Higher Weight-Based Doses Are Required to Achieve and Maintain Therapeutic Voriconazole Serum Trough Concentrations in Children.

OBJECTIVE: Children require weight-based voriconazole doses proportionately larger than adults to achieve therapeutic serum trough concentrations (1-6 mcg/mL). The objective of this quality improvement project was to determine the initial dose, proportion of patients achieving target concentrations with initial dosing, and subsequent therapeutic drug monitoring and dose modifications needed to achieve and maintain therapeutic voriconazole concentrations in children. METHODS: This retrospective study evaluated children aged <18 years treated with voriconazole during the study period. Dosing and therapeutic drug monitoring (TDM) values were collected and compared by age. Data are presented as median (IQR), unless otherwise stated. RESULTS: Fifty-nine patients, aged 10.4 (3.7-14.7) years and 49% female, met inclusion criteria; 42 had at least 1 steady-state voriconazole serum trough concentration measured. Twenty-one of 42 (50%) achieved the target concentration at the first steady-state measurement. An additional 13 of 42 (31%) achieved the target following 2 to 4 dose modifications. The dose required to first achieve a value in the target range was 22.3 (18.0-27.1) mg/kg/day in children aged <12 years and 12.0 (9.8-14.0) mg/kg/day in children aged ≥12 years. After reaching the target, 59% and 81% of repeated steady-state measurements were in the therapeutic range in patients aged <12 years and ≥12 years, respectively. CONCLUSIONS: Reaching therapeutic voriconazole serum trough concentrations required doses larger than currently recommended by the American Academy of Pediatrics. Multiple dose adjustments and TDM measurements were required to achieve and maintain therapeutic voriconazole serum concentrations.

Pediatric Orbital Cellulitis/Abscess: Microbiology and Pattern of Antibiotic Prescribing.

INTRODUCTION: The treatment for pediatric orbital cellulitis/abscess is trending towards intravenous antibiotic management alone in appropriate cases. Without cultures to guide therapy, knowing the local microbiology is of utmost importance in managing these patients. METHODS: We conducted a retrospective case series for patients age 2 months to 17 years, who were hospitalized between January 1, 2013, and December 31, 2019, to evaluate the local microbiology and pattern of antibiotic prescribing in pediatric orbital cellulitis. RESULTS AND DISCUSSION: Of 95 total patients, 69 (73%) received intravenous antibiotics only and 26 (27%) received intravenous antibiotics plus surgery. The most common organism cultured was Streptococcus anginosus, followed by Staphylococcus aureus, and group A streptococcus. Methicillin-resistant Staphylococcus aureus (MRSA) prevalence was 9%. MRSA-active antibiotics remain the most frequently used antibiotics.

COVID-19 Pandemic Exacerbates Childhood Immunization Disparities.

BACKGROUND: The objective of this study was to measure the recovery of routine pediatric immunization after a period of reduced vaccine administrations in the early weeks of the COVID-19 pandemic. METHODS: We recorded data on vaccines administered in Children's Wisconsin primary care or urgent care clinics from January 2019 through December 2020 and aggregated data by date and insurance type. RESULTS: During the gradual reopening period after week 21 in 2020, vaccine administration returned to prepandemic levels for children with commercial insurance but remained below baseline rates until the end of 2020 for children with Medicaid insurance. DISCUSSION: The decline in pediatric vaccination in 2020 disproportionately affected children with Medicaid insurance.

Two cases of multi-inflammatory syndrome in children (MIS-C) in adults in 2020.

BACKGROUND: Late complications and longer-lasting sequelae of COVID-19 infection in adults can occur. Cardiovascular involvement including reduced ejection fraction, coronary artery aneurysms, and pericardial involvement have been reported. Prompt recognition is the first step and secondly, these cardiovascular phenomena require an alternative set of therapeutics from the standard of care for acute COVID-19 infection. CASE PRESENTATION: Here we describe two cases that fulfill the current case definition of the recently defined multisystem inflammatory syndrome in adults (MIS-A). One patient is a 27-year-old white female and the other a 21-year-old French creole male, both without any prior medical history. Both were hospitalized and found to have significant cardiac dysfunction and treated with IVIG, high dose aspirin, and corticosteroids with resolution of their acute illnesses and cardiac sequelae. CONCLUSION: Not only does the immediate impact of this viral infection need to be addressed, but also the long-term complications that could arise if not recognized and treated promptly as seen in our two cases. Patients can develop acute cardiovascular collapse and cardiogenic shock which requires high level of care and treatment within an intensive care unit. Depending on the complications, patients may require treatment for congestive heart failure, pericarditis, or even coronary artery disease acutely with close follow up to ensure improvement or resolution.

Evaluation and Medical Management of the Pediatric Patient With Orbital Cellulitis/Abscess: A Systematic Review.

BACKGROUND AND OBJECTIVES: Pediatric orbital cellulitis/abscess (OCA) can lead to vision loss, intracranial extension of infection, or cavernous thrombosis if not treated promptly. No widely recognized guidelines exist for the medical management of OCA. The objective of this review was to summarize existing evidence regarding the role of inflammatory markers in distinguishing disease severity and need for surgery; the role of imaging in OCA evaluation; and the microbiology of OCA over the past 2 decades. METHODS: This review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Searches were performed in MEDLINE (Ovid), Web of Science Core Collection, Scopus, CINAHL (EBSCO), and Cochrane Central Register of Controlled Trials (CENTRAL), most recently on February 9, 2021. RESULTS: A total of 63 studies were included. Most were descriptive and assessed to have poor quality with high risk of bias. The existing publications evaluating inflammatory markers in the diagnosis of OCA have inconsistent results. Computed tomography imaging remains the modality of choice for evaluating orbital infection. The most common organisms recovered from intraoperative cultures are Streptococcus species (Streptococcus anginosus group, group A Streptococcus, and pneumococcus) and Staphylococcus aureus. Methicillin-resistant S aureus in culture-positive cases had a median prevalence of 3% (interquartile range, 0%-13%). CONCLUSION: This systematic review summarizes existing literature concerning inflammatory markers, imaging, and microbiology for OCA evaluation and management. High-quality evidence is still needed to define the optimal medical management of OCA.

Using Electronic Health Record Tools to Decrease Antibiotic Exposure in Infant Sepsis Evaluation.

BACKGROUND: Our internal infant sepsis evaluation clinical practice guideline recommends infants with negative culture results who are undergoing sepsis evaluation receive antibiotics until culture results are negative for a maximum of 36 hours. The aims of our project were to decrease the percentage of patients who received >30 hours of administered antibiotic doses (recognizing effective concentrations last until hour 36) and increase 36-hour phrase documentation by using clinical decision support tools. METHODS: We used quality improvement methodology to study infants aged ≤60 days with negative culture results. The outcome measures were the percentage of patients who received >30 hours of administered antibiotic doses, the percentage of history and physical (H&P) notes that included a statement of the anticipated 36-hour antibiotic discontinuation time (36-hour phrase), and length of stay. The process measure was the use of an illness-specific H&P template or an influencer smartphrase. Balancing measures were readmissions for positive culture results. Interventions included education, an illness-specific H&P template, a criteria-based rule to default to this H&P template, and editing influencer smartphrases. RESULTS: Over 33 months, 311 patients were included. Percentage of patients who received >30 hours of administered antibiotic doses decreased from 75.6% to 62%. Percentage of H&P notes documenting the 36-hour phrase increased from 4.9% to 75.6%. Illness-specific H&P template and influencer smartphrase usage increased to a mean of 51.5%; length of stay did not change. No readmissions for positive culture results were reported. CONCLUSIONS: Clinical decision support techniques and educational interventions popularized the "36-hour phrase" and were associated with a reduction in the antibiotic exposure in infants with negative culture results hospitalized for sepsis evaluation.

Blastomycosis in 64 Wisconsin Children: Unanticipated Infection Risk and Severity in Urban Residents.

BACKGROUND: Blastomycosis, an endemic mycosis of immunocompetent individuals, is typically seen after exposure to waterways within rural wooded regions. It is not considered a disease of urban environments. Infection can be solely pneumonic or disseminate to skin, bone or central nervous system. Unknown factors influence disease acquisition and severity in children. METHODS: We analyzed acquisition risks and disease characteristics of blastomycosis in children seen at a tertiary care center from 1998 to 2018 to identify potential exposure sources, measure disease severity and assess the effect of race upon disease severity. RESULTS: Of 64 infected children, mean age was 12.9 years, with median time to diagnosis 38.5 days. About 72% were male, 38% resided in urban counties and 50% had typical environmental exposure. Isolated pulmonary infection occurred in 33 (52%). The remainder had evidence of dissemination to skin (N = 13), bone (N = 16; 7 clinically silent) and cranium (N = 7; 3 clinically silent). Infection was moderate/severe in 19 (30%). Two children (3%) died. About 79% of children with moderate/severe disease (P = 0.008) and 71% of urban children (P = 0.007) lacked typical environmental exposure. Comparing children from urban counties to other residences, 63% versus 5% were black (P < 0.001) and 71% versus 35% developed extrapulmonary dissemination (P = 0.006). Moderate/severe disease was seen in 7/17 (42%) black children but only 12/47 (26%) children of other races (P = 0.23). CONCLUSIONS: Blastomycosis, can be endemic in urban children in the absence of typical exposure history, have frequent, sometimes clinically silent, extrapulmonary dissemination and possibly produces more severe disease in black children.

Nutritional Advancement in the Hospitalized Child After NPO: A Retrospective Cohort Study.

OBJECTIVES: A clear-liquid diet is commonly used after a nil per os (NPO) order in children recovering from acute gastrointestinal (GI) illnesses. Our purpose for this study was to compare outcomes in patients receiving a clear-liquid diet after an NPO order with outcomes in those receiving a regular diet. METHODS: In this retrospective cohort study, patients aged 1 to 18 years admitted to a tertiary care children's hospital between 2016 and 2017 were screened to identify those who had an NPO order placed for acute GI illnesses. Patients with complex medical needs, a feeding disorder, or chronic GI disorders were excluded. RESULTS: Of 39 total patients, 17 (44%) received a clear-liquid diet after an NPO order. There was no difference in diet tolerance between patients receiving a clear-liquid diet and those receiving a regular diet on the basis of emesis in the first 12 hours (P = .40), pain scores after the first oral intake (P = .86), return to clear-liquid diet (P = .57), or return to NPO status (P > .99). Patients started on a clear-liquid diet had a longer length of stay (LOS) after diet initiation compared with those receiving a regular diet (median: 43.7 hours [interquartile range: 29.8-53.4] vs median: 20.8 hours [interquartile range 6.7-47.3]), both in the univariate analysis (P = .01) and after controlling for age, diagnosis category, and pain score before and after the first oral intake (P = .03). CONCLUSIONS: Patients transitioned to a clear-liquid diet after NPO status have a longer LOS after the first oral intake independent of patient age, diagnosis, and pretransition abdominal pain. Both groups had similar diet tolerance, suggesting that transition to a regular diet after NPO status may decrease LOS without significant adverse effects.

Changes in Bone Mass After Discontinuation of Preexposure Prophylaxis With Tenofovir Disoproxil Fumarate/Emtricitabine in Young Men Who Have Sex With Men: Extension Phase Results of Adolescent Trials Network Protocols 110 and 113.

Human immunodeficiency virus-seronegative men aged 15-22 years who lost bone mineral density (BMD) during tenofovir disoproxil fumarate/emtricitabine preexposure prophylaxis (PrEP) showed BMD recovery 48 weeks following PrEP discontinuation. Lumbar spine and whole body BMD z-scores remained below baseline 48 weeks off PrEP in participants aged 15-19 years. Clinical Trials Registration. NCT01772823 (ATN 110) and NCT01769456 (ATN 113).

Factors Associated With HSV PCR CSF Testing and Empiric Acyclovir Therapy in Young Febrile Infants.

Herpes simplex virus (HSV) infection in infants is a devastating disease with an often subtle presentation. We examined cerebrospinal fluid (CSF) HSV PCR (polymerase chain reaction) testing and empiric acyclovir therapy in young febrile infants. Chart review identified hospitalized infants aged ≤60 days with fever ≥38°C who had undergone lumbar puncture. Previously published criteria were used to define patients at high risk for HSV. Primary outcomes were CSF HSV PCR testing and empiric acyclovir therapy. Of 536 febrile infants, 23% had HSV testing; empiric acyclovir was started in 15%. HSV testing and therapy were associated with younger age, seizure, maternal vaginal lesions, postnatal HSV contact, vesicles, poor tone, CSF pleocytosis, and enteroviral testing. Sixty-two percent of high-risk infants did not undergo HSV testing, and 75% did not receive acyclovir. High-risk infants were untested and untreated at relatively high rates. Evidence-based criteria to guide HSV testing and treatment are needed.

Short Communication: Association of Vitamin D Insufficiency and Protective Tenofovir Diphosphate Concentrations with Bone Toxicity in Adolescent Boys and Young Men Using Tenofovir Disoproxil Fumarate/Emtricitabine for HIV Pre-Exposure Prophylaxis.

We examined associations of 25-hydroxy vitamin D (25-OHD), tenofovir disoproxil fumarate (TDF), and bone toxicity. We studied TDF/emtricitabine (FTC) HIV pre-exposure prophylaxis (PrEP) in young men who have sex with men (YMSM). Bone toxicity was predefined using bone mineral density/content change from baseline to week 48. Baseline serum 25-OHD was dichotomized as <20 ng/mL (insufficient/deficient) versus ≥20 (sufficient), and week 48 dried blood spot tenofovir diphosphate (TFV-DP) as >700 fmol/punch (protective against HIV acquisition) versus ≤700. Associations were examined by univariate and multivariable logistic regression, reporting crude and adjusted odds ratios (ORs), with 95% confidence intervals (CIs). Of 101 enrolled, 69 had complete bone assessments and 25-OHD; of these, 59 had week 48 TFV-DP data. Median (Q1-Q3) age was 20 (18-21) years; 54% were black/African American. In univariate analysis, participants with baseline 25-OHD <20 ng/mL (OR = 5.4; 95% CI = 1.9-16.5) and blacks (OR = 4.9; 95% CI = 1.7-15.2) had greater odds of bone toxicity than those with 25-OHD ≥20 or other races. TFV-DP was not associated with bone toxicity (OR = 1.6; 95% CI = 0.5-5.5). In multivariable analysis, compared with those with 25-OHD ≥20 and TFV-DP ≤700, those with 25-OHD ≥20 and TFV-DP >700 (OR = 11.5; 95% CI = 1.4-169.6), 25-OHD <20 and TFV-DP ≤700 (OR = 19.4; 95% CI = 3.0-228.7), and 25-OHD <20 and TFV-DP >700 (OR = 32.3; 95% CI = 3.3-653.6) had greater odds of bone toxicity after adjusting for race. In multivariable models, 25-OHD insufficiency, protective TFV-DP concentrations, and black race were significantly associated with bone toxicity after 48 weeks of TDF/FTC PrEP in YMSM. Clinical Trials Registration: NCT01769469.

Population Pharmacokinetics of Lopinavir/Ritonavir: Changes Across Formulations and Human Development From Infancy Through Adulthood.

Lopinavir/ritonavir (LPV/r) is recommended by the World Health Organization as first-line treatment for HIV-infected infants and young children. We performed a composite population pharmacokinetic (PK) analysis on LPV plasma concentration data from 6 pediatric and adult studies to determine maturation and formulation effects from infancy to adulthood. Intensive PK data were available for infants, children, adolescents, and adults (297 intensive profiles/1662 LPV concentrations). LPV PK data included 1 adult, 1 combined pediatric-adult, and 4 pediatric studies (age 6 weeks to 63 years) with 3 formulations (gel-capsule, liquid, melt-extrusion tablets). LPV concentrations were modeled using nonlinear mixed effects modeling (NONMEM v. 7.3; GloboMax, Hanover, Maryland) with a one compartment semiphysiologic model. LPV clearance was described by hepatic plasma flow (QHP ) times hepatic extraction (EH ), with EH estimated from the PK data. Volume was scaled by linear weight (WT/70)1.0 . Bioavailability was assessed separately as a function of hepatic extraction and the fraction absorbed from the gastrointestinal tract. The absorption component of bioavailability increased with age and tablet formulation. Monte Carlo simulations of the final model using current World Health Organization weight-band dosing recommendations demonstrated that participants younger than 6 months of age had a lower area under the drug concentration-time curve (94.8 vs >107.4 µg hr/mL) and minimum observed concentration of drug in blood plasma (5.0 vs > 7.1 µg/mL) values compared to older children and adults. Although World Health Organization dosing recommendations include a larger dosage (mg/m2 ) in infants to account for higher apparent clearance, they still result in low LPV concentrations in many infants younger than 6 months of age receiving the liquid formulation.

Tenofovir disoproxil fumarate appears to disrupt the relationship of vitamin D and parathyroid hormone.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) increases serum parathyroid hormone (PTH) and 1,25 dihydroxy vitamin D (1,25-(OH)2D), and decreases bone mineral density (BMD). Optimal treatment of TDF-associated BMD loss requires an understanding of the primary cause of these abnormalities. METHODS: Secondary review of data from two studies of TDF use in youth, comparing the relationship of PTH, 25-hydroxy vitamin D (25-OHD) and 1,25-(OH)2D in three groups with varying exposures to TDF: youth without HIV enrolled in a trial of TDF/emtricitabine (FTC) for HIV pre-exposure prophylaxis (PrEP) at baseline (no TDF exposure) and after 12 weeks of TDF (short-term TDF exposure); and youth with HIV treated with TDF-containing combination antiretroviral therapy (cART) for at least 6 months at study entry (long-term TDF exposure). Relationships were evaluated by correlation analyses. RESULTS: Participants ranged in age from 17 to 24 years and >50% were Black/African American. In persons not treated with TDF, PTH had the physiologically appropriate negative correlation with 25-OHD (r=-0.3504, P=0.004). Correlations between PTH and 25-OHD in groups treated with TDF were weaker or absent. With longer term TDF treatment in persons with HIV, 25-OHD and 1,25-(OH)2D had the positive correlation similar to that found in vitamin D deficiency. CONCLUSIONS: TDF changes the relationship of 25-OHD to PTH, suggesting that in persons using TDF for PrEP or cART, a higher than usual target for serum 25-OHD concentration might be needed to reduce PTH and optimize bone health. CLINICAL TRIALS REGISTRATION: NCT01751646 (ATN 109) and NCT01769469 (ATN 117).

Vitamin D3 Supplementation Increases Spine Bone Mineral Density in Adolescents and Young Adults With Human Immunodeficiency Virus Infection Being Treated With Tenofovir Disoproxil Fumarate: A Randomized, Placebo-Controlled Trial.

Background: Tenofovir disoproxil fumarate (TDF) decreases bone mineral density (BMD). We hypothesized that vitamin D3 (VITD3) would increase BMD in youth receiving TDF. Methods: This was a randomized, double-blind, placebo-controlled trial of directly observed VITD3 vs placebo every 4 weeks for 48 weeks in youth aged 16-24 years with HIV, RNA load <200 copies/mL, taking TDF-containing combination antiretroviral therapy (TDF-cART) for ≥180 days. Participants (N = 214) received a daily multivitamin containing VITD3 400 IU and calcium 162 mg, plus monthly randomized VITD3 50000 IU (n = 109) or placebo (n = 105). Outcome was change from baseline to week 48 in lumbar spine BMD (LSBMD). Data presented are median (Q1, Q3). Results: Participants were aged 22.0 (21.0, 23.0) years, 84% were male, and 74% were black/African American. At baseline, 62% had 25-hydroxy vitamin D (25-OHD) <20 ng/mL. Multivitamin adherence was 49% (29%, 69%), and VITD3/placebo adherence 100% (100%, 100%). Vitamin D intake was 2020 (1914, 2168) and 284 (179, 394) IU/day, and serum 25-OHD concentration was 36.9 (30.5, 42.4) and 20.6 (14.4, 25.8) ng/mL at 48 weeks in VITD3 and placebo groups, respectively (P < .001). From baseline to week 48, LSBMD increased by 1.15% (-0.75% to 2.74%) in the VITD3 group (n = 99; P < .001) and 0.09% (-1.49% to 2.61%) in the placebo group (n = 89; P = .25), without between-group difference (P = .12). VITD3 group changes occurred with baseline 25-OHD <20 ng/mL (1.17% [-.82% to 2.90%]; P = .004) and ≥20 ng/mL (0.93% [-.26% to 2.15%]; P = .033). Conclusions: For youth taking TDF-cART, LSBMD increased through 48 weeks with VITD3 plus multivitamin, but not with placebo plus multivitamin, independent of baseline vitamin D status. Clinical Trials Registration: NCT01751646.

Low near infrared spectroscopic somatic oxygen saturation at admission is associated with need for lifesaving interventions among unplanned admissions to the pediatric intensive care unit.

To investigate the association between low near infrared spectroscopy (NIRS) somatic oxygen saturation (<70%) at admission and the need for lifesaving interventions (LSI) in the initial 24 h of a PICU admission. Retrospective chart review of all unplanned admissions to the pediatric intensive care unit (PICU) with NIRS somatic oxygen saturation data available within 4 h of admission, excluding admissions with a cardiac diagnosis. LSI data were collected for the first 24 h after admission. Hemodynamic parameters, laboratory values, illness severity scores and diagnoses were collected. Included PICU admissions were stratified by lowest NIRS value in the first 4 h after admission: low NIRS (<70%) and normal NIRS (≥70%) groups. Rate of LSI from 4 h to 24 h was compared between the two groups. Association of LSI with NIRS saturation and other clinical and laboratory parameters was measured by univariate and multivariate methods. We reviewed 411 consecutive unplanned admissions to the PICU of which 184 (44%) patients underwent NIRS monitoring. A higher proportion of patients who underwent somatic NIRS monitoring required LSIs compared to those without NIRS monitoring (36.4 vs 5.7% respectively, p < 0.0001). The proportion of patients who required LSI was higher in the group with low NIRS (<70%) within the first 4 h compared to those with normal NIRS (≥70%) (77.1 vs 22.1%, p < 0.0001). Fluid resuscitation, blood products and vasoactive medications were the most common LSIs. Multivariable modeling showed NIRS < 70% and heart rate > 2SD for age to be associated with LSIs. ROC curve analysis of the combination of NIRS < 70% and HR >2SD for age had an area under the curve of 0.79 with 78% sensitivity and 76% specificity for association with LSI. Compared to the normal NIRS group, the low NIRS group had higher mortality (10.4 vs 0.7%, p = 0.005) and longer median hospital length of stay (2.9 vs 1.6 days, p < 0.0001). Low somatic NIRS oxygen saturation (<70%) in the first 4 h of an unplanned PICU admission is associated with need for higher number of subsequent lifesaving interventions up to 24 h after admission. Noninvasive, continuous, somatic NIRS monitoring may identify children at high risk of medical instability.

Decline in Bone Mass With Tenofovir Disoproxil Fumarate/Emtricitabine Is Associated With Hormonal Changes in the Absence of Renal Impairment When Used by HIV-Uninfected Adolescent Boys and Young Men for HIV Preexposure Prophylaxis.

BACKGROUND: We aimed to define the relative importance of renal and endocrine changes in tenofovir disoproxil fumarate (TDF)-related bone toxicity. METHODS: In a study of daily TDF/emtricitabine (FTC) preexposure prophylaxis (PrEP) in human immunodeficiency virus (HIV)-uninfected young men who have sex with men, we measured changes from baseline in blood and urine markers of the parathyroid hormone (PTH)-vitamin D-fibroblast growth factor 23 (FGF23) axis, creatinine, and renal tubular reabsorption of phosphate (TRP). We explored the relationship of those variables to changes in bone mineral density (BMD). Tenofovir-diphosphate (TFV-DP) in red blood cells was used to categorize participants into high and low drug exposure groups. RESULTS: There were 101 participants, median age 20 years (range 15 to 22). Compared with low drug exposure, high-exposure participants showed increase from baseline in PTH and decline in FGF23 by study week 4, with no differences in creatinine, phosphate, or TRP. At 48 weeks, the median (interquartile range) percent decline in total hip BMD was greater in those with high- compared to low- exposure (-1.59 [2.77] vs +1.54 [3.34] %, respectively; P = .001); in high-exposure participants, this correlated with week 4 TFV-DP (inversely; r = -0.60, P = .002) and FGF23 (directly; r = 0.42; P = .039) but not other variables. CONCLUSIONS: These findings support the short-term renal safety of TDF/FTC PrEP in HIV-seronegative young men and suggest that endocrine disruption (PTH-FGF23) is a primary contributor to TDF-associated BMD decline in this age group. CLINICAL TRIALS REGISTRATION: NCT01769469.

An Optimized Voriconazole Dosing Strategy to Achieve Therapeutic Serum Concentrations in Children Younger than 2 Years Old.

STUDY OBJECTIVE: To describe our experience with voriconazole in three patients younger than 2 years using an optimized dosing strategy for voriconazole that incorporates intensive therapeutic drug monitoring (TDM). DESIGN: Case series. SETTING: Large pediatric hospital. PATIENTS: Three patients younger than 2 years who received voriconazole therapy and had serum trough concentrations measured between January 1, 2010, and October 31, 2015. MEASUREMENTS AND MAIN RESULTS: A clinical practice guideline developed at our institution was used to standardize initial dosing, appropriate use and timing of TDM, and dosage modifications based on TDM. TDM was used to guide dosing to achieve a target voriconazole serum trough concentration of 2-6 µg/ml. Voriconazole samples were assayed by using a high-performance liquid chromatography analytical method with solid-phase extraction. Initial dosages for the three patients were 9 mg/kg intravenously every 12 hours (one patient) and 9 mg/kg enterally twice/day (two patients). Multiple dose escalations and a more frequent dosing interval were required to achieve trough concentrations within the target range. The final dosages were 12 mg/kg intravenously every 8 hours, 17.7 mg/kg enterally 3 times/day, and 8.5 mg/kg enterally 3 times/day, respectively. In addition to voriconazole trough concentrations, TDM included evaluations for drug toxicities. Visual, neurologic, or hepatic adverse effects were not encountered in the three patients. CONCLUSION: Our data support higher initial doses and perhaps a 3 times/day dosing schedule to achieve voriconazole serum concentrations in the target range for children younger than 2 years. Implementation of a clinical practice guideline with the participation of pharmacists specializing in pharmacokinetics allows for effective use of voriconazole in young children.

Intrapleural alteplase decreases parapneumonic effusion volume in children more than saline irrigation.

OBJECTIVE: In this prospective, double-blind, randomized crossover trial, we determined the effect of intrapleural fibrinolysis with alteplase compared to that of normal saline irrigation on the thoracostomy tube output and pleural effusion volume in children with complicated parapneumonic effusion. METHODS: Twenty seven children, median age 3.5 years, referred to the interventional radiology service for thoracostomy tube drainage of a parapneumonic effusion were studied. Seventeen patients with pleural fluid thickness greater than 2 cm or >20% ipsilateral chest volume after 8 hr of thoracostomy tube drainage entered the treatment arm. They were randomized to receive alteplase 0.1 mg/kg twice a day on days 1 and 3, or on days 2 and 4, with normal saline irrigation on the alternate days. Daily pleural fluid volume measured by low dose chest computed tomography (CT) and thoracostomy tube output was compared between the saline and alteplase groups. RESULTS: Compared to normal saline irrigation, alteplase irrigation resulted in increased thoracostomy tube drainage and to a greater decline in pleural fluid volume. Earlier alteplase administration resulted in increased fluid mobilization compared to administration later in the hospital course. There were no bleeding complications. CONCLUSIONS: Intrapleural fibrinolysis with alteplase safely increases pleural drainage and decreases the volume of pleural inflammatory debris compared to intrapleural administration of normal saline. The benefit of intrapleural alteplase on decreasing the volume of pleural inflammatory debris occurs for up to 72 hr with repeated twice daily dosing.