JAC- Antimicrobial Resistance JAC Antimicrob Resist doi:10.1093/jacamr/dlaa079 Impact of changes in the WHO’s 2019 update of DDDs on the measurement of adult hospital antibacterial consumption in Catalonia (Spain), 2008–18 Santiago Grau1, Sergi Hernández 2 *, Enric Limón2, Esther Calbo2,3 and Juan P. Horcajada4 on behalf of the Catalan Infection Control and Antimicrobial Stewardship National Program (VINCat-PROA)† 1 Service of Pharmacy, Hospital del Mar, Infectious Pathology and Antimicrobials Research Group, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona, Barcelona, Spain; 2VINCat Program Surveillance of healthcare related infections in Catalonia, Barcelona, Spain; 3Infectious Diseases Unit, Department of Internal Medicine, Hospital Universitari Mútua Terrassa, Barcelona, Spain; Universitat Internacional de Catalunya, Barcelona, Spain; 4Service of Infectious Diseases, Hospital del Mar, Infectious Pathology and Antimicrobials Research Group, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona, Universitat Pompeu Fabra, Barcelona, Spain *Corresponding author. E-mail: hernandez.sergi@gmail.com; shernandezbaeza@iconcologia.net †Members are listed in the Acknowledgements section. Received 5 June 2020; accepted 17 August 2020 Objectives: In 2019 the WHO fully adopted new DDD values. The objective of this study is to analyse their impact on the measurement of consumption of antibacterials in hospitals participating in the Catalan Infection Control and Antimicrobial Stewardship National Program (VINCat-PROA) in Catalonia (Spain) between 2008 and 2018. Methods: The anatomical therapeutic chemical/DDD system was used to monitor adult hospital antibacterial consumption expressed in DDD/100 bed-days. Consumption from 2008 to 2018 was calculated using both pre- and post-update DDD values. Differences were calculated as the percentage variation in DDD/100 bed-days and analysed with Student’s t-test. Simple linear regressions were performed to evaluate the trends in adult antimicrobial consumption over the study period. Results: The overall consumption according to post-update DDD values decreased by 12.2% (P , 0.001) com- pared with the pre-update DDD values. Penicillins (#19.6.%; P , 0.001) and carbapenems (#19.0%; P " 0.023) showed the greatest reduction, followed by cephalosporins (#7.7%; P " 0.021) and quinolone antibacterials (#7.7%; P " 0.017). ICU services showed the greatest overall reduction (#13.1%; P , 0.001). From 2008 to 2018 there was a statistically significant decrease in consumption of penicillins and quinolone antibacterials and a statistically significant increase in cephalosporin and carbapenem consumption with both pre- and post-update DDD values. There were no variations in the ranking of consumption between the pre- and post-update DDD values. Conclusions: The WHO’s updates of DDDs have had a significant impact on the measurement of antibacterial consumption. In our region, they have corrected an overestimation of penicillin and carbapenem consumption amounting to 19%. It is essential to bear these findings in mind for an accurate assessment of temporal trends and benchmarking. Introduction The anatomical therapeutic chemical/DDD (ATC/DDD) system, WHO1 and ECDC2 agree that the analysis of the consumption of developed and updated by the WHO Collaborating Centre for Drug antibacterials is crucial in order to optimize their use and to Statistics Methodology, has become an international standard for bring down resistance rates. A relationship between the use drug metrics and facilitates the presentation and comparison of of certain antimicrobials and increased resistance has been drug consumption statistics at international, national and regional proposed.3 levels.4 In 2008 the Catalan Infection Control and Antimicrobial C The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. V This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecom mons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 1 of 5 Grau et al. Stewardship National Program (VINCat-PROA) adopted the ATC/ extended use (25.3% and 23.0% of the total antibacterial DDD system as a standardized measure. consumption with pre- and post-update DDD values, respectively). In 2018, the WHO International Working Group for Drug Antibiotics of special interest such as meropenem (#31.6%, Statistics Methodology updated the DDD of eight commonly used P " 0.03) and cefepime (#50.1%, P , 0.001) also presented not- antibiotics as a result of a review of the doses used in clinical able reductions in consumption. practice. These new DDD values were fully adopted in 2019.5 The objective of this study is to analyse the impact of these Impact of DDD update on the evolution of consumption changes on the measurement of the consumption of hospital anti- of antibacterials for systemic use bacterials for systemic use by adults in Catalonia (Spain) between 2008 and 2018. From 2008 to 2018 (Figure 1, annual overall consumption data on demand) there was a decrease in consumption of penicillins with both pre-update DDD values (33.5 versus 29.4 DDD/100 bed-days, Materials and methods Pc " #0.92, P , 0.001) and post-update DDD values (26.10 versus During the study period the number of hospitals participating in VINCat- 24.24 DDD/100 bed-days, Pc " #0.72, P " 0.012). Differences PROA rose from 46 in 2008 to 63 in 2018. These figures represented 68.8% between pre- and post-update values showed a reduction and 85.7% of all adult acute hospital beds in Catalonia (a region of 7.6 mil- from #22.2% in 2008 to #17.5% in 2018, mainly due to a decrease lion people), respectively. The number of bed-days recorded increased from in amoxicillin/b-lactamase inhibitor consumption (23.6 versus 2 991 053 in 2008 to 3 714 938 in 2018. 17.3 DDD/100 bed-days with pre-update DDD values, and 17.8 The ATC/DDD system was used to monitor adult hospital antibacterial versus 14.2 DDD/100 bed-days with post-update DDD values). consumption.6 The pharmacy departments at the participating hospitals Consumption of quinolone antibacterials showed a statistically reported the number of units of each antibacterial for systemic use (J01) significant reduction with both pre-update (12.4 versus 10.4 DDD/ dispensed and bed-days data from the whole hospital and from the medic- al and surgical services and ICUs. Annual antibacterial consumption, 100 bed-days, Pc"#0.76, P , 0.001) and post-update values (11.6 expressed in DDD/100 bed-days, was calculated using both pre-update versus 9.6 DDD/100 bed-days, Pc " #0.78, P " 0.004). Differences DDD values (WHO ATC/DDD index 2017) and post-update DDD values increased from #5.9% in 2008 to #7.5% in 2018. (WHO ATC/DDD index 2019), keeping the number of units used and bed- Cephalosporin consumption increased from 2008 to 2018 with days of every single year. both pre-update (12.0 versus 14.7 DDD/100 bed-days, Pc " 0.94, The percentage difference in mean consumption between pre- and P , 0.001) and post-update DDD values (10.9 versus 13.9 DDD/100 post-update DDD values was calculated and the significance of differences bed-days, Pc " 0.95, P , 0.001). Differences fell from #9.5% in between values was established by Student’s t-test. Simple linear regres- 2008 to #5.5% in 2018, mainly due to an increase in cefazoline sions were performed to evaluate the trends in consumption over the study (1.9 versus 3.3 DDD/100 bed-days) and ceftriaxone (3.8 versus period. The linear relationship was checked by ANOVA tests, and Pearson’s 5.5 DDD/100 bed-days) consumption and the maintenance of correlation coefficients (Pc values) were obtained. Values of P , 0.05 were cefepime consumption both pre-update (1.6 versus 1.6 DDD/ considered statistically significant. A two-tailed distribution was assumed for all P values. 100 bed-days) and post-update (0.7 versus 0.7 DDD/100 bed- days). Consumption of carbapenems increased from 2008 to 2018 Results with both pre-update (3.4 versus 6.9 DDD/100 bed-days, Impact of DDD update on the mean consumption of Pc " 0.99, P , 0.001) and post-update DDD values (3.4 versus antibacterials for systemic use 5.4 DDD/100 bed-days, Pc " 0.99, P , 0.001). Differences rose from #3.5% in 2008 to #22.3% in 2018, due to a reduction in During 2008–18 the overall mean adult hospital antibacterial con- imipenem consumption (1.8 versus 0.9 DDD/100 bed-days) sumption calculated with post-update DDD values decreased by combined with an increase in meropenem consumption with both 12.2% (P , 0.001) compared with the pre-update DDD values: 79.4 pre-update (1.2 versus 4.6 DDD/100 bed-days) and post-update versus 69.7 DDD/100 bed-days (Table 1). Penicillins showed the DDD values (1.1 versus 3.1 DDD/100 bed-days). greatest reduction [#19.6% (P , 0.001), 31.7 versus 25.5 DDD/ 100 bed-days], followed by carbapenems [#19.0% (P " 0.023), 5.4 versus 4.4 DDD/100 bed-days], cephalosporins [#7.7% Impact of DDD update on relative consumption of (P " 0.021), 13.8 versus 12.7 DDD/100 bed-days] and quinolone antibacterials for systemic use antibacterials [#7.7% (P " 0.017), 12.3 versus 11.3 DDD/100 bed- There were no variations in the ranking of consumption between days]. the pre- and post-update DDD values regarding the total con- Mean consumption decrease in all services and ICUs showed sumption of all antibiotic groups during the study period. Penicillins the greatest overall reduction (#13.1%, P , 0.001). In ICUs, carba- were the most used and represented 35.0% and 32.2% of the total penems were the most affected by the update (#25.1%, adult hospital antibacterial consumption with both pre- and post- P , 0.001). Penicillins had the greatest reduction in both medical update DDD values, followed by cephalosporins (17.5% and (#20.9%, P , 0.001) and surgical services (#18.4%, P , 0.001). 18.4%, respectively) and quinolone antibacterials (12.4% and Ampicillin and colistin had the largest reductions in consump- 12.8%, respectively). The group ‘other antibacterials’ (J01X) occu- tion (#66.4%, P , 0.001 and #59.6%, P , 0.001, respectively); pied the fourth place (11.7% and 12.5%, respectively) followed by however, amoxicillin/b-lactamase inhibitors showed the greatest carbapenems, which represented 8.3% and 7.2% of all antibacter- impact in terms of overall reduction in consumption, due to its ial consumption, respectively. 2 of 5 Impact of WHO’s DDD update on antibacterial use measurement JAR Table 1. Mean antibacterial consumption pre- and post-update of the WHO DDDs according to drugs and hospital service (Catalonia 2008–18) Pre-update values, Post-update DDD/100 bed-days, values, DDD/100 bed- Percentage Service ATC classification mean (SD) days, mean (SD) decrease P Total J01 Antibacterials for systemic use 79.44 (2.13) 69.75 (2.51) 12.2 ,0.001 J01C Penicillins 31.66 (1.67) 25.46 (0.83) 19.6 ,0.001 J01CA01 Ampicillin 2.38 (0.24) 0.80 (0.08) 66.4 ,0.001 J01CA04 Amoxicillin 1.59 (0.27) 1.06 (0.16) 33.6 ,0.001 J01CR02 Amoxicillin/b-lactamase inhibitor 20.14 (2.24) 16.06 (1.22) 20.3 ,0.001 J01DBCDE Cephalosporins 13.80 (0.90) 12.73 (1.09) 7.7 0.021 J01DE01 Cefepime 1.76 (0.14) 0.88 (0.09) 50.1 ,0.001 J01DH Carbapenems 5.40 (1.18) 4.37 (0.73) 19.0 0.023 J01DH02 Meropenem 3.15 (1.19) 2.15 (0.71) 31.6 0.030 J01M Quinolone antibacterials 12.29 (0.91) 11.34 (0.79) 7.7 0.017 J01MA02 Ciprofloxacin 5.80 (0.59) 4.91 (0.52) 15.3 0.001 J01XB01 Colistin 0.75 (0.12) 0.31 (0.10) 59.6 ,0.001 ICU J01 Antibacterials for systemic use 143.65 (4.32) 124.78 (3.70) 13.1 ,0.001 J01C Penicillins 42.89 (3.62) 37.47 (2.81) 12.6 0.001 J01CA01 Ampicillin 4.79 (0.43) 1.59 (0.12) 66.9 ,0.001 J01CA04 Amoxicillin 1.11 (0.46) 0.71 (0.27) 36.1 ,0.001 J01CR02 Amoxicillin/b-lactamase 17.10 (2.70) 15.45 (1.81) 9.7 0.022 inhibitor J01DBCDE Cephalosporins 22.71 (1.21) 19.72 (0.85) 13.1 ,0.001 J01DE01 Cefepime 5.54 (1.14) 2.66 (0.47) 50.2 ,0.001 J01DH Carbapenems 20.49 (2.64) 15.35 (1.16) 25.1 ,0.001 J01DH02 Meropenem 15.38 (4.21) 10.36 (2.41) 32.7 ,0.001 J01M Quinolone antibacterials 13.94 (1.24) 12.03 (1.24) 13.6 0.002 J01MA02 Ciprofloxacin 6.93 (0.91) 4.82 (0.71) 30.5 ,0.001 J01XB01 Colistin 5.32 (1.01) 1.99 (0.52) 62.6 ,0.001 Medical J01 Antibacterials for systemic use 78.99 (2.79) 69.14 (1.94) 12.5 ,0.001 J01C Penicillins 33.04 (2.23) 26.12 (1.32) 20.9 ,0.001 J01CA01 Ampicillin 2.36 (0.31) 0.81 (0.08) 65.8 ,0.001 J01CA04 Amoxicillin 1.87 (0.34) 1.24 (0.20) 33.6 ,0.001 J01CR02 Amoxicillin/b-lactamase 21.86 (2.63) 17.01 (1.54) 22.2 ,0.001 inhibitor J01DBCDE Cephalosporins 13.80 (0.90) 12.73 (1.09) 10.3 0.002 J01DE01 Cefepime 2.44 (0.21) 1.19 (0.11) 51.2 ,0.001 J01DH Carbapenems 4.78 (1.19) 4.00 (0.73) 16.4 0.078 J01DH02 Meropenem 2.63 (1.01) 1.86 (0.54) 29.2 ,0.001 J01M Quinolone antibacterials 14.61 (1.20) 13.98 (1.02) 4.3 0.197 J01MA02 Ciprofloxacin 4.57 (0.46) 3.93 (0.41) 13.7 0.003 J01XB01 Colistin 0.70 (0.14) 0.29 (0.12) 58.4 ,0.001 Surgical J01 Antibacterials for systemic use 74.76 (3.86) 66.55 (4.38) 11.0 ,0.001 J01C Penicillins 29.78 (1.19) 24.38 (0.82) 18.4 ,0.001 J01CA01 Ampicillin 2.31 (0.23) 0.78 (0.09) 66.4 ,0.001 J01CA04 Amoxicillin 1.48 (0.29) 0.97 (0.15) 34.8 ,0.001 J01CR02 Amoxicillin/b-lactamase 18.68 (1.64) 15.27 (0.82) 18.2 ,0.001 inhibitor J01DBCDE Cephalosporins 14.34 (1.50) 13.81 (1.63) 3.7 0.443 J01DE01 Cefepime 0.69 (0.16) 0.34 (0.08) 51.3 ,0.001 J01DH Carbapenems 4.63 (0.99) 3.78 (0.64) 18.3 0.027 J01DH02 Meropenem 2.48 (0.97) 1.66 (0.61) 32.9 ,0.001 J01M Quinolone antibacterials 9.39 (0.69) 8.36 (0.71) 10.9 0.003 J01MA02 Ciprofloxacin 7.12 (0.69) 6.09 (0.66) 14.5 0.002 J01XB01 Colistin 0.37 (0.12) 0.15 (0.07) 60.0 ,0.001 3 of 5 Grau et al. 40 35 30 −22.2% Pre-update Penicillins −17.5% Post-update Penicillins 25 Pre-update Cephalosporins DDD/100 bed days Post-update Cephalosporins 20 Pre-update Quinolones Post-update Quinolones 15 −5.9% Pre-update Carbapenems −5.5% Post-update Carbapenems 10 −7.5% −9.5% −22.3% 5 −3.5% 0 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 Figure 1. Evolution of consumption of antibacterials for systemic use (J01) pre- and post-update of the WHO DDDs (Catalonia 2008–18). Percentages show differences in consumption values between pre- and post-update in 2008 and 2018. Discussion (J01F), aminoglycoside antibacterials (J01G) or other antibacterials (J01X); however, the general ranking of relative consumption has The reduction in the measurement of adult hospital antibacterial not been affected. Penicillins and carbapenems presented the consumption in our study (12.2%) is similar to that reported largest relative reductions in the ranking of consumption in our by Robertson et al.,7 who estimated a total DDD per area since they were the ones most affected by the DDD changes. 1000 inhabitants-day reduction on average by 12.0%, and con- Cephalosporins and quinolones increased their share of the total firms that the WHO’s 2019 DDD update corrects an overestimation since changes in DDDs affected them less and they continue to of the consumption of antibacterials for systemic use (especially in be widely consumed. These results corroborate the estimations penicillins) that had already been detected by Haug and Reikvam8 published by Robertson et al.7 in Norway, Charra et al.9 in France and the EU, and Klein et al.10 in A limitation of this study is the increase in participating hospitals their study of antibiotic consumption in 76 countries. between 2008 and 2018. This could have caused changes in Carbapenems (meropenem) were more affected by DDD changes consumption patterns. However, high-complexity hospitals have in ICU services since patients are more complex and the use participated from the beginning and the use of average consump- of broad-spectrum antibiotics is higher. tion from the last 10 years contributes to mitigating the possible This reduction in the measurement related to the update of selection bias. DDD values did not affect the main trends in the evolution of In conclusion, the WHO’s updates of DDDs have had a signifi- antibacterial consumption observed during our study period. cant impact on the measurement of antibacterial consumption. Similar reductions in penicillin use were observed by Dickstein In our region, they have corrected an overestimation of penicillin et al.11 in Israel and an increase in the consumption of first- and and carbapenem consumption amounting to 19%. third-generation cephalosporins was observed by Kwint et al.12 in It is essential to bear these findings in mind for an accurate the Netherlands and Grau et al.13 in Catalonia. The reduction assessment of temporal trends and benchmarking. in quinolone consumption from 2008 to 2018 observed with both pre- and post-update DDD values could be related to the associ- ation of fluoroquinolones with an increased risk of aortic aneurysm Acknowledgements and dissection.14 Meropenem is the only carbapenem affected by the DDD update and the upward trend in its consumption, together Members of VINCat-PROA with the downward trend in the consumption of imipenem due We thank all the Pharmacy Department members of the participating to adverse effects associated with its use,15 can explain the great hospitals in VINCat-PROA from 2008 to 2018: Manuel Cano, Laura Canadell, Esther Julián, Laura Gratacós, Natàlia Carrasco, Ariadna increase in the difference between the pre- and post-update ~ ones, David Campany, Antònia Balet, Montse Lladó, Padulles, Carles Quin consumption in 2008 (#3.5%) and 2018 (#22.3%). Despite the ~ ez, Esther López, Leonor Glòria Gayola, Isabel Frigola, Ludivina Ibán increase in the use of carbapenems, in the last few years their Munell, Virginia Gol, Maite Barrera, Ma Rosa Garriga, Usúe Manso, Núria consumption has stabilized throughout Europe.16 Miserachs, Esperanza Gil, Núria Bosacoma, Anisi Morón, Anna Capellà, The changes in DDD values have not included other groups of ~ ó, Maria Sagalés, Olga Curiel, Mireia Fuster, Camilla Valls, Marisa Gran antibiotics such as tetracyclines (J01A), sulphonamides and tri- Begon ~ a Pascual, Silvia Sardà, Eugènia Òdena, Susana Terrè, Pilar methoprim (J01E), macrolides, lincosamides and streptogramins Alemany, Pilar Salvador, Marta Martı́, Isabel Martı́nez, Ma José Fraile, 4 of 5 Impact of WHO’s DDD update on antibacterial use measurement JAR Emilia de Puig, Montserrat Navarro, Edurne Fernández, Lidia Salsé, Ana 6 WHO Collaborating Centre for Drug Statistics Methodology, Norwegian Montero Leno, Virginia Maria Martı́nez, Josep Torrent, Magda Montserrat, Institute of Public Health. 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