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

Pharmacologic Management of Pediatric Hypertension

Hypertension in children is common, and the prevalence of primary hypertension is increasing with the obesity epidemic and changing dietary choices. Careful measurement of blood pressure is important to correctly diagnose hypertension, as many factors can lead to inaccurate blood pressure measurement. Hypertension is diagnosed based on comparison of age-, sex-, and height-based norms with the average systolic and diastolic blood pressures on three separate occasions. In the absence of hypertensive target organ damage (TOD), stage I hypertension is managed first by diet and exercise, with the addition of drug therapy if this fails. First-line treatment of stage I hypertension with TOD and stage II hypertension includes both lifestyle changes and medications. First-line agents include angiotensin-converting enzyme (ACE) inhibitors, thiazide diuretics, and calcium-channel blockers. Hypertensive emergency with end-organ effects requires immediate modest blood pressure reduction to alleviate symptoms. This is usually accomplished with IV medications. Long-term reduction in blood pressure to normal levels is accomplished gradually. Specific medication choice for outpatient hypertension management is determined by the underlying cause of hypertension and the comparative adverse effect profiles, along with practical considerations such as cost and frequency of administration. Antihypertensive medication is initiated at a starting dose and can be gradually increased to effect. If ineffective at the recommended maximum dose, an additional medication with a complementary mechanism of action can be added

System-Wide Implementation of the Use of an Extended-Infusion Piperacillin/Tazobactam Dosing Strategy: Feasibility of Utilization From a Children\u27s 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 children\u27s hospital. Methods This was a prospective observational study of patients aged \u3e30 days who received PT after admission to a freestanding, tertiary care children\u27s 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 children\u27s hospital. Ninety-two percent of patients received our institution\u27s preferred dosing regimen; a small percentage of patients still needed to receive traditional infusion times

Optimized Antimicrobial Dosing Strategies: A Survey of Pediatric Hospitals

Background Extended-interval aminoglycoside (EIAG) and extended- and continuous-infusion β-lactam (EIBL and CIBL) dosing strategies are increasingly used in adults, but pediatric literature is limited. Objective The objective of this study was to describe the use of EIAG, EIBL, and CIBL dosing in pediatric hospitals in the USA. Study Design, Setting, and Participants A national survey of children’s hospitals was conducted. A single practitioner from each target hospital was identified through the Children’s Hospital Association. Practice-based survey questions identified whether hospitals utilize EIAG, EIBL, and CIBL dosing. Main Outcome Measure The main outcome measure was the percentage utilization of the dosing strategies, with secondary outcomes being the reasons for not using these dosing strategies. Results Seventy-seven of 215 identified practitioners (36 %) participated in the survey. EIAG, EIBL, and CIBL dosing were utilized in 63 %, 24 %, and 13 % of responding hospitals, respectively. The most common reasons for not using EIAG were concern regarding lack of efficacy data (56 %) and concern regarding the duration of the drug-free period (41 %). Respondents who did not utilize EIBL cited concern due to lack of pediatric EIBL efficacy data (54 %), the need for more intravenous access (54 %), intravenous medication compatibility issues (39 %), and the time during which the patient is attached to an intravenous infusion (31 %). Conclusion This survey of children’s hospitals indicates that EIAG is used in over 50 % of hospitals, but there is some lag in adoption of EIBL and CIBL dosing, both of which are used in fewer than 25 % of hospitals. Additional studies may provide much-needed evidence to increase the utilization of these strategies

Cinacalcet Administration by Gastrostomy Tube in a Child Receiving Peritoneal Dialysis

A 2-year-old male with chronic kidney disease with secondary hyperparathyroidism developed hypercalcemia while receiving calcitriol, without achieving a serum parathyroid hormone concentration within the goal range. Cinacalcet 15 mg (1.2 mg/kg), crushed and administered via gastrostomy tube, was added to the patient’s therapy. This therapy was effective in achieving targeted laboratory parameters in our patient despite instructions in the prescribing information that cinacalcet should always be taken whole

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

Vancomycin and Gentamicin Pharmacokinetic Alterations in an Adolescent Amputee

A 14-year-old male with bilateral above-the-knee amputations presented to our hospital for treatment of a skin and soft-tissue infection. We report the experience of vancomycin and gentamicin therapy in this patient. Because these medications require weight-based dosages and pharmacokinetic monitoring of serum levels, it was necessary to obtain peak and trough levels of the two drugs in order to determine the pharmacokinetic differences in this patient compared to those in an adolescent male without amputations. To our knowledge, this is the first report describing pharmacokinetic differences in an adolescent amputee

Cefepime Neurotoxicity in an Adolescent Cystic Fibrosis Patient with Aminoglycoside-Induced Acute Kidney Injury

Objective: To describe a case of cefepime neurotoxicity in an adolescent with cystic fibrosis and aminoglycoside-associated acute kidney injury (AKI). Case Summary: A 15-year-old, 46-kg male with cystic fibrosis (CF) and chronic sinusitis was admitted to the hospital for CF exacerbation. The patient was subsequently discharged to complete home antibiotic therapy with intravenous gentamicin and cefepime. Thirteen days after discharge, while still receiving intravenous antibiotics, the patient presented to an outside hospital complaining of vomiting, fatigue, decreased appetite, and decreased urine output. The patient was diagnosed with AKI and was transferred to our institution, where he displayed signs and symptoms consistent with encephalopathy. Encephalopathy was thought to be consistent with cefepime-associated neurotoxicity. After 2 hemodialysis sessions, the encephalopathy resolved. Over the course of admission, the patient\u27s renal function improved. Discussion: This patient experienced neurotoxicity thought to be secondary to cefepime in the setting of AKI. Aminoglycoside therapy most likely led to the AKI. We believe that our patient represents the fourth pediatric patient with cefepime-associated encephalopathy described in the literature and the second without chronic renal dysfunction. Conclusions: Children receiving cefepime should be monitored for AKI. In the presence of AKI, cefepime doses may need to be adjusted and the patient should be monitored for signs and symptoms of neurotoxicity

Late-Occurring Vancomycin-Associated Acute Kidney Injury in Children Receiving Prolonged Therapy

Background: Acute kidney injury (AKI) in patients receiving vancomycin has been associated with trough concentrations ≥15 mg/L and longer therapy duration. The objective of this study was to determine the incidence and factors associated with late AKI in children receiving ≥8 days of vancomycin therapy. Methods: Children aged 30 days to 17 years who were admitted to our institution and received intravenous vancomycin for at least 8 days during January to December of 2007 and 2010 and had a suspected or proven gram-positive infection were included. Late AKI was categorized as AKI occurring after the first 7 days of therapy and within 48 hours following vancomycin discontinuation. The primary outcome was incidence of late AKI as determined by modified pRIFLE criteria. Results: One-hundred sixty-seven patients were included, with a median (interquartile range) age (years) and weight (kg) of 2 (1-7) and 12.5 (8.9-23.8). Late AKI was identified in 12.6% (21/167). A higher percentage of late AKI patients received concomitant treatment with intravenous acyclovir, amphotericin products, or piperacillin-tazobactam. Age \u3c1 year was the only factor independently associated with late AKI development (odds ratio = 4.4; 95% confidence interval = 1.3-15.4). Conclusions: Late AKI occurred in nearly 13% of children receiving ≥8 days of vancomycin therapy. This study suggests that vancomycin trough concentrations are not associated with late AKI, but that age \u3c1 year and concomitant administration of certain nephrotoxins may be factors associated with increased risk

Population Pharmacokinetics and Pharmacodynamics of Extended-Infusion Piperacillin and Tazobactam in Critically Ill Children

The study objective was to evaluate the population pharmacokinetics and pharmacodynamics of extended-infusion piperacillintazobactam in children hospitalized in an intensive care unit. Seventy-two serum samples were collected at steady state from 12 patients who received piperacillin-tazobactam at 100/12.5 mg/kg of body weight every 8 h infused over 4 h. Population pharmacokinetic analyses were performed using NONMEM, and Monte Carlo simulations were performed to estimate the piperacillin pharmacokinetic profiles for dosing regimens of 80 to 100 mg/kg of the piperacillin component given every 6 to 8 h and infused over 0.5, 3, or 4 h. The probability of target attainment (PTA) for a cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (TMIC) of\u3e50% was calculated at MICs ranging from 0.25 to 64 mg/liter. The mean ± standard deviation (SD) age, weight, and estimated glomerular filtration rate were 5 ± 3 years, 17 ± 6.2 kg, and 118 ± 41 ml/min/1.73m2, respectively. A one-compartment model with zero-order input and first-order elimination best fit the pharmacokinetic data for both drugs. Weight was significantly associated with piperacillin clearance, and weight and sex were significantly associated with tazobactam clearance. Pharmacokinetic parameters (mean ± SD) for piperacillin and tazobactam were as follows: clearance, 0.22 ± 0.07 and 0.19 ± 0.07 liter/h/kg, respectively; volume of distribution, 0.43 ± 0.16 and 0.37 ± 0.14 liter/kg, respectively. All extended-infusion regimens achieved PTAs of\u3e90% at MICs of/liter. Only the 3-h infusion regimens given every 6 h achieved PTAs of\u3e90% at an MIC of 32 mg/liter. For susceptible bacterial pathogens, piperacillin-tazobactam doses of\u3e80/10 mg/kg given every 8 h and infused over 4 h achieve adequate pharmacodynamic exposures in critically ill children