Kristen R. Nichols

Are Elevated Vancomycin Serum Trough Concentrations Achieved Within the First 7 Days of Therapy Associated With Acute Kidney Injury in Children

BACKGROUND In 2008, the empiric vancomycin dosing recommendation in children at our institution was changed from 40 to 60 mg/kg per day. Subsequently, an increased incidence of acute kidney injury (AKI) in patients receiving vancomycin was suspected. The objective of this study was to evaluate AKI in children receiving vancomycin and to determine risk factors for AKI development. METHODS Medical records of patients aged 30 days through 17 years who received vancomycin for at least 72 hours between January and December 2007 (40 mg/kg per day) and January and December 2010 (60 mg/kg per day) were reviewed. Patients with cystic fibrosis, an elevated baseline serum creatinine, or without a serum creatinine concentration obtained after receipt of vancomycin were excluded. Acute kidney injury was defined using adapted pediatric RIFLE criteria as an increase in serum creatinine from baseline of 50% or more. RESULTS Acute kidney injury occurred in 19.4% of the 859 children included, with no difference between the 2007 and 2010 periods (18.8% vs 20%, respectively; P = .636). Intensive care unit admission (odds ratio [OR], 1.86; 95% confidence interval [CI], 1.20-2.94) and an initial vancomycin trough concentration ≥15 mg/L (OR, 2.18; 95% CI, 1.21-3.92) were determined to be significantly associated with AKI. CONCLUSIONS These results suggest an initial vancomycin serum trough concentration of ≥15 mg/L and intensive care unit admission are predictors of AKI in this pediatric population.

System-Wide Implementation of the Use of an Extended- Infusion Piperacillin/Tazobactam Dosing Strategy: Feasibility of Utilization From a Children's Hospital Perspective

BACKGROUND Use of extended infusions of piperacillin/tazobactam (PT) in adult patients has been described, but data in children are limited. OBJECTIVE The goal of this study was to determine the feasibility of using an extended-infusion PT dosing strategy as the standard of care in a childrens hospital. METHODS This was a prospective observational study of patients aged >30 days who received PT after admission to a freestanding, tertiary care childrens hospital. After institution of an extended-infusion PT dosing protocol as the standard dosing option, patients receiving PT were prospectively assessed for presence of and reasons for changes in dosing regimen. RESULTS A total of 332 patients, with a median age of 5 years (interquartile range, 1.9-12 years) and median weight of 19.9 kg (interquartile range, 11.7 - 37.6 kg) received PT (100 mg/kg based on piperacillin component). Extended-infusion PT was used for the duration of PT therapy in 92% (n = 304) of patients. Twenty-eight patients (8%) received a traditional infusion over 30 minutes, with 19 of 28 being changed from extended infusion and 9 of 28 being empirically prescribed traditional infusion PT. The most commonly encountered reason for not using extended infusions was coadministration of vancomycin (17 of 28 [61%]) and lack of compatibility data with PT. Dosing errors, which were voluntarily reported, were infrequent (1.8% [n = 6]). The few observed dosing errors were likely attributable to the overall ordering process at our institution, which requires ordering as the milligram per kilogram dose as total PT rather than based on piperacillin component as is commonly documented in pediatric dosing references. CONCLUSIONS Results of this study suggest that extended-infusion PT dosing was feasible in this specific childrens hospital. Ninety-two percent of patients received our institutions preferred dosing regimen; a small percentage of patients still needed to receive traditional infusion times.

Acid-Suppressing Agents and Risk for Clostridium difficile Infection in Pediatric Patients

Background. Acid-suppressing agents have been associated with increased Clostridium difficile infection (CDI) in adults. The objective of this study was to evaluate the association of acid-suppressing therapy with the development of CDI in the pediatric population. Methods. This was a retrospective case-control study. Children aged 1 through 17 years with a positive C difficile polymerase chain reaction (PCR) result obtained between June 1, 2008, and June 1, 2012, were randomly matched to a control population selected from patients with negative PCR. Results. A total of 458 children were included. No difference was observed in acid-suppressive therapy prior to PCR in CDI-positive versus -negative patients (n = 131 [57.2%] vs n = 121 [52.8%], P = .348). Among patients receiving acid-suppressing therapy prior to obtaining a PCR, no difference was observed in proton pump inhibitor use (45% vs 46.3%, P = .843), but histamine-2 receptor antagonist (H2RA) use was greater in the CDI-positive patients (32.8% vs 14.9%, P = .001). Logistic regression analysis demonstrated that H2RA therapy at home (odds ratio = 4.6; 95% confidence interval = 1.5-14.5) was an independent CDI predictor. Conclusion. In this pediatric population, CDI risk in children receiving home acid-suppressive therapy with H2RAs is nearly 4.5 times greater than that of children not receiving H2RA therapy. These results suggest the need for continued monitoring and study of H2RA therapy in children.

Y-Site Compatibility of Vancomycin and Piperacillin/ Tazobactam at Commonly Utilized Pediatric Concentrations

Background Vancomycin and piperacillin/tazobactam are common empiric antibiotics in hospitalized pediatric patients. Studies evaluating intravenous (IV) compatibility at various concentrations show inconsistent results. Objective The objective of this study was to determine the Y-site compatibility of vancomycin 10 mg/mL and piperacillin/tazobactam 112.5 mg/mL. Methods Vancomycin (10 g vial) was reconstituted using sterile water for injection (SWFI) and diluted with 5% dextrose in water (D5W) to a final concentration of 10 mg/mL in an evacuated IV bag. Piperacillin/tazobactam (40.5 g vial) was reconstituted and diluted with SWFI to a final concentration of 112.5 mg/mL (100 mg/mL piperacillin) in an evacuated IV bag. Both antibacterial stock solutions were then stored in a refrigerator at 4°C (39.2°F). Initial solution appearances, including color, clarity, and particulates, were documented. Diluted solutions were mixed in a quantity of 3 mL of each vancomycin and piperacillin/tazobactam in glass test tubes. Subsequent evaluation included pH assessment and visual evaluation with unaided eye, magnifying glass, high-beam light, and via Spec-20 turbidimeter. Solution mixtures were evaluated upon mixing and again at 30 minutes, 1 hour, and 4 hours after mixing. Results Initial combination of vancomycin and piperacillin/tazobactam resulted in a milky precipitate, visible to the unaided eye, which dissipated 15 seconds after mixing. No precipitate was visualized via any method at any additional time point. Turbidimetry and pH readings did not demonstrate differences from baseline measurements. Conclusions A combination of vancomycin 10 mg/mL and piperacillin/tazobactam 112.5 mg/mL demonstrated precipitation immediately upon mixing. Co-infusion of vancomycin and piperacillin/tazobactam via Y-site should be considered incompatible.

Pediatric Antimicrobial Stewardship Programs

The frequent use of antimicrobials in pediatric patients has led to a significant increase in multidrug-resistant bacterial infections among children. Antimicrobial stewardship programs have been created in many hospitals in an effort to curtail and optimize the use of antibiotics. Pediatric-focused programs are necessary because of the differences in antimicrobial need and use among this patient population, unique considerations and dosing, vulnerability for resistance due to a lifetime of antibiotic exposure, and the increased risk of adverse events. This paper serves as a position statement of the Pediatric Pharmacy Advocacy Group (PPAG) who supports the implementation of antimicrobial stewardship programs for all pediatric patients. PPAG also believes that a pediatric pharmacy specialist should be included as part of that program and that services be covered by managed care organizations and government insurance entities. PPAG also recommends that states create legislation similar to that in existence in California and Missouri and that a federal Task Force for Combating Antibiotic-Resistant Bacteria be permanently established. PPAG also supports post-doctoral pharmacy training programs in antibiotic stewardship.

Sharing Antimicrobial Reports for Pediatric Stewardship (SHARPS): A Quality Improvement Collaborative

Background Although many childrens hospitals have established antimicrobial stewardship programs (ASPs), data-driven benchmarks for optimizing antimicrobial use across centers are lacking. We developed a multicenter quality improvement collaborative focused on sharing data reports and benchmarking antimicrobial use to improve antimicrobial prescribing among hospitalized children. Methods A national antimicrobial stewardship collaborative among childrens hospitals, Sharing Antimicrobial Reports for Pediatric Stewardship (SHARPS), was established in 2013. Characteristics of the hospitals and their ASPs were obtained through a standardized survey. Antimicrobial-use data reports were developed on the basis of input from the participating hospitals. Collaborative learning opportunities were provided through monthly webinars and annual meetings. Results Since 2013, 36 US hospitals have participated in the SHARPS collaborative. The median full-time equivalent (pharmacist and physician) dedicated to 30 of these ASPs was 0.75 (interquartile range, 0.45-1.4). To date, the collaborative has developed 26 data reports that include benchmarking reports according to specific antimicrobial agents, indications, and clinical service lines. The collaborative has conducted 27 webinars and 3 in-person meetings to highlight the stewardship work being conducted in the hospitals. The data reports and learning opportunities have resulted in approximately 36 distinct stewardship interventions. Conclusion A pediatric antimicrobial stewardship collaborative has been successful in promoting the development of and innovation among pediatric ASPs. Additional research is needed to determine the impact of these efforts.

Optimizing Guideline-Recommended Antibiotic Doses for Pediatric Infective Endocarditis

The American Heart Association recently published an updated scientific statement on the management of infective endocarditis in childhood. The recommendations included for vancomycin, aminoglycoside, and β-lactam dosing and monitoring are based primarily on expert opinion and do not consider available evidence for dose optimization based on pharmacokinetic and pharmacodynamic principles in pediatric patients. This is concerning because even when clinically necessary, some practitioners may be hesitant to deviate from guideline-recommended doses. In this perspective, we highlight potential areas for improvement in the statement-recommended doses and summarize evidence supporting antibiotic dosing optimization. The addition of a pediatric clinical pharmacist with expertise in antibiotic dosing to the panel would be beneficial for future updates.

Success With Extended-Infusion Meropenem After Recurrence of Baclofen Pump-Related Achromobacter Xylosoxidans Meningitis in an Adolescent

A 13-year-old female experienced a recurrence of baclofen pump-related central nervous system (CNS) infection caused by Achromobacter, despite absence of retained foreign material. Due to the failure of meropenem (120 mg/kg/d in divided doses every 8 hours and infused over 30 minutes) in the initial infection, the dose was infused over 4 hours during the recurrence. Meropenem is an antibiotic for which efficacy is time dependent, and 4-hour versus 30-minute infusions have been shown to prolong the time the concentration of the antibiotic exceeds the minimum inhibitory concentration (MIC) of the organism at the site of infection (T>MIC). Meropenem serum concentrations were obtained and indicated that T>MIC was at least 75% of the dosing interval. Our patient improved with no noted recurrences or adverse effects on the extended-infusion meropenem regimen. Utilization of extended-infusion beta-lactam dosing whenever possible in the treatment of serious infections caused by gram-negative organisms should be considered, as this dosing appears to be safe and improves the probability of achieving pharmacokinetic/pharmacodynamic goals.

Implementing Extended-Infusion Cefepime as Standard of Care in a Children’s Hospital A Prospective Descriptive Study

Background: Extended-infusion cefepime (EIC) has been associated with decreased mortality in adults, but to our knowledge, there are no studies in children. Objective: The objective of this study was to determine the feasibility of implementing EIC as the standard dosing strategy in a pediatric population. Methods: This was a descriptive study of children aged 1 month to 17 years, including patients in the intensive care unit, who received cefepime after admission to a freestanding, tertiary care children’s hospital. Patients were excluded if they were admitted to the neonatal intensive care unit or received cefepime in the outpatient, operating, or emergency department areas. Demographic and clinical data for patients who received cefepime from April through August 2013, the period following EIC implementation, were extracted from the medical records. Results: A total of 150 patients were included in the study, with a median age (interquartile range [IQR]) of 6 years (2-12.3 years) and median weight (IQR) of 20.7 kg (13.2-42.8 kg); 143 patients received cefepime via extended infusions, and 10 (7.0%) of those were changed to a 30-minute infusion during treatment. The most common reasons for infusion time change were intravenous (IV) incompatibility and IV access concerns, responsible for 50% of changes. Dosing errors and reported incidents during therapy were sparse (n = 12, 8.0%) and were most commonly related to renal dosing errors and/or initial dose error by prescriber. Conclusions: Because 93.0% of the patients who initially received EIC remained on EIC, implementation of EIC as the standard dosing strategy was feasible in this pediatric hospital.

Compatibility of Vancomycin and Oxacillin During Simulated Y-Site Delivery

Background Vancomycin and oxacillin may be used together as empiric coverage in patients with proven or suspected Staphylococcus aureus infections. Though vancomycin hydrochloride 20 mg/mL and oxacillin sodium 160 mg/mL are reported to be compatible via Y-site delivery, Y-site compatibility of commonly used concentrations, vancomycin 10 mg/mL and oxacillin 20 mg/mL, has not yet been reported. Objective To determine the Y-site compatibility of vancomycin 10 mg/mL and oxacillin 20 mg/mL. Methods One vancomycin hydrochloride 1 g vial was reconstituted with 10 mL sterile water for injection (SWFI) and diluted with 90 mL 5% dextrose in water (D5W) in an evacuated intravenous (IV) bag. One oxacillin sodium 2 g vial was reconstituted with 11.5 mL sterile water for injection and diluted with 88 mL sterile water for injection in an evacuated IV bag. Three mL of each vancomycin and oxacillin were mixed in 4 test tubes to simulate Y-site delivery. Spectrometry, pH evaluation, and visual examination were performed for each test tube immediately following mixing and at 30 minutes, 1 hour, and 2 hours after mixing. Results Upon visual examination with multiple backgrounds, a white precipitant was immediately evident in the test tubes with vancomycin and oxacillin combined. Spectrometry results strongly supported evidence of precipitation throughout the duration of the experiment. Conclusions Vancomycin 10 mg/mL and oxacillin 20 mg/mL were determined to be physically incompatible for Y-site delivery in this study, despite prior evidence that the 2 medications in different concentrations were suitable for Y-site co-administration.