Over 50,000 Cuban health professionals are currently working overseas in 67 different countries. They work in conjunction with local health professionals. The majority work in primary care in deprived areas. The aim is to reduce morbidity and mortality but also improve health in the long term by training local health professionals, and building both institutions and a structure to deliver health care alongside educating the local population. Cuba is a small, middle-income country. It has, however, made a significant international contribution in relation to medical collaboration. Cuba’s international collaboration is based on the principles of social justice and equity for all. It has set an example for other countries to emulate.
child health; Cuba; access to healthcare
To explore whether pharmacokinetic (PK) studies in paediatric patients are becoming less invasive. This will be evaluated by analysing the number of samples and volume of blood collected for each study within four different decades.
A systematic literature review was performed to identify PK papers describing number of samples and volume of blood collected in studies of children aged 0–18 years. The following databases were searched: MEDLINE (1946 to December 2015), EMBASE (1974 to December 2015), International Pharmaceutical Abstracts (1970 to December 2015), CINAHL and Cochrane Library.
A total of 549 studies were identified between 1974 and 2015. There were 52 studies between 1976 and 1985, 105 between 1986 and 1995, 201 between 1996 and 2005 and 191 between 2006 and 2015. The number of blood samples collected per participant increased between the first two decades (p=0.013), but there was a decrease in the number of samples in the subsequent two decades (p=0.044 and p<0.001, respectively). Comparing the first and last decades, there has been no change in the number of blood samples collected. There were no significant differences in volume collected per sample or total volume per child in any of the age groups. There was however a significant difference in the frequency of blood sampling between population PK studies (median 5 (IQR 3–7)) and non-population PK studies (median 8 (IQR 6–10); p=<0.001).
The number of blood samples collected for PK studies in children rose in 1985–1995 and subsequently declined. There was no overall change in the volume of blood collected over the 4 decades. The usage of population PK methods reduces the frequency of blood sampling in children.
Blood; Sampling; Pharmacokinetics; Children
Short-course oral corticosteroids are commonly used in children but are known to be associated with adverse drug reactions (ADRs). This review aimed to identify the most common and serious ADRs and to determine their relative risk levels.
A literature search of EMBASE, MEDLINE, International Pharmaceutical Abstracts, CINAHL, Cochrane Library and PubMed was performed with no language restrictions to identify studies in which oral corticosteroids were administered to patients aged 28 days to 18 years of age for up to and including 14 days of treatment. Each database was searched from their earliest dates to December 2013. All studies providing clear information on ADRs were included.
Thirty-eight studies including 22 randomised controlled trials (RCTs) met the inclusion criteria. The studies involved a total of 3200 children in whom 850 ADRs were reported. The three most frequent ADRs were vomiting, behavioural changes and sleep disturbance, with respective incidence rates of 5.4%, 4.7% and 4.3% of patients assessed for these ADRs. Infection was one of the most serious ADRs; one child died after contracting varicella zoster. When measured, 144 of 369 patients showed increased blood pressure; 21 of 75 patients showed weight gain; and biochemical hypothalamic–pituitary–adrenal axis suppression was detected in 43 of 53 patients.
Vomiting, behavioural changes and sleep disturbance were the most frequent ADRs seen when short-course oral corticosteroids were given to children. Increased susceptibility to infection was the most serious ADR.
Trial registration number
CRD42014008774. By PROSPERO International prospective register of systematic reviews.
General Paediatrics; Paediatric Practice; Pharmacology; Therapeutics
To identify adverse events (AEs) associated with Levetiracetam (LEV) in children.
Databases EMBASE (1974-February 2015) and Medline (1946-February 2015) were searched for articles in which paediatric patients (≤18 years) received LEV treatment for epilepsy. All studies with reports on safety were included. Studies involving adults, mixed age population (i.e. children and adults) in which the paediatric subpopulation was not sufficiently described, were excluded. A meta-analysis of the RCTs was carried out and association between the commonly reported AEs or treatment discontinuation and the type of regimen (polytherapy or monotherapy) was determined using Chi2 analysis.
Sixty seven articles involving 3,174 paediatric patients were identified. A total of 1,913 AEs were reported across studies. The most common AEs were behavioural problems and somnolence, which accounted for 10.9% and 8.4% of all AEs in prospective studies. 21 prospective studies involving 1120 children stated the number of children experiencing AEs. 47% of these children experienced AEs. Significantly more children experienced AEs with polytherapy (64%) than monotherapy (22%) (p<0.001). Levetiracetam was discontinued in 4.5% of all children on polytherapy and 0.9% on monotherapy (p<0.001), the majority were due to behavioural problems.
Behavioural problems and somnolence were the most prevalent adverse events to LEV and the most common causes of treatment discontinuation. Children on polytherapy have a greater risk of adverse events than those receiving monotherapy.
Drug toxicity is, unfortunately, a significant problem in children both in the hospital and in the community. Drug toxicity in children is different to that seen in adults. At least one in 500 children will experience an adverse drug reaction each year. For children in hospital, the risk is far greater (one in ten). Additionally, different and sometimes unique adverse drug reactions are seen in the paediatric age groups. Some of the major cases of drug toxicity historically have occurred in neonates. It is important that we understand the mechanism of action of adverse drug reactions. Greater understanding alongside rational prescribing should hopefully reduce drug toxicity in children in the future.
drug toxicity; children; drug metabolism; rational drug use
To identify the use and adverse drug reactions associated with azithromycin in neonates.
Databases MEDLINE (1948–August 2015), EMBASE (1980–August 2015) and Pubmed (August 2015) were searched for studies on azithromycin in neonates.
All studies involving neonates (<28 days old) who have received at least a single dose of azithromycin for which safety was evaluated.
Primary and secondary outcome measures
The primary outcome was adverse event (AE) associated with use of azithromycin. Use of azithromycin in neonates was the secondary outcome.
A total of 11 articles involving 473 neonates were identified. 371 AEs were reported. Adverse events were mainly respiratory (358/1000 neonate), neurological (273/1000 neonates) and gastrointestinal (196/1000 neonates) in origin. Azithromycin significantly reduced the risk of bronchopulmonary dysplasia (BPD) in extremely premature neonates (RR=0.83, 95% CI 0.71 to 0.98, p=0.02). There was no significant difference in the incidence of elevated liver enzymes between the azithromycin and placebo group (p=0.76). There were four cases of infantile hypertrophic pyloric stenosis (IHPS).
Azithromycin significantly reduces the risk of BPD in preterm neonates. The relationship between azithromycin and IHPS requires further investigation.
CLINICAL PHARMACOLOGY; NEONATOLOGY
The UK has a high child mortality rate, whereas Sweden's is lower (under-five mortality rates of five and three, respectively, in 2011).We therefore wished to compare causes of death in young children aged <5 years in the two countries.
Under-five mortality data were obtained from the Office of National Statistics for each of the individual countries within the UK for 3 years (2006–2008). Data for Sweden for the same period were obtained from the National Board of Health and Welfare. Causes of death were compared statistically using χ2 test.
There were a total of 14 104 and 1036 deaths aged <5 years in the UK and Sweden, respectively, between 2006 and 2008. The total numbers of live births during the same period were 2 295 964 and 315 884, respectively. The overall mortality rate in the UK was 614 per 100 000 children which was significantly higher than that in Sweden (328; p<0.001). The mortality rates for the three main causes of death in the UK (prematurity, congenital malformations and infections) were 138.5, 112.1 and 63.9, respectively, per 100 000 children. The mortality rates for the same three conditions in Sweden were 10.1, 88.6 and 34.8, respectively. They were all significantly more frequent in the UK than in Sweden (p<0.001), as were the majority of the disorders. Treatable infections, such as pneumonia, meningitis and septicaemia, in both neonates and young children had significantly higher mortality rates in the UK than in Sweden (p<0.001).
In order to reduce the mortality rate in the UK, we need to try and reduce the causes of prematurity. Additionally, the care of children with treatable infections should be reviewed to understand ways in which to reduce the differences in mortality seen.
Health services research; Pharmacology; Outcomes research; Comm Child Health
To identify adverse drug reactions associated with lamotrigine in children and compare the safety profile with other antiepileptic drugs.
Databases EMBASE (1974–April 2015), MEDLINE (1946–April 2015), PubMed and the Cochrane library for randomised controlled trials were searched for studies on safety of lamotrigine.
All studies involving paediatric patients aged ≤18 years who have received at least a single dose of lamotrigine with safety as an outcome measure were included.
Primary and secondary outcome measures
The primary outcome measure was safety of lamotrigine. Drug interaction of lamotrigine was the secondary outcome.
A total of 78 articles involving 3783 paediatric patients were identified. There were 2222 adverse events (AEs) reported. Rash was the most commonly reported AE, occurring in 7.3% of the patients. Stevens-Johnson syndrome was rarely reported, with a risk of 0.09 per 100 patients. Discontinuation due to an adverse drug reaction (ADR) was recorded in 72 children (1.9% of all treated patients). Fifty-eight per cent of treatment discontinuation was attributed to different forms of rash and 21% due to increased seizures. Children on lamotrigine monotherapy had lower incidences of AEs. Headache (p=0.02), somnolence (<0.001), nausea (p=0.01), vomiting (p<0.001), dizziness (p<0.001) and abdominal pain (p=0.01) were significantly lower among children on monotherapy.
Rash was the most common ADR of lamotrigine and the most common reason for treatment discontinuation. Children receiving polytherapy have a higher risk of AEs than monotherapy users.
Trial registration number
To prospectively determine the nature and rate of adverse drug reactions (ADRs) in children on antiepileptic drugs (AEDs) and to prospectively evaluate the effect of AEDs on behaviour.
A single centre prospective observational study.
Children (<18 years old) receiving one or more AEDs for epilepsy, at each clinically determined follow-up visit.
Primary and secondary outcomes
Primary outcome was adverse reactions of AEDs. Behavioural and cognitive functions were secondary outcomes.
180 children were recruited. Sodium valproate and carbamazepine were the most frequently used AEDs. A total of 114 ADRs were recorded in 56 of these children (31%). 135 children (75%) were on monotherapy. 27 of the 45 children (60%) on polytherapy had ADRs; while 29 (21%) of those on monotherapy had ADRs. The risk of ADRs was significantly lower in patients receiving monotherapy than polytherapy (RR: 0.61, 95% CI 0.47 to 0.79, p<0.0001). Behavioural problems and somnolence were the most common ADRs. 23 children had to discontinue their AED due to an ADR.
Behavioural problems and somnolence were the most common ADRs. Polytherapy significantly increases the likelihood of ADRs in children.
Trail registration number
The aim of the study was to determine the extent of inter-individual variation in clearance of intravenous morphine in children and to establish which factors are responsible for this variation.
A systematic literature review was performed to identify papers describing the clearance of morphine in children. The following databases were searched: Medline, Embase, International Pharmaceutical Abstracts, CINAHL, and Cochrane library. From the papers, the range in plasma clearance and the coefficient of variation (CV) in plasma clearance were determined.
Twenty-eight studies were identified. After quality assessment, 20 studies were included. Only 10 studies gave clearance values for individual patients. The majority of the studies were in critically ill patients. Inter-individual variability of morphine clearance was observed in all age groups, but greatest in critically ill neonates (both preterm and term) and infants. In critically ill patients, the CV was 16–9 7 % in preterm neonates, 24–87 % in term neonates, 35 and 134 % in infants, 39 and 55 % in children, and 74 % in adolescents. The CV was 37 and 44 % respectively in non-critically ill neonates and infants. The mean clearance was higher in children (32 and 52 ml min-1 kg-1) than in neonates (2 to 16 ml min-1 kg-1).
Large inter-individual variation was seen in morphine clearance values in critically ill neonates and infants.
Electronic supplementary material
The online version of this article (doi:10.1007/s00228-015-1843-x) contains supplementary material, which is available to authorized users.
Morphine; Pharmacokinetics; Clearance; Children; Variation
Pharmacology; Pain; General Paediatrics
To determine the extent of inter-individual variation in clearance of midazolam in children and establish which factors are responsible for this variation.
A systematic literature review was performed to identify papers describing the clearance of midazolam in children. The following databases were searched: Medline, Embase, International Pharmaceutical Abstracts, CINAHL and Cochrane Library. From the papers, the range in plasma clearance and the coefficient of variation (CV) in plasma clearance were determined.
25 articles were identified. Only 13 studies gave the full range of clearance values for individual patients. The CV was greater in critically ill patients (18%–170%) than non-critically ill patients (13%–54%). Inter-individual variation was a major problem in all age groups of critically ill patients. The CV was 72%–106% in preterm neonates, 18%–73% in term neonates, 31%–130% in infants, 21%–170% in children and 47%–150% in adolescents. The mean clearance was higher in children (1.1–16.7 mL/min/kg) than in neonates (0.78–2.5 mL/min/kg).
Large inter-individual variation was seen in midazolam clearance values in critically ill neonates, infants, children and adolescents.
Pharmacology; General Paediatrics
To explore the quality and safety of medicines in Canada.
A retrospective review of drug recalls and risk communication documents conveying issues relating to defective (ie, substandard and falsified) medicines.
The Health Canada website search for drug recalls and risk communication documents issued between 2005 and 2013.
Drug recalls and risk communication documents related to quality defect in medicinal products.
Main outcome measure
Relevant data about defective medicines reported in drug recalls and risk communication documents, including description of the defect, type of formulation, year of the recall and category of the recall or the document.
There were 653 defective medicines of which 649 were substandard. The number of defective medicines reported by Health Canada increased from 42 in 2005 to 143 in 2013. The two most frequently reported types of defects were stability (205 incidents) and contamination issues (139 incidents). Some of these defects were found to be more prominent and repetitive over other types within some manufacturers. Tablet formulation (251 incidents) was the formulation most frequently compromised. No significant differences were observed between the manufacturers and distributors in the number of substandard medicines reported under each defect type. There were only four falsified medicines reported over the 9-year period.
Substandard medicines are a problem in Canada and have resulted in an increasing number of recalled medicines. Most of the failures were related to stability issues, raising the need to investigate the root causes and for stringent preventative measures to be implemented by manufacturers.
Substandard medicines; Falsified medicines; Drug recalls
Valproic acid is an effective first line drug for the treatment of epilepsy. Hepatotoxicity is a rare and potentially fatal adverse reaction for this medicine.
Firstly to characterise valproic acid reports on children with fatal outcome and secondly to determine reporting over time of hepatotoxicity with fatal outcome.
Individual case safety reports (ICSRs) for children ≤17 years with valproic acid and fatal outcome were retrieved from the WHO Global ICSR database, VigiBase, in June 2013. Reports were classified into hepatotoxic reactions or other reactions. Shrinkage observed-to-expected ratios were used to explore the relative reporting trend over time and for patient age. The frequency of polytherapy, i.e. reports with more than one antiepileptic medicine, was investigated.
There have been 268 ICSRs with valproic acid and fatal outcome in children, reported from 25 countries since 1977. A total of 156 fatalities were reported with hepatotoxicity, which has been continuously and disproportionally reported over time. There were 31 fatalities with pancreatitis. Other frequently reported events were coma/encephalopathy, seizures, respiratory disorders and coagulopathy. Hepatotoxicity was disproportionally and most commonly reported in children aged 6 years and under (104/156 reports) but affected children of all ages. Polytherapy was significantly more frequently reported for valproic acid with fatal outcome (58%) compared with non-fatal outcome (34%).
Hepatotoxicity remains a considerable problem. The risk appears to be greatest in young children (6 years and below) but can occur at any age. Polytherapy is commonly reported and seems to be a risk factor for hepatotoxicity, pancreatitis and other serious adverse drug reactions with valproic acid.
Antibiotics are a key resource for the management of infectious diseases in neonatology and their evaluation is particularly challenging. We reviewed medical literature to assess the characteristics and quality of randomized controlled trials on antibiotics in neonatal infections.
We performed a systematic search of PubMed, Embase and the Cochrane Library from January 1995 to March 2010. Bibliographies of relevant articles were also hand-searched. We included all randomized controlled trials that involved neonates and evaluated the use of an antibiotic agent in the context of a neonatal infectious disease. Methodological quality was evaluated using the Jadad scale and the Cochrane Risk of Bias Tool. Two reviewers independently assessed studies for inclusion and evaluated methodological quality.
A total of 35 randomized controlled trials were evaluated. The majority were conducted in a single hospital institution, without funding. Median sample size was 63 (34–103) participants. The most frequently evaluated antibiotic was gentamicin. Respectively, 18 (51%) and 17 (49%) trials evaluated the therapeutic or prophylactic use of antibiotics in various neonatal infections. Overall, the methodological quality was poor and did not improve over the years. Risk of bias was high in 66% of the trials.
Design and reporting of randomized controlled trials of antibacterial agents in neonates should be improved. Nevertheless, the necessity of implementing such trials when antibacterial efficacy has already been established in other age groups may be questioned and different methods of evaluation should be further developed.
antibiotics; controlled trials; infections; neonatology; randomization
The aim of this study was to provide an overview of studies in which the impact of the 2008 economic crisis on child health was reported. Structured searches of PubMed, and ISI Web of Knowledge, were conducted. Quantitative and qualitative studies reporting health outcomes on children, published since 2007 and related to the 2008 economic crisis were included. Two reviewers independently assessed studies for inclusion. Data were synthesised as a narrative review. Five hundred and six titles and abstracts were reviewed, from which 22 studies were included. The risk of bias for quantitative studies was mixed while qualitative studies showed low risk of bias. An excess of 28,000–50,000 infant deaths in 2009 was estimated in sub-Saharan African countries, and increased infant mortality in Greece was reported. Increased price of foods was related to worsening nutrition habits in disadvantaged families worldwide. An increase in violence against children was reported in the U.S., and inequalities in health-related quality of life appeared in some countries. Most studies suggest that the economic crisis has harmed children’s health, and disproportionately affected the most vulnerable groups. There is an urgent need for further studies to monitor the child health effects of the global recession and to inform appropriate public policy responses.
adolescent; child health; economic and financial crisis; inequalities
To explore the evidence available of poor-quality (counterfeit and substandard) medicines in the literature.
Databases used were EMBASE, MEDLINE, PubMed and the International Pharmaceutical Abstracts, including articles published till January 2013.
Prevalence studies containing original data. WHO definitions (1992) used for counterfeit and substandard medicines.
Study appraisal and synthesis
Two reviewers independently scored study methodology against recommendations from the MEDQUARG Checklist. Studies were classified according to the World Bank classification of countries by income.
Data extracted: place of study; type of drugs sampled; sample size; percentage of substandard/counterfeit medicines; formulations included; origin of the drugs; chemical analysis and stated issues of counterfeit/substandard medicines.
44 prevalence studies were identified, 15 had good methodological quality. They were conducted in 25 different countries; the majority were in low-income countries (11) and/or lower middle-income countries (10). The median prevalence of substandard/counterfeit medicines was 28.5% (range 11–48%). Only two studies differentiated between substandard and counterfeit medicines. Prevalence data were limited to antimicrobial drugs (all 15 studies). 13 studies involved antimalarials, 6 antibiotics and 2 other medications. The majority of studies (93%) contained samples with inadequate amounts of active ingredients. The prevalence of substandard/counterfeit antimicrobials was significantly higher when purchased from unlicensed outlets (p<0.000; 95% CI 0.21 to 0.32). No individual data about the prevalence in upper middle-income countries and high-income countries were available.
Studies with strong methodology were few. The majority did not differentiate between substandard and counterfeit medicines. Most studies assessed only a single therapeutic class of antimicrobials.
The prevalence of poor-quality antimicrobial medicines is widespread throughout Africa and Asia in lower income countries and lower middle-income countries . The main problem identified was inadequate amounts of the active ingredients.
counterfeit drug; substandard drug; fake drug; anti-infective ; drug counterfeiting
To determine the extent of substandard and falsified medicines in the UK.
A retrospective review of drug alerts and company-led recalls.
The Medicines and Healthcare Products Regulatory Agency (MHRA) website search for drug alerts issued between 2001 and 2011.
Drug alerts related to quality defect in medicinal products.
Main outcome measure
Relevant data about defective medicines reported in drug alerts and company-led recalls, including description of the defect, type of formulation, year of the alert and category of the alert.
There were 280 substandard medicines of which 222 were recalled. The two most frequent problems were contamination (74 incidents) and issues related to packaging (98 incidents). Formulations for parenteral administration (117 incidents) were the formulation most frequently affected. There were 11 falsified medicines, as defined by the MHRA, reported over the 11-year period. The number of defective medicines reported by the MHRA increased 10-fold from 5 in 2001 to 50 in 2011.
Substandard medicines are a significant problem in the UK. It is uncertain whether the increasing number of reports relates to improved detection or an increase in the number of substandard medicines.
Falsified; Substandard; Defective; Medicines
To determine the safety of fluconazole in neonates and other paediatric age groups by identifying adverse events (AEs) and drug interactions associated with treatment.
A search of EMBASE (1950–January 2012), MEDLINE (1946–January 2012), the Cochrane database for systematic reviews and the Cumulative Index to Nursing and Allied Health Literature (1982–2012) for any clinical study about fluconazole use that involved at least one paediatric patient (≤17 years) was performed. Only articles with sufficient quality of safety reporting after patients’ exposure to fluconazole were included.
We identified 90 articles, reporting on 4,209 patients, which met our inclusion criteria. In total, 794 AEs from 35 studies were recorded, with hepatotoxicity accounting for 378 (47.6 %) of all AEs. When fluconazole was compared with placebo and other antifungals, the relative risk (RR) of hepatotoxicity was not statistically different [RR 1.36, 95 % confidence interval (CI) 0.87–2.14, P = 0.175 and RR 1.43, 95 % CI 0.67–3.03, P = 0.352, respectively]. Complete resolution of hepatoxicity was achieved by 84 % of patients with follow-up available. There was no statistical difference in the risk of gastrointestinal events of fluconazole compared with placebo and other antifungals (RR 0.81, 95 % CI 0.12–5.60, P = 0.831 and RR 1.23, 95 %CI 0.87–1.71, P = 0.235, respectively). There were 41 drug withdrawals, 17 (42 %) of which were due to elevated liver enzymes. Five reports of drug interactions occurred in children.
Fluconazole is relatively safe for paediatric patients. Hepatotoxicity and gastrointestinal toxicity are the most common adverse events. It is important to be aware that drug interactions with fluconazole can result in significant toxicity.
Fluconazole; Safety; Neonates; Paediatrics; Hepatotoxicity
Medication errors are a significant global concern and can cause serious medical consequences for patients. Little is known about medication errors in Middle Eastern countries. The objectives of this systematic review were to review studies of the incidence and types of medication errors in Middle Eastern countries and to identify the main contributory factors involved.
A systematic review of the literature related to medication errors in Middle Eastern countries was conducted in October 2011 using the following databases: Embase, Medline, Pubmed, the British Nursing Index and the Cumulative Index to Nursing & Allied Health Literature. The search strategy included all ages and languages. Inclusion criteria were that the studies assessed or discussed the incidence of medication errors and contributory factors to medication errors during the medication treatment process in adults or in children.
Forty-five studies from 10 of the 15 Middle Eastern countries met the inclusion criteria. Nine (20 %) studies focused on medication errors in paediatric patients. Twenty-one focused on prescribing errors, 11 measured administration errors, 12 were interventional studies and one assessed transcribing errors. Dispensing and documentation errors were inadequately evaluated. Error rates varied from 7.1 % to 90.5 % for prescribing and from 9.4 % to 80 % for administration. The most common types of prescribing errors reported were incorrect dose (with an incidence rate from 0.15 % to 34.8 % of prescriptions), wrong frequency and wrong strength. Computerised physician rder entry and clinical pharmacist input were the main interventions evaluated. Poor knowledge of medicines was identified as a contributory factor for errors by both doctors (prescribers) and nurses (when administering drugs). Most studies did not assess the clinical severity of the medication errors.
Studies related to medication errors in the Middle Eastern countries were relatively few in number and of poor quality. Educational programmes on drug therapy for doctors and nurses are urgently needed.
Medication error; Middle East countries; Prescribing; Administration; Transcribing
To describe the use of ciprofloxacin and fluconazole for the treatment of sepsis in European neonatal intensive care units (NICUs) in order to better orient research aimed at acquiring essential knowledge in this critical area.
The survey consisted of an online questionnaire for all participating NICUs on treatment schemes employed, rationales behind drug choices and interest in participation in research involving the two drugs.
A total of 189 level II and III NICUs participated in the survey, representing 25 countries, with Italy, UK and France providing the greatest number of centres (54 % of total). Ciprofloxacin is used in 25 % of NICUs that responded, although the indications for administering it vary between centres and the dosage ranges vary considerably, with 25 % of NICUs giving ≤10 mg/kg/day and another 25 % giving ≥21 mg/kg/day. Factors given as affecting the decision to use ciprofloxacin are uncertainty about its safety and pharmacokinetics and level of penetration in the cerebrospinal fluid. Among the 70 % of responding units that use fluconazole to treat fungal infection, 45 % administer 6 mg/kg unit doses while 33 % administer 12 mg/kg; 41 % of NICUs use a 24-h interval between administrations while 20 % wait 72 h. Among the responding NICUs, 57 % were willing to participate in a project on ciprofloxacin and 59 % would consider participating in a randomized controlled trial evaluating fluconazole versus micafungin.
Great variability in therapies exists within and between countries. Numerous centres are interested in participating in research on these drugs, highlighting the need for further knowledge on sepsis treatment and European centres’ interest in off-patent medicine research.
Data collection; Intensive care units, neonatal; Sepsis; Ciprofloxacin; Fluconazole
Neonatal fungal infections are associated with substantial mortality and morbidity. Although prophylactic use of several antifungals has been proposed, this practice remains controversial. In order to evaluate the use of fluconazole prophylaxis in European NICUs, we conducted a cross-sectional survey by means of a structured questionnaire that was sent to European level II and III neonatal intensive care units, over a 9-month period, as part of a neonatal research FP7 European project. A total of 193 questionnaires from 28 countries were analysed. Use of antifungal prophylaxis was reported by 55% of the responders, and the most frequently used antifungal agent was fluconazole (92%). Main indications for prophylaxis were low gestational age (<28 weeks) and birth weight (<1,000 g). A dose of 3 mg/kg was used in 66% of NICUs using fluconazole, with an administration interval of 72 h in 52% of them. All responders acknowledged the need for additional trials on the efficacy of prophylactic fluconazole. Non-users of fluconazole prophylaxis were more likely to be influenced by the local incidence of candidiasis, the risk of increasing antifungal resistance and the absence of specific recommendations by paediatric societies. Conclusions: Major concerns about the use of fluconazole prophylaxis include its efficacy, the risk of emergence of resistant species and the absence of clear consensus to support routine use. Future studies that address these issues will contribute to a more rational use of fluconazole prophylaxis.
Fluconazole; Prophylaxis; Neonatology; Intensive care; Survey
There is now greater involvement of children in drug trials to ensure that paediatric medicines are supported by sound scientific evidence. The safety of the participating children is of paramount importance. Previous research shows that these children can suffer moderate and severe adverse drug reactions (ADRs) in clinical trials, yet very few of the trials designated a data safety monitoring board (DSMB) to oversee the trial.
Safety data from a systematic review of paediatric drug randomised controlled trials (RCTs) published in 2007 were analysed. All reported adverse events (AEs) were classified and assessed to determine whether an ADR had been experienced. ADRs were then categorised according to severity. Each trial report was examined as to whether an independent DSMB was in place.
Of the 582 paediatric drug RCTs analysed, 210 (36%) reported that a serious AE had occurred, and in 15% mortality was reported. ADRs were detected in more than half of the RCTs (305); 66 (11%) were severe, and 79 (14%) were moderate. Severe ADRs involved a wide range of organ systems and were frequently associated with cytotoxic drugs, antiparasitics, anticonvulsants and psychotropic drugs. Two RCTs reported significantly higher mortality rates in the treatment group. Only 69 (12%) of the RCTs stated there was a DSMB. DSMBs terminated five RCTs and changed the protocol in one.
Children participating in drug RCTs experience a significant amount and a wide range of ADRs. DSMBs are needed to ensure the safety of paediatric participants in clinical drug trials.
Paediatric clinical trials; Adverse drug reactions (ADRs); Drug safety; Data safety monitoring boards (DSMBs); Systematic review
New legislation encourages the drug industry to produce high quality transparent research