Diversity and antibiotic resistance among nonvaccine serotypes of Streptococcus pneumoniae carriage isolates in the post-heptavalent conjugate vaccine era

BACKGROUND: In response to the selective pressure of pneumococcal conjugate vaccine, increased asymptomatic carriage of antibiotic-nonsusceptible nonvaccine serotypes (NVTs) has been observed. Possible mechanisms include de novo acquisition of resistance, serotype switching, introduction of new clones, and expansion of existing clones. METHODS: To investigate the process of increased antibiotic nonsusceptibility among replacing serotypes, we applied multilocus sequence typing to samples of 126 and 222 pneumococci collected in 2001 and 2004, respectively, from the nasopharynges of children <7 years of age in 16 Massachusetts communities. RESULTS: We found no evidence of penicillin resistance due to either serotype switching or de novo acquisition. Nonetheless, resistance increased through the expansion of previously recognized clones of NVTs, particularly in serotypes 19A, 15A, and 35B. In 19A, several unrelated clones increased in frequency, whereas, in the other 2 serotypes, single resistant lineages were responsible for the increased prevalence of resistant strains. CONCLUSIONS: The decreased prevalence of antibiotic resistance with the introduction of heptavalent pneumococcal conjugate vaccine is likely to be partially eroded over time as vaccine-included serotypes are replaced by resistant clones of NVTs. The clinical significance of this will depend on the pathogenic potential of replacing clones to cause local (e.g., otitis media) or invasive disease.     

Indirect effect of conjugate vaccine on adult carriage of Streptococcus pneumoniae: an explanation of trends in invasive pneumococcal disease

BACKGROUND: Use of heptavalent protein-polysaccharide pneumococcal conjugate vaccine (PCV7) has been associated with decreases in PCV7-type invasive pneumococcal disease and nasopharyngeal (NP) carriage in children. Vaccine use has also indirectly decreased the rate of invasive disease in adults, presumably through decreased transmission of pneumococci from vaccinated children to adults. METHODS: We conducted NP carriage surveys in 8 villages in Alaska in 1998-2004. Streptococcus pneumoniae isolates were characterized by serotype and antimicrobial susceptibility. We analyzed trends in serotype distribution, antibiotic resistance, and factors associated with adult carriage of PCV7-serotype pneumococci before and after the introduction of PCV7 in 2001. RESULTS: We collected 15,598 NP swabs; overall, 52% of adults living in the villages surveyed participated in the colonization study. The proportion of adult carriers with PCV7-type pneumococcal carriage decreased from 28% of carriers in 1998-2000 to 4.5% of carriers in 2004 (P<.0001). Among adults, the proportion of colonizing isolates that were resistant to penicillin decreased from 13% in 1998-2000 to 6% in 2004 (P=.05), whereas the percentage of isolates with intermediate susceptibility to penicillin increased from 12% in 1998-2000 to 19% in 2004 (P<.01). Adults were more likely to carry PCV7-type pneumococci if they lived with a child <5 years old or if they lived with a child who had not been age-appropriately vaccinated with PCV7. CONCLUSIONS: Pediatric vaccination with PCV7 has resulted in decreased PCV7-type pneumococcal carriage among adults and helps to explain recent decreases in the rate of PCV7-type invasive pneumococcal disease among adults.     

Reduction of nasopharyngeal carriage of Streptococcus pneumoniae after administration of a 9-valent pneumococcal conjugate vaccine to toddlers attending day care centers

A double-blind, randomized study involving 264 toddlers attending day care centers was conducted to document the effect of a 9-valent pneumococcal conjugate vaccine on the carriage rate of pneumococci. Of 3750 cultures done on nasopharyngeal samples obtained from subjects during a 2-year follow-up period after vaccination, 65% were positive for Streptococcus pneumoniae. In all age windows, the rate of carriage of vaccine-type pneumococci was lower among subjects who received the pneumococcal vaccine than among control subjects, because the acquisition rate was lower in the former group. The effect was most pronounced among subjects aged < or =36 months. The sample size enabled us to study protection against carriage of S. pneumoniae serotypes 6B, 9V, 14, 19F, and 23F; significant protection against all serotypes except 19F was seen in the pneumococcal-vaccine group. The rate of carriage of serotype 6A (not included in the vaccine) was also reduced significantly, but the rate of carriage of serotype 19A (not included in the vaccine) was not. The rate of carriage of non-vaccine-type pneumococci (excluding serotype 6A) was higher in the pneumococcal-vaccine group than in the control group.     

Strain characteristics of Streptococcus pneumoniae carriage and invasive disease isolates during a cluster-randomized clinical trial of the 7-valent pneumococcal conjugate vaccine

Widespread use of 7-valent pneumococcal conjugate vaccine (PCV7) has led to significant reductions in disease while changing pneumococcal population dynamics via herd immunity and serotype replacement. We performed multilocus sequence typing (MLST) on 590 pneumococcal isolates obtained during the American Indian clinical trial of PCV7, in which communities were randomized for eligible children to receive either PCV7 or a meningococcal conjugate vaccine (MCV). Sequence types (STs) were analyzed to determine the impact of the vaccine on pneumococcal population structure and to assess the possible impact of pneumococcal genetic background on vaccine effects. One hundred forty-three STs were obtained, the most frequent being ST199, the only one that included vaccine serotypes (VTs), non-vaccine-associated nonvaccine serotypes (NVA/NVTs), and vaccine-associated serotypes (VATs). Serotype replacement observed in the PCV communities was due to a diverse population of STs, most of which also existed in the MCV communities. Possible capsular switching to create novel ST associations with NVA/NVTs was detected only once. Reductions in VTs and changes in VATs in PCV communities did not show evidence of variation by ST, after accounting for lower vaccine effectiveness against serotype 19F. These observations suggest the hypothesis that the vaccine acts as a "serotype filter": its effect on a particular strain can be predicted on the basis of the serotype of the strain, with little effect of genetic background (as assessed by MLST) over and above capsule. If sustained, such patterns provide some cause for optimism that rapid evolution of PCV escape strains with drug resistance or high virulence is unlikely.     

Streptococcus pneumoniae meningitis in Alberta pre- and postintroduction of the 7-valent pneumococcal conjugate vaccine

OBJECTIVE:

To describe the epidemiology, clinical characteristics, microbiology and outcomes of patients of all ages with Streptococcus pneumoniae meningitis two years pre- and postintroduction of a S pneumoniae 7-valent conjugate vaccine program in Alberta in children <2 years of age.

METHODS:

Between 2000 and 2004, all cases of invasive pneumococcal disease in Alberta were identified. From this cohort, patients with S pneumoniae meningitis were identified by chart review. Clinical data, laboratory data and in-hospital outcomes were collected.

RESULTS:

Of the 1768 cases of invasive pneumococcal disease identified between 2000 and 2004, 110 (6.2%) had S pneumoniae meningitis. The overall incidence was 0.7 per 100,000 persons and remained unchanged over the study period. The rate in children <2 years of age appeared to fall over time, from 10.5 per 100,000 persons in 2000 to five per 100,000 persons in 2004, although there was insufficient evidence of a statistically significant time trend within any age group. Overall, the mean age was 30 years and 47% were male. In-hospital mortality was 20%, ranging from 6% in those ≤2 years of age to 31% for those ≥18 years of age, despite appropriate antimicrobial therapy.

CONCLUSION:

The high mortality rate associated with S pneumoniae meningitis suggests that prevention by vaccination is critical. In children <2 years of age, there was a downward trend in the rate of S pneumoniae meningitis after implementation of the S pneumoniae 7-valent conjugate vaccine program, but rates were still high.     

Emergence of penicillin-nonsusceptible Streptococcus pneumoniae clones expressing serotypes not present in the antipneumococcal conjugate vaccine

BACKGROUND: Penicillin-nonsusceptible Streptococcus pneumoniae isolates are confined mainly to a few serogroups. Capsular transformation may serve as a mechanism for spreading antibiotic resistance to new serotypes. METHODS: Antibiogram and molecular typing, by pulsed-field gel electrophoresis (PFGE), were performed on 46 nasopharyngeal and middle ear fluid (MEF) isolates expressing serotype 11A, 45 MEF isolates expressing serotype 15B/C (recovered during 1998-2003 from Israeli children <5 years old), and 57 MEF isolates expressing serotype 19F (recovered during 1998-2001 from Costa Rican children <7.5 years old). RESULTS: PFGE patterns showed that 49 (86%) of 57 serotype 19F isolates and 19 (41%) of 46 serotype 15B/C isolates were closely related. The vast majority of these isolates (80% of serotype 19F and 100% of serotype 15B/C isolates) were nonsusceptible to penicillin. Multilocus sequence typing (MLST) data show that the serotype 15B/C isolates belonged to the ST346 cluster, whereas the serotype 19F isolates were a single-locus variant of ST346. For serotype 11A isolates, PFGE patterns and MLST analysis showed that 8 (80%) of the 10 penicillin-nonsusceptible isolates belonged to a single clone--namely, ST156--which was identical to the international Spain9V-3 clone. CONCLUSIONS: Penicillin-nonsusceptible pneumococcal clones of serotypes not related to those included in the 11-valent conjugate vaccines may derive from capsular transformation of vaccine-related serotypes. Of particular concern was the detection of serotype 11A variants of the successful international Spain9V-3 clone. This phenomenon, although seemingly rare at present, can have implications for the long-term effectiveness of the conjugate vaccines.     

Immunogenicity and impact on nasopharyngeal carriage of a nonavalent pneumococcal conjugate vaccine.

The safety, immunogenicity, and impact on carriage of a nonvalent pneumococcal vaccine given at ages 6, 10, and 14 weeks were examined in a double-blind, randomized, placebo-controlled trial in 500 infants in Soweto, South Africa. No serious local or systemic side effects were recorded. Significant antibody responses to all pneumococcal serotypes were observed 4 weeks after the third dose. Haemophilus influenzae type b polyribosylribitol phosphate (geometric mean titer, 11.62 microg/mL) and diphtheria (1.39 IU/mL) antibodies were significantly higher in children receiving pneumococcal conjugate, compared with placebo recipients (4.58 microgram/mL and 0.98 IU/mL, respectively). Nasopharyngeal carriage of vaccine serotypes decreased in vaccinees at age 9 months (18% vs. 36%), whereas carriage of nonvaccine serotypes increased (36% vs. 25%). Carriage of penicillin-resistant pneumococci (21% vs. 41%) and cotrimoxazole-resistant pneumococci (23% vs. 35%) were significantly reduced 9 months after vaccination, compared with controls.     

Independent risk factors for carriage of penicillin-non-susceptible Streptococcus pneumoniae

Antibiotic treatment, day-care center (DCC) attendance and young age are associated with penicillin-non-susceptible Streptococcus pneumoniae (PNSSp) carriage. Yet, it is unclear whether each is an independent risk factor for the individual. This cross-sectional surveillance study was designed to answer this question. Nasopharyngeal cultures were obtained from 429 children (< 6 y) during a visit to the pediatrician's office. Two risk rates were calculated: the individual's absolute risk to carry PNSSp [simple odds ratio (ORS)] and the risk of an individual who is already a carrier [conditional odds ratio (ORC)]. Streptococcus pneumoniae was isolated from 52.7% of 401 children. PNSSp was detected in 37.1% of carriers. Independent risk factors were: young age [ORS 2.24, 95% confidence interval (95% CI) 1.2-4.2], DCC attendance (ORS 3.8, 95% CI 1.9-7.5), having young siblings (ORS 2.3, 95% CI 0.95-5.57) and each antibiotic treatment during the previous 3 months (ORS 1.5, 95% CI 1.25-1.85). The only significant risk factor among carriers was prior antibiotic treatment (ORC 2.24, 95% CI 1.64-3.05). Young children, who attended DCC and received 1 antibiotic course (9% of the population) had a risk 12.9 times higher than children without these features.     

Antibody responses to nasopharyngeal carriage of Streptococcus pneumoniae in adults: a longitudinal household study

BACKGROUND: Natural immunity to Streptococcus pneumoniae is thought to be induced by exposure to S. pneumoniae or cross-reactive antigens. No longitudinal studies of carriage of and immune responses to S. pneumoniae have been conducted using sophisticated immunological laboratory techniques. METHODS: We enrolled 121 families with young children into this study. Nasopharyngeal (NP) swabs were collected monthly for 10 months from all family members and were cultured in a standard fashion. Cultured S. pneumoniae isolates were serotyped. At the beginning (month 0) and end (month 10) of the study, venous blood was collected from family members >18 years old. Serotype-specific antipolysaccharide immunoglobulin G (IgG) and functional antibody and antibodies to pneumolysin, pneumococcal surface protein A (PspA), and pneumococcal surface antigen A (PsaA) were measured in paired serum samples. RESULTS: Levels of anticapsular IgG increased significantly after carriage of serotypes 9V, 14, 18C, 19F, and 23F by an individual or family member. For serotype 14, a higher level of anticapsular IgG at the beginning of the study was associated with reduced odds of carriage (P = .006). There was a small (approximately 20%) but significant increase in titers of antibodies to PsaA and pneumolysin but no change in titers of antibody to PspA. CONCLUSIONS: Adults respond to NP carriage by mounting anticapsular and weak antiprotein antibody responses, and naturally induced anticapsular IgG can prevent carriage.     

Impact of meningococcal serogroup C conjugate vaccines on carriage and herd immunity

BACKGROUND: In 1999, meningococcal serogroup C conjugate (MCC) vaccines were introduced in the United Kingdom for those under 19 years of age. The impact of this intervention on asymptomatic carriage of meningococci was investigated to establish whether serogroup replacement or protection by herd immunity occurred. METHODS: Multicenter surveys of carriage were conducted during vaccine introduction and on 2 successive years, resulting in a total of 48,309 samples, from which 8599 meningococci were isolated and characterized by genotyping and phenotyping. RESULTS: A reduction in serogroup C carriage (rate ratio, 0.19) was observed that lasted at least 2 years with no evidence of serogroup replacement. Vaccine efficacy against carriage was 75%, and vaccination had a disproportionate impact on the carriage of sequence type (ST)-11 complex serogroup C meningococci that (rate ratio, 0.06); these meningococci also exhibited high rates of capsule expression. CONCLUSIONS: The impact of vaccination with MCC vaccine on the prevalence of carriage of group C meningococci was consistent with herd immunity. The high impact on the carriage of ST-11 complex serogroup C could be attributed to high levels of capsule expression. High vaccine efficacy against disease in young children, who were not protected long-term by the schedule initially used, is attributed to the high vaccine efficacy against carriage in older age groups.     

Capsular serotype-specific attack rates and duration of carriage of Streptococcus pneumoniae in a population of children

BACKGROUND: The relative invasiveness rates (attack rates) of Streptococcus pneumoniae of different capsular serotypes in children are not known. Estimates of capsular serotype invasiveness (designated "invasive odds ratios") that are based on cross-sectional prevalence carriage data have been published, but these estimates could be biased by variation in the duration of carriage. METHODS: The relative attack rates of invasive pneumococci were measured using national UK surveillance data on invasive pneumococcal disease (IPD) incidence and data on incidence of pneumococcal acquisition from longitudinal studies of nasopharyngeal pneumococcal carriage. RESULTS: We found significant differences in capsular serotype-specific attack rates. For example, capsular serotypes 4, 14, 7F, 9V, and 18C were associated with rates of >20 IPD cases/100,000 acquisitions, whereas capsular serotypes 23F, 6A, 19F, 16F, 6B, and 15B/C were associated with <10 IPD cases/100,000 acquisitions. There was an inverse relationship between duration of carriage and attack rate by capsular serotype (P<.0001). Attack rates were significantly correlated with invasive odds ratios (P<.0001). CONCLUSIONS: The capsular serotype is a major determinant of both pneumococcal duration of carriage and attack rate. Published invasive odds ratios are a reliable and practical method of determining capsular serotype invasiveness and will be valuable for investigating and characterizing emerging capsular serotypes in the context of conjugate vaccination.     

Streptococcus pneumoniae carriage and penicillin/ ceftriaxone resistance in hospitalised children in Darwin

Background: The prevalence of resistant Streptococcus pneumoniae (SP) is increasing worldwide. Pneumococcal prevalence and susceptibility patterns are not known for children in the Top End of the Northern Territory.
Aims: To determine the prevalence of nasopharyngeal carriage of pneumococci in children hospitalised in Darwin, and the extent of penicillin and ceftriaxone resistance in these isolates.
Methods: Nasopharyngeal swabs were collected on admission from 85 children who had not received antimicrobials for their admission illness. Antimicrobial resistance was determined following selective culture for SP isolates. Minimal inhibitory concentrations (MICs) for penicillin and ceftriaxone were determined using the E-test method.
Results: The overall prevalence of nasopharyngeal SP carriage was 44%. Carriage occurred more often in Aboriginal children from rural areas (56%) than in urban children (24%) (OR 3.94, 95% CI 1.35 - 11.78, p <0.01). Thirty per cent of isolates were penicillin resistant, 35% were ceftriaxone resistant, and 49% were resistant to at least one of these. One isolate showed high-level resistance to both antimicrobials; all other resistant isolates were of intermediate-level resistance. For the same isolate, MICs for ceftriaxone were more often higher than those for penicillin. Five isolates had intermediate resistance to ceftriaxone whilst remaining sensitive to penicillin.
Conclusions: The prevalence of pneumococcal resistance to penicillin and ceftriaxone in hospitalised children in Darwin is much higher than previously reported in Australia. This has implications for future antimicrobial management and highlights the need for regular regional surveillance of SP resistance. The development of conjugate pneumococcal vaccines for children under two years is a priority.     

Nasopharyngeal carriage of Streptococcus pneumoniae in Finnish children younger than 2 years old

To describe the natural course of nasopharyngeal carriage of Streptococcus pneumoniae and its relationship to acute otitis media (AOM), 329 Finnish children were followed from ages 2 to 24 months. In total, 3024 nasopharyngeal (NP) swabs (obtained at 10 scheduled healthy visits) and 2007 NP aspirates (obtained during respiratory infections) were cultured. Carriage during health increased gradually (9%-43%) with age. Within 4 age intervals, carriage was lower during health (13%-43%) than during respiratory infection without AOM (22%-45%). Higher proportions of positive samples were found during AOM (45%-56%), in particular during pneumococcal AOM (97%-100%). Antimicrobial treatment reduced carriage only temporarily. The most frequent NP serotypes were 6B, 6A, 11, 19F, and 23F. Both age and health status were important determinants of NP carriage of S. pneumoniae and these features should be considered carefully during analysis of carriage rates.