Kanecia O. Zimmerman

Simultaneous determination of trimethoprim and sulfamethoxazole in dried plasma and urine spots.

BACKGROUND Trimethoprim-sulfamethoxazole (TMP-SMX) is an antimicrobial drug combination commonly prescribed in children and adults. The study objectives were to validate and apply an HPLC-MS/MS method to quantify TMP-SMX in dried plasma spots (DPS) and dried urine spots (DUS), and perform a comparability analysis with liquid matrices. RESULTS For TMP the validated range was 100-50,000 ng/ml for DPS and 500-250,000 ng/ml for DUS; for SMX, the validated range was 1000-500,000 ng/ml for both DPS and DUS. Good agreement was noted between DPS/DUS and liquid plasma and urine samples for TMP, while only modest agreement was observed for SMX in both matrices. CONCLUSION A precise, accurate and reproducible method was developed to quantify TMP-SMX in DPS and DUS samples.

Sedatives and Analgesics Given to Infants in Neonatal Intensive Care Units at the End of Life

OBJECTIVE To describe the administration of sedatives and analgesics at the end of life in a large cohort of infants in North American neonatal intensive care units. STUDY DESIGN Data on mortality and sedative and analgesic administration were from infants who died from 1997-2012 in 348 neonatal intensive care units managed by the Pediatrix Medical Group. Sedatives and analgesics of interest included opioids (fentanyl, methadone, morphine), benzodiazepines (clonazepam, diazepam, lorazepam, midazolam), central alpha-2 agonists (clonidine, dexmedetomidine), ketamine, and pentobarbital. We used multivariable logistic regression to evaluate the association between administration of these drugs on the day of death and infant demographics and illness severity. RESULTS We identified 19 726 infants who died. Of these, 6188 (31%) received a sedative or analgesic on the day of death; opioids were most frequently administered, 5366/19 726 (27%). Administration of opioids and benzodiazepines increased during the study period, from 16/283 (6%) for both in 1997 to 523/1465 (36%) and 295/1465 (20%) in 2012, respectively. Increasing gestational age, increasing postnatal age, invasive procedure within 2 days of death, more recent year of death, mechanical ventilation, inotropic support, and antibiotics on the day of death were associated with exposure to sedatives or analgesics. CONCLUSIONS Administration of sedatives and analgesics increased over time. Infants of older gestational age and those more critically ill were more likely to receive these drugs on the day of death. These findings suggest that drug administration may be driven by severity of illness.

Clinical outcomes in very low birth weight infants with major congenital heart defects

BACKGROUND The combination of major congenital heart disease (CHD) and prematurity is associated with poor prognosis, but previous studies have not fully characterized morbidity and mortality in this population. We conducted a retrospective cohort study of very low birth weight (VLBW) infants with major CHD to describe outcomes, including mortality, over time. METHODS We included all infants <1500 g birth weight with major CHD discharged from Pediatrix Medical Group neonatal intensive care units from 1997 to 2012. We report incidences of major CHD in VLBW infants and compare mortality and morbidity by infant birth weight, type of major CHD, and time period. RESULTS Of 105,539 VLBW infants, 299 (0.3%) were diagnosed with 15 different major CHDs. Coarctation of the aorta (n=67, 22%), atrioventricular septal defect (n=58, 19%), and tetralogy of Fallot (n=53, 18%) were the most common major CHDs identified. Overall mortality was 163/299 (55%). Mortality was ≥70% for 10 lesions and <30% for isolated aortic valve stenosis (6/30, 20%). Mortality in infants with major CHD did not significantly change over time: 76/133 (57%) in 1997-2005, 49/95 (52%) in 2006-2009, and 38/71 (54%) in 2010-2012 (p=0.70). The majority of infants suffered ≥1 comorbidity or died (218/299, 73%). CONCLUSION Major CHD is associated with high morbidity and mortality. While mortality varies by lesion, overall survival and incidence of major morbidity have not improved over time.

Pharmacologic studies in vulnerable populations: Using the pediatric experience

Historically, few data exist to guide dosing in children and pregnant women. Multiple barriers to inclusion of these vulnerable populations in clinical trials have led to this paucity of data. However, federal legislation targeted at pediatric therapeutics, innovative clinical trial design, use of quantitative clinical pharmacology methods, pediatric thought leadership, and collaboration have successfully overcome many existing barriers. This success has resulted in improved knowledge on pharmacokinetics, safety, and efficacy of therapeutics in children. To date, research in pregnant women has not been characterized by similar success. Wide gaps in knowledge remain despite the common use of therapeutics in pregnancy. Given the similar barriers to drug research and development in pediatric and pregnant populations, the route toward success in children may serve as a model for the advancement of drug development and appropriate drug administration in pregnant women.

Exposure Matching of Pediatric Anti-infective Drugs: Review of Drugs Submitted to the Food and Drug Administration for Pediatric Approval

PURPOSE Over the last decade, few new antibiotics have been approved by the Food and Drug Administration (FDA) for pediatric use. For most anti-infective agents, including antibiotics, extrapolation of efficacy from adults to children is possible if the disease and therapeutic exposures are similar between the 2 populations. This approach reduces the number of studies required in children, but relies heavily on exposure matching between children and adults. Failures in exposure matching can lead to delays in pediatric approvals of new anti-infective agents. We sought to determine the extent of exposure matching, defined by a comparison of area under the concentration-time curve, between children and adults, for anti-infective drug products submitted to the FDA for approval. METHODS We reviewed anti-infective submissions to the FDA (2002-2014) for pediatric indication. We included drug products administered via oral, intravenous, or intramuscular administration routes, and those with AUC estimates for children in available FDA reports. Our main outcome of interest was the proportion of drugs with median (or mean) pediatric AUC within 20% of the median (or mean) reported adult value. FINDINGS We identified 29 drug products that met inclusion criteria, 14 (48%) of which had mean (or median) AUCs of all submitted age groups within 20% of that in adults. Only route of administration and drug class were associated with pediatric AUC within 20% of adult AUC. IMPLICATIONS Future research is needed to define criteria for and predictors of successful exposure matching of anti-infectives between children and adults.

Detection of multiple respiratory viruses associated with mortality and severity of illness in children

Objective: Respiratory viral infection is a common source of morbidity and mortality in children. Coinfection with multiple viruses occurs frequently; however, the clinical significance of concomitant viral pathogens is unclear. We hypothesized that presence of more than one respiratory virus is associated with increased morbidity and mortality when compared with children with a single respiratory virus. Design: Retrospective cohort study. Setting: A tertiary care hospital. Patients: All children at Duke Children’s Hospital over a 2-year period with isolation of a virus on an extended viral respiratory panel result. Demographic data, comorbidities, and details of hospital encounter were recorded. Interventions: None. Measurements and Main Results: Two hundred thirty-five hospital encounters demonstrated positive extended viral respiratory panels. Immunocompromised status (37%) and respiratory comorbidities (23%) were common. Twenty-eight patients (12%) tested positive for multiple viruses, with adenovirus (23/28) and respiratory syncytial virus (15/28) most prevalent in patients with multiple viruses. Viral codetection was associated with increased use of noninvasive ventilation (p = 0.02), extracorporeal membrane oxygenation (p = 0.02), increased likelihood of moderate or severe illness (p = 0.005), and increased mortality (p = 0.01). Subgroup analysis demonstrated that this mortality association persisted for children with normal immune function (p = 0.003) and children with no comorbidities (p = 0.007). Conclusions: Children with multiple respiratory viruses may be at increased risk of moderate or severe illness and mortality, with previously healthy children potentially being at greatest risk. Further studies are indicated to determine the significance and generalizability of this finding and to better understand the pathophysiology of viral coinfection.

Therapeutic drug monitoring, electronic health records, and pharmacokinetic modeling to evaluate sirolimus drug exposure-response relationships in renal transplant patients.

Background: Sirolimus, an immunosuppressive agent used in renal transplantation, can prevent allograft rejection. Identification of the therapeutic index (the ratio of minimum toxic concentration to minimum therapeutic concentration) for immunosuppresants is necessary to optimize the care of patients and set standards for bioequivalence evaluation of sirolimus products. However, the therapeutic index for sirolimus has been inconsistently defined, potentially because of inconsistencies in sirolimus exposure–response relationships. Methods: The authors used retrospective therapeutic drug monitoring data from the electronic health records of patients treated in a tertiary health care system from 2008 to 2014 to (1) develop a population pharmacokinetic (PK) model, (2) use the model to simulate sirolimus concentrations, and (3) characterize the exposure–response relationship. Using Wilcoxon rank-sum and Fisher exact tests, the authors determined relationships between sirolimus exposure and adverse events (AEs) (anemia, leukopenia, thrombocytopenia, hyperlipidemia, and decline in renal function) and the composite efficacy end point of graft loss or rejection. Results: The developed 2-compartment population PK model showed appropriate goodness of fit. In a late-phase (>12 months), postrenal transplant population of 27 inpatients, the authors identified statistically significant relationships between 83 simulated peak and trough sirolimus concentrations and outcomes: graft loss or rejection (P = 0.018) and decline in renal function (P = 0.006), respectively. Conclusions: Use of therapeutic drug monitoring results and PK modeling permitted correlation of sirolimus concentrations with graft loss or rejection and decline in renal function. However, the method was limited in its assessment of other AEs. To better evaluate sirolimus exposure–response relationships, the method should be applied to a larger sample of newly transplanted patients with a higher propensity toward AEs or efficacy failure.

Acute Upper-Airway Obstruction by a Lingual Thyroglossal Duct Cyst and Implications for Advanced Airway Management

Respiratory failure in infants and children is a common cause of ICU admission, and diseases that jeopardize the airway are the most frequent cause of cardiac arrest in neonatal and pediatric patients.[1][1],[2][2] In neonates specifically, there are numerous causes for respiratory distress, with

Current Epidemiology and Management of Invasive Candidiasis in Infants

Invasive candidiasis (IC) is common in premature infants and is associated with significant morbidity and mortality. Although the incidence of IC in infants is decreasing, there is marked variability in number of cases by center and geographical region, and current methods for diagnosis are suboptimal. Nonabsorbable antifungals, probiotics, and systemic antifungals have been shown to decrease IC in select populations. Although empirical antifungal therapy may provide benefit to infants with IC, prediction of the disease is difficult. While available antifungal agents appear to be effective in the treatment of IC in infants, knowledge of the optimal type, dose, and duration of antifungal therapy is limited by the low number of available infant studies.

A Systematic Literature Review Approach to Estimate the Therapeutic Index of Selected Immunosuppressant Drugs After Renal Transplantation.

Background: Drugs that exhibit close margins between therapeutic and toxic blood concentrations are considered to have a narrow therapeutic index (NTI). The Food and Drug Administration has proposed that NTI drugs should have more stringent bioequivalence standards for approval of generic formulations. However, many immunosuppressant drugs do not have a well-defined therapeutic index (TI). Methods: We sought to determine whether safety, efficacy, and pharmacokinetic data obtained from the medical literature through a comprehensive literature search could be used to estimate the TI of cyclosporine, tacrolimus, and sirolimus. In this analysis, we considered TI ⩽2 as a criterion to define a drug as having an NTI. Results: Published literature indicates that cyclosporine has a TI of 2–3, which falls just short of our criteria to be classified as having an NTI. We found sirolimus and tacrolimus to have a therapeutic range of 5–12 ng/mL and of 5–20 ng/mL, respectively, but were unable to calculate the TI. Conclusions: Although the current literature does not provide a clear indication that these drugs have an NTI, the routine use of therapeutic drug monitoring in clinical practice suggests that more stringent testing of their pharmacokinetic and pharmacodynamic properties should be performed before the approval of generic formulations.