Emergence of pneumococcal 19A empyema in UK children.

INTRODUCTION: Invasive pneumococcal disease due to serotype 19A has become a major concern, particularly in the USA and Asia. We describe the characteristics of pneumococcal serotype 19A related empyema and changes in its incidence in the UK. METHODS: Data from paediatric empyema patients between September 2006 and March 2011 were collected from 17 respiratory centres in the UK. Pneumococcal serotypes were identified as part of the Health Protection Agency enhanced paediatric empyema surveillance programme. RESULTS: Four serotypes accounted for over 80% of 136 cases (Serotype 1 : 43%, 3 : 21%, 7 : 11% and 19A:10%). The incidence of empyema due to serotype 19A quadrupled from 0.48 (0.16-1.13) cases per million children in 2006/2007 to 2.02 (1.25-3.09) in 2010/2011. Severity of disease was significantly increased in children with 19A infection when compared to other serotypes. CONCLUSIONS: The incidence of empyema due to pneumococcal serotype 19A infection has increased significantly and is associated with substantial morbidity.

Impact and effectiveness of 23-valent pneumococcal polysaccharide vaccine against invasive pneumococcal disease in the elderly in England and Wales.

In 2003 the existing 23-valent pneumococcal vaccine (PPV23) programme for high risk groups was extended to include all ≥ 65 year olds in England and Wales, starting with ≥ 80 year olds and moving to 75-79 and 65-74 year olds by 2005. We conducted an ecological study to assess the impact of the extended PPV23 programme on serotype-specific incidence of invasive pneumococcal disease (IPD) and a case-control study to assess vaccine effectiveness (VE) using the national IPD surveillance dataset. Between 1998 and 2006 IPD incidence caused by PPV23 serotypes in the targeted age-groups was unchanged. IPD caused by the serotypes covered by the 7-valent conjugate vaccine (PCV7) introduced for children in 2006 declined in ≥ 65 year olds after 2006 but was offset by an increase in non-PCV7 serotypes. This increase was similar for the additional 16 serotypes covered by PPV23 and the non-PPV23 serotypes. For the VE study, vaccine history was obtained for controls (n=1270) with non-PPV23 IPD diagnosed between November 2003 and December 2010 and a subset of cases (n=1272) matched for age and time period. VE declined from 48% (95% confidence interval; 32-60%) within two years of vaccination to 15% (-3% to 30%) after five years. Although differences in VE by age and having risk conditions were not statistically significant the highest estimates were in the youngest age group (65-74 years) and in those without risk conditions with a VE estimate of 65% (23-84%) within 2 years of vaccination for non-risk 65-74 year olds. VE differed by serotype (p=0.005), from -23% (-85% to 19%) for serotype 3 to 63% (29-81%) for 12F. In conclusion PPV23 was effective, particularly in healthy under 75 year olds, but protection waned after 5 years. There was no discernible impact of PPV23 on IPD incidence or PCV7-induced serotype replacement, consistent with the modest overall effectiveness, the 45% increased coverage over the former risk-based programme and lack of herd immunity from the PPV23 programme. Based on the VE estimates PPV23 was still considered a cost-effective intervention for the low risk elderly.

Accelerating control of pertussis in England and Wales.

Results of an accelerated pertussis vaccination schedule for infants introduced in 1990 in England and Wales were examined. Earlier scheduling and sustained high vaccine coverage resulted in fewer reported cases of pertussis among infants, reinforcing the World Health Organization drive for on-time completion of the infant vaccination schedule. As determined by using the screening method, the first dose of vaccine was 61.7% effective in infants <6 months of age, and effectiveness increased with subsequent doses. Three doses of a good whole-cell pertussis vaccine were 83.7% effective in children 10-16 years of age; a preschool booster vaccination further reduced pertussis incidence in children <10 years of age. As in other industrialized countries, surveillance data during 1998-2009 showed that pertussis in England and Wales mainly persists in young infants (i.e., <3 months of age), teenagers, and adults. Future vaccine program changes may be beneficial, but additional detail is required to inform such decisions.

Using the indirect cohort design to estimate the effectiveness of the seven valent pneumococcal conjugate vaccine in England and Wales.

BACKGROUND: The 7-valent pneumococcal conjugate vaccine (PCV-7) was introduced in the United Kingdom in 2006 with a 2, 3 and 13 month schedule, and has led to large decreases in invasive pneumococcal disease (IPD) caused by the vaccine serotypes in both vaccinated and unvaccinated cohorts. We estimated the effectiveness of PCV-7 against IPD. METHODS AND FINDINGS: We used enhanced surveillance data, collated at the Health Protection Agency, on vaccine type (n = 153) and non vaccine type (n = 919) IPD cases eligible for PCV-7. The indirect cohort method, a case-control type design which uses non vaccine type cases as controls, was used to estimate effectiveness of various numbers of doses as well as for each vaccine serotype. Possible bias with this design, caused by differential serotype replacement in vaccinated and unvaccinated individuals, was estimated after deriving formulae to quantify the bias. The results showed good effectiveness, increasing from 56% (95% confidence interval (CI): -7-82) for a single dose given under one year of age to 93% (95% CI: 70-98) for two doses under one year of age plus a booster dose in the second year of life. Serotype specific estimates indicated higher effectiveness against serotypes 4, 14 and 18C and lower effectiveness against 6B. Under the assumption of complete serotype replacement by non vaccine serotypes in carriage, we estimated that effectiveness estimates may be overestimated by about 2 to 5%. CONCLUSIONS: This study shows high effectiveness of PCV-7 under the reduced schedule used in the UK. This finding agrees with the large reductions seen in vaccine type IPD in recent years in England and Wales. The formulae derived to assess the bias of the indirect cohort method for PCV-7 can also be used when using the design for other vaccines that affect carriage such as the recently introduced 13 valent pneumococcal conjugate vaccine.

Effectiveness of the new serotypes in the 13-valent pneumococcal conjugate vaccine.

Efficacy of the new serotypes in the 13-valent pneumococcal conjugate vaccine (PCV13) against invasive pneumococcal disease (IPD) was based on a putative correlate of protection. In England and Wales, PCV13 replaced PCV7 in the 2, 4, and 13 month schedule in April 2010. Using non-vaccine type IPD cases as controls, we estimated vaccine effectiveness (VE) for the new serotypes. Among 166 IPD cases in PCV13 eligible children reported by July 2011 with known serotype and vaccination status, VE for 2 doses under a year was 78% (95% confidence interval -18% to 96%) and 77% (38-91%) for one dose over a year. VE for 7F and 19A was 76% (21-93%) and 70% (10-90%) respectively for ≥one dose. VE for serotypes 1 and 3 was 62% and 66% respectively although confidence intervals spanned zero. IPD due to PCV13-only serotypes halved in children under 2 years in the study period.

Herd immunity and serotype replacement 4 years after seven-valent pneumococcal conjugate vaccination in England and Wales: an observational cohort study.

BACKGROUND: The seven-valent pneumococcal conjugate vaccine (PCV7) has reduced vaccine-type (VT) invasive pneumococcal disease but increases in non-vaccine-type (NVT) disease have varied between countries. We assess the effect of the PCV7 vaccination on VT and NVT disease in England and Wales. METHODS: The study cohort was the population of England and Wales from July, 2000, to June, 2010. We calculated incidence rate ratios (IRRs) to compare incidences of VT and NVT disease before (2000-06) and after (2009-10) the introduction of PCV7. We used data from the national surveillance database. Cases included in our analysis were restricted to those confirmed by culture linked with isolates referred for serotyping at the national reference centre by laboratories in England and Wales. We adjusted for potential bias from missing data (serotype and age of patient) and changes in case ascertainment rates during the study period. FINDINGS: 5809 cases of invasive pneumococcal disease were reported in 2009-10, giving an incidence of 10·6 per 100,000 population in 2009-10, which, when compared with the adjusted average annual incidence of 16·1 in 2000-06, gives an overall reduction of 34% (95% CI 28-39). VT disease decreased in all age groups, with reductions of 98% in individuals younger than 2 years and 81% in those aged 65 years or older. NVT disease increased by 68% in individuals younger than 2 years and 48% in those aged 65 years or older, giving an overall reduction in invasive pneumococcal disease of 56% in those younger than 2 years and 19% in those aged 65 years or older. After vaccine introduction, more NVT serotypes increased in frequency than decreased, which is consistent with vaccine-induced replacement. Key serotypes showing replacement were 7F, 19A, and 22F. Increases in NVT invasive pneumococcal disease were not associated with antimicrobial resistance. INTERPRETATION: Despite much serotype replacement, a substantial reduction in invasive pneumococcal disease in young children can be achieved with PCV7 vaccination, with some indirect benefit in older age groups. Further reductions should be achievable by use of higher valency vaccines. Robust surveillance data are needed to properly assess the epidemiological effect of multivalent pneumococcal disease vaccines. FUNDING: Health Protection Agency.

Empirical treatment of influenza-associated pneumonia in primary care: a descriptive study of the antimicrobial susceptibility of lower respiratory tract bacteria (England, Wales and Northern Ireland, January 2007-March 2010).

OBJECTIVES: To determine the susceptibility of lower respiratory tract (LRT) isolates of Streptococcus pneumoniae, Staphylococcus aureus and Haemophilus influenzae to antimicrobial agents recommended by UK guidelines for treatment of pneumonia associated with influenza-like illness. METHODS: Analysis of antimicrobial susceptibility data from sentinel microbiology laboratories in England, Wales and Northern Ireland was carried out. Subjects comprised patients who had an LRT specimen taken in a general practitioner surgery or hospital outpatient setting between January 2007 and March 2010. The main outcome measurements were antimicrobial susceptibility trends of LRT isolates over time, between patient age groups and in different geographical regions. RESULTS: Susceptibility to tetracyclines or co-amoxiclav was high. Of the 70,288 and 45,288 isolates with susceptibility results for tetracyclines or co-amoxiclav, 96% and 92%, respectively, were susceptible. Overall susceptibility to ciprofloxacin, ampicillin/amoxicillin and macrolides was lower than for tetracyclines or co-amoxiclav and varied markedly by organism. There were few clinically relevant variations in susceptibility to doxycycline or co-amoxiclav over time, geographically or between age groups. CONCLUSIONS: The data support the use of doxycycline or co-amoxiclav as appropriate empiric treatment for LRT infection caused by the pathogens investigated, for patients in primary care.

Development of a sensitive, multiplexed immunoassay using xMAP beads for detection of serotype-specific streptococcus pneumoniae antigen in urine samples.

In support of the surveillance of pneumococcal infections in the era of conjugate vaccines, a sensitive and specific multiplex immunoassay using xMAP beads has been developed for direct detection of pneumococcal serotype-specific polysaccharides in clinical samples, particularly urine. The assay was tested on panels of spiked urine specimens, clinical urine specimens and bacterial isolates. Each of the 14 serotypes in the multiplex assay can be detected to 0.1 ng purified polysaccharide ml(-1), or less. Testing of a panel of urine specimens from patients with culture-confirmed pneumococcal or non-pneumococcal disease indicated that the multiplex assay is both sensitive and specific. The correct pneumococcal serotype was identified directly from urine in 46/58 (79.3 %) patients who had a contemporaneous blood culture isolate of a multiplex assay serotype. Furthermore, the specificity of the assay on this panel of samples was 99.3 % (145/146). This multiplex assay could be useful, in conjunction with the pneumococcal screening test Binax NOW, in urine for diagnosis of pneumococcal disease and the identification of the aetiological serotype, and potentially be of benefit in culture-negative patients.

Streptococcus pneumoniae isolates expressing a capsule with epitopes of both serotypes 6A and 6B.

Four Streptococcus pneumoniae isolates expressing both 6A and 6B capsular serotypes were detected by a multiplex immunoassay. The sequence of WciP, a GT2-family glycosyltransferase, indicates that point mutation has compromised linkage specificity, allowing two alternative oligosaccharides to be synthesized. This finding highlights that mutation as well as recombination can mediate serotype change.

Mutation frequency in antibiotic-resistant and -susceptible isolates of Streptococcus pneumoniae.

Development of multiple antibiotic resistance in Streptococcus pneumoniae typically involves either mutation or transformation at several well-separated chromosomal loci. We postulated that this series of genetic events would be more likely to occur in organisms with deficient DNA repair mechanisms. Investigation of 27 antibiotic-resistant or -susceptible clinical isolates of S. pneumoniae revealed a broad range of mutation frequencies, but no isolate was as mutable as a mismatch repair (MMR)-deficient laboratory isolate. No correlation was observed between antibiotic resistance and higher mutation frequency. Examination of a further 180 clinical isolates using a newly developed rapid screen method also failed to identify any isolates with a mutation frequency as high as the MMR-deficient control strain. We argue that there is currently no clear evidence of a distinct population of mutators among clinical pneumococci.

Role of PCR in the diagnosis of pertussis infection in infants: 5 years' experience of provision of a same-day real-time PCR service in England and Wales from 2002 to 2007.

As part of an enhanced surveillance programme for pertussis in England and Wales, a real-time PCR service for the detection of Bordetella pertussis was introduced for infants aged

Diagnosis of Streptococcus pneumoniae infections in adults with bacteremia and community-acquired pneumonia: clinical comparison of pneumococcal PCR and urinary antigen detection.

The diagnosis of severe Streptococcus pneumoniae infection relies heavily on insensitive culture techniques. To improve the usefulness of PCR assays, we developed a dual-PCR protocol (targeted at pneumolysin and autolysin) for EDTA blood samples. This was compared to the Binax NOW S. pneumoniae urine antigen test in patients with bacteremic pneumococcal infections. Patients with nonbacteremic community-acquired pneumonia also were tested by these methods to determine what proportion could be confirmed as pneumococcal infections. A direct comparison was made in a group of patients who each had both tests performed. The Binax NOW S. pneumoniae urine antigen test was positive in 51 of 58 bacteremic pneumococcal cases (sensitivity, 88%; 95% confidence interval [CI], 77 to 95%), whereas the dual PCR was positive in 31 cases (sensitivity, 53.5%; 95% CI, 40 to 67%; P < 0.0001), and all of these had detectable urinary antigens. Both tests gave positive results in 2 of 51 control patients (referred to as other-organism septicemia), giving a specificity of 96% (95% CI, 86.5 to 99.5%). In 77 patients with nonbacteremic community-acquired pneumonia, urinary antigen was detected significantly more often (in 21 patients [27%]) than a positive result by the dual-PCR protocol (6 [8%]) (P = 0.002). The development of a dual-PCR protocol enhanced the sensitivity compared to that of the individual assays, but it is still significantly less sensitive than the Binax NOW urine antigen test, as well as being more time-consuming and expensive. Urinary antigen detection is the nonculture diagnostic method of choice for patients with possible severe pneumococcal infection.

Non-susceptibility trends among enterococci and non-pneumococcal streptococci from bacteraemias in the UK and Ireland, 2001-06.

OBJECTIVES: To describe the current patterns and trends in antimicrobial susceptibility in enterococci and streptococci (excepting pneumococci) from bacteraemia in the UK and Ireland from 2001 to 2006. METHODS: In each year 2001-06, blood culture isolates were collected by 25 laboratories distributed across the UK and Ireland. In total, there were 1408 isolates of enterococci, 1332 of beta-haemolytic streptococci and 1012 of alpha- and non-haemolytic streptococci. A single central laboratory re-identified the isolates and measured MICs by the BSAC agar dilution method. RESULTS: The prevalence of reduced susceptibility in streptococci and enterococci did not change significantly for most antibiotics, but trends were noted to increased ampicillin, imipenem and vancomycin resistance in Enterococcus faecium. The prevalence of reduced susceptibility to macrolides and tetracycline in streptococci, to tetracycline and gentamicin (high level) in enterococci and to beta-lactams and glycopeptides in E. faecium were all high, with some differences in the prevalence among species or groups. CONCLUSIONS: Reduced susceptibility to some antimicrobial agents among streptococci and enterococci remains common and continued surveillance is warranted.

Non-susceptibility trends and serotype distributions among Streptococcus pneumoniae from community-acquired respiratory tract infections and from bacteraemias in the UK and Ireland, 1999 to 2007.

OBJECTIVES: Pneumococcal disease is prevalent and is a cause of significant morbidity and mortality in the UK and Ireland. We describe the antimicrobial susceptibility and serotype distributions of Streptococcus pneumoniae causing bacteraemia and community-acquired pneumonia in these countries from 1999/2000 to 2006/7, predominantly prior to the introduction of the heptavalent pneumococcal conjugate vaccine (PCV7) into the standard vaccination schedule in September 2006. METHODS: The BSAC Respiratory and Bacteraemia Resistance Surveillance Programmes collected S. pneumoniae from sentinel laboratories distributed across the UK and Ireland. A central laboratory for each programme re-identified the isolates, determined their serotypes and measured MICs by the BSAC agar dilution method. RESULTS: The prevalence of antimicrobial non-susceptibility, although significant, was generally below the global average. There was no convincing evidence of increasing non-susceptibility over time in either study. The results showed clear differences in the serotype distribution between respiratory and blood isolates, but suggested that PCV7 would provide adequate coverage of invasive isolates in the UK and Ireland. A significant and rapid increase of the non-vaccine serotype 1 among blood isolates from 2001 to 2006 was worrying, given the spread of hypervirulent serotype 1 clones elsewhere in the world. CONCLUSIONS: Continued surveillance of both antimicrobial non-susceptibility and serotype distribution changes following the introduction of PCV7 into the routine immunization schedule in the UK and Ireland is imperative. The data presented here, largely obtained prior to the introduction of PCV7 in the UK, provide a valuable baseline against which to monitor changes in antimicrobial non-susceptibility and serotype distribution and hence to identify the expansion of any significant clones.

Morbidity and mortality of pneumococcal meningitis and serotypes of causative strains prior to introduction of the 7-valent conjugant pneumococcal vaccine in England.

OBJECTIVES: To assess the incidence of pneumococcal meningitis, associated deaths and serotypes of causative pneumococci in England prior to the inclusion of the 7-valent conjugated pneumococcal vaccine in the routine childhood immunisation programme in 2006. METHODS: Cases were identified using hospital episode statistics (HES) and voluntary reports or submission of isolates to the Health Protection Agency. Mortality data and population estimates were from the Office for National Statistics. RESULTS: Based on HES, the annual incidence of pneumococcal meningitis was about 1 case per 100,000 population between 1998 and 2005 (an average of approximately 480 cases per year) with case fatality rates increasing from 5% in <15 year olds to 30% in >64 year olds. Enhanced surveillance comprising a combination of voluntary reporting of cases and referral of isolates gave case ascertainment rates of 50-70% compared to those derived from HES, and similar case fatality rates. The age distribution of pneumococcal meningitis was similar with both datasets, infection being reported mostly commonly in children aged less than 5 years, with the highest incidence in children aged 2-11 months. Based on the serotype distribution of isolates obtained in 2005, the serotype coverage afforded by the 7-valent conjugate vaccine is 72% for patients aged less than 2 years. CONCLUSIONS: These data provide baseline information on the incidence of pneumococcal meningitis and associated mortality, together with the serotypes of infecting strains of pneumococci, which will be critical for evaluation of the public health impact of the 7-valent conjugated pneumococcal vaccine in England.

Presence of nonhemolytic pneumolysin in serotypes of Streptococcus pneumoniae associated with disease outbreaks.

Pneumolysin is an important virulence factor of the human pathogen Streptococcus pneumoniae. Sequence analysis of the ply gene from 121 clinical isolates of S. pneumoniae uncovered a number of alleles. Twenty-two strains were chosen for further analysis, and 14 protein alleles were discovered. Five of these had been reported previously, and the remaining 9 were novel. Cell lysates were used to determine the specific hemolytic activities of the pneumolysin proteins. Six strains showed no hemolytic activity, and the remaining 16 were hemolytic, to varying degrees. We report that the nonhemolytic allele reported previously in serotype 1, sequence type (ST) 306 isolates is also present in a number of pneumococcal isolates of serotype 8 that belong to the ST53 lineage. Serotype 1 and 8 pneumococci are known to be associated with outbreaks of invasive disease. The nonhemolytic pneumolysin allele is therefore associated with the dominant clones of outbreak-associated serotypes of S. pneumoniae.

Trends in penicillin and macrolide resistance among pneumococci in the UK and the Republic of Ireland in relation to antibiotic sales to pharmacies and dispensing doctors.

It is widely believed that reducing antimicrobial usage should reduce resistance, although observational evidence is mixed. Pneumococci make ideal subjects to test this belief as they are widely surveyed and lack an animal reservoir. Accordingly, susceptibility data for pneumococci in the UK and Ireland were retrieved from the Health Protection Agency's LabBase/CoSurv system and from the European Antimicrobial Resistance Surveillance System (EARSS) and British Society for Antimicrobial Chemotherapy (BSAC) databases. The BSAC surveillance examines respiratory pneumococci; the other systems focus upon invasive organisms only, with the LabBase/CoSurv system being the most comprehensive, capturing data on most bacteraemias in England and Wales. National pharmacy sales data were obtained from the IMS Health MIDAS database and were modelled to the resistance data by logistic and linear regression analysis. All systems except for the BSAC respiratory surveillance data indicated that penicillin resistance has fallen significantly since 1999 in the UK, whereas macrolide resistance has been essentially stable, or has risen slightly. The data for Ireland were based on smaller sample sizes but suggested a fall in penicillin non-susceptibility from 1999 to 2004, with conflicting evidence for macrolide resistance. The recent decreasing trend in penicillin resistance is in contrast to a rising trend in England and Wales until (at least) 1997 and strongly rising macrolide resistance from 1989 to 1993. UK pharmacy sales of macrolides and oral beta-lactams fell by ca. 30% in the late 1990s following increased concern about resistance, before stabilising or rising weakly; sales in Ireland were stable or rose slightly in the study period. We conclude that falling penicillin resistance in pneumococci followed reduced sales of oral beta-lactams to pharmacies in the UK, but a similar fall in macrolide sales was not associated with any fall in resistance. Stabilisation or decline in penicillin resistance has occurred in Ireland despite stable or increasing oral beta-lactam sales.

Detection of anti-pertussis toxin IgG in oral fluids for use in diagnosis and surveillance of Bordetella pertussis infection in children and young adults.

Bordetella pertussis infection is being increasingly recognized as a cause of prolonged, distressing cough (without whooping symptoms) in children and young adults. Diagnosis of infection in this population is important for treatment and surveillance purposes, and may also prove useful in reducing transmission to unvaccinated babies, for whom disease can be fatal. Serum IgG titres against pertussis toxin (PT) are routinely used as a marker of recent or persisting B. pertussis infection. However, collection of serum from young children is difficult, and compliance amongst these subjects to give samples is low. To circumvent these problems, an IgG-capture ELISA capable of detecting anti-PT IgG in oral fluid was devised. The assay was evaluated by comparison to a serum ELISA, using 187 matched serum and oral fluid samples from children (aged 5-16 years) with a history of prolonged coughing, whose serum anti-PT titre had already been determined (69 seropositive, 118 seronegative). The results showed that, using a cutoff of 70 arbitrary units (AU), the oral fluid assay detected seropositive subjects with a sensitivity of 79.7% [95% confidence interval (CI) 68.3-88.4] and a specificity of 96.6% (95% CI 91.5-99.1). Thus, oral fluid titres of >or=70 AU would possess a positive predictive value of 76.2-93.2% for pertussis amongst children with chronic coughs when used as a surrogate for the serum ELISA (assuming disease prevalence of 12-37%). This oral fluid ELISA will greatly assist in the convenience of B. pertussis disease diagnosis and surveillance.