Utilizing therapeutic drug monitoring to optimize therapy with eculizumab and mycophenolate mofetil in a child with C3 glomerulonephritis.

BACKGROUND: C3 glomerulonephritis (C3GN) can be a devastating disease with poor response to immunosuppressive therapy. Complement inhibition with eculizumab has had equivocal results in patients with C3GN. CASE-DIAGNOSIS/TREATMENT: We report a case of a 6-year-old boy with C3GN presenting with nephrotic syndrome, severe hypertension and impaired kidney function. He did not respond to initial treatment with prednisone and mycophenolate (mofetil and sodium), and subsequent treatment with standard dosing of eculizumab. Pharmacokinetic studies identified a lack of eculizumab exposure and subsequent intensification of treatment with weekly dosing of eculizumab led to significant clinical improvement: his kidney function normalized, hypertension (weaned off 3 antihypertensive drugs), edema and proteinuria improved. Additionally, exposure to mycophenolic acid (MPA), active metabolite of mycophenolate, determined by area under the concentration-time curve of MPA was low throughout, despite significant dosing escalation. CONCLUSIONS: This case report demonstrates that individualized therapy guided by therapeutic drug monitoring might be needed in patients with nephrotic range proteinuria treated with eculizumab and mycophenolate (mofetil and sodium), an important finding that needs to be considered for further treatment trials.

Peritoneal dialysis-related peritonitis caused by Gordonia bronchialis: first pediatric report.

INTRODUCTION: Gordonia species, aerobic, weakly acid-fast, Gram-positive bacilli, are a rare cause of peritonitis in patients undergoing peritoneal dialysis (PD). We report the first pediatric case of PD-related peritonitis caused by Gordonia bronchialis. CASE PRESENTATION: A 13-year-old girl with chronic kidney disease (CKD) stage 5D, on continuous cycling PD (CCPD) for 8 years, presented with cloudy PD effluent, with no abdominal discomfort or fever. Intra-peritoneal (IP) loading doses of vancomycin and ceftazidime were started at home after obtaining a PD effluent sample, which showed WBC 2,340 × 10 /L (59% neutrophils) and Gram-positive bacilli. On admission, she was clinically well and afebrile, with no history of methicillin-resistant Staphylococcus aureus (MRSA) infection, so vancomycin was discontinued, and IP ceftazidime and cefazolin were started, following a loading dose of intravenous cefazolin. Gordonia species grew after 5 days of incubation and later identified as Gordonia bronchialis. IP vancomycin was restarted as monotherapy, empirically for a total of 3 weeks therapy. A 2-week course of oral ciprofloxacin was added, based on susceptibility testing. PD catheter replacement was advised due to the risk of recurrence but was refused. A relapse occurred 16 days after discontinuing antibiotics, successfully treated with a 2-week course of IP ceftazidime and vancomycin. The PD catheter was removed and hemodialysis initiated. She received a further 2-week course of oral ciprofloxacin and amoxicillin-clavulanate post PD catheter removal. CONCLUSIONS: Gordonia bronchialis is an emerging pathogen in PD peritonitis and appears to be associated with a high risk of relapse. PD catheter replacement is strongly suggested.

Pharmacokinetics of Vancomycin in Pediatric Patients Receiving Intermittent Hemodialysis or Hemodiafiltration.

INTRODUCTION: Vancomycin is a common antibiotic used to treat hemodialysis (HD) or hemodiafiltration (HDF)-related infections in pediatric patients, but optimal dosing remains unknown. This is the first observational study to characterize the pharmacokinetics and evaluate dosing of vancomycin in this population. METHODS: Eligible patients received IV vancomycin 10 mg/kg per dose postdialysis followed by a series of serum vancomycin concentrations collected before, immediately after, 1 hour after, and 4 hours after dialysis. The pharmacokinetic parameters were estimated using 1- and 2-compartment models and a nonlinear least-squares algorithm. RESULTS: Among 42 vancomycin courses in 16 patients, 1 compartment model had the best fit for observed data. The net drug removal was 43 ± 13% (39% for HD and 50% for HDF) from an average 3-hour HD/HDF session. The mean elimination constant was 0.28 h-1 (standard deviation [SD], 0.11 h-1) during the intradialytic period compared with 0.0049 h-1 (SD, 0.004 h-1) when off dialysis. The mean volume of distribution was 0.65 (SD, 0.19) L/kg. Duration of dialysis session and mode of dialysis (HD vs. HDF) were significant predictors of vancomycin pharmacokinetic parameters. Half-life was shorter for HDF compared with HD (2.1 vs. 3.5 hours). CONCLUSIONS: Based on the simulations, an initial vancomycin dose of 10 mg/kg per dose and redosing postdialysis was optimal to achieve a vancomycin concentration range of 5 to 12 mg/L at 4 hours postdialysis and 24-hour area under the curve over minimum inhibitory concentration of ≥400 hours. Therapeutic drug monitoring is necessary to account for residual variability in vancomycin elimination in pediatric patients receiving HD/HDF.

Measuring Gastric pH in Tube-fed Children With Neurologic Impairments and Gastroesophageal Disease.

OBJECTIVES: The aim of the study was to determine the extent of agreement between pH paper and handheld pH meter with a laboratory pH meter for gastric pH measurement in children with neurologic impairments and gastrostomy tubes who have gastroesophageal reflux disease (GERD). METHODS: In this prospective observational study, gastric contents were aspirated from gastric or nasogastric tubes and the pH measured using 3 techniques: pH paper, handheld pH meter, and laboratory pH meter (the gold standard). Agreement between techniques was assessed with intraclass correlation coefficient (ICC), Bland-Altman analysis, and kappa statistic. RESULTS: Among 43 patients contributing 67 gastric samples, the ICC was 0.75 (95% confidence interval [CI]: 0.69-0.97) between the handheld and laboratory meters, 0.69 (95% CI: 0.63--0.94) between the pH paper and laboratory meter and 0.69 (95% CI: 0.63-0.94) between the handheld meter and paper. The Bland-Altman analysis between the handheld and lab meters showed a mean difference of -0.03 pH units (limits of agreement: -0.52 to 0.47 pH units) and 0.17 pH units (limits of agreement: -0.99 to 1.33 pH units) between the paper and lab meter. The kappa coefficients for a pH ≥4 were 1.0 (95% CI: 1.0--1.0) between the handheld and lab meters and 0.9 (95% CI: 0.77--1.0) between the paper and lab meter. CONCLUSIONS: The findings suggest that both point-of-care tests, the pH meter and pH paper, correlate well with the gold standard for testing pH with a laboratory pH meter, indicating usefulness in point-of-care testing for monitoring gastric pH in tube-fed children with neurologic impairments and GERD.

A Pilot Project for Clinical Pharmacy Services in a Clinic for Children With Medical Complexity.

OBJECTIVE: The primary objective of the project was to assess the impact of clinical pharmacy services in a clinic for children with medical complexity. Secondary objectives were to identify and characterize the drug-related needs of these patients and to describe and develop the role of a pharmacist in the clinic. METHODS: This was a prospective descriptive study in which a clinical pharmacist staffed the clinic for children with medical complexity for 11 weeks, from January to March 2011. This allowed for the collection of baseline data, such as patient characteristics and measurements of pharmacist workload and assessment (eg, types of drug therapy problems, medication reconciliation, medication teaching). RESULTS: A pharmacist participated in 46 clinic visits with 43 patients, identifying a total of 42 drug therapy problems. Of the 42 problems, 35 actual and 7 potential drug problems were identified, resulting in approximately 1 problem per patient. The most common actual problems included "dose too small" (37.1%) and "patient requires a medication for untreated condition" (20%). Common potential problems included "drug interactions" (43%) and "adverse effects" (57%). CONCLUSIONS: The pilot study demonstrates that children with medical complexity are at high risk for drug therapy problems and the presence of a clinic pharmacist is beneficial in the identification, prevention, and resolution of drug therapy problems, while helping ensure continuity of care in this population.

Efficacy and safety of proton pump inhibitors in the management of pediatric gastroesophageal reflux disease.

Proton pump inhibitors (PPIs) are commonly prescribed to infants and children for managing gastroesophageal reflux disease (GERD). Recently published literature illustrates conflicting evidence on the efficacy of PPIs in infants and children. Randomized controlled trials and systematic reviews have demonstrated a lack of efficacy of PPIs, specifically in young infants. Furthermore, emerging evidence also suggests that PPIs are not as benign as once thought, with newer data implicating a potential association of PPIs with an increased risk of respiratory tract infections, gastrointestinal infections, bone fractures, hypomagnesemia, and the occurrence of rebound hyperacidity after discontinuation of PPI therapy. To summarize the emerging data in children, we reviewed the literature to assess the efficacy and safety of PPIs in managing pediatric GERD. Despite conflicting evidence on the efficacy of PPIs, most studies in children demonstrated some benefit when compared with placebo. With respect to the safety of PPIs in children, only a few small studies and case reports indicated a potential association of PPIs with an increased risk of respiratory tract or gastrointestinal infections, bone fractures, and hypomagnesemia; however, many of those studies had their own limitations. From the review, it is clear that further well-designed trials and observational studies are needed to shed more light on the efficacy and safety of PPIs in the pediatric population.

Pharmacokinetic modelling of a once-daily dosing regimen for intravenous tobramycin in paediatric cystic fibrosis patients.

OBJECTIVES: This study was designed to determine an optimal dose range for the once-daily dosing (ODD) of tobramycin in the treatment of an acute pulmonary exacerbation in paediatric cystic fibrosis (CF) patients. In addition, we aimed to assess whether certain patient characteristics affect tobramycin pharmacokinetics and, therefore, dosing. METHODS: Patient characteristics and pharmacokinetic parameters of patients receiving tobramycin three times daily from 1 January 1992 to 31 October 2005 were analysed using univariate analysis and multiple linear regression to determine statistically significant relationships and to derive dosing models. The binary partitioning method was used to derive critical values to determine stratification within the chosen dosing model. RESULTS: Using multiple linear regression, age and sex were significantly associated with the volume of distribution divided by the body weight (V/kg). By the binary partitioning method, the critical value for age was 13.75 years. CONCLUSIONS: Age and sex were used to derive an ODD regimen for tobramycin in paediatric CF. Using a target peak concentration range of 25-35 mg/L, the initial dose for female CF patients at least 14 years of age was calculated to be 7 mg/kg/day given intravenously as a single daily dose. All other CF patients would receive an initial dose of 9 mg/kg/day given intravenously as a single daily dose. These dosing guidelines will require prospective evaluation for safety and efficacy.

Recurrent anaphylaxis associated with gonadotropin-releasing hormone analogs: case report and review of the literature.

An 8-year-old girl with idiopathic central precocious puberty experienced multiple episodes of anaphylaxis after receiving a goserelin acetate implant. She was hospitalized and treated with epinephrine, antihistamine, and corticosteroids. The goserelin implant was surgically excised; however, anaphylactic symptoms continued for 4 days after excision. Less severe systemic symptoms recurred 6 weeks after removal; these were possibly due to leakage of the depot drug into subcutaneous tissues. It was noted that 3 years earlier, the patient had developed a similar, milder systemic allergic reaction to leuprolide acetate that required treatment with oral prednisone and antihistamines. Intradermal testing yielded positive results for leuprolide. Gonadotropin-releasing hormone (GnRH) analogs, including leuprolide acetate and goserelin acetate, are commonly prescribed for patients with prostatic carcinoma, endometriosis, and precocious puberty. A literature review identified a single case report of a systemic hypersensitivity reaction involving goserelin acetate and several reports of systemic hypersensitivity reactions associated with leuprolide acetate. We found no reports of systemic reactions to GnRH analogs in pediatric patients. Clinicians should be aware of the potential association of GnRH analogs with systemic reactions. They should also recognize that recurrent anaphylaxis may occur due to the long half-life of these therapeutic agents in tissue.