Kevin J. Downes

Impact of Kinship Care on Behavioral Well-being for Children in Out-of-Home Care

OBJECTIVE To examine the influence of kinship care on behavioral problems after 18 and 36 months in out-of-home care. Growth in placement of children with kin has occurred despite conflicting evidence regarding its benefits compared with foster care. DESIGN Prospective cohort study. SETTING National Survey of Child and Adolescent Well-Being, October 1999 to March 2004. PARTICIPANTS One thousand three hundred nine children entering out-of-home care following a maltreatment report. MAIN EXPOSURE Kinship vs general foster care. MAIN OUTCOME MEASURES Predicted probabilities of behavioral problems derived from Child Behavior Checklist scores. RESULTS Fifty percent of children started in kinship care and 17% of children who started in foster care later moved to kinship care. Children in kinship care were at lower risk at baseline and less likely to have unstable placements than children in foster care. Controlling for a childs baseline risk, placement stability, and attempted reunification to birth family, the estimate of behavioral problems at 36 months was 32% (95% confidence interval, 25%-38%) if children in the cohort were assigned to early kinship care and 46% (95% confidence interval, 41%-52%) if children were assigned to foster care only (P = .003). Children who moved to kinship care after a significant time in foster care were more likely to have behavioral problems than children in kinship care from the outset. CONCLUSIONS Children placed into kinship care had fewer behavioral problems 3 years after placement than children who were placed into foster care. This finding supports efforts to maximize placement of children with willing and available kin when they enter out-of-home care.

Polymicrobial Bloodstream Infections among Children and Adolescents with Central Venous Catheters Evaluated in Ambulatory Care

BACKGROUND Bloodstream infections (BSIs) are an ever-present concern for clinicians evaluating ill-appearing pediatric patients with central venous catheters (CVCs) in the ambulatory care setting. METHODS We performed a case-control study of a cohort of 200 pediatric patients who were evaluated in the ambulatory care setting and who were found to have laboratory-confirmed BSI in the context of a CVC. This study sought to compare patients with polymicrobial versus monomicrobial BSIs to identify potential risk factors for polymicrobial BSI. RESULTS Of the 200 patients enrolled in the study, 73 (37%) had a polymicrobial BSI. Patients with polymicrobial BSI were more likely than those with monomicrobial BSI to be younger (P=.002) and less likely to have been recently discharged from the hospital (P=.01). The odds of a polymicrobial BSI were >4 times greater for patients aged <3 years than for those aged >or=3 years (odds ratio, 4.54; 95% confidence interval, 1.68-12.29), and the odds were 50% lower for those discharged from the hospital in the prior 7 days than for those without recent hospitalization (odds ratio, 0.46; 95% confidence interval, 0.22-0.95) after controlling for an underlying cancer diagnosis and the time of year during which a patient presented. Recent antibiotic use, recent BSI, duration that the CVC had been in place, and underlying gastrointestinal dysfunction were not associated with a risk of polymicrobial BSI. CONCLUSIONS Younger children and those who had not recently been discharged from the hospital had an increased risk of developing catheter-related polymicrobial BSI. Special consideration should be given to the increased likelihood of polymicrobial BSIs in these pediatric patients when initiating empirical antimicrobial therapy.

Dose optimisation of antibiotics in children: application of pharmacokinetics/pharmacodynamics in paediatrics

The judicious use of antibiotics to combat infections in children relies upon appropriate selection of an agent, dose and duration to maximise efficacy and to minimise toxicity. Critical to dose optimisation is an understanding of the pharmacokinetics and pharmacodynamics of available drugs. Optimal dosing strategies may take advantage of pharmacokinetic/pharmacodynamic (PK/PD) principles so that antibiotic dosing can be individualised to assure effective bacterial killing in patients who have altered pharmacokinetics or who have infections with less susceptible or resistant organisms. This review will outline the fundamentals of antimicrobial pharmacokinetics/pharmacodynamics through discussion of antibacterial agents most often used in children. We aim to highlight the importance of dose optimisation in paediatrics and describe non-conventional dosing strategies that can take advantage of PK/PD principles at the bedside.

Daily serum creatinine monitoring promotes earlier detection of acute kidney injury in children and adolescents with cystic fibrosis

BACKGROUND The epidemiology of aminoglycoside-associated acute kidney injury (AG-AKI) has not been well described in pediatric patients with cystic fibrosis (CF). We aimed to assess the impact of daily serum creatinine (SCr) measurement on detection of AG-AKI at our institution. METHODS We examined a cohort of hospitalized patients with CF who received an intravenous (IV) aminoglycoside for ≥ 3 days. We compared the rate, timing, and medical management surrounding detection of AG-AKI during 2 periods: January 2010-May 2011 (Era 1, SCr measured at the discretion of the medical team, N=124) and June 2011-June 2012 (Era 2, SCr measured daily, N=103). Our primary outcome was detection of AG-AKI defined as ≥ 50% increase in SCr from baseline (lowest value in prior 6 months), or ≥ 0.3mg/dL rise within 48 h, occurring after day 2. RESULTS The use of once daily tobramycin (p=0.02) and IV fluids (p<0.001) was higher during Era 2, while AG courses were shorter (p=0.04), and fewer concomitant nephrotoxins (p=0.04) were given; higher daily tobramycin doses (p<0.001) were administered. Although the rate of AG-AKI was not significantly different (12% during Era 1 vs. 20% during Era 2, p=0.09), the number of AG-AKI days detected increased (5.5 vs. 2.9 per 100 AG days, p=0.003), and detection occurred earlier (median 6 vs. 9 days, log rank test p=0.02) during the daily SCr period. CONCLUSIONS Daily SCr measurement promoted earlier and increased detection of AG-AKI in patients with CF at our institution. We suggest systematic evaluation for AKI during aminoglycoside administration in patients with CF.

Association of Acute Kidney Injury With Concomitant Vancomycin and Piperacillin/Tazobactam Treatment Among Hospitalized Children

Importance &bgr;-Lactam antibiotics are often coadministered with intravenous (IV) vancomycin hydrochloride for children with suspected serious infections. For adults, the combination of IV vancomycin plus piperacillin sodium/tazobactam sodium is associated with a higher risk of acute kidney injury (AKI) compared with vancomycin plus 1 other &bgr;-lactam antibiotic. However, few studies have evaluated the safety of this combination for children. Objective To assess the risk of AKI in children during concomitant therapy with vancomycin and 1 antipseudomonal &bgr;-lactam antibiotic throughout the first week of hospitalization. Design, Setting, and Participants This retrospective cohort study focused on children hospitalized for 3 or more days who received IV vancomycin plus 1 other antipseudomonal &bgr;-lactam combination therapy at 1 of 6 large children’s hospitals from January 1, 2007, through December 31, 2012. The study used the Pediatric Health Information System Plus database, which contains administrative and laboratory data from 6 pediatric hospitals in the United States. Patients with underlying kidney disease or abnormal serum creatinine levels on hospital days 0 to 2 were among those excluded. Patients 6 months to 18 years of age who were admitted through the emergency department of the hospital were included. Data were collected from July 2015 to March 2016. Data analysis took place from April 2016 through July 2017. (Exact dates are not available because the data collection and analysis processes were iterative.) Main Outcomes and Measures The primary outcome was AKI on hospital days 3 to 7 and within 2 days of receiving combination therapy. Acute kidney injury was defined using KDIGO criteria and was based on changes in serum creatinine level from hospital days 0 to 2 through hospital days 3 to 7. Multiple logistic regression was performed using a discrete-time failure model to test the association between AKI and receipt of IV vancomycin plus piperacillin/tazobactam or vancomycin plus 1 other antipseudomonal &bgr;-lactam antibiotic. Results A total of 1915 hospitalized children who received combination therapy were identified. Of the 1915 patients, a total of 866 (45.2%) were female and 1049 (54.8%) were male, 1049 (54.8%) were identified as white in race/ethnicity, and the median (interquartile range) age was 5.6 (2.1-12.7) years. Among the cohort who received IV vancomycin plus 1 other antipseudomonal &bgr;-lactam antibiotic, 157 patients (8.2%) had antibiotic-associated AKI. This number included 117 of 1009 patients (11.7%) who received IV vancomycin plus piperacillin/tazobactam combination therapy. After adjustment for age, intensive care unit level of care, receipt of nephrotoxins, and hospital, IV vancomycin plus piperacillin/tazobactam combination therapy was associated with higher odds of AKI each hospital day compared with vancomycin plus 1 other antipseudomonal &bgr;-lactam antibiotic combination (adjusted odds ratio, 3.40; 95% CI, 2.26-5.14). Conclusions and Relevance Coadministration of IV vancomycin and piperacillin/tazobactam may increase the risk of AKI in hospitalized children. Pediatricians must be cognizant of the potential added risk of this combination therapy when making empirical antibiotic choices.

Symptoms and time to medical care in children with accidental extremity fractures.

Background And Objective: Delay in seeking medical care is one criterion used to identify victims of abuse. However, typical symptoms of accidental fractures in young children and the time between injury and the seeking of medical care have not been reported. We describe patient and injury characteristics that influence the time from injury to medical care. Methods: Parental interviews were conducted for children <6 years old with accidental extremity fractures. Demographic characteristics, signs and symptoms of the injury, and fracture location and severity were described and examined for their association with a delay (>8 hours) in seeking medical care. Results: Among 206 children, 69% had upper extremity fractures. The median time to the first medical evaluation was 1 hour, but 21% were seen at >8 hours after injury. Although 91% of children cried after the injury, only 83% were irritable for >30 minutes. Parents observed no external sign of injury in 15% of children, and 12% used the injured extremity normally. However, all parents noted at least 1 sign or symptom. Minority children (odds ratio [OR]: 2.54 [95% confidence interval [CI]: 1.18–5.47), those with lower extremity injuries (OR: 2.23 [95% CI: 1.01–4.90]), those without external signs of injury (OR: 3.40 [95% CI: 1.36–8.51]), and those with continued extremity use (OR: 3.26 [95% CI: 1.22–8.76]) were more likely to delay seeking medical care. Conclusions: Although some children did not manifest all expected responses, no child with an accidental fracture was asymptomatic. Delay in seeking medical care was associated with more subtle signs of injury; however, delays identified in minority patients are unexplained.

Practice Variation in Screening for Sexually Transmitted Infections with Nucleic Acid Amplification Tests During Prepubertal Sexual Abuse Evaluations

BACKGROUND Although recent recommendations for children after suspected sexual abuse incorporate nucleic acid amplification tests (NAATs) in algorithms that detect sexually transmitted infections (STIs), screening practices in the community remain uncertain. STUDY OBJECTIVE We examined screening practices over time and across a variety of pediatric settings for the evaluation of STIs in sexually abused children. METHODS A consecutive cohort of prepubertal children younger than 11 years of age who were suspected to have been sexually abused were identified between May 2002 and April 2005 at a large tertiary childrens hospital and its supporting primary care network. Detailed histories and examinations based on chart abstraction were linked to hospital laboratory records to identify those who were screened for Chlamydia trachomatis and Neisseria gonorrhoeae by means of cultures, NAATs, or both. Chi-square and logistic regression analyses identified factors associated with screening, including the effects of screening location and year of study on the likelihood that particular tests were obtained. RESULTS Among the initial visits of 1068 children, 32% occurred in the specialty child abuse clinic (CARE Clinic), 62% in the emergency department, and 6% in the primary care setting. Follow-up visits occurred in only 7% of children. The performance of at least one screening test increased each year, from 12% in year 1 to 18% in year 3 (P = 0.01). Among the 162 children in whom tests were obtained, there was a significant decrease in the use of culture techniques over time, from 100% in year 1 to 75% in year 3 (P < 0.001). At the same time, there was a steady increase in the use of NAATs in total (from 2% in year 1 to 41% in year 3, P < 0.001), and in the absence of culture techniques (from 0% in year 1 to 26% in year 3, P < 0.001). This growth in the use of NAATs alone was particularly seen in the emergency department setting, where 33% of children were screened only by NAAT by year 3 (P = 0.001). CONCLUSIONS Screening rates for STIs increased over time, a trend that is explained primarily by the use of NAATs in the absence of other tests. The increasing use of NAATs will have to be addressed more fully in creating future guidelines for this population.

A Pragmatic Biomarker-Driven Algorithm to Guide Antibiotic Use in the Pediatric Intensive Care Unit: The Optimizing Antibiotic Strategies in Sepsis (OASIS) Study

Background. Biomarkers that identify critically ill children with systemic inflammatory response syndrome (SIRS) at low risk for bacterial infection may help clinicians reduce unnecessary antibiotic use. Methods. We conducted a prospective cohort study of children with SIRS and suspected infection admitted to a pediatric intensive care unit from January 5, 2012 to March 7, 2014. We enrolled patients upon initiation of new antibiotics (Time 0) and measured a panel of 8 serum biomarkers daily over 72 hours. Microbiology, imaging, and clinical data were reviewed to classify bacterial infections using Centers for Disease Control and Prevention definitions. We identified cut points of biomarker combinations to maximize the negative predictive value (NPV) and specificity for bacterial infection. Excess antibiotics were calculated as days of therapy beyond day 2 after SIRS onset in patients without bacterial infection. Results. Infections were identified in 46 of 85 patients: bacterial (n = 22) and viral (24), whereas 39 patients had no infection identified. At Time 0, C-reactive protein (CRP) <5 mg/dL plus serum amyloid A <15.0 µg/mL had an NPV of 0.92 (95% confidence interval [CI], 0.79-1.0) and specificity of 0.54 (95% CI, 0.42-0.66) to identify patients without bacterial infection, whereas CRP <4 mg/dL plus procalcitonin <1.75 ng/mL had an NPV of 0.90 (95% CI, 0.79-1.0) and specificity of 0.43 (95% CI, 0.30-0.55). Patients without bacterial infection received a mean of 3.8 excess days of therapy. Conclusions. Early measurement of select biomarkers can identify children with SIRS in whom antibiotics might be safely discontinued when there is no other objective evidence of infection at 48 hours.

Urinary kidney injury biomarkers and tobramycin clearance among children and young adults with cystic fibrosis: a population pharmacokinetic analysis

Background Tobramycin is frequently used for treatment of bronchopneumonia in patients with cystic fibrosis (CF). Variability in tobramycin clearance (CL) is high in this population with few reliable approaches to guide dosing. Objectives We sought to evaluate the pharmacokinetics of once-daily intravenous tobramycin in patients with CF and test the influence of covariates on tobramycin CL, including serum creatinine (SCr) and urinary biomarkers: neutrophil gelatinase-associated lipocalin (NGAL), retinol-binding protein (RBP) and kidney injury molecule-1 (KIM-1). Methods This was a prospective, observational cohort study of children/young adults with CF receiving once-daily intravenous tobramycin from October 2012 to May 2014 at Cincinnati Childrens Hospital Medical Center. Therapeutic drug monitoring data were prospectively obtained. Population pharmacokinetic analyses were performed using non-linear mixed-effects modelling. Results Thirty-seven patients (median age 15.3 years, IQR 12.7–19.5) received 62 tobramycin courses. A one-compartment model with allometrically scaled weight for tobramycin CL and volume of distribution (V) best described the data. Urinary NGAL was associated with tobramycin CL (P < 0.001), as was urinary RBP (P < 0.001). SCr, estimated glomerular filtration rate and urinary KIM-1 were not significant covariates. The population pharmacokinetic parameter estimates were CL = 8.60 L/h/70 kg (relative standard error 4.3%) and V = 31.3 L/70 kg (relative standard error 4.7%). Conclusions We describe urinary biomarkers as predictors of tobramycin CL using a population pharmacokinetic modelling approach. Our findings suggest that patient weight and urinary NGAL or RBP could be used to individualize tobramycin therapy in patients with CF.

Increased Vancomycin Exposure and Nephrotoxicity in Children: Therapeutic Does Not Mean Safe

Vancomycin-associated nephrotoxicity has been the subject of renewed debate over recent years. In 2011, the Infectious Diseases Society of America recommended vancomycin doses of 15 mg/kg per dose every 6 hours for children with serious or invasive infections due to methicillinresistant Staphylococcus aureus [1]. These guidelines also suggest targeting trough concentrations (Cmin) of 15–20 μg/mL for children to maximize the likelihood of achieving a 24-hour vancomycin area under the curve over the minimum inhibitory concentration (AUC24/MIC) 400 for isolates with a vancomycin MIC 1 μg/mL, which is the pharmacokinetic/pharmacodynamic (PK/PD) index that best predicts efficacy in adults. After incorporation of these more aggressive dosing recommendations into clinical practice, several authors have reported an association between larger vancomycin doses, increased vancomycin troughs, and nephrotoxicity in pediatric patients [2, 3]. Consequently, discussion surrounds whether the recommended troughs of 15–20 μg/mL are optimal for pediatric patients and lead to added risk of toxicity. Acute kidney injury (AKI) has important shortand long-term ramifications in children. Patients who sustain AKI are at risk for prolonged intensive care unit (ICU) and hospital admission [4], increased mortality [4, 5], and development of chronic kidney disease [5, 6]. Critically ill children who develop AKI during vancomycin therapy, specifically, have higher mortality [2, 7]. Therefore, a tenuous balance exists between the successful treatment of infection and the safe administration of vancomycin in our most vulnerable patients. In this issue of the Journal of the Pediatric Infectious Diseases Society, Le et al [8] applied population-based PK/PD modeling with Bayesian estimation to examine the relationship between vancomycin drug exposure (AUC24 and Cmin) and nephrotoxicity. Utilizing a retrospective cohort design, the authors combined established population PK-modeling techniques with Bayesian estimation to estimate PK parameters for individuals in the study. After a series of analyses, the authors concluded that both vancomycin AUC24 800 mg h/L and Cmin 15 μg/mL are strong independent predictors of nephrotoxicity in children. These findings substantiate an exposure-response relationship between vancomycin and renal toxicity and support the need to identify the optimal dosing and monitoring strategies in children. However, this study has some limitations and raises additional questions. The authors utilized a onecompartment model with firstorder kinetics in this study. A one-compartment model assumes that the drug in the blood is in rapid equilibrium with the tissues, whereas first-order kinetics refers to a proportional relationship between drug concentration in the blood and elimination. Meanwhile, both AUC24 and Cmin are related directly to dose and inversely to total body clearance. Although Cmin is affected by dosing interval and AUC24 is not, these parameters are highly related to one another. This association actually provides the basis for using trough concentrations as a proxy for AUC24 in clinical practice. The strong correlation between AUC24 and Cmin in the current study (Spearman’s coefficient = 0.963, P < .001) confirms this interrelationship and raises questions about if and how these parameters confer independent nephrotoxic risks. Animal studies demonstrate that vancomycin causes nephrotoxicity via dose-dependent oxidative stress on renal proximal tubules cells [9], so the association between increased vancomycin exposure and AKI is expected. However, teasing out whether AUC24, Cmin, or both drive toxicity Editorial Commentary