Invasive fungal disease in children with solid tumors: An Australian multicenter 10-year review.

Invasive fungal disease (IFD) occurs less frequently during treatment for solid compared to hematological malignancies in children, and risk groups are poorly defined. Retrospective national multicenter cohort data (2004-2013) were analyzed to document prevalence, clinical characteristics, and microbiology of IFD. Amongst 2067 children treated for solid malignancy, IFD prevalence was 1.9% overall and 1.4% for proven/probable IFD. Of all IFD episodes, 42.5% occurred in patients with neuroblastoma (prevalence 7.0%). Candida species comprised 54.8% of implicated pathogens in proven/probable IFD. In children with solid tumors, IFD is rare, and predominantly caused by yeasts.Routine prophylaxis may not be warranted.

Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM.

Cryptococcosis is a major worldwide disseminated invasive fungal infection. Cryptococcosis, particularly in its most lethal manifestation of cryptococcal meningitis, accounts for substantial mortality and morbidity. The breadth of the clinical cryptococcosis syndromes, the different patient types at-risk and affected, and the vastly disparate resource settings where clinicians practice pose a complex array of challenges. Expert contributors from diverse regions of the world have collated data, reviewed the evidence, and provided insightful guideline recommendations for health practitioners across the globe. This guideline offers updated practical guidance and implementable recommendations on the clinical approaches, screening, diagnosis, management, and follow-up care of a patient with cryptococcosis and serves as a comprehensive synthesis of current evidence on cryptococcosis. This Review seeks to facilitate optimal clinical decision making on cryptococcosis and addresses the myriad of clinical complications by incorporating data from historical and contemporary clinical trials. This guideline is grounded on a set of core management principles, while acknowledging the practical challenges of antifungal access and resource limitations faced by many clinicians and patients. More than 70 societies internationally have endorsed the content, structure, evidence, recommendation, and pragmatic wisdom of this global cryptococcosis guideline to inform clinicians about the past, present, and future of care for a patient with cryptococcosis.

The Challenge of Diagnosing Invasive Pulmonary Aspergillosis in Children: A Review of Existing and Emerging Tools.

Invasive pulmonary aspergillosis remains a major cause of morbidity and mortality for immunocompromised children, particularly for patients with acute leukaemia and those undergoing haematopoietic stem cell transplantation. Timely diagnosis, using a combination of computed tomography (CT) imaging and microbiological testing, is key to improve prognosis, yet there are inherent challenges in this process. For CT imaging, changes in children are generally less specific than those reported in adults and recent data are limited. Respiratory sampling by either bronchoalveolar lavage or lung biopsy is recommended but is not always feasible in children, and serum biomarkers, including galactomannan, have important limitations. In this review we summarise the current paediatric data on available diagnostic tests for IPA and highlight key emerging diagnostic modalities with potential for future use.

Phage Therapy of Mycobacterium Infections: Compassionate Use of Phages in 20 Patients With Drug-Resistant Mycobacterial Disease.

BACKGROUND: Nontuberculous Mycobacterium infections, particularly Mycobacterium abscessus, are increasingly common among patients with cystic fibrosis and chronic bronchiectatic lung diseases. Treatment is challenging due to intrinsic antibiotic resistance. Bacteriophage therapy represents a potentially novel approach. Relatively few active lytic phages are available and there is great variation in phage susceptibilities among M. abscessus isolates, requiring personalized phage identification. METHODS: Mycobacterium isolates from 200 culture-positive patients with symptomatic disease were screened for phage susceptibilities. One or more lytic phages were identified for 55 isolates. Phages were administered intravenously, by aerosolization, or both to 20 patients on a compassionate use basis and patients were monitored for adverse reactions, clinical and microbiologic responses, the emergence of phage resistance, and phage neutralization in serum, sputum, or bronchoalveolar lavage fluid. RESULTS: No adverse reactions attributed to therapy were seen in any patient regardless of the pathogen, phages administered, or the route of delivery. Favorable clinical or microbiological responses were observed in 11 patients. Neutralizing antibodies were identified in serum after initiation of phage delivery intravenously in 8 patients, potentially contributing to lack of treatment response in 4 cases, but were not consistently associated with unfavorable responses in others. Eleven patients were treated with only a single phage, and no phage resistance was observed in any of these. CONCLUSIONS: Phage treatment of Mycobacterium infections is challenging due to the limited repertoire of therapeutically useful phages, but favorable clinical outcomes in patients lacking any other treatment options support continued development of adjunctive phage therapy for some mycobacterial infections.

Disease and economic burden of infections in hospitalised children in New South Wales, Australia.

Objectives To describe the burden of disease and hospitalisation costs in children with common infections using statewide administrative data. Methods We analysed hospitalisation prevalence and costs for 10 infections: appendicitis, cellulitis, cervical lymphadenitis, meningitis, osteomyelitis, pneumonia, pyelonephritis, sepsis, septic arthritis, and urinary tract infections in children aged <18 years admitted to hospital within New South Wales, Australia, using an activity-based management administrative dataset over three financial years (1 July 2016-30 June 2019). Results Among 339 077 admissions, 28 748 (8.48%) were coded with one of the 10 infections, associated with a total hospitalisation cost of AUD230 905 190 and a per episode median length-of-stay of 3 bed-days. Pneumonia was the most prevalent coded infection (3.1% [n = 10 524] of all admissions), followed by appendicitis (1.61%; n = 5460), cellulitis (1.22%; n = 4126) and urinary tract infections (0.94%; n = 3193). Eighty per cent of children (n = 22 529) were admitted to a non-paediatric hospital. Mean costs were increased 1.18-fold per additional bed-day, 2.14-fold with paediatric hospital admissions, and 5.49-fold with intensive care unit admissions, which were both also associated with greater total bed-day occupancy. Indigenous children comprised 9.7% of children admitted with these infections, and mean per episode costs, and median bed-days were reduced compared with non-Indigenous children (0.84 [95% CI 0.78, 0.89] and 3 (IQR: 2,5) vs 2 (IQR: 2,4), respectively. Conclusions Infections in children requiring hospitalisation contributea substantial burden of disease and cost to the community. This varies by infection, facility type, and patient demographics, and this information should be used to inform and prioritise programs to improve care for children.

Antifungal use in children with acute leukaemia: state of current evidence and directions for future research.

Invasive fungal disease (IFD) remains a common and serious complication in children treated for leukaemia. Antifungal prescription in children with leukaemia presents unique challenges, particularly due to variation in IFD risk between and within leukaemia treatment protocols, drug toxicities and interactions between antifungals and chemotherapeutic agents. With recent advances in the understanding of IFD epidemiology and large clinical trials in adults assessing antifungals for IFD treatment and prophylaxis, together with paediatric clinical and pharmacokinetic studies, there is a growing body of data to inform optimal antifungal use in children. A panel of infectious diseases and haematology-oncology clinicians with expertise in IFD management compiled a list of 10 key clinical questions following development of the 2021 Australia and New Zealand Mycology Antifungal Consensus Guidelines. A focused literature review was conducted to explore available evidence and identify gaps in knowledge to direct future research. With the changing epidemiology of IFD globally, the ongoing evolution of paediatric leukaemia treatment and the increasing availability of novel antifungal agents, advocacy for paediatric clinical studies will remain vital to optimize IFD prevention and treatment in children with leukaemia.

COVID-19 in children. II: Pathogenesis, disease spectrum and management.

The global disruption of the COVID-19 pandemic has impacted the life of every child either directly or indirectly. This review explores the pathophysiology, immune response, clinical presentation and treatment of COVID-19 in children, summarising the most up-to-date data including recent developments regarding variants of concern. The acute infection with SARS-CoV-2 is generally mild in children, whilst the post-infectious manifestations, including paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) and 'long COVID' in children, are more complex. Given that most research on COVID-19 has focused on adult cohorts and that clinical manifestations, treatment availability and impacts differ markedly in children, research that specifically examines COVID-19 in children needs to be prioritised.

COVID-19 in children: I. Epidemiology, prevention and indirect impacts.

Children globally have been profoundly impacted by the coronavirus disease 2019 (COVID-19) pandemic. This review explores the direct and indirect public health impacts of COVID-19 on children. We discuss in detail the transmission dynamics, vaccination strategies and, importantly, the 'shadow pandemic', encompassing underappreciated indirect impacts of the pandemic on children. The indirect effects of COVID-19 will have a long-term impact beyond the immediate pandemic period. These include the mental health and wellbeing risks, disruption to family income and attendant stressors including increased family violence, delayed medical attention and the critical issue of prolonged loss of face-to-face learning in a normal school environment. Amplification of existing inequities and creation of new disadvantage are likely additional sequelae, with children from vulnerable families disproportionately affected. We emphasise the responsibility of paediatricians to advocate on behalf of this vulnerable group to ensure the longer-term effects of COVID-19 public health responses on the health and wellbeing of children are fully considered.

Invasive fungal disease in children with acute myeloid leukaemia: An Australian multicentre 10-year review.

BACKGROUND: Invasive fungal disease (IFD) is a common and important complication in children with acute myeloid leukaemia (AML). We describe the epidemiology of IFD in a large multicentre cohort of children with AML. METHODS: As part of the retrospective multicentre cohort TERIFIC (The Epidemiology and Risk factors for Invasive Fungal Infections in immunocompromised Children) study, proven/probable/possible IFD episodes occurring in children with primary or relapsed/refractory AML from 2003 to 2014 were analysed. Crude IFD prevalence, clinical characteristics, microbiology and treatment were assessed. Kaplan-Meier survival analysis was used to estimate 6-month survival. RESULTS: There were 66 IFD episodes diagnosed in 63 children with AML. The majority (75.8%) of episodes occurred in the context of primary AML therapy. During primary AML therapy, the overall prevalence was 20.7% (95% CI 15.7%-26.5%) for proven/probable/possible IFD and 10.3% (95% CI 6.7%-15.0%) for proven/probable IFD. Of primary AML patients, 8.2% had IFD diagnosed during the first cycle of chemotherapy. Amongst pathogens implicated in proven/probable IFD episodes, 74.4% were moulds, over a third (37.9%) of which were non-Aspergillus spp. Antifungal prophylaxis preceded 89.4% of IFD episodes, most commonly using fluconazole (50% of IFD episodes). All-cause mortality at 6 months from IFD diagnosis was 16.7% with IFD-related mortality of 7.6% (all in cases of proven IFD). CONCLUSIONS: IFD is a common and serious complication during paediatric AML therapy. Mould infections, including non-Aspergillus spp. predominated in this cohort. A systematic approach to the identification of patients at risk, and a targeted prevention strategy for IFD is needed.

Antifungal prescribing in neonates: Using national point prevalence survey data from Australia.

We describe contemporary antifungal use in neonates, with point-prevalence survey data from the National Antimicrobial Prescribing Survey across Australian hospitals from 2014 to 2018. There were 247 antifungal prescriptions in 243 neonates in 20 hospitals, median age six days (range 0-27 days). In 219/247 prescriptions (89%) antifungals were prescribed as prophylaxis. Topical (oral) nystatin was the most frequently prescribed in 233/247 prescriptions (94%), followed by fluconazole 11/227 (4%), with substantial variation in dosing for both. Two of 243 neonates (0.8%) had invasive fungal infection. Nystatin use dominates current antifungal prescribing for Australian neonates, in contrast to other countries, and invasive fungal infection is rare. LAY SUMMARY: Novel nationwide surveillance found newborn infants in Australian hospitals commonly receive antifungal medications, mostly oral nystatin. This is given mainly to prevent rather than treat infection, which is rare. There is substantial unexplained variation in dosing of antifungal drugs nationally.

Impact of Infectious Diseases Consultation on Management and Outcome of Staphylococcus aureus Bacteremia in Children.

BACKGROUND: To examine the impact of infectious diseases consultation (IDC) on the management and outcome of Staphylococcus aureus bacteremia (SAB) in children. METHODS: A retrospective cohort study of children with SAB at a teritary pediatric hospital (January 2009-June 2015) identified by medical record review as to whether they received an IDC for SAB at the discretion of the admitting physician or surgeon was conducted. Differences in management and outcomes for those with and without IDC were evaluated, and multivariate regression analysis was used to determine factors associated with cure. RESULTS: There were 100 patients included in the analysis. Fifty-five patients received IDC and 45 had no IDC (NIDC). Appropriate directed therapy within 24 hours (54/55 = 98.2% vs 34/45 = 75.6%, P < .01), choice (54/55 = 98.2% vs 37/45 = 82.2%, P < .01), dose (54/55 = 98.2% vs 36/45 = 80%, P < .01), and duration (52/55 = 94.5% vs 24/45 = 53.3%, P < .01) of directed antibiotic therapy were appropriate in more IDC group patients. Achievement of source control in indicated cases was also more common in the IDC group (28/32 = 87.5% vs 5/26 = 19.1%, P < .01). Appropriate investigation with repeat blood cultures and echocardiograms was not significantly different. All 55 patients in the IDC group had a complete response (cure) compared with 40 of the 45 (88.9%) patients in the NIDC group: 2 patients died and 3 patients had a relapse of infection with subsequent cure. In multivariate regression analysis, methicillin-susceptible SAB and IDC were factors independently associated with cure. CONCLUSIONS: Children who received IDC for SAB in a tertiary pediatric setting were more likely to have appropriate investigations and management and had improved outcomes.

Aminoglycoside use in paediatric febrile neutropenia - Outcomes from a nationwide prospective cohort study.

Aminoglycosides are commonly prescribed to children with febrile neutropenia (FN) but their impact on clinical outcomes is uncertain and extent of guideline compliance is unknown. We aimed to review aminoglycoside prescription and additional antibiotic prescribing, guideline compliance and outcomes for children with FN. We analysed data from the Australian Predicting Infectious ComplicatioNs in Children with Cancer (PICNICC) prospective multicentre cohort study, in children <18 years with FN between November 2016 and January 2018. Impact of aminoglycoside use in the first 12 hours of FN on composite unfavourable outcome of death, ICU admission, relapse of infection or late-onset sepsis was assessed using multivariable Cox regression. The study was conducted in Australia where antimicrobial resistance among gram negative organisms is relatively low. Data from 858 episodes of FN in 462 children from 8 centres were assessed, median age 5.8 years (IQR 3.5-10.8 years). Early empiric aminoglycosides were prescribed in 255 episodes (29.7%). Guideline non-compliance was common: in 46% (184/400) of eligible episodes, patients did not receive aminoglycosides, while aminoglycosides were prescribed in 9% (39/458) of guideline-ineligible episodes. Adjusted hazard of the composite unfavourable outcome was 3.81 times higher among patients prescribed empiric aminoglycosides than among those who weren't (95% confidence interval, 1.89-7.67), with no increased risk of unfavourable outcome in eligible patients who did not receive aminoglycosides. In a large paediatric FN cohort, aminoglycoside prescription was common and was often non-compliant with guidelines. There was no evidence for improved outcome with aminoglycosides, even in those who met guideline criteria, within a low-resistance setting. Empiric aminoglycoside prescription for children with FN requires urgent review in guidelines and in national practice.

SARS-CoV-2 in children: spectrum of disease, transmission and immunopathological underpinnings.

As the SARS-CoV-2 pandemic unfolds across the globe, consistent themes are emerging with regard to aspects of SARS-CoV-2 infection and its associated disease entities in children. Overall, children appear to be less frequently infected by, and affected by, SARS-CoV-2 virus and the clinical disease COVID-19. Large epidemiological studies have revealed children represent less than 2% of the total confirmed COVID-19 cases, of whom the majority experience minimal or mild disease that do not require hospitalisation. Children do not appear to be major drivers of SARS-CoV-2 transmission, with minimal secondary virus transmission demonstrated within families, schools and community settings. There are several postulated theories regarding the relatively low SARS-CoV-2 morbidity and mortality seen in children, which largely relate to differences in immune responses compared to adults, as well as differences in angiotensin converting enzyme 2 distribution that potentially limits viral entry and subsequent inflammation, hypoxia and tissue injury. The recent emergence of a multisystem inflammatory syndrome bearing temporal and serological plausibility for an immune-mediated SARS-CoV-2-related disease entity is currently under investigation. This article summarises the current available data regarding SARS-CoV-2 and the paediatric population, including the spectrum of disease in children, the role of children in virus transmission, and host-virus factors that underpin the unique aspects of SARS-CoV-2 pathogenicity in children.

Clinical Management of Staphylococcus aureus Bacteremia in Neonates, Children, and Adolescents.

Staphylococcus aureus is a common cause of community and health care-associated bacteremia, with authors of recent studies estimating the incidence of S aureus bacteremia (SAB) in high-income countries between 8 and 26 per 100 000 children per year. Despite this, <300 children worldwide have ever been randomly assigned into clinical trials to assess the efficacy of treatment of SAB. A panel of infectious diseases physicians with clinical and research interests in pediatric SAB identified 7 key clinical questions. The available literature is systematically appraised, summarizing SAB management in children in relation to these priority clinical questions. The management of neonates, children, and adolescents with SAB is predominantly based on clinical experience and trial data extrapolated from adult studies, with limited high-quality evidence available to guide management. The optimal, comprehensive management strategies for SAB in children will remain unknown until the questions outlined are answered through prospective observational cohorts and inclusion of children with SAB in clinical trials.

Successful treatment of invasive carbapenemase-producing Enterobacteriaceae infections in children using carbapenem-aminoglycoside combination therapy: A case series.

Multidrug-resistant infections present a treatment challenge for pediatric clinicians and these infections have been associated with increased morbidity and mortality. There are very limited published data to support safe and effective treatment regimens for carbapenemase-producing Enterobacteriaceae (CPE) infections, particularly in children. We report the successful treatment of three children with invasive CPE infections using a combination of extended-infusion meropenem and amikacin.

Penicillin - getting prescribing right for children.

Penicillins are commonly prescribed to children. Recommendations in the product information may not be the most appropriate doses for children and may list clinical indications that are preferably treated with other antibiotics Reputable guidelines, for example Therapeutic Guidelines: Antibiotic, offer up-to-date advice on optimal choice, route, dosage and duration of oral penicillins in children In most instances, the child's weight should be used to calculate the dose in mg per kg without exceeding the maximum adult dose When prescribing higher weight-based doses of amoxicillin or flucloxacillin, check the volume of oral liquid required to complete a treatment course to ensure adequate supply

Epidemic and Inter-epidemic Burden of Pediatric Human Parechovirus Infection in New South Wales, Australia, 2017-2018.

BACKGROUND: Human parechovirus (HPeV) typically infects young children, and although infection is often asymptomatic, some types (eg, HPeV3) are associated with severe clinical manifestations, including central nervous system infection or sepsis-like syndrome, particularly affecting young infants. The third documented national epidemic of HPeV occurred in Australia in 2017-2018. METHODS: Four public laboratories that perform almost all of the HPeV PCR testing in New South Wales provided data regarding HPeV tests performed from July 1, 2017 to June 30, 2018. Limited demographic and clinical data were obtained from electronic medical records for laboratory test-positive cases that presented to each of the 3 pediatric hospitals in New South Wales. RESULTS: Five hundred eighty-one HPeV-positive samples obtained from 395 cases were included in the analysis. The peak of the outbreak occurred in late November 2017 (approximately 35 new cases each week), with the main HPeV epidemic occurring between the spring and summer months of September 2017 to January 2018; although this seasonality was observed primarily in infants less than 12 months of age. Among the 388 pediatric cases, almost half were younger than 2 months (188; 47%) and only 10 were children older than 2 years. The annualized estimated incidence of laboratory confirmed HPeV infection in children was approximately 142.4 cases per 100,000 children younger than 5 years in New South Wales during the epidemic season. CONCLUSIONS: The large burden of HPeV infection and disease identified in young infants in this and previous Australian studies highlight the need for more comprehensive national surveillance of HPeV infections and improved prevention strategies.

Antibiotic appropriateness and guideline adherence in hospitalized children: results of a nationwide study.

BACKGROUND: Information on the nature and appropriateness of antibiotic prescribing for children in hospitals is important, but scarce. OBJECTIVES: To analyse antimicrobial prescribing and appropriateness, and guideline adherence, in hospitalized children across Australia. PATIENTS AND METHODS: We analysed data from the National Antimicrobial Prescribing Survey (NAPS) from 2014 to 2017. Surveys were performed in hospital facilities of all types (public and private; major city, regional and remote). Participants were admitted children <18 years old. Risk factors associated with inappropriate prescribing were explored using logistic regression models. RESULTS: Among 6219 prescriptions for 3715 children in 253 facilities, 19.6% of prescriptions were deemed inappropriate. Risk factors for inappropriate prescribing included non-tertiary paediatric hospital admission [OR 1.37 (95% CI 1.20-1.55)] and non-major city hospital location [OR 1.52 (95% CI 1.30-1.77)]. Prescriptions for neonates, immunocompromised children and those admitted to an ICU were less frequently inappropriate. If a restricted antimicrobial was prescribed and not approved, the prescription was more likely to be inappropriate [OR 12.9 (95% CI 8.4-19.8)]. Surgical prophylaxis was inappropriate in 59% of prescriptions. CONCLUSIONS: Inappropriate antimicrobial prescribing in children was linked to specific risk factors identified here, presenting opportunities for targeted interventions to improve prescribing. This information, using a NAPS dataset, allows for analysis of antimicrobial prescribing among different groups of hospitalized children. Further exploration of barriers to appropriate prescribing and facilitators of best practice in this population is recommended.