ABSTRACT
Valganciclovir, the ganciclovir prodrug, is an antiviral agent used to prevent cytomegalovirus infection in renal transplant children. Therapeutic drug monitoring is still necessary to ensure optimal therapeutic area under the concentration-time curve from 0 to 24 h (AUC0-24) of 40 to 60 µg·h/mL since valganciclovir presents a high pharmacokinetic variability. To calculate ganciclovir AUC0-24 with the trapezoidal method, 7 samples are needed. The objective of this study was to develop and validate a reliable and clinically applicable limited sampling strategy (LSS) for individualizing valganciclovir dose in renal transplant children. Rich pharmacokinetic data from ganciclovir plasmatic dosages measured in renal transplant children who received valganciclovir to prevent cytomegalovirus infection at Robert Debré University Hospital were collected retrospectively. Ganciclovir AUC0-24s were calculated using the trapezoidal method. The LSS was developed using a multilinear regression approach to predict AUC0-24. The patients included were divided into two groups for model development (50 patients) and validation (30 patients). A total of 80 patients were included between February 2005 and November 2018. Multilinear regression models were developed on 50 pharmacokinetic profiles (50 patients) and validated with an independent group of 43 pharmacokinetic profiles (30 patients). Regressions based on samples collected at T1h-T4h-T8h, T2h-T4h-T8h, or T1h-T2h-T8h presented the best AUC0-24 predictive performances with an average difference between reference and predicted AUC0-24 of -0.27, 0.34, and -0.40 µg·h/mL, respectively. In conclusion, valganciclovir dosage adaptation was required in children to achieve the target AUC0-24. Three LSS models using three pharmacokinetic blood samples instead of seven will be useful for individualizing valganciclovir prophylaxis in renal transplant children.
Subject(s)
Cytomegalovirus Infections , Kidney Transplantation , Humans , Child , Valganciclovir/therapeutic use , Valganciclovir/pharmacokinetics , Ganciclovir/pharmacokinetics , Retrospective Studies , Antiviral Agents/pharmacokinetics , Cytomegalovirus Infections/drug therapy , Cytomegalovirus Infections/prevention & controlABSTRACT
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.
ABSTRACT
BACKGROUND: Pharmacokinetics data on ceftazidime are sparse for the paediatric population, particularly for children with cystic fibrosis (CF) or severe infections. OBJECTIVES: To characterize the population pharmacokinetics of ceftazidime in critically ill children, identify covariates that affect drug disposition and evaluate the current dosing regimens. METHODS: The study was registered with Clinicaltrials.gov (NCT01344512). Children receiving ceftazidime were selected in 13 French hospitals. Plasma concentrations were determined by UPLC-MS/MS. Population pharmacokinetic analyses were performed using NONMEN software. RESULTS: One hundred and eight patients, aged 28 days to 12 years, with CF (n = 32), haematology and/or oncology disorders (n = 47) or severe infection (n = 29) were included. Ceftazidime was administered by continuous or intermittent infusions; 271 samples were available for analysis. A two-compartment model with first-order elimination and allometric scaling was developed and covariate analysis showed that ceftazidime pharmacokinetics were also significantly affected by CLCR and CF. Ceftazidime clearance was 82% higher in CF than in non-CF patients. Monte Carlo simulations showed that the percentage of target attainment (PTA) for the target of T>MIC = 65% was (i) lower in CF than in non-CF children with intermittent infusions and (ii) higher with continuous than intermittent infusion in all children. CONCLUSIONS: The population pharmacokinetics model for ceftazidime in children was influenced by body weight, CLCR and CF. A higher PTA was obtained with continuous versus intermittent infusions. Further studies should explore the benefits of continuous versus intermittent infusion of ceftazidime, including current versus increased doses in CF children.
Subject(s)
Ceftazidime , Cystic Fibrosis , Anti-Bacterial Agents/therapeutic use , Child , Chromatography, Liquid , Critical Illness , Cystic Fibrosis/complications , Cystic Fibrosis/drug therapy , Humans , Microbial Sensitivity Tests , Monte Carlo Method , Tandem Mass SpectrometryABSTRACT
BACKGROUND: Valganciclovir, the ganciclovir prodrug, is an antiviral agent administered orally to prevent or treat cytomegalovirus infection in solid organ transplant recipients. Dosing regimen of valganciclovir is still controversial in children, as the number of patients reaching the Area Under the Curve at steady state (AUCss) target (40 - 60 mg.h/L) remains highly variable. The aim of this study was to determine the population pharmacokinetics of valganciclovir in paediatric renal transplant recipients and propose an appropriate dosing regimen. METHODS: Renal transplant children who received valganciclovir to prevent or treat cytomegalovirus infection at Robert Debré University Hospital were included. Plasma ganciclovir concentrations were determined by high performance liquid chromatography and ultraviolet detection. Population pharmacokinetic analysis was performed with NONMEM software. RESULTS: 104 patients, aged 2 to 20 years, treated with valganciclovir administered at a mean dose of 17.3 ± 6.1 mg/kg to prevent and/or treat cytomegalovirus infection after renal transplantation were included. A total of 1212 samples were available. A two-compartment model with first-order elimination best fitted the data: ganciclovir clearance increased with body surface area, was 15% higher in boys and decreased with increasing creatinine concentration. Central volume of distribution increased with body surface area and was 14% higher in boys. According to the personalized dosing regimen, 65.7% and 65.4% of children were predicted to achieve the AUCss target for cytomegalovirus prophylaxis and treatment, respectively. CONCLUSION: A new pharmacokinetic model was built allowing to propose individualised dose adapted to renal transplanted paediatric patients characteristics.
ABSTRACT
Objectives: To determine the ciprofloxacin population pharmacokinetics in paediatric patients and the impact of underlying disease and evaluate the appropriateness of current dosage regimens. Patients and methods: Plasma concentrations of ciprofloxacin from children treated with ciprofloxacin were measured by HPLC. The pharmacokinetic population analysis was performed using NONMEM v7.2 (Icon Development Solutions, USA). Results: Two datasets were combined and 128 plasma concentrations in 60 patients aged 5.6 years (range 0.3-18.9), treated with a median daily dose of 30.0âmg/kg (range 6.5-52.0) presenting with sickle cell disease (SCD; nâ=â20, 33%), haemopathy (nâ=â15, 25%), cystic fibrosis (CF; nâ=â3, 5%) and other diseases (nââ=ââ22, 37%) were analysed. Data were best described by a two-compartment model with first-order elimination. Ciprofloxacin clearance (meanâ±ââSD) was 0.81â±â0.30âL/h/kg, increased allometrically with weight, decreased with increasing creatinine concentration, was 89% higher in SCD compared with non-SCD patients and increased by 0.95 L/h/kg per year of age. The volume of distribution was 6.9 L/kg and depended only on the weight. Monte Carlo simulations were performed separately in SCD and non-SCD patients to target an AUC/MIC ratio >125 at steady-state, required for antibacterial efficacy, and recommendations of dosing regimens were proposed. Conclusions: In addition to known covariates, ciprofloxacin clearance is greater in SCD children compared with non-SCD patients. The dosing of this agent needs to be adapted to this subgroup of patients.
Subject(s)
Anemia, Sickle Cell , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacokinetics , Ciprofloxacin/administration & dosage , Ciprofloxacin/pharmacokinetics , Child , Child, Preschool , Chromatography, High Pressure Liquid , Female , Humans , Infant , Infant, Newborn , Male , Metabolic Clearance Rate , Plasma/chemistry , United StatesABSTRACT
AIMS: The pharmacokinetics (PK) of fluconazole and micafungin differ in neonates compared with children and adults. Dosing instructions in product labels appear to be inconsistent with the emerging scientific evidence. Limited information is available on the safety profile of these agents in neonates. Our objective was to study the population PK and safety of both drugs, randomly administered in neonates with suspected or confirmed systemic candidiasis. METHODS: Neonates were randomized 1:1 to fluconazole (loading dose 25 mg kg-1 ; maintenance dose 12 mg kg-1 day-1 or 20 mg kg-1 day-1 , respectively, for infants <30 weeks or ≥30 weeks' corrected gestational age) or micafungin (loading dose 15 mg kg-1 day-1 ; maintenance dose 10 mg kg-1 day-1 ). PK samples were taken on treatment days 1 and 5. Population parameters were determined using NONMEM and Monte Carlo simulations performed to reach predefined targets. Clinical and laboratory data, and adverse events were collected up to 36 weeks' corrected gestational age or hospital discharge. RESULTS: Thirty-six neonates were enrolled. The median (range) gestational age was 28.2 (24.1-40.1) and 26.8 (23.5-40.0) weeks for fluconazole and micafungin, respectively. Based on 163 PK samples, the median population clearance (l h-1 kg-1 ) and volume of distribution (l kg-1 ) for fluconazole were: 0.015 [95% confidence interval (CI) 0.008, 0.039] and 0.913, and for micafungin were: 0.020 (95% CI 0.010, 0.023) and 0.354 (95% CI 0.225, 0.482), respectively. The loading dose was well tolerated. No adverse events associated with micafungin or fluconazole were reported. CONCLUSION: Based on Monte Carlo simulations, a loading dose for fluconazole and dosing higher than recommended for both drugs are required to increase the area under the plasma drug concentration-time curve target attainment rate in neonates.
Subject(s)
Antifungal Agents/pharmacokinetics , Candidiasis/drug therapy , Fluconazole/pharmacokinetics , Micafungin/pharmacokinetics , Age Factors , Animals , Antifungal Agents/administration & dosage , Antifungal Agents/adverse effects , Area Under Curve , Female , Fluconazole/administration & dosage , Fluconazole/adverse effects , Humans , Infant , Infant, Newborn , Infant, Premature , Male , Micafungin/administration & dosage , Micafungin/adverse effects , Mice , Prospective StudiesABSTRACT
Many factors (physiological, pathological, environmental or genetic) are associated with variability in drug effect. Most patients respond to a standard treatment but the drug may be ineffective or toxic. In this review, we focused on genetic markers of posttransplant diabetes mellitus (PTDM) after renal transplantation, a frequent complication of immunosuppressive therapy and important risk factor of graft loss and mortality. An initial literature search identified 100 publications and among them 32 association studies were retrieved under 'Pharmacogenetics and PTDM'. Thirty-five variants in 25 genes with an impact on insulin secretion, disposition or effect were significantly associated with PTDM. The population studied, immunosuppressive regimen, follow-up, PTDM diagnostic and genetic variations tested were highly variable between studies. Although pharmacogenetic biomarkers are key tools of great promise for preventing toxicities and improving event-free survival rates, replication studies are required to select validated biomarkers linked to the occurrence of PTDM and select appropriate immusuppressive treatment to improve renal graft and patient outcome.
Subject(s)
Diabetes Mellitus/genetics , Immunosuppressive Agents/adverse effects , Kidney Transplantation/adverse effects , Mutation , Pharmacogenetics , Pharmacogenomic Variants , Polymorphism, Single Nucleotide , Blood Glucose/metabolism , Diabetes Mellitus/blood , Diabetes Mellitus/chemically induced , Genetic Predisposition to Disease , Humans , Insulin/blood , Insulin/metabolism , Insulin Secretion , Odds Ratio , Pharmacogenomic Testing , Phenotype , Risk Assessment , Risk Factors , Treatment OutcomeABSTRACT
WHAT IS KNOWN: The neonatal intensive care units (NICUs) are at the highest risk of drug dose error of all hospital wards. NICUs also have the most complicated prescription modalities. The computerization of the prescription process is currently recommended to decrease the risk of preventable adverse drug effects (pADEs) in NICUs. However, Computer Prescribing Order Entry-Clinical Decision Support (C.P.O.E./C.D.S.) systems have been poorly studied in NICUs, and their technical compatibility with neonatal specificities has been limited. OBJECTIVES: We set up a performance study of the preselected prescription of drugs for neonates, which limited the role of the prescriber to choosing the drugs and their indications. METHODS: A single 29 bed neonatal ward used this neonatal C.P.O.E./C.D.S. system for all prescriptions of all hospitalized newborns over an 18-month period. The preselected prescription of drugs was based on the indication, gestational age, body weight and post-natal age. The therapeutic protocols were provided by a formulary reference (330 drugs) that had been specifically designed for newborns. The preselected prescription also gave complete information about preparation and administration of drugs by nurses. The prescriber was allowed to modify the preselected prescription but alarms provided warning when the prescription was outside the recommended range. The main clinical characteristics and all items of each line of prescription were stored in a data warehouse, thus enabling this study to take place. RESULTS: Seven hundred and sixty successive newborns (from 24 to 42 weeks' gestation) were prescribed 52 392 lines of prescription corresponding to 65 drugs; About 30·4% of neonates had at least one out of licensed prescription; A prescription out of the recommended range for daily dose was recorded for 1·0% of all drug prescriptions. WHAT IS NEW?: The C.P.O.E./C.D.S. systems can currently provide a complete preselected prescription in NICUs according to dose rules, which are specific to newborns and also comply with local specificities (therapeutic protocols and formulation of drugs). The role of the prescriber is limited to the choice of drugs and their indications. The prescriber still retains the possibility of modifying each item of the prescription, with all other prescription items being calculated by the C.P.O.E. system. In these conditions, the prescribers rarely modified the preselected prescription and the rate of out of range prescription was low. A multicentric study is required to confirm and extend these observations. CONCLUSIONS: This study showed the feasibility of preselected prescription in NICUs and a low rate of out of range prescriptions. The preselected prescription could play a key role in lowering the dose error rate in NICUs.
Subject(s)
Decision Support Systems, Clinical/statistics & numerical data , Drug Prescriptions/statistics & numerical data , Drug-Related Side Effects and Adverse Reactions/prevention & control , Intensive Care Units, Neonatal/statistics & numerical data , Prescription Drugs/therapeutic use , Female , Humans , Infant, Newborn , Male , Medication Errors/prevention & control , Medication Errors/statistics & numerical data , Pilot Projects , Prescription Drugs/adverse effectsABSTRACT
There is wide variation in neonatal dosages of antibiotics in clinical practice, both nationally and internationally. This reflects the lack of evaluation of drugs in this therapeutic class, although widely prescribed. Given this situation, optimization of antibiotic prescription is required to ensure efficacy and safety of neonatal treatment and reduce microbial resistance. Rational prescription should be based on the knowledge of developmental pharmacokinetics and pharmacodynamics. Rigorous studies, conducted in collaboration between neonatologists and pharmacologists, are essential to develop and validate evidence-based neonatal dosage regimens.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacokinetics , Dose-Response Relationship, Drug , Humans , Infant, Newborn , Reference Books, MedicalABSTRACT
OBJECTIVES: CoNS are the most common cause of neonatal late-onset sepsis. Information on the vancomycin pharmacokinetics/pharmacodynamics against CoNS is limited. The aim of this study was to characterize vancomycin pharmacokinetic/pharmacodynamic relationships for CoNS and investigate neonatal optimal dosage regimens. METHODS: A hollow fibre and a novel rabbit model of neonatal central line-associated bloodstream CoNS infections were developed. The results were then bridged to neonates by use of population pharmacokinetic techniques and Monte Carlo simulations. RESULTS: There was a dose-dependent reduction in the total bacterial population and C-reactive protein levels. The AUC/MIC and Cmax/MIC ratios were strongly linked with total and mutant resistant cell kill. Maximal amplification of resistance was observed in vitro at an fAUC/MIC of 200 mgâ·âh/L. Simulations predicted that neonates <29 weeks post-menstrual age are underdosed with standard regimens with respect to older age groups. CONCLUSIONS: The AUC/MIC and Cmax/MIC ratios are the pharmacodynamic indices that best explain total and resistant cell kill in CoNS infection. This suggests that less-fractionated regimens are appropriate for clinical use and continuous infusions may be associated with increased risk of emergence of antimicrobial resistance. This study has provided the pharmacodynamic evidence to inform an optimized neonatal dosage regimen to take into a randomized controlled trial.
Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Neonatal Sepsis/drug therapy , Vancomycin/pharmacokinetics , Algorithms , Animals , Animals, Newborn , Anti-Bacterial Agents/administration & dosage , Disease Models, Animal , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Models, Theoretical , Monte Carlo Method , Neonatal Sepsis/etiology , Rabbits , Staphylococcal Infections , Staphylococcus/drug effects , Staphylococcus/genetics , Vancomycin/administration & dosageABSTRACT
Ethical and regulatory documents frame informed consent in pediatric research; their application is obligatory but may be complex. In this specific context, pediatric investigators have a central ethical role to play to ensure the strict respect of regulatory and ethical requirements adapted to the French legal, social, and cultural context as well as good clinical practices. This article attempts to shed light on the considerations that can allow researchers to come to terms with industrial and institutional demands while responding to the needs of patients, particularly in the domain of pediatric research.
Subject(s)
Biomedical Research/ethics , Informed Consent/ethics , Legal Guardians , Pediatrics/ethics , Biomedical Research/legislation & jurisprudence , Child , France , Humans , Informed Consent/legislation & jurisprudenceABSTRACT
In pediatric research, the patient is legally a minor and therefore protected by law. Research can only be conducted after parental consent and patient assent have been obtained. In this context, this review discusses the historical events and documents related to all ethical precautions and obligations. It also underlines that physicians shall respect all legal measures, but that individual involvement must comply with ethical standards while taking into account issues particular to pediatric research related to parental consent and child assent to clinical trials.
Subject(s)
Biomedical Research/legislation & jurisprudence , Parental Consent/legislation & jurisprudence , Pediatrics/legislation & jurisprudence , Physician-Patient Relations , Biomedical Research/ethics , Child , Europe , France , Humans , Parental Consent/ethics , Pediatrics/ethics , Physician-Patient Relations/ethicsABSTRACT
BACKGROUND/OBJECTIVE: To determine gastrointestinal (GI) responses and maximum tolerated dose of erythritol in young children given as a single oral dose in a 250-ml non-carbonated fruit-flavoured beverage in between meals. This is a multicentre double-blind study with sequential design for multiple dose groups and randomised crossover for comparators of placebo vs dose. SUBJECTS/METHODS: A total of 185 healthy young children aged 4-6 years were recruited at three clinical investigation centres after informed consent of both parents; 184 children completed the study. Children were included in one of the four dose groups (5, 15, 20 or 25 g erythritol) and exposed randomly to only one single dose vs an isosweet sucrose placebo. After consumption in the clinic and an observation period, GI symptoms and stooling patterns were recorded during the next 48 h. RESULTS: Statistically significantly more episodes of diarrhoea and/or severe GI symptoms were observed in the 20 and 25 g groups compared with placebo, but not in the 5 and 15 g groups. Stool consistency, as measured by Bristol stool scale, was lower in the 15-, 20- and 25 g groups for the first 24 -h period, but not at later time points. Incidences of nausea, vomiting, borborygmi, excess flatus and abdominal pain were not significantly different from the placebo controls at all doses of erythritol. CONCLUSIONS: Rapid ingestion of up to and including 15 g (6% w/v) of erythritol in a beverage in between meals by young children aged 4-6 years was well tolerated. The no observed effect level for diarrhoea and/or severe GI symptoms was 15 g (0.73 g/kg body weight (bw)). Children appeared not to be more sensitive to the GI effects of erythritol than published for adults on a g/kg bw basis.
Subject(s)
Beverages/adverse effects , Diarrhea/etiology , Diet, Reducing , Erythritol/adverse effects , Gastroenteritis/etiology , Nutritive Sweeteners/adverse effects , Snacks , Abdominal Pain/etiology , Child , Child, Preschool , Cohort Studies , Cross-Over Studies , Diarrhea/epidemiology , Diarrhea/physiopathology , Diarrhea/urine , Double-Blind Method , Erythritol/administration & dosage , Erythritol/urine , Female , Gastroenteritis/epidemiology , Gastroenteritis/physiopathology , Gastroenteritis/urine , Humans , Incidence , Male , Nutritive Sweeteners/administration & dosage , Nutritive Sweeteners/metabolism , Renal Elimination , Severity of Illness IndexABSTRACT
UNLABELLED: 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 EMA-Paediatric 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 off-patent drugs and many unmet therapeutic needs in paediatrics remain, it is crucial foreseeing new similar initiatives in forthcoming European funding programmes.
Subject(s)
Biomedical Research/economics , Financial Management/methods , Nonprescription Drugs/economics , Pediatrics/economics , Child , European Union , HumansABSTRACT
BACKGROUND: We sought to describe the incidence, pathogen distribution, and mortality associated with blood culture-proven sepsis in young infants with congenital heart disease (CHD) admitted to a neonatal intensive care unit (NICU). METHODS: Cohort study of all blood cultures obtained from infants with CHD between 4 and 120 days of age cared for in 250 NICUs managed by the Pediatrix Medical Group in the United States between 1996 and 2007. RESULTS: Of 11,638 infants with CHD, 656 (6%) had 821 episodes of sepsis: a cumulative incidence of 71/1000 admissions. Gram-positive organisms were the most common cause (64%), and coagulase-negative Staphylococcus and Staphylococcus aureus were the most frequently isolated species. On multivariable regression, infants with sepsis were more likely to die compared to infants with sterile blood cultures (odds ratio [OR] = 1.53 [95% confidence interval: 1.09, 2.13]). Infants with Gram-negative bacteraemia and candidaemia were more likely to die than infants with sterile blood cultures (OR = 2.01 [1.20, 3.37], and OR = 3.18 [1.60, 6.34], respectively). CONCLUSION: Infants with CHD have a high incidence of culture-proven sepsis, especially with staphylococcal organisms. Gram-negative bacteraemia and candidaemia are strongly associated with increased mortality in this group of young infants.
Subject(s)
Candidemia/complications , Gram-Negative Bacterial Infections/complications , Heart Defects, Congenital/complications , Sepsis/complications , Staphylococcal Infections/complications , Candidemia/microbiology , Candidemia/mortality , Cohort Studies , Female , Gram-Negative Bacterial Infections/microbiology , Gram-Negative Bacterial Infections/mortality , Humans , Infant , Infant, Newborn , Intensive Care Units, Neonatal , Male , Sepsis/mortality , Staphylococcal Infections/microbiology , Staphylococcal Infections/mortality , Staphylococcus/isolation & purificationABSTRACT
Invasive Candida infections (ICI) have a high burden of morbidity and mortality in the neonatal setting. Although the identification of effective prophylactic strategies has recently led to the prevention of many episodes of systemic fungal disease, the identification of effective treatment strategies is still a priority. The correct choice of the most appropriate antifungal drug for treatment of such infections requires specific expertise, as well as careful consideration of a number of variables related both to the characteristics of the patient and to the peculiarities of these infections in neonates. The ideal antifungal drug for preterm neonates should have a good ability to target fungal biofilms, in order to prevent or improve the course of end-organ localisations. It should also be active against fluconazole-resistant species, as well as safe enough to be used with no or limited interference with other neonatal drugs. In this view, the echinocandin class of antifungal agents has recently proven to be a suitable option for treatment. However, further studies are warranted to better establish kinetics and appropriate dosing of these agents in premature and term infants, as well as their ability to improve late outcomes of ICI.
Subject(s)
Antifungal Agents/therapeutic use , Candidiasis, Invasive/drug therapy , Echinocandins/therapeutic use , Infant, Premature, Diseases/drug therapy , Biofilms/drug effects , Candida/drug effects , Candidiasis, Invasive/prevention & control , Fluconazole/therapeutic use , Humans , Infant , Infant, Newborn , Infant, Premature , Infant, Premature, Diseases/prevention & control , Infant, Very Low Birth WeightABSTRACT
Fluconazole is a triazole antifungal agent that is widely used in the nursery. It is available in both intravenous and oral formulation, and is active against most of the fungal pathogens that require treatment when retrieved from culture samples in neonatal intensive care units. Although clinical use has been wide for over 15 years, there have been small safety and efficacy studies completed in young infants. Randomised clinical trials assessing effectiveness of this agent in prevention of systemic fungal infections in neonates have been published in the last decade, and one large additional randomised study has been recently completed. Nevertheless, a certain degree of uncertainty still exists regarding the kinetics and appropriate dosing of this agent in premature and term infants, as well as regarding safety. Areas of poignant debate include the feasibility of loading dose strategies, appropriate dosages in the early days of life in the different subgroups of preterm infants, and long-term safety of fluconazole administered in prophylaxis during the first weeks of life in extremely premature infants. This paper reviews the most recent evidence on fluconazole and its role in the NICU settings.
Subject(s)
Antifungal Agents/adverse effects , Antifungal Agents/therapeutic use , Candidiasis, Invasive/drug therapy , Fluconazole/adverse effects , Fluconazole/therapeutic use , Infant, Premature, Diseases/drug therapy , Antifungal Agents/administration & dosage , Candida/drug effects , Candidiasis, Invasive/prevention & control , Fluconazole/administration & dosage , Humans , Infant , Infant, Newborn , Infant, Premature , Infant, Premature, Diseases/microbiology , Intensive Care Units, Neonatal , Nurseries, InfantABSTRACT
Candida infections are a major cause of morbidity and mortality in neonatal intensive care units. Mortality following Candida bloodstream infections is as high as 40%, and neurodevelopmental impairment is common among survivors. Because invasive fungal infections are common and extremely difficult to diagnose, empirical treatment with antifungal therapy should be considered in high-risk, low-birth-weight infants who fail to quickly respond to empirical antibacterial treatment. Risk factors to consider when deciding to administer empirical antifungal therapy include: prior exposure to third-generation cephalosporins, extreme prematurity, and presence of central venous catheters.