Holly D. Maples

Intravenous voriconazole therapy in a preterm infant.

A preterm infant younger than 3 months developed a disseminated fluconazole‐resistant Candida albicans infection that was treated with liposomal amphotericin B for 52 days, followed by the combination of intravenous voriconazole and liposomal amphotericin B for an additional 19 days. The infant received concomitant phenobarbital throughout the hospital stay. The infection resolved after addition of voriconazole to the treatment regimen. Intravenous voriconazole was begun at a high dosage, 6 mg/kg every 12 hours, for anticipated developmental and drug‐induced changes in volume of distribution and clearance. On day 4 of therapy, serum concentrations of voriconazole were 3.27 μg/ml immediately after infusion and 0.33 μg/ml 6 hours after infusion. These levels were significantly lower than those achieved in adult pharmacokinetic and safety studies. After the infants dosage was increased to 6 mg/kg every 8 hours, serum concentrations were 5.33 μg/ml 30 minutes after infusion and 2.67 μg/ml 6 hours after infusion. These levels were similar to those observed in adults. Intravenous voriconazole 6 mg/kg every 8 hours was administered safely, with concomitant phenobarbital therapy, in this preterm infant with developmentally diminished renal function.

Prevalence and Characteristics of Antimicrobial Stewardship Programs at Freestanding Children's Hospitals in the United States

BACKGROUND AND OBJECTIVE Antimicrobial stewardship programs (ASPs) are a mechanism to ensure the appropriate use of antimicrobials. The extent to which ASPs are formally implemented in freestanding childrens hospitals is unknown. The objective of this study was to determine the prevalence and characteristics of ASPs in freestanding childrens hospitals. METHODS We conducted an electronic survey of 42 freestanding childrens hospitals that are members of the Childrens Hospital Association to determine the presence and characteristics of their ASPs. For hospitals without an ASP, we determined whether stewardship strategies were in place and whether there were barriers to implementing a formal ASP. RESULTS We received responses from 38 (91%) of 42. Among responding institutions, 16 (38%) had a formal ASP, and 15 (36%) were in the process of implementing a program. Most ASPs (13 [81%] of 16) were started after 2007. The median number of full-time equivalents dedicated to ASPs was 0.63 (range, 0.1-1.8). The most common antimicrobials monitored by ASPs were linezolid, vancomycin, and carbapenems. Many hospitals without a formal ASP were performing stewardship activities, including elements of prospective audit and feedback (9 [41%] of 22), formulary restriction (9 [41%] of 22), and use of clinical guidelines (17 [77%] of 22). Antimicrobial outcomes were more likely to be monitored by hospitals with ASPs (100% vs 68%; P = .01), although only 1 program provided support for a data analyst. CONCLUSIONS Most freestanding childrens hospitals have implemented or are developing an ASP. These programs differ in structure and function, and more data are needed to identify program characteristics that have the greatest impact.

Antimicrobial Stewardship in Pediatrics: How Every Pediatrician Can Be a Steward

Antimicrobial stewardship (AS) programs are effective in improving clinical outcomes associated with antimicrobial therapies while improving patient safety by reducing adverse events and development of bacterial resistance. Understanding the basic principles of AS is essential to the successful development and implementation of AS strategies. Identifying and developing strategies to address barriers and challenges to AS can facilitate the establishment of financial, administrative, and organizational support, and agreement and participation by individual prescribers. Review of published outcomes of AS demonstrates the effectiveness in reducing unnecessary antimicrobial use and adverse events such as Clostridium difficile infections. We also illustrate the need for further research and expansion of AS activities to office-based practices and communities by using novel and innovative AS strategies and by influencing regional and national policies.

Nonadherence with pediatric human immunodeficiency virus therapy as medical neglect

Objective. To examine the results of an interventionist approach applied to human immunodeficiency virus (HIV)-infected children for whom caregiver nonadherence was suspected as the cause of treatment failure. Methods. The medical records of a cohort of 16 perinatally HIV-infected children whose care was managed at the Arkansas Children’s Hospital Pediatric HIV Clinic for an uninterrupted period of ≥3 years were reviewed through July 2003. Data collected included date of birth, dates of and explanations for clinic visits and hospitalizations, dates of laboratory evaluations, CD4+ T cell percentages, plasma HIV-1 RNA levels, antiretroviral medications, viral resistance tests (eg, phenotype and genotype), and physician-initiated interventions to enhance adherence to the medication regimen. A stepwise interventionist approach was undertaken when patients continued to demonstrate high viral loads, despite documented viral sensitivity to the medication regimen and caregivers’ insistence that medications were being administered regularly. Step 1 was prescribing a home health nurse referral, step 2 was administering directly observed therapy (DOT) while the patient was hospitalized for 4 days, and step 3 was submitting a physician-initiated medical neglect report to the Arkansas Department of Human Services. Results. The results for 6 patients for whom this stepwise approach was initiated are reported. Home health nurse referrals failed to result in sustained improvements in adherence in all 6 cases. Viral load assays performed before and after DOT provided an objective measure of the effect of adherence, with 12 hospitalizations resulting in a mean ± SD decrease in HIV RNA levels of 1.09 ± 0.5 log10 copies per mL, with a range of 0.6 to 2.1 log10 copies per mL. Four families responded to DOT hospitalization, and sustained decreases in the respective patients’ viral loads were noted. In 2 cases, medical neglect reports were submitted when DOT did not result in improved adherence. These patients were eventually placed in foster care, with subsequent improvements in their viral loads and CD4+ T cell percentages. Conclusions. Nonadherence with antiretroviral therapy can be established on the basis of persistently elevated HIV RNA levels that decrease with DOT. Nonadherence poses a danger to the child that is grave and potentially irreversible. Caregivers should be offered all available resources to help them adhere to a sound treatment plan. In cases of demonstrated inability to provide needed care, it is necessary to consider seeking child protection, even for apparently healthy children.

Pharmacokinetics of intravenously administered azithromycin in pediatric patients.

Background: The objective of this study was to characterize the pharmacokinetics and tolerance of a single intravenous (IV) azithromycin dose in children. Methods: Subjects were stratified into 4 age groups: 0.5–2 years; >2–<6 years; 6–<12 years; and 12–<16 years. Each subject received a single 10 mg/kg dose (500 mg maximum) infused in 1 hour. Serial venous blood samples were obtained for a 168-hour period, and laboratory safety evaluations were performed immediately preceding azithromycin administration and at the conclusion of the study. Serum azithromycin concentrations were quantified with a validated high performance liquid chromatography method with mass spectrometric detection. Pharmacokinetic indices were calculated for each subject by noncompartmental techniques. Results: Thirty-two subjects (6.7 ± 5.0 years, 11 boys) participated. Mean serum concentration-time data were comparable for the 4 age groups. For all subjects with evaluable data, the mean area under the curve from 0 to 72 hours (AUC0–72) was 8.2 μg · h/mL (n = 26), the maximum concentration (Cmax) was 2.4 μg/mL and the elimination half-life (t1/2) was 65.2 hours (n = 25). The AUC0–72 and Cmax were not associated with age. The dose was well-tolerated with no serious adverse events. Conclusion: The disposition of azithromycin after a single 10-mg/kg IV dose (maximum labeled adult dose of 500 mg) is comparable in pediatric patients between 0.5 and 16 years of age. These pharmacokinetic data can be used to guide dose selection for future therapeutic trials of IV azithromycin in pediatric patients.

Description of Respiratory Microbiology of Children With Long-Term Tracheostomies

BACKGROUND: There is little evidence in the medical literature to guide empiric treatment of pediatric patients with long-term tracheostomies who present with signs and symptoms of a bacterial respiratory infection. The overall goal of this study was to describe the respiratory microbiology in this study population at our institution. METHODS: This study was a retrospective chart review of all subjects with tracheostomies currently receiving care at the Arkansas Center for Respiratory Technology Dependent Children. Descriptive statistics were used to describe the respiratory microbiology of the full study group. Several subgroup analyses were conducted, including description of microbiology according to time with tracheostomy, mean time to isolation of specific organisms after the tracheostomy tube was placed, association between Pseudomonas aeruginosa or methicillin-resistant Staphylococcus aureus isolation and prescribed antibiotic courses, and description of microbiology according to level of chronic respiratory support. Available respiratory culture results up to July 2011 were collected for all eligible subjects. Descriptive statistics were used to describe subject characteristics, and chi-square analysis was used to analyze associations between categorical data. P < .05 was considered statistically significant. RESULTS: A total of 93 subjects met inclusion criteria for the study. The median (interquartile range) age at time of tracheotomy was 0.84 (0.36–3.25) y, and the median (interquartile range) time with tracheostomy was 4.29 (2.77–9.49) y. The most common organism isolated was P. aeruginosa (90.3%), with Gram-negative organisms predominating. However, 55.9% of the study population had a respiratory culture positive for methicillin-resistant S. aureus. The first organism isolated after tracheostomy placement was Methiciliin-sensitive S. aureus was isolated the soonest after tracheostomy placement. Specific organisms were not related to level of chronic respiratory support or likelihood of receiving antibiotics. CONCLUSIONS: This study provides an updated overview of the variety of potential pathogens isolated from respiratory cultures of pediatric subjects with long-term tracheostomies.

Famotidine disposition in children and adolescents with chronic renal insufficiency.

The pharmacokinetics of intravenous famotidine (0.5 mg/kg, maximum 20 mg) were evaluated in 18 pediatric patients (ages 1–18 years) with stable, chronic renal insufficiency. Subjects were stratified by calculated creatinine clearance (Clcr) into mild (Clcr ≥ 50 to < 90 mL/min/1.73 m2), moderate (Clcr ≥ 25 to < 50 mL/min/1.73 m2), and severe (Clcr ≤ 10 mL/min/1.73 m2) renal insufficiency groups. Significant differences between the mild, moderate, and severe groups were found for elimination rate (Kel), apparent elimination half‐life (t1/2), area under the curve (AUC), and total plasma clearance (Clp) (p < 0.01). Famotidine renal clearance (Clr) was found to be significantly different between the mild and severe groups (p < 0.05). A linear relationship was observed between Clcr and Clp (p < 0.0001; R2 = 0.70). No significant differences in nonrenal clearance (Clnr) were found between groups; however, Clnr as a percentage of Clp was significantly different in the severe group (92.9% ± 7.3% Clnr) compared to the combined mild and moderate groups (21.9% ± 45.6% Clnr) (p < 0.05). It was concluded that the pharmacokinetics of famotidine are significantly altered in children with chronic renal insufficiency; accordingly, dosing should be based on glomerular filtration rate (i.e., Clcr).

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.

Expanding Existing Antimicrobial Stewardship Programs in Pediatrics: What Comes Next

The prevalence of pediatric antimicrobial stewardship programs (ASPs) is increasing. We review strategies for ASPs to adapt and report standardized metrics, expand activities to specialized populations, and implement novel diagnostics for continued progress in improving antibiotic use and patient outcomes.

Association of Acid Suppression and Antimicrobial Use with Clostridium difficile Infection in Children

Abstract Background Clostridium difficileinfections (CDIs) can cause severe diarrhea and be potentially life-threatening, especially in children. Possible risk factors include age, being immunocompromised, prior antibiotic exposure, the use of antacids, and diseases that alter intestinal microbiota. Data in adults are vast while limited data is available in children. The objectives of this study are to identify pediatric risk factors and determine if an association between acid suppression and CDI’s in children exists. Methods A retrospective study was conducted between November 1, 2013 and October 31, 2016 at Arkansas Children’s Hospital. Children ages 1 – 18 years with a positive C. diff PCR test and ≥3 loose stools documented were included. Cases were excluded if previous positive PCR was within 60 days. Data collection included age, sex, encounter type (inpatient or outpatient), acid suppressing agents, previous antimicrobials within last 90 days and comorbidities including transplant, chronic pulmonary, hematology/oncology, and GI tract diseases. Statistical methods included descriptive analyses, χ2test, and Kruskal–Wallis test. Results A total of 139 cases of CDI among 123 patients were evaluated. Of these cases, the median (IQR) age is 8 years (3–13) with 77 (55.4%) being male and 86 (61.9%) of CDI cases identified inpatient of which 75 came from outpatient. Pediatric risk factors identified in C. diff cases included exposure to acid suppressing agents [61 (43.9%)] and antimicrobials [98 (70.5%)] with 90 (64.7%) having ≥1 comorbidities. Cases having ≥1 comorbidities were found to be associated with previous antacid exposure (P < 0.0005) while antimicrobial(s) use was associated with CDI hospitalization (P = 0.001). Similarly, exposure to either antacid suppression or antimicrobials or both with comorbidities were found to have a significant association (P < 0.0005) and associated with CDI hospitalization (P = 0.001). Conclusion Exposure to acid suppression in patients with comorbidities was associated with increased risk of CDI. Antimicrobial usage was associated with increased risk for hospitalization due to CDI. As pediatric outpatient antimicrobial stewardship evolves, improving CDI rates can center on improving antimicrobial and acid suppressive agents usage. Disclosures All authors: No reported disclosures.