Antibiotic use and pneumococcal resistance to penicillin: the French experience

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1 Antibiotic use and pneumococcal resistance to penicillin: the French experience Clin Microbiol nfect 1999; 5: 4S3-4S42 Didier Guillemot ' and Claude Carbon 'nstitut National de la Sant6 et de la Recherche MCdicale, Unit6 25, 'Service de Medecine nterne, Centre Hospitalo-Universitaire Bichat-Claude Bernard, Paris, and nstitut National de la SantC et de la Recherche MCdicale EP 9933, France ANTBOTC SELECTON PRESSURE Antibiotic selection pressure is defined with reference to the environmental conditions promoting the emergence and spread of antimicrobial resistance, whatever the mechanism of resistance. Antibiotic exposure is considered as essential for the emergence of resistance, and there is universal agreement that increasing antimicrobial resistance is related to the selective pressure exerted by the use of antibiotics [l]. Studies on antibiotic selective pressure are generally focused on only one aspect of the problem (genes, bacteria, individuals, population) (Figure 1). These aspects correspond to a specific scientific approach (genetic, cellular, clinical, epidemiologic). Now it is time to consider antimicrobial resistance as an environmental problem and to develop a pharmacoepidemiologic approach, tahng into account the individual's antimicrobial exposure and cross-transmission as well as genetic, cellular, individual and population effects. This is required to improve knowledge on population dynamics of resistance, develop epidemiologic models which would predict the evolution of antimicrobial drug resistance and to find the best strategies for the optimal use of antibiotics with regard to the control of antimicrobial resistance. The lack of such studies has limited our knowledge and understanding ofbacterial resistance dynamics in populations. As a result, policies regarding antibiotic treatment of outpatients have been hindered. Corresponding author and reprint requests: Didier Guillemot, lnstitut National de la Sante et de la Recherche Medicale, Unite 25, 15 avenue Paul Vaillant- Couturier 947 Villejuif Cedex, France Tel: Fax: guillemot@vjf.inserm.fr PENCLLN-RESSTANT srwrococcus PNEUMONAE The risk factors n the community, the spread of drug-resistant Streptococcus pneumoniae is now particularly worrying, especially because of the increase of high-level third-generation cephalosporin resistance and increasing multiresistance. n France, the resistance rates for 1995 and 1996 were respectively: for penicillin, 65.4% and 7.3% (1.6% and 24.9% of intermediately resistant strains, 46.% and 45.4% of fully resistant strains); for erythromycin, 57.5% and 6.5%; for tetracycline, 43.2% and 42.6%; and for trimethoprim-sulfamethoxazole, 47.5% and 5.9% [2]. Many authors have suggested that the dominant factor in the spread of penicillin-resistant Streptococcus pneumoniae (PRSp) in the community is the increasing use of antibiotics [ 1,3]. Ecological correlations have been found between invasive PRSp and antibiotic use in the community [4], and time concordance can be observed. These analyses do not allow an estimate of the risk, and the chain of causality remains unclear. Futhermore, while carriage of pneumococci is the precondition for interindividual transmission, most epidemiologic studies estimating the risk of PRSp with p-lactam use have been focused on invasive strains. Few pharmacoepidemiologic studies have analyzed the risk factors associated with drug-resistant pneumococcal pharyngeal carriage. Among these risk factors, recent p-lactam use is the most consistent [5,6]. Nevertheless, these studies do not explain how antimicrobial drug use is a risk factor for human colonization by PRSp and for its diffusion throughout the population. The causality From an epidemiologic point of view, the criteria for the causal nature of an association are the agreement with existing information (biological plausibility), the consistency of the association, the time sequence, 4S3

2 - Guillernot and Carbon: Antibiotic use and pneurnococcal resistance to penicillin-the French experience 4S39 Mutation Genes Genetransfer... Acquisition of resistance 7 Survival resistant strains/ Antibiotic of sensitive strains Bacteria individual Population i i Emergence of resistant strains selection pressure.... Colonization of the pharyngeal or digestive.. ecosystem + lnterindividual transmission - between humans... animal -humans Spread in the populations z s piants Figure 1 Antibiotic selection pressure. the specificity of the association, and the strength of the association (quantitative strength, dose-response relationship and study design) [7]. n the case of studies of PKSp and p-lactam use, most of these criteria are satisfied. To test the hypothesis that PRSp carriage is related to daily dose and duration of p-lactam use, we conducted a study of pharyngeal carriage of S. pnetrmoniae and antimicrobial use in children. This 1995 study was published at the beginning of 199 []. t explored PKSp pharyngeal carriage and oral p-lactam use during the preceding month, the dose and the duration of treatment in a random sample of 941 children, 3-6 years old. The daily dose in mg/kg was calculated for the last used antimicrobial drug generic and coded as a high or low daily dose, with reference to French clinical recommendations As recent studies suggested efficacy in community respiratory infectious diseases with an antibiotic given for 5 or fewer days, we considered more than 5 days to be a long duration of treatment. 1th 75 median 25 CDX CFL _... _...._... CDX : Penicillin susceptibility (MC) in mg/l Figure 2 Sensitivity of S. pneumoniae and percentile of daily dose of p-lactam:, aminopenicillin; CDX, cefadroxil; CFL, cefaclor; CFX, cefuroxime.

3 4S4 Clinical Microbiology and nfection, Volume 5 Supplement 4 Odds ratio AM NOPE N. OR=5.6 Duration of treatment - Figure 3 3days. Odds ratio for PRSp carriage accordmg to daily dose and duration of the last p-lactam used during the previous % 1 9 Pharyngitis * R h ino-p ha ry ng it is._ issi 1995 Year Figure 4 Frequency of antibiotic prescription according to different respiratory tract infections (source: MS-DOREMA) [ 11. We calculated the percentile of the daily dose for each antibiotic generic and defined two classes with reference to the median (greater or lower than the median). Considering children with pneumococcal carriage who used a p-lactam during the previous month, the median daily dose in mg/kg was 46.2 for amoxycillin, 31. for cefaclor, 43.5 for cefadroxil, 41.6 for cefatrizin, 23.4 for cefuroxime axetil,.4 for cefpodoxime proxetil and.9 for cefixime. Seventy-seven per cent of the S. pneumoniae isolates from children who had not taken a p-lactam had a penicillin G MC lower than.1 mg/l. All of the S. pneumoniae isolates from children who had taken a daily dose of p-lactam lower than the median had a penicillin G MC higher than.1 mg/l. n contrast, all S. pneumoniae isolates from children who had a daily dose of p-lactam higher than the

4 Guillemot and Carbon: Antibiotic use and pneumococcal resistance to penicillin-the French experience 4S41 median had a penicillin G MC lower than.1 mg/l (p=.3) (Figure 2). These two groups did not have different mean durations of treatment, or different mean numbers of daily doses. Grouped according to the combined value for daily dose and duration of aminopenicillin and cephalosporin of the last P-lactam, the percentage of low dose with a long duration was 46.6%, and that of high dose or short duration 39.1%. As compared with no use, low dose with a long duration of treatment was associated with an increased risk of PRSp carriage, for both aminopenicillin and cephalosporin (Figure 3). Even with all epidemiologic criteria, the chain of causality remains unclear. The two determinants for the spread of PRSp in the community are antibiotic selective pressure in individuals and interindividual transmission [9]. Several factors could help to explain the antibiotic selective pressure: bacterial antagonism in regulating the bacterial flora of the human pharynx [lo-121, horizontal gene transfer [13], or the selection of mutants of S. pneumoniae, due to a low tissue concentration of antibiotic [ 141. Another possibility could be the following: when a population of children is exposed to an oral P-lactam, the increased risk of PRSp carriage might be the result of a difference in the average duration of carriage between PRSp and PSSp. This difference induces an increased transmission of PRSp throughout the population, as suggested in recent studies, where PRSp carriage persisted longer than that of fully susceptible clones [15]. The reversibility Can optimal use of antibiotics decrease PRSp evolution? n order to answer this question, we have first to look at antibiotic prescription in the community. An audit of anti-infective prescribing in ofice-based medical practice in the Loiret, a French administrative department, showed that respiratory tract infections with a presumed viral etiology accounted for 36% of prescriptions. Furthermore, a high percentage of antibiotic prescriptions in children were underdosed as compared to clinical recommendations and, whatever the clinical hypothesis, the duration of treatment was close to days [16]. Furthermore, based on national representative samples, we showed that, in France, respiratory tract infections with a presumed viral etiology were the most frequent infections associated with antibiotic use in The increase in these antibiotic-treated infections between 19-1 and was 6.2% for adults and 115.3% for children [17]. n order to control drug-resistant S. pneumoniae, community-wide education programs for clinicians and the general public are important. Such programs should focus on the appropriate use of antibiotics. Our investigations identified three main areas for improving antimicrobial drug prescribing in order to control PRSp: (1) to reduce the number of useless prescriptions in respiratory tract infections with a presumed viral etiology, especially rhinopharyngitis, which is the main community infection associated with antibiotic prescription; (2) to increase the prescribed daily dose of antimicrobials to the recommended levels; and (3) to reduce the duration of treatment. THE FUTURE: THE AUBEPPN PROJECT (AMELORATON DE CUTlLlSATlON DES P-ACTAMNES ET PORTAGE DU PNEUMOCOQUE DE SENSBLTE DMNUEE A LA PENCLLNE G) A retrospective analysis based on the French MS- Dorema data showed that, in France, antibiotic prescription in rhinopharyngitis is not a recent practice and did not increase very much between 194 and 1995 (Figure 4) [1], suggesting that antibiotic prescription in this indication in general practice has not changed very much. t may be more difficult to change old habits than to change new fashions. The obvious need is for long-term educational efforts at different levels, to make both general practitioners and patients accept a reduction in the number of prescriptions. Another, parallel, option is to modify some more practical aspects of prescription. For this, we need first to assess the effect of changing antibiotic use in terms of dosage and duration of treatment. n order to distinguish a possible natural decrease in resistance from the impact of such an intervention, the methodology must be an epidemiologic trial. This is the main objective of the AUBEPPN project. We plan to select at random two geographic areas in the Loiret. The first will be the site of an intervention aiming to increase the dosage above that of the French clinical recommendations and to reduce the duration of treatment to 5 days, by education programs for clinicians and pharmacists. The second will be the control group without any intervention. The intervention will be conducted between October 1999 and April 2. Before and after the intervention, nasopharyngeal carriage of S. pneumoniae will be surveyed in the two groups, each containing 15 healthy 3-6-year-old schoolchildren, selected by sampling schools at random in each group. The parents of included children will complete, each month, a short questionnaire on physician consultations and diagnosis as stated by the practitioner, and drug consumptionincluding the type of drug, the duration of treatment and the number of daily doses-over 6 months. The main criterion will be the PRSp to PSSp ratio, with an expected reduction of 3%. Futhermore, in order to

5 4542 Clinical Microbiology and nfection, Volume 5 Supplement 4 compare the duration of carriage, nasopharyngeal cultures will be obtained every 2 weeks for 6 months from those children who were the pneumococcal carriers at the beginning of the study. n order to take into account the inter-individual transmission inside the school, there will be a genetic analysis of the strains. At least two types of important information can be expected from this project: the reversibility of the development of penicillin G resistance among S. pneumoniae isolates when the conditions of use of antibiotics are modified. the effect of a simple message- to use optimal dosage and short duration of treatment -that could be added to other actions aimed at developing optimal use of antibiotics, such as reducing the number of undue prescriptions. n any case, these types of intervention would lead to decreased costs and, hopefully, have a positive impact on bacterial resistance. References 1. Tenover FC, Hughes JM. The challenges of emerging infectious diseases. JAMA 1996; 275: Geslin P, Fremaux A, Sissia G, Spicq C, Georges S. Development of resistance to beta-lactams and other antibiotics of pneumococci isolated from acute otitis media in France: statement of the National Reference Center Arch Pediatr 199; 5: Neu HC. The crisis in antibiotic resistance. Science 1992; 257: Baquero F, Martinez-Beltran J, Loza E. A review of antibiotic resistance patterns of Streptococctrs pneumoniae in Europe. J Antimicrob Chemother 1991; 2: Kristinsson KG, Hjalmarsdottir MA, Steingrimsson. ncreasing penicfin resistance in pneumococci in celand. Lancet 1992; 339: Arason V, Kristinsson K, Sigurdsson J, Stefansdottir G, Molstad S, Gudmundson S. Do antimicrobials increase the carriage rate of penicillin resistant pneumococci in children? Cross sectional prevalence study Br Med J 1996; 313: Strom B. Study designs for pharmacoepidemiology studies. n: Strom B, ed. Pharmacoepideiniology, 2nd edn. Chichester: John Wdey & Sons Ltd, 1994: Guillemot D, Carbon C, Balkau B, et al. Low dosage and long treatment duration of P-lactam: risk-factors for the carriage of penicillin-resistant Streptococcus pneumoniae. JAMA 199; 279: Soares S, Kristinsson KG, Musser JM, Tomasz A. Evidence for the introduction of a multiresistant clone of serotype 6B Streptococcus pneumoniae from Spain to celand in the late 19s. J nfect Dis 1993; 16: Johanson WG, Blackstock R, Pierce AK, Sanford JP. The role of bacterial antagonism in pneurnococcal colonization of the human pharynx. J Lab Clin Med 197; 75: Sanders W. Bacterial interference.. Occurrence among the respiratory tract flora and characterization of inhibition of group A streptococci by viridans streptococci. J nfect Dis 1969; 12: Crowe CC, Sanders W, Longley S. Bacterial interierence. 11. Role of the normal throat flora in prevention of colonization by group A streptococcus. J nfect Dis 1973; 12: Coffey TJ, Dowson CG, Daruels M, et al. Horizontal transfer of multiple penicillin-binding protein genes, and capsular biosynthetic genes, in natural populations of Streptococcuspneumoniae. Mol Microbiol 1991; 5: Negri MC, Morosini M, Loza E, Baquero E n vitro selective antibiotic concentrations of beta-lactams for penicillin-resistant Streptococcus pneumoniae populations. Antimicrob Agents Chemother 1994; 3: Yagupsky P, Porat N, Fraser D, et al. Acquisition, carriage, and transmission of pneumococci with decreased antibiotic susceptibility in young children attending a day care facility in southern srael. J nfect Dis 199; 177: Guillemot D, Carbon C, Balkau B, et al. nappropriateness and variability of antibiotic prescription, among French office based physicians. J Clin Epidemiol 199; 51: Guillemot D, Maison P, Carbon C, et al. Trends in antimicrobial drug use in the community between 191 and 1992, in France. J nfect Dis 199; 177: Obervatoire National des Prescriptions et Consommations des Medicaments. Etude de la prescription et de la consommation des antibiotiques en ambulatoire (en France). Saint Denis: Obervatoire National des Prescriptions et Consommations des MCdicaments, 199.