Acute kidney injury is associated with abnormal cefepime exposure among critically ill children and young adults.

BACKGROUND: Elevated cefepime blood concentrations can cause neurotoxicity in adults. The consequences of elevated cefepime concentrations among pediatric patients are unknown. Future exploration of such effects requires first identifying patients at risk for elevated cefepime exposure. We investigated the role of acute kidney injury as a risk factor for increased cefepime concentrations in critically ill children. METHODS: This was a retrospective analysis at a single pediatric intensive care unit. Analyzed patients received at least 24 h of cefepime and had at least two opportunistic samples collected for total cefepime concentration measurement. Individual pharmacokinetic (PK) profiles during treatment courses were reconstructed using Bayesian estimation with an established population PK model. Elevated trough concentration (Cmin) was defined as ≥ 30 mg/L based on adult toxicity studies. The effect of kidney dysfunction on cefepime PK profiles was interrogated using a mixed-effect model. RESULTS: Eighty-seven patients were included, of which 13 (14.9%) had at least one estimated Cmin ≥ 30 mg/L. Patients with elevated Cmin were more likely to have acute kidney injury (AKI) during their critical illness (92% vs. 57%, p = 0.015 for any AKI; 62% vs. 26%, p = 0.019 for severe AKI). Patients who had AKI during critical illness had significantly higher cefepime exposure, as quantified by the area under the concentration-time curve over 24 h (AUC24h) and Cmin. CONCLUSIONS: Among critically ill children, AKI is associated with elevated cefepime concentrations. Identifying these high-risk patients is the first step toward evaluating the clinical consequences of such exposures.

Ceftriaxone Pharmacokinetics and Pharmacodynamic Target Attainment for Three Pediatric Patients Receiving Continuous Kidney Replacement Therapy.

Ceftriaxone is used commonly for sepsis, including in children requiring continuous kidney replacement therapy (CKRT). No reports exist of pharmacokinetic (PK) parameters for children receiving ceftriaxone on CKRT. We enrolled children admitted to our pediatric intensive care unit (PICU) who received CKRT for >24 hours and received >1 dose of ceftriaxone while on and off CKRT. We measured free ceftriaxone -concentrations from residual blood samples then used Bayesian estimation with PK modeling software to generate concentration-time profiles and determine PK parameters and the percentage of time free ceftriaxone concentrations were above 1× or 4× MIC (% fT >MIC). Three patients aged 2 to 17 years were included; all were anuric at CKRT initiation and received 50 mg/kg (max 2000 mg) ceftriaxone every 12 to 24 hours. Total ceftriaxone clearance (CL) was 0.50 to 3.67 L/hr while receiving CKRT and 0.29 to 2.71 L/hr while off, indicating CKRT provided 25% to 42% of total ceftriaxone CL. All achieved 100% fT >1× and 4× MIC using an estimated MIC (1 mg/L) for patients 1 to 2 (no culture data) and a measured MIC (0.016 mg/L) for patient 3. Therefore, CKRT contributed significantly to total ceftriaxone clearance in 3 children though the dosing strategies used in each patient attained PD targets.

Cystatin C Outperforms Creatinine in Predicting Cefepime Clearance in Pediatric Stem Cell Transplant Recipients.

Pediatric hematopoietic stem cell transplant (HSCT) patients are at risk of developing both sepsis and altered kidney function. Cefepime is used for empiric coverage post-HSCT and requires dose adjustment based on kidney function. Since cefepime's antimicrobial efficacy is determined by the time free concentrations exceed bacterial minimum inhibitory concentration (MIC), it is important to assess kidney function accurately to ensure adequate concentrations. Serum creatinine (SCr) is routinely used to estimate glomerular filtration rate (eGFR) but varies with muscle mass, which can be significantly lower in HSCT patients, making SCr an inaccurate kidney function biomarker. Cystatin C (CysC) eGFR is independent of muscle mass, though steroid use increases CysC. Objectives of this study were to describe how eGFR impacts cefepime pharmacokinetic/pharmacodynamic (PK/PD) target attainment in pediatric HSCT patients, to investigate which method of estimating GFR (SCr, CysC, combined) best predicts cefepime clearance, and to explore additional predictors of cefepime clearance. Patients admitted to the pediatric HSCT unit who received ≥2 cefepime doses were prospectively enrolled. We measured total cefepime peak/trough concentrations between the second and fourth cefepime doses and measured SCr and CysC if not already obtained clinically within 24h of cefepime samples. eGFRs were calculated with Chronic Kidney Disease in Children U25 equations. Bayesian estimates of cefepime clearance were determined with a pediatric cefepime PK model and PK software MwPharm++. Simple linear regression was used to compare cefepime clearance normalized to body surface area (BSA) to BSA-normalized SCr-, CysC-, and SCr-/CysC-eGFRs, while multiple linear regression was used to account for additional predictors of cefepime clearance. For target attainment, we assessed the percentage of time free cefepime concentrations exceeded 1x MIC (%fT>1x MIC) and 4x MIC (%fT>4x MIC) using a susceptibility breakpoint of 8 mg/L for Pseudomonas aeruginosa. We enrolled 53 patients (ages 1 to 30 years, median 8.9 years). SCr- and CysC-eGFRs were lower in patients who attained 100% fT>1xMIC compared to those who did not attain this target: 115 versus 156 mL/min/1.73m2 (p = .01) for SCr-eGFR and 73.5 versus 107 mL/min/1.73m2 (p < .001) for CysC-eGFR. SCr-eGFR was weakly positively correlated with cefepime clearance (adjusted [a]r2= 0.14), while CysC-eGFR and SCr-/CysC-eGFR had stronger positive correlations (ar2 = 0.30 CysC, ar2 = 0.28 combo. There was a weak, significant linear association between increasing CysC-eGFR and decreased %fT>1xMIC (ar2 = 0.32) and %fT>4xMIC (ar2 = 0.14). No patients with a CysC-eGFR >120 mL/min/1.73 m2 achieved 100% fT>1xMIC or 50% fT>4x MIC. In multiple regression models, underlying diagnosis of hemoglobinopathy (in all models) and being pretransplant (in SCr and combined models) were associated with increased cefepime clearance, while concomitant use of calcineurin inhibitors was associated with decreased cefepime clearance in all models. Overall, the combo-eGFR model with timing pretransplant, hemoglobinopathy, and use of calcineurin inhibitors had the best performance (ar2 = 0.63). CysC-based eGFRs (CysC alone and combined) predicted cefepime clearance better than SCr-eGFR, even after considering steroid use. Increasing CysC eGFR correlated with decreased probability of PD target attainment, raising concerns for underdosing at high eGFRs. CysC should be included when estimating kidney function to provide adequate dosing of cefepime in pediatric HSCT patients.

Tutorial on model selection and validation of model input into precision dosing software for model-informed precision dosing.

There has been rising interest in using model-informed precision dosing to provide personalized medicine to patients at the bedside. This methodology utilizes population pharmacokinetic models, measured drug concentrations from individual patients, pharmacodynamic biomarkers, and Bayesian estimation to estimate pharmacokinetic parameters and predict concentration-time profiles in individual patients. Using these individualized parameter estimates and simulated drug exposure, dosing recommendations can be generated to maximize target attainment to improve beneficial effect and minimize toxicity. However, the accuracy of the output from this evaluation is highly dependent on the population pharmacokinetic model selected. This tutorial provides a comprehensive approach to evaluating, selecting, and validating a model for input and implementation into a model-informed precision dosing program. A step-by-step outline to validate successful implementation into a precision dosing tool is described using the clinical software platforms Edsim++ and MwPharm++ as examples.

Guideline-Concordant Antiviral Treatment in Children at High Risk for Influenza Complications.

BACKGROUND: National guidelines recommend antiviral treatment for children with influenza at high risk for complications regardless of symptom duration. Little is known about concordance of clinical practice with this recommendation. METHODS: We performed a cross-sectional study of outpatient children (aged 1-18 years) at high risk for complications who were diagnosed with influenza during the 2016-2019 influenza seasons. High-risk status was determined using an existing definition that includes age, comorbidities, and residence in a long-term care facility. The primary outcome was influenza antiviral dispensing within 2 days of influenza diagnosis. We determined patient- and provider-level factors associated with guideline-concordant treatment using multivariable logistic regression. RESULTS: Of the 274 213 children with influenza at high risk for influenza complications, 159 350 (58.1%) received antiviral treatment. Antiviral treatment was associated with the presence of asthma (aOR, 1.13; 95% confidence interval [CI], 1.11-1.16), immunosuppression (aOR, 1.10; 95% CI, 1.05-1.16), complex chronic conditions (aOR, 1.04; 95% CI, 1.01-1.07), and index encounter in the urgent care setting (aOR, 1.3; 95% CI, 1.26-1.34). Factors associated with decreased odds of antiviral treatment include age 2-5 years compared with 6-17 years (aOR, 0.95; 95% CI, .93-.97), residing in a chronic care facility (aOR, .61; 95% CI, .46-.81), and index encounter in an emergency department (aOR, 0.66; 95% CI, .63-.71). CONCLUSIONS: Among children with influenza at high risk for complications, 42% did not receive guideline-concordant antiviral treatment. Further study is needed to elucidate barriers to appropriate use of antivirals in this vulnerable population.

Opportunities for Stewardship in the Transition From Intravenous to Enteral Antibiotics in Hospitalized Pediatric Patients.

BACKGROUND/OBJECTIVE: Pediatric patients hospitalized with bacterial infections often receive intravenous (IV) antibiotics. Early transition to enteral antibiotics can reduce hospital duration, cost, and complications. We aimed to identify opportunities to transition from IV to enteral antibiotics, describe variation of transition among hospitals, and evaluate feasibility of novel stewardship metrics. METHODS: This multisite retrospective cohort study used the Pediatric Health Information System to identify pediatric patients hospitalized with pneumonia, neck infection, orbital infection, urinary tract infection (UTI), osteomyelitis, septic arthritis, or skin and soft tissue infection (SSTI) between 2017 and 2018. Opportunity days were defined as days on which patients received both IV antibiotics and enteral medications, suggesting enteral tolerance. Percent opportunity was defined as opportunity days divided by days on any antibiotics. Both outcomes excluded IV antibiotics that have no alternative oral formulation. We evaluated outcomes per infection and antibiotic and assessed across-hospital variation. RESULTS: We identified 88,522 aggregate opportunity days in 100,103 hospitalizations. On 57% of the antibiotic days, there was an opportunity to switch patients to enteral therapy, with greatest opportunity days in SSTI, neck infection, and pneumonia encounters, and with clindamycin, ceftriaxone, and ampicillin-sulbactam. Percent opportunity varied by infection (73% in septic arthritis to 40% in pneumonia). There was significant across-hospital variation in percent opportunity for all infections. CONCLUSION: This multicenter study demonstrated the potential opportunity to transition from IV to enteral therapy in over half of antibiotic days. Opportunity varied by infection, antibiotic, and hospital. Across-hospital variation demonstrated likely missed opportunities for earlier transition and the need to define optimal transition times. Stewardship efforts promoting earlier transition for highly bioavailable antibiotics could reduce healthcare utilization and promote high-value care. We identified feasible stewardship metrics.

Clinical Guideline Highlights for the Hospitalist: Therapeutic Monitoring of Vancomycin.

GUIDELINE TITLE: Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: A revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists RELEASE DATE: Online: March 19, 2020 PRIOR VERSION: 2009 DEVELOPERS: American Society of Health-System Pharmacists (ASHP), the Infectious Diseases Society of America (IDSA), the Pediatric Infectious Diseases Society (PIDS), and the Society of Infectious Diseases Pharmacists (SIDP) FUNDING SOURCE: ASHP, IDSA, PIDS, SIDP TARGET POPULATION: Adults, children, and neonates treated for documented or presumed methicillin-resistant Staphylococcus aureus infection.

Clinical Guideline Highlights for the Hospitalist: Maintenance Intravenous Fluids in Infants and Children.

GUIDELINE TITLE: 2018 American Academy of Pediatrics (AAP) Clinical Practice Guideline: Maintenance Intravenous Fluids in Children RELEASE DATE: November 26, 2018 PRIOR VERSION: Not Applicable DEVELOPER: Multidisciplinary subcommittee of experts assembled by the AAP FUNDING SOURCE: AAP TARGET POPULATION: Patients 28 days to 18 years of age requiring maintenance intravenous fluids (IVFs).