A review of antibiotic resistance patterns of Streptococcus pneumoniae in Europe

Journal of Antimicrobial Chemotherapy (1991) 28, Suppl. C, 31-38 A review of antibiotic resistance patterns of Streptococcus pneumoniae in Europe F. Baqoero*, J. Martfnez-Beltran and E. Loza Servicio de Microbiologla, Hospital Ramdn y Cajal, Institute National de la Salud, 2834 Madrid, Spain Streptococcus pneumoniae no longer has predictable antibiotic susceptibility. There are two areas of high prevalence of resistance (over 25%) to /J-lactam antibiotics in the South-West and North-East of Europe. In Spain, a close relationship has been found between the yearly rate of aminopenicillin consumption and penicillin resistance. High level resistance (MIC ^ 1 mg/l) has developed against a previous background of low level resistance. The serotypes involved in penicillin resistance in Spain are widespread in other countries. Macrolide resistance is high in France (over 15%) and is also increasing in other countries. All these resistant isolates remain susceptible to the most recent fluoroquinolones, such as tcmafloxacin. Prospective surveillance, more rational use of antibiotics and a diversification of antibiotic use in respiratory tract infections may serve to limit the threat of antibiotic resistance in 5. pneumoniae. Introduction Streptococcus pneumoniae remains a common bacterial pathogen in human infections. Antibiotic use in Europe has commonly been targetted against streptococcal infections, particularly those of the respiratory tract in children, young adults and the elderly. The enormous empirical use of penicillins in community practice over the last quarter of a century has frequently been based on the wide acceptability and tolerance of these drugs, and the belief that the treatment of streptococcal infections was not limited by antibiotic resistance. Unfortunately, this has clearly been an underestimate of the adaptational and evolutional capabilities of the genus Streptococcus. Microbiologjsts, although concerned for years by plasmid mediated resistance in Gram-negative bacteria, have only realized during the last decade that streptococci may be equally resistant to antibiotics. Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on April 8, 216 Distribution of penicillin-resistance of S. pneumoniae in Europe From information available in the literature an estimate of the current distribution of penicillin resistance in European countries is shown in Figure 1. Spain, as well as Poland and Hungary are the main centre 5 of resistance, with more than a third of the isolates with MICs > 1 mg/l; the United Kingdom has a low prevalence of resistance, under 4% (Ridgway & Allen, 1991). Most other European countries have overall Correspondence to: Dr F. Baquero. 35-7453/91/28C31 +8 $2./ 31 1991 The British Society for Antimicrobial Chemotherapy

32 F. Baqnero et al Spain Hungary Poland Belgium Italy France U.K. Swtz. Germany Figure 1. S. pneumoniar. penicillin resistance in Europe (1986/1989). resistance rates < 9%. Nevertheless, local pockets of resistance (over 1%) have been recently communicated to us by microbiologists from France and the United Kingdom. Penicillin resistance world-wide has recently been reviewed (Klugman, 199). Evolution of peniefflin-resistant S. pneumoniae isolates in Spain: a predictive model for Europe? In 1973, our group in Madrid recorded 3% of S. pneumoniae with reduced susceptibility to penicillin. The development of resistance can be traced from the data obtained Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on April 8, 216 1979 198 1981 1982 1983 1984 1985 1986 1987 1988 1989 Flgare 2. The incidence of penicillin resistance among strains of S. pneumoniae causing systemic infections (2197 strains)., MIC -21-1 mg/l; O. MIC > 2mg/L.

Pneamococcal resistance Europe 33 24 25 26 27 28 29 3 31 32 33 Unrtt (xl,o,o/yeor) Figure 3. 5. pmumoniae resistance to penicillin by penicillin usage. 34 35 36 in a continuous survey of penicillin susceptibility among clinical isolates of S.pneumoniae during the last decade in the Central Laboratory for Sanitary Microbiology, Madrid (Fenoll & Casal, 199; Fenoll et al., 1991) (Figure 2). Low-level resistance (MIC -12-1 mg/l) increased"" 51 " with a high level of antibiotic resistance (MIC > 1 mg/l) appearing in 1984, and rising to nearly 17% in 199. Antibiotic use and S. pneumoniae resistance There is a very clear relationship between the annual aminopenicillin consumption and the rate of penicillin resistance in S. pneumoniae in Spain over the past decade (Figure 3), with a similar significant correlation between resistance rates and the use of aminopenicillins in community acquired respiratory tract infections (Baquero et al., 199). This correlation was present in each of the Spanish regions analysed: in Northern Spain and Valencia antibiotics are used in less than 2% of the patients who attend out-patient clinics for respiratory tract infections, and here less than 15% of pneumococci are resistant. On the contrary, antibiotics are prescribed for more than 3% of patients in Aragon, Catalonia and Madrid, and here the rate of penicillin resistance is over 3%. There is a relationship between the overall consumption of aminopenicillins and the emergence and spread of penicillin-resistant S.pneumoniae. 1983 was a very significant year for the evolution of penicillin resistance in Spain (see Figure 2); 27 million units were prescribed in comparison to 18 in France, 16 in Italy and 5 million in the United Kingdom. Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on April 8, 216

34 F. Bsqnero et al -1 I 2 3 4 5 6 7 8 9 1 II 13 14 15 18 19 2 23 33 34 Figure 4. Serotypes of S. pneumoniae and penicillin susceptibility: the higher limit in MIC range is represented for each icrotype. Epidemiology of penicillin-resistant S. pneumoniae Serotyping of 5. pneumoniae (Fenoll & Casal, 199; Fenoll et al., 1991) isolates during the last decade in Spain has revealed some important epidemiological features. Serotypes presenting resistance to penicillin are the common serotypes to be found in the population. This indicates that selective antibiotic pressure is exerted among endemic strains. Isolates showing a higher level of penicillin resistance belong predominantly to the more frequent serotypes 6, 9, 14, 15, 19 and 23 (Figure 4). The same serotypes are also frequently associated with antibiotic resistance in other European countries, such as France (serotypes 6, 14, 15, 19,23; Acar & Buu-Hoi, 1988), Belgium (serotypes 6, 9, 14, 15, 19, 23; Verhaegen et al., 199), Germany (serotypes 6, 14, 19) and Russia (scrotype 19) (Katosova et al., 199). However, some common serotypes present a very low rate of penicillin resistance. This may be due to a specific susceptibility to acquire resistance in some strains. Nevertheless, as shown in Figure 4, almost all serotypes can acquire penicillin resistance. Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on April 8, 216 The natural history of penicillin resistant S. pneumoniae The evolution and spread of penicillin resistant S. pneumoniae appears to closely parallel the use of /Mactam drugs. One hypothesis for this development of resistance suggests a progressive reduction of highly susceptible strains. This is followed by a change in the respiratory tract flora to streptococci with tolerance or low level penicillin resistance. The modified PBP2b of S. pneumoniae (conferring high level penicillin resistance) is the consequence of a long process involving the mutational alteration of 74 nucleotides thereby changing at least 17 aminoacids in the transpeptidase area of the PBP (Dowson et al., 1989, 199). During this molecular evolution of the enzyme, a wide range of 'low resistance' phenotypes may appear.

Pnenmococcalresistance Europe 35 Natural selection will produce an increase among some low level resistant strains which in turn may colonize not only patients but the normal population. The selective effect of antibiotic consumption in populations colonized by low-level resistance strains will gradually encourage the emergence of high-level resistance variants. This process will be accelerated by genetic transformation. Pieces of DNA encoding altered PBPs are exchanged between streptococci leading to a highly complex genetic polymorphism among such organisms (Jabes, Nachman & Tomasz, 1989; Markiewicz & Tomasz, 1989; Tomasz et al., 1989; Dowson et al., 199). If the streptococci with high level resistance are not successfully treated, dissemination may occur independently of antibiotic usage. There may be modulation of the colonizing ability of resistant strains by the phenomenon of 'herd immunity' among the human population. Eventually, this may disadvantage resistant streptococci, leading to a resurgence of more susceptible strains. This may also be the consequence of changes in the PBP of resistant strains, so that the enzymes become altered for their reactivity toward natural substrates. That may cause ecological disadvantages, unless the strains acquire auxiliary mutations that assure a sufficient supply of cell wall precursors (Jabes, et al., 1989). These changes could eventually be incorporated into the chromosome. There has been an unexpected high rate of penicillin resistance among the viridans streptococci group. Nearly 5% of such isolates from blood cultures during the last three years showed increased MICs of penicillin, particularly in S. sanguis, S. mitis S. salivarius and 5. mutans (Loza et al., 199). The evolution of macrolide resistance in S. pneumonia* As with penicillin resistance, macrolide resistance among S. pneumoniae tends to correlate with the consumption of these drugs. This is highest in France, where the rates were around 6% in the 197s and exceeded 25% in 1985. The rate of macrolide consumption outside hospitals is also higher in France than in other European countries (12-5 million units in 1983, compared with 8 million in Spain or 2-3 million in Germany or in the United Kingdom). As in the rest of Europe, the rate of erythromycin resistance in Spain was under 4% in 1985-1986. Two years later, the rate had doubled (8-4% in 1987), and reflects the significant increase in consumption (8-6 million of units in 1984 and 11-8 million in 1987). A similar increase seems to have occurred in Belgium, where resistant rates increased from nearly 3% in 1983 to 12% in 1988 (Verhaegen et al., 199). Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on April 8, 216 The evolution of cmorampbenkol and tetracycline resistance In Spain, chloramphenicol consumption decreased from 2 million of units in 1976 to less than -5 million in 1985, with a decrease in chloramphenicol resistance from 7% in 1976 to 36% in 1983. The same trend was seen with tetracyclines: the reduction in consumption (from 2 million in 1976 to nearly 5 million in 1988), parallels the reduction in resistance (77% in 1979 and 42% in 1988). Some resistance is maintained despite lower use from the selective pressure of the aminopenicillins, due to the frequent association of resistance mechanisms in the same organism (particularly frequent in serotype 23).

36 F. Baquero et al Table. Susceptibility of S. pneumoniae and viridans streptococci to temafloxacin Percentage of strains inhibited at each concentration (mg/l) 1 3-6 -1-2 -5 " 1-2 4 S. pneumoniae Pen-S (13) Pen-I(116) Pen-R(117) viridans streptococci Pen-S (39) Pen-I (23) Pen-R (1) Pen S, I, R., Susceptible, intermediate or resistant to penicillin. 2 1 2 1 1 4 3 11 13 5 3 37 37 38 33 4 2 41 32 48 34 17 2 8 12 8 19 56 5 Antibiotic resistance in S. pneumoniae. the role of fluoroquinolones The recent development of fluoroquinolones with increased activity for Gram-positive organisms represents a new possibility for the treatment of resistant S. pneumoniae infections. The good activity of temafloxacin for S. pneumoniae isolates has recently been reported (Mazzuli et al., 199; Swanson et al., 1991). The susceptibility of Spanish isolates of S. pneumoniae and viridans streptococci to temafloxacin is presented in the Table. Penicillin resistance does not influence significantly the MIC of temafloxacin for 5. pneumoniae; both penicillin susceptible and resistant isolates are inhibited by 1 mg/l although penicillin susceptible streptococci exhibit a slightly lower MIC. PBP modifications may affect cell wall growth, which can modulate the DNA replicative or transcriptional mechanisms, where quinolones act. The bronchial mucosal concentrations of temafloxacin will exceed those required to inhibit most penicillin resistant streptococci (Baldwin etal., 199; Swanson et al., 1991). However, the widespread use of fluoroquinolones with low activity for Gram-positive organisms may contribute to the development of resistance to this family of antibiotics. Selection of quinolone resistant variants of S. pneumoniae, associated with therapeutic failure, may occur during treatment of pneumonia with ciprofloxacin (Perez-Trallero et al., 199). New quinolones with improved efficacy could be used for pneumococcal infections. 1 7 13 1 2 7 3 Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on April 8, 216 The future: what to do? Continuous monitoring of streptococcal susceptibility should be carried out. When predicting antibiotic resistance, S. pneumoniae and the Enterobacteriaceae have similarities. Regular surveillance of resistance in normal flora, particularly in school children and the elderly should be done, with an exchange of data obtained in different countries. The use of antibiotics in the community should be limited as far as possible. The indications for antibiotic therapy in respiratory tract infections should bereviewed.the use of pneumococcal vaccines may diminish the need for antibiotics but is unsubstantiated.

Pneumococcal resistance Europe 37 Treatment of patients carrying penicillin resistant S. pnewnoniae (even as commensal flora) with any /J-lactam drug can contribute to the spread and evolution of resistance. Even viral respiratory tract infections contribute to the spread of resistant organisms. Diversification in the use of antimicrobials used to treat respiratory tract infections will reduce the selective pressure. Part of this strategy may include the use of macrolides, or new Gram-positive active fluoroquinolones, such as temafloxacin. The widespread use of quinoloncs with low activity for Gram-positive organisms and/or very low concentrations in respiratory secretions should be discouraged. In summary, better selection of patients for treatment is necessary, particularly in respiratory tract infections of the community. There should also be better selection of the antimicrobial agents, considering the danger of spread of resistant pathogenic organisms. New antimicrobials, like temafloxacin, may help to implement this strategy. Acknowledgements To A. Fenoll, J. Casal, J. Acar, J. A. Saez-Nieto, I. Phillips, J. Lifiares, J. Campos, A. Tomasz and R. Lopez, for providing data, constructive criticism and discussion. References Acar, J. F. & Buu-Hoi, A. Y. (1988). Resistance patterns of important Gram-positive pathogens. Journal of Antimicrobial Chemotherapy 21, Suppl. C, 41-7. Baldwin, D. R., Wilkinson, L., Andrews, J. M., Ashby, J. P., Wise, R. & Honeybourne, D. (199). Concentrations of temafloxacin in serum and bronchial mucosa. European Journal of Clinical Microbiology and Infectious Diseases 9, 432-4. Baquero, F., Bernal, B., Garau, X. & Gobernado, M. (Eds) (199). E.N.I.R.:Estudio Nacional de la Infeccidn Respiratoria, SOCIMED, Madrid. Dowson C. G., Hutchison, A., Brannigan, J. A., George, R. C, Hansman, D., Linares, J. et al. (1989). Horizontal transfer of penicillin-binding protein genes in penicillin-resistant clinical isolates of Streptococcus pneumoniae. Proceedings of the National Academy of Sciences USA 86, 8842-6. Dowson, C. G., Hutchison, A., Woodford, N., Johnson, A. P., George, R. C. & Spratt, B. G. (199) Penicillin-resistant viridans streptococci have obtained altered penicillin-binding protein genes from penicillin-resistant strains of Streptococcus pneumoniae. Proceedings of the National Academy of Sciences USA 87, 5858-62. Fenoll Comes, A. & Casal Lombos, J. (199). Origen y bases moleculares de la resistencia a penicilina en S. pneumoniae. Revista EspaRola de Quimioterapia 3, 111-3. Fenoll, A., Martin Bourgon, C, Munoz, R., Vicioso, D. & Casal, J. (1991). Serotype distribution and antimicrobial resistance of Streptococcus pneumoniae isolates causing systemic infections in Spain, 1979-1989. Reviews of Infectious Diseases 13, 56-6. Jabes, D., Nachman S. & Tomasz, A. (1989). Penicillin-binding protein families: evidence for the clonal nature of penicillin resistance in clinical isolates of pneumococci. Journal of Infectious Diseases 159, 16-25. Katosova, L. K., Sidorina, T. M., Baturo, A. P. & Sotnikova, G.D. (198) Serotypes of pneumococci in children with chronic inflammatory diseases on respiratory organs. Microbiology, Epidemiology and Immunobiology 2, 36-8. Klugman, K. P. (199). Pneumococcal resistance to antibiotics. Clinical Microbiology Reviews 3, 171-96. Loza, E., Martinez-Beltran J., Elia, M., Almaraz, F., Negri, C, Morosini, M. I. et al. (199). High incidence of penicillin resistance in viridans streptococci blood isolates: their susceptibility patterns. In Program and Abstracts of the Thirtieth Interscience Conference on Antimicrobial Agents and Chemotherapy. Atlanta, 199, Abstract 694. American Society for Microbiology, Washington, DC. Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on April 8, 216

38 F- Baquero et al Markiewicz, Z. & Tomasz, A. (1989). Variation in penicillin-binding protein patterns of penicillin-resistant clinical isolates of pneumococci. Journal of Clinical Microbiology 27, 45-1. Mazzuli, T., Simor, A. E., Jaeger, R., Fuller, S. & Low, D. E. (199). Comparative in vitro activity of several new fluoroquinolones and -lactam antimicrobial agents against community isolates of Streptococcus pneumoniae. Antimicrobial Agents and Chemotherapy 34, 467-9. Perez-Trallero, E., Garcia-Arenzana, J. M. Jimenez, J. A. & Peris, A. (199). Therapeutic failure and selection of resistance to quinolones in a case of pneumococcal pneumonia treated with ciprofloxacin. European Journal of Clinical Microbiology and Infectious Diseases 9, 95-6. Ridgway, E. J. & Allen, K. D. (1991). Penicillin resistance in pneumococci. Journal of Antimicrobial Chemotherapy 27, 251-2. Swanson, R. N., Hardy, D. J., Chu, D. T. W., Shipkowitz, N. L. & Clement, J. C. (1991). Activity of temafloxacin against respiratory pathogens. Antimicrobial Agents and Chemotherapy 35, 423-9. Tomasz, A., Jabes, D., Markiewicz, Z., Garcia-Bustos, J. & Nachman, S. (1989) Multiple penicillin binding protein profiles in penicillin resistant pneumococci: evidence for the clonal nature of resistance among clinical isolates. Current Topics in Infectious Diseases and Clinical Microbiology 2, 11-2 Verhaegen, J., Glupczynslci, Y., Verbist L., Blogie, M., Vandeven, J., Yourassowsky, E. et al. (199). Capsular types and antibiotic sensitivity of pneumococci isolated from patients with serious infections in Belgium 198 to 1988. European Journal of Clinical Microbiology and Infectious Diseases 9, 39-5. Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on April 8, 216