RESUMO
SUMMARYFungal infections are on the rise, driven by a growing population at risk and climate change. Currently available antifungals include only five classes, and their utility and efficacy in antifungal treatment are limited by one or more of innate or acquired resistance in some fungi, poor penetration into "sequestered" sites, and agent-specific side effect which require frequent patient reassessment and monitoring. Agents with novel mechanisms, favorable pharmacokinetic (PK) profiles including good oral bioavailability, and fungicidal mechanism(s) are urgently needed. Here, we provide a comprehensive review of novel antifungal agents, with both improved known mechanisms of actions and new antifungal classes, currently in clinical development for treating invasive yeast, mold (filamentous fungi), Pneumocystis jirovecii infections, and dimorphic fungi (endemic mycoses). We further focus on inhaled antifungals and the role of immunotherapy in tackling fungal infections, and the specific PK/pharmacodynamic profiles, tissue distributions as well as drug-drug interactions of novel antifungals. Finally, we review antifungal resistance mechanisms, the role of use of antifungal pesticides in agriculture as drivers of drug resistance, and detail detection methods for antifungal resistance.
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Antifúngicos , Farmacorresistência Fúngica , Infecções Fúngicas Invasivas , Antifúngicos/uso terapêutico , Antifúngicos/farmacocinética , Antifúngicos/farmacologia , Humanos , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/microbiologia , Fungos/efeitos dos fármacos , Animais , Resultado do TratamentoRESUMO
BACKGROUND: Human metapneumovirus (hMPV) epidemiology, clinical characteristics and risk factors for poor outcome after allogeneic stem cell transplantation (allo-HCT) remain a poorly investigated area. METHODS: This retrospective multicenter cohort study examined the epidemiology, clinical characteristics, and risk factors for poor outcomes associated with human metapneumovirus (hMPV) infections in recipients of allo-HCT. RESULTS: We included 428 allo-HCT recipients who developed 438 hMPV infection episodes between January 2012 and January 2019. Most recipients were adults (93%). hMPV infections were diagnosed at a median of 373 days after allo-HCT. The infections were categorized as upper respiratory tract disease (URTD) or lower respiratory tract disease (LRTD), with 60% and 40% of cases, respectively. Patients with hMPV LRTD experienced the infection earlier in the transplant course and had higher rates of lymphopenia, neutropenia, corticosteroid use, and ribavirin therapy. Multivariate analysis identified lymphopenia and corticosteroid use (>30 mg/d) as independent risk factors for LRTD occurrence. The overall mortality at day 30 after hMPV detection was 2% for URTD, 12% for possible LRTD, and 21% for proven LRTD. Lymphopenia was the only independent risk factor associated with day 30 mortality in LRTD cases. CONCLUSIONS: These findings highlight the significance of lymphopenia and corticosteroid use in the development and severity of hMPV infections after allo-HCT, with lymphopenia being a predictor of higher mortality in LRTD cases.
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Transplante de Células-Tronco Hematopoéticas , Linfopenia , Metapneumovirus , Infecções por Paramyxoviridae , Infecções Respiratórias , Adulto , Humanos , Estudos de Coortes , Estudos Retrospectivos , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/etiologia , Infecções Respiratórias/tratamento farmacológico , Infecções por Paramyxoviridae/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Corticosteroides/uso terapêuticoRESUMO
Pneumocystis jirovecii can cause life-threatening pneumonia (PjP), and patients with haematological malignancies are at high risk of this infection. Prophylactic measures have significantly decreased morbidity and mortality, but there is a paucity of contemporary data on the incidence and clinical course of PjP in well-defined and homogenous patient populations, such as children suffering from acute lymphoblastic leukaemia (ALL). In the multi-international trial AIEOP-BFM ALL2009, PjP was diagnosed in six children (incidence 1/1000) and was associated with insufficient prophylaxis in five of them. Although none of the patients died of PjP, the long-term impact of the infection is unclear.
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Protocolos de Quimioterapia Combinada Antineoplásica , Pneumocystis carinii , Pneumonia por Pneumocystis , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Criança , Masculino , Feminino , Pré-Escolar , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adolescente , IncidênciaRESUMO
BACKGROUND: Little is known about the distribution of posaconazole in brain tissue and CSF. We therefore analysed trough concentrations of posaconazole in paediatric leukaemia patients in non-inflamed CSF. PATIENTS AND METHODS: The study included paediatric patients <18 years of age with acute leukaemia in remission who underwent repeat therapeutic lumbar punctures as part of their anti-leukaemia treatment. CSF and blood were obtained 20-24 h after dosing, and posaconazole was measured by LC-MS/MS. RESULTS: Six patients (median age: 10 years; range, 6-14) with acute lymphatic (three) or acute myeloid (three) leukaemia were included who received posaconazole gastroresistant tablets at weight-banded doses (five) or the oral solution (one). In contrast to 14 control samples, posaconazole was detectable in all 11 samples of treated patients. CSF concentrations ranged from 8.3 to 42 ng/mL with a median CSF concentration of 13.6 ng/mL. Concurrent serum concentrations were between 965 and 5177 ng/mL with a median of 1716 ng/mL. CONCLUSIONS: Trough concentrations of posaconazole in the CSF after systemic administration were low but detectable in all subjects. Concurrent serum concentrations were in the target range for prophylaxis and treatment in 100% and 90%, respectively.
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Antifúngicos , Leucemia Mieloide Aguda , Triazóis , Humanos , Criança , Cromatografia Líquida , Administração Oral , Espectrometria de Massas em Tandem , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/tratamento farmacológico , Estudos RetrospectivosRESUMO
Systemic antifungal therapy is critical for reducing the mortality from many invasive and chronic fungal infections. Triazole antifungals are the most frequently prescribed antifungals but require attention to dosing and drug interactions. Nearly 600 severe drug-drug interactions and over 1100 moderate interactions requiring dose modifications are described or anticipated with systemic antifungal agents (see https://www.aspergillus.org.uk/antifungal-drug-interactions/). In this article, we address the common and less common, but serious, drug interactions observed in clinical practice with triazole antifungals, including a group of drugs that cannot be prescribed with all or most triazole antifungals (ivabradine, ranolazine, eplerenone, fentanyl, apomorphine, quetiapine, bedaquiline, rifampicin, rifabutin, sirolimus, phenytoin and carbamazepine). We highlight interactions with drugs used in children and new agents introduced for the treatment of haematological malignancies or graft versus host disease (midostaurin, ibrutinib, ruxolitinib and venetoclax). We also summarize the multiple interactions between oral and inhaled corticosteroids and triazole antifungals, and the strategies needed to optimize the therapeutic benefits of triazole antifungal therapy while minimizing potential harm to patients.
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Antifúngicos , Interações Medicamentosas , Triazóis , Humanos , Antifúngicos/uso terapêutico , Antifúngicos/administração & dosagem , Antifúngicos/farmacologia , Triazóis/uso terapêutico , Triazóis/administração & dosagem , Micoses/tratamento farmacológico , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêuticoRESUMO
BACKGROUND: Melanomas of the central nervous system (CNS) based on neurocutaneous melanocytosis (NCM) are exceptionally rare in childhood and have been described only sporadically. Rapidly progressive disease may represent a major challenge for treating physicians, especially given the limited knowledge about this condition. This analysis aimed to increase knowledge about the occurrence and treatment of these malignancies. PROCEDURE: Data on diagnosis, treatment, and outcome of patients aged 0-18 years with CNS melanoma based on NCM recorded in the German Registry for Rare Pediatric Tumors (STEP registry) were analyzed. Additionally, published case reports on this condition were analyzed. RESULTS: In STEP, five patients with leptomeningeal melanoma based on NCM were identified, with a median age at melanoma diagnosis of 3.7 years. Various multimodal treatments were performed: (partial) resection (n = 4), irradiation (n = 2), trametinib (n = 3), different cytostatics (n = 2), and anti-GD2 immunotherapy (n = 1). All patients died between 0.3 and 0.8 years after diagnosis. Including published case reports, 27 patients were identified with a median age of 2.8 years at melanoma diagnosis (range: 0.2-16.6). Fourteen of 16 cases with reported data had a NRAS alteration (88%), particularly NRAS p.Q61K (85%). In the expanded cohort, no patient survived longer than 1 year after diagnosis despite multimodal therapy (including trametinib; n = 9), with a median survival of 0.4 years (range 0.1-0.9). CONCLUSIONS: CNS melanomas based on NCM in childhood are aggressive malignancies without curative treatment to date. Therapeutic approaches must be individualized. Genetic tumor sequencing is essential to improve understanding of tumorigenesis and potentially identify new therapeutic targets.
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Neoplasias do Sistema Nervoso Central , Melanoma , Melanose , Síndromes Neurocutâneas , Criança , Humanos , Pré-Escolar , Melanoma/genética , Sistema Nervoso Central/patologia , Síndromes Neurocutâneas/tratamento farmacológico , Síndromes Neurocutâneas/genética , Melanose/tratamento farmacológico , Melanose/etiologia , Neoplasias do Sistema Nervoso Central/complicaçõesRESUMO
BACKGROUND: Antibacterial prophylaxis in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) is controversial and not recommended by international guidelines. We analyzed relevant posttransplant outcomes following discontinuation of antibacterial prophylaxis at a major European pediatric transplant center. METHODS: The single-center retrospective audit included all pediatric allogeneic HCT patients (pts) transplanted between 2011 and 2020 before (≤2014) and after (≥2015) stopping routine antibacterial prophylaxis with penicillin, metronidazole, and ciprofloxacin upon start of the conditioning regimen. The primary endpoint was overall survival until the first hospital discharge. Secondary endpoints included the occurrence of fever; bacterial infections; and cumulative days with antibacterial agents until discharge. RESULTS: A total of 257 HCT procedures were performed in 249 pts (median age: 10 years, range, 0.2-22.5) for leukemia/lymphoma (n = 150) and nonmalignant disorders (n = 107). Of these, 104 procedures were performed before (cohort 1) and 153 after (cohort 2) stopping prophylaxis. Overall survival until discharge was 90.4% in cohort 1 and 96.1% in cohort 2 (p = .06). No differences were observed in the occurrence of fever (92.3 vs. 94.1%; p = .57) and bacterial infections (34.6 vs. 25.5%; p = .11). The median number of days on antibacterial agents was significantly lower in cohort 2 (39 vs. 34; p = .002). Detection rates of resistant organisms were overall low. CONCLUSION: In this single-center audit, the stop of routine antibacterial prophylaxis had no effect on the occurrence of fever, bacterial infections, resistant organisms, and GVHD. Overall antibiotic use was significantly reduced, and survival was noninferior to the historical control cohort.
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Infecções Bacterianas , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Adolescente , Humanos , Criança , Estudos Retrospectivos , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Antibacterianos/uso terapêutico , Infecções Bacterianas/prevenção & controleRESUMO
BACKGROUND: Vaccination against SARS-CoV-2 is recommended for cancer patients. However, long-term data on the effectiveness in the pediatric setting are lacking. METHODS: Pediatric patients < 18 years on active treatment for cancer and without prior SARS-CoV-2 infection received three doses of an mRNA vaccine. The clinical course and humoral and cellular immunity were evaluated at the end of the follow-up period of ≥ 1 year after the third dose of vaccine. RESULTS: SARS-CoV-2 infection occurred in 17 of 19 analyzed patients (median age 16.5 years) during the follow-up period (median 17 months), but no severe symptoms were seen. At ≥ 1 year after the last SARS-CoV-2 antigen exposure, 4 of 17 patients had received the recommended booster vaccine. At the end of the follow-up period, all evaluable 15 patients had anti-SARS-CoV-2 receptor-binding domain IgG antibodies. Twelve of the 15 patients had neutralizing antibody titers ≥ 1:10 against the Delta variant and 12/15 and 13/15 against the BA.1 and BA.5 variants, respectively. Specific T cells against SARS-CoV-2 antigens were seen in 9/13 patients. CONCLUSIONS: Most SARS-CoV-2-vaccinated pediatric cancer patients had SARS-CoV-2 infections and limited interest in booster vaccination. At 1 year after the last antigen exposure, which was mostly an infection, humoral immune responses remained strong. TRIAL REGISTRATION: German Clinical Trials Register DRKS00025254, May 26, 2021.
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COVID-19 , Neoplasias , Vacinas , Humanos , Criança , Adolescente , SARS-CoV-2 , COVID-19/prevenção & controle , Seguimentos , Anticorpos Antivirais , Neoplasias/terapia , VacinaçãoRESUMO
Invasive fungal diseases (IFDs) play an important role in the supportive care of paediatric patients with acute leukaemia and those undergoing allogeneic haematopoietic cell transplantation, and they are associated with significantly decreased overall survival rates in affected individuals. Relative to adults, children and adolescents are distinct in terms of host biology, predisposing conditions, presentation and epidemiology of fungal diseases, and in the pharmacology of antifungal agents. The paediatric development of antifungal agents has moved forward in a coordinated manner, and major advances have been made regarding concepts and recommendations for the prevention and treatment of IFDs. However, antifungal therapy is increasingly complex, and a solid knowledge of the available options is needed more than ever for successful management. This narrative review provides a summary of the paediatric development of agents that have been recently approved (anidulafungin, posaconazole) or are in advanced stages of development (isavuconazole). It also reviews the emerging evidence for the efficacy of echinocandins for prophylaxis of invasive aspergillosis, presents new data on alternative dosing regimens of echinocandins and voriconazole, and provides a brief overview of new antifungal agents in clinical development that are expected to be developed for paediatric patients.
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Infecções Fúngicas Invasivas , Micoses , Adolescente , Humanos , Criança , Antifúngicos/uso terapêutico , Antifúngicos/farmacologia , Micoses/tratamento farmacológico , Micoses/prevenção & controle , Micoses/microbiologia , Equinocandinas/uso terapêutico , Anidulafungina/uso terapêutico , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/prevenção & controleRESUMO
Our study in 21 pediatric cancer patients demonstrates that 3 doses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA vaccine (BioNTech/Pfizer) elicited both humoral and cellular immunity in most patients during chemotherapy. Immunity was stronger in children with solid tumors and during maintenance therapy compared to those with hematological malignancies or during intensive chemotherapy. Clinical Trials Registration.ÈGerman Registry for Clinical Trials (DRKS00025254).
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COVID-19 , Neoplasias , Criança , Humanos , Anticorpos Antivirais , COVID-19/prevenção & controle , Imunidade Celular , Vacinas de mRNA , Neoplasias/tratamento farmacológico , RNA Mensageiro , SARS-CoV-2 , VacinaçãoRESUMO
The rapid pace of name changes of medically important fungi is creating challenges for clinical laboratories and clinicians involved in patient care. We describe two sources of name change which have different drivers, at the species versus the genus level. Some suggestions are made here to reduce the number of name changes. We urge taxonomists to provide diagnostic markers of taxonomic novelties. Given the instability of phylogenetic trees due to variable taxon sampling, we advocate to maintain genera at the largest possible size. Reporting of identified species in complexes or series should where possible comprise both the name of the overarching species and that of the molecular sibling, often cryptic species. Because the use of different names for the same species will be unavoidable for many years to come, an open access online database of the names of all medically important fungi, with proper nomenclatural designation and synonymy, is essential. We further recommend that while taxonomic discovery continues, the adaptation of new name changes by clinical laboratories and clinicians be reviewed routinely by a standing committee for validation and stability over time, with reference to an open access database, wherein reasons for changes are listed in a transparent way.
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Fungos , Humanos , Filogenia , Bases de Dados Factuais , Fungos/genéticaRESUMO
BACKGROUND: Meropenem is a carbapenem antibiotic often used in pediatric intensive care units due to its broad spectrum of activity. Therapeutic drug monitoring (TDM) is a useful tool to increase the effectiveness of meropenem by adjusting the dose based on plasma levels; however, the relatively large sample volume required for TDM can limit its use in children. Therefore, this study aimed to determine meropenem concentrations and consequently perform TDM effectively using the smallest possible sample volume. Volumetric absorptive microsampling (VAMS) is a sampling technology developed to collect a small, precise volume of blood. For the applicability of VAMS in TDM, plasma concentrations must be reliably calculated from whole blood (WB) collected by VAMS. METHODS: VAMS technology using 10 µL of WB was evaluated and compared with EDTA-plasma sampling. High-performance liquid chromatography with UV detection was applied to quantify meropenem in VAMS and plasma samples after the removal of proteins by precipitation. Ertapenem was used as the internal standard. Samples were collected simultaneously from critically ill children receiving meropenem using VAMS and traditional sampling. RESULTS: It was found that no consistent factor could be determined to calculate meropenem plasma concentrations from the WB, indicating that VAMS was not reliable in the TDM of meropenem. Therefore, to reduce the required sample amount in pediatric patients, a method for quantifying meropenem from 50 µL of plasma with a lower limit of quantification of 1 mg/L was developed and successfully validated. CONCLUSIONS: A simple, reliable, and low-cost method was established using high-performance liquid chromatography-UV to determine the concentration of meropenem in 50 µL of plasma. VAMS using WB does not seem to be suitable for TDM of meropenem.
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Coleta de Amostras Sanguíneas , Espectrometria de Massas em Tandem , Humanos , Criança , Meropeném , Coleta de Amostras Sanguíneas/métodos , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida de Alta Pressão/métodos , Antibacterianos , Monitoramento de Medicamentos/métodos , Teste em Amostras de Sangue Seco/métodosRESUMO
Infections continue to be major causes of morbidity and mortality in immunocompromised children and adolescents with cancer or undergoing allogeneic hematopoietic cell transplantation. This report summarizes new clinical research data presented at the 33rd European Congress on Clinical Microbiology and Infectious Diseases on infections in this vulnerable population, with a focus on the epidemiology, diagnosis, and prevention of invasive fungal diseases and de-escalation strategies in neutropenic patients with fever of unknown origin.
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Doenças Transmissíveis , Transplante de Células-Tronco Hematopoéticas , Infecções Fúngicas Invasivas , Criança , Adolescente , Humanos , Doenças Transmissíveis/diagnóstico , Infecções Fúngicas Invasivas/diagnóstico , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/epidemiologia , Febre , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hospedeiro ImunocomprometidoRESUMO
BACKGROUND: Parvovirus B19 (B19V) infection following pediatric hematopoietic cell transplantation (HCT) is a rare complication and available data is scarce. Therefore, we present the experience with B19V Infection in allogeneic pediatric HCT recipients at our transplant center together with a systematic review of the literature. METHODS: Pediatric HCT patients with Parvovirus B19 infection treated at the University Children's Hospital Münster between 1999 and 2021 were retrospectively identified and clinical data were analyzed. Additionally, a systematic MEDLINE search to identify relevant articles was performed. RESULTS: We identified three out of 445 patients (0.6%) with B19V infection post-transplantation. B19V infection occurred in combination with other complications like Graft-versus-Host disease, additional infections, or autoimmune-mediated hemolysis potentially triggered by B19V. In one patient these complications lead to a fatal outcome. The review of the literature showed considerable morbidity of B19V infection with the potential for life-threatening complications. Most patients were treated by red blood cell transfusion and intravenous immunoglobulins (IVIG) with a high succession rate. CONCLUSION: Symptomatic B19V infection following HCT remains a rare but potentially challenging complication. A causal antiviral therapy does not exist as well as general recommendations on dosage and duration of IVIG therapy. Despite this, most patients are treated successfully with these measures. Additionally, transmission via blood or stem cell products is also rare and no general recommendations on B19V screenings exist.
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Eritema Infeccioso , Transplante de Células-Tronco Hematopoéticas , Infecções por Parvoviridae , Parvovirus B19 Humano , Humanos , Criança , Eritema Infeccioso/epidemiologia , Eritema Infeccioso/complicações , Estudos Retrospectivos , Imunoglobulinas Intravenosas/uso terapêutico , Infecções por Parvoviridae/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , DNA ViralRESUMO
Voriconazole (VCZ) is an important first-line option for management of invasive fungal diseases and approved in paediatric patients ≥24 months at distinct dosing schedules that consider different developmental stages. Information on dosing and exposures in children <24 months of age is scarce. Here we report our experience in children <24 months who received VCZ due to the lack of alternative treatment options. This retrospective analysis includes 50 distinct treatment episodes in 17 immunocompromised children aged between 3 and <24 months, who received VCZ between 2004 and 2022 as prophylaxis (14 patients; 47 episodes) or as empirical treatment (3 patients; 3 episodes) by mouth (46 episodes) or intravenously (4 episodes) based on contraindications, intolerance or lack of alternative options. Trough concentrations were measured as clinically indicated, and tolerability was assessed based on hepatic function parameters and discontinuations due to adverse events (AEs). VCZ was administered for a median duration of 10 days (range: 1-138). Intravenous doses ranged from 4.9 to 7.0 mg/kg (median: 6.5) twice daily, and oral doses from 3.8 to 29 mg/kg (median: 9.5) twice daily, respectively. The median trough concentration was 0.63 mg/L (range: 0.01-16.2; 38 samples). Only 34.2% of samples were in the recommended target range of 1-6 mg/L; 57.9% had lower and 7.9% higher trough concentrations. Hepatic function parameters analysed at baseline, during treatment and at end of treatment did not show significant changes during VCZ treatment. There was no correlation between dose and exposure or hepatic function parameters. In three episodes, VCZ was discontinued due to an AE (6%; three patients). In conclusion, this retrospective analysis reveals no signal for increased toxicity in paediatric patients <24 months of age. Empirical dosing resulted in mostly subtherapeutic exposures which emphasises the need for more systematic study of the pharmacokinetics of VCZ in this age group.
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Antifúngicos , Infecções Fúngicas Invasivas , Humanos , Criança , Lactente , Voriconazol/efeitos adversos , Antifúngicos/uso terapêutico , Estudos Retrospectivos , Infecções Fúngicas Invasivas/tratamento farmacológico , Hospedeiro ImunocomprometidoRESUMO
BACKGROUND: Optimizing antifungal therapy is important to improve outcomes in severely immunocompromised patients. OBJECTIVES: We analysed the in vitro interaction between pulmonary surfactant and antifungal agents used for management of invasive pulmonary aspergillosis. METHODS: Amphotericin B formulations, mould-active triazoles and echinocandins were tested in vitro against 24 clinical isolates of different Aspergillus spp. with and without the addition of a commercial porcine surfactant (Curosurf®; Poractant alfa, Nycomed, Austria). The data are presented as MIC or minimum effective concentration (MEC) ranges, as MIC or MEC values that inhibited 90% of the isolates (MIC90 or MEC90) and as geometric mean (GM) MIC or MEC values. RESULTS: For amphotericin B products, addition of surfactant to a final concentration of 10% led to a statistically significant reduction of the GM MIC for all Aspergillus isolates tested after 24 h (0.765 versus 0.552 mg/L; P < 0.05). For the mould-active triazoles, addition of 10% surfactant resulted in a significantly higher GM MIC at 48 h (0.625 versus 0.898 mg/L; P < 0.05). For the echinocandins, the addition of 10% surfactant led to a significantly higher GM MEC after both 24 h (0.409 versus 0.6532 mg/L; P < 0.01) and 48 h (0.527 versus 0.9378 mg/L; P < 0.01). There were no meaningful differences between individual members of the three existing classes of antifungal agents or between the different Aspergillus spp. tested. CONCLUSIONS: Using EUCAST methodology, addition of porcine surfactant up to a concentration of 10% had a minor, and presumably non-relevant, impact on the in vitro activity of antifungal agents used in prophylaxis and treatment of invasive pulmonary aspergillosis.
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Aspergilose , Infecções Fúngicas Invasivas , Surfactantes Pulmonares , Animais , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Humanos , Testes de Sensibilidade Microbiana , Surfactantes Pulmonares/uso terapêutico , SuínosRESUMO
BACKGROUND: Echinocandins are commonly used in treatment and prophylaxis of invasive fungal diseases. Intravenous daily dosing for prophylaxis in the outpatient setting can however become a hurdle for adequate compliance in the paediatric population. OBJECTIVES: Simulations were performed to assess extended twice-weekly dosing for antifungal prophylaxis using caspofungin. METHODS: A population pharmacokinetic model was developed based on previously published data from children aged 3â months to 17â years. Using the final model, Monte Carlo simulations were performed to assess the dose needed for adequate exposure in a twice-weekly setting. Mean weekly AUC0-24â h/MIC together with reported AUC0-24â h from previously reported paediatric trials were used to guide adequate exposure. RESULTS AND CONCLUSIONS: A two-compartment model with linear elimination and allometric scaling using fixed exponents was found most adequate to describe the given paediatric populations. Simulations showed that a 200â mg/m2 twice-weekly regimen with maximal 200â mg total dose should result in exposures matching registered daily dosing as well as commonly used pharmacokinetic/pharmacodynamic targets.
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Antifúngicos , Infecções Fúngicas Invasivas , Antifúngicos/farmacologia , Caspofungina , Criança , Equinocandinas , Humanos , Infecções Fúngicas Invasivas/tratamento farmacológico , Método de Monte CarloRESUMO
PURPOSE: Children and adolescents undergoing treatment for cancer or allogeneic hematopoietic cell transplantation are at increased risk for methicillin-resistant Staphylococcus aureus (MRSA). We therefore examined the occurrence and outcome of MRSA colonization and infection in patients of a large European pediatric cancer center. METHODS: In a prospective observational cohort study conducted between 2007 and 2018, nasopharyngeal swabs for culture of MRSA were obtained from all admitted patients. The primary endpoint of the study was the colonization rate over time. Secondary endpoints included genetic relatedness of isolates, time burden of isolation measures, and results of decolonization efforts. RESULTS: During the study period, MRSA screening identified 34 colonized patients (median age: 10 years; range: 0-21) without trends over time. MRSA colonization was associated with the presence of classical risk factors. There was no molecular evidence of patient-to-patient transmission. A standard MRSA eradication regimen led to a lasting eradication of the organism in 26 of 34 patients. MRSA infection occurred in two patients with no associated fatalities. CONCLUSION: Prospective monitoring revealed low rates of MRSA colonization and infection at our center. These low rates and the absence of patient-to-patient transmission support the effectiveness of the management bundle of MRSA identification, isolation, and decolonization.
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Staphylococcus aureus Resistente à Meticilina , Neoplasias , Infecções Estafilocócicas , Adolescente , Criança , Humanos , Estudos Prospectivos , Fatores de Risco , Infecções Estafilocócicas/diagnóstico , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/epidemiologiaRESUMO
Paediatric patients with cancer and those undergoing allogeneic haematopoietic cell transplantation have an increased susceptibility to invasive fungal diseases. In addition to differences in underlying conditions and comorbidities relative to adults, invasive fungal diseases in infants, children, and adolescents are unique in terms of their epidemiology, the validity of current diagnostic methods, the pharmacology and dosing of antifungal agents, and the absence of phase 3 clinical trials to provide data to guide evidence-based interventions. To re-examine the state of knowledge and to further improve invasive fungal disease diagnosis, prevention, and management, the 8th European Conference on Infections in Leukaemia (ECIL-8) reconvened a Paediatric Group to review the literature and to formulate updated recommendations according to the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and European Confederation of Medical Mycology (ECMM) grading system, which are summarised in this Review.
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Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia/terapia , Micoses/terapia , Antifúngicos/uso terapêutico , Congressos como Assunto , Guias como Assunto , Humanos , Leucemia/complicações , Leucemia/epidemiologia , Leucemia/microbiologia , Micoses/complicações , Micoses/epidemiologia , Micoses/microbiologia , Pediatria/tendênciasRESUMO
Paediatric patients with cancer and those undergoing haematopoietic cell transplantation are at high risk of bacterial infections. The 8th European Conference on Infections in Leukaemia (ECIL-8) convened a Paediatric Group to review the literature and to formulate recommendations for the use of antibiotics according to the European Society of Clinical Microbiology and Infectious Diseases grading system. The evaluation of antibacterial prophylaxis included mortality, bloodstream infection, febrile neutropenia, emergence of resistance, and adverse effects as endpoints. Initial antibacterial therapy and antibiotic de-escalation or discontinuation focused on patients with a clinically stable condition and without previous infection or colonisation by resistant bacteria, and on patients with a clinically unstable condition or with previous infection or colonisation by resistant bacteria. The final considerations and recommendations of the ECIL-8 Paediatric Group on antibacterial prophylaxis, initial therapy, and de-escalation strategies are summarised in this Policy Review.