Liposomal amphotericin B-the present.

Most invasive fungal infections are opportunistic in nature but the epidemiology is constantly changing, with new risk groups being identified. Neutropenia is a classical risk factor for fungal infections, while critically ill patients in the ICU are now increasingly at risk of yeast and mould infections. Factors to be considered when choosing antifungal treatment include the emergence of rarer fungal pathogens, the risk of resistance to azoles and echinocandins and the possibility of drug-drug interactions. Liposomal amphotericin B has retained its place in the therapeutic armamentarium based on its clinical profile: a broad spectrum of antifungal activity with a low risk of resistance, predictable pharmacokinetics with a rapid accumulation at the infection site (including biofilms), a low potential for drug-drug interactions and a low risk of acute and chronic treatment-limiting toxicities versus other formulations of amphotericin B. It is a suitable choice for the first-line empirical or pre-emptive treatment of suspected fungal infections in neutropenic haematology patients and is an excellent alternative for patients with documented fungal disease who can no longer tolerate or continue their first-line azole or echinocandin therapy, both in the haematology setting and in the ICU. Moreover, it is the first-line drug of choice for the treatment of invasive mucormycosis. Finally, liposomal amphotericin B is one of the few antifungal agents approved for use in children of all ages over 1 month and is included in paediatric-specific guidelines for the management of fungal disease.

The impact of anti-mould prophylaxis on Aspergillus PCR blood testing for the diagnosis of invasive aspergillosis.

BACKGROUND: The performance of the galactomannan enzyme immunoassay (GM-EIA) is impaired in patients receiving mould-active antifungal therapy. The impact of mould-active antifungal therapy on Aspergillus PCR testing needs to be determined. OBJECTIVES: To determine the influence of anti-mould prophylaxis (AMP) on the performance of PCR blood testing to aid the diagnosis of proven/probable invasive aspergillosis (IA). METHODS: As part of the systematic review and meta-analysis of 22 cohort studies investigating Aspergillus PCR blood testing in 2912 patients at risk of IA, subgroup analysis was performed to determine the impact of AMP on the accuracy of Aspergillus PCR. The incidence of IA was calculated in patients receiving and not receiving AMP. The impact of two different positivity thresholds (requiring either a single PCR positive test result or ≥2 consecutive PCR positive test results) on accuracy was evaluated. Meta-analytical pooling of sensitivity and specificity was performed by logistic mixed-model regression. RESULTS: In total, 1661 (57%) patients received prophylaxis. The incidence of IA was 14.2%, significantly lower in the prophylaxis group (11%-12%) compared with the non-prophylaxis group (18%-19%) (P < 0.001). The use of AMP did not affect sensitivity, but significantly decreased specificity [single PCR positive result threshold: 26% reduction (P = 0.005); ≥2 consecutive PCR positive results threshold: 12% reduction (P = 0.019)]. CONCLUSIONS: Contrary to its influence on GM-EIA, AMP significantly decreases Aspergillus PCR specificity, without affecting sensitivity, possibly as a consequence of AMP limiting the clinical progression of IA and/or leading to false-negative GM-EIA results, preventing the classification of probable IA using the EORTC/MSGERC definitions.

Prospective multicenter international surveillance of azole resistance in Aspergillus fumigatus.

To investigate azole resistance in clinical Aspergillus isolates, we conducted prospective multicenter international surveillance. A total of 3,788 Aspergillus isolates were screened in 22 centers from 19 countries. Azole-resistant A. fumigatus was more frequently found (3.2% prevalence) than previously acknowledged, causing resistant invasive and noninvasive aspergillosis and severely compromising clinical use of azoles.

Systemic antifungal prescribing in neonates and children: outcomes from the Antibiotic Resistance and Prescribing in European Children (ARPEC) Study.

The appropriate use of systemic antifungals is vital in the prevention and treatment of invasive fungal infection (IFI) in immunosuppressed children and neonates. This multicenter observational study describes the inpatient prescribing practice of antifungal drugs for children and neonates and identifies factors associated with prescribing variability. A single-day point prevalence study of antimicrobial use in hospitalized neonates and children was performed between October and December 2012. The data were entered through a study-specific Web-based portal using a standardized data entry protocol. Data were recorded from 17,693 patients from 226 centers. A total of 136 centers recorded data from 1,092 children and 380 neonates receiving at least one antifungal agent. The most frequently prescribed systemic antifungals were fluconazole (n=355) and amphotericin B deoxycholate (n=195). The most common indications for antifungal administration in children were medical prophylaxis (n=325), empirical treatment of febrile neutropenia (n=122), and treatment of confirmed or suspected IFI (n=100 [14%]). The treatment of suspected IFI in low-birthweight neonates accounted for the majority of prescriptions in the neonatal units (n=103). An analysis of variance (ANOVA) demonstrated no significant effect of clinical indication (prophylaxis or treatment of systemic or localized infection) on the total daily dose (TDD). Fewer than one-half of the patients (n=371) received a TDD within the dosing range recommended in the current guidelines. Subtherapeutic doses were prescribed in 416 cases (47%). The predominance of fluconazole and high incidence of subtherapeutic doses in participating hospitals may contribute to suboptimal clinical outcomes and an increased predominance of resistant pathogenic fungi. A global consensus on antifungal dosing and coordinated stewardship programs are needed to promote the consistent and appropriate use of antifungal drugs in neonates and children.

Dynamics of nasopharyngeal bacterial colonisation in HIV-exposed young infants in Tanzania.

OBJECTIVES: To estimate the prevalence of nasopharyngeal bacterial colonisation (NPBC) patterns in young Tanzanian HIV-exposed infants and to analyse the influence of maternal NPBC and of the infant's HIV status on the NPBC pattern. METHODS: Longitudinal cohort study of neonates born to HIV-infected mothers visiting Kilimanjaro Christian Medical Centre, Tanzania, between 2005 and 2009. Demographic and clinical data and nasopharyngeal bacterial cultures were obtained at the age of 6 weeks, 3 and 6 months, and at one time point, a paired mother-infant nasopharyngeal swab was taken. RESULTS: Four hundred and twenty-two swabs were taken from 338 eligible infants. At 6 weeks of age, colonisation rates were 66% for Staphylococcus aureus, 56% for Streptococcus pneumoniae, 50% for Moraxella catarrhalis and 14% for Haemophilus influenzae. Colonisation with S. aureus diminished over time and was more common in HIV-infected infants. S. pneumoniae and H. influenzae colonisation rose over time and was more prevalent in HIV-uninfected children. Co-colonisation of S. pneumoniae with H. influenzae or M. catarrhalis was mostly noticed in HIV-infected infants. S. pneumoniae and M.catarrhalis colonisation of the mother was a risk factor for colonisation in HIV-uninfected infants, while maternal S. aureus colonisation was a risk factor for colonisation in HIV-infected infants. Among the 104 S. pneumoniae isolates, 19F was most prevalent, and 57 (55%) displayed capsular serotypes represented in the 13-valent pneumococcal conjugate vaccine. CONCLUSIONS: NPBC was common in Tanzanian HIV-exposed infants. The significant prevalence of pneumococcal vaccine serotypes colonising this paediatric population justifies the use of the 13-valent pneumococcal vaccine to reduce the burden of pneumococcal invasive disease.

Pharmacokinetics of anti-tuberculosis drugs in Venezuelan children younger than 16 years of age: supportive evidence for the implementation of revised WHO dosing recommendations.

OBJECTIVES: The World Health Organization (WHO) recently issued revised first-line antituberculosis (anti-TB) drug dose recommendations for children, with dose increases proposed for each drug. No pharmacokinetic data are available from South American children. We examined the need for implementation of these revised guidelines in Venezuela. METHODS: Plasma isoniazid, rifampicin, pyrazinamide and ethambutol concentrations were assessed prior to and at 2, 4 and 8 h after intake of TB drugs by 30 TB patients aged 1-15 years. The effects of dose in mg/kg, age, sex, body weight, malnutrition and acetylator phenotype on maximum plasma drug concentrations (Cmax) and exposure (AUC0-24) were determined. RESULTS: 25 patients (83%) had an isoniazid Cmax below 3 mg/l and 23 patients (77%) had a rifampicin Cmax below 8 mg/l. One patient (3%) had a pyrazinamide Cmax below 20 mg/l. The low number of patients on ethambutol (n = 5) precluded firm conclusions. Cmax and AUC0-24 of all four drugs were significantly and positively correlated with age and body weight. Patients aged 1-4 years had significantly lower Cmax and AUC0-24 values for isoniazid and rifampicin and a trend to lower values for pyrazinamide compared to those aged 5-15 years. The geometric mean AUC0-24 for isoniazid was much lower in fast acetylators than in slow acetylators (5.2 vs. 12.0, P < 0.01). CONCLUSION: We provide supportive evidence for the implementation of the revised WHO pediatric TB drug dose recommendations in Venezuela. Follow-up studies are needed to describe the corresponding plasma levels that are achieved by the recommended increased doses of TB drugs.

Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide.

Artemis deficiency is known to result in classical T-B- severe combined immunodeficiency (SCID) in case of Artemis null mutations, or Omenn's syndrome in case of hypomorphic mutations in the Artemis gene. We describe two unrelated patients with a relatively mild clinical T-B- SCID phenotype, caused by different homozygous Artemis splice-site mutations. The splice-site mutations concern either dysfunction of a 5' splice-site or an intronic point mutation creating a novel 3' splice-site, resulting in mutated Artemis protein with residual activity or low levels of wild type (WT) Artemis transcripts. During the first 10 years of life, the patients suffered from recurrent infections necessitating antibiotic prophylaxis and intravenous immunoglobulins. Both mutations resulted in increased ionizing radiation sensitivity and insufficient variable, diversity and joining (V(D)J) recombination, causing B-lymphopenia and exhaustion of the naive T-cell compartment. The patient with the novel 3' splice-site had progressive granulomatous skin lesions, which disappeared after stem cell transplantation (SCT). We showed that an alternative approach to SCT can, in principle, be used in this case; an antisense oligonucleotide (AON) covering the intronic mutation restored WT Artemis transcript levels and non-homologous end-joining pathway activity in the patient fibroblasts.

Respiratory medicines for children: current evidence, unlicensed use and research priorities.

This European Respiratory Society task force has reviewed the evidence for paediatric medicines in respiratory disease occurring in adults and children. We describe off-licence use, research priorities and ongoing studies. Off-licence and off-label prescribing in children is widespread and potentially harmful. Research areas in asthma include novel formulations and regimens, and individualised prescribing. In cystic fibrosis, future studies will focus on screened infants and robust outcome measures are needed. Other areas include new enzyme and antibiotic formulations and the basic defect. Research into pneumonia should include evaluation of new antibacterials and regimens, rapid diagnostic tests and, in pleural infection, antibiotic penetration, fibrinolytics and surveillance. In uncommon conditions, such as primary ciliary dyskinesia, congenital pulmonary abnormalities or neuromuscular disorders, drugs indicated for other conditions (e.g. dornase alfa) are commonly used and trials are needed. In neuromuscular disorders, the beta-agonists may enhance muscle strength and are in need of evaluation. Studies of antibiotic prophylaxis, immunoglobulin and antifungal drugs are needed in immune deficiency. We hope that this summary of the evidence for respiratory medicines in children, highlighting gaps and research priorities, will be useful for the pharmaceutical industry, the paediatric committee of the European Medicines Agency, academic investigators and the lay public.

ESCMID-ECMM guideline: diagnosis and management of invasive aspergillosis in neonates and children.

SCOPE: Presenting symptoms, distributions and patterns of diseases and vulnerability to invasive aspergillosis (IA) are similar between children and adults. However, differences exist in the epidemiology and underlying conditions, the usefulness of newer diagnostic tools, the pharmacology of antifungal agents and in the evidence from interventional phase 3 clinical trials. Therefore, the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) and the European Confederation of Medical Mycology (ECMM) have developed a paediatric-specific guideline for the diagnosis and management of IA in neonates and children. METHODS: Review and discussion of the scientific literature and grading of the available quality of evidence was performed by the paediatric subgroup of the ESCMID-ECMM-European Respiratory Society (ERS) Aspergillus disease guideline working group, which was assigned the mandate for the development of neonatal- and paediatric-specific recommendations. QUESTIONS: Questions addressed by the guideline included the epidemiology of IA in neonates and children; which paediatric patients may benefit from antifungal prophylaxis; how to diagnose IA in neonates and children; which antifungal agents are available for use in neonates and children; which antifungal agents are suitable for prophylaxis and treatment of IA in neonates and children; what is the role of therapeutic drug monitoring of azole antifungals; and which management strategies are suitable to be used in paediatric patients. This guideline provides recommendations for the diagnosis, prevention and treatment of IA in the paediatric population, including neonates. The aim of this guideline is to facilitate optimal management of neonates and children at risk for or diagnosed with IA.

Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline.

The European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology and the European Respiratory Society Joint Clinical Guidelines focus on diagnosis and management of aspergillosis. Of the numerous recommendations, a few are summarized here. Chest computed tomography as well as bronchoscopy with bronchoalveolar lavage (BAL) in patients with suspicion of pulmonary invasive aspergillosis (IA) are strongly recommended. For diagnosis, direct microscopy, preferably using optical brighteners, histopathology and culture are strongly recommended. Serum and BAL galactomannan measures are recommended as markers for the diagnosis of IA. PCR should be considered in conjunction with other diagnostic tests. Pathogen identification to species complex level is strongly recommended for all clinically relevant Aspergillus isolates; antifungal susceptibility testing should be performed in patients with invasive disease in regions with resistance found in contemporary surveillance programmes. Isavuconazole and voriconazole are the preferred agents for first-line treatment of pulmonary IA, whereas liposomal amphotericin B is moderately supported. Combinations of antifungals as primary treatment options are not recommended. Therapeutic drug monitoring is strongly recommended for patients receiving posaconazole suspension or any form of voriconazole for IA treatment, and in refractory disease, where a personalized approach considering reversal of predisposing factors, switching drug class and surgical intervention is also strongly recommended. Primary prophylaxis with posaconazole is strongly recommended in patients with acute myelogenous leukaemia or myelodysplastic syndrome receiving induction chemotherapy. Secondary prophylaxis is strongly recommended in high-risk patients. We strongly recommend treatment duration based on clinical improvement, degree of immunosuppression and response on imaging.

Tongue reconstruction: recent advances.

PURPOSE OF REVIEW: To examine the recent literature concerning advances in tongue reconstruction after tumor resection. RECENT FINDINGS: Reconstruction following resection of malignant tongue tumors remains one of the most difficult problems in head and neck oncology. Recent trends in tongue reconstruction have focused on optimizing speech and swallowing function and maximizing quality of life. In the recent literature, several new reconstructive strategies including omohyoid musculocutaneous and myofascial flaps overlayed with radial forearm free flaps have been described. In addition, several older reconstructive options, such as trapezius and pectoralis rotational flaps, have been revisited. There has also been a trend toward restoring innervation to these flaps rather than leaving them insensate. SUMMARY: Tongue cancer resection and subsequent reconstruction pose interesting challenges to the surgeon to maximize postoperative function and quality of life. Attention to the principles of tongue reconstruction and knowledge of the range of available reconstructive options can result in more favorable functional outcomes.

[Invasive zygomycosis in patients treated for haematological malignancies]. / Invasieve zygomycose bij patiënten die worden behandeld voor een hematologische maligniteit.

A 52-year-old man underwent haematopoietic stem-cell transplant for myelodysplastic syndrome; after treatment with voriconazole for invasive aspergillosis, he was diagnosed with invasive zygomycosis caused by Rhizopus microsporus. He died despite treatment with intravenous liposomal amphotericin B and posaconazole. A 5-year-old boy with acute lymphatic leukaemia was diagnosed with invasive zygomycosis at autopsy. In a third case, a 16-year-old boy with acute myeloid leukaemia received repeated courses of empiric antifungal therapy, although the presence of an invasive fungal infection was not demonstrated. The patient died, and disseminated invasive zygomycosis caused by Rhizomucor pusillus was found at autopsy. Invasive infections by Zygomycetes are difficult to diagnose and are associated with a high mortality rate. The incidence of invasive zygomycosis appears to be increasing. Therefore, awareness of this type of invasive fungal infection is warranted. Lipid formulations ofamphotericin B remain the first choice for therapy.

[The first newborn with congenital rubella syndrome during the rubella epidemic in The Netherlands in 2004/'05]. / De eerste pasgeborene met congenitaal rubellasyndroom tijdens de rubella-epidemie in Nederland in 2004/'05.

A newborn male was diagnosed with congenital rubella syndrome. His 31-year-old mother had had erythematous exanthema during a period of amenorrhea lasting 7 weeks; she was not vaccinated and had never had a rubella infection. The infection was confirmed serologically. The mother gave birth to an icteric, microcephalic, dysmature neonate with hepatosplenomegaly and exanthema with multiple, small purple-red spots. Ultrasound cardiography revealed a persistently open arterial duct and a small defect of the ventricular septum. Radiological evaluation of the long bones showed the characteristic longitudinal lucent strands ('celery stalk appearance'). Ultrasound of the cerebrum showed diffuse widespread calcifications in the white matter and basal ganglia, striatal vasculopathy and diffuse parenchymal disorders. Psychomotor development was impaired. The patient was completely deaf in the left ear and had severely poor hearing in the right ear. After the introduction of the rubella vaccine in the Netherlands in 1974 a substantial decrease was seen in the incidence of rubella infections as well as congenital rubella syndrome. An epidemic of rubella infections has been present within the non-vaccinated population since September 2004. Recognition of the clinical symptoms and confirmation of the clinical suspicion with proper viral diagnostic methods are needed to control the current epidemic and to prevent secundary spread. Infants born with congenital rubella syndrome remain infectious to non-vaccinated individuals for a prolonged period of time; the virus is excreted in the urine and faeces. Long-term medical follow-up is necessary because the congenital rubella infection can cause abnormalities after the neonatal period.

Diagnosis of Candida lung abscesses by 18F-fluorodeoxyglucose positron emission tomography.

In three patients with catheter-associated candidaemia, use of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) led to the diagnosis of Candida lung abscesses, which was confirmed by computed tomography and a favourable response to antifungal therapy. It was concluded that FDG-PET is a promising new imaging technique that enables early identification of sites of disseminated candidiasis, and that this technique can be used in the evaluation of therapy.

[A Dutchman from Mali with a perianal ulcer caused by cutaneous amoebiasis]. / Een nederlander uit mali met een perianaal ulcus veroorzaakt door cutane amoebiasis.

A 66-year-old Dutchman, living in Mali, presented with an extensive progressive perianal ulcer despite local and antibiotic treatment. Microscopic examination of the stool revealed Entamoeba histolytica/dispar cysts and phagocytosing trophozoites were seen in fresh scrapings of the ulcer, a diagnostic feature of infection with E. histolytica. The diagnosis was cutaneous amoebiasis and the patient was effectively treated with metronidazole and local debridements. Primary cutaneous amoebiasis is a rare disease. Diagnosis and treatment are relatively simple but lack of familiarity with the disease may lead to misdiagnosis or diagnosis at a late stage ofthe infection.

Olfactomedin 4 Serves as a Marker for Disease Severity in Pediatric Respiratory Syncytial Virus (RSV) Infection.

BACKGROUND: Respiratory viral infections follow an unpredictable clinical course in young children ranging from a common cold to respiratory failure. The transition from mild to severe disease occurs rapidly and is difficult to predict. The pathophysiology underlying disease severity has remained elusive. There is an urgent need to better understand the immune response in this disease to come up with biomarkers that may aid clinical decision making. METHODS: In a prospective study, flow cytometric and genome-wide gene expression analyses were performed on blood samples of 26 children with a diagnosis of severe, moderate or mild Respiratory Syncytial Virus (RSV) infection. Differentially expressed genes were validated using Q-PCR in a second cohort of 80 children during three consecutive winter seasons. FACS analyses were also performed in the second cohort and on recovery samples of severe cases in the first cohort. RESULTS: Severe RSV infection was associated with a transient but marked decrease in CD4+ T, CD8+ T, and NK cells in peripheral blood. Gene expression analyses in both cohorts identified Olfactomedin4 (OLFM4) as a fully discriminative marker between children with mild and severe RSV infection, giving a PAM cross-validation error of 0%. Patients with an OLFM4 gene expression level above -7.5 were 6 times more likely to develop severe disease, after correction for age at hospitalization and gestational age. CONCLUSION: By combining genome-wide expression profiling of blood cell subsets with clinically well-annotated samples, OLFM4 was identified as a biomarker for severity of pediatric RSV infection.

Recovery of filamentous fungi from water in a paediatric bone marrow transplantation unit.

In order to determine whether water or water-related surfaces are a reservoir for opportunistic filamentous fungi, water sampling in the paediatric bone marrow transplantation (BMT) unit of the National Hospital University of Oslo, Norway was performed. During a six-month period 168 water samples and 20 samples from water-related surfaces were taken. The water samples were taken from the taps and showers in the BMT unit and from the main pipe supplying the paediatric department with water. In addition, 20 water samples were taken at the intake reservoir supplying the city of Oslo with drinking water. Filamentous fungi were recovered from 94% of all the water samples taken inside the hospital with a mean colony forming unit (cfu) count of 2.7/500mL of water. Aspergillus fumigatus was recovered from 49% and 5.6% of water samples from the taps and showers, respectively (mean 1.9 and 1.0cfu/500mL). More than one third (38.8%) of water samples from the main pipe revealed A. fumigatus (mean 2.1cfu/500mL). All water samples taken at the intake reservoir were culture positive for filamentous fungi, 85% of the water samples showed A. fumigatus (mean 3.1cfu/500mL). Twenty-five percent of water-related surfaces yielded filamentous fungi, but A. fumigatus was recovered from only two samples. We showed that filamentous fungi are present in the hospital water and to a lesser extent on water-related surfaces. The recovery of filamentous fungi in water samples taken at the intake reservoir suggests that the source of contamination is located outside the hospital.

Hospital sources of Aspergillus: New routes of transmission?

With the continuing increase in the number of severely immunocompromised patients, hospitals are faced with the growing problem of invasive aspergillosis and other opportunistic fungal infections. Since treatment of these infections are difficult and outcome is often fatal, preventive measures are of major importance in the control of invasive filamentous fungal infections. Until recently, inhalation of airborne conidia was believed to be the primary route of acquiring Aspergillus infection. Despite the fact, that efforts to filter the hospital air has led to a reduction of airborne conidia paralleled by a decrease in the frequency of invasive infections, the correlation between the concentration of Aspergillus conidia in hospital air and the risk of invasive infections remains unclear. Furthermore, alternative modes of transmission may exist and should be recognized and investigated. The discovery of hospital water as a potential source of Aspergillus fumigatus and other filamentous fungi may suggest a new route for the transmission of invasive filamentous fungal infections. Epidemiological studies, based on molecular characterization and comparisons of fungal isolates recovered from patients and environment, are needed to expand our understanding of these alternative routes of transmission.