Effect of a national 4C antibiotic stewardship intervention on the clinical and molecular epidemiology of Clostridium difficile infections in a region of Scotland: a non-linear time-series analysis.

BACKGROUND: Whereas many antibiotics increase risk of Clostridium difficile infection through dysbiosis, epidemic C difficile ribotypes characterised by multidrug resistance might depend on antibiotic selection pressures arising from population use of specific drugs. We examined the effect of a national antibiotic stewardship intervention limiting the use of 4C antibiotics (fluoroquinolones, clindamycin, co-amoxiclav, and cephalosporins) and other infection prevention and control strategies on the clinical and molecular epidemiology of C difficile infections in northeast Scotland. METHODS: We did a non-linear time-series analysis and quasi-experimental study to explore ecological determinants of clinical burdens from C difficile infections and ribotype distributions in a health board serving 11% of the Scottish population. Study populations were adults (aged ≥16 years) registered with primary carer providers in the community (mean 455 508 inhabitants) or admitted to tertiary level, district general, or geriatric hospitals (mean 33 049 total admissions per month). A mixed persuasive-restrictive 4C antibiotic stewardship intervention was initiated in all populations on May 1, 2009. Other population-specific interventions considered included limiting indications for macrolide prescriptions, introduction of alcohol-based hand sanitiser, a national hand-hygiene campaign, national auditing and inspections of hospital environment cleanliness, and reminders to reduce inappropriate use of proton-pump inhibitors. The total effect of interventions was defined as the difference between observations and projected scenarios without intervention. Primary outcomes were prevalence density of C difficile infection per 1000 occupied bed-days in hospitals or per 100 000 inhabitant-days in the community. FINDINGS: Between Jan 1, 1997, and Dec 31, 2012, we identified 4885 cases of hospital-onset C difficile infection among 1 289 929 admissions to study hospitals, and a further 1625 cases of community-onset C difficile infection among 455 508 adults registered in primary care. Use of 4C antibiotics was reduced by 50% in both hospitals (mean reduction 193 defined daily doses per 1000 occupied bed-days, 95% CI 45-328, p=0·008) and the community (1·85 defined daily doses per 1000 inhabitant-days, 95% CI 0·23-3·48, p=0·025) during antibiotic stewardship. Falling 4C use predicted rapid declines in multidrug-resistant ribotypes R001 and R027. Hospital-onset C difficile infection prevalence densities were associated with fluoroquinolone, third-generation cephalosporin, macrolides, and carbapenem use, exceeding hospital population specific total use thresholds. Community-onset C difficile infection prevalence density was predicted by recent hospital C difficile infection rates, introduction of mandatory surveillance in individuals older than 65 years, and primary-case use of fluoroquinolones and clindamycin exceeding total use thresholds. Compared with predictions without intervention, C difficile infection prevalence density fell by 68% (mean reduction 1·01 per 1000 occupied bed-days, 0·27-1·76, p=0·008) in hospitals and 45% (0·083, 0·045-0·121 cases per 100 000 inhabitant-days, p<0·0001) in the community, during antibiotic stewardship. We identified no significant effects from other interventions. INTERPRETATION: Limiting population use of 4C antibiotics reduced selective pressures favouring multidrug-resistant epidemic ribotypes and was associated with substantial declines in total C difficile infections in northeast Scotland. Efforts to control C difficile through antibiotic stewardship should account for ribotype distributions and non-linear effects. FUNDING: NHS Grampian Microbiology Endowment Fund.

Effects of national antibiotic stewardship and infection control strategies on hospital-associated and community-associated meticillin-resistant Staphylococcus aureus infections across a region of Scotland: a non-linear time-series study.

BACKGROUND: Restriction of antibiotic consumption to below predefined total use thresholds might remove the selection pressure that maintains antimicrobial resistance within populations. We assessed the effect of national antibiotic stewardship and infection prevention and control programmes on prevalence density of meticillin-resistant Staphylococcus aureus (MRSA) infections across a region of Scotland. METHODS: This non-linear time-series analysis and quasi-experimental study explored ecological determinants of MRSA epidemiology among 1,289,929 hospital admissions and 455,508 adults registered in primary care in northeast Scotland. Interventions included antibiotic stewardship to restrict use of so-called 4C (cephalosporins, co-amoxiclav, clindamycin, and fluoroquinolones) and macrolide antibiotics; a hand hygiene campaign; hospital environment inspections; and MRSA admission screening. Total effects were defined as the difference between scenarios with intervention (observed) and without intervention (predicted from time-series models). The primary outcomes were prevalence density of MRSA infections per 1000 occupied bed days (OBDs) in hospitals or per 10,000 inhabitants per day (IDs) in the community. FINDINGS: During antibiotic stewardship, use of 4C and macrolide antibiotics fell by 47% (mean decrease 224 defined daily doses [DDDs] per 1000 OBDs, 95% CI 154-305, p=0·008) in hospitals and 27% (mean decrease 2·52 DDDs per 1000 IDs, 0·65-4·55, p=0·031) in the community. Hospital prevalence densities of MRSA were inversely related to intensified infection prevention and control, but positively associated with MRSA rates in neighbouring hospitals, importation pressures, bed occupancy, and use of fluoroquinolones, co-amoxiclav, and third-generation cephalosporins, or macrolide antibiotics that exceeded hospital-specific thresholds. Community prevalence density was predicted by hospital MRSA rates and above-threshold use of macrolides, fluoroquinolones, and clindamycin. MRSA prevalence density decreased during antibiotic stewardship by 54% (mean reduction 0·60 per 1000 OBDs, 0·01-1·18, p=0·049) in hospital and 37% (mean reduction 0·017 per 10,000 IDs, 0·004-0·029, p=0·012) in the community. Combined with infection prevention and control measures, MRSA prevalence density was reduced by 50% (absolute difference 0·94 cases per 1000 OBDs, 0·27-1·62, p=0·006) in hospitals and 47% (absolute difference 0·033 cases per 10,000 IDs, 0·018-0·048, p<0·0001) in the community. INTERPRETATION: Alongside infection control measures, removal of key antibiotic selection pressures during a national antibiotic stewardship intervention predicted large and sustained reductions in hospital-associated and community-associated MRSA. FUNDING: NHS Grampian Research & Development Fund.

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.