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Trimethoprim (TMP)-sulfamethoxazole (SMX) is used to treat various types of infections, including community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) and Pneumocystis jirovecii infections in children. Pharmacokinetic (PK) data for infants and children are limited, and the optimal dosing is not known. We performed a multicenter, prospective PK study of TMP-SMX in infants and children. Separate population PK models were developed for TMP and SMX administered by the enteral route using nonlinear mixed-effects modeling. Optimal dosing was determined on the basis of the matching adult TMP exposure and attainment of the surrogate pharmacodynamic (PD) target for efficacy, a free TMP concentration above the MIC over 50% of the dosing interval. Data for a total of 153 subjects (240 samples for PK analysis) with a median postnatal age of 8 years (range, 0.1 to 20 years) contributed to the analysis for both drugs. A one-compartment model with first-order absorption and elimination characterized the TMP and SMX PK data well. Weight was included in the base model for clearance (CL/ F ) and volume of distribution ( V / F ). Both TMP and SMX CL/ F increased with age. In addition, TMP and SMX CL/ F were inversely related to the serum creatinine and albumin concentrations, respectively. The exposure achieved in children after oral administration of TMP-SMX at 8/40 mg/kg of body weight/day divided into administration every 12 h matched the exposure achieved in adults after administration of TMP-SMX at 320/1,600 mg/day divided into administration every 12 h and achieved the PD target for bacteria with an MIC of 0.5 mg/liter in >90% of infants and children. The exposure achieved in children after oral administration of TMP-SMX at 12/60 and 15/75 mg/kg/day divided into administration every 12 h matched the exposure achieved in adults after administration of TMP-SMX at 640/3,200 mg/day divided into administration every 12 h in subjects 6 to

OBJECTIVE:To evaluate the effect of anaerobic antimicrobial therapy for necrotizing enterocolitis (NEC) on clinical outcomes in very low birth weight (≤1500 g) infants.METHODS:We identified very low birth weight infants with NEC from 348 US NICUs from 1997 to 2012. Anaerobic antimicrobial therapy was defined by antibiotic exposure on the first day of NEC. We matched (1:1) infants exposed to anaerobic antimicrobial therapy with infants who were not exposed by using a propensity score stratified by NEC severity (medical and surgical). The primary composite outcome was in-hospital death or intestinal stricture. We assessed the relationship between anaerobic antimicrobial therapy and outcome by using a conditional logistic regression on the matched cohort.RESULTS:A total of 1390 infants exposed to anaerobic antimicrobial therapy were matched with 1390 infants not exposed. Mean gestational age and birth weight were 27 weeks and 946 g, respectively, and were similar in both groups. We found no significant difference in the combined outcome of death or strictures, but strictures as a single outcome were more common in the anaerobic antimicrobial therapy group (odds ratio 1.73; 95% confidence interval, 1.11–2.72). Among infants with surgical NEC, mortality was less common with anaerobic antimicrobial therapy (odds ratio 0.71; 95% confidence interval, 0.52–0.95).CONCLUSIONS:Anaerobic antimicrobial therapy was not associated with the composite outcome of death or strictures but was associated with an increase in intestinal strictures. This higher incidence of intestinal strictures may be explained by the fact that death is a competing outcome for intestinal strictures, and mortality was slightly lower in the anaerobic cohort. Infants with surgical NEC who received anaerobic antimicrobial therapy had lower mortality.

Background: Extended piperacillin-tazobactam (TZP) infusions have been associated with favorable outcomes. There are currently no pediatric dosing recommendations. Objective: To determine appropriate TZP dosing strategies in children 2 months – 6 years according to age and different minimal inhibitory concentrations (MICs). Methods: Age and weight were simulated for 1000 children. Post-hoc pharmacokinetic parameter estimates were generated using published clearance and volume of distribution data. For different dosing regimens, we estimated the probability of target attainment (PTA) over a range of MICs from 4 to 128 mg/L. The pharmacodynamic (PD) target was defined as free piperacillin concentrations above the MIC for ≥ 50% of the dosing interval. A PTA ≥ 90% was defined as optimal. Results: PTA decreased as MIC and age increased. In all age groups, standard dosing regimens (240-300 mg/kg/day, 0.5h infusions) failed to reach PTAs ≥ 90% at MICs ≥ 16 mg/L. Standard 0.5h infusions reached PTAs ≥ 90% at MICs up to 8 mg/L in infants > 2 to 6m. No 0.5h infusion reached PTAs ≥ 90% for MICs ≥ 4 mg/L in children > 6m. While none of the tested regimens were optimal at MICs > 16 mg/L in children > 6m, 100 mg/kg/dose every 6h as a 3h infusion reached PD target at MICs of 32 mg/L in infants > 2 to 6m. Conclusion: Up to MICs of 16 mg/L, 90 mg/kg/dose every 8h as a 2h infusion in infants > 2 to 6m and 100 mg/kg/dose every 8h as a 4h infusion in children > 6m-6y achieved PTAs ≥ 90%.

We hypothesized that concomitant pharmacological inhibition of the endothelin and adenosine pathway is safe and improves exercise performance in hypoxic humans, via a mechanism that does not involve augmentation of blood oxygenation. To test this hypothesis, we established safety and drug interactions for aminophylline (500 mg) plus ambrisentan (5 mg) in normoxic volunteers. Subsequently, a placebo‐controlled study was employed to test the combination in healthy resting and exercising volunteers at simulated altitude (4,267 m). No serious adverse events occurred. Drug interaction was minimal or absent. Aminophylline alleviated hypoxia‐induced headaches. Aminophylline, ambrisentan, and their combination all significantly (P < 0.05 vs. placebo) improved submaximal hypoxic exercise performance (19.5, 20.6, and 19.1% >placebo). Single‐dose ambrisentan increased blood oxygenation in resting, hypoxic subjects. We conclude that combined aminophylline and ambrisentan offer promise to safely increase exercise capacity in hypoxemic humans without relying on increasing blood oxygen availability.

Systemic juvenile idiopathic arthritis (sJIA) is a disease characterized by arthritis in children

Clindamycin is commonly prescribed to treat children with skin and skin structure infections (including those caused by community-acquired methicillin-resistant Staphylococcus aureus [CA-MRSA]), yet little is known about the pharmacokinetics (PK) across pediatric age groups. A population PK analysis was performed in NONMEM using samples collected in an opportunistic study from children receiving intravenous clindamycin per standard of care. The final model was used to optimize pediatric dosing to match adult exposure proven effective against CA-MRSA. A total of 194 plasma PK samples collected from 125 children were included in the analysis. Median age (range) was 3.3 years (0–20). Median dosing was 9.9 mg/kg/dose (3.8–15.1). A 1-compartment model described the data well. The final model included body weight and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (L/h)=13.7*(weight/70)0.75*(PMA3.1/(43.63.1+PMA3.1)); V (L)=61.8*(weight/70). Maturation reached 50% adult CL values at ~44 weeks PMA. Our findings support age-based dosing.

BackgroundChildren with sickle cell disease (SCD) are at high risk of intractable pain and severe infections despite early and aggressive drug treatment. SCD is a multisystemic disease potentially leading to liver and renal dysfunction. Altogether, those may lead to pharmacokinetic (PK) alterations, which may contribute to therapeutic failure or drug toxicity. We performed a systematic literature review to describe the current evidence on the effect of SCD on drug disposition in children.MethodsA systematic literature search was conducted by a librarian on 5 databases until 08.2018 and independently assessed by two reviewers. All full-text articles, containing PK data in children, were included. The reported differences in PK parameters between SCD and non-SCD children were examined.ResultsAmong 4213 retrieved abstracts, 50 full-text articles were assessed and 27 studies were included (13 exclusively children). Data on 15 drugs was available from which 5 were exclusively developed for SCD (impeding any comparison). From the remaining 10 drugs, a comparison of PK parameters was available in 8. Six were investigated in adults and children. Three (37.5%) showed significant PK alterations (morphine, cefotaxime,lidocaine) while 5 did not (hydroxyurea, sulfadoxine-pyrimethamine, methadone, rofecoxib,arginine butyrate). In children with SCD, clearance was higher by 42–61% for IV morphine, and by 24–62% for cefotaxime, compared with non-SCD controls. This difference led to a new dosing recommendation only for cefotaxime (400 mg/kg/day). Hepatic drug metabolism assessed by lidocaine was impaired in children with SCD compared to healthy controls.ConclusionSCD alters drug disposition of commonly used drugs but data is scarce. A significant increase in clearance of morphine and cefotaxime, two commonly used drugs in patients with SCD, suggests that recommended doses may not be sufficient to provide adequate analgesia and antimicrobial control. PK data is urgently needed to ensure adequate drug efficacy and safety in this high-risk population.ReferencesDong M, McGann PT, Mizuno T, et al. Development of a pharmacokinetic-guided dose individualization strategy for hydroxyurea treatment in children with sickle cell anaemia. Brit J Clin Pharmacol. 2016;81:742–52.Gremse DA, et al. Hepatic function as assessed by lidocaine metabolism in sickle cell disease. J Pediatr 1998;132:989–93.Dampier CD, et al. Intravenous morphine pharmacokinetics in pediatric patients with sickle cell disease. J Pediatr 1995;126:461–7.Kopecky EA, et al. Systemic exposure to morphine and the risk of acute chest syndrome in sickle cell disease. Clin Pharmacol Ther 2004;75:140–6.Maksoud E, et al. Population Pharmacokinetics of Cefotaxime and Dosage Recommendations in Children with Sickle Cell Disease. Antimicrob Agents Chemother. 2018;62: e00637–1.Disclosure(s)Nothing to disclose

Osteoarticular infections lead to significant morbidity in children. Cephalexin has in vitro activity against methicillin-susceptible Staphylococcus aureus, a predominant pathogen in osteoarticular infection. However, cephalexin pharmacokinetics (PK) and pharmacodynamics (PD) are poorly described in children. This study described cephalexin PK in children treated for osteoarticular infection and assessed the proportion of children achieving surrogate PK/PD target for efficacy in methicillin-susceptible S. aureus infection.Children with osteoarticular infection, 1 to 18 years of age, were eligible for this study if they were receiving oral cephalexin per standard of care. PK plasma samples were collected at specified times after multiple doses. PK parameters were estimated using noncompartmental analysis. PK/PD target for efficacy was calculated using the child's PK parameters, minimum inhibitory concentration (MIC) of the isolate when available and previously described MIC of 2 and 4 mg/L.Twelve children were enrolled and PK profiles were obtained from 11 of them. Median age was 7 years, and median cephalexin dose was 40 mg/kg/dose every 8 hours. Median apparent oral clearance, apparent oral volume of distribution and elimination half-life (T1/2) were 0.29 L/h/kg, 0.44 L/kg and 1.1 h, respectively. Time above MIC (TMIC) was greater than 40% of the dosing interval in 100%, 90% and 80% of the children when MICs were 0.25, 2 and 4 mg/L, respectively.Oral cephalexin achieved optimal plasma exposure and was well tolerated in children with osteoarticular infection. Correlation between osteoarticular infection clinical outcome and PK/PD parameters needs further evaluation.

Children with cystic fibrosis are commonly colonized with multi-resistant bacteria. In such patients, infectious exacerbation may require salvage therapy with uncommonly used antimicrobials, including chloramphenicol. Chloramphenicol is rarely used nowadays because of the associated severe adverse events. We describe the case of a 15-year-old female with terminal cystic fibrosis who required intravenous (IV) chloramphenicol treatment for a Burkholderia cepacia (B. cepacia) exacerbation. The child subsequently developed lactic acidosis and secondary respiratory compensation adding to her baseline respiratory distress. Based on the Naranjo scale, the probability of chloramphenicol being the cause of the hyperlactatemia and associated respiratory distress was rated as probable, as the adverse effects resolved upon discontinuation of the drug. Subsequent genotyping for mitochondrial polymorphism (G3010A) confirmed a possible susceptibility to lactic acidosis from mitochondrial RNA-inhibiting agents such as chloramphenicol. Hyperlactatemia is a rare but life threatening adverse effect that has been previously reported with chloramphenicol exposure, but is not generally thought of. Clinicians should be aware of this potentially life threatening, but reversible adverse event. Lactate should be monitored under chloramphenicol and it should be discontinued as soon as this complication is suspected, especially in patients with low respiratory reserve.

BACKGROUND AND OBJECTIVES: A new noninvasive bladder stimulation technique has been described to obtain clean-catch urine (CCU) in infants aged METHODS: A prospective cohort study was conducted in a tertiary pediatric emergency department among infants RESULTS: A total of 126 infants were included (64 boys, median age: 55 days). The CCU procedure was effective in 62 infants (49%; median time: 45 seconds). Infants 0 to 29 days; 30 to 59 days, and 60 to 89 days had more successful procedures, compared with infants >89 days (odds ratios [95% confidence interval (CI)]: 4.3 [1.4 to 13.4]; 3.2 [1.2 to 8.4]; and 4.44 [1.5 to 13.3], respectively). The contamination proportion was 16% (95% CI: 8% to 27%) in the CCU group. This proportion was not statistically different compared with the invasive method group (6%, 95% CI: 3% to 15%). CONCLUSIONS: The CCU procedure is a quick and effective noninvasive method in children aged

Plasma posaconazole exposure was assessed in 13 children who underwent a hematopoietic stem cell transplant. The median dosage was 12.5 mg/kg per day, divided into 3 doses. Of these 13 patients, 46.2% (6) and 30.8% (4) achieved concentrations higher than 0.7 and 1.25 mg/L, respectively. In children at high risk, a higher dosage might be needed to achieve target concentrations.

Background Children with Epstein–Barr virus (EBV) viremia after hematopoietic stem cell transplantation (HSCT) are at increased risk of post-transplant lymphoproliferative disease (PTLD). Our aim was to assess whether pre-emptive rituximab reduced EBV-viral load (EBV-VL) and the risk of developing PTLD. Methods We retrospectively included all children who had a positive EBV-VL within 12 months after an allogenic HSCT (2007–2015) in a single tertiary pediatric hospital. Whole blood EBV-VL was monitored weekly using a real-time PCR, during the first 100 days after HSCT and then monthly until 6 months post-HSCT or until EBV-VL became undetectable. EBV-VL clearance was defined as two negative EBV-VL at least 1 week apart. Pre-emptive rituximab was defined as a treatment administered before the occurrence of PTLD. We determined the impact of pre-emptive rituximab on EBV-VL clearance, using a marginal structural cox model, adjusting for age at transplant, time between transplant and first positive EBV-VL, in-vivo T-cell depletion at induction, value of EBV-VL at the first dose of rituximab, and the EBV-VL value at the current and previous time point. Results Of 214 children who underwent allogenic HSCT, EBV DNA was detected in 87 (41%) children. Children who received rituximab after diagnosis of PTLD were excluded, leading to a cohort of 78 children. Twenty-two (28%) children received pre-emptive rituximab. Mean (SD) age was similar in both groups (10 [5] year). First post-transplant positive EBV-VL was earlier in the pre-emptive rituximab group (mean of 55 [54] vs. 113 [96] days; P < 0.05) and first positive EBV-VL was higher in the pre-emptive rituximab group (mean of 3.4 [0.6] vs. 3.0 [0.6] log10/mL; P < 0.05). In adjusted analyses, pre-emptive rituximab was associated with a higher likelihood of EBV-VL clearance (hazard ratio 1.86; 95% confidence interval 1.10–3.14; Figure 1). Of the 10 children who developed PTLD, none had received pre-emptive rituximab. Conclusion EBV viremia is frequent in children with allogenic HSCT. Our results suggest that pre-emptive rituximab is associated with more rapid EBV-VL clearance. The effect of rituximab on the risk of PTLD needs to be better defined. Figure 1. Inverse probability of EBV viremia clearance in children. Disclosures All authors: No reported disclosures.

Background Candida is a leading cause of infection in infants on extracorporeal membrane oxygenation (ECMO). Optimal micafungin dosing is unknown in this population because ECMO can alter drug pharmacokinetics (PK). Methods To characterize micafungin pharmacokinetics and safety in infants on ECMO, we conducted an open-label pharmacokinetics trial. Infants on ECMO either received intravenous micafungin 4 mg/kg every 24 h for invasive candidiasis prophylaxis or 8 mg/kg every 24 h when a fungal infection was suspected or confirmed. We collected plasma samples after single and multiple micafungin doses. We defined the therapeutic target as the adult exposure associated with efficacy in phase III trials and the prophylactic target as one-half of the therapeutic target. Results We enrolled 12 infants (124 samples) with a median age of 59 days. Using a 1-compartment model, median weight-normalized volume of distribution and clearance were 0.64 L/kg and 0.041 L/kg/h, respectively. Dose-exposure simulations revealed that doses of 2.5 and 5 mg/kg every 24 h matched exposure targets for prophylaxis and treatment of invasive candidiasis, respectively. We did not observe any drug-related adverse events. Conclusions In infants on ECMO, micafungin volume of distribution was higher and clearance was in the upper range of previously published values for infants not on ECMO. Based on these data, we recommend dosing of 2.5 and 5 mg/kg every 24 h for prophylaxis and treatment of invasive candidiasis, respectively, to match adult exposure proven effective against Candida spp.

Background Diagnosis of Kawasaki Disease (KD) can be challenging in the absence of a confirmatory test or pathognomonic finding, especially when clinical criteria are incomplete. We recently proposed serum NT-proBNP as an adjunctive diagnostic test. Methods We retrospectively tested a new algorithm to help KD diagnosis based on NT-proBNP, coronary artery dilation (CAD) at onset, and abnormal serum albumin or C-reactive protein (CRP) levels. The goal was to assess the performance of the algorithm and compare its performance to the 2004 American Heart Association (AHA)/ American Academy of Pediatrics (AAP) algorithm. Results The algorithm was tested on 124 KD patients who had NT-proBNP on admission at our institutions between 2007 and 2013. Age at diagnosis was 3.4±3.0 years, with a median of 5 diagnostic criteria, of whom 55/124 (44%) had incomplete KD. CA complications occurred in 64 (52%) patients, with aneurysm in 14 (11%) of patients. Using this algorithm, 120/124 (97%) were to be treated: based on high NT-proBNP alone for 79 (64%), onset CAD for 14 (11%), and high CRP or low albumin levels for 27 (22%). Applying the AHA/AAP algorithm to our patients with incomplete KD, 22/47 (47%) of eligible patients would not have been referred for treatment, compared to 3/55 (5%) with the NT-proBNP algorithm, p

Staphylococci are common pathogens in the neonatal period. Increased survival of premature infants leads to prolonged hospital stay with associated risk factors for developing invasive staphylococcal disease. Challenges of diagnosing coagulase-negative staphylococcal infections result in conflicting definitions and inconsistent clinical practice. Resistance to methicillin influences the choice of empirical therapy.

Invasive fungal disease (IFD) remains life threatening in premature infants and immunocompromised children despite the recent development of new antifungal agents. Optimal dosing of antifungals is one of the few factors clinicians can control to improve outcomes of IFD. However, dosing in children cannot be extrapolated from adult data because IFD pathophysiology, immune response, and drug disposition differ from adults. We critically examined the literature on pharmacokinetics (PK) and pharmacodynamics (PD) of antifungal agents and highlight recent developments in treating pediatric IFD. To match adult exposure in pediatric patients, dosing adjustment is necessary for almost all antifungals. In young infants, the maturation of renal and metabolic functions occurs rapidly and can significantly influence drug exposure. Fluconazole clearance doubles from birth to 28 days of life and, beyond the neonatal period, agents such as fluconazole, voriconazole, and micafungin require higher dosing than in adults because of faster clearance in children. As a result, dosing recommendations are specific to bracketed ranges of age. PD principles of antifungals mostly rely on in vitro and in vivo models but very few PD studies specifically address IFD in children. The exposure-response relationship may differ in younger children compared with adults, especially in infants with invasive candidiasis who are at higher risk of disseminated disease and meningoencephalitis, and by extension severe neurodevelopmental impairment. Micafungin is the only antifungal agent for which a specific target of exposure was proposed based on a neonatal hematogenous Candida meningoencephalitis animal model. In this review, we found that pediatric data on drug disposition of newer triazoles and echinocandins are lacking, dosing of older antifungals such as fluconazole and amphotericin B products still need optimization in young infants, and that target PK/PD indices need to be clinically validated for almost all antifungals in children. A better understanding of age-specific PK and PD of new antifungals in infants and children will help improve clinical outcomes of IFD by informing dosing and identifying future research areas.

This study described the cerebrospinal fluid (CSF) exposure of vancomycin in 8 children prescribed intravenous vancomycin therapy for cerebral ventricular shunt infection. Vancomycin CSF concentrations ranged from 0.06 to 9.13 mg/L and the CSF: plasma ratio ranged from 0 to 0.66. Two of 3 children with a staphylococcal CSF infection had CSF concentrations greater than minimal inhibitory concentration at the end of the dosing interval.

Infants are therapeutic orphans. Many drugs used in infants are used "off-label", increasing the risk of drug toxicity and suboptimal efficacy in this vulnerable population. This knowledge gap in clinical pharmacology is partly attributed to challenges associated with conducting clinical trials in infants. Consequently, there is a need for novel and efficient study designs more suited to this population. Available literature describing the use of minimal-risk approaches to characterize the pharmacokinetics (PK) of drugs in infants was critically reviewed. Population PK approach with sparse sampling was found to be well established. Other, more recent alternatives, like dried blood spots sampling, opportunistic design, and the use of non-blood matrices are promising strategies with an increasing number of applications in infants. Physiologically based pharmacokinetic modeling provides valuable insight in drug disposition but still needs more prospective validation. Increasing experience with these methods provides understanding of their strengths and limitations and will help improve the design of future PK studies in infants.

BACKGROUND: The diagnosis of Kawasaki disease (KD) is challenging due to similarities with infections, which often defers clinicians from diagnosing KD and administering intravenous immunoglobulins (IVIG). However, concurrent infection was reported in 1/3 patients with complete KD. No study has evaluated the prevalence of infection in patients with incomplete clinical criteria. OBJECTIVES: The aim of the study was to describe the prevalence and nature of concurrent infections in patients with KD. DESIGN/METHODS: A retrospective study including consecutive patients suspected for KD between 2008 and 2014 in a tertiary pediatric university hospital. RESULTS: From 134 patients (3.3±2.7 yo), infectious workup was performed for 129 (96%) patients, and positive in 32 (25%). A diagnosis of infection was maintained at discharge in 28/126 (22%) patients, of which 13 (46%) had a positive workup. Infections were diagnosed in a similar proportion of patients with complete and incomplete KD (25% vs 18%, p=0.29). During clinical course, 70 (54%) patients received antibiotics, with treatment failure in 42 (63%). Patients who received antibiotics were more likely to be resistant to IVIG (34% vs 10%, p=0.001), and need steroids (20% vs 3%, p=0.006). Patients with IVIG resistance had a higher rate of coronary artery aneurysm or dilatation (69% vs 45%, p=0.03). Patients with an infectious diagnosis at discharge were less likely to received IVIG (100% vs 89%, p=0.01). NT pro-BNP Z-score, indicating myocardial inflammation, was similar between patients with and without infection (2.3±2.2 vs 2.7±1.6, p=0.37). Coronary artery dilatations (Z-score>2.5) at diagnosis were present in 6/28 (21%) of patients with infection, and 30/98 (31%) of those without infection (p=0.34), which persisted at convalescence in 2/28 (7%) and 9/98 (9%), respectively (p=0.74). Finally, coronary aneurysms were present in 1/28 (4%) of patients with infections, and 17/98 (17%) of those without (p=0.07). CONCLUSION: KD and infection are not mutually exclusive, including cases with incomplete KD criteria. Recognizing that both can coexist will hopefully ensure timely IVIG treatment for patients.

We report the case of a patient highly susceptible to invasive aspergillosis who received treatment with voriconazole (VRC). As part of therapeutic drug monitoring, VRC plasma trough concentrations were measured, showing undetectable levels (

Prevention of cytomegalovirus (CMV) disease with ganciclovir has led to decrease morbidity and mortality in hematopoietic stem cell transplant (HSCT) recipients. In the present report, we describe a case of ganciclovir treatment failure in a HSCT child who presented a refractory CMV infection despite harbouring a susceptible strain. The failure was partly attributed to sub-therapeutic plasma ganciclovir levels. Our experience emphasizes the importance of drug monitoring in immunocompromised patients.