Neonatal Drug Research Articles

Correct choices for correct treatments: key issues in the management of Candida infections in preterm neonates

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.

Safety in glomerular numbers

A low nephron number is, according to Brenner’s hyperfiltration hypothesis, associated with hypertension, glomerular damage and proteinuria, and starts a vicious cycle that ends in renal failure over the long term. Nephron endowment is set during foetal life, and there is no formation of nephrons after 34–36 weeks of gestation, indicating that many factors before that time-point may have an impact on kidney development and reduce nephron numbers. Such factors include maternal malnutrition, stress, diseases, such as diabetes, uteroplacental insufficiency, maternal and neonatal drugs and premature birth. However, other congenital anomalies, such as renal hypoplasia, unilateral renal agenesis or multicystic dysplastic kidney, may also lead to a reduced nephron endowment, with an increased risk for hypertension, renal dysfunction and the need for renal replacement therapy. This review focusses on the causes and consequences of a low nephron endowment and will illustrate why there is safety in glomerular numbers.•

Hospitalised Estonian newborns are exposed to a significant amount of potentially toxic excipients

BackgroundThe information on neonatal exposure to excipients is limited. Previous studies have focused on the excipients known to be toxic, but have not evaluated the general extent of excipient use...

Pharmacokinetics of Drugs in Neonates: Pattern Recognition Beyond Compound Specific Observations

Although the principles of drug disposition also apply in neonates, their specific characteristics warrant focussed assessment. Children display maturation in drug disposition, but this is most prominent in the first year of life. Besides maturational aspects of drug absorption and distribution, maturation mainly relates to (renal) elimination and (hepatic) metabolic clearance. Renal elimination clearance in early life is low and almost completely depends on glomerular filtration. Despite the overall low clearance, interindividual variability is already extensive and can be predicted by covariates like postmenstrual age, postnatal age, co-administration of a non-selective cyclo-oxygenase inhibitor, growth restriction or peripartal asphyxia. These findings are illustrated by observations on amikacin and vancomycin. Variation in phenotypic metabolic clearance is based on constitutional, environmental and genetic characteristics. In early life, it mainly reflects ontogeny, but other covariates may also become relevant. Almost all phase I and phase II metabolic processes display ontogeny in a iso-enzyme specific pattern. The impact of covariates like postmenstrual age, postnatal age, disease state characteristics and polymorphisms are illustrated based or 'probe' drugs (paracetamol, tramadol, propofol) administered as part of their medical treatment in critically ill neonates. The description of a compound specific pattern is beyond compound specific relevance. The maturational patterns described and the extent of the impact of covariates can subsequently be applied to predict in vivo time-concentration profiles for compounds that undergo similar routes of elimination. Through improved predictability, such maturational models can serve to improve both the clinical care and feasibility and safety of clinical studies in neonates.

Pediatric analgesic clinical trial designs, measures, and extrapolation: report of an FDA scientific workshop.

Analgesic trials pose unique scientific, ethical, and practical challenges in pediatrics. Participants in a scientific workshop sponsored by the US Food and Drug Administration developed consensus on aspects of pediatric analgesic clinical trial design. The standard parallel-placebo analgesic trial design commonly used for adults has ethical and practical difficulties in pediatrics, due to the likelihood of subjects experiencing pain for extended periods of time. Immediate-rescue designs using opioid-sparing, rather than pain scores, as a primary outcome measure have been successfully used in pediatric analgesic efficacy trials. These designs maintain some of the scientific benefits of blinding, with some ethical and practical advantages over traditional designs. Preferred outcome measures were recommended for each age group. Acute pain trials are feasible for children undergoing surgery. Pharmacodynamic responses to opioids, local anesthetics, acetaminophen, and nonsteroidal antiinflammatory drugs appear substantially mature by age 2 years. There is currently no clear evidence for analgesic efficacy of acetaminophen or nonsteroidal antiinflammatory drugs in neonates or infants younger than 3 months of age. Small sample designs, including cross-over trials and N of 1 trials, for particular pediatric chronic pain conditions and for studies of pain and irritability in pediatric palliative care should be considered. Pediatric analgesic trials can be improved by using innovative study designs and outcome measures specific for children. Multicenter consortia will help to facilitate adequately powered pediatric analgesic trials.

Maturation of the Glomerular Filtration Rate in Neonates, as Reflected by Amikacin Clearance

During the newborn period and early infancy, renal function matures, resulting in changes in the glomerular filtration rate (GFR). This study was performed to quantify developmental changes in the GFR in (pre)term neonates by use of amikacin clearance as proof of concept. The model was used to derive a rational dosing regimen in comparison with currently used dosing regimens for amikacin. Population pharmacokinetic modelling was performed in nonlinear mixed-effect modelling software (NONMEM version 6.2) using data from 874 neonates obtained from two previously published datasets (gestational age 24-43 weeks; postnatal age 1-30 days; birthweight 385-4650 g). The influence of different age-related, weight-related and other covariates was investigated. The model was validated both internally and externally. Postmenstrual age was identified as the most significant covariate on clearance. However, the combination of birthweight and postnatal age proved to be superior to postmenstrual age alone. Birthweight was best described using an allometric function with an exponent of 1.34. Postnatal age was identified using a linear function with a slope of 0.2, while co-administration of ibuprofen proved to be a third covariate. Current bodyweight was the most important covariate for the volume of distribution, using an allometric function. The external evaluation supported the prediction of the final pharmacokinetic model. This analysis illustrated clearly that the currently used dosing regimens for amikacin in reference handbooks may possibly increase the risk of toxicities and should be revised. Consequently, a new model-based dosing regimen based on current bodyweight and postnatal age was derived. Amikacin clearance, reflecting the GFR in neonates, can be predicted by birthweight representing the antenatal state of maturation of the kidney, postnatal age representing postnatal maturation, and co-administration of ibuprofen. Finally, the model reflects maturation of the GFR, allowing for adjustments of dosing regimens for other renally excreted drugs in preterm and term neonates.

Neonatal Drug Withdrawal

Maternal use of certain drugs during pregnancy can result in transient neonatal signs consistent with withdrawal or acute toxicity or cause sustained signs consistent with a lasting drug effect. In addition, hospitalized infants who are treated with opioids or benzodiazepines to provide analgesia or sedation may be at risk for manifesting signs of withdrawal. This statement updates information about the clinical presentation of infants exposed to intrauterine drugs and the therapeutic options for treatment of withdrawal and is expanded to include evidence-based approaches to the management of the hospitalized infant who requires weaning from analgesics or sedatives.

NEONATAL SÜNNET İÇİN UYGULANAN İKİ FARKLI BUPİVAKAİN DOZUNUN KARŞILAŞTIRILMASI: RANDOMİZE KLİNİK ÇALIŞMA

We aimed to compare the analgesia quality of caudal block of low volume, high concentration bupivacaine to the conventionally used volumes and concentrations of the drug in neonates undergoing circumcision with sole caudal anesthesia.Fifty neonates, undergoing circumcision were randomly assigned to low volume high concentration (group LVHC, n=25) and control groups (group C, n=25). Both groups received a caudal injection: Group LVHC 0.5 ml/kg bupivacaine 0.375% (1.875 mg/kg) and group C 1 ml/ kg bupivacaine 0.25% (2.5 mg/kg). Hemodynamic parameters, block onsets and analgesia periods were compared among the groups. Pain scores were evaluated hourly for 3 hours postoperatively with NIPS (neonatal infant pain score). Statistical analyses were performed with Student's t-test for continuous variables. X(2) and Mann-Whitney U-tests were used for nominal and/or categorical variables.Demographic, hemodynamic data, block onset time (group LVHC and C values were 4.9 +/- 1 vs 5.2 +/- 2 mins, respectively; p=0.53) was similar and postoperative median NIPS (a median value of 0 at postoperative 1, 2, and 3. hours) were identical among the groups (p=0.7, p=0.9, p=1). None of the neonates required additional analgesic for the first 24 hours following the surgery; therefore postoperative analgesic requirement was similar among the groups (p>0.1).Low volume high concentration caudal bupivacaine provided a similar perioperative analgesia quality, time and safety profile compared to conventional bupivacaine doses in awake neonates undergoing circumcision. Low volume, high concentration bupivacaine may be used to reduce the risk of local anesthetic toxicity in outpatient neonates.

Effects of Neonatal Antiepileptic Drug Exposure on Cognitive, Emotional, and Motor Function in Adult Rats

Despite the potent proapoptotic effect of several antiepileptic drugs (AEDs) in developmental rodent models, little is known about the long-term impact of exposure during brain development. Clinically, this is of growing concern. To determine the behavioral consequences of such exposure, we examined phenobarbital, phenytoin, and lamotrigine for their effects on adult behaviors after administration to neonatal rats throughout the second postnatal week. AED treatment from postnatal days 7 to 13 resulted in adult deficits in spatial learning in the Morris water maze and decreased social exploration for all drugs tested. Phenobarbital exposure led to deficits in cued fear conditioning, risk assessment in the elevated plus maze, and sensorimotor gating as measured by prepulse inhibition, but it did not affect motor coordination on the rotorod task. In contrast, phenytoin and lamotrigine exposure led to impaired rotorod performance, but no deficits in sensorimotor gating. Phenytoin, but not lamotrigine or phenobarbital, increased exploration in the open field. Phenytoin and phenobarbital, but not lamotrigine, disrupted cued fear conditioning. These results indicate that AED administration during a limited sensitive postnatal period is sufficient to cause a range of behavioral deficits later in life, and the specific profile of behavioral deficits varies across drugs. The differences in the long-term outcomes associated with the three AEDs examined are not predicted by either the mechanism of AED action or the proapoptotic effect of the drugs. Our findings suggest that a history of AED therapy during development must be considered as a variable when assessing later-life cognitive and psychiatric outcomes.

Pharmacokinetics of Drugs in Neonates: Pattern Recognition Beyond Compound Specific Observations

Although the principles of disposition and elimination of exogenous compounds also apply in neonates, their specific characteristics warrant a focussed assessment. Children display maturation in drug disposition, but this is most prominent in the first year of life. Elimination clearance is mainly through either renal or metabolic elimination clearance. Renal elimination clearance in early life is low and almost completely depends on glomerular filtration. Despite this overall low clearance, interindividual variability is already extensive and can be predicted by covariates like postmenstrual age, postnatal age, co-administration of a non-selectiveCyclo-oxygenase inhibitor, growth restriction or peripartal asphyxia. These findings are illustrated by observations on amikacin, vancomycin and cefazolin disposition in perinatal life. Variation in phenotypic metabolic clearance is based on constitutional, environmental and genetic characteristics. In early life, it mainly reflects ontogeny, but other covariates may also become relevant. Almost all phase I and phase II metabolic processes display ontogeny in a iso-enzyme specific pattern. The impact of various covariates like postmenstrual age, postnatal age, disease state characteristics and polymorphisms are illustrated based or ‘probe’ drugs (paracetamol, tramadol, propofol) administered as part of their medical treatment in critically ill neonates. The description of a compound specific pattern is beyond compound specific relevance. The patterns described and the extent of the impact of covariates can subsequently be applied to predict in vivo time-concentration profiles for compounds that undergo similar routes of elimination. Through improved predictability, such maturational models can serve to improve both the clinical care and clinical studies in neonates.

The Role of Drugs in Neonatal Resuscitation

Background: Approximately 10% of newborns require skilled neonatal resuscitation with airway and breathing management. Neonatal resuscitation drugs and cardiac compressions are used in less than 1% of deliveries. These infants have a poor prognosis and use of drugs in neonatal resuscitation remains one of the most controversial topics. Objective: To document the outcome, in terms of morbidity and mortality in extreme and mature preterm's, term and near term infants receiving resuscitation drugs. Methods: We retrospectively reviewed the records of all infants who received drugs during resuscitation between July 2006 and February 2011 from the neonatal database and follow up clinic letters. Results: During the study period 26,881 infants were delivered of whom 17(0.06%) infants received resuscitation drugs and 69(0.25%) infants received chest compressions. Overall 10 (58%) infants survived, mortality was high (50%) in infants born extreme preterm (≤ 26weeks), infants born in asystole and in all infants receiving more than one dose of adrenaline. Significant neurodevelopmental disability was noted in surviving extreme preterm infants (100%) compared to term infants (25%). Abnormal cranial imaging was seen in 78% of all surviving preterm and in 62% of the term infants. Conclusions: There is a role for resuscitation drugs in term, near term and mature preterm infants in restoring circulation in depressed neonates. In extremely preterm infants it is associated with significant mortality and neurodisability. Drugs should not be considered if adequate ventilation and cardiac compressions fail to stabilise extreme preterm infant.

The Role of Drugs in Neonatal Resuscitation

Background: Approximately 10% of newborns require skilled neonatal resuscitation with airway and breathing management. Neonatal resuscitation drugs and cardiac compressions are used in less than 1% of deliveries. These infants have a poor prognosis and use of drugs in neonatal resuscitation remains one of the most controversial topics. Objective: To document the outcome, in terms of morbidity and mortality in extreme and mature preterm's, term and near term infants receiving resuscitation drugs. Methods: We retrospectively reviewed the records of all infants who received drugs during resuscitation between July 2006 and February 2011 from the neonatal database and follow up clinic letters. Results: During the study period 26,881 infants were delivered of whom 17(0.06%) infants received resuscitation drugs and 69(0.25%) infants received chest compressions. Overall 10 (58%) infants survived, mortality was high (50%) in infants born extreme preterm (≤ 26weeks), infants born in asystole and in all infants receiving more than one dose of adrenaline. Significant neurodevelopmental disability was noted in surviving extreme preterm infants (100%) compared to term infants (25%). Abnormal cranial imaging was seen in 78% of all surviving preterm and in 62% of the term infants. Conclusions: There is a role for resuscitation drugs in term, near term and mature preterm infants in restoring circulation in depressed neonates. In extremely preterm infants it is associated with significant mortality and neurodisability. Drugs should not be considered if adequate ventilation and cardiac compressions fail to stabilise extreme preterm infant.

Urine Phenobarbital Drug Screening

This study was done to determine if urine phenobarbital measurements provide a reliable indicator of presence of the drug in neonates. Urine was collected from neonates treated with phenobarbital for clinical indications within 4 to 6 hours of clinically indicated collection of serum phenobarbital levels. Urine samples were also collected from control neonates not treated with phenobarbital. One aliquot was assayed fresh, another frozen at -30°C and assayed 1 to 3 months later. Phenobarbital was assayed using the ONLINE TDM Roche/Hitachi automated clinical chemistry analyzer. Serum and urine concentrations were compared as were fresh and frozen urine measurements. Serum phenobarbital ranged from 5.6 to 52.7 μg/mL. Matched urine samples were 56.6 ± 12.5% of the serum level. Frozen samples were 98.3 ± 8.0% of the fresh samples. Urine phenobarbital concentrations, either fresh or frozen, can be used in neonates as a noninvasive estimate of drug levels.

Neonatal drug development

Drug development is crucial to improving the care given to neonates through new and existing medicines. Pressure from regulatory agencies has improved the way in which pharmaceutical companies work with neonates. This provides new opportunities for the neonatal community. This paper describes the issues that arise during the development of new drugs and considers how the contemporary approach to new drugs can inform research on existing drugs.

MODELING ANTIBIOTIC RESISTANCE IN PREGNANT WOMAN AND FETUS

Infection caused by antibiotic-resistant pathogens is one of global public health problems. Many factors contribute to the emergence and spread of these pathogens. A model which describes the transmission dynamics of susceptible and resistant bacteria in a pregnant woman and the fetus is presented. Detailed qualitative analysis about positivity, boundedness, global stability and uniform persistence of the model is carried out. Numerical simulation and sensitivity analysis show that antibiotic input has potential impact for neonatal drug resistance. Our results show that the resistant bacteria in baby mainly come from antibiotics which are wrongly-used during gestational period, or foods containing antibiotic residues.

Update on the pharmacologic management of neonatal abstinence syndrome

Although a statement on Neonatal Drug Withdrawal was published in 1998 by the American Academy of Pediatrics, pharmacologic management of neonatal abstinence syndrome (NAS) remains a challenge. Published clinical trials are limited, restricting treatment decision making to practitioner's experience and preference rather than evidence-based medicine. To optimize withdrawal symptom prevention, drug selection is often based on the offending agent (opioids versus polysubstance exposure), clinical presentation, mechanism of action (agonist versus partial agonist/antagonist, receptor effects), pharmacokinetic parameters and available drug formulations. This review addresses risk factors and pathophysiology of NAS, summarizes parameters of common drugs used for the management of NAS, and reviews published literature of standard therapies as well as newer agents. Based on the current literature, paregoric is no longer recommended and oral morphine solutions remain the mainstay of therapy for opiate withdrawal. Other potential therapies include methadone, buprenorphine, phenobarbital and clonidine with the latter two agents as adjunctive therapies.

Acetyl salicylic acid treatment in neonatal Bartter syndrome—a commentary letter

Acetyl salicylic acid treatment in neonatal Bartter syndrome—a commentary letter

Drug utilisation pattern and off-label use of medicines in Estonian neonatal units

To characterise neonatal hospital drug use and to compare the availability of drug information between Estonian Summaries of Product Characteristics (SPCs) and other sources. This was a prospective cohort study in which pharmacotherapy information on neonates admitted to Tartu University Clinics between 1 February and 1 August 2008 and to Tallinn Children's Hospital between 1 February and 1 August 2009 was collected. Drug labelling status was determined according to Estonian SPCs, and neonatal information was compared with the British National Formulary for Children (BNFC) and the Thomson Micromedex database. Of 490 hospitalised neonates, 71% received pharmacotherapy. Within the entire study period, there were 1981 prescriptions for 115 products, with a median of four (interquartile range 2-7) products per child. Antibacterial, cardiovascular and central nervous system drugs were the most commonly prescribed. All treated preterm neonates received at least one unlicensed or age-related off-label prescription. All prescriptions for alimentary, genitourinary, musculoskeletal and sensory system drugs were off-label. There were large differences in the neonatal information provided by the different sources, with the largest differences found for term neonates, for whom the information was available for 67, 38 and 24% of prescriptions according to the BNFC, Micromedex and Estonian SPC, respectively. The high rate of age-related off-label prescribing for neonates calls for urgent action from medical professionals and others to reinforce effective and safe pharmacotherapy for this age group. The existing SPCs should be regularly updated and more closely harmonised to each other.

Safety and Pharmacokinetics of Multiple-Dose Anidulafungin in Infants and Neonates

Candida infections are common and often fatal in infants and neonates. Anidulafungin has excellent activity against Candida species, but the pharmacokinetics (PK) and safety of the drug in infants and neonates are unknown. The object of our study was to determine the PK and safety of anidulafungin in infants and neonates at risk for invasive candidiasis. Intravenous anidulafungin (1.5mg/kg/day maintenance dose) was administered to 15 infants and neonates over 3 to 5 days. Plasma samples were collected after the first dose and again after the third to fifth doses. The pharmacokinetic parameters of the drug were determined by noncompartmental analysis. Safety was assessed using National Cancer Institute common toxicity criteria. The study showed that drug exposure levels were similar between neonates and infants; the median areas under the concentration-time curve (range) was 75 (30-109) µg·h/ml and 98 (55-278) µg·h/ml (P = 0.12) for neonates and infants, respectively. No drug-related serious adverse events were observed. The study results indicate that neonates and infants receiving 1.5mg/kg/day have anidulafungin exposure levels similar to those in children receiving similar weight-based dosing and in adult patients receiving 100mg/day.

An investigation of drug manipulation for dose accuracy in paediatric practice: the modric study

ObjectiveThe use of unlicensed and off-label drugs for administration to children and neonates is well established and this necessitates the manipulation of some drugs at the point of administration with...