Lea S. Eiland

Assessment of Vancomycin Dosing and Subsequent Serum Concentrations in Pediatric Patients

Background Because of concerns regarding increasing microbial resistance to vancomycin, adult treatment guidelines recommend higher trough concentrations based on the type of infectious process. Although these recommendations are not specific to pediatrics, the principles can be extrapolated. Desired higher trough serum concentrations will require escalated dosages of vancomycin in children. Objective: To evaluate current dosing regimens and subsequent trough serum concentrations of vancomycin in children, compare these to reference recommended dosages and guidelines, and predict a dosing equation to achieve desired serum concentrations. Methods: Pharmacokinetic parameters of children in a community teaching hospital who were prescribed vancomycin from January 2005 to May 2010 were evaluated in this retrospective chart review. Vancomycin dosing and subsequent serum concentrations were analyzed. Therapeutic serum concentrations were evaluated and compared to vancomycin prescribing and monitoring guidelines by year. Results: Four hundred thirty-five trough serum concentrations determined in 295 patients were analyzed. The average dosages, when evaluated by year, were 48 mg/kg/day (2005-2008) and 59 mg/kg/day (2009-2010). Using trough concentration recommendations of 5-15 mg/L, vancomycin regimens provided therapeutic trough concentrations 78% of the time from 2005 to 2008. Using 10-20 mg/L as the trough recommendations in 2009-2010, only 49% of serum concentrations reached a therapeutic level. Based on our predictive equation for children aged 1 month-18 years with normal renal function, a vancomycin dosage of 70 mg/kg/day is required to provide trough serum concentrations of 10 mg/L; a dosage of 85 mg/kg/day is required to provide trough serum concentrations of 15 mg/L. Conclusions: Our institution was primarily using vancomycin dosing regimens that were recommended in pediatric references (40-60 mg/kg/day), which resulted in subtherapeutic serum concentrations in our population based on new monitoring recommendations. Considering that the currently desired therapeutic trough concentrations of vancomycin are 10-20 mg/L, the total daily dosage should be increased.

Pediatric Migraine: Pharmacologic Agents for Prophylaxis

Objective: To identify and evaluate the data regarding medication use for migraine prophylaxis in the pediatric population. Data Sources: Literature was obtained through searches in PubMed (Mid 1950s–March 2007), Iowa Drug Information Service/Web (1966–February 2007), International Pharmaceutical Abstracts (1970–Pebruary 2007), and the Cochrane Library. The terms migraine, prophylaxis, child, and children were used and cross referenced with all drug names. Reference citations from publications identified were also reviewed and included. Study Selection and Data Extraction: Only trials that evaluated migraine headaches in the pediatric population were included. Trials including adolescent and adult populations are briefly listed, but not reviewed. Trials involving nonprescription medication were also included in the evaluation. Due to the limited information, all clinical trials, retrospective reviews, and abstracts evaluated were included in this review. Data Synthesis: Few controlled clinical trials regarding prophylaxis therapy are available. Currently, no medications are approved by the Food and Drug Administration for prophylaxis of migraines in children. Seventeen drugs were identified and included in the review. Of the drugs with available data, topiramate, valproic acid, flunarizine, amitriptyline, and cyproheptadine have shown efficacy in decreasing migraine frequency and duration in children. However, larger clinical trials are necessary to validate the utility of these agents. Conflicting data exist for propranolol and pizotifen, and additional data are needed for gabapentin, leve-tiracetam, zonisamide, naproxen, and trazodone. In clinical trials, nimodipine, clonidine, and natural supplements have shown a lack of efficacy versus placebo for prophylaxis of migraines in children. Conclusions: Topiramate, valproic acid, and amitriptyline have the most data on their use for prophylaxis of migraines in children. Numerous agents have limited data in this population and several agents lack efficacy. Prospective, well designed, controlled clinical trials that include quality-of-life and functional outcomes are needed for guiding therapy of migraine prophylaxis for children.

The Use of Triptans for Pediatric Migraines

Migraine headaches frequently occur in the pediatric population, with a prevalence of 3% in children 2–7 years of age, 4–11% in children 7–11 years of age, and 8–23% in children 11 years of age and older. Migraine without aura is more than twice as common as migraine with aura in children. Headaches are the third leading cause of emergency room referrals and rank in the top five health problems of children. The 2004 American Academy of Neurology’s treatment parameter for migraine in children and adolescents recommended that nasal sumatriptan be considered for acute treatment; however, data were lacking to make a decision regarding the available oral triptans at that time. The more recently released European guidelines discuss three different triptans for use in children but no specific triptan was recommended.Currently, six of the seven available triptans have been studied for efficacy and safety in the pediatric population; however, only a few well controlled clinical studies have been conducted. Sumatriptan has the most available data on outcomes in general, with nasal sumatriptan showing the most positive results. Nasal sumatriptan is approved in children older than 12 years of age in Europe. Oral sumatriptan does not show any clinical benefit versus placebo in children. Rizatriptan and zolmitriptan have conflicting efficacy and safety data, with most studies favoring the use of oral rizatriptan and nasal zolmitriptan. Almotriptan is the first triptan to obtain a US FDA indication in adolescents with migraines lasting 4 or more hours. This approval was based upon two studies, one large clinical trial and one very small, open-label, pilot study. At this time, there are insufficient data to recommend naratriptan and eletriptan for first- or second-line use in pediatric patients with migraines. There are currently no efficacy data for frovatriptan in pediatric patients, which limits its use in this population. Adverse effects of triptans and pharmacokinetic data in children and adolescents are similar to those in adults.The triptan class should be considered as an acute treatment option for children and adolescents with migraines, although their use is mostly ‘off-label’. Of the available triptans, there are more positive efficacy data for sumatriptan and zolmitriptan nasal sprays, and rizatriptan and almotriptan tablets than for the other triptans.

Use of Second-Generation Antiepileptic Drugs in the Pediatric Population

Epilepsy is common in the pediatric population. Nine second-generation antiepileptic drugs have been approved in the US for use in epilepsy over the past 15 years: felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, zonisamide, and pregabalin. Their use in pediatric patients is fairly widespread, despite most of these agents not having US FDA indications for use.Felbamate and gabapentin were the first two second-generation antiepileptic drugs to be approved in the US. Felbamate use has been limited because of the occurrence of hepatotoxicity and aplastic anemia. Although gabapentin is a fairly well tolerated antiepileptic drug, its use has also been limited as a result of inconsistent efficacy and concern about seizure exacerbation. Lamotrigine and topiramate are broad-spectrum antiepileptic drugs with efficacy in a wide variety of seizure types. Both agents have some tolerability concerns: rash with lamotrigine and neuropsychiatric events with topiramate. There are very little data on tiagabine use in children, but this agent appears to be effective and to have a good tolerability profile. Levetiracetam is a second-generation antiepileptic agent that is available intravenously. Considering its good efficacy, fast onset of action, and low incidence of serious adverse effects, its use in the acute setting could potentially increase. Oxcarbazepine and zonisamide have been relatively well studied in pediatric seizure patients, including use as monotherapy. Both agents have demonstrated good efficacy and tolerability for patients as young as 1 month old. Vigabatrin and rufinamide are currently not available in the US, but have been shown to have some success in other countries. Pregabalin is the newest antiepileptic agent, but lacks pediatric data currently.

A Review of Antibiotic Use in Pregnancy

During pregnancy, untreated sexually transmitted or urinary tract infections are associated with significant morbidity, including low birth weight, preterm birth, and spontaneous abortion. Approximately one in four women will be prescribed an antibiotic during pregnancy, accounting for nearly 80% of prescription medications in pregnant women. Antibiotic exposures during pregnancy have been associated with both short‐term (e.g., congenital abnormalities) and long‐term effects (e.g., changes in gut microbiome, asthma, atopic dermatitis) in the newborn. However, it is estimated that only 10% of medications have sufficient data related to safe and effective use in pregnancy. Antibiotics such as beta‐lactams, vancomycin, nitrofurantoin, metronidazole, clindamycin, and fosfomycin are generally considered safe and effective in pregnancy. Fluoroquinolones and tetracyclines are generally avoided in pregnancy. Physiologic changes in pregnancy lead to an increase in glomerular filtration rate, increase in total body volume, and enhanced cardiac output. These changes may lead to pharmacokinetic alterations in antibiotics that require dose adjustment or careful monitoring and assessment.

Intrathecal Baclofen Withdrawal Resembling Serotonin Syndrome in an Adolescent Boy With Cerebral Palsy

Intrathecal baclofen (ITB) is increasingly being used to reduce spasticity among children with cerebral palsy, dystonia, and spinal cord injuries. However, complications such as withdrawal, which is a potentially life-threatening condition, can occur. Intrathecal baclofen withdrawal should be differentiated with autonomic dysreflexia, malignant hyperthermia, neuroleptic malignant syndrome, and serotonin syndrome. We report a case of ITB withdrawal secondary to low residual volume in the pump reservoir and resembling serotonin syndrome in an adolescent with cerebral palsy. He presented with agitation, diaphoresis, increasing spasticity, rigidity, jitteriness, hyperreflexia, clonus, tachycardia, hypertension, and rhabdomyolysis. Treatment consisted of emergent refilling of the pump, intravenous diazepam, and oral cyproheptadine. We also emphasize the importance of prompt recognition of ITB withdrawal among high-risk patients.

Atomoxetine Treatment of Attention-Deficit/Hyperactivity Disorder

OBJECTIVE: To review the literature of the first nonstimulant approved for treatment of attention-deficit/hyperactivity disorder (ADHD). data sources: Primary literature and review articles were obtained through PubMed/MEDLINE (1966–February 2003). STUDY SELECTION AND DATA EXTRACTION: Literature evaluating atomoxetine in ADHD was selected. Animal data were excluded. DATA SYNTHESIS: Stimulants are currently first-line therapy for ADHD. However, their use raises several concerns including the potential for abuse and adverse effects. Atomoxetine introduces a new therapeutic drug class, selective norepinephrine-reuptake inhibitors, for ADHD management. This additional treatment option offers potential advantages over current therapies. CONCLUSIONS: Clinical trials demonstrate that atomoxetine is a safe and effective alternative for ADHD treatment in children and adults; however, its disadvantages may hinder it from becoming a first-line agent.

Glycopyrrolate for chronic drooling in children.

BACKGROUND Sialorrhea, or drooling, is seen in the pediatric population, especially in patients with cerebral palsy and other neurodevelopmental disabilities. If medication use is warranted, anticholinergic agents are the drug of choice; however, adverse effects limit their use. Glycopyrrolate, a synthetic anticholinergic that acts at peripheral muscarinic receptors, has been used off-label for excessive drooling in children with neurodevelopmental disabilities for years. Product formulations restricted the use of glycopyrrolate. However, an oral solution was approved by the US Food and Drug Administration for children ages 3 to 16 years with neurologic disorders for chronic severe drooling in 2010; it became available for use in 2011. OBJECTIVE This article provides an overview of the pharmacology, clinical efficacy, and tolerability of glycopyrrolate when used for sialorrhea in children. METHODS To evaluate the efficacy and safety profile of glycopyrrolate for the treatment of sialorrhea in children, a comprehensive search was performed of the MEDLINE database (1966-February 25, 2012) and International Pharmaceutical Abstracts as well as references from additional review articles identified. Searches were conducted using the terms glycopyrrolate, sialorrhea, drooling, secretion, and pediatrics. The terms drug-induced and Parkinson disease-associated sialorrhea were excluded from the search. The pharmaceutical manufacturer of the oral solution was contacted for medical and study information. RESULTS Oral bioavailability of glycopyrrolate varies widely, with a median of 3.3%. Mean C(max) in children was determined to be 0.37 μg/mL, and mean T(max) was 3.1 hours. The clearance in children ranges from 0.6 to 1.43 L/kg/h. The t(½) ranges from 22 to 130 minutes and 19 to 99 minutes in infants and children, respectively. Six studies describing the use of glycopyrrolate for drooling in children were identified. A double-blind, crossover trial of 27 patients (age range, 4-19 years) demonstrated a reduced mean drooling score (modified Teachers Drooling Scale [1 = never drools to 9 = clothing, hands, and objects frequently become wet]) for glycopyrrolate (mean highest tolerated dose, 0.11 mg/kg) compared with placebo of 1.85 versus 6.33 (P < 0.001). In a parallel study of 36 patients (age range, 3-16 years), 14 of 20 patients randomized to receive glycopyrrolate solution showed improvement in the mean modified Teachers Drooling Scale score compared with only 3 patients receiving placebo (-3.5 vs -0.1, respectively). Glycopyrrolate was initiated at 0.02 mg/kg per dose orally TID (Max dose: 3 mg) and titrated over a 4-week period. Adverse effects identified in studies include dry mouth (9%-41%), constipation (9%-39%), and behavioral changes (18%-36%). CONCLUSIONS Glycopyrrolate is effective in decreasing sialorrhea in children with cerebral palsy or other neurodevelopmental disabilities. Adverse effects did occur, more frequently at higher doses, and should be monitored.

Treatment of Acute Seizures: Is Intranasal Midazolam a Viable Option?

Seizures in the pediatric population commonly occur, and when proper rescue medication is not administered quickly, the risk of neurologic compromise emerges. For many years, rectal diazepam has been the standard of care, but recent interest in a more cost-effective, safe alternative has led to the investigation of intranasal midazolam for this indication. Although midazolam and diazepam are both members of the benzodiazepine class, the kinetic properties of these 2 anticonvulsants vary. This paper will review available data pertaining to the efficacy, safety, cost, and pharmacokinetics of intranasal midazolam versus rectal diazepam as treatment for acute seizures for children in the prehospital, home, and emergency department settings.

Caregivers’ Baseline Understanding and Expectations of Antibiotic Use for Their Children

Although there is evidence that oral antibiotic prescriptions for children have decreased since the 1990s, antibiotic resistance continues to be a problem. This study evaluated the caregivers’ understanding of antibiotic use for their children and identified demographic characteristics that may contribute to inappropriate antibiotic-seeking behavior. Caregivers were asked how often the child should receive antibiotics for common medical conditions and about factors to improve patient compliance. This study found that caregivers overexpected antibiotic use with upper respiratory infection, ear infection, and pneumonia. Caretakers with lower incomes and on Medicaid comprised the higher percentage of overusers. The most important factors to improve patient compliance were explanation of the name and indication for antibiotic use. This study showed that demographic variables play a role in caregivers’ expectations of antibiotic use. Effective communication of physicians with caregivers on antibiotic use can be an important strategy to improve patient compliance.