Turning the tide or riding the waves? Impacts of antibiotic stewardship and infection control on MRSA strain dynamics in a Scottish region over 16 years: non-linear time series analysis.

OBJECTIVES: To explore temporal associations between planned antibiotic stewardship and infection control interventions and the molecular epidemiology of methicillin-resistant Staphylococcus aureus (MRSA). DESIGN: Retrospective ecological study and time-series analysis integrating typing data from the Scottish MRSA reference laboratory. SETTING: Regional hospital and primary care in a Scottish Health Board. PARTICIPANTS: General adult (N=1,051,993) or intensive care (18,235) admissions and primary care registrations (460,000 inhabitants) between January 1997 and December 2012. INTERVENTIONS: Hand-hygiene campaign; MRSA admission screening; antibiotic stewardship limiting use of macrolides and '4Cs' (cephalosporins, coamoxiclav, clindamycin and fluoroquinolones). OUTCOME MEASURES: Prevalence density of MRSA clonal complexes CC22, CC30 and CC5/Other in hospital (isolates/1000 occupied bed days, OBDs) and community (isolates/10,000 inhabitant-days). RESULTS: 67% of all clinical MRSA isolates (10,707/15,947) were typed. Regional MRSA population structure was dominated by hospital epidemic strains CC30, CC22 and CC45. Following declines in overall MRSA prevalence density, CC5 and other strains of community origin became increasingly important. Reductions in use of '4Cs' and macrolides anticipated declines in sublineages with higher levels of associated resistances. In multivariate time-series models (R(2)=0.63-0.94) introduction of the hand-hygiene campaign, reductions in mean length of stay (when >4 days) and bed occupancy (when >74 to 78%) predicted declines in CC22 and CC30, but not CC5/other strains. Lower importation pressures, expanded MRSA admission screening, and reductions in macrolide and third generation cephalosporin use (thresholds for association: 135-141, and 48-81 defined daily doses/1000 OBDs, respectively) were followed by declines in all clonal complexes. Strain-specific associations with fluoroquinolones and clindamycin reflected resistance phenotypes of clonal complexes. CONCLUSIONS: Infection control measures and changes in population antibiotic use were important predictors of MRSA strain dynamics in our region. Strategies to control MRSA should consider thresholds for effects and strain-specific impacts.

Trends in serotypes and sequence types among cases of invasive pneumococcal disease in Scotland, 1999-2010.

INTRODUCTION: The 7-valent pneumococcal conjugate vaccine (Prevenar(®), Wyeth; PCV7) was introduced to the UK paediatric immunisation schedule in 2006. This study investigates trends in serotypes and multi locus sequence types (STs) among cases of invasive pneumococcal disease (IPD) in Scotland prior to, and following, the introduction of PCV7. METHODS: Scottish Invasive Pneumococcal Disease Enhanced Surveillance has records of all cases of IPD in Scotland since 1999. Cases diagnosed from blood or cerebrospinal fluid isolates until 2010 were analysed. Logistic and poisson regression modelling was used to assess trends prior to and following the introduction of PCV7. RESULTS: Prior to PCV7 use, on average 650 cases of IPD were reported each year; 12% occurred in those aged <5 years and 35% affected those aged over 65 years. Serotypes in PCV7 represented 47% of cases (68% in <5 year olds). The serotype and ST distribution was relatively stable with only serotype 1 and associated ST 306 showing an increasing trend. PCV7 introduction was associated with a 69% (95% CI: 50%, 80%) reduction in the incidence of IPD among those aged <5 years, a 57% (95% CI: 47%, 66%) reduction among those aged 5-64 years but no significant change among those aged 65 years and over where increases in non-PCV7 serotypes were observed. Serotypes which became more prevalent post-PCV7 are those which were associated with STs related to the PCV7 serotypes. CONCLUSIONS: Routine serotyping and sequence typing in Scotland allowed the assessment of the relationship between the capsule and the clones in the post vaccination era. Changes in the distribution of serotypes post PCV7 introduction appear to be driven by associations between serotypes and STs prior to PCV7 introduction. This has implications for the possible effects of the introduction of higher valency vaccines and could aid in predicting replacement serotypes in IPD.

Death or survival from invasive pneumococcal disease in Scotland: associations with serogroups and multilocus sequence types.

We describe associations between death from invasive pneumococcal disease (IPD) and particular serogroups and sequence types (STs) determined by multilocus sequence typing (MLST) using data from Scotland. All IPD episodes where blood or cerebrospinal fluid (CSF) culture isolates were referred to the Scottish Haemophilus, Legionella, Meningococcal and Pneumococcal Reference Laboratory (SHLMPRL) from January 1992 to February 2007 were matched to death certification records by the General Register Office for Scotland. This represented 5959 patients. The median number of IPD cases in Scotland each year was 292. Deaths, from any cause, within 30 days of pneumococcal culture from blood or CSF were considered to have IPD as a contributing factor. Eight hundred and thirty-three patients died within 30 days of culture of Streptococcus pneumoniae from blood or CSF [13.95 %; 95 % confidence interval (13.10, 14.80)]. The highest death rates were in patients over the age of 75. Serotyping data exist for all years but MLST data were only available from 2001 onward. The risk ratio of dying from infection due to particular serogroups or STs compared to dying from IPD due to all other serogroups or STs was calculated. Fisher's exact test with Bonferroni adjustment for multiple testing was used. Age adjustment was accomplished using the Cochran-Mantel-Haenszel test and 95 % confidence intervals were reported. Serogroups 3, 11 and 16 have increased probability of causing fatal IPD in Scotland while serogroup 1 IPD has a reduced probability of causing death. None of the 20 most common STs were significantly associated with death within 30 days of pneumococcal culture, after age adjustment. We conclude that there is a stronger association between a fatal outcome and pneumococcal capsular serogroup than there is between a fatal outcome and ST.

Pneumococci causing invasive disease in children prior to the introduction of pneumococcal conjugate vaccine in Scotland.

This study aimed to determine the serotypes and sequence types (STs) of pneumococci causing paediatric invasive disease in Scotland prior to the introduction of pneumococcal conjugate vaccines (PCVs). All invasive pneumococci isolated between 2000 and 2004 from children aged less than 5 years in Scotland were used. The isolates were characterized by serotyping and multi-locus sequence typing. Two hundred and seventeen pneumococci were characterized into 22 different serogroups/types, the most common, in rank order, being 14, 19F, 6B, 18C, 23F, 9V, 4, 1, 19A and 6A. They were further genotyped into 77 different STs, the three most common being 9, 162 and 176. Common serotypes possessed multiple STs, but pneumococci of a particular clone were mostly associated with a particular serotype. The seven most common serotypes are included in the 7-valent polysaccharide conjugate vaccine (PCV7). Serotype coverage for PCV7 was 76.5% in those aged less than 5 years but increased to 88.9% for those aged 1 year. The introduction of PCV7 into the childhood immunization schedule would reduce the burden of pneumococcal disease in children, although continued surveillance of invasive pneumococcal disease will be required before, during and after the introduction of PCVs.

Potential impact of conjugate vaccine on the incidence of invasive pneumococcal disease among children in Scotland.

We sought to determine the potential impact of seven-valent pneumococcal conjugate vaccine on the incidence of invasive pneumococcal disease (IPD) among children in Scotland. Invasive pneumococci from blood and cerebrospinal fluid, isolated between 2000 and 2004 from all children aged less than 5 years in Scotland, were characterized by serotyping. Using reported efficacy data of the seven-valent pneumococcal conjugate vaccine (PCV7) along with likely coverage rates, we made an estimation of the potential impact on the incidence of IPD among children in Scotland. A total of 217 pneumococci were characterized into 22 different serogroups/types, the most common, in rank order, being 14, 19F, 6B, 18C, 23F, 9V, 4, 1, 19A, and 6A. Estimated serotype coverage for PCV7 was 76.5% in those aged less than 5 years of age but increased to 88.9% for those aged 1 year. By using serotype coverage and estimates of vaccine efficacy and uptake, the potential impact of the vaccine for those greater than 2 months of age, but less than 5 years, was estimated as 67.3%, leading to an average of 29 preventable cases per year. The introduction of PCV7 into the childhood immunization schedule would reduce the burden of pneumococcal disease in children, and the incidence would be particularly reduced in those children aged 1 year. Additional benefits may be gained in adults through herd protection. Continued surveillance of IPD is required before, during, and after the introduction of PCV7.

Laboratory diagnosis of legionnaires' disease due to Legionella pneumophila serogroup 1: comparison of phenotypic and genotypic methods.

Laboratory results of 67 cases of legionnaires' disease caused by Legionella pneumophila serogroup (Sg) 1 spanning a 6-year period were analysed by both phenotypic and genotypic methods. The methods compared were urinary antigen enzyme immunoassay (EIA), an immunofluorescent antibody (IFA) test, direct fluorescent antibody (DFA), culture and a 5S rRNA PCR with Southern blotting confirmation. Urine was available in 53 cases, of which 35 (66%) were positive, with an antigen peak observed at 5-10 days after onset of disease symptoms. The IFA test was positive in 62 (92.5%) cases, with 56 (90.3%) cases producing a greater than fourfold rise in titre and 6 (9.7%) giving presumptive high titres of > or =1:128. There were two antibody peaks, one at 10-15 days and another at >25 days after onset. In 23 cases where samples were available, DFA and culture were respectively positive in 5 (22%) and 10 (48%) cases. There was a peak in culture-positives 5-10 days after onset of disease. A Legionella-specific 5S rRNA PCR on patient serum was positive in 54 (80.5%) cases, with a peak in PCR positivity at 6-10 days after disease onset. In 22 of the 67 cases, the full panel of diagnostic methods was available for comparison. The relative sensitivity and specificity of the urinary antigen EIA and the serum PCR was 100%. The IFA gave relative sensitivity and specificity values of 93.8 and 95%. DFA and culture, although 100% specific, produced only low sensitivities, of 19 and 42.8%, respectively. This study has shown that urinary antigen and serum PCR are valuable tests in the acute phase of disease, with excellent sensitivity and specificity values. At present, the Legionella species causing infection requires to be verified by IFA serology and/or culture, but this could become unnecessary as new antigen and L. pneumophila Sg 1-specific PCR tests become available.