Abstract

Background.Streptococcus pneumoniae (pneumococcus) caused approximately 44000 US invasive pneumococcal disease (IPD) cases in 2008. Antibiotic nonsusceptibility complicates IPD treatment. Using penicillin susceptibility breakpoints adopted in 2008, we evaluated antibiotic-nonsusceptible IPD trends in light of the introductions of a 7-valent pneumococcal conjugate vaccine (PCV7) in 2000 and a 13-valent pneumococcal conjugate vaccine (PCV13) in 2010.

Methods. IPD cases were defined by isolation of pneumococcus from a normally sterile site in individuals residing in Active Bacterial Core surveillance (ABCs) areas during 1998–2008. Pneumococci were serotyped and tested for antibiotic susceptibility using broth microdilution.

Results. During 1998–2008, ABCs identified 43198 IPD cases. Penicillin-nonsusceptible strains caused 6%–14% of IPD cases, depending on age. Between 1998–1999 and 2008, penicillin-nonsusceptible IPD rates declined 64% for children aged <5 years (12.1–4.4 cases per 100000), and 45% for adults aged ≥65 (4.8–2.6 cases per 100000). Rates of IPD nonsusceptible to multiple antibiotics mirrored these trends. During 2007–2008, serotypes in PCV13 but not PCV7 caused 78%–97% of penicillin-nonsusceptible IPD, depending on age.

Conclusions. Antibiotic-nonsusceptible IPD rates remain below pre-PCV7 rates for children <5 and adults ≥65 years old. PCV13 vaccines hold promise for further nonsusceptibility reductions.

Streptococcus pneumoniae (pneumococcus) caused approximately 63000 invasive pneumococcal disease (IPD) cases annually in the late 1990s in the United States, leading to about 6100 deaths [1]. During the first 7 years after the introduction in the United States of a 7-valent pneumococcal conjugate vaccine (PCV7) for children, an estimated 211000 fewer cases of IPD occurred among all ages than would have occurred without the vaccine [2]; however, approximately 44000 IPD cases continue to occur annually [3]. Antibiotic resistance and intermediate susceptibility, together termed nonsusceptibility, complicate management of pneumococcal disease [4–6]. Despite increasing during the 1990s [7], the incidence of antibiotic-nonsusceptible IPD in the United States fell following the introduction of PCV7 [8, 9]. The 7 serotypes covered by PCV7 accounted for 78% of nonsusceptible serotypes in 1998 [7], and the incidence rate of these serotypes decreased 78% among children aged <2 years by 2001 [9]. However, by 2003, the incidence of antibiotic-nonsusceptible IPD in children aged <5 years was increasing again [8], coinciding with the emergence of serotypes not included in PCV7, particularly serotype 19A [10]. A new 13-valent pneumococcal conjugate vaccine (PCV13) [11] could help reverse the rise in antibiotic-nonsusceptible IPD, depending in part on the proportion of antibiotic-nonsusceptible IPD caused by PCV13 serotypes.

Rates and proportions of antibiotic-nonsusceptible IPD depend on the definition of antibiotic nonsusceptibility used. In 2008, the Clinical and Laboratory Standards Institute (CLSI) established new, higher minimum inhibitory concentration (MIC) breakpoints for defining pneumococcal susceptibility to parenterally administered penicillin when treating pneumococcal disease other than meningitis [12–14]. The breakpoints for orally administered penicillin and for parenterally administered penicillin for the treatment of meningitis did not change [12, 13]. Since penicillin is the drug of choice for treatment of penicillin-susceptible pneumococcal disease [4], this breakpoint change could impact both individual clinical treatment and public health surveillance for pneumococcal disease. We used a population-based surveillance system to determine how trends in antibiotic-nonsusceptible IPD in the United States had changed since 1998, how much IPD was caused by individual serotypes, and how large was the impact of the revised penicillin susceptibility breakpoints on nonsusceptible IPD trends.

METHODS

The Active Bacterial Core surveillance (ABCs) system performs active, population-based surveillance for IPD, defined as occurring when pneumococcus is isolated from a normally sterile site, such as blood, cerebrospinal fluid (CSF), or pleural fluid, from a person who is a resident of an ABCs area on the date of culture [1, 7, 8, 15]. We analyzed IPD cases detected using the ABCs system from 1 January 1998 through 31 December 2008. In 1998, ABCs pneumococcal surveillance covered the entire state of Connecticut and 49 counties in California, Georgia, Maryland, Minnesota, New York, Oregon, and Tennessee [15]. By 2008, the ABCs pneumococcal surveillance system had added 2 California counties, 5 Colorado counties, the rest of Minnesota, all of New Mexico, 8 New York counties, and 6 Tennessee counties. The total population under surveillance was 16515110 in 1998 and 28856774 in 2008. Before beginning our analysis and to better characterize trends in IPD from less common serotypes, we chose to use data from all counties in the ABCs system, not just those with continuous surveillance since 1998. We calculated annual IPD incidence rates (cases per 100000 population) using the total number of cases identified by ABCs in a given year and the population of the areas under surveillance as reported by the US Census Bureau.

We abstracted case medical records for demographic and clinical information, including diagnoses. S. pneumoniae isolates were serotyped by the Quellung method at the Centers for Disease Control and Prevention (CDC) or the Minnesota Department of Health and classified in 1 of 6 ways: (1) serotypes in PCV7 (4, 6B, 9V, 14, 18C, 19F, 23F); (2) additional PCV13 serotypes (1, 3, 5, 6A, 7F, 19A); (3) serotypes in PCV13 (PCV7 serotypes plus serotypes 1, 3, 5, 6A, 7F, 19A); (4) serotype 6A; (5) serotype 19A, which, like serotype 6A, was analyzed separately because of its unique epidemiology [2, 16]; and (6) serotypes not found in PCV13, including the newly identified 6C [17, 18]. Serotype 6C was distinguished from serotype 6A using multiplex polymerase chain reaction (PCR) containing primer pairs specific for cpsA, serogroup 6, and a wciN6C gene fragment [19].

Pneumococcal isolates were tested for antibiotic susceptibility using reference broth microdilution at the CDC, the Minnesota Department of Health, or the University of Texas Health Science Center at San Antonio. We determined penicillin susceptibility for all isolates using the new CLSI standard that recommends different sets of breakpoints depending on whether penicillin is administered orally, parenterally for meningitis, or parenterally for nonmeninigitis disease [13], and using the single set of old breakpoints that applied to all administration routes and clinical syndromes [14]. The old breakpoints classified isolates as penicillin susceptible (S; MIC ≤0.06 μg/mL), penicillin intermediate (I; MIC 0.12–1.0 μg/mL), or penicillin resistant (R; MIC ≥2 μg/mL), regardless of the clinical syndrome. The new CLSI standards still specify these breakpoints for pneumococcal disease treated orally. The new parenteral breakpoints classify isolates from nonmeningitis cases as penicillin susceptible, intermediate, or resistant at MICs of ≤2, 4, and ≥8 μg/mL, respectively; isolates from meningitis cases are considered penicillin susceptible (MIC ≤0.06 μg/mL) or resistant (MIC ≥0.12 μg/mL). We considered intermediate and resistant isolates to be nonsusceptible, so isolates were nonsusceptible under the old/oral/meningitis breakpoints with an MIC ≥0.12 μg/mL and nonsusceptible under the new parenteral-nonmeningitis breakpoints with an MIC ≥4 μg/mL. The new meningitis breakpoints were applied to all isolates from CSF and to isolates from blood if the case had a clinical diagnosis of meningitis. The new nonmeningitis breakpoints were applied to all other isolates. To estimate the total number of penicillin-nonsusceptible IPD cases under the new parenteral breakpoints, we added the number of penicillin-nonmeningitis IPD cases that were nonsusceptible under the new parenteral-nonmeningitis breakpoints (MIC ≥4 μg/mL) to the number of meningitis cases with a penicillin MIC ≥0.12 μg/mL. Susceptibilities to all other antibiotics were determined using only the 2008 CLSI susceptibility standards [13].

We considered an isolate to be nonsusceptible to multiple drugs if it was not susceptible to 3 or more of the following drugs: penicillin, clindamycin, cotrimoxazole, erythromycin, tetracycline, levofloxacin, vancomycin, and chloramphenicol. Cases with missing isolates (12%) were assumed to have the same distribution among the different age groups as cases with known antibiotic susceptibility and serotypes. We estimated changes in rates of penicillin-nonsusceptible IPD since the introduction of PCV7 by comparing the average rate during the 1998–1999 prevaccine baseline period with the rate in 2008, the most recent year for which data are available (χ2 test). We examined the effect of replacement disease by comparing the lowest rates of penicillin-nonsusceptible IPD (2002 for children aged <5 years as previously reported [8], 2004 for all other age groups) with the rates in 2008. We considered 2-sided P values ≤.05 to be statistically significant and did not adjust for multiple comparisons. The proportions of penicillin-nonsusceptible IPD caused by different serotypes were determined for the 1998–1999 prevaccine period and 2007–2008; the years were combined to compensate for annual random variation due to the small numbers of cases involved for many serotypes. We analyzed all data using SAS 9.2 (SAS Institute, Cary, NC).

ABCs case reporting and isolate collection were considered to be public health surveillance activities exempt from CDC institutional review. Each participating surveillance site evaluated the surveillance protocol and either decided the protocol was exempt from review or obtained appropriate local institutional review board approval. Neither the CDC nor individual site institutional review boards required informed consent.

RESULTS

Overall Incidence Rates

During 1998–2008, ABCs identified 43198 IPD cases, of which 7273 (17%) were among children aged <5 years. Meningitis accounted for 2485 cases, 483 (19%) of which were in children aged <5 years. Strains not susceptible to penicillin caused 6%–14% of IPD cases under the new parenteral breakpoints and 19%–35% of IPD cases under the old/oral/meningitis breakpoints, varying with age. Depending on which set of breakpoints was used, the 2008 rates of penicillin-nonsusceptible IPD among children aged <5 years and adults aged ≥65 years were 64%–78% and 30%–45% below the 1998–1999 baseline period rates, respectively (Table 1). However, the 2008 rates of penicillin-nonsusceptible IPD were 33%–137% higher than the 2002 rates among children aged <5 years and 23%–84% higher than the 2004 rates among adults aged ≥65 years, depending on the breakpoints used (Figure 1). Both the baseline levels of and the magnitudes of the subsequent changes in the penicillin-nonsusceptible IPD rates among individuals aged 5–17, 18–49, and 50–64 years were less than those among young children and older adults under both the old/oral/meningitis and new parenteral breakpoints (Figure 1). Rates of penicillin-nonsusceptible IPD were higher under the old/oral/meningitis breakpoints than under the new parenteral breakpoints, but the trends were similar. Rates of IPD by penicillin MIC showed declines between 1998–1999 and 2008, similar to the declines seen in rates of penicillin-nonsusceptible IPD (Figure 2), especially in children aged <5 years.

Table 1.

Changes in Incidence of Penicillin-nonsusceptible Invasive Pneumococcal Disease, by Age Group, Serotype, and Penicillin Breakpointa

 Incidence, Cases Per 100 000 Population
 
Changes in Rate (2008 vs Baseline)
 
 1998–1999
 
2008
 
Rate Difference, Cases per 100 000 Population
 
Change, Percent (95% CI)
 
Age Group, Serotype New Parenteral Old/Oral/Meningitis New Parenteral Old/Oral/Meningitis New Parenteral Old/Oral/Meningitis New Parenteral Old/Oral/Meningitis 
Aged <5 years         
    All types 12.1 33.3 4.4 7.4 −7.7 −25.1 −64 (−66 to −61) −78 (−79 to −77) 
    PCV7 typesb 11.4 27.6 0.1 −11.4 −27.5 NA −99.6 (−99.8 to −99.4) 
    Additional PCV13 typesc 0.5 4.4 4.2 6.1 3.7 1.7 708 (593–842) 38 (28–48) 
    6A 0.4 2.8 0.1 −0.4 −2.7 NA −97.8(−98.7 to −96.2) 
    19A 0.04 1.5 4.3 6.1 4.26 4.6 10 000 (6060–16 500) 298 (261–339) 
    Non-PCV13 typesd 0.2 1.3 0.2 1.2 −0.1 −10 (−37–30) −6 (−19 to −9) 
Aged 5–17 years         
    All types 0.3 0.8 0.2 0.4 −0.1 −0.4 −50 (−60 to −36) −46 (−54 to −38) 
    PCV7 typesb 0.3 0.7 0.02 0.04 −0.28 −0.66 −93 (−96 to −88) −94 (−96 to −91) 
    Additional PCV13 typesc 0.02 0.2 0.1 0.2 0.07 332 (158–622) 61 (27–103) 
    6A 0.01 0.05 0.02 −0.01 −0.03 NA −61.4 (−79.8 to −26.3) 
    19A 0.1 0.1 0.2 0.1 0.1 NA 107 (60–168) 
    Non-PCV13 typesd 0.01 0.04 0.2 0.04 0.19 NA 1040 (550–1920) 
Aged 18–49 years         
    All types 0.7 2.3 0.6 1.6 −0.1 −0.7 −17 (−24 to −10) −30 (−33 to −26) 
    PCV7 typesb 0.7 1.8 0.04 0.2 −0.66 −1.6 −94 (−95 to −92) −90 (−91 to −88) 
    Additional PCV13 typesc 0.1 0.3 0.5 0.9 0.4 0.6 640 (526–774) 171 (148–196) 
    6A 0.05 0.15 0.01 0.07 −0.04 −0.08 −84.3 (−91.5 to −71.0) −55.9 (−64.9 to −44.6) 
    19A 0.01 0.2 0.5 0.8 0.49 0.6 3880 (2690–5580) 370 (322–424) 
    Non-PCV13 typesd 0.01 0.2 0.1 0.5 0.09 0.3 385 (220–634) 239 (200–283) 
Aged 50–64 years         
    All types 1.4 4.8 1.9 4.6 0.5 −0.2 40 (29–53) −6 (−10 to −1) 
    PCV7 typesb 1.3 3.6 0.1 0.4 −1.2 −3.2 −95 (−96 to −93) −90 (−92 to −89) 
    Additional PCV13 typesc 0.02 0.7 1.3 2.5 1.28 1.8 5930 (3620–9650) 252 (219–289) 
    6A 0.26 0.08 −0.18 NA −67.7 (−76.6 to −55.5) 
    19A 0.4 1.3 2.4 1.3 NA 510 (439–591) 
    Non-PCV13 typesd 0.1 0.5 0.3 1.7 0.2 1.2 386 (259–558) 256 (216–301) 
Aged ≥65 years         
    All types 4.8 15.0 2.6 10.5 −2.0 −4.5 −45 (−49 to −41) −30 (−33 to −28) 
    PCV7 typesb 4.4 11.2 0.4 1.1 −4.0 −10.1 −92 (−93 to −90) −90 (−91 to −90) 
    Additional PCV13 typesc 0.3 2.6 2.0 4.0 1.4 1.5 607 (505–726) 57 (47–68) 
    6A 0.14 1.25 0.03 0.20 −0.11 −1.05 −76.5 (−86.8 to −58.0) −83.8 (−87.1 to −79.6) 
    19A 0.1 1.3 2.0 3.8 1.9 2.5 1250 (996–1560) 197 (174–223) 
    Non-PCV13 typesd 0.1 1.3 0.2 5.4 0.1 4.1 65 (24–119) 302 (272–335) 
 Incidence, Cases Per 100 000 Population
 
Changes in Rate (2008 vs Baseline)
 
 1998–1999
 
2008
 
Rate Difference, Cases per 100 000 Population
 
Change, Percent (95% CI)
 
Age Group, Serotype New Parenteral Old/Oral/Meningitis New Parenteral Old/Oral/Meningitis New Parenteral Old/Oral/Meningitis New Parenteral Old/Oral/Meningitis 
Aged <5 years         
    All types 12.1 33.3 4.4 7.4 −7.7 −25.1 −64 (−66 to −61) −78 (−79 to −77) 
    PCV7 typesb 11.4 27.6 0.1 −11.4 −27.5 NA −99.6 (−99.8 to −99.4) 
    Additional PCV13 typesc 0.5 4.4 4.2 6.1 3.7 1.7 708 (593–842) 38 (28–48) 
    6A 0.4 2.8 0.1 −0.4 −2.7 NA −97.8(−98.7 to −96.2) 
    19A 0.04 1.5 4.3 6.1 4.26 4.6 10 000 (6060–16 500) 298 (261–339) 
    Non-PCV13 typesd 0.2 1.3 0.2 1.2 −0.1 −10 (−37–30) −6 (−19 to −9) 
Aged 5–17 years         
    All types 0.3 0.8 0.2 0.4 −0.1 −0.4 −50 (−60 to −36) −46 (−54 to −38) 
    PCV7 typesb 0.3 0.7 0.02 0.04 −0.28 −0.66 −93 (−96 to −88) −94 (−96 to −91) 
    Additional PCV13 typesc 0.02 0.2 0.1 0.2 0.07 332 (158–622) 61 (27–103) 
    6A 0.01 0.05 0.02 −0.01 −0.03 NA −61.4 (−79.8 to −26.3) 
    19A 0.1 0.1 0.2 0.1 0.1 NA 107 (60–168) 
    Non-PCV13 typesd 0.01 0.04 0.2 0.04 0.19 NA 1040 (550–1920) 
Aged 18–49 years         
    All types 0.7 2.3 0.6 1.6 −0.1 −0.7 −17 (−24 to −10) −30 (−33 to −26) 
    PCV7 typesb 0.7 1.8 0.04 0.2 −0.66 −1.6 −94 (−95 to −92) −90 (−91 to −88) 
    Additional PCV13 typesc 0.1 0.3 0.5 0.9 0.4 0.6 640 (526–774) 171 (148–196) 
    6A 0.05 0.15 0.01 0.07 −0.04 −0.08 −84.3 (−91.5 to −71.0) −55.9 (−64.9 to −44.6) 
    19A 0.01 0.2 0.5 0.8 0.49 0.6 3880 (2690–5580) 370 (322–424) 
    Non-PCV13 typesd 0.01 0.2 0.1 0.5 0.09 0.3 385 (220–634) 239 (200–283) 
Aged 50–64 years         
    All types 1.4 4.8 1.9 4.6 0.5 −0.2 40 (29–53) −6 (−10 to −1) 
    PCV7 typesb 1.3 3.6 0.1 0.4 −1.2 −3.2 −95 (−96 to −93) −90 (−92 to −89) 
    Additional PCV13 typesc 0.02 0.7 1.3 2.5 1.28 1.8 5930 (3620–9650) 252 (219–289) 
    6A 0.26 0.08 −0.18 NA −67.7 (−76.6 to −55.5) 
    19A 0.4 1.3 2.4 1.3 NA 510 (439–591) 
    Non-PCV13 typesd 0.1 0.5 0.3 1.7 0.2 1.2 386 (259–558) 256 (216–301) 
Aged ≥65 years         
    All types 4.8 15.0 2.6 10.5 −2.0 −4.5 −45 (−49 to −41) −30 (−33 to −28) 
    PCV7 typesb 4.4 11.2 0.4 1.1 −4.0 −10.1 −92 (−93 to −90) −90 (−91 to −90) 
    Additional PCV13 typesc 0.3 2.6 2.0 4.0 1.4 1.5 607 (505–726) 57 (47–68) 
    6A 0.14 1.25 0.03 0.20 −0.11 −1.05 −76.5 (−86.8 to −58.0) −83.8 (−87.1 to −79.6) 
    19A 0.1 1.3 2.0 3.8 1.9 2.5 1250 (996–1560) 197 (174–223) 
    Non-PCV13 typesd 0.1 1.3 0.2 5.4 0.1 4.1 65 (24–119) 302 (272–335) 

Abbreviations: CI, confidence interval; NA, not applicable.

a

Pneumococcal penicillin susceptibility breakpoints. The old/oral/meningitis breakpoints classify isolates as penicillin nonsusceptible at a minimum inhibitory concentration (MIC) ≥0.12 μg/mL. The new parenteral breakpoints classify isolates as penicillin nonsusceptible at an MIC ≥4 μg/mL for nonmeningitis disease and ≥0.12 μg/mL for meningitis.

b

Serotypes included in the 7-valent pneumococcal conjugate vaccine (PCV7).

c

Additional serotypes included in the 13-valent pneumococcal conjugate vaccine (PCV13) but not in PCV7. The additional PCV13 types include serotypes 6A and 19A.

d

Serotypes not included in PCV13.

Figure 1.

Penicillin-nonsusceptible (NS) invasive pneumococcal disease (IPD) rates using old/oral/meningitis and new parenteral breakpoints for all ages (A), children aged <5 years (B), children aged 5–17 years (C), adults aged 18–49 years (D), adults aged 50–64 years (E), and adults aged ≥65 years (E). The old/oral/meningitis penicillin breakpoints classify isolates as penicillin nonsusceptible at a minimum inhibitory concentration (MIC) ≥0.12 μg/mL. The new parenteral penicillin breakpoints classify isolates as penicillin nonsusceptible at an MIC ≥4 μg/mL for nonmeningitis disease and ≥0.12 μg/mL for meningitis.

Figure 1.

Penicillin-nonsusceptible (NS) invasive pneumococcal disease (IPD) rates using old/oral/meningitis and new parenteral breakpoints for all ages (A), children aged <5 years (B), children aged 5–17 years (C), adults aged 18–49 years (D), adults aged 50–64 years (E), and adults aged ≥65 years (E). The old/oral/meningitis penicillin breakpoints classify isolates as penicillin nonsusceptible at a minimum inhibitory concentration (MIC) ≥0.12 μg/mL. The new parenteral penicillin breakpoints classify isolates as penicillin nonsusceptible at an MIC ≥4 μg/mL for nonmeningitis disease and ≥0.12 μg/mL for meningitis.

Figure 2.

Rates of 1998–1999 and 2008 invasive pneumococcal disease cases among all ages by minimum inhibitory concentration (MIC) and penicillin breakpoints.

Figure 2.

Rates of 1998–1999 and 2008 invasive pneumococcal disease cases among all ages by minimum inhibitory concentration (MIC) and penicillin breakpoints.

Incidence Rates by Serotype

To assess the impact of PCV7 and the possible future impact of PCV13, we stratified penicillin-nonsusceptible IPD rates by serotype. The rate of penicillin-nonsusceptible disease caused by serotypes in PCV7 dropped substantially among all age groups between 1998–1999 and 2008 (Table 1), especially among young children and older adults. In contrast, the rate of penicillin-nonsusceptible IPD from serotypes not in PCV7 increased for all age groups. In each age group, these absolute rate increases were larger under the new parenteral breakpoints for the additional serotypes in PCV13 than for the serotypes not included in PCV13 despite substantial decreases in the rate of penicillin-nonsusceptible IPD caused by serotype 6A, one of the additional serotypes in PCV13. Almost all of the increase in penicillin-nonsusceptible IPD caused by the additional PCV13 serotypes during 1998–2008 was due to serotype 19A (Table 1).

The increase in penicillin-nonsusceptible IPD from serotype 19A resulted from both an increase in the incidence of IPD from serotype 19A [2] and an increase in the proportion of serotype 19A that was penicillin-nonsusceptible. Depending on age, the proportion of serotype 19A IPD that was not susceptible to penicillin increased from 0%–7% in 1998–1999 to 20%–53% in 2008 under the new parenteral breakpoints, and went from 52%–71% to 50%–77% under the old/oral/meningitis breakpoints. We observed generally similar trends among other serotypes, such as serotypes 6C, 15A, 23A, and 35B (data not shown), which had smaller increases in their rates of penicillin-nonsusceptible IPD than serotype 19A.

Association Between Penicillin Nonsusceptibility and Serotype

By 2007–2008, the proportion of penicillin-nonsusceptible IPD cases caused by serotypes in PCV7 had fallen dramatically in all age groups (Table 2). In contrast, in 2007–2008, the additional PCV13 serotypes caused ≥77.8% of penicillin-nonsusceptible IPD cases among all groups under the new parenteral breakpoints and 42.5%–78.5% under the old/oral/meningitis breakpoints, depending on age (Table 2). Serotype 19A alone accounted for 82.0% of all penicillin-nonsusceptible IPD for all ages combined under the new parenteral breakpoints, and 52.1% of all cases under the old/oral/meningitis breakpoints in 2007–2008. Unlike the additional PCV13 serotypes, in 2007–2008, the serotypes not included in PCV13 caused a lower proportion of cases (3.1%–15.6%) in the different age groups under the new parenteral breakpoints than the 16.0%–49.0% of cases they caused under the old/oral/meningitis breakpoints.

Table 2.

Proportion of Penicillin-Nonsusceptible Strains by Age Group, Year, Penicillin Susceptibility Breakpoints,a and Serotype

 Aged <5 Years
 
Aged 5–64 Years
 
Aged >65 Years Old
 
 1998–1999
 
2007–2008
 
1998–1999
 
2007–2008
 
1998–1999
 
2007–2008
 
Vaccine Serotype and Formulation New Parenteral (n = 259) Old/Oral/Meningitis (n = 703) New Parenteral (n = 161) Old/Oral/Meningitis (n = 307) New Parenteral (n = 183) Old/Oral/Meningitis (n = 597) New Parenteral (n = 275) Old/Oral/Meningitis (n = 822) New Parenteral (n = 167) Old/Oral/Meningitis (n = 516) New Parenteral (n = 144) Old/Oral/Meningitis (n = 588) 
14 49.4% 38.1% 0.0% 0.3% 32.2% 21.6% 1.8% 1.3% 39.5% 23.1% 4.2% 1.4% 
19F 12.7% 12.1% 0.0% 0.3% 7.7% 5.5% 1.8% 0.9% 6.0% 4.3% 4.2% 1.4% 
06B 8.9% 11.9% 0.0% 0.3% 4.9% 9.0% 0.0% 2.1% 4.2% 11.2% 2.1% 2.7% 
18C 0.0% 0.6% 0.0% 0.0% 0.0% 0.3% 0.0% 0.0% 0.6% 0.4% 0.0% 0.0% 
23F 17.4% 10.7% 0.0% 0.0% 21.3% 13.9% 1.1% 1.0% 23.4% 12.8% 0.7% 0.7% 
0.4% 0.1% 0.0% 0.0% 0.5% 1.3% 0.0% 0.0% 0.0% 0.8% 0.0% 0.0% 
09V 4.6% 9.1% 0.0% 0.0% 23.5% 26.1% 1.8% 4.1% 17.4% 22.1% 0.0% 2.4% 
PCV7b 93.4% 82.6% 0.0% 1.0% 90.2% 77.9% 6.5% 9.4% 91.0% 74.6% 11.1% 8.5% 
0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 
07F 0.0% 0.0% 0.0% 0.3% 0.0% 0.0% 0.0% 0.2% 0.0% 0.2% 0.0% 0.0% 
0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 
0.4% 0.3% 0.0% 0.0% 1.1% 0.5% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 
06A 3.9% 8.5% 0.0% 0.7% 4.4% 5.9% 0.4% 3.5% 3.0% 8.3% 2.1% 4.1% 
19A 0.4% 4.6% 96.9% 82.1% 1.1% 8.0% 77.5% 51.0% 3.0% 8.5% 76.4% 38.4% 
Additional PCV13c 4.6% 13.4% 96.9% 83.1% 6.6% 14.4% 77.8% 54.7% 6.0% 17.1% 78.5% 42.5% 
06C 0.0% 0.0% 0.6% 1.3% 0.0% 0.2% 1.5% 5.6% 0.0% 0.4% 1.4% 8.0% 
09A 1.5% 2.1% 0.0% 0.0% 1.6% 3.2% 0.0% 0.1% 0.0% 2.5% 0.0% 0.2% 
15A 0.0% 0.0% 0.0% 4.2% 0.0% 0.0% 2.5% 10.7% 0.0% 0.4% 2.8% 12.8% 
22F 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 
23A 0.4% 0.4% 0.6% 2.0% 0.5% 0.3% 4.0% 7.8% 0.6% 0.4% 4.2% 12.9% 
23B 0.0% 0.0% 0.0% 1.6% 0.0% 0.0% 2.2% 1.7% 0.0% 0.0% 0.0% 0.5% 
35B 0.0% 0.6% 1.2% 4.9% 0.0% 1.2% 3.3% 6.9% 1.8% 2.5% 1.4% 12.6% 
NT 0.0% 0.1% 0.0% 0.3% 0.0% 0.3% 0.4% 0.4% 0.0% 0.4% 0.0% 0.3% 
Other 0.0% 0.8% 0.7% 1.7% 1.2% 2.5% 1.7% 2.6% 0.6% 1.8% 0.6% 1.7% 
Non-PCV13d 1.9% 4.0% 3.1% 16.0% 3.3% 7.7% 15.6% 35.8% 3.0% 8.4% 10.4% 49.0% 
 Aged <5 Years
 
Aged 5–64 Years
 
Aged >65 Years Old
 
 1998–1999
 
2007–2008
 
1998–1999
 
2007–2008
 
1998–1999
 
2007–2008
 
Vaccine Serotype and Formulation New Parenteral (n = 259) Old/Oral/Meningitis (n = 703) New Parenteral (n = 161) Old/Oral/Meningitis (n = 307) New Parenteral (n = 183) Old/Oral/Meningitis (n = 597) New Parenteral (n = 275) Old/Oral/Meningitis (n = 822) New Parenteral (n = 167) Old/Oral/Meningitis (n = 516) New Parenteral (n = 144) Old/Oral/Meningitis (n = 588) 
14 49.4% 38.1% 0.0% 0.3% 32.2% 21.6% 1.8% 1.3% 39.5% 23.1% 4.2% 1.4% 
19F 12.7% 12.1% 0.0% 0.3% 7.7% 5.5% 1.8% 0.9% 6.0% 4.3% 4.2% 1.4% 
06B 8.9% 11.9% 0.0% 0.3% 4.9% 9.0% 0.0% 2.1% 4.2% 11.2% 2.1% 2.7% 
18C 0.0% 0.6% 0.0% 0.0% 0.0% 0.3% 0.0% 0.0% 0.6% 0.4% 0.0% 0.0% 
23F 17.4% 10.7% 0.0% 0.0% 21.3% 13.9% 1.1% 1.0% 23.4% 12.8% 0.7% 0.7% 
0.4% 0.1% 0.0% 0.0% 0.5% 1.3% 0.0% 0.0% 0.0% 0.8% 0.0% 0.0% 
09V 4.6% 9.1% 0.0% 0.0% 23.5% 26.1% 1.8% 4.1% 17.4% 22.1% 0.0% 2.4% 
PCV7b 93.4% 82.6% 0.0% 1.0% 90.2% 77.9% 6.5% 9.4% 91.0% 74.6% 11.1% 8.5% 
0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 
07F 0.0% 0.0% 0.0% 0.3% 0.0% 0.0% 0.0% 0.2% 0.0% 0.2% 0.0% 0.0% 
0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 
0.4% 0.3% 0.0% 0.0% 1.1% 0.5% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 
06A 3.9% 8.5% 0.0% 0.7% 4.4% 5.9% 0.4% 3.5% 3.0% 8.3% 2.1% 4.1% 
19A 0.4% 4.6% 96.9% 82.1% 1.1% 8.0% 77.5% 51.0% 3.0% 8.5% 76.4% 38.4% 
Additional PCV13c 4.6% 13.4% 96.9% 83.1% 6.6% 14.4% 77.8% 54.7% 6.0% 17.1% 78.5% 42.5% 
06C 0.0% 0.0% 0.6% 1.3% 0.0% 0.2% 1.5% 5.6% 0.0% 0.4% 1.4% 8.0% 
09A 1.5% 2.1% 0.0% 0.0% 1.6% 3.2% 0.0% 0.1% 0.0% 2.5% 0.0% 0.2% 
15A 0.0% 0.0% 0.0% 4.2% 0.0% 0.0% 2.5% 10.7% 0.0% 0.4% 2.8% 12.8% 
22F 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 
23A 0.4% 0.4% 0.6% 2.0% 0.5% 0.3% 4.0% 7.8% 0.6% 0.4% 4.2% 12.9% 
23B 0.0% 0.0% 0.0% 1.6% 0.0% 0.0% 2.2% 1.7% 0.0% 0.0% 0.0% 0.5% 
35B 0.0% 0.6% 1.2% 4.9% 0.0% 1.2% 3.3% 6.9% 1.8% 2.5% 1.4% 12.6% 
NT 0.0% 0.1% 0.0% 0.3% 0.0% 0.3% 0.4% 0.4% 0.0% 0.4% 0.0% 0.3% 
Other 0.0% 0.8% 0.7% 1.7% 1.2% 2.5% 1.7% 2.6% 0.6% 1.8% 0.6% 1.7% 
Non-PCV13d 1.9% 4.0% 3.1% 16.0% 3.3% 7.7% 15.6% 35.8% 3.0% 8.4% 10.4% 49.0% 
a

Pneumococcal penicillin susceptibility breakpoints. The old/oral/meningitis breakpoints classify isolates as penicillin nonsusceptible at a minimum inhibitory concentration (MIC) ≥0.12 μg/mL. The new parenteral breakpoints classify isolates as penicillin nonsusceptible at an MIC ≥4 μg/mL for nonmeningitis disease and ≥0.12 μg/mL for meningitis.

b

Serotypes included in the 7-valent pneumococcal conjugate vaccine (PCV7).

c

Additional serotypes included in the 13-valent pneumococcal conjugate vaccine (PCV13) but not in PCV7. The additional PCV13 types include serotype 19A.

d

Serotypes not included in PCV13.

Nonsusceptibility to Other Antibiotics

Rates of IPD caused by strains not susceptible to antibiotics other than penicillin dropped after 1999 in children aged <5 years (Figure 3) and after 2001 in adults aged ≥65 years (Figure 4). Despite increases in rates of nonsusceptible IPD that were evident by 2003–2004 in children aged <5 years and in 2005 in adults aged ≥65 years, the 2008 rates of nonsusceptible IPD were below the 1999–2001 rates for almost all antibiotics tested in both age groups (Figures 3 and 4) as well as in youth aged 5–17 years (data not shown). The 2008 rates of nonsusceptible IPD were less than the 1999–2001 rates for most antibiotics tested in adults aged 18–49 years but were higher than the 1999–2001 rates for all antibiotics tested in adults aged 50–64 years (data not shown). Rates of multidrug-nonsusceptible IPD, which were lower under the new parenteral breakpoints than under the old ones, were less in 2008 than in 1999–2001 under all breakpoints among all age groups except adults aged 50–64 years. In contrast to these general trends, all isolates were fully susceptible to vancomycin, rates of levofloxacin-nonsusceptible IPD remained very low for all age groups between 1998 and 2008, and the 2008 rates of clindamycin-nonsusceptible IPD among all age groups aged ≥5 years were higher than the 2001 rates.

Figure 3.

Rates of antibiotic nonsusceptible (NS) invasive pneumococcal disease among children aged <5 years. aNot susceptible to 3 or more of the antibiotic classes tested. bThe old/oral/meningitis penicillin breakpoints classify isolates as penicillin nonsusceptible at a minimum inhibitory concentration (MIC) ≥0.12 μg/mL. cThe new parenteral penicillin breakpoints classify isolates as penicillin nonsusceptible at an MIC ≥4 μg/mL for nonmeningitis disease and ≥0.12 μg/mL for meningitis.

Figure 3.

Rates of antibiotic nonsusceptible (NS) invasive pneumococcal disease among children aged <5 years. aNot susceptible to 3 or more of the antibiotic classes tested. bThe old/oral/meningitis penicillin breakpoints classify isolates as penicillin nonsusceptible at a minimum inhibitory concentration (MIC) ≥0.12 μg/mL. cThe new parenteral penicillin breakpoints classify isolates as penicillin nonsusceptible at an MIC ≥4 μg/mL for nonmeningitis disease and ≥0.12 μg/mL for meningitis.

Figure 4.

Rates of antibiotic nonsusceptible (NS) invasive pneumococcal disease among persons aged ≥65 years. aNot susceptible to 3 or more of the antibiotic classes tested. bThe old/oral/meningitis penicillin breakpoints classify isolates as penicillin nonsusceptible at a minimum inhibitory concentration (MIC) ≥0.12 μg/mL. cThe new parenteral penicillin breakpoints classify isolates as penicillin nonsusceptible at an MIC ≥4 μg/mL for nonmeningitis disease and ≥0.12 μg/mL for meningitis.

Figure 4.

Rates of antibiotic nonsusceptible (NS) invasive pneumococcal disease among persons aged ≥65 years. aNot susceptible to 3 or more of the antibiotic classes tested. bThe old/oral/meningitis penicillin breakpoints classify isolates as penicillin nonsusceptible at a minimum inhibitory concentration (MIC) ≥0.12 μg/mL. cThe new parenteral penicillin breakpoints classify isolates as penicillin nonsusceptible at an MIC ≥4 μg/mL for nonmeningitis disease and ≥0.12 μg/mL for meningitis.

Regardless of the choice of penicillin breakpoints, 2008 IPD isolates were most likely to be susceptible to vancomycin, levofloxacin, and cefotaxime (Figure 5). Under the old/oral/meningitis breakpoints, isolates were most likely to be nonsusceptible to erythromycin and penicillin, but under the new parenteral breakpoints, isolates were more likely to be nonsusceptible to erythromycin, cotrimoxazole, cefuroxime, and meropenem than to penicillin. Isolates were most likely to be nonsusceptible to erythromycin under the new parenteral breakpoints for all age groups except adults aged 50–64 years.

Figure 5.

Percentage of 2008 invasive pneumococcal disease (IPD) isolates not susceptible to selected antibiotics by age group. aNot susceptible to 3 or more of the antibiotic classes tested. bThe old/oral/meningitis penicillin breakpoints classify isolates as penicillin nonsusceptible at a minimum inhibitory concentration (MIC) ≥0.12 μg/mL. cThe new parenteral penicillin breakpoints classify isolates as penicillin nonsusceptible at an MIC ≥4 μg/mL for nonmeningitis disease and ≥0.12 μg/mL for meningitis.

Figure 5.

Percentage of 2008 invasive pneumococcal disease (IPD) isolates not susceptible to selected antibiotics by age group. aNot susceptible to 3 or more of the antibiotic classes tested. bThe old/oral/meningitis penicillin breakpoints classify isolates as penicillin nonsusceptible at a minimum inhibitory concentration (MIC) ≥0.12 μg/mL. cThe new parenteral penicillin breakpoints classify isolates as penicillin nonsusceptible at an MIC ≥4 μg/mL for nonmeningitis disease and ≥0.12 μg/mL for meningitis.

DISCUSSION

Regardless of whether the old/oral/meningitis or new parenteral penicillin susceptibility breakpoints are used, penicillin-nonsusceptible IPD caused by PCV7 serotypes has decreased significantly for all age groups and has almost disappeared except among adults aged ≥65 years. Rates of penicillin-nonsusceptible IPD remain markedly below the rates that existed before PCV7 introduction for all age groups except adults aged 50–64 year under the new parenteral breakpoints. These findings highlight the dramatic herd effects of PCV7 resulting from decreased nasopharyngeal colonization of children and, subsequently, decreased transmission from children to older persons of serotypes in PCV7 [2]. The incidence of IPD caused by strains not susceptible to antibiotics besides penicillin also generally remains below pre-PCV7 levels for all age groups except adults aged 50–64 years. The serotypes included in PCV13 accounted for the majority of penicillin-nonsusceptible disease in 2008 (≥78% depending on age under the new parenteral breakpoints). Our results are consistent with trends in nonsusceptible IPD seen elsewhere in the United States [20–24].

Despite continued use of PCV7, rates of penicillin-nonsusceptible IPD have been gradually increasing since 2002–2004, largely because of higher rates of IPD caused by serotype 19A and increases in the proportion of serotype 19A IPD that is penicillin nonsusceptible. The rise of penicillin-nonsusceptible 19A may be due, in part, to continued selective pressure from antibiotic use among children and transmission to adults [25–28]. Azalides such as azithromycin may be particularly effective in selecting for nonsusceptible strains [25, 29–31]. Even countries that have not introduced PCV7 have observed increases in the proportion of pneumococcal carriers colonized by serotype 19A coinciding with extensive antibiotic use [30]. However, it is also possible that the major emergent clonal complex 320, which causes the majority of penicillin-nonsusceptible 19A IPD in the United States [16], has additional advantageous traits that have contributed to the increased proportion of pneumococcal carriage and IPD attributable to serotype 19A. Other serotype 19A clonal complexes in the Netherlands have replaced the serotypes previously associated with nasopharyngeal colonization among young children, despite being generally susceptible to antibiotics [32]. The ability of serotype 19A to cause both invasive disease [33–37] and nasopharyngeal carriage [33, 37] may also have played a role in the rise of 19A.

The new parenteral CLSI penicillin pneumococcal susceptibility breakpoints offer an opportunity to increase use of penicillin, which may reduce antimicrobial costs, decrease risk of healthcare-associated infections, and possibly forestall resistance to broader-spectrum antibiotics [5]. The CLSI changed the breakpoints for nonmeningitis pneumococcal disease in 2008 because recent data indicated that parenteral penicillin could be effective even if isolates had MICs above the old/oral/meningitis breakpoints [14]. In our study, under the new parenteral CLSI breakpoints the probability that a pneumococcus from an individual with IPD in an ABCs area was susceptible to parenteral penicillin was comparable to the probability that it was susceptible to carbapenems, cephalosporins, and other β-lactams and higher than the probability that it was susceptible to macrolides or cotrimoxazole. Whether the use of parenteral penicillin increases as a result of this change in breakpoints remains to be seen.

Clinicians and surveillance staff need to be aware of the effects on apparent penicillin susceptibility of applying the old/oral/meningitis breakpoints versus the new parenteral breakpoints because the incidence of penicillin nonsusceptible IPD is much lower with the new parenteral CLSI breakpoints [12]. Although the new breakpoints are more appropriate for guiding parenteral treatment of nonmeningitis pneumococcal disease, the old/oral/meningitis breakpoints are still useful in monitoring emerging pneumococcal antibiotic resistance. The old/oral/meningitis breakpoints are more suitable for identifying strains with MICs between 0.12 and 1 μg/mL that perhaps have more potential to accumulate additional penicillin-binding protein gene mutations that could lead to full penicillin resistance [38, 39]. For example, the proportion of penicillin-nonsusceptible IPD caused by serotypes not included in PCV13 is more prominent under the old breakpoints because many isolates from these serotypes were classified as intermediate under the old breakpoints but susceptible under the new breakpoints. In addition, the breakpoints recommended for choosing oral treatment are unchanged from the ones used prior to the 2008 revision of the CLSI standards for antibiotic susceptibility [29]. The relatively high proportions of IPD isolates not susceptible to cotrimoxazole and cefuroxime support the recommendations for choosing other agents as first-line empiric therapy for diseases that can be caused by pneumococcus [40–43], recommendations that have contributed to declines in outpatient use of sulfonamides and cephalosporins for acute respiratory tract infections [44]. Given the even higher proportions of IPD isolates not susceptible to erythromycin [20–22, 24] and the macrolides’ proclivity for selecting for antibiotic nonsusceptibility among S. pneumoniae [25, 29–31], it may be important to reconsider the empiric use of macrolides for outpatient treatment of community-acquired pneumonia.

Although notable progress has been made in reducing rates of antibiotic-nonsusceptible IPD since the introduction of PCV7, further efforts are needed for the United States to reach the Healthy People 2020 goals of 3 and 2 cases per 100000 people per year of penicillin-nonsusceptible IPD among children aged <5 years and adults aged ≥65 years, respectively [45]. Reducing antibiotic usage enough to meet the Healthy People 2020 goals of a 50% reduction of antibiotic courses prescribed for the common cold and a 25% reduction in antibiotic courses prescribed for ear infections among children aged <5 years could help minimize antibiotic-nonsusceptible IPD [27, 45, 46]. Provision of PCV13 to all individuals for whom the Advisory Committee on Immunization Practices has recommended it [11] may also reduce rates of antibiotic-nonsusceptible IPD, particularly if PCV13 is as effective against serotype 19A as PCV7 was against PCV7 serotypes. Use of PCV13 may have a secondary effect on antibiotic resistance rates through reduced outpatient use of antibiotics for respiratory infections [47].

Our study has a number of limitations. First, ABCs data may not be generalizable to non-ABCs areas. Second, as an ecological study the ABCs data can suggest but not prove a direct connection between the introduction of PCV7 and subsequent trends in nonsusceptible pneumococcal infections. Changes in IPD trends may reflect factors we did not account for, such as changes in blood culturing practices. Third, our data are limited to IPD, so serotype distributions and susceptibility patterns among noninvasive pneumococcal syndromes might be different. Finally, the ABCs data do not capture cases of undiagnosed IPD. Some cases may have been missed due to a lack of sterile site culturing or because of treatment with antibiotics before sample collection. Antibiotic treatment prior to sample collection would both decrease the rate of overall disease detected and potentially increase the proportion of detected cases that were nonsusceptible to antibiotics.

Our data indicate that PCV7 has reduced rates of antibiotic-nonsusceptible IPD in the United States and that PCV13 has the potential to further reduce those rates. Although novel antibiotic-nonsusceptible pneumococcal strains emerged after the introduction of PCV7, it is unknown whether this pattern will be repeated after PCV13 introduction. Judicious use of antibiotics and the development of effective new vaccines, including those targeting antigens other than the polysaccharide capsule, are likely needed to effectively prevent antibiotic-nonsusceptible pneumococcal infections. Although the old/oral/meningitis penicillin susceptibility breakpoints have a role in monitoring the impact of pneumococcal vaccines, the new parenteral breakpoints provide a renewed opportunity for the treatment of nonmeningitis pneumococcal infections with a safe, effective, and narrow-spectrum antibiotic.

Notes

Acknowledgments.

We thank the following members of the Active Bacterial Core surveillance/Emerging Infections Program Network for their assistance with this project:

California Emerging Infections Program: Mirasol Apostol, Susan Brooks, Pam Daily Kirley, Joelle Nadle, and Lauren Pasutti.

Colorado Emerging Infections Program: Deborah Aragon.

Connecticut Emerging Infections Program: Zack Fraser and James L. Hadler.

Georgia Emerging Infections Program: Wendy Baughman, Amy Holst, and Stephanie Thomas.

Maryland Emerging Infections Program: Kim D. Holmes, Rosemary Hollick, and Kathleen Shutt.

Minnesota Emerging Infections Program: Brenda Jewell, Billie Ann Juni, Catherine Lexau, Lindsey Lesher, and Lori Triden.

New Mexico Emerging Infections Program: Kathy Angeles, Joseph Bareta, Lisa Butler, Sarah Khanlian, Robert Mansmann, and Megin Nichols.

New York Emerging Infections Program: Geetha Nattanmai, Glenda Smith, Suzanne Solghan, and Nancy Spina.

Oregon Emerging Infections Program: Karen Stefonek.

Tennessee Emerging Infections Program: Brenda G. Barnes and Terry McMinn.

University of Texas Health Sciences Center, San Antonio: Letitia C. Fulcher, M. Leticia McElmeel, and Christa Trippy.

CDC: Felicita David, Melissa Lewis, Tamara Pilishvili, Karrie-Ann Toews, Chris Van Beneden, Carolyn Wright, and the entire staff of the CDC Streptococcus laboratory.

Financial support.

This work was supported by the Emerging Infections Programs and the Office of Antimicrobial Resistance of the Centers for Disease Control and Prevention. The Centers for Disease Control and Prevention’s Emerging Infections Programs provided funding but made no other contributions to the design and conduct of this study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of this manuscript.

Potential conflicts of interest.

W. S. has served as a consultant to Pfizer, Novartis, GSK, Sanofi-Pasteur, and Dynavex, and is a member of Data Safety Monitoring Boards for Merck. L. H. H. has served as a consultant to and received lecture fees from Merck and Pfizer. J. H. J. has been a member of advisory boards for BD Microbiology Systems and for Rib-X Pharmaceuticals and has received research funding from BD, bioMerieux, Merck, Pfizer, and Siemens Healthcare. E. Z. owns stock in Pfizer, Merck, and Johnson and Johnson. All other authors report no potential conflicts.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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Author notes

Presented in part: 7th International Conference on Emerging Infectious Diseases, Atlanta, Georgia, 11–14 July 2010.