Patterns of Antibiotic Prescribing in Children: a comparison between Emilia Romagna and Norway

INTRODUZIONE Il consumo eccessivo e talvolta inappropriato di farmaci antibiotici rappresenta una delle principali cause di sviluppo di resistenza batterica; ciò accade principalmente nella popolazione pediatrica. Numerosi studi riportano differenze tra i Paesi del Nord e Sud Europa in ambito di terapia antibiotica. Scopo del progetto di ricerca è confrontare le modalità prescrittive di farmaci antibiotici nei bambini di età compresa fra 0 e 5 anni, in Emilia Romagna e in Norvegia. METODI I dati sono stati ottenuti dalla bancadati regionale dell’Assistenza Farmaceutica Territoriale (AFT) per l’Emilia Romagna e dal Norwegian Prescription Database (NORPD) per la Norvegia. E’ stata condotta un’analisi descrittiva dei dati italiani in cinque differenti gruppi di età: 0-12 mesi, 13-24 mesi, 25-36 mesi, 37-48 mesi e 49-60 mesi. I risultati sono stati quindi messi a confronto con i dati norvegesi. RISULTATI In Emilia Romagna si osserva un uso maggiore di antibiotici (prevalenza variabile dal 68% al 59% nel periodo in studio), mentre in Norvegia il 29% circa dei bambini ha ricevuto almeno una prescrizione di antibiotici. In tutti i gruppi di età, i bambini italiani hanno ricevuto un numero di prescrizioni per anno maggiore rispetto a quelli norvegesi. Importanti differenze emergono anche in relazione alla tipologia di farmaci prescritti: amoxicillina, da sola e in combinazione ad acido clavulanico sono i principi attivi più prescritti in Emilia Romagna contro la fenossimetilpenicillina in Norvegia. CONCLUSIONI I risultati dello studio mostrano differenze nell’utilizzo di terapie antibiotiche nei bambini in Emilia Romagna e Norvegia. In particolare, è emerso un utilizzo eccessivo di antibiotici nella popolazione pediatrica italiana considerata e un approccio terapeutico spesso non coerente con quanto riportato dalle linee guida e dalle raccomandazioni nazionali e internazionali. Il confronto con una realtà più virtuosa pone le basi per una riflessione sulle strategie di miglioramento da attuare in ambito di antibiotico-terapia.INTRODUCTION Population level exposure to antibiotics is associated with antibiotic resistance, and frequent antibiotic prescribing to children is accepted as an indicator for sub-optimal prescribing to outpatients. There are a number of European studies investigating antibiotic prescribing to children and adolescents that report large variations between countries in choice of therapy and periodic prevalence of prescribing. Aim of this study is to analyse and compare the pattern of antibiotic prescription and use in children 0-5 years in Norway and in Italy (Emilia-Romagna Region). METHODS A retrospective observational study was conducted; data on antibiotic prescribing were obtained from the Norwegian Prescription Database (NorPD) and from Emilia-Romagna Health Authority Database (AFT). All outpatients between 0 and 5 years, with a dispensed prescription on antibiotics (Anatomical Therapeutic Chemical, ATC code J01) were included and a descriptive analysis was made to compare patients, prescriptions of antibiotics and prescribers characteristics among the following 5 age groups: 0-12 months, 13-24 months, 25-36 months, 37-48 months, 49-60 months. RESULTS In Emilia Romagna a greater use of antibiotics was registered (prevalence ranging from 68% to 59% in the study period), while in Norway about 29% of children received at least one prescription of antibiotics. Important differences also emerged in relation to the type of drugs prescribed: amoxicillin, alone and in combination with clavulanic acid, was the most used in Emilia Romagna against phenoxymethylpenicillin in Norway. CONCLUSION The results of the study showed differences in the use of antibiotic therapies in children in Emilia Romagna and Norway. In particular, excessive use of antibiotics has emerged in the Italian pediatric population; this therapeutic approach was often not consistent with national and international guidelines and recommendations. The comparison with a more virtuous reality leads to a reflection on the improvement strategies to be implemented in the field of antibiotic therapy

No differences between men and women in adverse drug reactions related to psychotropic drugs: a survey from France, Italy and Spain

Producción CientíficaA large number of studies have suggested that being a woman represents a potential risk factor for the development of adverse drug reactions (ADRs). The aim of this study is to further explore the differences between men and women with regard to reported ADRs, particularly those associated with psychotropic drugs. We used spontaneous reports of suspected ADRs collected by Midi-Pyrénées (France), Veneto (Italy) and Castilla y León (Spain) Regional Pharmacovigilance Centres (January 2007-December 2009). All the reports including a psychotropic medication were selected in a first step; age distribution, seriousness and type of ADRs were compared between men and women. Reports of nonpsychotropic drugs were similarly identified and treated. The absolute number of reports and the proportion, considering population, were higher in women than in men. This was observed for all reports, but was particularly higher for psychotropic drugs (592 vs. 375; P < 0.001) than for nonpsychotropics drugs (5193 vs. 4035; P < 0.001). Antidepressants were the most reported (women, 303; men, 141; P < 0.001); the reporting rates (number of reports divided by exposed patients in the same period, estimated through sales data) for these drugs, however, were not significantly different between women (0.87 cases per 10 000 treated persons per year) and men (0.81 cases per 10 000 treated persons per year). Although there was a higher number of reports of ADRs in women, ADR reporting rates might be similar as highlighted by the case of antidepressants. Antidepressant ADRs in fact were similarly reported in men and in women. Gender differences are sometimes subtle and difficult to explore. International networks, as the one established for this study, do contribute to better analyse problems associated with medications.Junta de Castilla y León. Consejería de Sanidad. Dirección General de Salud Pública e Investigación, Desarrollo e Innovación

Liver injury due to amoxicillin vs. amoxicillin/clavulanate: a subgroupnalysis of a drug-induced liver injury case-control study in Italy

Several studies showed that amoxicillin plus clavulanic acid (co-amoxiclav) is one of the most common agents associated to serious Drug Induced Liver Injury (DILI). We estimated the risk of acute serious DILI associated with amoxicillin alone compared with co-amoxiclav, through a multicenter case-control study carried out in nine Italian hospitals from October 2010 to January 2014.Cases were adults, with a diagnosis of acute liver injury. Controls presented acute clinical disorders, not related to chronic conditions and not involving the liver. Adjusted Odds Ratio (ORs) with 95% CI were calculated initially with a bivariate and then multivariate analysis. We analysed 179 cases matched to 1770 controls. Seven cases were exposed to amoxicillin (adjusted OR 1.69, 95% CI 0.72-3.98) and 22 cases to co-amoxiclav (adjusted OR 3.00, 95% CI 1.76-5.40). Co-amoxiclav almost doubled the risk of serious acute liver injury compared to amoxicillin alone. The incidence of co-amoxiclav induced DILI is very low but the widespread use of this drug by the general population makes the risk clinically relevant. The often inappropriate prescription of antimicrobial agents, and in particular of co-amoxiclav, could expose a given patient to a life-threatening risk compared to a negligible clinical benefit

Signal detection activity on EudraVigilance data: analysis of the procedure and findings from an Italian Regional Centre for Pharmacovigilance

Background: In July 2012 a new European legislation (Directive 2010/84/EU and Regulation No. 1235/2010) regarding pharmacovigilance has become effective. It has boosted the activity of Signal Detection through a monthly analysis of potential safety signals on EudraVigilance (EV). Our aim is to describe the procedure of signal detection on EV data and to present results obtained by the our pharmacovigilance centre. Method: Data are extracted from EV database, which collects suspected Adverse Drug Reactions (ADRs) of medicinal products in Europe. We are appointed to supervise digoxin, nicardipine, delapril, manidipine and hydrochlorothiazide/ramipril. ADRs are coded through MedDRA Preferred Terms and collected in the electronic Reaction Monitoring Report (eRMR). Statistical analysis is based on the Proportional Reporting Ratio (PRR) as a measure of disproportionality. Results: Up to April 2016 we have analyzed 45 eRMR for each drug. Two signals for nicardipine were submitted to the Pharmacovigilance Risk Assessment Committee of European Medicines Agency (EMA): acute pulmonary oedema (off-label use as tocolytic) and thrombocytopenia. Conclusions: Our experience shows the scientific and regulatory value of signal detection activity on EV data in order to continuously evaluate the benefit/risk profile of recent and older drugs

Ibuprofen-associated hypothermia in children: analysis of the Italian spontaneous reporting database

Purpose: An analysis of Italian spontaneous adverse drug reactions (ADR) reporting database highlighted a potential association between hypothermia and ibuprofen in children. Hypothermia is defined as a core body temperature of 35\ua0\ub0C (95\ua0\ub0F). Ibuprofen is the most prescribed NSAID for the treatment of fever and moderate pain in children. We aimed to analyze the cases of ibuprofen-associated hypothermia retrieved in the Italian database in order to contribute to the discussion on this potential association. Methods: We extracted all suspected cases of ibuprofen-associated hypothermia from the Italian spontaneous reporting database and from VigiBase up to December 2015. We considered the proportional reporting ratio (PRR) as a measure of disproportionality for the Italian cases and the information component (IC) for the reports from VigiBase. We performed a case-by-case analysis to exclude duplicates. Results: Nineteen cases of hypothermia associated with ibuprofen use were retrieved from the Italian spontaneous reporting database (PRR 19.8, CI 95\ua0%, 12.0\u201332.9). The reports concerned ten females and nine males with an average age of 2.5\ua0years. Up to 31 December 2015, 168 cases of hypothermia associated with ibuprofen were reported to VigiBase, with an IC of 2.05 (IC025, 1.82). Among these, 126 cases involved children (49\ua0% males) with an average age of 4.4\ua0years. Conclusions: Although the risk of this ADR is unknown so far, the widespread use of this drug recommends the need for further studies to better characterize this possible association. Clinicians and pharmacists but also parents should be aware that this risk is theoretical as not yet been confirmed

Comparative risk/benefit profile of biosimilar and originator erythropoiesis-stimulating agents (ESAs): data from an Italian observational study in nephrology

Purpose: The aim of this multicenter prospective study was to evaluate efficacy and safety of biosimilar erythropoiesis-stimulating agents (ESAs) vs originator, based on data from clinical practice in patients with chronic kidney disease (CKD). Methods: We collected data of the patients with diagnosis of CKD on conservative treatment from nine Italian structures. Patients were enrolled applying different exclusion criteria, and various individual parameters were registered at the beginning for descriptive analysis. Patients were treated with epoetin alfa, beta, and darbepoetin as originator and epoetin zeta as biosimilar. Hemoglobin levels have been analyzed at baseline and after 3, 6, and 12 months. Descriptive statistics were used to analyze the results. Results: At baseline, 47 patients were in the biosimilar group and 57 in the originator; the basal level of hemoglobin was similar between the groups (mean Hb 9.4 and 9.3 g/dL, respectively). Median age, weight, and comorbidities were almost comparable. After 3 months, 44 patients remained in the biosimilar group and 48 in the originator; hemoglobin increase was significantly greater in patients treated with biosimilar [absolute increase 1.6 vs 1.0 g/dL, p < 0.001]. After 6 and 12 months, number of patients fall furthermore. Hemoglobin levels increased more in the biosimilar group after 6 months (2.1 vs 1.1 g/dL, p < 0.001) and 12 months (2.0 vs 1.0 g/dL, p < 0.001). Conclusions: Biosimilar ESAs have similar risk/benefit profile compared to originators. Our data are in agreement with relevant scientific literature and, on the other hand, they are in contrast with common thought that considers biosimilar less efficacious and less safe than originators

Safety profile of the direct oral anticoagulants: an analysis of the WHO database of adverse drug reactions

Aim: Direct oral anticoagulants (DOACs) have shown noninferiority to warfarin for stroke prevention in nonvalvular atrial fibrillation (AF) and a more promising safety profile. Unanswered safety aspects remain to be addressed and available evidence on the risk associated with these drugs are conflicting. In order to contribute to the debate on their safety profile, we conducted a comparative analysis of the reports of suspected adverse drug reactions (ADRs) associated with DOACs in VigiBase. Methods: Study based on reports of suspected ADRs held in VigiBase as at December 2014, in which a DOAC or warfarin were administered in patients with nonvalvular AF and listed as suspected/interacting drugs. Medical Dictionary for Regulatory Activities was used to classify ADRs. Reporting odds ratio (ROR) with 95% confidence interval were calculated. Results with P \ue2\u89\ua4\uc2\ua00.05 were statistically significant. Results: We retrieved 32\uc2\ua0972 reports. We identified 204 ADRs with a ROR >1 (P \ue2\u89\ua4\uc2\ua00.05) and we focused on 105 reactions. Positive ROR emerged for DOACs and gastrointestinal haemorrhage compared with warfarin [(1.6 (1.47\ue2\u80\u931.75)], but no disproportionality with cerebral haemorrhage was found [0.31 (0.28\ue2\u80\u930.34)]. We identified other potential signals that have not been associated with DOACs previously. Conclusions: As well as premarketing authorization clinical trial studies, we found a reduced risk of intracranial haemorrhage, but an increased risk of gastrointestinal haemorrhage in patients treated with DOACs compared to warfarin. We provide new data and we highlight several differences between the three novel oral anticoagulants, in the rate and type of ADRs occurred

Drug-Induced Progressive Multifocal Leukoencephalopathy: A Comprehensive Analysis of the WHO Adverse Drug Reaction Database

Objective To identify safety signals concerning the association between the use of various drug classes and the onset of progressive multifocal leukoencephalopathy (PML). Methods All reports containing suspected or interacting PML-related or leukoencephalopathy-related drugs, held in the World Health Organization spontaneous individual case safety reports database as at 1 September 2014, were retrieved.Weidentified safety signals by analysing the drug– reaction pairs, using the reporting odds ratio as a measure of disproportionality. A safety signal was defined if a drug was reported more than twice in PML cases with a reporting odds ratio[2 and a lower 95 % confidence limit[1. Results We retrieved 2452 reports associated with PML (N = 1612), leukoencephalopathy (N = 835) or both (N = 5), corresponding to 343 different drugs. PML was reported similarly in male and female adults (18–64 years), and almost 30 % of the cases had a fatal outcome. The most frequent Anatomical Therapeutic Chemical (ATC) classification groups concerned antineoplastic agents (23.5 %), antivirals for systemic use (10.1 %) or immunostimulants (4.6 %). Significant disproportionality was found for 88 drugs in the overall analysis (of cases with ‘progressive multifocal leukoencephalopathy’ or ‘leukoencephalopathy’ as the Preferred Term), and a new safety signal was identified for 59 active substances (e.g. muromonab-CD3, basiliximab and antithymocyte Ig), as no information on a possible risk of PML was acknowledged in their Summary of Product Characteristics documents. Some safety signals were confirmed also after sensitivity analysis adjustment for several confounding factors (underlying diseases and considering only ‘progressive multifocal leukoencephalopathy’ as the Preferred Term). Conclusion We report a possible association between several drugs and PML that has not been previously described. In addition, we have confirmed previously reported signals in a number of drugs. We highlight the need for follow-up by regulatory agencies

Safety profile of H1-antihistamines in pediatrics: an analysis based on data from VigiBase

Purpose: H1-antihistamines are commonly used in infants and children for the relief of histamine-mediated symptoms in a variety of conditions. Little is known about their safety profile in these patients. We performed a comparative analysis of the safety profiles of H1-antihistamines using data from the WHO database (VigiBase). Methods: We selected adverse drug reaction (ADR) reports on H1-antihistamines in children (0â16 years) up to June 2014 from VigiBase. ADRs were codified according to MedDRA terminology. The reporting odds ratios (RORs) with 95% confidence for drug-reaction pairs were calculated. Results: The analysis was performed on 8918 reports related to antihistamines, corresponding to 19503 drug reaction pairs for 68 different drugs. Most of reports involved children aged 2 to 6 years (32%) and 6 to 12 years (34%). Most reported drugs were cetirizine (1608 reports, corresponding to 18%), loratadine (16%), and diphenhydramine (10%). ADRs were classified as serious in 23% of cases, and 400 cases had a fatal outcome. We found a significant associations for several drug-reaction pairs such as levocetirizine and epilepsy (ROR, 6.57; 95% confidence interval [CI], 1.51â28.53) and chlorphenamine and toxic epidermal necrolysis (ROR, 7.29; 95% CI, 2.39â22.2). Conclusions: H1-antihistamines are among the most used drugs in pediatrics, also in an off-label manner. Our data highlights associations with serious and unexpected ADRs. Educative intervention to clinicians and parents are needed to help doctors to make proper choices on the drug treatment and for the early detection of ADRs to maximize the benefits and reduce the risk of ADRs in these patients

Use of Antibiotics in Pediatrics: 8-Years Survey in Italian Hospitals

<div><p>Objectives</p><p>To evaluate antibiotic consumption in the pediatric wards of Emilia-Romagna Region, from 2004 to 2011, with a focus on the antibiotics reserved to the most serious infections, and to analyse the ADRs reported for antibiotics by the pediatric wards of Emilia-Romagna hospitals.</p><p>Methods</p><p>Reference population was represented by all the patients (0–14 years old) admitted to the pediatric wards of all the hospitals of Emilia-Romagna Region. Drug consumption was expressed as number of DDDs per 100 Bed-Days (BD) and data were analysed by active substance, by therapeutic subgroups or by ward type. The time trends of antibiotic consumption were statistically analysed by linear regression. All the suspected ADR reports associated with antibiotics, reported between January 2004 and December 2011 were drawn by the Italian Spontaneous Reporting Database.</p><p>Results</p><p>Overall antibiotic consumption showed only a slight increase (p = 0.224). Among the pediatric wards, pediatric surgery showed the highest increase from 2004 to 2011 (p = 0.011). Penicillins and β-lactamase inhibitors was the first therapeutic group with a statistically significant increase over years (p = 0.038), whereas penicillins with extended spectrum presented a statistically significant reduction (p = 0.008). Moreover, only 5 drugs out of the 8 antibiotics reserved to the most serious infections were used. Pharmacovigilance data showed 27 spontaneous ADR reports associated to ATC J01 drugs. Amoxicillin/clavulanic acid had the highest number of ADR reports (n = 7).</p><p>Conclusions</p><p>The steadily increasing consumption in penicillins and β-lactamase inhibitors, in association with a considerable decrease of plain penicillins, raises a serious concern. Pharmacovigilance reports seem to suggest a safe use of antibiotics in the hospital setting of Emilia-Romagna. Further studies to investigate the reason for prescribing antibiotics in children inpatients are needed.</p></div