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Emergence of Streptococcus pneumoniae Serotypes 19A, 6C, and 22F and Serogroup 15 in Cleveland, Ohio, in Relation to Introduction of the Protein-Conjugated Pneumococcal Vaccine

  1. Michael R. Jacobs,
  2. Caryn E. Good,
  3. Saralee Bajaksouzian, and
  4. Anne R. Windau
  1. Department of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio
  1. Reprints or correspondence: Dr. Michael R. Jacobs, Dept. of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, 11100 Euclid Ave., Cleveland, OH 44106 (mrj6{at}cwru.edu).
 
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Abstract

Background. A 7-valent conjugate pneumococcal vaccine (PCV7) was introduced in 2000.

Methods. We determined serotypes and assessed antimicrobial susceptibility of 1235 invasive and noninvasive isolates of Streptococcus pneumoniae recovered from children and adults at University Hospitals Case Medical Center (Cleveland, OH) during the period 1999–2007.

Results. The annual number of cases of S. pneumoniae infection decreased from 218 in 2000 to 86–130 during the period 2002–2007, with the number of cases involving invasive strains decreasing from 96 to 18–35. For 1999 versus 2005–2007, the annual incidence of vaccine serotypes decreased by 92% (95% confidence interval [CI], −96.3% to −87.0%), whereas that of vaccine-related and nonvaccine serotypes increased 207.4% (95% CI, 135.0%–297.7%) and 18.4% (95% CI, −10.0% to 52.3%), respectively. Serotypes 19A, 6C, and 22F and serogroup 15 accounted for most of these increases. For the period 2005–2007, antimicrobial susceptibility testing revealed that ceftriaxone was the most active parenteral β-lactam for both meningeal and nonmeningeal infections (72% and 88% of isolates, respectively, were susceptible to this agent); only 52% were susceptible to penicillin G at the meningeal breakpoint, whereas 77% were susceptible at the new nonmeningeal breakpoint of 2 µg/mL. Amoxicillin was the most active oral β-lactam (72% of isolates were susceptible), whereas 53% of isolates were susceptible to azithromycin, 69% to clindamycin, 63% to trimethoprim-sulfamethoxazole, and 100% to levofloxacin.

Conclusions. This study documents decreases in the incidence of infections involving vaccine serotypes, increases in infections involving other serotypes, and decreases in the activity of macrolides and clindamycin after conjugate vaccine introduction.

Streptococcus pneumoniae is a common respiratory pathogen estimated to have caused >5500 deaths in the United States in 2002 [1]. Since the recent recognition of a new serogroup 6 serotype, 6C, there are now 48 serogroups comprising 91 serotypes of S. pneumoniae [2, 3]. Serotype 6C, which cross-reacts with serotype 6A serologically, resulted from a change in the wciN gene region of the capsular locus that encodes galactosyl transferase [2]. The various serotypes differ greatly in virulence, invasiveness, and ability to acquire drug resistance, and their population distributions differ among age groups [4]. A 23-valent polysaccharide vaccine (Pneumovax 23; Merck), which includes antigen from the 23 serotypes that cause 88% of cases of invasive disease in adults, is estimated to be approximately 60%–70% effective against invasive disease in adults [1]. This vaccine is inappropriate for the immune systems of children aged <2 years; for persons of that age, a 7-valent protein conjugated vaccine (PCV7) (Prevnar; Wyeth-Lederle) was developed [5]. This vaccine, which was introduced in the United States in 2000, contains polysaccharide from the 7 serotypes that are commonly responsible for invasive disease in children (4, 6B, 9V, 14, 18C, 19F, and 23F), including the 5 serotypes most often found to be highly drug resistant or resistant to multiple drugs. PCV7 is currently included in the recommended childhood vaccine schedule, with nearly 87% coverage achieved in the United States by 2006 [6]. Recent studies have shown that PCV7 is efficacious for the prevention of invasive disease and carriage and associated respiratory infections caused by the vaccine serotypes [7]. The expectation of cross-coverage by PCV7 of vaccine-related serotypes was not fulfilled, and serotype 19A, above all, has filled the gap left by the effectiveness of the vaccine [8]. Although the predominant replacement serotype is 19A, 6A has become increasingly common, and other emerging serotypes have been documented [9].

This study determined the serotypes for all isolates collected at our health care center during the period 1999–2007, as well as susceptibility to representatives of several classes of antimicrobial agents, including penicillins, cephalosporins, macrolides or azalides, lincosamides, quinolones, and trimethoprim-sulfamethoxazole.

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Methods

The tested isolates represented sequentially collected S. pneumoniae isolated in the clinical microbiology laboratory of the University Hospitals Case Medical Center (Cleveland, OH) from January 1999 through December 2007.

Strains included in the study were isolated from specimens of blood, sputum, CSF, bronchoalveolar lavage, middle ear fluid, paranasal sinuses, and other sites. Nasopharyngeal specimens were excluded, because the presence of S. pneumoniae represents colonization. Only one isolate per patient was included in the study. Identification of each isolate was confirmed in accordance with standard procedures [10]. Isolates were classified as invasive if they had been recovered from sterile sites (predominantly blood and CSF) and as noninvasive if they had been recovered from nonsterile sites (predominantly specimens obtained from the lower respiratory tract, paranasal sinuses, and middle ear).

Susceptibility testing was conducted by broth microdilution MIC determination, in accordance with Clinical and Laboratory Standards Institute (CLSI) procedures [11], using custom frozen microdilution trays (TREK Diagnostic Systems), as described elsewhere [12]. Quality-control organisms specified by CLSI, including S. pneumoniae ATCC 49619 and E. coli ATCC 35218, were used [13]. MICs were interpreted on the basis of CLSI interpretive criteria, including the new nonmeningeal penicillin breakpoints (susceptible, ⩽2 µg/mL; intermediate, 4 µg/mL; resistant, ⩾8 µg/mL) [14].

Serotyping was performed by capsular swelling reaction using commercial serogroup- and serotype-specific antisera (Statenserum Institute), in accordance with the manufacturer's instructions [15]. Serotype 6C was identified by PCR of DNA extracts of isolates identified serologically as serotype 6A using primers described by Park et al. [3], as follows: DNA was extracted from isolate suspensions by heating 10 colonies suspended in 100 µL of water at 95°C for 10 min, and a multiplex PCR was performed using 3 primers (2 forward primers [5101 and 5106] and 1 common reverse primer [3101]) [3]. The primer pair 5101–3101 produces products of 958 or 1267 kb with serotypes 6A and 6B, whereas no product is produced with serotype 6C [16]. The primer pair 5106–3101 produces wciN PCR products of 2.0 and 1.8 kb with serotypes 6A and 6C, respectively, whereas no product is produced with serotype 6B. PCR reactions were performed in a total volume of 25 µL, consisting of 1 µL of DNA lysate, 12.5 µL of HotStar Taq Plus Mastermix (Qiagen), 2.5 µL of CoralLoad loading dye (Qiagen), 6 µL of RNase-free water (Qiagen), 1 pmol of each forward primer (0.5 µL each), 2 pmol (1 µL) of the reverse primer (Integrated DNA Technologies), and 1 µL of 25 mmol/L MgCl2 (Promega). Amplification of PCR products was performed by a denaturation step at 95°C for 5 min and 35 cycles of 95°C for 30 s, 58°C for 30 s, and 72°C for 2 min, followed by a final extension at 72°C for 10 min in a thermal cycler (BioRad). Control strains of serotypes 6A, 6B, and 6C were included in each run. PCR products were detected on 1% agarose gels incorporating 50 µg of ethidium bromide, run for 1 h at 200 volts and visualized under UV light. A 1 kb DNA ladder (Promega) was included on each gel.

Serotype data were analyzed in relation to the introduction of PCV7 in 2000, to examine changes in serotype distribution. Serotypes were classified into vaccine, vaccine-related, and nonvaccine groups in relation to PCV7 serotypes. The last full year before vaccine introduction (1999) was used as the baseline for statistical comparisons of the years of increasing vaccine coverage, because data for this year were consistent with previously reported serotype data in Cleveland before PCV7 use [12]. The Centers for Disease Control and Prevention vaccination estimates for children aged 19–35 months report coverage rates for PCV7 (3 doses) in Cuyahoga County, Ohio, which includes approximately two-thirds of the population of the Greater Cleveland area, of 54.0% in 2002, 67.3% in 2003, 79.7% in 2004, 82.3% in 2005, and 89.3% in 2006 (national coverage rates were 40.8%, 68.1%, 73.2%, 82.8%, and 82%, respectively, for these years) [6, 17]. Statistical comparisons were performed using Poisson distribution with 95% CIs; 95% CIs for which the upper and lower bounds did not include 0 were interpreted as statistically significant. Data on the 5-county Greater Cleveland area served by our hospital showed that the population was stable during the study period, at ∼2.15 million people, based on the 2000 Census and estimates for 2001–2007 [18]. The numbers of adult and pediatric beds were also relatively constant during the study period. Thus, the proportion of patients in the Greater Cleveland area admitted to our hospital was assumed to be constant for the purpose of comparisons of incidence over time.

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Results

During the 9-year surveillance period, 1235 S. pneumoniae isolates were recovered at University Hospitals Case Medical Center, of which 338 were invasive isolates. Invasive isolates were predominantly recovered from blood or CSF specimens. The number of recovered isolates peaked in 2000 at 218, decreasing to 86–130 per year during the period 2002–2007. The number of invasive strains also decreased from a peak of 96 isolates in 2000 to 18–35 isolates per year during the period 2002–2007 (figure 1). The number of isolates recovered from the lower respiratory tract decreased from a peak of 109 isolates in 1999 to 44 isolates by 2003, but the number increased thereafter to 61–72 isolates per year. The number of isolates recovered per year from other sources remained fairly constant throughout the study period.

Figure 1
Figure 1

Sources of isolates of Streptococcus pneumoniae, by year, 1999–2007

The decrease in the annual number of isolates was primarily driven by PCV7 vaccine serotypes, which decreased in number from 160 isolates in 2000 to 10 isolates in 2007 (figure 2A). However, the decrease in the number of vaccine serotypes was countered, to some extent, by increases in the number of nonvaccine serotypes (32–47 per year prior to 2004 vs. 51–66 per year during the period 2004–2007) and of 2 vaccine-related serotypes, 19A and 6C (table 1 and figure 2). The number of isolates of serotype 19A increased from 5–11 isolates per year before 2003 to 34–38 isolates per year for the period 2004–2007, whereas isolates of serotype 6C first appeared in 2002, increasing in number to 6 isolates per year in 2006 and 2007 (figure 2).

Figure 2
Figure 2

Isolates of Streptococcus pneumoniae, by year and serotype, 1999–2007. A, Vaccine, vaccine-related, and nonvaccine serotypes, excluding emerging serotypes. B, Serogroup 6 isolates. C, Serogroup 19 isolates. D, Serogroup 15 and serotype 22F isolates.

Table 1
Table 1

Changes in annual incidence of isolates, by serotype and period, for all isolates of Streptococcus pneumoniae based on vaccine-relatedness of serotypes

Changes in the mean annual incidence of individual serotypes, by time period, are shown in table 1. An overall significant decrease in annual incidence of 48.6% was noted in 2002–2004, compared with the baseline year (1999), with a slightly lower decrease of 38.4% during 2005–2007, compared with baseline. Changes in the incidences of vaccine, vaccine-related, and nonvaccine serotypes are shown below.

Vaccine serotypes. Statistically significant decreases between the baseline year (1999), compared with 2002–2004 and 2005–2007, were noted for all 7 vaccine serotypes together (a 92.6% decrease by 2005–2007), as well as individually for 5 of the 7 vaccine serotypes, with decreases ranging from 81.3% to 99.0% by 2005–2007.

Vaccine-related serotypes. In contrast to vaccine serotypes, statistically significant increases were noted for all vaccine-related serotypes together for 1999 versus 2002–2004 and 2005–2007, with increases of 87.0% by 2002–2004 and 207.4% by 2005–2007. These increases were predominantly associated with serotypes 19A and 6C (figure 2). The annual number of serotype 19A isolates increased from 7 isolates per year in 1999 to 36.0 isolates per year by 2005–2007. Serotype 6C first appeared in 2002, with 24 isolates detected through 2007 (2–4 isolates per year detected through 2005 and 6 isolates per year in 2006 and 2007). Serotypes 19A and 6C were predominantly associated with noninvasive disease, more often in children than in adults (table 2). In addition, serotype 19A was primarily responsible for the increase in lower respiratory isolates noted after 2003.

Table 2
Table 2

Distribution of replacement serotypes among invasive and noninvasive Streptococcus pneumoniae isolates recovered from adult and pediatric subjects.

Nonvaccine serotypes. The overall annual incidence in this group did not change significantly over the study period (table 1). However, the mean annual incidence of serogroup 15 and serotype 22F increased from 2.0 and 0.5 isolates, respectively, in 2000–2001 to 7.7 and 4.3, respectively, in 2005–2007 (figure 2D). Thirteen of the serogroup 15 isolates were serotype 15A, 14 were serotype 15B, and 15 were serotype 15C (table 1).

Changes in the annual incidence of isolates according to invasiveness, age group (adult, >18 years; pediatric, ⩽18 years), and PCV7 vaccine relatedness of serotypes for the periods 1999 versus 2005–2007 are shown in table 3. There were statistically significant decreases in the incidence of vaccine serotypes for adult invasive (−92.9%) and noninvasive groups (−78.2%), as well as for pediatric invasive (−98.8%) and noninvasive groups (−88.9%). In contrast, there were statistically significant increases in the incidence of vaccine-related serotypes for adult (206.7%) and pediatric (900%) noninvasive isolates. The 900% increase in the incidence of noninvasive pediatric vaccine-related isolates was mainly associated with serotypes 19A, 6A, and 6C, which accounted for 67.8%, 7.8%, and 10.0%, respectively, of 2005–2007 isolates. There were statistically significant increases in the incidence of nonvaccine serotypes in both pediatric groups (300.0% for invasive and 104.2% for noninvasive serotypes), but this occurred only for the noninvasive serotypes for adults (100.0%).

Table 3
Table 3

Changes in annual number of isolates based on 7-valent conjugate pneumococcal vaccine relatedness, 1999 versus 2005–2007, for invasive and noninvasive adult and pediatric isolates of Streptococcus pneumoniae.

The incidence of infection due to 6 serotypes (6C, 15A, 15B, 15C, 19A, and 22F) increased after the introduction of PCV7. The distribution of these replacement serotypes among adult and pediatric invasive and noninvasive isolates is shown in table 2. These serotypes were isolated more frequently from children than adults. Serotypes 6C, 15A, and 15C were predominantly associated with noninvasive infections, whereas serotypes 15B, 19A, and 22F were associated with both invasive and noninvasive infections. Serotype 19A was prominently associated with middle ear isolates, accounting for 43 (44.8%) of 96 isolates recovered from this source, with 41 of those isolates having been recovered after 2000. In contrast, serotype 14, a serotype included in PCV7, was the predominant serotype recovered from middle ear fluid specimens during 1999–2000, accounting for 9 (37.5%) of 24 isolates.

Antimicrobial susceptibility of isolates is shown in table 4. Susceptibility to β-lactams and levofloxacin varied little during the study period. Ceftriaxone was the most active parenteral β-lactam for both meningeal and nonmeningeal infections: 72% and 88% of isolates, respectively, were susceptible during 2005–2007. Although 52% of isolates recovered during 2005–2007 were susceptible to penicillin G used for meningeal infections, 77% were susceptible at the new nonmeningeal breakpoint of 2 µg/mL, whereas 21% had intermediate susceptibility (MIC, 4 µg/mL). The rate of susceptibility to azithromycin decreased from 69% in 1999 to 53% by 2005–2007, whereas the rate of susceptibility to clindamycin decreased from 95% to 69%. The rate of susceptibility to trimethoprim-sulfamethoxazole increased from 54% in 1999 to 63% in 2007. Resistance patterns were defined as follows: P, penicillin nonsusceptible (MIC, ⩾0.12 µg/mL); A, amoxicillin resistant; M, macrolide resistant; C, clindamycin resistant; and S, trimethoprim-sulfamethoxazole resistant. Analysis of resistance patterns revealed that the predominant nonsusceptibility pattern was PAMCS (n=173), which was associated with serotype 19F (n=19) during the early years of the study and with serotype 19A (n=146) during 2004–2007. The next most common nonsusceptibility pattern was PAMS (n=159), which was associated with serotypes 14 (n=90) and 19F (n=38) during the early years of the study, with the serotype 14 isolates chiefly responsible for the increase in vaccine types between 1999 and 2000 (figure 2A). The PMS pattern (n=62) was mainly associated with serotypes 19F (n=16), 6A (n=13), 6C (n=8), and 19A (n=19); the S pattern (n=52) was mainly associated with serotypes 23F (n=13) and 6A (n=19); and the P pattern (n=63) was mainly associated with serotypes 9V (n=10), 23A/B (n=10), and 35B (n=16). Single penicillin-nonsusceptible isolates of serotypes 3, 29, and 33 were also found.

Table 4
Table 4

MIC50 and MIC90 values for Streptococcus pneumoniae and percentage of drug-susceptible isolates in 1999, 2000–2001, 2002–2004, and 2005–2007.

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Discussion

This study documents the remarkable direct and herd effects of the introduction of PCV7 in 2000 on the incidence of pneumococcal disease in our patient population. These effects included an overall decrease of 92.6% in vaccine-type pneumococcal isolates in 2005–2007, compared with 1999, and a decrease of 38.4% in all pneumococcal isolates. However, the decrease in vaccine types was countered, in part, by the increase in or emergence of several vaccine-related and nonvaccine serotypes, particularly serotypes 6C, 19A, and 22F and serogroup 15. We noted decreases in vaccine types of 98.8% for invasive isolates in children and of 92.9% in adults, as well as decreases of 88.9% in noninvasive isolates in children and of 78.2% in adults. Significant increases in vaccine-related and nonvaccine isolates occurred primarily in noninvasive isolates in both adults and children. These increases were 900% and 104.2% in pediatric vaccine-related and nonvaccine serotypes, respectively, and 206.7% and 100%, respectively, in adults. Serotypes 6C, 19A, and 22F and serogroup 15 were predominantly associated with these increases (figure 2), with serotype 19A frequently recovered from middle ear fluid specimens.

Antimicrobial susceptibility of β-lactams and quinolones remained stable during the study period, whereas susceptibility to trimethoprim-sulfamethoxazole increased somewhat, likely in association with decreased use of this agent. In contrast, the susceptibilities of azithromycin and clindamycin decreased.

Other studies have documented changes in the incidence of invasive pneumococcal isolates after the introduction of PCV7 [7, 19–32], as well as carriage [33–40], but little information is available on noninvasive isolates. Our data are in agreement with published data on invasive disease and extend these findings into noninvasive disease, for which the pattern of change differs considerably. A particularly notable finding in our study is the 900% increase in noninvasive pediatric vaccine-related isolates that was associated with serotypes 19A, 6A, and 6C. It is noteworthy that serotype 19A—the original multidrug-resistant serotype reported from South Africa in 1978 [41]—emerged in the United States after the introduction of PCV7 in 2000, and many of these isolates are multidrug resistant [8, 31, 32, 42, 43]. Despite the similarities in resistance patterns, these recent US isolates are not clonally related to the original South African strains [44]. There are, however, differences in susceptibility patterns of multidrug-resistant isolates: South African isolates are resistant to chloramphenicol but susceptible to amoxicillin, whereas US isolates are to susceptible to chloramphenicol but resistant to amoxicillin, reflecting differences in selective pressure, with use of chloramphenicol in South Africa and amoxicillin in the United States [45].

Serotype 6C is a recently described serotype, with the earliest known isolate recovered in 1980 [2, 3]. This new serotype cannot currently be distinguished from serotype 6A using antisera, but it is now known that it was occasionally found before the availability of PCV7 [46]. Our study identified 24 serotype 6C isolates, with the first isolate detected in 2002. The serotype 6B antigen in PCV7 has been highly effective in reducing the incidence of this serotype, with some apparent cross-protection provided against serotype 6A but not serotype 6C (figure 2C). However, the incidence of serotype 6C (4.4% in 2005–2007) is still considerably lower than that of serotype 6B before the availability of PCV7 (8.2% in 1999). The serotype 19F antigen in PCV7 has also been highly effective in reducing the incidence of this serotype but appears to provide no cross-protection against serotype 19A, which reached pre-PCV7 levels of serotype 19F (∼35 isolates per year) by 2004 (figure 2B). Other serotypes that we found had increased after PCV7 use are serotype 22F and all 3 serotypes of serogroup 15 (serotypes 15A, 15B, and 15C), although their combined incidence in 2005–2007 was modest (9.9%) (table 1 and figure 2D).

In summary, the overall incidence of pneumococcal disease—particularly invasive disease—during 1999–2007 at University Hospitals Case Medical Center decreased after the introduction of PCV7 in 2000. The decrease in vaccine serotypes was, however, partially offset by increases in vaccine-related and nonvaccine types—particularly serotypes 6C, 19A, 15A, 15B, 15C, and 22F. The implications of these findings on clinical practice are that only quinolones, glycopeptides, and oxazolidinones have retained their activity against pneumococci, whereas β-lactams, macrolides/azalides, lincosamides, and trimethoprim-sulfamethoxazole have significant limitations. Our findings highlight the need to develop new classes of antimicrobial agents and to formulate vaccines that either include additional serotypes or that are based on alternative targets.

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Acknowledgments

Potential conflicts of interest. M.R.J. has served as consultant to or has received research grants from GlaxoSmithKline and Wyeth Ayerst/Lederle. All other authors: no conflicts.

  • Received May 21, 2008.
  • Accepted August 16, 2008.
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  1. Clin Infect Dis. (2008) 47 (11): 1388-1395. doi: 10.1086/592972
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