- Email: [email protected]
Management of antibiotic-resistant Streptococcus pneumoniae infections and the use of pneumococcal conjugate vaccines
MINI REVIEW
10.1111/j.1469-0691.2009.02723.x
Management of antibiotic-resistant Streptococcus pneumoniae infections and the use of pneumococcal conjugate vaccines J. J. Picazo Clinical Microbiology, Hospital Clinico San Carlos, Madrid, Spain
Abstract The epidemiology of Streptococcus pneumoniae, a major cause of meningitis, pneumonia, bacteraemia and acute otitis media in both children and adults, has been altered by the availability of the seven-valent pneumococcal conjugate vaccine (PCV7) and selection pressure from broad-spectrum antibiotics. In Spain, the rates of antimicrobial consumption and resistance are high; of all S. pneumoniae isolates collected between 2001 and 2003, 9.2% were penicillin-resistant and 26.4% were penicillin-intermediate. These rates were even higher in children aged £4 years; 52.3% of isolates were penicillin-resistant or penicillin-intermediate. Serogroup 14 comprises nearly 9% of pneumococcal strains and exhibits the highest resistance to penicillin (69%). Since the introduction of PCV7 in Madrid, the isolates collected from hospitalized children aged <15 years from 21 hospitals revealed that only 8% of cases involving S. pneumoniae isolates were due to PCV7 serotypes, and no PCV7 vaccination failures were identified. These isolates demonstrated low rates of penicillin–non-susceptible and erythromycin–non-susceptible strains. Among multiresistant strains, serotype 19A was identified as most important. Although the recent WHO position paper on childhood immunizations speaks to the growing resistance of pneumococci, antibiotic resistance in Spain is noted to be decreasing and must be evaluated in conjunction with global studies. Keywords:
Antibiotic resistance, pneumococcal conjugate vaccine, Spain, S. pneumoniae
Clin Microbiol Infect 2009; 15 (Suppl. 3): 4–6 Corresponding author and reprint requests: Juan J. Picazo, MD, Clinical Microbiology, Hospital Clinico San Carlos, Plaza Cristo Rey s/n, 28040, Madrid, Spain E-mail: [email protected]
Introduction Streptococcus pneumoniae is a major cause of meningitis, pneumonia, bacteraemia and acute otitis media in both children and adults [1,2]. With the widespread availability and overuse of antibiotics, multidrug-resistant strains of pneumococci have become increasingly prevalent [3]. The availability of the sevenvalent pneumococcal conjugate vaccine (PCV7) and its incorporation into national immunization programmes has significantly reduced both the morbidity and the mortality associated with pneumococcal disease [4–6]. Both PCV7 and selection pressure from broad-spectrum antibiotics have altered the epidemiology of S. pneumoniae and its various serotypes [7].
The Spanish Experience The European Antimicrobial Resistance Surveillance System (http://www.rivm.nl/earss/) documents temporal variations in
antimicrobial resistance, in part to assess the effectiveness of prevention programmes. The rates of antimicrobial resistance (using previous breakpoints) and antimicrobial consumption in Spain are high. Between 2001 and 2003, system data documented invasive S. pneumoniae isolated from 1968 Spanish patients, 17.4% of whom were children aged £4 years [8]. Of all isolates collected, penicillin-resistant strains constituted 9.2% and penicillin-intermediate strains constituted 26.4%. In children aged £4 years, 52.3% of isolates were penicillin-resistant or penicillin-intermediate strains. Overall rates of reduced penicillin susceptibility (resistant plus intermediate) decreased from 39.5% in 2001 to 33% in 2003 (p = 0.05) [8]. The reduction was principally due to changes noted in children aged £14 years. In this age group, the frequency of reduced penicillin susceptibility decreased from 60.4% in 2001 to 41.2% in 2003 (p = 0.002). Overall antibiotic use dropped from 21.66 defined daily doses/1000 inhabitants/day in 1998 to 19.71 defined daily doses/1000 inhabitants/day in 2002 (p <0.001) [8]. In Spain, nearly 9% of pneumococcal strains are serogroup 14 and have the highest resistance to penicillin, at 69%, whereas serogroup 3 was found to be fully susceptible. Strains resistant to penicillin were often found to be resistant to erythromycin as well [9]. The Surveillance of Antimicrobial Resistance (VIRA; Vigilancia de la Resistencia a los Antimicrobianos) project began in 2001, with the aim of tracking antimicrobial sensitivity
ª 2009 The Author Journal Compilation ª 2009 European Society of Clinical Microbiology and Infectious Diseases
Picazo
CMI
Management of antibiotic-resistant Streptococcus pneumoniae infections
patterns of multiresistant bacteria [10,11]. Forty hospitals from 15 autonomous Spanish communities participated in this ongoing, epidemiological surveillance project. The number of penicillin-resistant (minimum inhibitory concentration: ‡2 mg/L) S. pneumoniae isolates decreased significantly from 59.8% in 2001 to 30.2% in 2004 (p <0.0001) to 14.3% in 2006 (p <0.001) [10,11]. Fenoll et al. recently analysed the evolution of antibiotic non-susceptibility in invasive S. pneumoniae isolates in Spain after the licensing of respiratory quinolones for adults and PCV7 for immunization of the paediatric population [12]. During the study period (January 2000 to August 2007; n = 12,957 isolates), the increase in PCV7 distribution correlated with a decrease in PCV7 serotype prevalence among invasive isolates in children and adults. This decrease in PCV7 serotypes correlated with a decrease in penicillin nonsusceptibility in children (r = 0.929; p <0.001) and adults (r = 0.905; p = 0.002), and with a decrease in erythromycin non-susceptibility in children (r = 0.833; p = 0.010), suggesting that PCV7 vaccination in children had an indirect (herd) effect in adults. The HERACLES study was instituted to assess changes in pneumococcal serotype distribution, antimicrobial susceptibility patterns, clinical syndromes, and underlying disease associated with invasive pneumococcal disease (IPD) since the introduction of PCV7 in Madrid, Spain [13,14]. Antimicrobial susceptibility was determined from invasive pneumococcal isolates collected from hospitalized children aged <15 years from 21 Madrid hospitals. Data from the first months (May 2007 to January 2008) of this 3-year epidemiological study are presented in Tables 1 and 2 [13,14]. Only 8% of cases with isolation of S. pneumoniae were due to a PCV7 seroTABLE 1. Distribution of pneumococcal serotypes causing
TABLE 2.
Antimicrobial
susceptibility
in
5
paediatric
Streptococcus pneumoniae isolates after PCV7 (n = 87). Picazo J et al. Poster presented at the 26th Annual Meeting of the European Society for Paediatric Infectious Diseases, Graz, Austria: 13–17 May 2008 [14] Resistance rate (%)
Antibiotic
Penicillin (intermediate + resistant) 19A serotype Erythromycin cMLSB phenotype iMLSB phenotype M phenotype 19A serotype Erythromycin + tetracycline cMLSB phenotype Multidrug-resistant (‡3 antibiotics) 19A serotype
24.1 43.0 21.8 68.4 15.8 15.8 47.3 84.2 75.0 13.8 66.6
cMLSB, constitutive macrolide–lincosamide–streptogramin B; iMLSB, inducible macrolide–lincosamide–streptogramin B.
TABLE 3. Serotype distribution of invasive Streptococcus pneumoniae isolates after PCV7 (n = 492). Sanz JC et al. 6th
International
Symposium
on
Pneumococci
and
Pneumococcal Diseases, Reykjavik, Iceland: 8–12 June 2008. Abstract P1-O11 [15] Prevalence (%)
Serotype 1 5 19A 7F 3 8 14 6A 4
All age groups
Aged <5 years
11.2 11.2 10.8 9.1 6.7 5.9 5.1 3.7 2.8
17.2 23.7 15.1 9.7
Aged >60 years
12.7 7.6 11.5
5.1
PCV7, seven-valent pneumococcal conjugate vaccine.
invasive pneumococcal disease among hospitalized children (n = 87). Picazo JJ et al. 6th International Symposium on Pneumococci
and
Pneumococcal
Diseases,
Reykjavik,
Iceland: 8–12 June 2008. Abstract P2-037 [13] Serotype
1 5 19A 7F 3 8 14a 24B 24F 15C 21 15A a
PCV7 serotype.
No. of isolates (%)
17 20 11 8 3 2 2 1 5 1 1 1
(19.5) (22.9) (12.6) (9.1) (3.4) (2.2) (2.2) (1.1) (5.7) (1.1) (1.1) (1.1)
Serotype
11A 17F 23B 19Fa 35B 6A 9Va 11F 22F 41F Non-typed
No. of isolates (%)
1 2 1 3 1 1 2 1 1 1 1
(1.1) (2.2) (1.1) (3.4) (1.1) (1.1) (2.2) (1.1) (1.1) (1.1) (1.1)
type, and no PCV7 vaccination failures were identified [14]. The results demonstrated low rates of penicillin-non-susceptible and erythromycin-non-susceptible strains. Serotype 19A was identified as the most important serotype among multiresistant strains [13]. The Autonomous Region of Madrid gave approval for the use of PCV7 in the childhood vaccination programme in November 2006, and a surveillance programme has been established to monitor IPD in all age groups. The serotype distribution of IPD isolates collected in 2007 is presented in Table 3. Serotype coverage afforded by PCV7 accounted for 17.5% of the group including all ages, and 7.5% of children aged <5 years [15].
ª 2009 The Author Journal Compilation ª 2009 European Society of Clinical Microbiology and Infectious Diseases, CMI, 15 (Suppl. 3), 4–6
6
Clinical Microbiology and Infection, Volume 15, Supplement 3, April 2009
Conclusions Pneumococcal infections remain a public health problem all over the world. The recent WHO position paper on childhood immunizations stated that the growing resistance of pneumococci needs to be addressed by implementing vaccination programmes [13]. The WHO has also stressed the major public health value provided by vaccines. Although, in general, antibiotic resistance in pneumococci is increasing, some interesting trends have been observed in Spain, where a decrease in resistance has been noted. The interpretation of these data must be evaluated in conjunction with other studies. Meanwhile, the efficacy of PCV7 in the reduction of pneumococcal disease is evident.
Acknowledgements The author thanks the staff of Excerpta Medica (Bridgewater, NJ) for professional writing assistance, which was funded by Wyeth Pharmaceuticals.
Transparency Declaration J. Picazo has acted as a paid consultant to Wyeth and GlaxoSmithKline.
References 1. Hawley LA, Walker F, Whitney CG. Pneumococcal disease. In: Wharton M et al., eds. VPD surveillance manual, 3rd edn. Atlanta, GA: Centers for Disease Control and Prevention, 2002. 2. Centers for Disease Control and Prevention. Prevention of pneumococcal disease, recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1997; 46: 1–24. 3. Appelbaum PC. Resistance among Streptococcus pneumoniae: implications for drug selection. Clin Infect Dis 2002; 34: 1613–1620.
CMI
4. Black S, Shinefield H, Fireman B et al. Northern California Kaiser Permanente Vaccine Study Center Group. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J 2000; 19: 187–195. 5. O’Brien KL, Moulton LH, Reid R et al. Efficacy and safety of sevenvalent conjugate pneumococcal vaccine in American Indian children: group randomised trial. Lancet 2003; 362: 355–361. 6. O’Brien KL, Santosham M. Potential impact of conjugate pneumococcal vaccines on pediatric pneumococcal diseases. Am J Epidemiol 2004; 159: 634–644. 7. Pelton SI, Loughlin AM, Marchant CD. Seven valent pneumococcal conjugate vaccine immunization in two Boston communities: changes in serotypes and antimicrobial susceptibility among Streptococcus pneumoniae isolates. Pediatr Infect Dis J 2004; 23: 1015–1022. 8. Oteo J, Lazaro E, de Abajo FJ, Baquero F, Campos J, Spanish Members of the European Antimicrobial Resistance Surveillance System. Trends in antimicrobial resistance in 1,968 invasive Streptococcus pneumoniae strains isolated in Spanish hospitals (2001 to 2003): decreasing penicillin resistance in children’s isolates. J Clin Microbiol 2004; 42: 5571–5577. 9. Perez-Trallero E, Garcia-de-la-Fuente C, Garcia-Rey C et al. Spanish Surveillance Group for Respiratory Pathogens. Geographical and ecological analysis of resistance, coresistance, and coupled resistance to antimicrobials in respiratory pathogenic bacteria in Spain. Antimicrob Agents Chemother 2005; 49: 1965–1972. 10. Picazo JJ, Betriu C, Rodriguez-Avial I et al. Surveillance of antimicrobial resistance: VIRA study 2004. Enferm Infecc Microbiol Clin 2004; 22: 517–525. 11. Picazo JJ, Betriu C, Rodriguez-Avial I et al. Surveillance of antimicrobial resistance: VIRA study 2006. Enferm Infecc Microbiol Clin 2006; 24: 617–628. 12. Fenoll A, Aguilar L, Granizo JJ et al. Has the licensing of respiratory quinolones for adults and the 7-valent pneumococcal conjugate vaccine (PCV-7) for children had herd effects with respect to antimicrobial non-susceptibility in invasive Streptococcus pneumoniae? J Antimicrob Chemother 2008; 62: 1430–1433. 13. Picazo JJ, Contreras JR, Mendez C et al. 6th International Symposium on Pneumococci and Pneumococcal Diseases, Reykjavik, Iceland: 8–12 June 2008. Abstract P2-037. 14. Picazo J, Contreras JR, Mendez C et al. Poster presented at the 26th Annual Meeting of the European Society for Paediatric Infectious Diseases, Graz, Austria: 13–17 May 2008. 15. Sanz JC, Ramosi B, Ochoa D et al. 6th International Symposium on Pneumococci and Pneumococcal Diseases, Reykjavik, Iceland: 8–12 June 2008. Abstract P1-011. 16. World Health Organization. Pneumococcal conjugate vaccine for childhood immunization—WHO position paper. Wkly Epidemiol Rec 2007; 82: 93–104.
ª 2009 The Author Journal Compilation ª 2009 European Society of Clinical Microbiology and Infectious Diseases, CMI, 15 (Suppl. 3), 4–6
10.1111/j.1469-0691.2009.02723.x
Management of antibiotic-resistant Streptococcus pneumoniae infections and the use of pneumococcal conjugate vaccines J. J. Picazo Clinical Microbiology, Hospital Clinico San Carlos, Madrid, Spain
Abstract The epidemiology of Streptococcus pneumoniae, a major cause of meningitis, pneumonia, bacteraemia and acute otitis media in both children and adults, has been altered by the availability of the seven-valent pneumococcal conjugate vaccine (PCV7) and selection pressure from broad-spectrum antibiotics. In Spain, the rates of antimicrobial consumption and resistance are high; of all S. pneumoniae isolates collected between 2001 and 2003, 9.2% were penicillin-resistant and 26.4% were penicillin-intermediate. These rates were even higher in children aged £4 years; 52.3% of isolates were penicillin-resistant or penicillin-intermediate. Serogroup 14 comprises nearly 9% of pneumococcal strains and exhibits the highest resistance to penicillin (69%). Since the introduction of PCV7 in Madrid, the isolates collected from hospitalized children aged <15 years from 21 hospitals revealed that only 8% of cases involving S. pneumoniae isolates were due to PCV7 serotypes, and no PCV7 vaccination failures were identified. These isolates demonstrated low rates of penicillin–non-susceptible and erythromycin–non-susceptible strains. Among multiresistant strains, serotype 19A was identified as most important. Although the recent WHO position paper on childhood immunizations speaks to the growing resistance of pneumococci, antibiotic resistance in Spain is noted to be decreasing and must be evaluated in conjunction with global studies. Keywords:
Antibiotic resistance, pneumococcal conjugate vaccine, Spain, S. pneumoniae
Clin Microbiol Infect 2009; 15 (Suppl. 3): 4–6 Corresponding author and reprint requests: Juan J. Picazo, MD, Clinical Microbiology, Hospital Clinico San Carlos, Plaza Cristo Rey s/n, 28040, Madrid, Spain E-mail: [email protected]
Introduction Streptococcus pneumoniae is a major cause of meningitis, pneumonia, bacteraemia and acute otitis media in both children and adults [1,2]. With the widespread availability and overuse of antibiotics, multidrug-resistant strains of pneumococci have become increasingly prevalent [3]. The availability of the sevenvalent pneumococcal conjugate vaccine (PCV7) and its incorporation into national immunization programmes has significantly reduced both the morbidity and the mortality associated with pneumococcal disease [4–6]. Both PCV7 and selection pressure from broad-spectrum antibiotics have altered the epidemiology of S. pneumoniae and its various serotypes [7].
The Spanish Experience The European Antimicrobial Resistance Surveillance System (http://www.rivm.nl/earss/) documents temporal variations in
antimicrobial resistance, in part to assess the effectiveness of prevention programmes. The rates of antimicrobial resistance (using previous breakpoints) and antimicrobial consumption in Spain are high. Between 2001 and 2003, system data documented invasive S. pneumoniae isolated from 1968 Spanish patients, 17.4% of whom were children aged £4 years [8]. Of all isolates collected, penicillin-resistant strains constituted 9.2% and penicillin-intermediate strains constituted 26.4%. In children aged £4 years, 52.3% of isolates were penicillin-resistant or penicillin-intermediate strains. Overall rates of reduced penicillin susceptibility (resistant plus intermediate) decreased from 39.5% in 2001 to 33% in 2003 (p = 0.05) [8]. The reduction was principally due to changes noted in children aged £14 years. In this age group, the frequency of reduced penicillin susceptibility decreased from 60.4% in 2001 to 41.2% in 2003 (p = 0.002). Overall antibiotic use dropped from 21.66 defined daily doses/1000 inhabitants/day in 1998 to 19.71 defined daily doses/1000 inhabitants/day in 2002 (p <0.001) [8]. In Spain, nearly 9% of pneumococcal strains are serogroup 14 and have the highest resistance to penicillin, at 69%, whereas serogroup 3 was found to be fully susceptible. Strains resistant to penicillin were often found to be resistant to erythromycin as well [9]. The Surveillance of Antimicrobial Resistance (VIRA; Vigilancia de la Resistencia a los Antimicrobianos) project began in 2001, with the aim of tracking antimicrobial sensitivity
ª 2009 The Author Journal Compilation ª 2009 European Society of Clinical Microbiology and Infectious Diseases
Picazo
CMI
Management of antibiotic-resistant Streptococcus pneumoniae infections
patterns of multiresistant bacteria [10,11]. Forty hospitals from 15 autonomous Spanish communities participated in this ongoing, epidemiological surveillance project. The number of penicillin-resistant (minimum inhibitory concentration: ‡2 mg/L) S. pneumoniae isolates decreased significantly from 59.8% in 2001 to 30.2% in 2004 (p <0.0001) to 14.3% in 2006 (p <0.001) [10,11]. Fenoll et al. recently analysed the evolution of antibiotic non-susceptibility in invasive S. pneumoniae isolates in Spain after the licensing of respiratory quinolones for adults and PCV7 for immunization of the paediatric population [12]. During the study period (January 2000 to August 2007; n = 12,957 isolates), the increase in PCV7 distribution correlated with a decrease in PCV7 serotype prevalence among invasive isolates in children and adults. This decrease in PCV7 serotypes correlated with a decrease in penicillin nonsusceptibility in children (r = 0.929; p <0.001) and adults (r = 0.905; p = 0.002), and with a decrease in erythromycin non-susceptibility in children (r = 0.833; p = 0.010), suggesting that PCV7 vaccination in children had an indirect (herd) effect in adults. The HERACLES study was instituted to assess changes in pneumococcal serotype distribution, antimicrobial susceptibility patterns, clinical syndromes, and underlying disease associated with invasive pneumococcal disease (IPD) since the introduction of PCV7 in Madrid, Spain [13,14]. Antimicrobial susceptibility was determined from invasive pneumococcal isolates collected from hospitalized children aged <15 years from 21 Madrid hospitals. Data from the first months (May 2007 to January 2008) of this 3-year epidemiological study are presented in Tables 1 and 2 [13,14]. Only 8% of cases with isolation of S. pneumoniae were due to a PCV7 seroTABLE 1. Distribution of pneumococcal serotypes causing
TABLE 2.
Antimicrobial
susceptibility
in
5
paediatric
Streptococcus pneumoniae isolates after PCV7 (n = 87). Picazo J et al. Poster presented at the 26th Annual Meeting of the European Society for Paediatric Infectious Diseases, Graz, Austria: 13–17 May 2008 [14] Resistance rate (%)
Antibiotic
Penicillin (intermediate + resistant) 19A serotype Erythromycin cMLSB phenotype iMLSB phenotype M phenotype 19A serotype Erythromycin + tetracycline cMLSB phenotype Multidrug-resistant (‡3 antibiotics) 19A serotype
24.1 43.0 21.8 68.4 15.8 15.8 47.3 84.2 75.0 13.8 66.6
cMLSB, constitutive macrolide–lincosamide–streptogramin B; iMLSB, inducible macrolide–lincosamide–streptogramin B.
TABLE 3. Serotype distribution of invasive Streptococcus pneumoniae isolates after PCV7 (n = 492). Sanz JC et al. 6th
International
Symposium
on
Pneumococci
and
Pneumococcal Diseases, Reykjavik, Iceland: 8–12 June 2008. Abstract P1-O11 [15] Prevalence (%)
Serotype 1 5 19A 7F 3 8 14 6A 4
All age groups
Aged <5 years
11.2 11.2 10.8 9.1 6.7 5.9 5.1 3.7 2.8
17.2 23.7 15.1 9.7
Aged >60 years
12.7 7.6 11.5
5.1
PCV7, seven-valent pneumococcal conjugate vaccine.
invasive pneumococcal disease among hospitalized children (n = 87). Picazo JJ et al. 6th International Symposium on Pneumococci
and
Pneumococcal
Diseases,
Reykjavik,
Iceland: 8–12 June 2008. Abstract P2-037 [13] Serotype
1 5 19A 7F 3 8 14a 24B 24F 15C 21 15A a
PCV7 serotype.
No. of isolates (%)
17 20 11 8 3 2 2 1 5 1 1 1
(19.5) (22.9) (12.6) (9.1) (3.4) (2.2) (2.2) (1.1) (5.7) (1.1) (1.1) (1.1)
Serotype
11A 17F 23B 19Fa 35B 6A 9Va 11F 22F 41F Non-typed
No. of isolates (%)
1 2 1 3 1 1 2 1 1 1 1
(1.1) (2.2) (1.1) (3.4) (1.1) (1.1) (2.2) (1.1) (1.1) (1.1) (1.1)
type, and no PCV7 vaccination failures were identified [14]. The results demonstrated low rates of penicillin-non-susceptible and erythromycin-non-susceptible strains. Serotype 19A was identified as the most important serotype among multiresistant strains [13]. The Autonomous Region of Madrid gave approval for the use of PCV7 in the childhood vaccination programme in November 2006, and a surveillance programme has been established to monitor IPD in all age groups. The serotype distribution of IPD isolates collected in 2007 is presented in Table 3. Serotype coverage afforded by PCV7 accounted for 17.5% of the group including all ages, and 7.5% of children aged <5 years [15].
ª 2009 The Author Journal Compilation ª 2009 European Society of Clinical Microbiology and Infectious Diseases, CMI, 15 (Suppl. 3), 4–6
6
Clinical Microbiology and Infection, Volume 15, Supplement 3, April 2009
Conclusions Pneumococcal infections remain a public health problem all over the world. The recent WHO position paper on childhood immunizations stated that the growing resistance of pneumococci needs to be addressed by implementing vaccination programmes [13]. The WHO has also stressed the major public health value provided by vaccines. Although, in general, antibiotic resistance in pneumococci is increasing, some interesting trends have been observed in Spain, where a decrease in resistance has been noted. The interpretation of these data must be evaluated in conjunction with other studies. Meanwhile, the efficacy of PCV7 in the reduction of pneumococcal disease is evident.
Acknowledgements The author thanks the staff of Excerpta Medica (Bridgewater, NJ) for professional writing assistance, which was funded by Wyeth Pharmaceuticals.
Transparency Declaration J. Picazo has acted as a paid consultant to Wyeth and GlaxoSmithKline.
References 1. Hawley LA, Walker F, Whitney CG. Pneumococcal disease. In: Wharton M et al., eds. VPD surveillance manual, 3rd edn. Atlanta, GA: Centers for Disease Control and Prevention, 2002. 2. Centers for Disease Control and Prevention. Prevention of pneumococcal disease, recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1997; 46: 1–24. 3. Appelbaum PC. Resistance among Streptococcus pneumoniae: implications for drug selection. Clin Infect Dis 2002; 34: 1613–1620.
CMI
4. Black S, Shinefield H, Fireman B et al. Northern California Kaiser Permanente Vaccine Study Center Group. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J 2000; 19: 187–195. 5. O’Brien KL, Moulton LH, Reid R et al. Efficacy and safety of sevenvalent conjugate pneumococcal vaccine in American Indian children: group randomised trial. Lancet 2003; 362: 355–361. 6. O’Brien KL, Santosham M. Potential impact of conjugate pneumococcal vaccines on pediatric pneumococcal diseases. Am J Epidemiol 2004; 159: 634–644. 7. Pelton SI, Loughlin AM, Marchant CD. Seven valent pneumococcal conjugate vaccine immunization in two Boston communities: changes in serotypes and antimicrobial susceptibility among Streptococcus pneumoniae isolates. Pediatr Infect Dis J 2004; 23: 1015–1022. 8. Oteo J, Lazaro E, de Abajo FJ, Baquero F, Campos J, Spanish Members of the European Antimicrobial Resistance Surveillance System. Trends in antimicrobial resistance in 1,968 invasive Streptococcus pneumoniae strains isolated in Spanish hospitals (2001 to 2003): decreasing penicillin resistance in children’s isolates. J Clin Microbiol 2004; 42: 5571–5577. 9. Perez-Trallero E, Garcia-de-la-Fuente C, Garcia-Rey C et al. Spanish Surveillance Group for Respiratory Pathogens. Geographical and ecological analysis of resistance, coresistance, and coupled resistance to antimicrobials in respiratory pathogenic bacteria in Spain. Antimicrob Agents Chemother 2005; 49: 1965–1972. 10. Picazo JJ, Betriu C, Rodriguez-Avial I et al. Surveillance of antimicrobial resistance: VIRA study 2004. Enferm Infecc Microbiol Clin 2004; 22: 517–525. 11. Picazo JJ, Betriu C, Rodriguez-Avial I et al. Surveillance of antimicrobial resistance: VIRA study 2006. Enferm Infecc Microbiol Clin 2006; 24: 617–628. 12. Fenoll A, Aguilar L, Granizo JJ et al. Has the licensing of respiratory quinolones for adults and the 7-valent pneumococcal conjugate vaccine (PCV-7) for children had herd effects with respect to antimicrobial non-susceptibility in invasive Streptococcus pneumoniae? J Antimicrob Chemother 2008; 62: 1430–1433. 13. Picazo JJ, Contreras JR, Mendez C et al. 6th International Symposium on Pneumococci and Pneumococcal Diseases, Reykjavik, Iceland: 8–12 June 2008. Abstract P2-037. 14. Picazo J, Contreras JR, Mendez C et al. Poster presented at the 26th Annual Meeting of the European Society for Paediatric Infectious Diseases, Graz, Austria: 13–17 May 2008. 15. Sanz JC, Ramosi B, Ochoa D et al. 6th International Symposium on Pneumococci and Pneumococcal Diseases, Reykjavik, Iceland: 8–12 June 2008. Abstract P1-011. 16. World Health Organization. Pneumococcal conjugate vaccine for childhood immunization—WHO position paper. Wkly Epidemiol Rec 2007; 82: 93–104.
ª 2009 The Author Journal Compilation ª 2009 European Society of Clinical Microbiology and Infectious Diseases, CMI, 15 (Suppl. 3), 4–6