Balancing access to antibiotics with control of antibiotic resistance is a global public health priority. Currently, antibiotic stewardship is informed by a 'use it and lose it' principle, in which population antibiotic use is linearly related to resistance rates. However, theoretical and mathematical models suggest use-resistance relationships are non-linear. One explanation is that resistance genes are commonly associated with 'fitness costs', impairing pathogen replication or transmissibility. Therefore, resistant genes and pathogens may only gain a survival advantage where antibiotic selection pressures exceed critical thresholds. These thresholds may provide quantitative targets for stewardship: optimising control of resistance while avoiding over-restriction of antibiotics. We evaluated the generalisability of a nonlinear time-series analysis approach for identifying thresholds using historical prescribing and microbiological data from five populations in Europe. We identified minimum thresholds in temporal relationships between use of selected antibiotics and rates of carbapenem-resistant Acinetobacter baumannii (in Hungary), extended spectrum β-lactamase producing Escherichia coli (Spain), cefepime-resistant Escherichia coli (Spain), gentamicin-resistant Pseudomonas aeruginosa (France), and methicillin-resistant Staphylococcus aureus (Northern Ireland) in different epidemiological phases. Using routinely generated data, our approach can identify context-specific quantitative targets for rationalising population antibiotic use and controlling resistance. Prospective intervention studies restricting antibiotic consumption are needed to validate Results Identifying non-linear temporal relationships: from experiment to applicationIn a Monte Carlo experiment we compared the ability of linear and non-linear time-series analysis (Multivariate Adaptive Regression Splines, MARS) to identify pre-defined relationships between simulated explanatory and outcome time-series (Supplementary Figure 1). Non-linear time-series analysis (NL-TSA) accurately identified both truly linear and nonlinear associations. However, linear time-series analysis provided biased estimations and overall poorer data-fit if relationships were non-linear. NL-TSA models applied to retrospective time-series data from five European study populations (examples 1-5), frequently identified minimum thresholds in antibiotic useresistance relationships, (figures 1-5 and Supplementary Table 1). 'Ceiling effects', in which further increases in explanatory variables did not affect resistance rates, were found at highlevels of use of some antibiotics and hand hygiene. Non-linearities in autoregression and population interaction terms further indicated the complexity of transmission dynamics within and between clinical populations. Example 1: Carbapenem-resistant Acinetobacter baumannii (Debrecen, Hungary) We examined ecological determinants of carbapenem-resistant A. baumannii (CRAb) in a tertiary hospital population in Debrecen, Hungary (figure 1). Betwee...

This quasi-experimental study investigated the effect of an antibiotic cycling policy based on time-series analysis of epidemiologic data, which identified antimicrobial drugs and time periods for restriction. Cyclical restrictions of amoxicillin/clavulanic acid, piperacillin/tazobactam, and clarithromycin were undertaken over a 2-year period in the intervention hospital. We used segmented regression analysis to compare the effect on the incidence of healthcare-associated Clostridioides difficile infection (HA-CDI), healthcare-associated methicillin-resistant Staphylococcus aureus (HA-MRSA), and new extended-spectrum β-lactamase (ESBL) isolates and on changes in resistance patterns of the HA-MRSA and ESBL organisms between the intervention and control hospitals. HA-CDI incidence did not change. HA-MRSA incidence increased significantly in the intervention hospital. The resistance of new ESBL isolates to amoxicillin/clavulanic acid and piperacillin/tazobactam decreased significantly in the intervention hospital; however, resistance to piperacillin/tazobactam increased after a return to the standard policy. The results question the value of antibiotic cycling to antibiotic stewardship.

BackgroundTo assess antimicrobial prescribing in a Northern Ireland hospital (Antrim Area Hospital (AAH)) and compare them with those of a hospital in Jordan (Specialty Hospital).MethodsUsing the Global-PPS approach, the present study surveyed patients admitted to the hospital in 2015, the prescribed antibiotics, and a set of quality control indicators related to antibiotics.ResultsUltimately, 444 and 112 inpatients in the AAH and the Specialty Hospital, respectively, were surveyed. For the medical group, 165 inpatients were prescribed 239 antibiotics in the AAH, while 44 patients in the Specialty Hospital were prescribed 65 antibiotics. In relation to the surgical group, 34 inpatients treated for infection were prescribed 66 antibiotics in the AAH, while 41 patients in the Specialty Hospital treated for infection were prescribed 56 antibiotics. For the medical patients, the most frequently prescribed antibiotics in the AAH were a combination of penicillins (18.8%) and penicillins with extended spectrum (18.8%). For the surgical patients, the most frequently prescribed antibiotics in the AAH were imidazole derivatives (24.2%). For the medical and surgical patients in the Specialty Hospital, the most frequently prescribed antibiotics were third-generation cephalosporins (26.2 and 37.5%, respectively). In medical patients, compliance to guidelines was 92.2% in the Specialty Hospital compared to 72.0% in the AAH (p < 0.001). In surgical patients, compliance to guidelines was 92.7% in the Specialty Hospital compared to 81.8% in the AAH (p = 0.012).ConclusionsThe present study highlighted differences in the utilisation of antimicrobials between two hospitals in two distinct regions and benchmarked antibiotic prescriptions across two hospitals.

Antimicrobial resistance is a limiting factor for the success of the treatment of infectious diseases and is associated with increased morbidity and cost. The present study aims to evaluate prescribing patterns of antimicrobials and quantify progress in relation to targets for quality improvement in the prescription of antimicrobials in Northern Ireland's secondary care sector using three repetitive point prevalence surveys (PPS) over a 6-year period: the European Surveillance of Antimicrobial Consumption (ESAC-PPS) in 2009 and 2011 and the Global-PPS on Antimicrobial Consumption and Resistance in 2015. Out of 3605 patients surveyed over the three time points, 1239 (34.4%) were treated with an antibiotic, the most frequently prescribed antibiotic groups were a combination of penicillins, including β-lactamase inhibitors. Compliance with hospital antibiotic policies in 2009, 2011 and 2015 were 54.5%, 71.5% and 79.9%, respectively. Likewise, an indication for treatment was recorded in patient notes 88.5%, 87.7% and 90.6% in 2009, 2011 and 2015, respectively, and surgical prophylactic antibiotic prescriptions for >24 h was 3.9%, 3.2% and 0.7% in 2009, 2011 and 2015, respectively. Treatment based on biomarker data was used in 61.5% of cases. In conclusion, a general trend in the improvement of key antimicrobial-related quality indicators was noted. The PPS tool provided a convenient, inexpensive surveillance system of antimicrobial consumption and should be considered an essential component to establish and maintain informed antibiotic stewardship in hospitals.

Healthcare acquired infections (HAI) pose a great threat in hospital settings and environmental contamination can be attributed to the spread of these. De-contamination and, significantly, prevention of re-contamination of the environment could help in preventing/reducing this threat. Goldshield (GS5) is a novel organosilane biocide marketed as a single application product with residual biocidal activity. We tested the hypothesis that GS5 could provide longer-term residual antimicrobial activity than existing disinfectants once applied to surfaces. Thus, the residual bactericidal properties of GS5, Actichlor and Distel against repeated challenge with Staphylococcus aureus ATCC43300 were tested, and showed that GS5 alone exhibited longer-term bactericidal activity for up to 6 days on 316I stainless steel surfaces. Having established efficacy against S. aureus, we tested GS5 against common healthcare acquired pathogens, and demonstrated that, on average, a 1 log10 bactericidal effect was exhibited by GS5 treated surfaces, although biocidal activity varied depending upon the surface type and the species of bacteria. The ability of GS5 to prevent Pseudomonas aeruginosa biofilm formation was measured in standard microtitre plate assays, where it had no significant effect on either biofilm formation or development. Taken together the data suggests that GS5 treatment of surfaces may be a useful means to reducing bacterial contamination in the context of infection control practices.