Therapeutic Drug Monitoring of Ganciclovir in Cytomegalovirus-Infected Patients With Solid Organ Transplants and Its Correlation to Efficacy and Toxicity.

BACKGROUND: Cytomegalovirus causes morbidity and mortality, especially in immunocompromised patients, and is treated with (val)ganciclovir. Therapeutic drug monitoring of ganciclovir is often performed; however, clinically established target trough levels corresponding to efficacy are lacking. In 2021, our clinic increased the target trough level for ganciclovir from 1 to 2 mg/L to 2-4 mg/L. This study aims to compare both target trough levels in efficacy, toxicity, and occurrence of resistance. METHODS: A retrospective cohort study was performed in adult solid organ recipients treated for cytomegalovirus infection with (val)ganciclovir. Clinical efficacy was defined as the absence of treatment failure, defined as > 1 log 10 increase in viral load within 2 weeks of treatment initiation, therapy switch to foscarnet, and/or request for resistance analysis. RESULTS: A total of 46 patients were involved in the study, with 200 ganciclovir trough levels obtained. The composite endpoint was recorded in 23 (69.7%) and 10 (76.9%) patients in the 1-2 mg/L and the 2-4 mg/L group, respectively ( P = 0.18). No association was found between ganciclovir trough levels and the composite endpoint ( P = 1.0). However, a correlation was found between ganciclovir trough levels and the occurrence of lymphopenia ( P = 0.02). CONCLUSIONS: Our study could not establish a difference in clinical efficacy or toxicity between target trough levels of 1-2 mg/L or 2-4 mg/L because of the lack of clinical differences between the compared groups. However, a correlation was found between ganciclovir trough levels and lymphopenia, which warrants further investigation.

A semi-supervised decision support system to facilitate antibiotic stewardship for urinary tract infections.

Urinary Tract Infections (UTIs) are among the most frequently occurring infections in the hospital. Urinalysis and urine culture are the main tools used for diagnosis. Whereas urinalysis is sufficiently sensitive for detecting UTI, it has a relatively low specificity, leading to unnecessary treatment with antibiotics and the risk of increasing antibiotic resistance. We performed an evaluation of the current diagnostic process with an expert-based label for UTI as outcome, retrospectively established using data from the Electronic Health Records. We found that the combination of urinalysis results with the Gram stain and other readily available parameters can be used effectively for predicting UTI. Based on the obtained information, we engineered a clinical decision support system (CDSS) using the reliable semi-supervised ensemble learning (RESSEL) method, and found it to be more accurate than urinalysis or the urine culture for prediction of UTI. The CDSS provides clinicians with this prediction within hours of ordering a culture and thereby enables them to hold off on prematurely prescribing antibiotics for UTI while awaiting the culture results.

Temporal Variation in Staphylococcus aureus Protein A Genotypes from Nose and Skin in Atopic Dermatitis Patients.

BACKGROUND: Staphylococcus aureus colonization is associated with disease severity in patients with atopic dermatitis (AD). OBJECTIVE: To investigate temporal variation in S. aureus protein A gene (spa)-types isolated from the nose and lesional skin and the correlation of spa-types with disease severity. RESULTS: This study included 96 adult AD patients who were assessed at baseline (T0) and after a strict 2-week follow-up period (T1) in which treatment was standardized with a topical corticosteroid. Fifty-five different spa-types were detected in the nose and skin cultures. Seventy-three patients were colonized with S. aureus in the nasal cavity at both time points (persistent carriership), 59 of whom (81%) had identical spa-types over time. For skin samples, 42 (75%) of the 56 persistent skin carriers had identical spa-types over time. The same spa-type was carried in the nose and skin in 79 and 77% of the patients at T0 and T1, respectively. More severe disease was not associated with specific spa-types or with temporal variation in spa-type. CONCLUSION: S. aureus strains in AD are highly heterogeneous between patients. The majority of patients carry the same spa-type in the nose and skin without temporal variation, suggesting clonal colonization within individual patients. No predominant spa-type or temporal variation is associated with increased disease severity.

The influence of treatment in alpine and moderate maritime climate on the composition of the skin microbiome in patients with difficult to treat atopic dermatitis.

BACKGROUND: The skin microbiome, characterized by an overgrowth of Staphylococcus aureus, plays an important role in the pathogenesis of atopic dermatitis (AD). Multidisciplinary treatment in alpine climate is known for its positive effect on disease severity in children with AD and can result in a different immune response compared with moderate maritime climate. However, the effect on the composition of the skin microbiome in AD is unknown. OBJECTIVE: To determine the effect of treatment in alpine climate and moderate maritime climate on the microbiome for lesional and non-lesional skin in children with difficult to treat AD. RESULTS: Alpine climate treatment led to a significant change in the microbiota on lesional skin, whereas no significant change was found after moderate maritime climate. On both lesional and non-lesional skin, we observed a significant increase in Shannon diversity and a significant decrease in both Staphylococcus abundance and S aureus load after alpine climate treatment. The decrease in S aureus was significantly larger on lesional skin following alpine climate treatment compared with moderate maritime climate treatment. Staphylococcus epidermidis load was stable over time. CONCLUSIONS AND CLINICAL RELEVANCE: Alpine climate treatment leads to significant changes in the composition of the skin microbiome in children with AD, mainly caused by a reduction in the Staphylococcus genus. This study shows new perspectives in the potential mode of action for therapies in AD.

Molecular clustering of genes related to the atopic syndrome: Towards a more tailored approach and personalized medicine?

BACKGROUND: The atopic syndrome consists of heterogeneous manifestations, in which multiple associated genetic loci have recently been identified. It is hypothesized that immune dysregulation plays a role in the pathogenesis. In primary immunodeficiency diseases (PIDs), which are often monogenic immunodysregulation disorders, the atopic syndrome is a frequently occurring comorbidity. Based on the genetic defects in PIDs, novel gene/pathway-targeted therapies have been evaluated, which could be relevant in the atopic syndrome as well. Therefore, we aimed to define subclasses within the atopic syndrome based on the expression profiles of immune cell lineages of healthy mice. METHODS: Overlap between known atopy-related genes as described in the Human Gene Mutation Database and disease-causing genes of monogenic PIDs was evaluated. Clusters of atopy-related genes were based on the overlap in their co-expressed genes using the gene expression profiles of immune cell lineages of healthy mice from the Immunological Genome Project. We analyzed pathways involved in the atopic syndrome using Ingenuity Pathway Analysis. RESULTS: Twenty-two (5.3%) genes were overlapping between the atopy-related genes (n = 160) and PID-related genes (n = 278). We identified seven distinct clusters of atopy-related genes. Functional pathway analysis of all atopy-related genes showed relevance of T helper cell-mediated pathways. CONCLUSIONS: This study shows a model to define clusters within the atopic syndrome based on gene expression profiles of immune cell lineages. Our results support the hypothesis that both genetic mechanisms and immune dysregulation play a role in the pathogenesis. It also opens up the possibility for novel therapeutic targets and a more tailored approach towards personalized medicine.

Fecal Microbiome and Food Allergy in Pediatric Atopic Dermatitis: A Cross-Sectional Pilot Study.

BACKGROUND: Exposure to microbes may be important in the development of atopic disease. Atopic diseases have been associated with specific characteristics of the intestinal microbiome. The link between intestinal microbiota and food allergy has rarely been studied, and the gold standard for diagnosing food allergy (double-blind placebo-controlled food challenge [DBPCFC]) has seldom been used. We aimed to distinguish fecal microbial signatures for food allergy in children with atopic dermatitis (AD). METHODS: Pediatric patients with AD, with and without food allergy, were included in this cross-sectional observational pilot study. AD was diagnosed according to the UK Working Party criteria. Food allergy was defined as a positive DBPCFC or a convincing clinical history, in combination with sensitization to the relevant food allergen. Fecal samples were analyzed using 16S rRNA microbial analysis. Microbial signature species, discriminating between the presence and absence food allergy, were selected by elastic net regression. RESULTS: Eighty-two children with AD (39 girls) with a median age of 2.5 years, and 20 of whom were diagnosed with food allergy, provided fecal samples. Food allergy to peanut and cow's milk was the most common. Six bacterial species from the fecal microbiome were identified, that, when combined, distinguished between children with and without food allergy: Bifidobacterium breve, Bifidobacterium pseudocatenulatum, Bifidobacterium adolescentis, Escherichia coli, Faecalibacterium prausnitzii, and Akkermansia muciniphila (AUC 0.83, sensitivity 0.77, specificity 0.80). CONCLUSIONS: In this pilot study, we identified a microbial signature in children with AD that discriminates between the absence and presence of food allergy. Future studies are needed to confirm our findings.

Targeted anti-staphylococcal therapy with endolysins in atopic dermatitis and the effect on steroid use, disease severity and the microbiome: study protocol for a randomized controlled trial (MAAS trial).

BACKGROUND: Atopic dermatitis (AD) is associated with reduced skin microbial diversity and overgrowth of Staphylococcus (S.) aureus. However, the importance of S. aureus colonisation in the complex pathogenesis remains unclear and studies on the effect of anti-staphylococcal therapy in non-infected AD show contradictory results. Long-term interventions against S. aureus might be needed to restore the microbial balance, but carry the risk of bacterial resistance induction. Staphefekt, an engineered bacteriophage endolysin, specifically kills S. aureus leaving other skin commensals unharmed. Bacterial resistance towards endolysins has not been reported, nor is it expected, which allows us to study its effect as long-term anti-staphylococcal treatment in non-infected AD. METHODS: This is a multi-centre, placebo-controlled, double-blinded and randomized superiority trial with a parallel group design. A total of 100 participants, aged 18 years or older, diagnosed with moderate to severe AD and using a topical corticosteroid in the weeks before enrolment are included in the study. The study is executed in the Erasmus MC University Medical Centre Rotterdam in collaboration with the Havenziekenhuis Rotterdam. After a 2-week run-in period to standardize the corticosteroid use with triamcinolone acetonide 0.1% cream, participants will be randomized to either treatment with Staphefekt in a cetomacrogol-based cream or a placebo for 12 weeks, followed by an 8-week follow-up period. The primary objective is to assess the difference in the need for corticosteroid co-therapy between the Staphefekt and the placebo group, measuring the number of days per week of corticosteroid cream (triamcinolone) use. Secondary outcomes include the difference in use of corticosteroid cream measured in grams, differences in clinical efficacy, quality of life (QoL), microbial composition (includi23ng S. aureus) between the Staphefekt and the placebo group, and the safety and tolerability. DISCUSSION: The results of this trial will provide data about the effect of long-term anti-staphylococcal therapy with Staphefekt on corticosteroid use, clinical symptoms and QoL in patients with moderate to severe AD. Additional data about growth characteristics of the skin microbiome, including S. aureus, will give insight into the role of the microbiome as a factor in the pathophysiology of AD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02840955 . Registered on 11 July 2016.

Successful Treatment of Chronic Staphylococcus aureus-Related Dermatoses with the Topical Endolysin Staphefekt SA.100: A Report of 3 Cases.

Staphylococcus aureus plays an important role in skin and soft tissue infections and contributes to the pathophysiology of complex skin disorders such as atopic dermatitis. Bacterial resistance against commonly used antibiotics has increased considerably in the last decades demanding alternative treatment approaches. We present 3 cases where patients with chronic and recurrent S. aureus-related dermatoses were successfully treated with Staphefekt SA.100. Staphefekt SA.100 is a recombinant phage endolysin for topical skin application that specifically targets both methicillin-sensitive and methicillin-resistant S. aureus. As a consequence of its specific mechanism of action, bacterial resistance is unlikely to develop. In our 3 cases, resistance induction was not observed. Our results indicate that targeted treatment with Staphefekt might be an attractive alternative for (long-term) classical antibiotic therapy, and confirmatory randomized controlled trials are warranted to evaluate its clinical efficacy and safety.

[E-health: the Skin House]. / E-health: het Huidhuis.

The Dutch Skin House (www.huidhuis.nl) is an innovative and interactive online platform for patients with skin conditions and others involved, including health care professionals. Currently the platform is primarily aimed at skin disease in children and adolescents. It offers reliable and specialist information about everything from diagnosis to treatment. Patients can also create their own online protected, personal health record in which they can start a diagnostic or treatment plan. The aim of the Skin House is to create transmural continuation of care which is centred upon the patient. Additionally, the Skin House is focusing on scientific research by means of fellow platform the Research House.

Treatment of Infantile Hemangioma in Regional Hospitals With eHealth Support: Evaluation of Feasibility and Acceptance by Parents and Doctors.

BACKGROUND: Since beta blockers became the preferred treatment for infantile hemangiomas (IH), the number of patients eligible for treatment is increasing. Currently treatment of IH with beta blockers is mainly reserved for expert centers, where wait times are lengthening. This demonstrated the need for development of a more efficient and accessible way of providing care for children needing treatment for IH. An eHealth intervention, Hemangioma Treatment Plan (HTP), was developed to treat IH in regional hospitals with online support from an academic doctor. OBJECTIVE: Our goal was to evaluate the feasibility of the eHealth intervention by determining its use, acceptance, and usability. By evaluating the feasibility, usage can be predicted and points for improvement can be defined, thereby facilitating implementation of the intervention. METHODS: Parents of children with an IH, presenting between October 2012 and November 2013 at the tertiary expert Center for Congenital Vascular Anomalies Utrecht, requiring treatment with a beta blocker, were asked to participate in the digital HTP. Both parents and regional doctors were sent a study questionnaire. Acceptance and usability of the HTP were evaluated by using the modified Technology Acceptance Model. RESULTS: A total of 31 parents and 22 regional doctors participated in the eHealth intervention and received the questionnaire, and 25 parents and 15 doctors responded (response rates respectively 81% and 68%). A majority of the parents (96%, 24/25) and the regional doctors (87%, 13/15) considered the eHealth intervention useful in the care for IH. Most parents (76%, 19/25) and over half of the regional doctors (53%, 8/15) found the HTP easy to use. Technical problems using the HTP were reported by 28% (7/25) of the parents and 73% (11/15) of the doctors. The majority of parents (92%, 23/25) felt positive about usage of the HTP during treatment of their child. All regional doctors (100%, 15/15) felt positive about transition of treatment from the tertiary expert center to them, and 93% (14/15) felt positive about using the HTP. CONCLUSIONS: Our eHealth intervention shows good feasibility, especially among parents. Improvement with respect to technical problems, training of regional doctors, and achieving organizational support might be needed for successful implementation in the future.

E-learning enables parents to assess an infantile hemangioma.

BACKGROUND: Infantile hemangiomas (IH) at risk for complications need to be recognized early. OBJECTIVE: We sought to determine if parents are able to assess, after e-learning, whether their child has an IH, is at risk for complications, and needs to be seen (urgently) by a specialist. METHODS: This was a prospective study of 158 parents participating in an IH e-learning module. Parents were asked to assess their child's skin abnormality. A dermatologist answered the same questions (by e-consult). The 2 assessments were compared. RESULTS: Parents showed a 96% concordance with the dermatologist for correct diagnosis after e-learning. Concordances were 79%, 75%, and 84% (P < .001), respectively, on assessing the risk of complications, the need to be seen by a specialist, and the urgency for specialized care. LIMITATIONS: Parents had a relatively high education level and were therefore not representative of the general population. CONCLUSION: Parents were able to correctly diagnose and evaluate an IH after completing an e-learning module. E-learning by parents could result in earlier presentation and treatment of high-risk IH.

Evaluation of the Compliance, Acceptance, and Usability of a Web-Based eHealth Intervention for Parents of Children With Infantile Hemangiomas: Usability Study.

BACKGROUND: Infantile hemangiomas (IH) are common benign vascular tumors in children. Recognition and timely referral of high risk IH to specialized centers is important. This might be achieved by involving parents in the care for IH by means of an eHealth intervention. OBJECTIVE: The objective of our study was to evaluate parent compliance, acceptance, and usability of an open access, Web-based eHealth intervention (including e-learning and e-consult) designed to increase parents' knowledge and (risk) evaluation of IH. METHODS: A cross-sectional study of parents who completed the eHealth intervention between October 2010 and November 2012 was carried out. All parents were sent a study questionnaire. Questions to evaluate compliance (to the advice given by a dermatologist during e-consultation) were asked. Acceptance and usability were evaluated by using the modified Technology Acceptance Model. RESULTS: A total of 224 parents completed the eHealth intervention and received the questionnaire, 135/224 parents responded (response rate was 60.3%). There were 128/135 questionnaires that were completed and included. A total of 110/128 (85.9%) parents were compliant to the advice of the dermatologist. There were 116.8/128 (91.3%) that perceived the eHealth intervention as useful and almost all parents (98.4%, 126/128) found the information in the e-learning clear. There were 29/128 (22.7%) that experienced technical problems. The majority of the parents (94.5%, 121/128) found the eHealth intervention reliable and most of them (98.4%, 126/128) would recommend the eHealth intervention to other parents. Noncompliant parents judged the eHealth intervention significantly less reliable compared to compliant parents (71%, 10/14 versus 97.3%, 107/110; P=.003). CONCLUSIONS: Parents of children with an IH showed a high compliance (85.9%, 110/128) to the advice of the dermatologist given via our Web-based eHealth intervention. This high compliance might be positively influenced by the good acceptance and usability of the eHealth intervention and might result in timely presentation and treatment of children with high risk IH in specialized centers.