JAC Advance Access originally published online on September 26, 2008
Journal of Antimicrobial Chemotherapy 2008 62(6):1430-1433; doi:10.1093/jac/dkn413
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Original research |
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?
1 Spanish National Reference Pneumococcal Laboratory, Instituto de Salud Carlos III, ctra. Majadahonda-Pozuelo Km. 2, 28220 Majadahonda, Madrid, Spain 2 Microbiology Department, School of Medicine, Univ. Complutense, Avda. Complutense s/n, 28040 Madrid, Spain 3 Grana Datos SL, c/ Demetrio de la Guerra 4, 28223 Pozuelo de Alarcón, Madrid, Spain 4 Medical Department, Wyeth Farma S.A., N-I Km. 23, Desvío Algete Km. 1, 28700 San Sebastián de los Reyes, Madrid, Spain
* Corresponding author. Tel: +34-91-3941505; Fax: +34-91-3941511; E-mail: laguilar{at}med.ucm.es
Received 9 June 2008; returned 20 July 2008; revised 18 August 2008; accepted 9 September 2008
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and methodsResultsDiscussionFundingTransparency declarationsReferences |
|---|
Objectives: The aim of the study was to analyse the evolution of antibiotic non-susceptibility in Spanish invasive Streptococcus pneumoniae after licensure of respiratory-quinolones for adults and 7-valent pneumococcal conjugate vaccine (PCV-7) for immunization of children.
Methods: All invasive pneumococci received in the Reference Laboratory (January 2000–August 2007; n = 12 957 isolates) were serotyped, and susceptibility to penicillin/erythromycin/levofloxacin was determined. Antibiotic consumption and PCV-7 doses/year were provided by IMS and the manufacturer, respectively.
Results: In 2000–07, PCV-7 distribution (doses/1000 inhabitants 
59 months age/year) increased from 0.0 to 411.90, and antibiotic consumption (DDD/1000 inhabitants/day) was maintained for β-lactams (
16), decreased for macrolides (from 4.4 to 2.7) and increased for respiratory fluoroquinolones (from 0.3 to 2.7). The increase in PCV-7 distribution correlated with a decrease in PCV-7 serotypes prevalence among invasive isolates in children (r = –0.976; P < 0.001) and adults (r = –0.905; P = 0.002). This decrease in PCV-7 serotypes correlated with a decrease in penicillin non-susceptibility in children (r = 0.929; P < 0.001) and adults (r = 0.905; P = 0.002) and with erythromycin non-susceptibility in children (r = 0.833; P = 0.010). Penicillin/erythromycin non-susceptibility in 2000 was significantly higher in paediatric versus adult isolates (penicillin: 51.4% versus 29.2%; erythromycin: 39.5% versus 20.4%), but similar in 2006–07 (20% to 24%). The increase in respiratory quinolones consumption correlated with the increase in levofloxacin non-susceptibility in adults (r = 0.926; P = 0.008) but not in children, with different non-susceptibility rates in 2007 (1.6% versus 0.0%; P = 0.013).
Conclusions: This ecological analysis suggests that PCV-7 vaccination in children had a herd effect in adults, but consumption of respiratory quinolones in adults had no effect on pneumococcal susceptibility to levofloxacin in children. Penicillin/erythromycin non-susceptibility decreased along the studied period among paediatric invasive S. pneumoniae isolates to a level similar to that seen in adults.
Keywords: antibiotic consumption , PCV-7 distribution , pneumococcal resistances , vaccination
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionFundingTransparency declarationsReferences |
|---|
In Europe, previous ecological studies have shown the relationship between resistance in Streptococcus pneumoniae and global/specific antibiotic consumption both at country level in the pre-conjugate vaccine/respiratory fluoroquinolones era in Spain1 and at European level after the licensure of respiratory fluoroquinolones and the 7-valent pneumococcal conjugate vaccine (PCV-7).2 In both cases, relationships between β-lactam/macrolide consumption and penicillin/macrolide resistance in S. pneumoniae were reported,1,2 but in the European study, no association was found between the consumption of any antibiotic class and resistance to fluoroquinolones, probably due to the low levels of fluoroquinolone resistance observed.2 On the contrary, it can be speculated that penicillin/macrolide resistance might have decreased after the introduction of respiratory fluoroquinolones for adult treatment, because of their intrinsic activity against penicillin/macrolide resistant pneumococci.
A relationship between the decrease in antibiotic resistance in paediatric strains causing disease and the introduction of PCV-7 for children has been reported,3 since this vaccine targets drug-resistant pneumococcal serotype (which accounted for 78% of all penicillin-resistant strains in the pre-licensure era).4 This effect in children may influence (being additive or not with the potential effect of fluoroquinolones) susceptibility rates in adults, since the vaccine may reduce pneumococcal transmission due to a herd effect.5 In Spain, PCV-7 was introduced in 2001, 1 year after the launch of levofloxacin, but only in the private market.
The aim of this study was to analyse the evolution of antibiotic non-susceptibility in invasive S. pneumoniae in Spain after the licensure of respiratory quinolones for treatment in adults and of PCV-7 for immunization of the paediatric population.
|
Materials and methods |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionFundingTransparency declarationsReferences |
|---|
All invasive pneumococci received in the Spanish Reference Pneumococcal Laboratory, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain, from January 2000 to August 2007 (n = 12 957 isolates) from hospitals in different regions of the country, were serotyped by Quellung reaction and/or dot blot assay.6 Vaccination status of the patients from whom invasive isolates were received was not known. Susceptibility to penicillin, erythromycin and levofloxacin was determined by the previously described agar dilution technique7 according to the criteria from CLSI.8 Breakpoints for non-susceptibility were those defined by CLSI:9 penicillin,
0.12 mg/L; erythromycin, 0.5 mg/L; and levofloxacin, 4 mg/L. Non-susceptibility rates were calculated yearly for children, adults and overall. Information on age was not available for 421 strains (3.2%), which were only included in the overall calculation.
Data on antibiotic consumption were gathered from IMS Health (Intercontinental Marketing Services, Madrid, Spain) as the total number of antibiotic wholesaler sales per presentation (package) per year. The consumption was calculated as daily defined doses (DDD) per 1000 inhabitants per day (DDD/1000 inhabitants/day), following the 2002 World Health Organization (WHO) Collaborating Center for Drug Statistics Methodology recommendation.10 PCV-7 doses delivered per year were provided by the manufacturer, and vaccine distribution was expressed as doses/1000 inhabitants 59 months age/year. Yearly population data were obtained from the ‘Instituto Nacional de Estadistica’ (www.ine.es).
Temporal trends were measured by the 
2 for trends test, and correlations between prevalence of non-susceptibility (intermediate + resistant) and antibiotic consumption or PCV-7 per year were calculated with the non-parametric correlation coefficient (Spearman' 
). Differences in non-susceptibility prevalence between isolates from children versus adults were compared yearly using the 2 test or Fisher's exact test when necessary.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionFundingTransparency declarationsReferences |
|---|
Antibiotic consumption and PCV-7 distribution in Spain along the study period are shown in Table 1. From 2000 to 2007, vaccine distribution (doses/1000 inhabitants
59 months age/year) increased from 0.0 to 411.90, and antibiotic consumption (DDD/1000 inhabitants/day) was maintained for β-lactams (16), decreased for macrolides (from 4.4 to 2.7) and increased for respiratory fluoroquinolones (from 0.3 to 2.7).
|
Table 2 shows the temporal evolution of penicillin, erythromycin and levofloxacin non-susceptibility together with the percentage of PCV-7 serotypes among the total invasive isolates received from children and adults in the study period. Non-susceptibility to penicillin and erythromycin significantly (P < 0.001) decreased in children, and to penicillin (but not to erythromycin) in adults over the studied period. Whereas significant (P < 0.001) differences in penicillin/erythromycin non-susceptibility between children and adults were found in the period 2000–05, no differences were found in 2007 with respect to penicillin (21.5% versus 22.1%; P = 0.975) and erythromycin (20.0% versus 20.4%; P = 0.715) non-susceptibilities, but significant differences were found in the case of levofloxacin non-susceptibility (0.0% versus 1.6%; P = 0.013). When comparing data in 2000 versus 2007, the prevalence of PCV-7 serotypes among invasive isolates significantly (P < 0.001) decreased in children (from 62.4% to 14.65%) and in adults (from 40.3% to 21.0%), with the prevalence of PCV-7 serotypes being significantly (P < 0.001) higher in children in 2000 and significantly (P < 0.001) higher in adults in 2007 (Table 2).
|
When relating antibiotic consumption with non-susceptibility, the decrease in macrolide consumption correlated with the decrease in erythromycin non-susceptibility in children (r = 0.810; P = 0.015) and with the decrease in penicillin non-susceptibility both in adults (r = 0.881; P = 0.004) and in children (r = 0.976; P < 0.001). The increase in the consumption of respiratory quinolones correlated with the increase in levofloxacin non-susceptibility in adults (r = 0.926; P = 0.008), but not in children (where all strains were susceptible to levofloxacin). The increase in fluoroquinolones consumption also correlated with penicillin non-susceptibility decrease both in adults (r = –0.905; P = 0.002) and in children (r = –1.000; P < 0.001) and with the decrease in erythromycin non-susceptibility in children (r = –0.833; P = 0.010). No relationship was found between the steady β-lactam consumption over time (yearly maintained at
16 DDD/1000 inhabitants) and the decrease in penicillin non-susceptibility in adults (r = –0.476; P = 0.233) and in children (r = –0.262; P = 0.531). When relating PCV-7 distribution with non-susceptibility, the increase in PCV-7 distribution correlated with penicillin non-susceptibility decrease both in children (r = –0.976; P < 0.001) and in adults (r = –0.881; P = 0.004) and with the decrease in erythromycin non-susceptibility in children (r = –0.810; P = 0.015).
When relating PCV-7 distribution with prevalence of PCV-7 serotypes, the increase in vaccine distribution significantly correlated with the decrease in the prevalence of PCV-7 serotypes among invasive isolates both in children (r = –0.976; P < 0.001) and in adults (r = –0.905; P = 0.002). Logically, the decrease in the prevalence of PCV-7 serotypes among invasive isolates correlated with penicillin non-susceptibility decrease both in children (r = 0.929; P < 0.001) and in adults (r = 0.905; P = 0.002) and with the decrease in erythromycin non-susceptibility in children (r = 0.833; P = 0.010) but not in adults (r = 0.180; P = 0.670).
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionFundingTransparency declarationsReferences |
|---|
It has been suggested that reduction in drug-resistant S. pneumoniae will require a combination of PCV-7 vaccine and a reduction in antimicrobial use.11 In Spain, penicillin resistance increased in the first half of the 1990s in relation to antibiotic consumption,1 but began to decrease slightly in the last years of the past decade.12 Thus, it is probable that factors other than those analysed in this ecological study may have also contributed to the decrease in penicillin non-susceptibility in the period analysed in this study. In the period 2000–07, the reduction in penicillin and erythromycin non-susceptibility among invasive paediatric isolates was statistically significant and statistically related to both a decrease in the prevalence of PCV-7 serotypes and a decrease in macrolide consumption (but not in β-lactam consumption). The reduction in non-susceptibility to both penicillin and erythromycin among paediatric invasive isolates reinforces the previously described penicillin/erythromycin co-resistance in Spain13 and resulted in penicillin/erythromycin non-susceptibility rates in paediatric isolates similar to those in adults in 2006–07 (20% to 24%) (non-susceptibility rates in the paediatric population at the beginning of the century were much higher than in adults: 51.4% versus 29.2% for penicillin and 39.5% versus 20.4% for erythromycin).
From the analysis of the prevalence of PCV-7 serotypes among invasive isolates, it seems that there is a herd effect of PCV-7 by reducing pneumococcal transmission from children to adults since there was also a significant but lower rate of decrease in PCV-7 serotypes in adults. This decrease in adults is important because it was related to a decrease in penicillin non-susceptibility (although much lower than in the paediatric population). Surprisingly, in adults, there was no decrease in erythromycin non-susceptibility, probably due to the increase in non-vaccine serotypes such as 19A (from 3.6% of all invasive serotypes in 2000 to 10.1% in 2007) that exhibits erythromycin non-susceptibility rates of 50% in this period (data not shown). On the contrary, the licensure of respiratory fluoroquinolones for the treatment of the adult population significantly increased levofloxacin resistance in adults, but not in children. The prevalence of strains that were non-susceptible was different in both populations in 2006 and 2007, suggesting the absence of a herd effect without a significant pneumococcal transmission from adults to children.
This study analyses the evolution of antibiotic non-susceptibility and PCV-7 serotypes from 2000 to 2007, but does not focus on prevalence or serotype replacement in invasive disease. In any case, it can be clearly deduced from the table that the percentages of non-vaccine serotypes (i.e. 100-vaccine serotype percentage) among invasive isolates received in the Reference Laboratory significantly increased (from 37.6% to 85.4% in children and from 59.7% to 79.0% in adults) from 2000 to 2007. Nevertheless, this does not directly imply that there has been a replacement in invasive pneumococcal disease, as previously reported.14,15 To date, some reports in Spain based on local human population data have indicated an increase in the rate of pneumococcal invasive disease,15 while others reported a decrease.16,17 From 2000 to 2006, there has been an increase in the number of isolates received in the Reference Laboratory per year (55.8% increase in the case of invasive isolates), but this has been due to the increase in the number of Spanish hospitals voluntarily participating in the surveillance system, reflecting the increasing interest in pneumococcal surveillance after PCV-7 licensure.
Although this is an ecological analysis and thus its aim is not to demonstrate a causal relationship, and caution should be taken about over-interpretation of statistical correlation data, the results of this analysis suggest an effect of vaccination on antibiotic susceptibility with a herd effect from the paediatric to adult population. On the contrary, there is an absence of translation of the effect of fluoroquinolones consumption in adults (increasing levofloxacin resistance from 0% to 1.6%) to children where fluoroquinolones are not prescribed and levofloxacin susceptibility was maintained at 100% over the study period. Along the study period, penicillin and erythromycin non-susceptibility rates in paediatric invasive isolates received in the Spanish Reference Laboratory decreased to a level similar to rates found in adults. Although antibiotic policies remain important for controlling antibiotic resistance in S. pneumoniae, administration of PCV-7 may contribute as an effective tool to combat antibiotic-resistant pneumococcal disease as previously suggested.18
|
Funding |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionFundingTransparency declarationsReferences |
|---|
This study was supported in part by an unrestricted grant from Wyeth Farma S.A., Spain.
|
Transparency declarations |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionFundingTransparency declarationsReferences |
|---|
C. M. is an employee (not owning stocks or options in the company) of Wyeth Farma S.A., Madrid, Spain. A. F. and D. T. have received travel fees for attending and/or speaking at symposium/congresses from Wyeth Farma. Other authors: none to declare.
|
References |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionFundingTransparency declarationsReferences |
|---|
1 Granizo JJ, Aguilar L, Casal J, et al. Streptococcus pneumoniae resistance to erythromycin and penicillin in relation to macrolide and β-lactam consumption in Spain (1979–1997). J Antimicrob Chemother (2000) 46:767–73.
2 Riedel S, Beekmann SE, Heilmann KP, et al. Antimicrobial use in Europe and antimicrobial resistance in Streptococcus pneumoniae. Eur J Clin Microbiol Infect Dis (2007) 26:485–90.[CrossRef][Web of Science][Medline]
3 Black S, Shinefield H, Baxter R, et al. Postlicensure surveillance for pneumococcal invasive disease after use of heptavalent pneumococcal conjugate vaccine in Northern California Kaiser Permanente. Pediatr Infect Dis J (2004) 23:485–9.[CrossRef][Web of Science][Medline]
4 Steenhoff AP, Shah SS, Ratner AJ, et al. Emergence of vaccine-related pneumococcal serotypes as a cause of bacteremia. Clin Infect Dis (2006) 42:907–14.[CrossRef][Web of Science][Medline]
5 World Health Organization. Pneumococcal vaccines. WHO position paper. Wkly Epidemiol Rec (1999) 74:177–83.[Medline]
6
Fenoll A, Jado I, Vicioso D, et al. Dot blot assay for the serotyping of pneumococci. J Clin Microbiol (1997) 35:764–6.
7 Fenoll A, Martín Bourgon C, Muñóz R, et al. Serotype distribution and antimicrobial resistance of Streptococcus pneumoniae isolates causing systemic infections in Spain, 1979–1989. Rev Infect Dis (1991) 13:56–60.[Web of Science][Medline]
8 Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically—Seventh Edition: Approved Standard M7-A7 (2006) Wayne, Pa, USA: CLSI.
9 Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Eighteenth Informational Supplement M100-S18 (2008) Wayne, PA, USA: CLSI.
10 World Health Organization Collaborating Center for Drug Statistics Methodology. ATC Index with DDDs (2002) Oslo, Norway: World Health Organization Collaborating Center for Drug Statistics Methodology.
11 McGee L. The coming of age of niche vaccines? Effect of vaccines on resistance profiles in Streptococcus pneumoniae. Curr Opin Microbiol (2007) 10:473–8.[CrossRef][Web of Science][Medline]
12 Fenoll A, Asensio G, Jado I, et al. Antimicrobial susceptibility and pneumococcal serotypes. J Antimicrob Chemother (2002) 50(Suppl S2):13–9.[Abstract]
13
Pérez-Trallero E, García-de-la-Fuente C, García-Rey C, et al. Geographical and ecological analysis of resistance, coresistance, and coupled resistance to antimicrobials in respiratory pathogenic bacteria in Spain. Antimicrob Agents Chemother (2005) 49:1965–72.
14 Barricarte A, Castilla J, Gil-Setas A, et al. Effectiveness of the 7-valent pneumococcal conjugate vaccine: a population-based case-control study. Clin Infect Dis (2007) 44:1436–41.[CrossRef][Web of Science][Medline]
15 Muñoz-Almagro C, Jordan I, Gene A, et al. Emergence of invasive pneumococcal disease caused by nonvaccine serotypes in the era of 7-valent conjugate vaccine. Clin Infect Dis (2008) 46:174–82.[CrossRef][Web of Science][Medline]
16 Aristegui J, Bernaola E, Pocheville I, et al. Reduction in paediatric invasive pneumococcal disease in the Basque Country and Navarre, Spain, after introduction of the heptavalent pneumococcal conjugate vaccine. Eur J Clin Microbiol Infect Dis (2007) 26:303–10.[CrossRef][Web of Science][Medline]
17 Calbo E, Díaz A, Cañadell E, et al. Invasive pneumococcal disease among children in a health district of Barcelona: early impact of pneumococcal conjugate vaccine. Clin Microbiol Infect (2006) 12:867–72.[CrossRef][Web of Science][Medline]
18 Talbot TR, Poehling KA, Hartert TV, et al. Reduction in high rates of antibiotic-nonsusceptible invasive pneumococcal disease in Tennessee after introduction of the pneumococcal conjugate vaccine. Clin Infect Dis (2004) 39:641–8.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. Fenoll, M.-J. Gimenez, M.-D. Vicioso, J.-J. Granizo, O. Robledo, and L. Aguilar Susceptibility of pneumococci causing meningitis in Spain and prevalence among such isolates of serotypes contained in the 7-valent pneumococcal conjugate vaccine J. Antimicrob. Chemother., December 1, 2009; 64(6): 1338 - 1340. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||