Abstract

Background. A dramatic decrease in the incidence of invasive pneumococcal disease (IPD) was observed among children and adults in the United States after the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7). Little is known about the incidence of IPD after PCV7 licensure in Europe. The objective of this study was to examine changes in the prevalence of IPD among adults in the PCV7 era.

Methods. We undertook a prospective study involving adults with IPD who required hospital admission in the southern area of Barcelona, Spain. Three periods were studied: the pre-PCV7 period (1997–2001), the early PCV7 period (2002–2004), and the late PCV7 period (2005–2007).

Results. A total of 1007 episodes of IPD were observed. Rates of IPD among adults increased from 13.9 to 14.6 episodes per 100,000 population between the pre-PCV7 period and the early PCV7 period (P=.6) and then to 19.55 episodes per 100,000 population in the late PCV7 period (P<.001). The rates of IPD among adults due to non-PCV7 serotypes increased from 8.4 to 9.7 episodes per 100,000 population between the pre-PCV7 period and the early PCV7 period (P=.15) and then to 15.3 episodes per 100,000 population in the late PCV7 period (P<.001); IPD due to PCV7 serotypes decreased from 5.6 to 4.9 episodes per 100,000 population between the pre-PCV7 period and the early PCV7 period (P=.3), then to 4.3 episodes per 100,000 population in the late PCV7 period (P=.056). Among people aged ⩾65 years, IPD due to PCV7 serotypes decreased from 19.5 to 14.6 episodes per 100,000 population between the pre-PCV7 period and the early PCV7 period (P=.13), then to 12.3 episodes per 100,000 population in the late PCV7 period (P=.02). A decrease in the prevalence of antibiotic-resistant pneumococci in the late PCV7 period was associated with a decrease in the prevalence of multidrug-resistant PCV7 clones (Spain23F-ST81, Spain6B-ST90, and ST8819F) and an increase in the prevalence of non-PCV7 antibiotic-susceptible clones (ST3061, ST1917F, ST98912F, and ST43322F).

Conclusions. Rates of IPD among adults increased in Barcelona in the late PCV7 period, coinciding with a clonal expansion of non-PCV7 serotypes. In contrast, rates of IPD caused by PCV7 serotypes decreased among people aged ⩾65 years, which suggests the development of a herd immunity.

Streptococcus pneumoniae is a major cause of morbidity and mortality worldwide and is responsible for a wide variety of invasive diseases, including bacteremic pneumonia, septicemia, and meningitis [1, 2]. The normal habitat for pneumococci is the nasopharynx, especially in children who attend day care centers [3]. Children are the main reservoir for pneumococci, and they represent the source of pneumococci that is spread to adults, especially to the elderly population. After the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7; introduced in the United States in 2000 and targeting serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F), which was followed by recommendations for the universal vaccination of children under 2 years of age, the incidence of invasive pneumococcal disease (IPD) due to PCV7 serotypes has dramatically decreased among both children and adults [4, 5]. However, new emerging serotypes have been detected in the late PCV7 period in the United States [6–10]. The changes observed in the serotype and genotype distributions after the introduction of PCV7 in the United States have been related to a serotype replacement phenomenon and/or a capsular switching phenomenon (genotypes associated with >1 serotype) [9–12].

In Spain, PCV7 was licensed in June 2001, but it was not included in the routine pediatric vaccination schedule, except for children who were at a high risk of IPD. However, PCV7 has been administered throughout the private sector among children aged <2 years, with a gradual increase of vaccination coverage up to 50% [13]. Two studies have been performed regarding IPD among children in our geographical area. The first study did not detect a significant decrease in the incidence of IPD among children aged ⩽5 years at 2 years after the introduction of PCV7 [14]. The second study demonstrated a reduction in the incidence of IPD caused by vaccine-serotypes among children aged ⩽2 years [15]. Both studies, as well as others performed in Spain, observed an increase in the incidence of IPD due to nonvaccine serotypes among children, especially pneumonia with empyema [16, 17].

To our knowledge, there are no available data on the incidence of IPD among adults after PCV7 introduction among children in Europe. In this prospective study, performed in the southern area of Barcelona, Spain, we analyze the incidence of all IPD among adult patients and those cases caused by PCV7 or non-PCV7 serotypes before and after PCV7 approval. We also describe the changes in antibiotic susceptibility, serotypes, and genotypes throughout an 11-year period.

Methods

Invasive disease surveillance. The Hospital Universitari de Bellvitge is located in the southern area of Barcelona and serves a population of ∼600,000 people. Trends in the incidence of IPD among adults were studied. Episodes of IPD were prospectively observed for all patients who required hospital admission. Episodes were defined as the growth of pneumococci in blood and other sterile fluids during the study period (1997–2007). We used as the denominator the number of persons, by age group per year, in the public database of the Web de l'Estadística Oficial de Catalunya [18].

To estimate the incidence of IPD due to vaccine or nonvaccine serotypes, we assumed that the distribution of serotypes for cases missing serotype information (2.7% of cases) was the same as the distribution for those cases with serotype information. PCV7 was licensed in Spain in June 2001. The vaccination schedule recommended for infants by the Spanish Pediatric Academy was to administer vaccine at 2, 4, and 6 months of age, with a booster dose at 15–16 months of age [19]. There was a 6-month period of vaccine shortage in 2004. Three periods were defined for this study: the pre-PCV7 period (1997–2001), the early PCV7 period (2002–2004), and the late PCV7 period (2005–2007).

Bacterial strains, serotyping, and antimicrobial susceptibility tests. From 1997 through 2007, 1007 episodes of IPD were detected in 968 adult patients. One strain was studied per episode. Of the strains studied, 980 (97.3%) were serotyped using the Quellung reaction at the Spanish Reference Laboratory [20]. Strains were isolated from specimens of blood (808 isolates), pleural fluid (88 isolates), CSF (74 isolates), ascitic fluid (26 isolates), joint fluid (6 isolates), and humor aqueous (5 isolates).

Antimicrobial susceptibility was tested using the microdilution method, following the Clinical Laboratory Standard Institute methods and criteria [21, 22]. S. pneumoniae ATCC 6303 and S. pneumoniae ATCC 49619 were used as control strains.

Molecular typing. Eight hundred and ninety-nine (89.3%) of the available isolates were studied using PFGE after restriction with SmaI. PFGE patterns were compared with those of representative international pneumococcal clones of the Pneumococcal Molecular Epidemiology Network [23].

Forty-nine representative isolates of PFGE clusters were studied using multilocus sequence typing, as described elsewhere [24]. Allele numbers and sequence types (STs) were assigned using the pneumococcal multilocus sequence typing Web site.

Statistical analysis. Statistical analyses were performed using SPSS for Windows, version 14.0 (SPSS), and EpiInfo, version 6.0 (Centers for Disease Control and Prevention). We used ç2 or Fisher's exact tests to compare proportions. Incidence rates of IPD were defined as the number of episodes per 100,000 population, and 95% CIs were calculated. Two-sided P values of <.05 were considered to be statistically significant.

Results

There were 1007 episodes of IPD that occurred in 968 adults; 66.2% of the patients were men, and the mean age of patients was 60.2 years (range, 18–101 years); 469 episodes (46.6%) occurred in patients aged ⩾65 years. There were no statistically significant differences in the proportion of patients who had underlying conditions in the pre-PCV7 and the early PCV7 periods. In contrast, a comparison of the pre-PCV7 period with the late PCV7 period revealed an increase in the percentage of patients with diabetes (66 [17.4%] of 380 patients vs. 86 [23.5%] of 366 patients; P=.038), especially among patients aged ⩾65 years (44 [23.9%] of 184 patients vs. 59 [34.9] of 169 patients; P=.02). The percentage of HIV-infected patients decreased from the pre-PCV7 period to the late PCV7 period (48 [12.6%] of 380 patients vs. 27 [7.4%] of 366 patients; P=.017), especially among persons aged 18–64 years (48 [24.7%] of 194 patients vs. 27 [13.7%] of 197 patients; P=.006). Overall, 67 patients aged ⩾65 years had been vaccinated with the 23-valent polysaccharide pneumococcal vaccine, including 20 (10.8%) of 186 patients in the pre-PCV7 period, 13 (11.4%) of 114 patients in the early PCV7 period (P=.9), and 34 (20.1%) of 169 patients in the late PCV7 period (P=.014).

Compared with the rate of IPD in the pre-PCV7 period, the overall rates of IPD increased by 4% (95% CI, −11% to 22%) in the early PCV7 period and 40% (95% CI, 21%–61%) in the late PCV7 period. The rates of IPD due to non-PCV7 serotypes increased by 81% (95% CI, 52%–116%) in the late PCV7 period, but IPD due to PCV7 serotypes tended to decrease in the late PCV7 period (change from pre-PCV7 period, −23%; 95% CI, −41% to 0.8%) (table 1). The rates of meningitis and bacteremic pneumonia increased by 137% (95% CI, 40%–303%; P=.001) and 39% (95% CI, 17%–65%; P<.001), respectively, in the late PCV7 period, mostly attributable to an increase in the prevalence of nonvaccine serotypes (table 1).

Table 1

The incidence of invasive pneumococcal disease (IPD) among adult patients before and after the introduction of 7-valent pneumococcal conjugate vaccine (PCV7) in the southern region of Barcelona, Spain.

Table 1

The incidence of invasive pneumococcal disease (IPD) among adult patients before and after the introduction of 7-valent pneumococcal conjugate vaccine (PCV7) in the southern region of Barcelona, Spain.

Among patients aged 18–64 years, the overall rate of IPD increased in the late PCV7 period (change from pre-PCV7 period, 49%; 95% CI, 22%–82%), and this finding was related to an increase in the prevalence of non-PCV7 serotypes (change from pre-PCV7 period, 86%; 95% CI, 46%–135%), although the prevalence of PCV7 serotypes remained stable. In contrast, among people aged ⩾65 years, the rates of PCV7 serotypes decreased by 37% (95% CI, −57% to −7%) from the pre-PCV7 period to the late PCV7 period, and the overall rates of IPD increased by 23% (95% CI, −0.3% to 51%) over the same time, because of an increase in the prevalence of non-PCV7 serotypes (change from pre-PCV7 period, 67%; 95% CI, 29%–151%) (table 1 and figure 1).

Figure 1

The incidence of invasive pneumococcal disease (IPD) by year and serotype group among adults aged 18–64 years (top) and among adults aged ⩾65 years (bottom). PCV7, 7-valent pneumococcal conjugated vaccine.

Figure 1

The incidence of invasive pneumococcal disease (IPD) by year and serotype group among adults aged 18–64 years (top) and among adults aged ⩾65 years (bottom). PCV7, 7-valent pneumococcal conjugated vaccine.

Because changes in blood culture practices could cause changes in the incidence of IPD, we have analyzed the number of episodes of bacteremia per 1000 blood cultures performed. The number of Escherichia coli bacteremia episodes remained stable during the 3 periods (27.8, 26.9, and 27.0 bacteremia episodes per 1000 blood cultures in the pre-PCV7, early PCV7, and late PCV7 periods, respectively); however, the number of pneumococcal bacteremia episodes increased in the late PCV7 period (5.4, 5.4, and 7.0 bacteremia episodes per 1000 blood cultures in the pre-PCV7, early PCV7, and late PCV7 periods, respectively; P<.001).

Serotypes. The percentage of PCV7 serotype isolates among all isolates in the pre-PCV7 period was 39.9%; the percentage of PCV7 serotype isolates remained stable in the early PCV7 period (33.6%) and decreased to 21.7% in the late PCV7 period (P<.001). No significant changes were observed among adults in the rate of IPD caused by each serotype, comparing pre-PCV7 with early PCV7 periods. However, in the late PCV7 period, rates of IPD due to 7 non-PCV7 serotypes significantly increased: the rate of IPD due to serotype 1 increased from 0.98 to 2.23 episodes per 100,000 population (change from pre-PCV7 period, 126%; 95% CI, 39%–266%; P<.001), the rate of IPD due to serotype 5 increased from 0.53 to 1.17 episodes per 100,000 population (change from pre-PCV7 period, 128%; 95% CI, 17%–346%; P=.01), the rate of IPD due to serotype 7F increased from 0.31 to 1.68 episodes per 100,000 population (change from pre-PCV7 period, 462%; 95% CI, 158%–1123%; P<.001), the rate of IPD due to serotype 12F increased from 0.15 to 0.90 episodes per 100,000 population (change from pre-PCV7 period, 516%; 95% CI, 107%–1732%; P<.001), the rate of IPD due to serotype 19A increased from 0.49 to 1.29 episodes per 100,000 population (change from pre-PCV7 period, 168%; 95% CI, 36%–426%; P=.003), the rate of IPD due to serotype 22F increased from 0.07 to 0.51 episodes per 100,000 population (change from pre-PCV7 period, 625%; 95% CI, 59%–3210%; P=.005), and the rate of IPD due to serotype 24 increased from 0.07 to 0.61 episodes per 100,000 population (change from pre-PCV7 period, 698%; 95% CI, 77%–3499%; P=.001). A trend toward a decrease in the rate of IPD due to PCV7 serotypes was observed in the late PCV7 period for the following serotypes: the rate of IPD due to serotype 4 decreased from 0.91 to 0.45 episodes per 100,000 population (change from pre-PCV7 period, −54%; 95% CI, −79 to 3; P=.05), the rate of IPD due to serotype 6B decreased from 0.60 to 0.22 episodes per 100,000 population (change from pre-PCV7 period, −64%; 95% CI, −88% to 9%; P=.06), and the rate of IPD due to serotype 19F decreased from 0.71 to 0.33 episodes per 100,000 population (change from pre-PCV7 period, −54.2%; 95% CI, −82% to 15%; P=.09).

Molecular typing. Among the 899 strains studied, the most frequent genotypes were Spain9V-ST156 (104 strains [11.6%]), ST2603 (57 strains [6.3%]), Sweden1-ST306 (54 strains [6.0%]), Netherlands7F-ST191 (39 strains [4.3%]), Colombia5-ST289 (37 strains [4.1%]), Netherlands3-ST180 (36 strains [4.1%]), and Spain23F-ST81 (34 strains [3.8%]). Comparing pre-PCV7 with early PCV7 periods, no significant changes were observed in the frequency of genotypes. In contrast, comparing pre-PCV7 with late PCV7 periods revealed that the prevalence of the following 4 genotypes significantly decreased: Spain23F-ST81 (5.8% vs. 0.3%; P<.001), ST2474 (4.9% vs. 0.9%; P=.003), Spain6B-ST90 (3.7% vs. 0.3%; P=.003), and ST8819F (2.7% vs. 0.3%; P=.02). However, the prevalence of the following 5 genotypes significantly increased: Sweden1-ST306 (3.7% vs. 9.5%; P=.003), Netherlands7F-ST191 (2.1% vs. 7.6%; P=.001), Denmark14-ST230 (0% vs. 3.8%; P<.001; serotypes 19A and 24), ST98912F (0% vs. 4.4%; P<.001), and ST43322F, 19A (0.3% vs. 2.8%; P=.010; serotypes 22F and 19A).

Antibiotic susceptibility. We observed a statistically significant decrease in the proportion of antibiotic-resistant pneumococci with a penicillin MIC ⩾2 µg/mL and a cefotaxime MIC of 1 µg/mL from the pre-PCV7 to the late PCV7 period (table 2). Neither penicillin- nor cefotaxime-resistant isolates were detected with use of resistance break points for nonmeningeal infection (penicillin MIC, ⩾8 µg/mL; cefotaxime MIC, ⩾4 µg/mL) [22]. Significant decreases in the rates of resistance to chloramphenicol, tetracycline, and cotrimoxazol were observed in the late PCV7 period.

Table 2

Antibiotic susceptibility of 1007 invasive Streptococcus pneumoniae strains isolated from adult patients to 7 antimicrobial in the Hospital Universitari de Bellvitge, Barcelona (1997–2007).

Table 2

Antibiotic susceptibility of 1007 invasive Streptococcus pneumoniae strains isolated from adult patients to 7 antimicrobial in the Hospital Universitari de Bellvitge, Barcelona (1997–2007).

Discussion

The introduction of PCV7 for children in the United States in 2000 was associated with a decrease in the rate of IPD among both children and adults. This was associated with a decrease in the rate of penicillin-resistant isolates, because PCV7 serotypes are often multidrug resistant [4, 25]. However, recent reports from the United States have described the emergence of infections due to non-PCV7 serotypes, especially serotype 19A, although the overall rate of IPD has remained below those observed in the period before PCV7 introduction [6, 8–11].

Few data about IPD are available from European countries after the introduction of PCV7. In Norway, the universal immunization program started in 2006 (coverage, 73%; uptake, >80%) and was followed by a 52% decrease in the rate of IPD among children in 2007 [26]. In France, a 21% decrease in IPD among children aged <2 years was observed in 2006 after PCV7 introduction (coverage, 68%; uptake, 44%), whereas the overall rate of IPD among adults increased [27]. In Portugal, with a PCV7 uptake of 54%, the rate of IPD among children aged <1 year decreased by 21% in the period 2002–2004, although the decrease was not statistically significant ( P=.53) [28]. In Spain, PCV7 covered 68% of the serotypes that were causing IPD in children during the prevaccine period [13, 20], and the estimated PCV7 uptake among children aged <2 years was 22%–29% in 2002–2004 and increased to 45%–50% in 2005–2006 [13–17]. Recent reports from Spain showed geographical differences in the trends of IPD after PCV7 introduction; in the northern region of Spain (Basque Country and Navarra), with an estimated coverage by 4-dose PCV7 of 28%–45% in 2003, the overall rate of IPD among children aged <2 years decreased significantly 2 years after the start of immunization, but in the southern region of Spain (Sevilla), there were no statistically significant changes in the rate of IPD among children [16, 17]. In contrast, in Barcelona (located in northeastern Spain), the rate of IPD among children remained unchanged in the early PCV7 period [14] and increased in the late PCV7 period [15]; all 4 studies reported a decrease in the prevalence of PCV7 serotypes, and 3 of the studies demonstrated a statistically significant increase in the prevalence of non-PCV7 serotypes [14–17].

This study, which is focused on adult patients in Barcelona, reveals different trends in IPD depending on the age group examined. The rate of IPD among adults remained stable in the pre-PCV7 and early PCV7 periods, whereas the rate increased significantly in the late PCV7 period. The rate of IPD due to non-PCV7 serotypes increased among adults, especially for serotypes 1, 7F, 12F, 19A, 22F, and 24, an observation also made among children in our geographical area [14–17]. Among people aged ⩾65 years, the rate of IPD due to PCV7-serotypes decreased in the late PCV7 period, suggesting a herd immunity, which has been described in other countries [5].

The introduction of PCV7 for children may have contributed, in part, to these epidemiological changes in IPD among adults. A decrease in oropharyngeal colonization by PCV7 serotypes, and an increase of non-PCV7 serotypes among children has been associated with PCV7 vaccination [6, 29]. Because children are the main reservoirs of pneumococcus, changes in serotype transmission and in the prevalence of IPD among adults could be expected. However, the epidemiological changes observed in IPD among adults should not be attributed only to PCV7 use among children, because other factors may play an important role.

First, fluctuations of serotype prevalences over time have been described worldwide. The most common serotypes (1, 3, 5, and 7F) isolated in IPD cases among adults in the 1979–1990 period in our institution were the same as those observed in the late PCV7 period of our study [30]. For instance, in 1979, serotype 1 accounted for 10% of invasive pneumococci isolated from adults at our institution; in 1996, it only accounted for 2%, and in the 2005–2007 late PCV7 period, it accounted for 11% [30]. The spread of serotype 1 (ST306) was described in Sweden in the late 1990s, when the prevalence of this serotype increased from 1% of IPD isolates in 1992 to 10% in 1997, which was related to the expansion of Sweden1-ST306 clone [31]. Currently, the prevalence of this serotype is also increasing in other European countries [28, 32]. Although the Sweden1-ST306 was detected in our area throughout the study period, its prevalence increased significantly in the late PCV7 period, when it accounted for 10% of invasive strains. In addition, the Sweden1-ST306 genotype has been associated with an increasing frequency of parapneumonic empyema among children in Spain [17], and it has been recently described in cases of pneumococcal colonization in healthy children in Lisbon, Portugal [33]. In contrast, no increase in the prevalence of serotype 1 was detected after the introduction of PCV7 in the United States. In the United States, the serotype 1 pneumococci are mainly represented by the ST227 clone, which is a double locus variant of ST306 [8, 34].

Second, the increase in the incidence of IPD could be related to outbreaks of infection in the community in a specific geographical area [35]. In this way, the peak of IPD incidence among adults aged ⩾65 years that we observed in 2005 was associated with a significant increase in the prevalence of serotype 5, which accounting for the highest percentage (15%) of invasive pneumococci isolated in 2005.

Third, the increase in the prevalence of non-PCV7 serotypes was related to the expansion of specific clones in our area. The incidence of IPD due to serotype 7F increased in the late PCV7 period, and it was associated with the expansion of the Netherlands7F-ST191 clone; this also occurred in the United States [34]. The prevalence of serotype 7F also increased in other European countries, such as France, Portugal, and the United Kingdom [27, 28, 32]. The increased rates of IPD due to serotypes 12F, 22F, and 24 were also associated with the clonal expansion of ST989, ST433, and ST230, respectively. Recently, an increase in the prevalence of serotype 19A has been described in many countries, both with and without PCV7 introduction [8, 9, 15, 27, 34, 36]. In our experience, the increase in the incidence of IPD caused by serotype 19A was associated with the emergence of 2 genotypes (ST276 of clonal complex 230 and ST433) in the late PCV7 period.

Fourth, changes in antimicrobial use could have influenced the selection and spread of multidrug-resistant clones [37]. In Spain, the rates of antibiotic use decreased from 21.66 defined daily doses per 1000 inhabitants per day in 1998 to 19.29 defined daily doses per 1000 inhabitants per day in 2005, which coincided with a decrease in penicillin resistance rates among S. pneumoniae strains isolated from children [38, 39]. In agreement with this observation, we have observed a decrease in the proportion of isolates with antibiotic resistance to penicillin among invasive pneumococcal isolates from adults in the late PCV7 period. Moreover, a decrease in the prevalence of cefotaxime, chloramphenicol, erythromycin, tetracycline, and cotrimoxazol resistance was observed in the late PCV7 period; this has been observed in other countries after PCV7 introduction [4, 25, 28]. This decrease in the prevalence of antimicrobial resistance was associated with a significant decrease in the prevalence of the multidrug-resistant PCV7 clones Spain23F-ST81, Spain6B-ST90, and ST8819F.

Fifth, changes in the incidence of comorbidities associated with an increased risk of IPD could have favored the increase in IPD. In our study, the prevalence of patients with underlying conditions remained stable in the pre-PCV7 and early PCV7 periods. However, in the late PCV7 period, the percentage of patients with diabetes increased among older patients, as reported elsewhere [5]. On the contrary, the percentage of patients with HIV infection decreased in the late PCV7 period among young adults in our study, probably because of the improvement in the effectiveness of HAART, which is subsidized by the state.

Finally, the recent increase in the population of immigrants to Spain could have contributed to changes in the epidemiology of IPD. The percentage of foreigners in the total population of our area increased from 1.8% in 2000 to 7.7% in 2007 [18], and this new population was mostly children and young adults. Thirty-one of 1007 episodes observed in the present study occurred in foreigners: 2 in the pre-PCV7 period, 10 in the early PCV7 period, and 19 in the late PCV7 period. However, no differences in the rate of IPD among native and foreign people were observed.

In conclusion, the increase in the incidence of IPD due to non-PCV7 serotypes observed among adults in Barcelona in the late PCV7 period was related to the dissemination of specific clones of non-PCV7 serotypes. The decrease in the incidence of IPD due to PCV7 serotypes observed among people aged ⩾65 years suggests the development of herd immunity. The decrease in the rate of antibiotic use in conjunction with the introduction of PCV7 has contributed to a decrease in antibiotic resistance in isolates from the late PCV7 period in Spain. Additional surveillance studies focused on the clinical and molecular epidemiology of IPD are needed to understand the impact of PCV7 and the upcoming PCV10 and PCV13 vaccines.

Acknowledgments

We thank the staff at the Microbiology Department of Hospital Universitari de Bellvitge, for daily contributions to this project, and Dr. Jordi Niubó at the Microbiology Department of Hospital Universitari de Bellvitge, for considerable assistance in sequencing genes for multilocus sequence typing.

Financial support. Fondo de Investigaciones Sanitarias de la Seguridad Social (PI060647), the Spanish Pneumococcal Infection Study Network G03/103 (Red Temática de Cooperación del FIS), Ciber de Enfermedades Respiratorias (CB06/06/0037 Ministry of Health, Instituto de Salud Carlos III, Madrid, Spain), and Institut d'Investigació Biomèdica de Bellvitge (to D.R.).

Potential conflicts of interest. All authors: no conflicts.

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Presented in part: 18th European Congress of Clinical Microbiology and Infectious Diseases, Barcelona, Spain, April 2008 (abstract P1336).

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