatment and the cost of fitness associated with the resistance [18]. But these models ignore the flow of bacteria between individuals or consider the exchange of bacteria only through an environmental reservoir. In the second model, individual hosts are considered to be in an interactive population and are differentiated according to their diseases and whether they are or are not exposed to antibiotics [19]. Both of these approaches try to address how antibiotic consumption influences the prevalence of the carriage of commensal bacteria in populations, to evaluate patterns in treatment protocols to prevent antibiotic resistance [20], and to predict the evolution of resistance [21]. Furthermore, they enable the local impact of infection control measures to be assessed, and are a valuable educational tool for staff in closed communities such as hospitals [22]. These models might also be useful in studying the role of the use of antibiotics in animals and antibacterial resistance in humans [23]. These models, however, are a simplistic view of reality based on a priori hypotheses. They must be considered as theoretical constructs and need to be validated by confrontation with reality.

prescriptions in developed countries [25,26,31]. Hence, the use of antimicrobials for VRTIs is the most important target for decreasing unnecessary antibiotic use in community medical practice [3234]. The unnecessary prescription of antibiotics has also been documented in many developing countries, particularly for viral respiratory infections, but also in infantile diarrhoea [24]. This must also be targeted for change. Several hypotheses may explain the increase in antibiotic use; for example, increase in misuse, increase in the incidence of respiratory infection with a presumed viral etiology, and increase in patient expectation of prescribers. For instance, a French retrospective analysis published in the recent National Report of Antibiotic Prescription and Use in Ambulatory Patient showed that in France antibiotic prescription for rhino-pharyngitis is not a recent practice and did not increase very much between 1984 and 1995 [35]. This suggests that antibiotic prescription for this indication has not changed very much in general practice and misuse is not increasing. Another plausible explanation for the increasing use of antibiotics in industrialised countries is the increasing incidence of VRTIs. The social change resulting in escalated use of child-care facilities has had a marked effect on the epidemiology of respiratory tract illness in young children. This may promote the high usage of antibiotics in children [36] and perhaps also in adults.

Does the optimal use of antibiotics have an effect on antimicrobial resistance?

This question remains contentious because the genetic mechanisms involved in acquiring antimicrobial resistance may favour stability of resistance genes even in the absence of ongoing exposure to antibiotics. Furthermore, it has been observed that the bacterial fitness costs associated with resistance may decline with compensatory mutation, which can be maintained in the absence of the antibiotic [37]. Also see the review by Andersson and Levin (this issue, pp 489493) for further discussion on the biological cost of antimicrobial resistance. There are two published studies on the decrease of community acquired antibacterial resistance after changes to antimicrobial policy. After noting an increase in macrolideresistance in S. pyogenes and identifying erythromycin use as a determining factor for this evolution, the Finnish Study Group for Antimicrobial Resistance responded by developing nation-wide recommendations for a reduction in erythromycin use for respiratory and skin infections in out-patients. This resulted in an almost 50% reduction of marolide prescription followed by about a 50% decrease of macrolide resistance in S. pyogenes [38]. There is also an Icelandic study reporting a diminished PRSP rate after a major publicity campaign directed at the public and prescribers [39]. In these two cases the impact of the modification in antimicrobial use is likely to be real, but the original resistance problem was mainly due to a clonal spread of a single strain [40] and the methodology does not

The use of antimicrobials

Factors related to antibiotic use in humans may determine the evolution of acquired bacterial resistance to antimicrobials: misuse of antibiotics by both practitioners and patients, and in developing countries the poor quality of drugs marketed [24]. In the community, the unnecessary prescription of antibiotics is mainly for viral respiratory tract illnesses (VRTIs) [25,26]. Despite inter-country variation in the frequency of antibiotic use, an increase in the use of antimicrobials has been observed in most developed countries [2628]. In children, from a cohort recruited at birth, it has been shown that at 200 days after birth more than 70% of the infants had used at least one antibiotic [29]. In older children, antibiotics have been shown to be prescribed in more than 40% of patients with common colds, upper respiratory infections (URIs) and bronchitis [30]. In adults, although antibiotics have little or no benefit for VRTIs, treatment for these diseases accounts for more than 20% of all antibiotic

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enable us to know whether the reduction in resistance is due to the change in antibiotic exposure or to the natural evolution of the epidemic phenomena. Furthermore, in the Finnish study the rate of resistance of S. pyogenes to tetracycline among isolates with the inducible-resistance or constitutive-resistance phenotype of macrolide increased after 1990 [41] and the use of the new macrolides, not concerned by the campaign, began to increase again at the end of the observation period [38]. In hospital, strategies to improve antibiotic use may result in a decrease in bacterial resistance [4244]. Recently, a programme of restriction of cephalosporin use was followed by a reduction in the frequency of -lactam resistance among Klebsiella spp. But, an unintended consequence of this programme was an increase in imipenem use and a concomitant increase in imipenem-resistant Pseudomonas aeruginosa [7]. This underlines the importance of not focusing policies only on a limited number of antibiotics. To assess the reversibility of resistance by modifying antibiotic exposure in populations is now one of the main research goals in the epidemiological field of bacterial resistance. Demonstrating such reversibility would be experimental evidence that it is possible to decrease antibacterial resistance in a population. Such studies must be designed as controlled trials. Several studies on more judicious antimicrobial use to control PRSP are actually underway or in project, both in the USA and in Europe [45,46].

the quality of patient care, in particular in selection of empiric antibiotics [52], in antibiotic-susceptibility mismatches, and in reducing antibiotic use [53]. It can also help to stabilise the emergence of antibiotic-resistant pathogens. But, a computer is only a tool. To be effective these strategies can only be viewed as a part of continuing education programme [54], in a cooperative interaction between infectious-disease physicians, clinical pharmacists, microbiology-laboratory personnel, and infectioncontrol specialists [55].
In the community

Strategies must take into account all factors influencing the prescription of antibiotics, medical and non-medical factors, as well as those involved in the patientdoctor relationship. In order to improve clinical judgement, rapid diagnostic tests [56] and clinical guidelines are certainly the most important tools to promote a more judicious use of antibiotics [57,58]. But these strategies must be supported by education programmes for the prescribers. Furthermore, as one of the factors contributing to antibiotic overuse includes the patients expectations and the physicians perception of these expectations [59]. To repeat the evidence of the lack of effectiveness of antibiotics in viral infection is unlikely to change a doctors prescriptions habits. Public education is required [45] as well as permanent and personalised counselling on antibiotic prescription for physicians. With such a perspective, computer assistance and interaction between physicians and pharmacist should be helpful.

How to modify antibiotic use

There is evidence from several studies that antibiotic prescribing policies can modify the prescription of antibiotics, although these policies focus more on drug cost than resistance. To modify antibiotic use in terms of a more judicious use, political decisions such as promoting the use of generic drugs, stopping the reimbursement and limiting the list of antibiotics available can reduce the costs, but are unlikely to have an effect on antibiotic resistance [47,48]. Studies have shown that education-based methods to modify the prescriptions habits of physicians, as opposed to coercion or economic measures, are effective in decreasing antibiotic resistance [49].
In hospital

Conclusions
Even with optimal antibiotic use, antibacterial resistances will probably not decline quickly and existing resistances are unlikely to vanish [60]. Therefore, we must limit the diffusion of existing antibacterial resistance in the population and avoid the emergence of new strains of resistant bacteria. Studies on antibiotic selective pressure are generally focused on only one aspect of the problem (i.e. genes, bacteria, individuals, or population) and the lack of pharmaco-epidemiologic studies has limited the knowledge and understanding of bacterial resistance dynamics in the population. As a result, policies regarding antibiotic treatment of outpatients have been hindered and the control of antimicrobial resistance has been delayed. To tackle this threat requires studies integrating microbiology and pharmacology with epidemiology, population genetics, ecology and mathematical biology. Also studies are required that focus on the association of bacterial mechanisms of antibiotic resistance and databases are needed linking antibacterial resistance and antibiotic use. Research is needed to find the best strategies for the optimal use of antibiotics and to estimate the effect of antibiotic exposure on the risk of emerging resistance, as well as on the dynamics of diffusion in the population [47,60].

Even in hospitals, antibiotic use is increasing, particularly for newer drugs such as glycopeptide [50]. This may contribute to the emergence of new resistance [51]. Advanced computer systems can assist the physician when deciding on antibiotic prescription by first, providing antimicrobial susceptibility patterns for the bacterial ecology in the hospital, second, recommending and monitoring dosage and duration of treatment, third, creating guidelines and reminders for antibiotic use, and fourth, identifying and correcting errors in antimicrobial prescribing to assure the appropriate use of therapeutic antibiotics. It has been demonstrated that such computer systems can improve

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Nevertheless, antibiotics are drugs to treat true pathogens. In the case of a justified use, the problem of resistance introduces questions about the length and the dosage of treatment, comparison between different drugs [61], multidrug strategies and patient compliance for the specific bacteria involved in the infection. Antibiotic treatment also concerns the commensal bacteria and, as a consequence, the unnecessary use of antibiotics in humans in hospital as well as in the community must be limited. This also requires us to consider antibiotic policies, especially in closed communities, since evolutionary processes adapt as a function of the antibiotic susceptibility of the commensal flora of the population.

14. Chen DK, McGeer A, de Azavedo JC, Low DE: Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. Canadian Bacterial Surveillance Network. N Engl J Med 1999, 341:233-239. 15. Cohen R, Bingen E, Varon E, de La Rocque F, Brahimi N, Levy C, Boucherat M, Langue J, Geslin P: Change in nasopharyngeal carriage of Streptococcus pneumoniae resulting from antibiotic therapy for acute otitis media in children. Pediatric Infect Dis J 1997, 16:555-560. 16. Guillemot D, Carbon C, Balkau B, Geslin P, Lecoeur H, VauzelleKervroedan F, Bouvenot G, Eschwege E: Low dosage and long treatment duration of beta-lactam: risk factors for carriage of penicillin-resistant Streptococcus pneumoniae. JAMA 1998, 279:365-370. 17. Baquero F: Evolving resistance patterns of Streptococcus pneumoniae: a link with long-acting macrolide consumption? J Chemother 1999, 11 (suppl 1):35-43.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

of special interest of outstanding interest

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18. Stewart FM, Antia R, Levin BR, Lipsitch M, Mittler JE: The population genetics of antibiotic resistance. II: analytic theory for sustained populations of bacteria in a community of hosts. Theor Popul Biol 1998, 53:152-165. Recent developments in mathematical models for the dynamics of antimicrobial resistance incorporating the effects of natural selection within untreated hosts, colonisation by bacteria from the environment, and the rapid increase of resistant bacteria in hosts who receive antibiotics. 19. Austin DJ, Kristinsson KG, Anderson RM: The relationship between the volume of antimicrobial consumption in human communities and the frequency of resistance. Proc Natl Acad Sci USA 1999, 96:1152-1156. Using population genetic methods and epidemiological observations, the influence of the selective pressure imposed by the volume of drug use on temporal changes in drug resistance is reported. The results highlight the need for early intervention once resistance is detected. 20. Bonhoeffer S, Lipsitch M, Levin BR: Evaluating treatment protocols to prevent antibiotic resistance. Proc Natl Acad Sci USA 1997, 94:12106-12111. 21. Levin BR, Lipsitch M, Perrot V, Schrag S, Antia R, Simonsen L, Walker NM, Stewart FM: The population genetics of antibiotic resistance. Clin Infect Dis 1997, 24 (suppl 1):9-16. 22. Sebille V, Valleron AJ: A computer simulation model for the spread of nosocomial infections caused by multidrug-resistant pathogens. Comput Biomed Res 1997, 30:307-322. 23. Witte W: Medical consequences of antibiotic use in agriculture. Science 1998, 279:996-997. 24. Okeke IN, Lamikanra A, Edelman R: Socioeconomic and behavioral factors leading to acquired bacterial resistance to antibiotics in developing countries. Emerg Infect Dis 1999, 5:18-27. A review describing factors associated with antibiotic resistance in developing tropical countries. 25. Guillemot D, Carbon C, Vauzelle-Kervroedan F, Balkau B, Maison P, Bouvenot G, Eschwege E: Inappropriateness and variability of antibiotic prescription among French office-based physicians. J Clin Epidemiol 1998, 51:61-68. 26. Guillemot D, Maison P, Carbon C, Balkau B, Vauzelle-Kervroedan F, Sermet C, Bouvenot G, Eschwege E: Trends in antimicrobial drug use in the community France, 19811992. J Infect Dis 1998, 177:492-497. 27. McCaig LF, Hughes JM: Trends in antimicrobial drug prescribing among office-based physicians in the United States. JAMA 1995, 273:214-219.

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Rahal JJ, Urban C, Horn D, Freeman K, Segal-Maurer S, Maurer J, Mariano N, Marks S, Burns JM, Dominick D, Lim M: Class restriction of cephalosporin use to control total cephalosporin resistance in nosocomial Klebsiella. JAMA 1998, 280:1233-1237. A before and after comparative two year trial showing the effect of a restriction programme of antibiotic use in hospital. A restriction programme focused on a selective class of antibiotic can lead to an increase bacterial resistance to another antibiotic class. 8. Dahms RA, Johnson EM, Statz CL, Lee JT, Dunn DL, Beilman GJ: Third-generation cephalosporins and vancomycin as risk factors for postoperative vancomycin-resistant enterococcus infection. Arch Surg 1998, 133:1343-1346.

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Monnet DL: Methicillin-resistant Staphylococcus aureus and its relationship to antimicrobial use: possible implications for control. Infect Control Hospital Epidemiol 1998, 19:552-559. A review pointing out the lack of studies specifically designed to investigate the relationship between MRSA epidemiology and antibiotic use in hospital. This review underlines the need to implement such studies quickly. 10. Fish DN, Piscitelli SC, Danziger LH: Development of resistance during antimicrobial therapy: a review of antibiotic classes and patient characteristics in 173 studies. Pharmacotherapy 1995, 15:279-291.

28. Davey PG, Bax RP, Newey J, Reeves D, Rutherford D, Slack R, Warren RE, Watt B, Wilson J: Growth in the use of antibiotics in the community in England and Scotland in 198093. Br Med J 1996, 312:613. 29. Bergus GR, Levy BT, Levy SM, Slager SL, Kiritsy MC: Antibiotic use during the first 200 days of life. Arch Fam Med 1996, 5:523-526. 30. Nyquist AC, Gonzales R, Steiner JF, Sande MA: Antibiotic prescribing for children with colds, upper respiratory tract infections, and bronchitis. JAMA 1998, 279:875-877. 31. Gonzales R, Steiner JF, Sande MA: Antibiotic prescribing for adults with colds, upper respiratory tract infections, and bronchitis by ambulatory care physicians. JAMA 1997, 278:901-904.

11. Brennen C, Wagener MM, Muder RR: Vancomycin-resistant Enterococcus faecium in a long-term care facility. J Am Geriatr Soc 1998, 46:157-160. 12. Espersen F: Resistance to antibiotics used in dermatological practice. Br J Dermatol 1998, 139 (suppl 53):4-8. 13. Raad I, Alrahwan A, Rolston K: Staphylococcus epidermidis: emerging resistance and need for alternative agents. Clin Infect Dis 1998, 26:1182-1187.

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32. Little P, Gould C, Williamson I, Warner G, Gantley M, Kinmonth AL: Reattendance and complications in a randomised trial of prescribing strategies for sore throat: the medicalising effect of prescribing antibiotics. Br Med J 1997, 315:350-352. 33. Mossad SB: Treatment of the common cold. Br Med J 1998, 317:33-36. 34. Oeffinger KC, Snell LM, Foster BM, Panico KG, Archer RK: Treatment of acute bronchitis in adults. A national survey of family physicians. J Fam Pract 1998, 46:469-475. 35. French National Observatory for Drug Use: Antibiotic prescription and use in ambulatory patients. Presse Med 1999, 28:343-350. 36. Nafstad P, Hagen JA, Oie L, Magnus P, Jaakkola JJ: Day care centers and respiratory health. Pediatrics 1999, 103:753-758. 37. Schrag SJ, Perrot V, Levin BR: Adaptation to the fitness costs of antibiotic resistance in Escherichia coli. Proc R Soc Lond B Biol Sci 1997, 264:1287-1291.

48. Carbon C, Bax RP: Regulating the use of antibiotics in the community. Br Med J 1998, 317:663-665. 49. Yates RR: New intervention strategies for reducing antibiotic resistance. Chest 1999, 115:24S-27S. 50. Jarvis WR: Epidemiology, appropriateness, and cost of vancomycin use. Clin Infect Dis 1998, 26:1200-1203. 51. Smith TL, Pearson ML, Wilcox KR, Cruz C, Lancaster MV, RobinsonDunn B, Tenover FC, Zervos MJ, Band JD, White E, Jarvis WR: Emergence of vancomycin resistance in Staphylococcus aureus. Glycopeptide-intermediate Staphylococcus aureus working group. N Engl J Med 1999, 340:493-501. 52. Evans RS, Pestotnik SL, Classen DC, Clemmer TP, Weaver LK, Orme JF Jr, Lloyd JF, Burke JP: A computer-assisted management program for antibiotics and other antiinfective agents. N Engl J Med 1998, 338:232-238. A computerised anti-infectives-management assessment suggesting that the use of the program led to significant reductions in excess drug dosages, antibiotic-susceptible bacteria, and in the mean number of days of excessive drug dosage. 53. Shojania KG, Yokoe D, Platt R, Fiskio J, Maluf N, Bates DW: Reducing vancomycin use utilizing a computer guideline: results of a randomized controlled trial. J Am Med Inform Assoc 1998, 5:554-562. 54. Lipsky BA, Baker CA, McDonald LL, Suzuki NT: Improving the appropriateness of vancomycin use by sequential interventions. Am J Infect Control 1999, 27:84-91. 55. Natsch S, Conrad C, Hartmeier C, Schmid B: Use of amoxicillinclavulanate and resistance in Escherichia coli over a 4-year period. Infect Control Hosp Epidemiol 1998, 19:653-656. 56. Kolmos HJ, Little P: Controversies in management: should general practitioners perform diagnostic tests on patients before prescribing antibiotics? Br Med J 1999, 318:799-802. 57. Dowell SF, Schwartz B, Phillips WR: Appropriate use of antibiotics for URIs in children: part I. Otitis media and acute sinusitis. The pediatric URI consensus team. Am Fam Physician 1998, 58:1113-1118.

38. Seppala H, Klaukka T, Vuopio-Varkila J, Muotiala A, Helenius H, Lager K, Huovinen P: The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. Finnish Study Group for Antimicrobial Resistance. N Engl J Med 1997, 337:441-446. The main published study on the consequences of a nationwide programme in restriction of antibiotic use in the community. 39. Kristinsson KG: Effect of antimicrobial use and other risk factors on antimicrobial resistance in pneumococci. Microb Drug Resist 1997, 3:117-123. 40. Kataja J, Huovinen P, Muotiala A, Vuopio-Varkila J, Efstratiou A, Hallas G, Seppala H: Clonal spread of group A streptococcus with the new type of erythromycin resistance. Finnish Study Group for Antimicrobial Resistance. J Infect Dis 1998, 177:786-789. 41. Kataja J, Huovinen P, Skurnik M, Seppala H: Erythromycin resistance genes in group A streptococci in Finland. The Finnish Study Group for Antimicrobial Resistance. Antimicrob Agents Chemother 1999, 43:48-52. 42. Chiew YF, Yeo SF, Hall LM, Livermore DM: Can susceptibility to an antimicrobial be restored by halting its use? The case of streptomycin versus Enterobacteriaceae. J Antimicrobial Chemotherapy 1998, 41:247-251. 43. Mebis J, Goossens H, Bruyneel P, Sion JP, Meeus I, Van Droogenbroeck J, Schroyens W, Berneman ZN: Decreasing antibiotic resistance of Enterobacteriaceae by introducing a new antibiotic combination therapy for neutropenic fever patients. Leukemia 1998, 12:1627-1629. 44. Pena C, Pujol M, Ardanuy C, Ricart A, Pallares R, Linares J, Ariza J, Gudiol F: Epidemiology and successful control of a large outbreak due to Klebsiella pneumoniae producing extendedspectrum beta-lactamases. Antimicrob Agents Chemother 1998, 42:53-58. 45. Schwartz B: Preventing the spread of antimicrobial resistance among bacterial respiratory pathogens in industrialized countries: the case for judicious antimicrobial use. Clin Infect Dis 1999, 28:211-213. 46. Guillemot D, Carbon C: Antibiotic use and pneumococcal resistance to penicillin The French experience. CMI 1999, 5(suppl 4):38-42. 47. Bax RP, Anderson R, Crew J, Fletcher P, Johnson T, Kaplan E, Knaus B, Kristinsson K, Malek M, Strandberg L: Antibiotic resistance what can we do? Nat Med 1998, 4:545-546.

58. Dowell SF, Schwartz B, Phillips WR: Appropriate use of antibiotics for URIs in children: part II. Cough, pharyngitis and the common cold. The pediatric URI consensus team. Am Fam Physician 1998, 58:1335-1342. 59. Mangione-Smith R, McGlynn EA, Elliott MN, Krogstad P, Brook RH: The relationship between perceived parental expectations and pediatrician antimicrobial prescribing behavior. Pediatrics 1999, 103:711-718. A study exploring the extent to which parental previsit expectations and physician perceptions of those expectations are associated with inappropriate antimicrobial prescribing. The authors suggest that physicians have inaccurate perceptions of parent desires for antimicrobials for viral infections. 60. Levin BR, Antia R, Berliner E, Bloland P, Bonhoeffer S, Cohen M, DeRouin T, Fields PI, Jafari H, Jernigan D et al.: Resistance to antimicrobial chemotherapy: a prescription for research and action. Am J Med Sci 1998, 315:87-94. 61. Carmeli Y, Troillet N, Eliopoulos GM, Samore MH: Emergence of antibiotic-resistant Pseudomonas aeruginosa: comparison of risks associated with different antipseudomonal agents. Antimicrob Agents Chemother 1999, 43:1379-1382. The first epidemiological study comparing the risks of emergence of resistance associated with several antibiotics, with a cohort study in hospital. There is an evident difference among antibiotics in the likelihood that their use would allow emergence of resistance.