Download Per Capita Antibiotic Consumption: How Does a North American

MAJOR ARTICLE
Per Capita Antibiotic Consumption: How Does a
North American Jurisdiction Compare with Europe?
David M. Patrick,1 Fawziah Marra,1 James Hutchinson,3 Dominique L Monnet,4 Helen Ng,1 and William R. Bowie2
1
Centre for Disease Control and 2Department of Medicine, University of British Columbia, Vancouver, and 3Department of Medicine,
Memorial University, St. John’s, Newfoundland, Canada, and 4Statens Serum Institut, Copenhagen, Denmark
(See the editorial commentary by Davies on pages 18–9)
Antibiotic consumption in populations affects the emergence of resistant organisms. We compared 1996–2000
trends in consumption in British Columbia, Canada, with those in Europe. Prescription data from the British
Columbia PharmaNet database were converted into SAS files and classified using the Anatomical Therapeutic
Chemical system, and weights of antibiotics were converted into defined daily doses (DDDs) using the 2001
definitions from the World Health Organization Collaborating Center for Drug Statistics Methodology. During
1996–2000, consumption in British Columbia decreased from 19.5 to 17.9 DDDs/1000 inhabitant-days. Although antibiotic consumption in British Columbia was less than the European median in 2000, it exceeded
that in northern European countries with established antibiotic surveillance and control programs. The consumption rates for fluoroquinolones, newer macrolides, and cephalosporins in British Columbia exceeded
those in Denmark (1.44 vs. 0.15, 1.59 vs. 0.92, and 1.86 vs. 0.02 DDDs/1000 inhabitant-days, respectively).
The observed increase in and pattern of consumption associated with newer antimicrobials may increase the
risk for emergence of antimicrobial-resistant organisms in British Columbia.
Overuse of antibiotics has contributed to the emergence
and spread of antimicrobial-resistant organisms
(AROs). AROs are a global threat affecting industrialized and developing nations [1, 2]. Until recently, the
major emphasis for study of bacterial resistance was
confined to hospital-acquired microorganisms, such as
Staphylococcus aureus, enterococci, and Pseudomonas
aeruginosa [3–5]. However, increasing resistance has
been observed in community-acquired microbes such
as Streptococcus pneumoniae, Haemophilus influenzae,
and Moraxella catarrhalis, which are key pathogens in
respiratory tract infections; Escherichia coli, which is a
common pathogen in urinary tract infections; and
group A streptococci, the cause of streptococcal pharyngitis and many skin and soft-tissue infections [4–9].
Received 8 December 2003; accepted 25 January 2004; electronically published
1 June 2004.
Reprints or correspondence: Dr. David M. Patrick, Div. of Communicable Disease
Epidemiology, UBC Centre for Disease Control, 655 W. 12th Ave., Vancouver, BC
V5Z 4R4 ([email protected]).
Clinical Infectious Diseases 2004; 39:11–7
2004 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2004/3901-0003$15.00
Factors contributing to antimicrobial resistance include natural selection imposed by widespread use of
antimicrobial agents in humans [10–12]. Reasons cited
for antimicrobial overuse include defensive and unnecessary prescribing, perceived or real pressure from
patients and parents of patients to prescribe drugs, inadequate knowledge of the proper indications for some
drugs, lack of awareness of prescription guidelines, lack
of time to explain to the patient that antimicrobials are
not needed, lack of education about resistance patterns
in the community, and fee-for-service remuneration of
physicians [2, 13, 14].
Enhanced antimicrobial surveillance is one of the
strategies that can be used to guide control of antimicrobial overuse or misuse. This is because the ability
to study population-based patterns of antimicrobial use
provides a more comprehensive understanding of how
the physician and patient use these agents. Countries
such as Denmark and Spain have databases containing
information on antimicrobials prescribed for all patients in the country. Prescription information for various populations (e.g., children versus adults) and between jurisdictions (i.e., provinces within the country)
Per Capita Antibiotic Consumption • CID 2004:39 (1 July) • 11
are analyzed to determine trends in antimicrobial use at the
population level and to determine key factors driving antimicrobial consumption [11, 12, 15–22].
Such data on the use of antimicrobial agents at the population level are comparatively lacking in North America. This
is partly because such databases are not available in the United
States, where separate records are maintained by health maintenance organizations. British Columbia, Canada, is one of the
only political jurisdictions in North America with a database
(British Columbia PharmaNet) that contains virtually all prescription drug data for outpatient residents. This study was
designed to determine trends in community-based antibiotic
consumption for 4.2 million residents of Canada’s westernmost province and to compare those trends with available data
from Europe.
METHODS
British Columbia’s PharmaNet system is a population-based
prescription drug database that captures nearly all antimicrobial
consumption by outpatient residents of the province on a prescription-by-prescription basis. Oral and parenteral antimicrobials may only be accessed by prescription at pharmacies, all
of which are required to enter drug and dosage information
into the Web-based PharmaNet system. A central data repository is held at the British Columbia Ministry of Health. Underreporting and misclassification appear to be minimal. Outpatient drugs that are not so captured are those dispensed by
the BC sexually transmitted diseases control program (0.02
defined daily doses [DDDs] per 1000 inhabitant-days; BC Centres for Disease Control pharmacy, unpublished data) and antiretroviral agents dispensed by the BC HIV treatment program
(not cogent to this analysis). Samples of antibiotics distributed
by physician offices represent small but unmeasured additional
contributions.
The data examined spanned September 1995 through December 2000 and included the patients’ age and sex; the antimicrobial agent prescribed, according to the Anatomical Therapeutic Chemical (ATC) classification system; and the date and
total quantity dispensed. The format of the downloaded data
from British Columbia PharmaNet allowed for precise measurement of the total dose consumed by each patient but did
not allow discernment of the total dose and dosage for each
individual prescription.
Drugs were classified according to the 5 different levels of
the ATC classification. For example, azithromycin would be
classified as follows: first level, general anti-infective drug for
systemic use; second level, antibacterial therapy for systemic
use; third level, macrolide and lincosamide; fourth level, macrolide; and fifth level, azithromycin.
Antimicrobials included in the database were for systemic
12 • CID 2004:39 (1 July) • Patrick et al.
use (ATC code J01). For this study, we evaluated trends for
penicillins (ATC code J01C), macrolides (J01FA), tetracyclines
(J01AA), cephalosporins (J01DA), fluoroquinolones (J01MA),
lincosamides (J01FF), trimethoprim and derivatives (J01EA),
and combinations of sulfonamides and trimethoprim (J01EE).
Dosage trends were standardized using the ATC/DDD index
for international drug consumption studies [23]. The DDD is
a technical unit based on the “assumed average maintenance
dose per day for a drug used for its main indication in adults.”
The consumption rate is most commonly expressed as the
number of DDDs per 1000 inhabitants per day. Population
estimates were provided by British Columbia Stats.
Raw data from 9,481,043 records of aggregate antimicrobial
use spanning September 1995 through December 2000 were
received from British Columbia PharmaNet on 192 separate
Excel spreadsheets (Microsoft). Data were imported into SAS
software (version 8.02; SAS Institute) and reviewed for completeness of fields. Frequency tables were produced to quantify
missing variables in all records. Less than 0.1% of data were
missing for each field used in these analyses. The generic sequencing numbers (GCNs; 5-digit codes that uniquely identify
specific drug/form/strength combinations in the raw data set)
were extracted, and a data dictionary was created by assigning
the appropriate ATC category and DDD conversion factor to
each GCN. DDD conversion factors were based on the 2001
version of the ATC/DDD index produced by the World Health
Organization Collaborating Center for Drug Statistics Methodology [23].
The analyses were performed using SAS software and focused
on data recorded between 1996 and 2000. Consumption was
plotted by year, age group, sex, geographic region, and antibiotic class or compound. Published comparisons were obtained using data posted on the Web by the European Surveillance of Antimicrobial Consumption Study [24–31],
DANMAP [32], and direct communication with a coauthor
(D.L.M.) of one of the ESAC studies [30]. Statistical tests suitable for assessing the accuracy of inference for a sample were
Figure 1. Median antibiotic consumption in British Columbia (BC) and
Europe, 1996–2000.
Figure 2. Antibiotic consumption in 2000 in British Columbia (BC) and select European countries. DK, Denmark; FR, France; GE, Germany; GR,
Greece; NL, The Netherlands; SE, Sweden; UK, United Kingdom.
not employed, because British Columbia and European data
used in this and comparative publications represented total
population ambulatory use and were not obtained from a sampling framework.
RESULTS
Overall antibiotic consumption. During 1996–2000, the rate
of antibiotic consumption (ATC group J01) in British Columbia
decreased 8.2%, from 19.5 to 17.9 DDDs/1000 inhabitant-days
(figure 1). This was just below the median European consumption rate (19–20 DDDs/1000 inhabitant-days) between
1998 and 2000. However, figure 2 underscores the heterogeneity
of consumption within Europe. British Columbia is consuming
fewer DDDs of antibiotics per capita than are high-consumption European countries (e.g., France and Greece). Yet antibiotic consumption in British Columbia considerably exceeded
that in northern European countries with more-developed antimicrobial-control programs.
Figure 3.
Seasonality, age, and sex distribution. An association between seasonality and antibiotic consumption was revealed by
the finding that peak use occurred between January and March
of each year of the study (figure 3). The mean seasonal variation
for British Columbia, calculated by comparing antibiotic consumption during quarters 1 and 4 with that during quarters 2
and 3 over this period, was 21.6%. Year 2000 consumption
rates by age and sex for the province are displayed in figure 4.
Recall that the apparent lower rates among children are an
artifact of the DDDs being based on typical adult doses. Overall,
female patients consumed 17% more antibiotics during 2000
than did male patients (19.3 vs 16.5 DDDs/1000 inhabitantdays). Overall antibiotic consumption was higher for patients
aged 15–19 and 165 years than for those in other age groups.
Class-specific trends. Figure 5 illustrates trends in consumption of the major classes of antibiotics for 1997–2000 in
British Columbia and Denmark. The rate of consumption was
∼50% higher in British Columbia during each year of the study.
Seasonal variation in antibiotic consumption in British Columbia (top) and Denmark (bottom), 1997–2000
Per Capita Antibiotic Consumption • CID 2004:39 (1 July) • 13
Figure 4.
Antibiotic consumption by age group and sex, British Columbia, 2000
Although overall b-lactam use was similar in the 2 jurisdictions,
comparatively few cephalosporins were used for outpatient care
in Denmark. It is also notable that the rate of outpatient fluoroquinolone consumption in British Columbia exceeded that in
Denmark by nearly 10-fold.
A comparison of antimicrobial use in British Columbia in
1996 and 2000 showed that b-lactams accounted for a high but
decreasing proportion of overall antibiotic consumption (45%
[8.77 DDDs/1000 inhabitant-days] vs. 42% [7.47 DDDs/1000
inhabitant-days]). Overall tetracycline and macrolide consumption remained stable between 1996 and 2000, but a dramatic 44% increase in the fluoroquinolone consumption rate
(1.01 vs. 1.44 DDDs/1000 inhabitant-days) was observed (figure
6). Of note, most of the overall increase in fluoroquinolone
consumption was accounted for by the use of 1 drug: ciprofloxacin consumption increased from 0.68 to 1.02 DDDs/1000
inhabitant-days during 1996–2000.
Although overall macrolide consumption has not changed
Figure 5.
substantially in British Columbia, there has been increased use
of the newer macrolides azithromycin and clarithromycin, with
a far greater consumption of the latter drug in British Columbia
than in Denmark (figure 7). Consumption of these compounds
increased 67% during 1996–2000, whereas consumption of
erythromycin steadily decreased.
DISCUSSION
To our knowledge, this is the first report of population-based
rates of antibiotic consumption in a province or state in North
America. The existence of a population-based pharmaceutical
prescription database and the earlier development by others of
widely accepted standards and methodology facilitated the
work.
Although British Columbia experienced an 8.2% decrease in
the rate of antibiotic prescribing between 1996 and 2000, antibiotics were consumed at a rate of 17.9 DDDs/1000 inhabi-
Antibiotic consumption by drug class, British Columbia (BC) and Denmark (DK), 1997–2000
14 • CID 2004:39 (1 July) • Patrick et al.
Figure 6.
Fluoroquinolone consumption in British Columbia (top) and Denmark (bottom), 1997–2000
tant-days during 2000, which was 46% higher than the consumption rate of 12.3 DDDs/1000 inhabitant-days recorded in
Denmark. Indeed, consumption rates in British Columbia consistently exceed those in northern European countries, such as
Denmark, Sweden, and the United Kingdom.
Of more concern than the overall rate of consumption is
that patients in British Columbia consumed proportionately
more DDDs of fluoroquinolones and newer macrolides per
capita than did patients in northern European countries. This
increase may be accounted for in part by the greater emphasis
on adherence to recent respiratory infection guidelines [33].
However, it is also likely that aggressive marketing of newer
agents and a lack of comprehensive antibiotic-control programs
have had an effect on consumption rates. These data do not
allow us to comment conclusively on whether this difference
is due to inappropriate prescription, but the magnitude of the
difference between British Columbia and a country, Denmark,
that has similar life expectancy and similar rates of reporting
of infectious diseases and infectious diseases–specific mortality
raises questions. The potential for emergence of resistance
among community-acquired organisms, especially pneumococci, to these classes of agents is of concern. In contrast, although b-lactams comprise a high but decreasing proportion
of antibiotics prescribed, a high rate of use would seem to be
appropriate because of their role as first-line therapy for many
common indications.
Further work planned by our group will address reasons for
the prescription of specific compounds. We also need to correlate antimicrobial consumption among humans with rates of
identification and emergence of antimicrobial-resistant organisms in British Columbia. It should be recognized that, although
use of antimicrobials in human populations may indeed drive
resistance, other variables also play a role. Population density,
the effect of importation and subsequent spread of antibioticresistant organisms from countries with established problems,
and antimicrobial use in animals may also influence the emergence of resistance among humans [2, 13, 34].
A few other observations are worthy of comment. The observed pattern of seasonal variation in British Columbia (22%
increase between quarters 1 and 4 and quarters 2 and 3) is a
pattern typical in northern European countries with lower overall antibiotic use [24]. Countries with higher use often see a
more marked (i.e., 130%) seasonal swing.
Consumption by female patients exceeded that by male patients, especially during the reproductive years. Females are
known to more actively seek health care and to attend physicians’ offices more frequently. Some classes of infection, such
as urinary tract infection, are also objectively more common
among females.
This study has a number of limitations. First, the format of
the download from British Columbia PharmaNet allowed for
precise measurement of total amounts of drugs consumed but
not discernment of the total dose, dosage, and volume of each
individual prescription. As a result, it was not possible to es-
Figure 7. Macrolide consumption by agent, British Columbia (BC) and
Denmark (DK), 1996–2000.
Per Capita Antibiotic Consumption • CID 2004:39 (1 July) • 15
timate how many individual prescriptions were supplied (e.g.,
to children). This will be addressed with future data exchanges.
The inability to count prescriptions in children leads to a reliance on describing consumption on the basis of DDDs for
adults. This creates a systematic underestimate of the extent of
antimicrobial consumption in infants and young children.
These deficiencies will be addressed in future downloads from
and collaborations with British Columbia PharmaNet.
We have reported the first population-based study of antimicrobial consumption in a North American province or
state and, in doing so, have demonstrated a measurably higher
rate of antimicrobial consumption in British Columbia than
that in northern Europe. This is a critical first step in designing approaches to prevent the emergence of antimicrobial
resistance through measurement and guidance of antimicrobial prescribing.
19.
Acknowledgments
20.
We thank the College of Pharmacists of British Columbia, for collaborating to arrange this analysis; the BC Ministry of Health, for assisting with
initial data compilation; and Rick White, for statistical and analytic
assistance.
Financial support. Pfizer Canada and the University of British Columbia Centre for Disease Control.
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