Simplified Dosing Regimens for Gentamicin in Neonatal Sepsis

Background: The effectiveness of antibiotics for the treatment of severe bacterial infections in newborns in resource-limited settings has been determined by empirical evidence. However, such an approach does not warrant optimal exposure to antibiotic agents, which are known to show different disposition characteristics in this population. Here we evaluate the rationale for a simplified regimen of gentamicin taking into account the effect of body size and organ maturation on pharmacokinetics. The analysis is supported by efficacy data from a series of clinical trials in this population. Methods: A previously published pharmacokinetic model was used to simulate gentamicin concentration vs. time profiles in a virtual cohort of neonates. Model predictive performance was assessed by supplementary external validation procedures using therapeutic drug monitoring data collected in neonates and young infants with or without sepsis. Subsequently, clinical trial simulations were performed to characterize the exposure to intra-muscular gentamicin after a q.d. regimen. The selection of a simplified regimen was based on peak and trough drug levels during the course of treatment. Results: In contrast to current World Health Organization guidelines, which recommend gentamicin doses between 5 and 7.5 mg/kg, our analysis shows that gentamicin can be used as a fixed dose regimen according to three weight-bands: 10 mg for patients with body weight <2.5 kg, 16 mg for patients with body weight between 2.5 and 4 kg, and 30 mg for those with body weight >4 kg. Conclusion: The choice of the dose of an antibiotic must be supported by a strong scientific rationale, taking into account the differences in drug disposition in the target patient population. Our analysis reveals that a simplified regimen is feasible and could be used in resource-limited settings for the treatment of sepsis in neonates and young infants with sepsis aged 0–59 days

Safety of fluconazole in paediatrics: a systematic review

Purpose: To determine the safety of fluconazole in neonates and other paediatric age groups by identifying adverse events (AEs) and drug interactions associated with treatment. Methods: 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. Results: 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. Conclusion: 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

Licensed medicines, off-label use or evidence based: which is most important?

Medicines are licensed for use in humans by regulatory authorities. The concept of licensing is that it helps ensure that medicines are safe, effective and of an adequate quality for regular use.1 Licensing was introduced due to concerns about safety not to ensure that medicines are effective. It was a response to specific examples of drug toxicity, notably the grey baby syndrome in neonates following the use of the antibiotic chloramphenicol and phocomelia in the developing fetus following ingestion of thalidomide by pregnant women.2 Within the UK, the Medicines Act was passed in 1968. The licensing of medicines is both a control on products of public interest as well as an authorisation to sell for pharmaceutical companies. Pharmaceutical companies are only allowed to promote licensed medicines. Prescribers, however, are free to prescribe the most appropriate medicine for their patient. This should be based on the best available scientific evidence. Medicines can be licensed (authorised) by either national regulatory agencies (national route) or the European Medicines Agenc

Wide intra- and inter-country variability in drug use and dosage in very-low-birth-weight newborns with severe infections

Purpose: 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. Methods: 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. Results: 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 72h. 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. Conclusions: 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

A Delphi process to optimize quality and performance of drug evaluation in neonates

Background Neonatal trials remain difficult to conduct for several reasons: in particular the need for study sites to have an existing infrastructure in place, with trained investigators and validated quality procedures to ensure good clinical, laboratory practices and a respect for high ethical standards. The objective of this work was to identify the major criteria considered necessary for selecting neonatal intensive care units that are able to perform drug evaluations competently. Methodology and Main Findings This Delphi process was conducted with an international multidisciplinary panel of 25 experts from 13 countries, selected to be part of two committees (a scientific committee and an expert committee), in order to validate criteria required to perform drug evaluation in neonates. Eighty six items were initially selected and classified under 7 headings: “NICUs description - Level of care” (21), “Ability to perform drug trials: NICU organization and processes (15), “Research Experience” (12), “Scientific competencies and area of expertise” (8), “Quality Management” (16), “Training and educational capacity” (8) and “Public involvement” (6). Sixty-one items were retained and headings were rearranged after the first round, 34 were selected after the second round. A third round was required to validate 13 additional items. The final set includes 47 items divided under 5 headings. Conclusion A set of 47 relevant criteria will help to NICUs that want to implement, conduct or participate in drug trials within a neonatal network identify important issues to be aware of. Summary Points 1) Neonatal trials remain difficult to conduct for several reasons: in particular the need for study sites to have an existing infrastructure in place, with trained investigators and validated quality procedures to ensure good clinical, laboratory practices and a respect for high ethical standards. 2) The present Delphi study was conducted with an international multidisciplinary panel of 25 experts from 13 countries and aims to identify the major criteria considered necessary for selecting neonatal intensive care units (NICUs) that are able to perform drug evaluations competently. 3) Of the 86 items initially selected and classified under 7 headings - “NICUs description - Level of care” (21), “Ability to perform drug trials: NICU organization and processes (15), “Research Experience” (12), “Scientific competencies and area of expertise” (8), “Quality Management” (16), “Training and educational capacity” (8) and “Public involvement” (6) - 47 items were selected following a three rounds Delphi process. 4) The present consensus will help NICUs to implement, conduct or participate in drug trials within a neonatal network

Pharmacokinetics of oral valganciclovir solution and intravenous ganciclovir in pediatric renal and liver transplant recipients

M.D. Pescovitz, R.B. Ettenger, C.F. Strife, J.R. Sherbotie, S.E. Thomas, S. McDiarmid, S. Bartosh, J. Ives, M.R. Bouw, J. Bucuvalas. Pharmacokinetics of oral valganciclovir solution and intravenous ganciclovir in pediatric renal and liver transplant recipients. Transpl Infect Dis 2010: 12: 195–203. All rights reservedIn an open-label, prospective, pharmacokinetic assessment, we evaluated total drug exposure (area under the curve [AUC]) of intravenous (IV) ganciclovir (GCV) and oral (p.o.) valganciclovir when normalized for body surface area (BSA) in pediatric liver ( n =20) and renal ( n =26) transplant patients Reference doses for IV GCV (200 mg/m 2 ) and p.o. valganciclovir (520 mg/m 2 ) were based on adult doses, and adjusted for BSA initially, and BSA and renal function (estimated via creatinine clearance [CrCL]) thereafter. Renal transplant patients received GCV on days 1–2, valganciclovir 260 mg/m 2 on day 3, and valganciclovir 520 mg/m 2 on day 4. Liver transplant patients received twice daily GCV from enrollment to day 12, and then valganciclovir twice daily on days 13–14. GCV pharmacokinetics were described using a population pharmacokinetic approach. Type of solid organ transplant (kidney or liver) had no effect on GCV pharmacokinetics. Median GCV exposure following valganciclovir 520 mg/m 2 was similar to that with IV GCV, and to that reported in adults. Patients <5 years of age had AUC values approximately 50% of those compared with older age ranges; dosing based on both BSA and CrCL increased drug exposure in younger patients. A dosing algorithm based on BSA and CrCL should be tested in future studies.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78598/1/j.1399-3062.2009.00478.x.pd

Integration of Pharmacogenetics and Pharmacogenomics in Drug Development: Implications for Regulatory and Medical Decision Making in Pediatric Diseases

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Successful private–public funding of paediatric medicines research: lessons from the EU programme to fund research into off-patent medicines

The European Paediatric Regulation mandated the European Commission to fund research on off-patent medicines with demonstrated therapeutic interest for children. Responding to this mandate, five FP7 project calls were launched and 20 projects were granted. This paper aims to detail the funded projects and their preliminary results. Publicly available sources have been consulted and a descriptive analysis has been performed. Twenty Research Consortia including 246 partners in 29 European and non-European countries were created (involving 129 universities or public funded research organisations, 51 private companies with 40 SMEs, 7 patient associations). The funded projects investigate 24 medicines, covering 10 therapeutic areas in all paediatric age groups. In response to the Paediatric Regulation and to apply for a Paediatric Use Marketing Authorisation, 15 Paediatric Investigation Plans have been granted by the EMAPaediatric Committee, including 71 studies of whom 29 paediatric clinical trials, leading to a total of 7,300 children to be recruited in more than 380 investigational centres. Conclusion: Notwithstanding the EU contribution for each study is lower than similar publicly funded projects, and also considering the complexity of paediatric research, these projects are performing high-quality research and are progressing towards the increase of new paediatric medicines on the market. Private–public partnerships have been effectively implemented, providing a good example for future collaborative actions. Since these projects cover a limited number of offpatent drugs and many unmet therapeutic needs in paediatrics remain, it is crucial foreseeing new similar initiatives in forthcoming European funding programmes

Supporting women farmers in a changing climate: five policy lessons

Policies, institutions and services to help farmers develop new approaches to deal with climate change will need to produce results for women farmers as well as men. This brief provides five policy lessons to support this process, based on evidence from research in low- and middle- income countries and offers guidelines for crafting gender-responsive climate policies at global and national levels. This research was presented in March 2015 at a seminar in Paris on ‘Closing the gender gap in farming under climate change’, co-organized by the CGIAR Research Program on Climate Change, Agriculture and Food Security (CCAFS), the International Social Science Council (ISSC) and Future Earth

Population pharmacokinetics of ciprofloxacin in neonates and young infants less than 3 months age

Ciprofloxacin is used in neonates with suspected or documented Gram-negative serious infections. Currently, its use is off-label partly because of lack of pharmacokinetic studies. Within the FP7 EU project TINN (Treat Infection in NeoNates), our aim was to evaluate the population pharmacokinetics of ciprofloxacin in neonates and young infants \u3c3 months of age and define the appropriate dose in order to optimize ciprofloxacin treatment in this vulnerable population. Blood samples were collected from neonates treated with ciprofloxacin and concentrations were quantified by high-pressure liquid chromatography-mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM software. The data from 60 newborn infants (postmenstrual age [PMA] range, 24.9 to 47.9 weeks) were available for population pharmacokinetic analysis. A two-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that gestational age, postnatal age, current weight, serum creatinine concentration, and use of inotropes had a significant impact on ciprofloxacin pharmacokinetics. Monte Carlo simulation demonstrated that 90% of hypothetical newborns with a PMA of \u3c34 weeks treated with 7.5 mg/kg twice daily and 84% of newborns with a PMA ≥34 weeks and young infants receiving 12.5 mg/kg twice daily would reach the AUC/MIC target of 125, using the standard EUCAST MIC susceptibility breakpoint of 0.5 mg/liter. The associated risks of overdose for the proposed dosing regimen were \u3c8%. The population pharmacokinetics of ciprofloxacin was evaluated in neonates and young infants \u3c3 months old, and a dosing regimen was established based on simulation