Clinical Infectious Diseases rr The Impact of a National Antimicrobial Stewardship Program on Antibiotic Prescribing in Primary Care: An Interrupted Time Series Analysis Violeta Batinskaite"* Alan P. Johnson” Alison Holmes,’ and Paul Aylin!” "UnfostrUnt Dprretof iaryCae andP Heath, pra Lov" fein Sac, Fob Hath Ere rl Naor tit fo Hah esac Heth Pots Fash Unt nike sos ain ad tinbil ssa, geri Caap Lolo ro Km (See the Major Article By Balinskaite etal on pages 233-42.) Background, "The Quality Premium was introduced in 2015 to financially reward local commissioners of healthcare in England for targeted reductions in antibiotic prescribing in primacy care. ‘Methods, We used a national antibiotic prescribing dataset ftom April 2013 until February 2017 to examine the number of an. tibjotic items prescribed, the total number of antibiotic items prescribed per STAR-PU (specific therapeutic group agelsex-related. prescribing units), the number of broad-spectrum antibiotic items prescribed, and broad-spectrum antibiotic items prescribed, expressed as a percentage ofthe total number of antibiotic items. To evaluate the impact of the Quality Premium on antibiotic pre scribing, we used a segmented regression analysis of interrupted time series data. Results. During the study period, over 140 million antibiotic items were prescribed in primary care. Following the introduction of the Quality Premium, antibiotic items prescribed decreased by 8.2%, representing 5933563 fewer antibiotic items prescribed. luring the 23 post-intervention months, as compared with the expected numbers based on the trend in the pre-intervention period, Afier adjusting forthe age and sex distribution in the population, the segmented regression model also showed a significant relative decrease in antibiotic items prescribed per STAR-PU. A similar effect was found for broad-spectrum antibiotics (comprising 10.1% of total antibiotic prescribing), with an 18.9% reduction in prescribing. Conclusions. This study shows that the introduction of financial incentives for local commissioners of healthcare to improve the quality of prescribing was associated with a significant reduction in both total and broad-spectrum antibiotic prescribing in primary care in England. Keywords. antimicrobial stewardship programs; antibiotic prescribing; interrupted time series. [Antimicrobial resistance is a serious public health problem and a global threat, with an estimated 10 million people a year predicted to die of drug-resistant infections by 2050 [1]. Itis known that prescribing and consumption of antibiotics is a key driver of resistance and, given the seriousness ofthe resist- ance threat, there was a clear need for a change in prescribing, policies to reduce the inappropriate use of antibiotics in both primary and secondary care, In the last decade, there were various antimicrobial stewardship programs with financial incentives (pay-for-performance) ot without financial incen- tives (educational, audits, guidelines) that were implemented across the globe with the intention to reduce antibiotic prescribing [2-10]. sd 7 i 08 tl don 1 Or 7018 sas 5 Ok 018 ps sole 8208 (Canepmter Gna, Fre Unt Sel of aie Hl, npr alge onion. Dost fi, ln Ey BEN UK interpol nial tection Disnases® —_zm8832)227-2 (©The 208 Pb y Od Unversity rs eth acs Ose Say 1 Aneien Arts sed Fr puetsin, eco joule permission, Dorinda Since 1999, there have heen various seasonal campaigns in the United Kingdom that attempted to reduce antibiotic pre scribing [11]. Despite this, the number of antibiotic items dis- pensed in the community per 100 inhabitants per year from. 2010 to 2014 remained relatively table [12]. In 2015, National Health Service England published a Quality Premium that was intended to financially reward Clinical Commissioning Groups (CCGs) for improvements in the quality ofthe services that they commission. CCGs are clinicallyled public bodies, responsible for the planning and commissioning of healthcare serviees for their local population [13, 14]. Among the specified improve: ‘ments in the 2015-16 Quality Premium was a requirement for CCGs to reduce both the total number of antibiotics prescribed and the proportion of broad-spectrum antibiotics (specifically, ‘co-amoxiclay, cephalosporins, and quinolones) prescribed in primary care [15]. In this study, we assessed the impact of the introduction of the Quality Premium on antibiotic prescribing in primary care using an interrupted time series (ITS) analysis to compare ‘pre-existing trends in prescribing before the intervention with, those seen subsequently, “The Impact of Antico Stewardship + CID 2019569 (15 July) « 227 3 uo tr Up 1202 1942090 £0 uo sanf Aa geeaeISHzeIZIED>OMENMETHODS. ‘Study Design and Seting ‘We conducted a quasi-experimental ITS analysis that covered a period of 47 months, comprising the 2 years prio tothe intro- duction of the Quality Premium (1 April 2013 to 31 March 2015) and a period of 23 months after its implementation (1 April 2015 to 28 February 2017), We used a national prescrib- ing dataset from the Information Service Portal, provided by [NHS Business Services Authority (hitps/wwwnhsbsa.nhs.uk! information-services-portal-isp). which was abtained by sub- rittinga freedom of information request. The dataset included information about the number of dispensed items per month and specific therapeutic group age/sex-related_ prescribing units (STAR-PUs) in England. A prescription item refers to a single item prescribed by a general practitioner on a prescrip tion form, Ifa prescription form included 3 different antibiot ies, then it was counted as 3 prescription items. The STAR-PU ‘was developed in 1995, and is a eost-based weighting method for overall prescribing that allows comparisons after adjusting for the age and sex distribution of each practice and CCG [16] ‘The dataset as analyzed to determine both the total number of antibacterial items prescribed and the number of broad-spec- ‘rum antibiotic (co-amoxiclay, cephalosporins, and quinolones) items prescribed over time. Intervention ‘The Quality Premium 2015-16 guidance for CCGs was pub- lished in April 2015 and isbased on 5 quality measures hat cover a combination of national and local priorities [15]. Among the ‘measures is the improvement of antibiotic prescribing in pri _mary care It consists of 3 parts: (1) reductions in the number of antibioties prescribed in primary care by 1% (or greater) from each CCG 2013-14 value; (2) reductions in the proportion of broad-spectrum antibioties, asa percentage ofthe total number of selected antibiotics prescribed in primary care, either by 10% from each CCG's 2013-14 value or to be below the 2013-14 ‘median proportion for English CG's; and (3) secondary care providers validating their total antibiotic prescription data. The ‘maximum Quality Premium payment for a CCG was expressed as £5 per head of population, calculated using the same meth- odology as for CCG running costs [15]. The measure of the {improvement of antibiotic prescribing in primary care make up 10% of Quality Premium, the amount awarded to CCGs. ‘Outcome Measures We used 4 antibiotic prescribing-outcome measures: the {otal number of antibiotic items prescribed, the total number of antibiotic items prescribed per STAR-PU, the number of broad-spectrum antibiotic items prescribed, and the number of broad-spectrum antibiotic items prescribed, expressed as a percentage ofthe total number of antibiotic items. Statistical Analyses To identify seasonal changes in antibiotic prescribing, we applied the X12 SAS procedure, which is an adaptation of the US Bureau of the Census X-12-Auto-Regressive Integrated Moving Average (ARIMA) model that produces a seasonal Iy-adjusted time series [17-21]. The combination of the F test for both stable (between months) and moving (between years) seasonalites, along with a Kruskal-Wallis test for stable season- ality, were used to test for identifiable seasonality ‘We used an ITS analysis, a strong quasi-experimental design, to evaluate the impact of the Quality Premium on antibiotic prescribing [22-26]. To assess an assumption that observations are independent, known as autocorrelation, we used a Durbin ‘Watson statistic. The ARIMA model was used to adjust for autocorrelation. For estimating seasonal autocorrelation, the auto-regression model needs to evaluate correlations between ‘error terms, separated by multiples of 12 months. Accounting for seasonally-correlated errors usually requires at least 24 months of data points [26]. Using a segmented regression model, we looked for changes inthe level and trend of antibi otic prescribing before and after the introduction ofthe Quality Premium, Changes in the level and trend with Ps < .05 were considered as statistically significant. To assess the fit of the ‘model parameters, the maximum likelihood ratio test was used. Furthermore, general recommendation to achieve robust esi mates of change is a minimum of 100 cases per time point [26]. ‘The absolute change was defined asthe ference between the ‘observed value and the estimated value i the Quality Premium had not been introduced (the counterfactual value, based on the pre-implementation trend) The relative change, expressed as a percentage, was defined as the ratio ofthe observed value tothe counterfactual value. We used bootstrapping methods devel- ‘oped by Chang et al [27, 28] to estimate the 95% confidence intervals (CIs) for absolute and relative change. All statistical analyses were performed using SAS version 9-4 (SAS Institute, Cary, NO) RESULTS During the period between April 2013 and February 2017, over 140 million antibiotic items were preseribed in England. Broad. spectrum antibiotic items (co-amoxicla, cephalosporins, and quinolones) comprised 10.1% of the total number of antibiotic items prescribed (Figure 1), Seasonal variation was observed, ‘with a higher number of antibiotic prescriptions in winter months compared with the summer periods (Supplementary “Table Before the Quality Premium was implemented, there was an increase in the average monthly number of all antibiotic items prescribed, from 3051822. (95% Cl 2870381-3233263) in 2013-14 to 3108827 (95% CI 2873893-3 343760) in 2014-15, representing a 1.9% increase in overall antibiotic preseribing 228 + CAD 2019569 (15 ly) + Baliskate tal 3 g 2 5 8 2 1202 1942090 £0 uo sanf Aa geeaeISHzeIZIED>OMEN4500 7 4000 23500 3000 2500 200 1300 1000 soo eRe & L i 2013 2014 Antibiotic tems per STAR-PU 00 350 3 i 30 = 3 oo a ee | wo 100g o 3 ° Hee ae SE | 2o1s m6 road pein 4 2 we a a # o ‘ I 2 = ° a ee 2o1s 2o16 '—Broad:-spectrum antibiotic (as percentage of total antibiotic items) Figure 1. Tho nunbor of ll ribo and boadspoctum antic co anoxia, copalspoins, and qiolons ams prescrbot; ann tams proscribod por STAE.PU: and broad spectrum antbititams peste (a percentage of ttl ations in gine practieby month, in England to Api'2013-Febuary 2017 [vertical aay ne represents the iplemeetaton ath Quality Premium) ABbvevaion: STAA-PL, pei erapautcroup aelse-latedpresebing unis in 2014-15 from 2013-14. However, looking atthe antibiotic items prescribed per STAR-PU, there was only a 0.6% increase {in 2014-15 from 2013-14, During the same period, the average ‘monthly broad-spectrum antibiotic items prescribed decreased from 341964 (95% CI 332269-351 658) to 330882 (05% CI 31971-341 992), representing a 32% decrease in broad-spec- trum antibiotic prescription in 2014-15 from 2013-14 Comparing financial year 2015-16 othe year 2013-L4,ade- reas in antibiotic prescribing was detected. The total number of antibiotic items prescribed dropped by 5.4%, representing almost 2 million fewer antibiotic items dispensed. During the same period, the number of broad-spectrum antibiotic items prescribed dropped by 18.5%, with over 750 thousand fewer broad-spectrum antibiotic items dispensed. Over the longer term, a segmented regression analysis of ‘monthly data indicated a significant decrease in the level of prescribing for all antibiotic items, for antibiotic items per STAR-PU, and for broad-spectrum antibiotic items following the introduction of the Quality Premium (Table 1, Figure 2) ‘The estimated relative decrease by the end of February 2017 ‘was 8.2% (95% CI -14.2--22%), representing 5933563 fewer antibiotic items prescribed during the 23 post-intervention ‘months, as compared with the expected numbers based on the trend in the pre-intervention period. After adjusting for the age and sex distribution in the population, the segmented regres sion model also showed a significant relative decrease in ani biotic items prescribed per STAR-PU, A significant decrease ‘was also estimated for broad-spectrum antibiotic items pre- scribed (-18.9%, 95% CI -24.1--13.7%), representing 1303410 fewer broad-spectrum antibiotic items prescribed during the 23 post-intervention months, as compared with the expected ‘numbers based on the trend in the pre-intervention period. “The Inpact of Antincrobial Stewardship » CID 2019569 (13 July) + 229 1202 1942090 £0 uo sanf Aa GeegeLS/EZeIZ/EB/eMETP!D]WOD dno-oMaPeDei'sdal WON PapE>LUMCGTable 1, Segmented Regression Analysis for Antibiotics Prescribing Measures ‘Absolute Change in Ratve Change utc por Month During by the End ofthe Pre inwrventon Change in Low! Post inierveauon the Festinorvenion Patiod Siu, Presebing Messures Constant Tend A @ Trend IP) Te6% C0 ‘95% i Rieibiote tome 3050861 288 “as 66 248 257881 “82 prserbod (a0 (<0) (85) ae2antio-6348s) 114210-221 Amibote tems pie 0.0085 0.00008 0.0652 “0.00007 “000% “i ered per STAR-PU 78) ‘on U5) 00910-0000) -I38t0-15) Broad-spectrum antb+ 350008, 1082 2012 2328 -56670 =189 ‘te itams prosebod <0) o1si6 ois? 201718 25 Original data Seasonally adjusted Figure 2. Sagrantedrgrsson analysis foal antibiotic and brad sptrun antibiotic tams prescribed. The soli ios foto estimates of tho sgnentodrogrsson mothe dotted ne fr he estate regression mel without intervention. knlementation of the Guay Premium presente by a veral ge ine) occured in pri 205, 230 + CAD 2019569 (15 aly) + Baliskate tal 1202 s9qwa0ec 0 uo an6 ka esc9e1SIZZzIz/SQ/OMIE!PO;We'dno-oWPEDe;r'sdal WOH popE>LUMCADISCUSSION ‘We found thatthe Quality Premium was associated witha sig- rifcant, 82% decrease in all antibiotic items prescribed and cant, 18.9% decrease in broad-spectrum antibio (co-amoxiclay, cephalosporins, and quinolones) items pre- scribed, when compared with the trend in prescribing before its introduction. a signi ‘An important strength of this study isthe use of ITS anal- ysis. ITS analysis is the strongest quasi-experimental research design and is useful when a randomized, controlled tral (RCT) is unfeasible or unethical. Segmented regression analysis addresses threats to internal validity by making multiple assess- ‘ments of the outcome variable, both before and after the inter- vention. The key advantage is that it considers the prevailing, ‘ends in the outcome prior tothe intervention, Furthermore it ‘can estimate the size of the association at different time points, as well as changes in the trend of the association overtime. (ur study has several limitations, Firstly, the dataset obtained from the Information Service Portal, provided by NHS Business Services Authority, only includes antibiotic prescriptions dis- pensed: that is it did not include prescriptions written but not dispensed. Secondly, the dataset does not include any informa tion related to general practitioners or clinical diagnoses. And finaly, while providing strong evidence for an association, our study was not able to identify a causal relationship between the Quality Premium and antibiotic prescribing. I is dificult and rarely possible to do RCTs to evaluate the impact of policy changes. However, observational studies based on ITS analyses area valid approach. Previous studies that investigated the association between antimicrobial stewardship programs with and without finan cial initiatives (pay-for-performance, educational programs, auuits, guidelines) and antibiotic preseribing in primary care have found mixed results [2-10]. A Chinese study using a smatched-pair, duster-randomized experiment found that a pay-for-performance intervention was associated with an approximate 158 reduction in antibiotic prescriptions [2]. Another study in the United States that investigated the impact of 2 pay-forperformance programs on improvements in healthcare quality in California found a 6% improvement of the :ate of appropriate antibiotic presribing [3]. However in these studies, pay-for-performance was used in conjunction with other important policy changes: a complete restructuring of the payment scheme from fee-for-service to capitation [2] and the introduction of other pay-for-performance indicators (3. A Sivedish study evaluate the effect of pay-for-performance for antibiotic prescribing in the treatment of children with resp ratory tract infections, though the financial incentives encou- aged physicians to select narrow-specteum antibiotics [4]. The authors found that pay-for-performance significantly increased the proportion of narrow-spectrum antibiotics (penicillin V) prescribed, which reflected a substitution of penicilin V for broad-spectrum antibiotis. A recent study in England found that the Quality Premium was associated with a 3% reduction in antibiotic prescribing for uncomplicated respiratory tract infec- tions [5]. A pracice-based RCT in Wales found that an educa- tional program was associated with significant, 4.2% reduction in total oral antibiotics dispensed fora yar (6]. Another clus ter-randomized trial in the United States, which evaluated the eflect of antimicrobial stewardship on broad-spectrum anti biotic prescribing for pediatric outpatients, showed that the intervention nearly halved prescribing of broad-spectrum ant biotics by I year after the intervention (7]. However, an RCT in Switzerland found no association between a natonvde anti ‘oti stewardship program and a change in antibiotic prescribing [8]. An antimicrobial stewardship program in Sweden was aso ciated with a reduction of antibiotic use [9]. A literature review that investigated the effect of physician-targted interventions between 1990 and 2009 on antibiotic prescribing for respira tory tract infections in primary cae, more than 90% of which had no financial element, found that interventions, on average, reduced antibiotic prescribing by 11.6% [10]. However, studies included in the literature review focused on the interventions directly targeting physicians rather than organizational str tures (CCGs in our case). CONCLUSIONS ‘The findings from this study show that the introduction of the 2015-16 Quality Premium was associated with a significant reduc- tion in all antibiotic items and broad-spectrum antibiotic items prescribed. Tis study shows that pay-for performance can signif cantly reduce antibiotic us, and specifically broad-spectrum ant biotic use. However, further research is needed to assess the impact, (if any) of the Quality Premium on adverse clinical outcomes to reassure the public, patients, general practitioners, and policymak- «rs that measures to reduce inappropriate antibiotic prescribing do not adversely affect patient safety. Supplementary Data Supplementary materials are avaiable a Clinical bfctious Disease online Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and arethe sole responsibility ofthe authors, 0 “questions or comments should be adresse tothe corresponding author Not Author contributions. All authors contribute tthe original research proposal. All authors helped refine he elassificaion ofthe outcome used VB. carried out the analysis. V. Band P. A. wrote the frst draft, and all authors commented on subsequent dats ofthe manuscript, Disclaimer. "The views expressed in this atic are those ofthe authocs and do not necessarily represent the postion ofthe funder. The findings achieved herein ae solely the responsibility ofthe authors. The Dr Foster Unita Imperial i affliated with the National Institue fr Health Research (IER) Imperial Patient Safety Translational Research Cente, a patner- shipheren the Imperial College Healthcare National Health Service Teast, and Imperial College Londen. “The Inpact of Antincrobial Stewardship » CHD 2019569 (13 July) + 231 1202 1942090 £0 uo sanf Aa GeegeLS/EZeIZ/EB/eMETP!D]WOD dno-oMaPeDei'sdal WON PapE>LUMCGFinancial support, This work was supported by the NIHR Palcy Research Programme (esearch to determine the impact of the national an microbial stewandehip programs on clinical somes and patient fey and toestablsh sustainable systems). The Dr Foster Unit-—an academic unit the Department of Primary Care and Pubic Health, within the School of Public eth, Imperial College London reeves reset funding rom the NIHR an Dr Foster inelgence, an independent health service research organiza tion (a wholly-owned subsidiary of Test). Tis wrk was supported bythe [NIHR Heskh Protection Research Unit in Healthoare Awocited Infctons and Antimicrobial Resistance at Imperial Callege London in partnership with Public Heath England. The Department of Primary Care & Public Heath a lperialCallge London i supported bythe North West Landon NIHR. Collaboration for Leadership in Applied Health Research & Care and the imperial NR Biomedical Research Centre. Potential conflict of interest. A. H, received an honorarium for preset Ing at a conference ented South African Anite Stewandsip Pregame Annual Workshop, sponsored by Merck (MSD Hoddesdon). Al other authors ‘epost no potential confit. 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