Non-hospital consumption of antibiotics in Spain: 1987–1997

A. Ruiz Bremóna, M. Ruiz-Tovara,*, B. Pérez Gorrichob, P. Díaz de Torresc and R. López Rodríguezc

a Centro Nacional de Epidemiología, Instituto de Salud Carlos III, Sinesio Delgado 6, 28029 Madrid, Spain; b Niño Jesús Children's Teaching Hospital; c Sub-Directorate General for Drug Regulation, Ministry of Health and Consumer Affairs

Abstract

Spain has one of the highest incidences of bacterial resistance to antimicrobials, possibly linked to drug consumption patterns. Using Ministry of Health and Consumer Affairs records, data were obtained on non-hospital sales of antibiotics for the period 1987–1997, and equivalents calculated in weight of active drug ingredient and defined daily doses per 1000 population per day (DDD/1000/day). The number of packages sold declined from 75 million in 1987 to 55 million in 1997. None the less, there was a gradual yet steady rise in consumption in tonnage terms (249 to 275 tonnes). Furthermore, in terms of DDD/1000/day, consumption rose sharply until 1995 and then held steady at 21 DDD/1000/day, a level comparable to the mean for other developed countries. Penicillins were the group to register the highest consumption in Spain, followed—in the latter years of the study—by macrolides, cephalosporins and quinolones. The marked rise in these latter three groups was noteworthy. Despite the decrease in the number of packages sold, antibiotic consumption in Spain has risen. This consumption pattern is different from that of other European countries and might serve to explain differences in the generation of resistance.

Introduction

Pharmacological surveillance, in the form of analysis of antibiotic consumption data, is essential for the study and control of the evolution of bacterial resistance.1 Knowledge of antibiotic consumption trends will enable measures to be adopted governing future use, with the aim of avoiding unnecessary healthcare costs and preventing possible ecological effects that might lead to selection of resistance.2 Many studies suggest that the dominant factor underlying the spread of bacterial resistance is the rise in consumption of antibiotics.3–5 Furthermore, infections caused by resistant bacteria are associated with higher morbidity, mortality and treatment costs than those caused by sensitive bacteria.6

According to the 1995 National Health Survey (Encuesta Nacional de Salud), 8% of the Spanish population reported having consumed an antibiotic of some sort in the 2 weeks immediately preceding the interview.7 In the average hospital, one out of every three patients admitted is reckoned to be on antibiotic therapy, with the cost of hospital use of antibiotics exceeding 25 billion pesetas (150 million Euros).8

In 1997, non-hospital expenditure financed by the National Health System amounted to 93 billion pesetas (559 million Euros) for the 55 million unit-packages of systemic antibiotics dispensed (group J01).9

In the scientific community, Spain is classified as having one of the highest bacterial resistance rates worldwide, particularly in the following community pathogens: Streptococcus pneumoniae, Haemophilus influenzae, Escherichia coli and Salmonella spp.10 This situation might be linked to consumption of the drugs in question in the community, accounting for 92% of total consumption.11–13

From a historical perspective, the hyperconsumption peak-plateau in unit-packages and daily doses per 1000 population per day (DDD/1000/day) of antimicrobials in Spain took place in the period immediately before 1976. According to International Marketing Statistics,11 in 1976, retail pharmacies in Spain dispensed a total of 110 million packages, yielding a breakdown of 31 DDD/1000/day. At present, the figures in unit-packages for other European countries, such as Denmark, England and Germany (all low-consumption countries in European terms), represent less than a quarter of the consumption in Spain.11,13–14 In terms of consumption, antimicrobials in Spain rank in the following order: extended spectrum penicillins (ESPs), tetracyclines, cephalosporins, aminoglycosides and reduced spectrum penicillins.11

This study sought to examine the overall trend for total non-hospital antibiotic prescriptions in Spain, expressed in number of packages sold, weight and DDD/1000/day, for the period 1987–1997, plus the specific trends for the major therapeutic groups.

Materials and methods

The Ministry of Health and Consumer Affairs keeps a drug database with a package-by-package record of all retail pharmacy sales of any drugs acquired on National Health System prescriptions. Since 1985, this information has been available in computerized format. This database was used to gather information on sales in Spain for the period 1987–1997, in respect of the following groups of antibiotics: ESPs (amoxycillin, ampicillin, pivampicillin, bacampicillin and similar types), ß-lactamase-sensitive penicillins (benzylpenicillin and phenoxymethylpenicillin) and -resistant penicillins (dicloxacillin, cloxacillin and flucloxacillin), macrolides, cephalosporins, amphenicols, aminoglycosides, quinolones, tetracyclines, lincosamides, monobactams, carbapenems, glycopeptides, polymyxins, fusidic acid and fosfomycin. Data collection covered all cases of systemic administration of antibiotics, including those where antimicrobials were combined with other drugs.

The information was tabulated by taking into account the number of packages of each proprietary brand sold every year, converting the number of units sold into their equivalent in weight of active drug ingredient and calculating the number of DDD/1000/day for each such active drug ingredient. For the purpose, we used daily doses as defined either by the WHO Collaborating Centre for Drug Statistics Methodology15 or, in cases where these were unavailable in this source, by the Andalusian Health System Working Group for DDD determination,16 always using the same DDD for any given active drug ingredient, regardless of the pharmaceutical form.

The percentage change in sales between the first and last year of the study period was calculated for each antibiotic group, in weight, DDD/1000/day and number of packages, and linear regression models were used to calculate annual changes in these same indicators for all antimicrobials as a whole.

Results

Figure 1Go shows antibiotic sales in Spain for the period 1987– 1997, by reference to the three indicators used, i.e. number of packages, their corresponding gross weight and equivalent in DDD/1000/day. In the non-hospital sector, a marked decline was observed in the number of packages sold (–27%), a decrease of 1.98 million p.a. (95% CI, 2.37–1.59). Tonnage-based consumption rose by 2.62 tonnes per year (95% CI, 1.52–3.72), amounting to a 10% increase for the period overall. The bottom section of the figure depicts consumption in DDD/1000/day, with a yearly rise of 0.45 DDD/1000/day (95% CI, 0.37–0.53). Consumption rose steadily until 1993 and appeared to flatten out thereafter.



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Figure 1. Non-hospital antibiotic sales in Spain, 1987–1997. Weight of active drug ingredients, number of packages and DDD/1000/day.

 
Figure 2Go shows proportional distribution of non-hospital sales by therapeutic group expressed in DDD/1000/day for 1987, 1990, 1993 and 1997. In each case, ESPs were by far the largest selling group.



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Figure 2. Proportional distribution of non-hospital antibiotic sales in Spain by therapeutic group. DDD/1000/day for 1987, 1990, 1993 and 1997.

 
Sales trends in Spain (1987–1997) for the major antibiotic groups are shown in Figure 3Go, plotted on a semi-logarithmic scale and expressed in defined daily doses per thousand population. The highest sales in the study period were recorded for the ESP therapeutic group (see also TableGo), registering small variations over the period and a gradual rise from 1994. Within this group, co-amoxiclav usage rose from 1.3 DDD/1000/day in 1987 to over 4 in 1997. Oral penicillin prescriptions remained stable at around 30 million packages p.a., while prescriptions of injectable solutions declined from 38 million packages in 1987 to 9 million in 1997.



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Figure 3. Non-hospital antibiotic sales in Spain 1987–1997. Temporal trends for the major antibiotic groups (semi-logarithmic scale). Symbols: (—), total consumption; (•), ESPs; ({blacktriangleup}), macrolides; ({diamondsuit}), quinolones; ({blacksquare}), cephalosporins; ({blacktriangledown}), tetracyclines; (x), ß-lactamase-resistant penicillins; ({triangleup}), ß-lactamase-sensitive penicillins; ({circ}), lincosamides; ({diamond}), aminoglycosides; ({square}), amphenicols; ({triangledown}), fosfomycin.

 

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Table. Sales of antibiotics (DDD/1000 population/day) in Spain for the years 1987 and 1997, and percentage change
 
Macrolides were the group to register the greatest increase in sales during the study period, especially from 1994 onwards. Trends in the group's components were not the same across the board however: erythromycin, which in 1987 accounted for 75% of its group's total consumption had, by 1997, fallen to representing 25%. In 1997, clarithromycin and azithromycin accounted for 50% of consumption of this group.

Sales of tetracyclines, which had ranked third at the beginning of the period, declined markedly from 1989 onwards to drop back to fifth place by 1997. The quinolone group also registered a considerable rise from 1987 to 1992, flattening out thereafter but none the less occupying third place in 1997. Cephalosporins went from fifth place in 1987 to fourth in 1997. Great variations were evident between the different active drug ingredients of the cephalosporin group: in 1987, 76% of this group's consumption was accounted for by first-generation cephalosporins, 22% by second-generation cephalosporins and 2% by thirdgeneration cephalosporins. In 1997 however, 60% of consumption was accounted for by second-generation, 35% by third-generation and only 4% by first-generation cephalosporins.

Among the antibiotics with a DDD/1000/day value less than 0.5, aminoglycosides and amphenicols registered a continuous decline across the period, with 1997 DDD/1000/ day values of 0.03 and 0.02, respectively. Lincosamides and fosfomycin remained stable from 1987 to 1997, with DDD/ 1000/day of approximately 0.1 for the former, and 0.01 for the latter.

Discussion

Our results reveal a pronounced decline in the number of packages sold in Spain over the study period, in contrast to a parallel rise in terms of gross weight of active drug ingredient and DDD/1000/day. In 1997 a total of 21 DDD/ 1000/day were sold. ESPs were the therapeutic group to register the highest sales, followed by macrolides, quinolones and cephalosporins.

DDD/1000/day figures were calculated by using the weight of active drug ingredient consumed per year, defined daily doses for each active drug ingredient and size of population. The same DDD were used for all study years, while the Spanish population remained at around 39 million. Hence, any time-trend differences between indicators would necessarily have to be directly related to the weight of active drug ingredient. The implication of these findings is either: (i) that use was made of new antibiotics having a greater quantity in terms of weight of active drug ingredient in each dosage unit; or alternatively, (ii) that there was an increase in the number of units per package over the course of the study period. In the light of the enormous drop observed in the prescription of injectable drugs within the ESP group, our data point to the second alternative. Given the overwhelming importance of penicillins in total antibiotic consumption, this drop would explain the decrease in the number of packages as being offset by a corresponding increase in antibiotic gross weight. Moreover, sight should not be lost of the fact that packages containing injectable forms of drugs tend to contain far fewer units than oral forms.

An earlier study for the period 1976–1985, reported a 5% decrease in the weight of antibiotics accompanied by a 27% decline in packages, a reflection of the high consumption of aminopenicillins, with a significant weight per unit.12

We are therefore of the opinion that any antibiotic consumption study should be approached from the perspective provided by the calculation of the three indicators used here, namely, number of packages sold, weight and DDD/ 1000/day. Consumption calculated in DDD/1000/day is the only standard measure that provides an estimate of the proportion of the population who may be treated daily with the drug concerned. It was for this reason that we selected measurement by DDD/1000/day as the most suitable yardstick, one which allowed for observation of trends in consumption over time, and comparisons at a national and international level.

An overall consumption figure for Spain of 21 DDD/ 1000/day would be in line with current mean consumption reported for other developed countries.17 With respect to the consumption profile by antibiotic group, our results differ from those described in other European countries. In Spain, the currently predominating pattern of consumption is ESPs, macrolides, quinolones and cephalosporins. In the United Kingdom in 1996 however, penicillins were the leading prescription group, followed by macrolides, sulphonamides, tetracyclines, cephalosporins and quinolones;18 and in Denmark in 1995, penicillins came first, followed by macrolides, tetracyclines, sulphonamides or trimethoprim and quinolones.19

This study only covers data on non-hospital antibiotic sales financed by the Spanish National Health System, thereby excluding drugs that were self-prescribed or bought under prescription from private physicians. In Spain, known data place private consumption at around 15% of total human consumption of antibiotics.11 Antibiotics rank third after analgesics and anti-influenza drugs among the group of medicines used by the Spanish population for self-medication purposes.20 While such self-medication stands at around 32%,21 antibiotic consumption at a hospital level in Spain does not exceed 10% of the total.12

As elsewhere, costs in Spain have risen considerably with the clear decrease in consumption in unit-package terms. In the last 20 years, Spaniards have consumed half the amount of unit-packages at double the cost, and, after declining during the 1980s, the number of persons on courses of treatment has risen steadily throughout the 1990s.9

The rise in bacterial resistance in Spain over the last 15 years has been and continues to be a cause for concern, possibly being an expression of the excessive consumption of antimicrobials in the past and of the distribution of the various therapeutic groups. In the early 1990s, penicillin-resistant strains of S. pneumoniae, in percentages rising as high as 35%, were first detected in Spain, a prevalence that is now becoming evident in France and is beginning to emerge in Portugal. S. pneumoniae resistant to macrolides first appeared in Spain in 1979, with an incidence of less than 1%; this rose to 5.5% by 1988, and currently stands at 17%, a 200% rise in 10 years.22 In our study, the rise in macrolide consumption from 1987 to 1997 in DDD/1000/ day was 190%. The incidence of ß-lactamase-producing strains of H. influenzae varies from one European country to another. Nevertheless, it is Spain, with a mean of 35%, that is the country with the highest prevalence. Furthermore, not only have locally published papers reported incidences in excess of 50%, but they are already sounding the alert about fluoroquinolone resistance.13,23 Both microorganisms are implicated in the most frequent bacterial respiratory infections, such as otitis, sinusitis and pneumonia, pathologies that rank foremost among antimicrobial indications and account for 80% of total antimicrobial prescriptions in the non-hospital sector.

At present, the principal problems relating to antibacterial use are: abuse; use of drugs inappropriate for the level of health care entailed, and a tendency to use new antibacterials which fail to offer substantial improvements over other drugs of the same group, come with less use-related experience and are more costly.24,25 Numerous clinical practice guidelines have been drawn up to ensure the proper choice of antimicrobial. Two as yet unsolved problems persist however, namely, the principles of antimicrobial therapy; and education strategies at different levels (patients, parents, medical practitioners, pharmacists, government authorities) in the judicious use of antimicrobials. Some countries have already explored possible solutions.26,27

The involvement of health professionals, the authorities and the general population must be secured with regard to developing use and consumption strategies that will allow for injudicious use in human consumption and veterinary medicine to be reduced by over 50% and 80%, respectively; implementing diagnostic improvements in bacterial infections; changing physicians' and patients' expectations vis-à-vis antimicrobials by drawing attention to the role of these drugs as resistance-inducing agents; and, lastly, encouraging the authorities, sponsors and researchers alike to broaden and expand the scope of research to ensure treatment of infectious diseases in the coming years.26,27 A heightened awareness of this problem now exists in neighbouring countries.28

In conclusion, the last 10 years have witnessed an increase in antibiotic consumption in Spain. The number of packages of antibiotics sold should not be used in isolation as an indicator of consumption; and the qualitative distribution of such consumption is distinct from that observed in other European countries. This may be explained by differences in infectious pathology or commercial factors, which could, in turn, lead to differences in the generation of resistance.

Acknowledgments

Financial support was provided by Spain's Health Research Fund (Fondo de Investigación Sanitaria), grant No. 97/0131

Notes

* Corresponding author. Tel: +34-91-387-78-02; Fax: +34-91-387-78-15; E-mail: mruiz{at}isciii.es Back

References

1 . Ministry of Health, Ministry of Food, Agriculture and Fisheries, Denmark. (1998). The Copenhagen Recommendations. Report from the Invitational EU Conference on the Microbial Threat. Denmark.

2 . Levy, S. B. (1991). Antibiotic availability and use: consequences to man and his environment. Journal of Clinical Epidemiology 44, Suppl. II, S83–7.[ISI]

3 . Baquero, F., Martínez Beltrán, J. & Loza, E. (1991). A review of antibiotic resistance patterns of Streptococcus pneumoniae in Europe. Journal of Antimicrobial Chemotherapy 28, Suppl. C, 31–8.[ISI][Medline]

4 . Seppälä, H., Klaukka, T., Lehtonen, R., Nenonen, E. & Huovinen, P. (1995). Outpatient use of erythromycin: link to increased erithromycin resistance in group A streptococci. Clinical Infectious Diseases 21, 1378–85.[ISI][Medline]

5 . Arason, V., Kristinsson, K., Sigurdsson, J., Stefansdottir, G., Molstad, S. & Gudmundsson, S. (1996). Do antimicrobials increase the carriage rate of penicillin resistant pneumococci in children? Cross-sectional prevalence study. British Medical Journal 313, 387–91.[Abstract/Free Full Text]

6 . Holmberg, S. D., Solomon, S. L. & Blake, P. A. (1987). Health and economic impacts of antimicrobial resistance. Review of Infectious Diseases 9, 1065–78.[ISI][Medline]

7 . Dirección General de Salud Pública. (1996). Encuesta Nacional de Salud de España 1995. Ministerio de Sanidad y Consumo, Madrid.

8 . Grupo de Trabajo EPINE. (1995). Prevalencia de las infecciones nosocomiales en los hospitales españoles. EPINE 1990–94. Sociedad Española de Higiene y Medicina Preventiva Hospitalaria, Barcelona.

9 . Pérez Gorricho, B. (1999). Consumo de antimicrobianos en España. In Antimicrobianos en Medicina, (Prieto Prieto, J., López García, R. & García-Rodríguez, J. A., Eds). Editorial Prous, Madrid, in press.

10 . Alós, L. & Carnicero, M. (1997). Consumo de antibióticos y resistencia bacteriana a los antibióticos: algo que te concierne. Medicina Clinica de Barcelona 109, 264–70.

11 . Pérez Gorricho, M. B. (1985). Farmacovigilancia de los antibióticos. Estructura de consumo y mecanismos de control. Doctoral Thesis. Universidad Complutense, Madrid.

12 . Pérez Gorricho, B. & Baquero, F. (1988). Antibiotic consumption in Spain: The last 10 years. Alliance for the Prudent Use of Antibiotics Newsletter, Spring, 6–7.

13 . Baquero, F. (1996). Antibiotic resistance in Spain: what can be done? Task Force of the General Directorate for Health Planning of the Spanish Ministry of Health. Clinical Infectious Diseases 23, 819–23.[ISI][Medline]

14 . Col, N. F. & O'Connor, R. W. (1987). Estimating worldwide current antibiotic usage: report of Task Force 1. Review of Infectious Diseases 9, Suppl 3, S232–43.[ISI][Medline]

15 . WHO Collaborating Centre for Drug Statistics Methodology. (1993). ATC INDEX, Oslo, Norway.

16 . Grupo de Trabajo del SAS para Determinación de DDD. (1996). Dosis diarias definidas y dosis diarias definidas por envases para especialidades farmacéuticas. Junta de Andalucía, Sevilla.

17 . Baird, R. (1997). Antibiotic prescribing, controls, and anti-microbial resistance: an Australian experience. Alliance for the Prudent Use of Antibiotics Newsletter 15, 1–2.

18 . Davey, P., Bax, R. P., Newey, J., Reeves, D., Rutherford, D., Slack, R. et al. (1996). Growth in the use of antibiotics in the community in England and Scotland in 1980–93. British Medical Journal 312, 613.[Free Full Text]

19 . Frimodt-Moller, N., Espersen, F., Jacobsen, B., Schlundt, J., Meyling, A. & Wegener, H. (1997). Problems with antibiotic resistance in Spain and their relation to antibiotic use in humans elsewhere. Clinical Infectious Diseases 25, 939–41.

20 . Viñuales, A., Giráldez, J. & Izue, E. (1993). Análisis de la automedicación VII: perfiles de utilización de los medicamentos. El Farmacéutico 123, 31–40.

21 . González, J. & Orero, A. (1996). Consumo de antibióticos en España. Revista Española de Quimioterapia 9, Suppl. 4, 155.

22 . Baquero, F., Barrett, J., Courvalin, P., Morrisey, I., Piddock, L. & Novick, W. (1998). Epidemiology and mechanisms of resistance among respiratory tract pathogens. Clinical Microbiology and Infection 4, Suppl. 2, 2S19–2S26.

23 . Doern, G. V. (1995). Trends in antimicrobial susceptibility of bacterial pathogens of the respiratory tract. American Journal of Medicine 99, Suppl. 6B, S3–7.[ISI]

24 . McCaig, L. F. & Hughes, J. M. (1995). Trends in antimicrobial drug prescribing among office-based physicians in the United States. Journal of the American Medical Association 273, 214–19.[Abstract]

25 . Llop, J. C. (1997). Evolución de la utilización de antibacterianos en Cataluña. Impacto de los nuevos fármacos comercializados. Atención Primaria 19, 230–6.

26 . Belongia, E. & Schwartz, B. (1998). Strategies for promoting judicious use of antibiotics by doctors and patients. British Medical Journal 317, 668–71.[Free Full Text]

27 . Dowell, S., Marcy, S. M., Phillips, W., Gerber, M. & Schwartz, B. (1998). Principles of judicious use of antimicrobial agents for pediatric upper respiratory tract infections. Pediatrics 101, 163–5.[Abstract/Free Full Text]

28 . Economic and Social Committee of the European Communities. (1998). Resistance to antibiotics as a threat to public health. EU: Directorate for Communications, Brussels.

Received 15 June 1999; returned 23 September 1999; revised 18 October 1999; accepted 26 October 1999