Sarah C. Campbell

Considerations in the Pharmacologic Treatment and Prevention of Neonatal Sepsis

The management of neonatal sepsis is challenging owing to complex developmental and environmental factors that contribute to inter-individual variability in the pharmacokinetics and pharmacodynamics of many antimicrobial agents. In this review, we describe (i) the changing epidemiology of early- and late-onset neonatal sepsis; (ii) the pharmacologic considerations that influence the safety and efficacy of antibacterials, antifungals, and immunomodulatory adjuvants; and (iii) the recommended dosing regimens for pharmacologic agents commonly used in the treatment and prevention of neonatal sepsis. Neonatal sepsis is marked by high morbidity and mortality, such that prompt initiation of antimicrobial therapy is essential following culture collection. Before culture results are available, combination therapy with ampicillin and an aminoglycoside is recommended. When meningitis is suspected, ampicillin and cefotaxime may be considered. Following identification of the causative organism and in vitro susceptibility testing, antimicrobial therapy may be narrowed to provide targeted coverage. Therapeutic drug monitoring should be considered for neonates receiving vancomycin or aminoglycoside therapies. For neonates with invasive fungal infections, the development of new antifungal agents has significantly improved therapeutic outcomes in recent years. Liposomal amphotericin B has been found to be safe and efficacious in patients with renal impairment or toxicity caused by conventional amphotericin B. Antifungal prophylaxis with fluconazole has also been reported to dramatically reduce rates of neonatal invasive fungal infections and to improve long-term neurodevelopmental outcomes among treated children. Additionally, several large multicenter studies are currently investigating the safety and efficacy of oral lactoferrin as an immunoprophylactic agent for the prevention of neonatal sepsis.

Pregnancy‐induced changes in the pharmacokinetics of caffeine and its metabolites

This study sought to assess the pharmacokinetic (PK) changes of caffeine and its CYP1A2 metabolites across the 3 trimesters of pregnancy. A prospective, multicenter PK study was conducted among 59 pregnant women (93.2% white) who were studied once during a trimester. One beverage with 30‐95 mg caffeine was consumed, and a blood/urine sample was collected within 1 hour postingestion. Concentrations of caffeine and its primary metabolites were quantified from serum and urine by LC‐MS/MS. There was a significant increase in dose‐normalized caffeine serum and urine concentrations between the first and third trimesters (P < .05 and P < .01, respectively). Normalized theophylline concentrations also increased significantly in the third trimester in serum (P < .001) and in urine (P < .05). The caffeine urine/serum concentration ratio also increased in the last trimester (P < .05). No significant difference was found in normalized paraxanthine or theobromine concentrations. This study identified decreased caffeine metabolism and an increase in the active metabolite theophylline concentrations during pregnancy, especially in the third trimester, revealing evidence of the large role that pregnancy plays in influencing caffeine metabolism.

Maternal Magnesium Sulphate Exposure Predicts Neonatal Magnesium Blood Concentrations

Tocolytic use of magnesium sulphate is associated with excess neonatal mortality and has been proposed to follow a dose–response relationship. This study aimed to define the correlation between maternal and neonatal magnesium blood concentrations. Magnesium blood concentrations were retrospectively obtained for mother–neonate pairs who were cared for at an Intermountain Healthcare facility from January 2009 to October 2011. Complete data were available for 231 mother–neonate pairs. Mean (±SD) maternal and neonatal magnesium concentrations were 5.43 ± 1.69 and 2.98 ± 0.94 mg/dL, respectively. Maternal and neonatal magnesium concentrations were highly correlated (p < 0.001). In univariate analyses, residual unexplained variability was high (r2 = 0.19). However, further multivariate analyses revealed that caesarian section, severe pre‐eclampsia and Apgar score at 5 min. were significantly associated with neonatal magnesium concentrations (p < 0.05 for all). Maternal magnesium concentrations correlate with neonatal exposure. This finding suggests that maternal monitoring deserves further evaluation as a marker of foetal toxicity.

Pediatric vancomycin dosing: Trends over time and the impact of therapeutic drug monitoring

Monitoring of vancomycin trough concentrations is recommended for pediatric patients in the product label and by several professional societies. However, among a network of freestanding childrens hospitals vancomycin therapeutic drug monitoring (TDM) practices were reported to be highly variable. In this study, we sought to evaluate whether trends in vancomycin use and TDM changed across a large healthcare delivery system in Utah and Idaho from 2006 to 2012. Children ≤18 years who received ≥2 vancomycin doses were included. Overall, vancomycin TDM was performed during 5,035 (80%) of 6,259 hospital encounters, in which 85,442 doses were administered and 7,935 concentrations were obtained. Across this time period, the median trough concentration increased from 10.9 to 13.7 µg/mL (P < .001), which temporally coincided with recommendations published by the Infectious Disease Society of America that recommend targeting higher trough concentrations. Two or more abnormally low trough concentrations were accompanied by an increase in the dose 75% of the time. Similarly, ≥2 abnormally high trough concentrations were followed by a decrease in the dose 35% of the time. In aggregate, these data suggest that vancomycin TDM is commonly performed among children and the majority of abnormal trough concentrations were associated with an appropriate modification to the dosing regimen.

Characteristics and publication patterns of obstetric studies registered in ClinicalTrials.gov

Physiologic changes during pregnancy alter the pharmacokinetics, safety, and efficacy of many drugs. For clinicians, there is often uncertainty regarding the safety of these drugs due to a scarcity of published data. This study aimed to comprehensively evaluate the characteristics and publication patterns of obstetric studies registered in ClinicalTrials.gov from 2007 to 2012. Primary outcome measures, funding sources, inclusion criteria, and the reporting of study results were evaluated. A manual review of Medline/PubMed was performed to identify publications associated with studies registered in ClinicalTrials.gov. Of 93,709 total studies, there were 5,203 (6%) obstetric studies registered in ClinicalTrials.gov. Interventional studies accounted for 70% and 30% were observational. Clinical trials of drugs (49%), procedures (13%), and behavioral interventions (12%) were most common. Among interventional drug trials, 84% featured randomized allocation to study arms and 93% included measures of safety and/or efficacy as primary endpoints. Of 946 (18%) studies completed more than 2 years ago, only 11% had reported results and <7% had been published. In an area with a great need for evidence of safe and effective therapies, the low publication rate of completed studies incorporating elements of high‐quality trial design is concerning. The sources of this trend should be closely investigated.

Optimizing the use of intravenous magnesium sulfate for acute asthma treatment in children.

Asthma is the most common pediatric chronic disease and currently affects 7.1 million children in the United States. Many children experience acute asthma exacerbations. Many children also require hospitalization despite treatment in an emergency department with current standard therapy (corticosteroids, albuterol, and ipratropium). These hospitalizations may be avoided if effective adjunctive therapies can be developed to adequately treat severe exacerbations.

Pharmacology and pharmacogenomics of neurological medications used in pregnancy.

Pregnancy increases the pharmacological management challenge of numerous neurological diseases as a result of complex physiological changes. Understanding pregnancy-induced changes in pharmacokinetic and pharmacodynamic parameters can lead to better outcomes for both the mother and baby. Although the application of pharmacogenomics in maternal-fetal medicine is in its infancy, further research and developments will provide important new developments for managing the efficacy of drug treatments during pregnancy and improving maternal-fetal safety. Although a wide variety of neurological medications are used during pregnancy, this article will focus on the drugs with currently known pharmacogenomic implications.

Intrapartum Magnesium Sulfate and the Potential for Cardiopulmonary Drug-Drug Interactions

Background: This study sought to determine the frequency of possible cardiopulmonary drug–drug interactions among pregnant women who received intrapartum magnesium sulfate (MgSO4). Methods: Pregnant women admitted to an Intermountain Healthcare facility between January 2009 and October 2011 were studied, if they received 1 or more doses of MgSO4. Concomitant medications were electronically queried from an electronic health records system. Adverse events were identified using administrative discharge codes. The frequency of cardiopulmonary drug–drug interactions was compared among women who did, and did not, receive aminoglycoside antibiotics, antacids/laxatives, calcium channel blockers, corticosteroids, diuretics, neuromuscular blocking agents, and vitamin D analogs, all of which were contraindicated for patients receiving MgSO4. Results: Overall, 683 women received intrapartum MgSO4 during the study period. A total of 219 MgSO4 potentially interacting drugs were identified among 155 (23%) unique patients. The most commonly identified potentially interacting agents included calcium channel blockers (26%), diuretics (25%), and antacids/laxatives (19%). Longer hospital stays were significantly associated with increasing numbers of MgSO4 interacting drugs (P < 0.001). Three of 53 (6%) women who received furosemide experienced a cardiac arrest, compared with 0 of 618 (0%) women who did not receive furosemide (Fisher exact test, P < 0.001). Conclusions: Intrapartum administration of drugs that interact with MgSO4 is common and associated with prolonged hospital stays and potentially cardiopulmonary drug–drug interactions. Caution is warranted when prescribing MgSO4 in combination with known interacting medications.

Metabolic and toxicological considerations for sepsis drug treatments

Introduction: Sepsis, a complex interaction between pathogen and host response, presents a difficult challenge for clinicians and researchers alike. With an increasing understanding of the pathophysiology of the disease, new treatment paradigms are evolving. Areas covered: This article reviews the metabolic and toxicological considerations in sepsis, including the unique issues involved in neonatal and pediatric populations that differentiate it from adult sepsis. The authors cover metabolic issues, such as perfusion, renal and hepatic dysfunction and fluid retention in conjunction with their impact on therapy. Furthermore, the authors examine toxicological considerations of nephrotoxicity, ototoxicity and adverse drug reactions. The authors also present novel biomarkers of sepsis and current clinical tests utilized for the diagnosis of sepsis, as well as the limitations in animal models of sepsis and newer therapies. An extensive literature search including relevant formulae, publications and textbooks serves as the basis for this review. Expert opinion: Improving understanding of the metabolic and toxicological issues in sepsis will allow the development of more effective multifaceted treatments and reduction of risks. Clinical research will need to more heavily involve neonatal and pediatric patients given the number of individuals who die from sepsis within these special populations. Development of a sepsis-specific inflammatory biomarker would allow more rapid detection as well as a method to determine the effectiveness of novel therapies.

Pharmacokinetics, pharmacodynamics and pharmacogenetics associated with nonsteroidal anti-inflammatory drugs and opioids in pediatric cancer patients

ABSTRACT Introduction: Advancing appropriate and adequate analgesic pharmacotherapy in pediatric patients with cancer is an area of clinical need. Few studies have been performed to evaluate the selection of an analgesic and appropriate dosing corresponding to analgesic effect among pediatric cancer patients. This review describes information related to pharmacokinetic, pharmacodynamic, and pharmacogenomic (when applicable) considerations for analgesics that are commonly used to manage pain experienced by pediatric patients with cancer. Areas covered: Analgesics commonly used to treat pediatric patients with malignancy patterned after the World Health Organization’s ‘analgesic ladder’ for cancer pain management. Expert opinion: Addressing pain management safely and effectively in pediatric patients with cancer will require advances in both drug development, to increase the armament of analgesics available for children, and our pharmacologic understanding of those analgesics in current use. However, performing the necessary types of studies to develop new analgesics, or gain knowledge of existing therapy, within a population that is relatively small, diverse, and who experience pain originating from a variety of sources, is a tremendous challenge.