Clinical Pharmacokinetics of Triazoles in Pediatric Patients

Triazoles represent an important class of antifungal drugs in the prophylaxis and treatment of invasive fungal disease in pediatric patients. Understanding the pharmacokinetics of triazoles in children is crucial to providing optimal care for this vulnerable population. While the pharmacokinetics is extensively studied in adult populations, knowledge on pharmacokinetics of triazoles in children is limited. New data are still emerging despite drugs already going off patent. This review aims to provide readers with the most current knowledge on the pharmacokinetics of the triazoles: fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole. In addition, factors that have to be taken into account to select the optimal dose are summarized and knowledge gaps are identified that require further research. We hope it will provide clinicians guidance to optimally deploy these drugs in the setting of a life-threatening disease in pediatric patients

Effect of Antibacterial Prophylaxis on Febrile Neutropenic Episodes and Bacterial Bloodstream Infections in Dutch Pediatric Patients with Acute Myeloid Leukemia:A Two-Center Retrospective Study

Bloodstream infections (BSIs), especially those caused by Gram-negative rods (GNR) and viridans group streptococci (VGS), are common and potentially life-threatening complications of pediatric acute myeloid leukemia (AML) treatment. Limited literature is available on prophylactic regimens. We retrospectively evaluated the effect of different antibacterial prophylaxis regimens on the incidence of febrile neutropenic (FN) episodes and bacterial BSIs. Medical records of children (0–18 years) diagnosed with de novo AML and treated at two Dutch centers from May 1998 to March 2021 were studied. Data were analyzed per chemotherapy course and consecutive neutropenic period. A total of 82 patients had 316 evaluable courses: 92 were given with single-agent ciprofloxacin, 138 with penicillin plus ciprofloxacin, and 51 with teicoplanin plus ciprofloxacin. The remaining 35 courses with various other prophylaxis regimens were not statistically compared. During courses with teicoplanin plus ciprofloxacin, significantly fewer FN episodes (43% vs. 90% and 75%; p < 0.0001) and bacterial BSIs (4% vs. 63% and 33%; p < 0.0001) occurred than with single-agent ciprofloxacin and penicillin plus ciprofloxacin, respectively. GNR and VGS BSIs did not occur with teicoplanin plus ciprofloxacin and no bacterial BSI-related pediatric intensive care unit (PICU) admissions were required, whereas, with single-agent ciprofloxacin and penicillin plus ciprofloxacin, GNR BSIs occurred in 8% and 1% (p = 0.004), VGS BSIs in 24% and 14% (p = 0.0005), and BSI-related PICU admissions were required in 8% and 2% of the courses (p = 0.029), respectively. Teicoplanin plus ciprofloxacin as antibacterial prophylaxis is associated with a lower incidence of FN episodes and bacterial BSIs. This may be a good prophylactic regimen for pediatric AML patients during treatment

Improved general health of international adoptees, but immunization status still insufficient

We studied the demographic and clinical data from 495 adopted children seen between January 2002 and January 2007 to evaluate the medical condition and immunization status of international adoptees. The data of children from Chinese origin (53.5%) were compared to children arriving from other countries. Medical problems requiring treatment were present in 42.8% of the children. Parasitic gastrointestinal infection (22.0%) and skin abnormalities (22.4%) were diagnosed most often. Hepatitis B (1.2%) and tuberculosis (1%) were documented in some children; HIV, hepatitis C, and syphilis were not seen in any of the children. Antibody levels against diphtheria and tetanus were insufficient in about half of all children, particularly in those from China. In conclusion, most adoptive children had a good general health, with only a few having major medical problems. Many adoptive children had an inadequate immunization status

Central Venous Catheter-related Bloodstream Infections Caused by Enterobacterales in Pediatric Oncology Patients: Catheter Salvage or Removal

Background: The aim was to determine whether salvage treatment with systemic antibiotics is a safe and effective strategy for Enterobacterales bloodstream infections (BSI) in pediatric oncology patients with a central venous catheter (CVC). Methods: A retrospective study was performed on oncology and stem cell recipient patients with a CVC and blood culture with Enterobacterales, at the Princess Máxima Centre for Pediatric Oncology, Utrecht, the Netherlands. Analyses were performed for all BSI and for episodes meeting central line-associated bloodstream infection (CLABSI) criteria. The cumulative incidence of an event (ie, removal, intensive care admission or death) was estimated after blood culture collection for episodes primarily treated with antibiotics. The effect of prognostic factors on the hazard of the event of interest was assessed by estimating a Cox proportional hazard regression model. Results: In total, 95 CVC-related Enterobacterales BSIs in 82 patients were included; 12 (13%) BSIs required immediate CVC removal and for 83 (87%) BSIs CVC salvage was attempted. The cumulative incidence of events at 60 days was 53.0% [95% confidence interval (CI): 41.7-63.1] for BSIs (n = 83), and 64.4% (95% CI: 48.3-76.7) for CLABSIs (n = 45). The events occurred after a median of 6 (Q1-Q3: 2-15) and 6 (Q1-Q3: 2-20) days for BSIs and CLABSIs, respectively. Intensive care admission after salvage treatment was required in 16% of the BSIs and CLABSIs, resulting in death in 5% and 2% of cases, respectively. No significant association between risk factors and events was found. Conclusions: The cumulative incidence of an event at 60 days after salvage treatment for Enterobacterales CLABSIs and BSIs in pediatric oncology patients is high. Immediate CVC removal appears recommendable for this patient group

The Role of Toll-Like Receptor 2 in Inflammation and Fibrosis during Progressive Renal Injury

Tissue fibrosis and chronic inflammation are common causes of progressive organ damage, including progressive renal disease, leading to loss of physiological functions. Recently, it was shown that Toll-like receptor 2 (TLR2) is expressed in the kidney and activated by endogenous danger signals. The expression and function of TLR2 during renal fibrosis and chronic inflammation has however not yet been elucidated. Therefore, we studied TLR2 expression in human and murine progressive renal diseases and explored its role by inducing obstructive nephropathy in TLR2−/− or TLR2+/+ mice. We found that TLR2 is markedly upregulated on tubular and tubulointerstitial cells in patients with chronic renal injury. In mice with obstructive nephropathy, renal injury was associated with a marked upregulation and change in distribution of TLR2 and upregulation of murine TLR2 danger ligands Gp96, biglycan, and HMGB1. Notably, TLR2 enhanced inflammation as reflected by a significantly reduced influx of neutrophils and production of chemokines and TGF-β in kidneys of TLR2−/− mice compared with TLR2+/+ animals. Although, the obstructed kidneys of TLR2−/− mice had less interstitial myofibroblasts in the later phase of obstructive nephropathy, tubular injury and renal matrix accumulation was similar in both mouse strains. Together, these data demonstrate that TLR2 can initiate renal inflammation during progressive renal injury and that the absence of TLR2 does not affect the development of chronic renal injury and fibrosis

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The 'omics' approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n = 20) and confirmed viral infection (n = 20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group. A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics

Opportunistic infections in immunosuppressed patients with juvenile idiopathic arthritis: Analysis by the Pharmachild Safety Adjudication Committee

Background: To derive a list of opportunistic infections (OI) through the analysis of the juvenile idiopathic arthritis (JIA) patients in the Pharmachild registry by an independent Safety Adjudication Committee (SAC). Methods: The SAC (3 pediatric rheumatologists and 2 pediatric infectious disease specialists) elaborated and approved by consensus a provisional list of OI for use in JIA. Through a 5 step-procedure, all the severe and serious infections, classified as per MedDRA dictionary and retrieved in the Pharmachild registry, were evaluated by the SAC by answering six questions and adjudicated with the agreement of 3/5 specialists. A final evidence-based list of OI resulted by matching the adjudicated infections with the provisional list of OI. Results: A total of 772 infectious events in 572 eligible patients, of which 335 serious/severe/very severe non-OI and 437 OI (any intensity/severity), according to the provisional list, were retrieved. Six hundred eighty-two of 772 (88.3%) were adjudicated as infections, of them 603/682 (88.4%) as common and 119/682 (17.4%) as OI by the SAC. Matching these 119 opportunistic events with the provisional list, 106 were confirmed by the SAC as OI, and among them infections by herpes viruses were the most frequent (68%), followed by tuberculosis (27.4%). The remaining events were divided in the groups of non-OI and possible/patient and/or pathogen-related OI. Conclusions: We found a significant number of OI in JIA patients on immunosuppressive therapy. The proposed list of OI, created by consensus and validated in the Pharmachild cohort, could facilitate comparison among future pharmacovigilance studies. Trial registration: Clinicaltrials.gov NCT 01399281; ENCePP seal: awarded on 25 November 2011

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection ar

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children