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.

Pharmacokinetic investigations of isavuconazole in paediatric cancer patients show reduced exposure of isavuconazole after opening capsules for administration via a nasogastric tube.

OBJECTIVES: To study the isavuconazole pharmacokinetics in a real-life paediatric cohort and confirm whether the isavuconazole exposures are within the adult exposure range. Furthermore, we are the first to describe unbound isavuconazole pharmacokinetics. METHODS: In this prospective, observational study, the isavuconazole dosing regimen was as follows (IV/oral/nasogastric tube): 5.4 mg/kg isavuconazole (maximum 200 mg/dose) three times daily on Days 1 and 2, followed by 5.4 mg/kg isavuconazole (maximum 200 mg/dose) once daily. At least one pharmacokinetic curve was assessed. Non-linear mixed effects modelling was used for analysis. Monte Carlo simulations were performed with the above mentioned maintenance dose for IV administrations and a weight band dosing regimen for oral/nasogastric tube administrations: I) <18 kg (100 mg daily); II) 18-37 kg (150 mg daily); III)>37 kg (200 mg daily). RESULTS: Seventeen paediatric patients with a median age of 9 years (range 1-17) and median weight of 26.0 kg (range 8.4-78.5) were evaluated. A two-compartment model describing linear pharmacokinetics of the unbound concentrations and saturable protein binding fitted the isavuconazole concentrations best. The absolute bioavailability of isavuconazole was 41.0% (95% CI: 32.4%-50.8%). The median (IQR) simulated exposures (AUC0-24h, SS) of the total isavuconazole concentrations after IV and oral/nasogastric tube administration were 87.7 mg·h/L (70.5-105.1) and 50.3 mg·h/L (39.0-62.4), respectively. The unbound isavuconazole fraction (unbound/total) ranged from 0.5% to 2.3%. CONCLUSIONS: This study revealed low bioavailability after nasogastric tube administration with opened capsules. Isavuconazole exposures were in the expected range following IV administration. Total and unbound isavuconazole pharmacokinetics were reported with a 5-fold range in the unbound fraction.

Adoption is not associated with immunological and virological outcomes in children with perinatally acquired HIV infection in the Netherlands.

OBJECTIVES: To provide an overview of the demographics, treatment characteristics and long-term outcomes of children with perinatal HIV-1 infection (PHIV) living in the Netherlands (NL) and to specifically investigate whether outcomes differ by children's adoption status. DESIGN: A prospective population-based open cohort including children with PHIV in NL. METHODS: We included children with PHIV who had entered HIV care in NL since 2007, in view of a sharp increase in the number of adopted children with PHIV since that year. We compared the proportion with virologic suppression and CD4+T-cell count over time between the following groups of children with PHIV: adopted and born outside NL, non-adopted born in NL, and non-adopted born outside NL, using generalized estimating equations and linear mixed effects models, respectively. To account for the variation in cohort inclusion, we analyzed data of children exposed to at least one year of antiretroviral therapy (ART). RESULTS: We included 148 children (827.5 person-years of follow-up, 72% adopted, age at start care in NL 2.4 (0.5-5.3)). Under-18 mortality was zero. Over the years, a boosted PI-based regimen was most often prescribed. The use of integrase inhibitors increased since 2015. Non-adopted children born in NL were less likely to achieve virological suppression compared to adopted children (OR 0.66, 95%CI 0.51-0.86, p = 0.001), which disappeared after excluding one child with suspected treatment nonadherence (OR 0.85, 95%CI 0.57-1.25, p = 0.400). CD4+T-cell Z-score trajectories were not significantly different between groups. CONCLUSIONS: Despite considerable and increasing diversity of the population of children with PHIV in NL, geographical origin and adoption status do not seem to pose important challenges in achieving good immunological and virological outcomes.

[Carbapenems: take it when needed but leave it if you can]. / Carbapenems: inzetten als het moet, vermijden als het kan.

Surveillance data and literature have shown a worldwide increase in infections with resistant bacteria, which has led to increased prescriptions of carbapenems, which in turn has led to increased carbapenem resistance. There is also an increasing use of carbapenems in the Netherlands, a county usually very conservative in antibiotic use. Carbapenem sparing strategies are essential in an attempt to prevent further rise of infections caused by carbapenem resistant bacteria. This article discusses carbapenem sparing strategies with old forgotten antibiotics and novel antibiotics from a Dutch perspective.

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.

Mucormycosis in Children With Hematologic Malignancies: A Case Series and Review of the Literature.

BACKGROUND: Mucormycosis is classified as the third leading cause of invasive fungal disease in immunocompromised patients and is characterized by high morbidity and mortality (33%-56%). The aim of this study is to describe presentation, treatment and outcome of Dutch pediatric hemato-oncology patients recently diagnosed with mucormycosis and to review the literature to gain more insight specifically into contemporary outcome data. METHODS: Ten cases were diagnosed in the Princess Máxima Center for Pediatric Oncology from 2018 to 2021 and were retrospectively reviewed. In addition, 9 case series (n = 148) were included from literature. RESULTS: In our case series, 5 patients of 10 children (age 2-17 years) had disseminated invasive fungal disease. Four patients had localized pulmonary disease and 1 had a localized renal infection. One diagnosis was made postmortem. The underlying diseases were acute lymphoblastic leukemia (n = 6), acute myeloid leukemia (n = 2) and lymphoma (n=2). Seven patients received combination therapy comprising of a lipid amphotericin B formulation and a triazole, surgery was performed in 67%. All neutropenic patients received granulocyte transfusions and/or granulocyte colony-stimulating factor. Mucormycosis-related mortality was 20%. In the literature review, mucormycosis-related mortality was 36% for all patients and 66% for patients with disseminated disease. Survival rates were similar over the past 2 decades. The most common underlying disorder was acute lymphoblastic leukemia. Liposomal amphotericin B was the mainstay of treatment. Seventy percent of patients underwent surgery. CONCLUSIONS: Although survival of mucormycosis improved significantly overtime, it plateaued in the past decades. This series shows that with screening, early diagnostics and early antifungal and if possible surgical treatment, mortality is low and even disseminated disease is salvageable if approached aggressively with a combination of surgery and antifungal treatment. Further research focused on diagnostics, combination antifungal and adjunctive therapy is necessary to enhance the survival of mucormycosis in children.

The diagnostic value of nasal microbiota and clinical parameters in a multi-parametric prediction model to differentiate bacterial versus viral infections in lower respiratory tract infections.

BACKGROUND: The ability to accurately distinguish bacterial from viral infection would help clinicians better target antimicrobial therapy during suspected lower respiratory tract infections (LRTI). Although technological developments make it feasible to rapidly generate patient-specific microbiota profiles, evidence is required to show the clinical value of using microbiota data for infection diagnosis. In this study, we investigated whether adding nasal cavity microbiota profiles to readily available clinical information could improve machine learning classifiers to distinguish bacterial from viral infection in patients with LRTI. RESULTS: Various multi-parametric Random Forests classifiers were evaluated on the clinical and microbiota data of 293 LRTI patients for their prediction accuracies to differentiate bacterial from viral infection. The most predictive variable was C-reactive protein (CRP). We observed a marginal prediction improvement when 7 most prevalent nasal microbiota genera were added to the CRP model. In contrast, adding three clinical variables, absolute neutrophil count, consolidation on X-ray, and age group to the CRP model significantly improved the prediction. The best model correctly predicted 85% of the 'bacterial' patients and 82% of the 'viral' patients using 13 clinical and 3 nasal cavity microbiota genera (Staphylococcus, Moraxella, and Streptococcus). CONCLUSIONS: We developed high-accuracy multi-parametric machine learning classifiers to differentiate bacterial from viral infections in LRTI patients of various ages. We demonstrated the predictive value of four easy-to-collect clinical variables which facilitate personalized and accurate clinical decision-making. We observed that nasal cavity microbiota correlate with the clinical variables and thus may not add significant value to diagnostic algorithms that aim to differentiate bacterial from viral infections.

Pharmacokinetic evaluation of twice-a-week micafungin for prophylaxis of invasive fungal disease in children with acute lymphoblastic leukaemia: a prospective observational cohort study.

OBJECTIVES: To determine the pharmacokinetics of twice-a-week micafungin prophylaxis in paediatric leukaemic patients to provide the rationale for this approach. METHODS: Twice-a-week micafungin at a dose of 9 mg/kg (maximum 300 mg) was given during the leukaemic induction treatment with at least one pharmacokinetic assessment. Non-linear mixed-effects modelling was used for analysis. For model building, our paediatric data were strengthened with existing adult data. Monte Carlo simulations were performed with twice-a-week dosing regimens of 5, 7 and 9 mg/kg and flat dosing per weight band. Simulated paediatric exposures were compared with the exposure in adults after a once-daily 100 mg regimen. RESULTS: Sixty-one paediatric patients were included with a median age and weight of 4.0 years (range 1.0-17) and 19.5 kg (range 8.60-182), respectively. A two-compartment model best fitted the data. CL and central Vd were lower (P < 0.01) in paediatric patients compared with adults. Predicted exposures (AUC0-168 h) for the 5, 7 and 9 mg/kg and flat dosing per weight band regimens exceeded the adult reference exposure. CONCLUSIONS: All twice-a-week regimens appeared to result in adequate exposure for Candida therapy, with simulated exposures well above the adult reference exposure. These findings provide the rationale for the pharmacokinetic equivalence of twice-a-week and once-daily micafungin regimens. The greater micafungin exposures seem to be caused by a slower-than-anticipated CL in our paediatric leukaemic patients. The generalizability of our results for Aspergillus prophylaxis cannot be provided without assumptions on target concentrations and within-class identical efficacy.

Allogenic Hematopoietic Stem Cell Transplantation Is Feasible in Pediatric Patients with an Active or Recently Diagnosed Invasive Fungal Infection.

Data on the outcome of allogenic hematopoietic stem cell transplantation (HSCT) in pediatric patients with a history of invasive fungal infection (IFI) are limited. The aim of this study was to report on the feasibility and outcome of allogenic HSCT in pediatric patients with an active or recently diagnosed IFI. In this retrospective, single-center study, 317 children underwent an allogenic HSCT (January 2012 to June 2020), of whom 23 had an active or recent (<6 months before transplantation) diagnosis of a probable or proven IFI before HSCT. Medical records were reviewed for data collection. Descriptive statistics were performed. One-year survival was described with Kaplan-Meier analysis. Four proven and 19 probable IFIs were diagnosed. The lungs were the main site of infection (22 out of 23 patients); brain involvement was diagnosed in six patients (26.1%). Aspergillus spp. were the most frequently identified organisms. Of the four patients diagnosed with mucormycosis, three had mixed infections with Aspergillus spp. One patient was diagnosed with Alternaria sinusitis and one patient with an infection with Curvularia spp. with both pulmonary and cutaneous involvement. One year after HSCT, 18 of the 23 patients (78.3%) were alive. Four of the five patients who did not survive died of non-IFI-related causes. One patient died due to a newly developed IFI post-transplant. Three patients showed non-fatal progression of their original IFIs that required prolonged antifungal treatment. Survival of this cohort of high-risk pediatric patients who underwent allogenic HSCT with an active or recently diagnosed IFI was favorable. An active IFI or recent history of IFI should not be a contraindication for proceeding to allogenic HSCT.

Safety and efficacy of early vaccination with live attenuated measles vaccine for hematopoietic stem cell transplant recipients and solid organ transplant recipients.

BACKGROUND AND OBJECTIVE: Vaccination with the live attenuated measles vaccine is currently recommended two years after hematopoietic stem cell transplantation (HSCT) and generally contraindicated after solid organ transplantation (SOT) due to safety concerns. However, in the last few years new data on the administration of the measles vaccine to HSCT recipients less two years post-transplantation and to SOT recipients have become available. This new data may change current guidelines and practices. The objective of this review is to provide an overview of the current data on the safety and efficacy of early measles vaccination for HSCT- and SOT recipients. METHOD: PubMed and EMBASE were searched from the earliest date available through October 2019 to identify all research that reported on the safety and efficacy of measles vaccination after SOT or less than two years after HSCT. RESULTS: A total of ten studies was included in this review. In the six studies that evaluated the efficacy of measles vaccination after SOT, seroconversion rates ranged from 41 to 100% after one dose and 73 to 100% after two doses. In the four studies that evaluated the efficacy of measles vaccination less than two years after HSCT, seroconversion rates ranged from 33 to 100% after one dose and 100% after two doses. In all studies, the administration of the measles vaccine after transplantation was considered to be safe. There were no cases of infection with the attenuated vaccine strain, and there were no adverse events related to the vaccination. CONCLUSION: Data on the administration of the measles vaccine after SOT and less than two years after HSCT is scarce. However, the current data available suggest that it is efficacious and well tolerable. Therefore, early measles vaccination could be considered in selected groups of SOT- and HSCT recipients during increased measles transmission or an outbreak setting.

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.

Clinical Characteristics of Invasive Fungal Infections in Pediatric Oncology Patients With Solid Tumors.

Invasive fungal infections (IFIs) are an important cause of morbidity and mortality in children with cancer. Studies on the clinical characteristics of IFI in children with solid tumors are limited. This Dutch retrospective cohort study reviewed the medical records of 61 children with solid tumors to analyze the clinical characteristics during their full treatment period. Seven IFI episodes were reported in 6/61 patients (10%), all diagnosed with intermediate-risk or high-risk Wilms tumor or neuroblastoma. Larger studies are necessary to reveal the determinants of IFI in this group of patients and the value of fungal prophylaxis.

[An infant with a red and swollen eyelid]. / Een zuigeling met een rood en gezwollen ooglid.

An 8-month-old girl was admitted with fever and a red and swollen left eye with purulent discharge. A CT scan revealed no postseptal (orbital) involvement. Preseptal cellulitis was diagnosed. Pus culture showed that Corynebacterium bovis, normally only seen in bovine colonization. C. bovis had been transmitted by the family's pet dog.

Expert panel diagnosis demonstrated high reproducibility as reference standard in infectious diseases.

OBJECTIVE: If a gold standard is lacking in a diagnostic test accuracy study, expert diagnosis is frequently used as reference standard. However, interobserver and intraobserver agreements are imperfect. The aim of this study was to quantify the reproducibility of a panel diagnosis for pediatric infectious diseases. STUDY DESIGN AND SETTING: Pediatricians from six countries adjudicated a diagnosis (i.e., bacterial infection, viral infection, or indeterminate) for febrile children. Diagnosis was reached when the majority of panel members came to the same diagnosis, leaving others inconclusive. We evaluated intraobserver and intrapanel agreement with 6 weeks and 3 years' time intervals. We calculated the proportion of inconclusive diagnosis for a three-, five-, and seven-expert panel. RESULTS: For both time intervals (i.e., 6 weeks and 3 years), intrapanel agreement was higher (kappa 0.88, 95%CI: 0.81-0.94 and 0.80, 95%CI: NA) compared to intraobserver agreement (kappa 0.77, 95%CI: 0.71-0.83 and 0.65, 95%CI: 0.52-0.78). After expanding the three-expert panel to five or seven experts, the proportion of inconclusive diagnoses (11%) remained the same. CONCLUSION: A panel consisting of three experts provides more reproducible diagnoses than an individual expert in children with lower respiratory tract infection or fever without source. Increasing the size of a panel beyond three experts has no major advantage for diagnosis reproducibility.

Frequency and Determinants of Invasive Fungal Infections in Children With Solid and Hematologic Malignancies in a Nonallogeneic Stem Cell Transplantation Setting: A Narrative Review.

Invasive fungal infections (IFIs) are an important cause of morbidity and mortality in children with cancer. An overview of studies on the frequency and determinants of IFI in pediatric oncology patients in nonallogeneic stem cell transplantation settings is lacking. We performed a literature review in Pubmed and Embase, and included 13 prospective and 23 retrospective studies. The IFI frequency (proven/probable based on EORTC criteria) in nonallogeneic stem cell transplantation pediatric cancer patients ranged between 1.0% and 38.0%, with the highest frequencies reported in hematologic malignancies. The most common fungal species seen in the studied population was Candida, followed by Aspergillus. IFI are not well investigated in solid tumor patients. Significant recurrent determinants from univariate analysis were the diagnosis acute myeloid leukemia, (prolonged) neutropenia and an older age (above 10 years). The only 2 significant determinants based on multivariate analysis were the preceding number of days of broad-spectrum antibiotics (odds ratio, 1.05; 95% confidence interval, 1.02-1.07; P=0.0006) and the number of days of corticosteroids (odds ratio, 1.05; 95% confidence interval, 1.02-1.09; P=0.005), that were both based on a group of acute myeloid leukemia patients only. Future studies are necessary to determine the frequency and determinants of IFI in pediatric oncology including a representative number of solid tumor patients.

Fatal Carbapenem Resistance Development in Pseudomonas Aeruginosa Under Meropenem Monotherapy, Caused by Mutations in the OprD Outer Membrane Porin.

A 13-year old neutropenic boy succumbed to bacteremia and sepsis with a Pseudomonas aeruginosa strain that rapidly developed resistance to carbapenems during meropenem monotherapy. Whole genome sequencing of the susceptible and resistant blood culture isolates revealed the meropenem-resistant phenotype to be caused by truncation of the OprD gene, which added to a preexisting inactivated mexR gene.

Antibiotic misuse in respiratory tract infections in children and adults-a prospective, multicentre study (TAILORED Treatment).

Respiratory tract infections (RTI) are more commonly caused by viral pathogens in children than in adults. Surprisingly, little is known about antibiotic use in children as compared to adults with RTI. This prospective study aimed to determine antibiotic misuse in children and adults with RTI, using an expert panel reference standard, in order to prioritise the target age population for antibiotic stewardship interventions. We recruited children and adults who presented at the emergency department or were hospitalised with clinical presentation of RTI in The Netherlands and Israel. A panel of three experienced physicians adjudicated a reference standard diagnosis (i.e. bacterial or viral infection) for all the patients using all available clinical and laboratory information, including a 28-day follow-up assessment. The cohort included 284 children and 232 adults with RTI (median age, 1.3 years and 64.5 years, respectively). The proportion of viral infections was larger in children than in adults (209(74%) versus 89(38%), p < 0.001). In case of viral RTI, antibiotics were prescribed (i.e. overuse) less frequently in children than in adults (77/209 (37%) versus 74/89 (83%), p < 0.001). One (1%) child and three (2%) adults with bacterial infection were not treated with antibiotics (i.e. underuse); all were mild cases. This international, prospective study confirms major antibiotic overuse in patients with RTI. Viral infection is more common in children, but antibiotic overuse is more frequent in adults with viral RTI. Together, these findings support the need for effective interventions to decrease antibiotic overuse in RTI patients of all ages.

The needs for diagnostic imaging in cases of group A streptococcal meningitis in children: a case report and review of the literature.

Group A streptococcus (GAS) is a rare cause of bacterial meningitis in children and is associated with a high cerebral complication rate. In this case report, we present a 9-year-old girl with GAS meningitis complicated with cerebritis. Clear guidelines about choice of treatment and indications of follow-up by imaging tests are lacking, making GAS meningitis unpredictable and difficult to treat. Eventually, we found 25 paediatric cases of GAS meningitis presented in the literature and reviewed their treatment choices, outcomes and follow-up by imaging tests. Penicillin and ceftriaxone are most preferred for the treatment of GAS meningitis and adding rifampicin to the antibiotic treatment could be of potential benefit. When considering the duration of antibiotic treatment and follow-up by imaging tests, no clear recommendations were found. We found that GAS meningitis is associated with higher mortality and cerebral complication rates compared to other, more common, bacterial causes of meningitis in children. This should alert the clinician to consider imaging tests routinely, even if the patient improves clinically. We advise clinicians to routinely evaluate for possible cerebral complications through magnetic resonance imaging (MRI) scans. When cerebral complications are found, antibiotic treatment should be prolonged and adding rifampicin to the antibiotic regime may be considered.