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Adverse drug reactions reported for systemic antibacterials in Danish children over a decade.

Systemic antibacterials are among the most frequently prescribed drugs in children to treat respiratory tract infections [1, 2]. Empirical studies have shown that Danish children receive more broad-spectrum penicillins compared with children in Italy, Canada and Scandinavia [3–5]. Worldwide, health authorities have published guidelines on appropriate antibacterial prescribing to minimize the development of antibacterial resistance at the population level [6]. In Denmark, the National Board of Health recommends phenoxymethylpenicillin as the drug of first choice to treat respiratory tract infections in children [7]. Use of antibacterials may have negative effects such as bacterial resistance, and may involve adverse drug reactions (ADRs) [8, 9]. ADRs from antibacterials are common, and although some are serious, knowledge about the occurrence and characteristics of these are scarce [10]. A recent study has shown that two-thirds of ADRs reported in Danish children were from systemic antibacterials and vaccines, the majority reported in children up to 2 years of age [11]. Information about the characteristics of serious ADRs from systemic antibacterials occurring in children has not yet been systematically assessed. Therefore we analyzed ADRs from systemic antibacterials in children reported from 1998 to 2007 to the Danish Medicines Agency (DKMA). The study examined the occurrence and characteristics of ADRs reported in children from 0 to 17 years of age including whether serious ADRs were labelled. 
 
We used data from the Danish ADR database, maintained by the DKMA, which contains information on all spontaneous reports made in Denmark including those reported directly to the pharmaceutical companies. We analyzed the ADRs with respect to medication involved, type (system organ class [SOC]), seriousness and age of children. ADR reports were placed at the disposal of this study with encrypted personal identifiers. The unit of analysis was one ADR. ADRs for medications belonging to the ATC group J01 (antibacterials for systemic use) were extracted. ADRs were classified as serious on the following international criteria: death, life-threatening, requiring hospitalization or prolongation of existing hospitalization, resulting in persistent or significant disability/incapacity, a congenital anomaly/birth defect and other medically important conditions [12]. 
 
In total 66 ADR reports corresponding to 113 ADRs were reported for systemic antibacterials. Equal shares were reported for boys and girls. Table 1 displays the number of ADRs distributed by medicines, criteria of seriousness, age groups, characteristics and labelling status of serious ADRs. The number of ADRs varied widely across age groups and type of medicine. Two-thirds of ADRs were reported for the medicines azithromycin, erythromycin and dicloxacillin, and almost all of these ADRs were serious. The reported ADRs were of the type ‘skin and subcutaneous tissue disorders’ (23 % of total), ‘general disorders and administration site conditions’ (16% of total) and ‘gastrointestinal disorders’ (15% of total). Almost two-thirds of all ADRs were serious including two fatal cases. One-fourth of serious ADRs were of the type ‘gastrointestinal disorders’. Two deaths due to decreased carnitine concentrations and vomiting, respectively, were reported for pivampicillin in two 14-year-old girls. For dicloxacillin the largest number of serious ADRs was reported in 6–7 year olds and for pivampicillin, all serious ADRs occurred in 14–15 year olds. Approximately 20% of the serious ADRs were not later included in the product information. Examples of unlabelled ADRs are cerebral palsy and hallucination (azithromycin), chest pain and anorexia (erythromycin), tympanic membrane perforation (oxytetracycline) and dental caries (spiramycin). 
 
 
 
Table 1 
 
Adverse drug reactions (ADRs) reported for systemic antibacterials (ATC group J01) by medicines, age group, seriousness (italic) and labelling status (1998 to 2007) 
 
 
 
The strength of our study is that the material consisted of all reported ADRs in one country over a decade, but it also has limitations due to the design, i.e. material being based on spontaneous reports. The purpose was to analyze information on ADRs in children reported to a national database, and not to calculate the incidence of ADRs in the paediatric population, as this is not feasible in material based on spontaneous reports, as the system does not monitor individual patients and it is dependent on the willingness to report. In this study, only few ADRs from systemic antibacterials were reported, but more than half of these were serious. The share of serious ADRs reported for antibacterials was higher than in the general Danish childhood population [10]. In previous studies, the majority of ADRs were reported in children under 2 years of age but for antibacterials the opposite was observed [11]. A large number of ADRs were reported for broad-spectrum antibacterials, although phenoxymethylpenicillin was prescribed in accordance with national guidelines [7]. A low number of ADRs has been reported for systemic antibacterials, which may be due to the relatively low prescription rate of antibacterials in Denmark [3–5], or because the majority of ADRs caused by antibacterials are well known and not considered relevant to report to the regulatory authorities. Further studies of ADRs reported for systemic antibacterials in other countries are recommended, as prescribing practice, problems with resistance and differences in paediatric populations may affect the occurrence and characteristics of ADRs from antibacterials.