Trends in incidence of pneumococcal disease before introduction of conjugate vaccine: South West England, 1996-2005.

Introduction of pneumococcal conjugate and polysaccharide vaccines into the United Kingdom's routine immunization programmes is expected to change the epidemiology of invasive pneumococcal disease (IPD). We have documented the epidemiology of IPD in an English region (South West) with high-quality surveillance data before these programmes were established. We analysed data on isolates of Streptococcus pneumoniae from blood and CSF between 1996 and 2005 from microbiology laboratories in the South West that were reported and/or referred for serotyping to the Health Protection Agency Centre for Infections. The mean annual incidence of IPD increased from 11.2/100 000 in 1996 to 13.6/100 000 in 2005 (P<0.04). After adjusting for annual blood-culture sampling rates in hospitals serving the same catchment populations, an increase in annual incidence of IPD was no longer observed (P=1.0). Variation in overall incidence between laboratories could also be explained by variation in blood culture rates. The proportion of disease caused by serotypes 6B, 9V and 14 decreased significantly (P=0.001, P=0.007, and P=0.027 respectively) whereas that caused by serotype 4, 7F and 1 increased (P=0.001, P=0.003, and P<0.001 respectively) between 2000 and 2005. The level of penicillin non-susceptibility and resistance to erythromycin remained stable (2% and 12% respectively). This study provides an important baseline to assess the impact of changing vaccination programmes on the epidemiology of IPD, thus informing future use of pneumococcal vaccines.

Changing epidemiology of bacterial meningitis among adults in England and Wales 1991-2002.

We examined the epidemiology of community-acquired bacterial meningitis among adults in England and Wales between 1991 and 2002. Among 3169 cases, meningococcal infection was predominant among young adults and pneumococcal meningitis among older adults. Whilst infection due to most causes decreased, the incidence of tuberculous (TB) meningitis doubled over the 12 years. The mortality rate among meningococcal and pneumococcal infections fell from 0.45/10(5) to 0.31/10(5) (P=0.0001). This study demonstrates important changes in the epidemiology of bacterial meningitis among UK adults. Improvements in clinical management, childhood vaccination programmes and the re-emergence of tuberculosis are likely to be drivers of these changes.

Diagnosis of invasive pneumococcal infection by PCR amplification of Streptococcus pneumoniae genomic fragments in blood: a multi-centre comparative study.

The increasing interest in the prevention of pneumococcal disease by immunisation necessitates improved organism-specific surveillance. This is particularly the case with regard to the contribution of Streptococcus pneumoniae infection to community-acquired pneumonia where blood cultures are often negative and sputum culture results ambiguous. Examination by PCR of blood samples taken at hospital admission offers one possibility for such improvement. The sensitivity, specificity and convenience of three pneumolysin gene PCR assays were compared in a large study, using EDTA blood from 175 patients (95 with proven pneumococcal bacteraemia, 80 with bacteraemia due to other organisms). The assays used were a PCR-enzyme immunoassay, a hybridisation probe assay run on the Roche LightCycler and a hydrolysis probe (TaqMan) assay run on an ABI 7700. Overall samples from only 57% of patients with bacteraemic pneumococcal infection yielded a positive result in at least one assay. Individual sensitivities ranged from 45% (TaqMan/ABI) through 35% (PCR-EIA) to 21% (Hybridisation/LightCycler). Specificity (PCR negative in the 80 control patients) ranged from 97-100%. The TaqMan/ABI assay was run in two centres and concordance between results was 91.4%, discrepancies being associated with very weakly positive samples. Overall, the TaqMan/ABI was the most sensitive and convenient assay; however, this method does not appear to offer any significant improvement over conventional blood cultures and is unlikely to be sufficiently sensitive to confirm a pneumococcal aetiology for non-bacteraemic pneumococcal pneumonia. For the present, therefore, blood culture is the preferred option.

Primary care workshops can reduce and rationalize antibiotic prescribing.

We describe a controlled study comparing the effects on primary care prescribing in west Gloucestershire, UK, where antibiotic workshops were offered, with those in east Gloucestershire, where microbiology tutorials were given. The year-on-year changes in quantity and costs of antibiotics dispensed following general practice prescriptions were measured. There was no significant difference in the number of antibiotic items prescribed across the county, but the number of prescriptions for broad-spectrum agents (quinolones, cephalosporins and co-amoxiclav) declined by 15.4% in west Gloucestershire, compared with a 6.5% increase in east Gloucestershire (P: = 0.002). Use of narrow-spectrum antibiotics (penicillin V, trimethoprim and nitrofurantoin), whose use was encouraged, did not change in west Gloucestershire practices, but decreased by 12% in east Gloucestershire practices (P: = 0.003). There was increased use of clarithromycin and azithromycin in both groups of practices. Antibiotic workshops held in the primary care setting can rationalize antibiotic prescribing. This can reduce prescribing costs and selection pressure by broad-spectrum antimicrobial agents and, perhaps, go some way to reducing the development of resistance.

Induction of immunological memory in UK infants by a meningococcal A/C conjugate vaccine.

The induction of immunological memory to serogroup A and C polysaccharides in UK infants immunized with three doses of a meningococcal A/C oligosaccharide CRM197 conjugate vaccine was investigated. Forty UK infants vaccinated previously with three doses of a meningococcal A/C oligosaccharide-CRM197 conjugate vaccine at 2, 3 and 4 months of age, were revaccinated at a mean age of 145.6 weeks with either a 10 or 50 microg dose of licensed meningococcal A/C polysaccharide vaccine. Serogroup-specific antibody and serum bactericidal antibody (SBA) responses were measured by enzyme-linked immunosorbent assay and serum bactericidal assays, respectively. Following challenge, anti-serogroup A and C polysaccharide antibody levels rose from pre-booster geometric mean concentrations (GMC) of 3.1 and 2.1 microg/ml respectively to 19.6 and 21.0 microg/ml 1 month post-booster. Serum bactericidal antibody geometric mean titres (GMTs) for serogroups A and C increased 156- and 113-fold from 2.1 and 7.1 pre-booster respectively to 327.4 and 800.7 post-booster. A serogroup A control group of 45 children received a 10 microg dose of licensed meningococcal A/C polysaccharide vaccine (with no prior history of serogroup A vaccination) had serogroup A SBA GMTs of 2.3 pre-vaccination rising to 8 post-vaccination with corresponding GMCs of 0.8 and 10.8 microg/ml. These rises in SBA following serogroup A/C conjugate vaccination are indicative of immunological priming.

Effect of sequence variation in meningococcal PorA outer membrane protein on the effectiveness of a hexavalent PorA outer membrane vesicle vaccine.

Though meningococcal serogroup C conjugate vaccines have been introduced into the UK infant immunisation schedule, there is currently no vaccine solution for serogroup B disease. PorA outer membrane protein (OMP) is a potential serogroup B vaccine candidate. A hexavalent PorA outer membrane vesicle (OMV) vaccine has been evaluated in phase I and II trials with promising results. This vaccine contains six different PorA OMPs each representing a different serosubtype. However, considerable sequence variation occurs in the variable regions (VRs) encoding these serosubtypes. By using recombinant P1.5,10 PorA variants we have demonstrated that the killing of this particular serosubtype combination was due mainly to the induction of antibody to the VR2 (P1.10) epitope region, and that after three or four doses of vaccine there was a significant reduction in the killing of variants P1.10a (three doses, p<0.0001; four doses, p = 0.003) and P1.10f (three doses, p<0.0001; four doses, p = 0.002), as compared to responses to the P1.10 strain, when the P1.10 serosubtype was used as the immunogen. Since large numbers of serosubtype variants are known to exist, this finding may have implications for the use of PorA as a meningococcal serogroup B vaccine.

Early management of meningococcal disease.

Meningococcal disease is increasing in incidence in many countries, and effective vaccines for serogroup B strains will not be available for at least 5 to 10 years. In the interim, it is attention to principles of good clinical practice, particularly in the early management of the disease, that have the potential to reduce by half the current case fatality rate of approximately 10%. As discussed in this article, those principles include increased awareness, understanding of the disease and its early symptoms by parents and healthcare professionals, and careful attention to the patient before admission and during the hospital stay.

Dynamics of carriage of Neisseria meningitidis in a group of military recruits: subtype stability and specificity of the immune response following colonization.

Meningococcal carriage and the immune response to colonization were studied in a group of military recruits undergoing basic training. Subtyping by determination of the class 1 protein sequence clearly differentiated between strains and demonstrated the dynamics of carriage and transmission. Expression of class 1 protein by each strain remained stable during prolonged carriage by different subjects. Following colonization, a marked increase in serum bactericidal response occurred, which was specific for the subtype of the acquired strain and was associated with an increase in reactivity by Western blot to the homologous class 1 protein. Subjects colonized by multiple strains showed evidence of a specific immune response to the class 1 protein of each strain acquired. The subtype specificity of the bactericidal response to meningococci and the stability of expression of the class 1 protein have important implications for the design of vaccines for prevention of serogroup B meningococcal disease.

Invasive pneumococcal infection in South and West England.

Variation in the incidence of invasive pneumococcal disease across South and West England, in 1995, was measured through a survey of microbiology laboratories. A 100% response rate was achieved. The incidence by laboratory varied between 5.2 and 20.4 per 100,000 catchment population (P < 0.001). Adjusting for pneumococcal vaccine uptake rate in over 65 year olds, hospital admission rates, blood culture system used and for the age and sex structure of the population, did not account for this variation. When blood culture sampling rates were included in a logistic regression model, the variation between laboratories was much less and of lower statistical significance (P = 0.019). Higher rates of blood culture sampling were associated with a higher incidence of invasive pneumococcal disease. Consistently high sampling should be encouraged because a higher diagnostic rate should result in more selective prescribing of antibiotics, and secondly because improved ascertainment of severe pneumococcal infections is a prerequisite for the evaluation of new pneumococcal conjugate vaccines.

Management of clusters of meningococcal disease. PHIS Meningococcus Working Group and Public Health Medicine Environmental Group.

Guidance on the management of clustered cases of meningococcal disease has been revised following a review of the clusters that occurred in England and Wales between 1 April 1995 and 31 March 1996. Public health action is indicated for confirmed and probable cases but not in response to possible cases. The importance of microbiological confirmation is re-emphasised. Intervention is recommended for defined target groups when two or more confirmed or probable cases occur in a preschool group or school within a four week period. We present a framework to assist in the management of clusters of invasive serogroup C infections in larger and less defined communities.

Successful control of Clostridium difficile infection in an elderly care unit through use of a restrictive antibiotic policy.

Toxin-producing Clostridium difficile is the commonest bacterial cause of nosocomial diarrhoea and is a well recognized cause of hospital outbreaks in elderly care units. High C. difficile disease rates have been associated with the use of broad-spectrum antibiotics, especially cephalosporins. An outbreak of C. difficile infection in the elderly care unit at Gloucestershire Royal NHS Trust continued despite increased ward cleaning and strict implementation of infection control measures. A restrictive antibiotic policy that would maintain colonization resistance in the gastrointestinal tract was introduced throughout this unit. Patients admitted with suspected infection were prescribed intravenous (i.v.) benzylpenicillin 1.2-1.8 g every 6 h to cover streptococcal infections and i.v. trimethoprim 200 mg twice daily to cover urinary tract pathogens and Haemophilus influenzae. If the patient had septic shock a single iv dose of gentamicin was given (120-180 mg) to cover more resistant gram-negative bacilli. The following were monitored before and after the policy change. The number of cases of C. difficile toxin-positive diarrhoea; cefuroxime and total antibiotic use on the elderly care wards; patient mortality rates; and length of hospital stay: two hundred and fifty-two and 234 patients respectively with a discharge diagnosis of infection were admitted before and after the antibiotic policy change. Mortality rates and length of hospital stay were unchanged. Cefuroxime prescribing and total antibiotic prescribing costs fell by 5150 pounds sterling and 8622 pounds sterling respectively in the 7 month period after the change. Thirty-seven cases of C. difficile diarrhoea occurred in the period before and 16 in the period after the policy change. The incidence of C. difficile diarrhoea and of cefuroxime use has remained low since then. The use of narrow-spectrum antibiotics for hospital treatment of community-acquired infections in the elderly should be encouraged. Outbreaks of C. difficile diarrhoea should be managed with the combined approach of infection control and strict antibiotic policies.

Hepatitis B markers in Gloucestershire firemen.

Occupational exposure to blood and body fluids and the prevalence of serological markers of hepatitis B virus (HBV) infection were studied in Gloucestershire firemen to assess the occupational risk of HBV infection. A high compliance was achieved (472/503, 94 per cent). Cumulative occupational exposure to blood or body fluids rose progressively to 68 per cent after 24 years' service. No sera were positive for hepatitis B surface antigen (HBsAg). Six sera were positive for hepatitis B surface antibody (anti-HBs) and were tested for hepatitis B core antibody (anti-HBc). The four subjects who were positive for anti-HBs alone had all received HBV vaccine. Two sera contained both anti-HBs and anti-HBc. Therefore, 2/472 firemen (0.42 per cent) showed evidence of previous HBV infection, a similar proportion to that found in a recent study in UK blood donors (0.49 per cent). Despite considerable exposure to blood and body fluids, an occupational risk of hepatitis B infection was not found in Gloucestershire firemen.