Albania, Armenia, Azerbaijan, Belarus, Bosnia and Herzegovina, Georgia, Kazakhstan, Kyrgyzstan, Montenegro, North Macedonia, the Republic of Moldova, the Russian Federation, Serbia, Tajikistan, Turkey, Ukraine and Uzbekistan, as well as Kosovo,2 currently are engaged in the WHO Europe AMC Network. Of these, 16 countries and Kosovo2 gave permission by the cut-off date of 20 March 2019 for the data to be published.
References
ECDC (2018). European Surveillance of Antimicrobial Consumption Network (ESAC-Net). In: European Centre for Disease Prevention and Control [website]. Solna: ECDC (https://ecdc. europa.eu/en/about-us/partnerships-and-networks/disease-and-laboratory-networks/esac-net, accessed 1 April 2019).
ECDC (2019). ESAC-Net Reporting Protocol 2018. Solna: ECDC (https://ecdc.europa.eu/en/publications-data/esac-net-reporting-protocol-2018, accessed 1 April 2019).
ECDC, European Food and Safety Authority, European Medicines Agency (2017a). ECDC/EFSA/
EMA second joint report on the integrated analysis of the consumption of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from humans and food-producing animals.
Joint Interagency Antimicrobial Consumption and Resistance Analysis (JIACRA) report. EFSA J.
15(7):4872. doi:10.2903/j. efsa.2017.4872.
ECDC, European Food and Safety Authority, European Medicines Agency (2017b). Joint scientific opinion on a list of outcome indicators as regards surveillance of antimicrobial resistance and antimicrobial consumption in humans and food-producing animals. Stockholm: European Centre for Disease Prevention and Control, European Food Safety Authority, European Medicines Agency;
2017 (https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2017.5017, accessed 1 April 2019).
World Health Organization (2018). WHO report on surveillance of antibiotic consumption 2016–2018:
early implementation. Geneva: World Health Organization (https://www.who.int/medicines/areas/
rational_use/oms-amr-amc-report-2016-2018/en/, accessed 1 April 2019).
3. DATA COLLECTION AND ANALYSIS
3�1 Methodology
3.1.1 Definitions
As in the previous WHO Regional Office for Europe report (WHO Regional Office for Europe, 2017) and in line with the WHO global protocol for data collection (WHO, 2016), a distinction is made between consumption data and antimicrobial-use data. This is done to recognize differences in the data sources and in the type of information that may be obtained from each approach.
• Consumption data are used to refer to estimates derived from aggregated data sources such as import or wholesaler data or aggregated health insurance data, where no information is available on the patients receiving the medicines or why the antimicrobials are used. These data sources provide a proxy estimate of use of antimicrobials. Consumption data may be presented as total consumption for a country/area or may be disaggregated by setting (community or hospital; public or private sectors).
• Antimicrobial-use data are used to refer to estimates derived from patient-level data. These may allow disaggregation based on patient characteristics (such as gender or age) or indications for which the medicine is being used.
3�1�2 Antimicrobials included in monitoring
The WHO Europe AMC Network programme focuses only on antimicrobials for systemic use – it excludes topical antimicrobials. The core set of agents that all countries and areas include in their monitoring is as follows:
• antibacterials (J01)
• antibiotics for alimentary tract and metabolism (A07AA)
• nitroimidazole derivatives against amoebiasis and other protozoal diseases (P01AB).
In addition, the WHO surveillance programme includes an optional list of antimicrobials that countries and areas may include in their surveillance programmes according to local needs and resources:
• antimycotics for systemic use (J02)
• antifungals for systemic use (D01BA)
• antivirals for systemic use (J05)
• drugs for treatment of tuberculosis (J04A)
• antimalarials (P01B).
This report builds on the early experience of data collection at country and area levels. It provides an analysis of data collected between 2011 and 2017 and includes several comparisons across the AMC Network for selected measures of AMC. The results mainly relate to analyses of antimicrobial agents in ATC group J01.
3�1�3 Health-care sectors monitored
In most of the countries and areas participating in the WHO Europe AMC Network, it is not possible to disaggregate data by sector (community or hospital; public or private), so total consumption data are reported in most cases. Analyses are also reported by community and hospital sectors separately where disaggregated data are available.
3�1�4 Measurements used
The WHO Europe AMC Network uses the ATC classification system, and the most commonly used measurement metric is the number of DDDs/1000 inhabitants per day. The ATC classification system allows flexibility in reporting by medicine or groups of medicines (WHO Collaborating Centre for Drug Statistics Methodology, 2018a). Medicines are classified in groups at five levels. Most antimicrobial agents are classified in ATC main group J: anti-infectives for systemic use.
The DDD is the assumed average maintenance dose per day for a medicine used for its main indication in adults (WHO Collaborating Centre for Drug Statistics Methodology, 2018b). The DDD is a technical unit of use and does not necessarily reflect the recommended or average prescribed daily dose. It is a useful metric that allows comparisons within and between countries and areas.
3�1�4�1 Changes to DDD values in 2019
In October 2017, following an application from the ECDC, the WHO International Working Group for Drug Statistics Methodology recommended changes to the DDDs for seven commonly used antibiotics (mainly penicillins) and endorsed new DDDs for oral colistin along with changes for several other products (Table 3.1) (WHO Collaborating Centre for Drug Statistics Methodology, 2018c). The changes were requested given evidence that current DDD allocations for commonly used medicines differed substantially from recommended doses and doses used in clinical practice. The DDD changes have been adopted fully since January 2019 and will affect estimates of total AMC and relative use of classes of antibiotics. The interpretation of national estimates and comparisons across the AMC Network over time will need to take account of these changed DDD values.
In addition to the changes shown in Table 3.1, new DDDs were assigned in 2019 for kanamycin oral (A07AA08), colistin oral (A07AA10), cefroxadine (J01DB11), cefteram (J01DD18), ceftriaxone and beta-lactamase inhibitor (J01DD63), tebipenem pivoxil (J01DH06), faropenem (J01DI03), midecamycin (J01FA03), lomefloxacin (J01MA07), gemifloxacin (J01MA15), garenoxacin (J01MA19), tosufloxacin (J01MA22) and delafloxacin (J01MA23).
Table 3.1 2019 changes to DDDs for commonly prescribed J01 antibacterials
ATCa code Medicine Previous DDDb New DDD
J01CA04 Amoxicillin 1 g Oc 1.5g O
J01CA04 Amoxicillin 1 g Pd 3g P
J01CA17 Temocillin 2 g 3 g P
J01CR02 Amoxicillin and beta-lactamase inhibitor 1 g O 1.5g O
J01CA01 Ampicillin 2 g P 6g P
J01DE01 Cefepime 2 g P 4g P
J01DH02 Meropenem 2 g P 3g P
J01MA02 Ciprofloxacin 0.5 g P 0.8g P
J01XB01 Colistin 3 MUe P 9 MU P
a ATC: Anatomical Therapeutic Chemical. b DDD: defined daily dose. c O: oral. d P: parenteral. e MU: million units.
Source: WHO Collaborating Centre for Drug Statistics Methodology (2018d).
3�1�4�2 Consumption according to the WHO Access, Watch and Reserve group classification
In April 2017, the Expert Committee on the Selection and Use of Essential Medicines recommended changes to the WHO model lists of essential medicines for adults (EML) and children (EMLc) following a comprehensive review of sections 6.2.1 (Beta-lactam medicines) and 6.2.2 (Other antibacterials) (WHO, 2017a, 2017b; Sharland et al., 2018). The Committee identified empirical first- and second-choice treatments for a number of common, community-acquired infections, focusing on treatment choices broadly applicable in most countries and areas.The Expert Committee also proposed a categorization of antibiotics into Access, Watch and Reserve groups (Table 3.2–3.5). Not all medicines on the model lists were assigned to the three groups, leaving a fourth “ungrouped” category, with the classification to be revised as additional clinical syndromes are reviewed. However, this classification could support antimicrobial stewardship efforts and focus attention on prescribing practices that should be reviewed further.
The Access group includes first- and second-choice antibiotics that should be widely available in all countries and areas. They should be affordable and quality-assured.
The Watch group includes antibiotic classes that generally are considered to have higher resistance potential and which remain recommended as first- or second-choice treatments but for a limited number of indications. These medicines should be “prioritized as key targets of local and national stewardship programmes and monitoring” (WHO, 2017a). The group includes the highest-priority agents on the critically important antibiotics list (World Organisation for Animal Health 2015; WHO, 2017c) and/or antibiotics that are at relatively high risk of selection of bacterial resistance.
The Reserve group of antibiotics includes antibiotics and antibiotic classes that the Expert Committee considered as last-resort agents, that is, those to be used when other alternatives would be inadequate or have already failed in, for example, serious life-threatening infections due to multidrug-resistant bacteria.
It is therefore useful to monitor the relative use of these classes of agents that should be used sparingly and judiciously to preserve their value for clinical medicine. Several agents in the Watch list are also included in the Access list but only for use in specific, limited indications. The analyses presented in this report use a Core Access group of agents that has no overlap with the Watch group antibiotics (see Table 3.3). The report also includes an assessment of the extent to which Watch and Reserve group antibiotics are included in the top 10 consumed oral and parenteral agents.
Table 3.2 WHO categories of antibiotics – descriptions
Group Definition
Access group First- and second-choice antibiotics that should be widely available in all countries and areas; they should be affordable and quality-assured
Watch group First- and second-choice antibiotics that should be used only for a specific, limited number of indications due to higher resistance potential
Reserve group Last-resort antibiotics that should be used only when other antibiotics have failed or for infections of multi-resistant bacteria
Ungrouped Medicines not specifically identified in the groups described above
Table 3.3 Access group
Medicine ATC codea Medicine ATC codea
Beta-lactam medicines Other antibacterials
amoxicillin J01CA04 amikacin J01GB06
amoxicillin + clavulanic acid J01CR02 azithromycinb –
ampicillin J01CA01 chloramphenicol J01BA01
benzathine benzylpenicillin J01CE08 ciprofloxacinb –
benzylpenicillin J01CE01 clarithromycinb –
cefalexin J01DB01 clindamycin J01FF01
cefazolin J01DB04 doxycycline J01AA02
cefiximeb – gentamicin J01GB03
cefotaximeb – metronidazole J01XD01, P01AB01
ceftriaxoneb – nitrofurantoin J01XE01
cloxacillin J01CF02 spectinomycin J01XX04
phenoxymethylpenicillin J01CE02 sulfamethoxazole + trimethoprim J01EE01
piperacillin + tazobactamb – vancomycin (oral, parenteral)b –
procaine benzylpenicillin J01CE09 – –
a ATC codes shown for medicines in the core access list – that is, no overlap with Watch group antibiotics.
b Watch group antibiotics included in the EML/EMLc only for specific, limited indications.
Table 3.4 Watch group
Medicines ATC code
Quinolones and fluoroquinolones
such as ciprofloxacin, levofloxacin, moxifloxacin, norfloxacin J01MA, J01MB Third-generation cephalosporins (with or without beta-lactamase inhibitor)
such as cefixime, ceftriaxone, cefotaxime, ceftazidime J01DD
Macrolides
such as azithromycin, clarithromycin, erythromycin J01FA
Glycopeptides
such as teicoplanin, vancomycin J01XA, A07AA09
Antipseudomonal penicillins with beta-lactamase inhibitor
such as piperacillin + tazobactam J01CR03, J01CR05
Carbapenems
such as meropenem, imipenem + cilastatin J01DH
Penems
such as faropenem J01DI03
Table 3.5 Reserve group
Medicine ATC code
Aztreonam J01DF01
Fourth-generation cephalosporins
such as cefepime J01DE
Fifth-generation cephalosporins
such as ceftaroline J01DI02, J01DI01, J01DI54
Fosfomycin IV J01XX01 (Only parenteral)
Oxazolidinone
such as linezolid J01XX08, J01XX11
Polymxyins
such as polymyxin B, colistin J01XB, A07AA10, A07AA05
Tigecycline J01AA12
Daptomycin J01XX09
Note: medicines not specifically identified in the groups described form an “ungrouped” medicines category.
A more detailed description of the WHO Access, Watch and Reserve (AWaRe) classification is available in the WHO global report on antimicrobial medicines consumption (WHO, 2018).