LETTER

REPLY TO CHARRA ET AL.: Global longitudinal assessment of 2019 changes in LETTER defined daily doses Eili Y. Kleina,b,c,1, Katie K. Tsenga, Simon A. Levind,e,f, Herman Goossensg, and Ramanan Laxminarayana,e,h

The concept of defined daily doses (DDDs) is rooted in DDDs, the total increased from 18.7 to 31.0 billion the understanding that to assess drug utilization and DDDs). Consumption, measured as DDDs per 1,000 to develop rational interventions at the patient level, a inhabitants per day (DIDs), decreased slightly more in common framework for comparing varied sources and high-income countries between 2000 and 2015 based forms of drug utilization data are necessary (1–3). A primary on the modified DDDs (−6% compared with −4%); how- aim of the WHO Collaborating Centre for Drug Statistics ever, globally, DIDs still increased 40%: from 10.0 to Methodology (WHO-CC-DSM), which maintains DDD val- 14.0 (as opposed to 11.3 to 15.7). The similarity in ues, is to keep DDD values as stable as possible for the global results despite changes in the DDDs for amox- purposes of evaluating longitudinal drug utilization data. icillin is because increases in antibiotic consumption of Because the DDDs for antibiotics have been a matter of cephalosporins, macrolides, and quinolones in low- and debate for many years, the WHO-CC-DSM decided to middle-income countries were greater than increases implement DDD changes for several Anatomical Ther- in amoxicillin consumption. apeutic Chemical (ATC) classification codes [ATC/ When DDDs are modified, it is necessary to DDD Index; e.g., amoxicillin (J01CA04) and amoxicil- recalculate longitudinal data using the modified val- lin/clavulanic acid (J01CR02)] starting January 1, 2019 ues for all years (6). While the methods in Charra et al. (Table 1). Charra et al. (4) stress the importance of rede- (4) are not described, we found that DIDs in France fining the DDDs of amoxicillin to provide robust indi- decreased 19% between 2000 and 2015 using the cators of consumption. Presumably, the catalyst for this modified DDDs, compared with the 13% we originally call is their calculation that this would change the trends found (5). However, the vast majority of that decline in antibiotic consumption in France and, by extrapola- occurred before 2005, as DIDs actually increased 1% tion, would have resulted in significant decreases in between 2005 and 2015 using the modified DDDs consumption globally, rather than what we note were (this compares to a 7% increase using the older large increases between 2000 and 2015 (5). DDDs). Because all countries were subject to the same To assess these claims, we recalculated the results recalculation, the relative consumption in France com- of our analysis using the changes and proposed pared with other countries remained similar (Fig. 1). It changes in DDDs for 2018 and 2019 (Table 1). We is important to accurately reflect the evolution of dos- found that while global levels of DDDs were lower, age regimens by altering DDD values when necessary. changes in consumption were qualitatively similar. However, when changes are made, researchers need As expected, the percentage of total DDDs that were to recalculate all longitudinal data, recognizing that broad-spectrum penicillins fell from 39 to 30%, but comparisons to other studies using different DDD val- overall antibiotic consumption still increased 66% ues can be misleading, and should appropriately (rather than a 65% increase from 21.1 to 34.8 billion caution readers.

aCenter for Disease Dynamics, Economics & Policy, Washington, DC 20005; bDepartment of Emergency Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21209; cDepartment of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205; dDepartment of Ecology and Evolutionary Biology, Princeton University, Princeton, NJ 08544; ePrinceton Environmental Institute, Princeton University, Princeton, NJ 08544; fBeijer Institute of Ecological Economics, SE-104 05 Stockholm, Sweden; gLaboratory of Medical Microbiology, Vaccine & Infectious Diseases Institute, University of Antwerp, 2610 Antwerp, Belgium; and hDepartment of Global Health, University of Washington, Seattle, WA 98104 Author contributions: E.Y.K. designed research; E.Y.K. and K.K.T. performed research; E.Y.K. and K.K.T. analyzed data; and E.Y.K., K.K.T., S.A.L., H.G., and R.L. wrote the paper. The authors declare no conflict of interest. Published under the PNAS license. 1To whom correspondence should be addressed. Email: [email protected].

www.pnas.org/cgi/doi/10.1073/pnas.1817182115 PNAS Latest Articles | 1of3 Downloaded by guest on September 25, 2021 Fig. 1. Global antibiotic consumption by country, 2015. Antibiotic consumption rate by country for 2015 in DIDs using modified DDD values for 2018 and 2019. The mean percentage decrease for countries from prior reported values (5) was −13% (SD, 5%). Data source: IQVIA MIDAS, 2000–2015, IQVIA Inc. All rights reserved (https://www.iqvia.com/solutions/commercialization/geographies/midas).

Table 1. Change of DDDs for molecules in the ATC/DDD Index Route of Previous New Year of ATC code Antibiotic administration DDD, g* DDD, g implementation

J01CA04 Amoxicillin Parenteral 1.00 3.00 2019 J01CA04 Amoxicillin Oral 1.00 1.50 2019 J01CR02 Amoxicillin/ Oral 1.00 1.50 2019 clavulanic acid J01CA01 Ampicillin Parenteral 2.00 6.00 2019 J01DE01 Cefepime Parenteral 2.00 4.00 2019 † J01DB11 Cefroxadine Oral 2.10 2.10 2019 J01DD18 Cefteram pivoxil Oral 0.60 0.40 2019 J01MA02 Ciprofloxacin Parenteral 0.50 0.80 2019 J01XB01 Colistin Oral/ 0.24 0.72 2019 parenteral † ‡ J01XA04 Dalbavancin Parenteral 1.50 1.50 — † J01MA19 Garenoxacin Oral 0.40 0.40 2019 † J01MA15 Gemifloxacin Oral 0.32 0.32 2019 J01MA07 Lomefloxacin Oral 0.60 0.40 2019 J01DH02 Meropenem Parenteral 2.00 3.00 2019 J01FA03 Midecamycin Oral 1.00 1.20 2019 J01DH06 Tebipenem Oral 0.84 0.56 2019 † ‡ J01XX11 Tedizolid Oral/ 0.20 0.20 — parenteral J01CA17 Temocillin Parenteral 2.00 4.00 2019 J01MA22 Tosufloxacin Oral 0.60 0.45 2019

*These are the values used in Klein et al. (5). † Molecules for which new DDDs for implementation in the ATC/DDD Index in 2019 were the same as those used in previous analyses. ‡ The DDDs will be reviewed at the March 2019 meeting (3-y revision).

2of3 | www.pnas.org/cgi/doi/10.1073/pnas.1817182115 Klein et al. Downloaded by guest on September 25, 2021 1 Engel A, Siderius P (1967) The Consumption of Drugs: Report of a Study 1966-1967 (World Health Organization, Geneva). 2 Bergman U, et al. (1975) The measurement of drug consumption. Drugs for diabetes in Northern Ireland, Norway and Sweden. Eur J Clin Pharmacol 8:83–89. 3 World Health Organization (2003) Introduction to Drug Utilization Research (World Health Organization, Geneva). Available at https://www.whocc.no/filearchive/ publications/drug_utilization_research.pdf. Accessed October 15, 2018. 4 Charra F, Berthelot P, Bergheau F (2018) Penicillins’ defined daily doses must be changed. Proc Natl Acad Sci USA, 10.1073/pnas.1816558115. 5 Klein EY, et al. (2018) Global increase and geographic convergence in antibiotic consumption between 2000 and 2015. Proc Natl Acad Sci USA 115:E3463–E3470. 6 Vlahovi´c-PalcevskiV, Gantumur M, Radosevi´cN,Palcevskiˇ G, Vander Stichele R (2010) Coping with changes in the defined daily dose in a longitudinal drug consumption database. Pharm World Sci 32:125–129.

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