How effective is topical miconazole or amorolfine for mild to moderately severe onychomycosis in primary care: the Onycho Trial - a randomised double-blind placebo-controlled trial.

OBJECTIVES: To evaluate the efficacy of topical miconazole or amorolfine compared to placebo for mild to moderately severe onychomycosis. DESIGN: Randomised, double-blind, placebo-controlled trial, with computer-generated treatment allocation at a 1:1:1 ratio. SETTING: Primary care, recruitment from February 2020 to August 2022. PARTICIPANTS: 193 patients with suspected mild to moderately severe onychomycosis were recruited via general practices and from the general public, 111 of whom met the study criteria. The mean age of participants was 51 (SD 13.1), 51% were female and onychomycosis was moderately severe (mean OSI 12.1 (SD 8.0)). INTERVENTIONS: Once-daily miconazole 20 mg/g or once-weekly amorolfine 5% nail lacquer solution was compared with placebo (denatonium benzoate solution). MAIN OUTCOME MEASURES: Complete, clinical and mycological cure at 6 months. Secondary outcomes were clinical improvement, symptom burden, quality of life, adverse effects, compliance, patient-perceived improvement and treatment acceptability. RESULTS: Based on intention-to-treat analysis, none of the participants receiving miconazole or amorolfine reached complete cure compared with two in the placebo group (OR not estimable (n.e.), p=0.493 and OR n.e., p=0.240, respectively). There was no evidence of a significant difference between groups regarding clinical cure (OR n.e., p=0.493 and OR 0.47, 95% CI 0.04 to 5.45, p=0.615) while miconazole and amorolfine were less effective than placebo at reaching both mycological cure (OR 0.25, 95% CI 0.06 to 0.98, p=0.037 and OR 0.23, 95% CI 0.06 to 0.92, p=0.029, respectively) and clinical improvement (OR 0.26, 95% CI 0.08 to 0.91, p=0.028 and OR 0.25, 95% CI 0.07 to 0.85, p=0.021, respectively). There was no evidence of a significant difference in disease burden, quality of life, adverse reactions, compliance, patient-perceived improvement or treatment acceptability. CONCLUSIONS: Topical miconazole and amorolfine were not effective in achieving a complete, clinical or mycological cure of mild to moderately severe onychomycosis, nor did they significantly alleviate the severity or symptom burden. These treatments should, therefore, not be advised as monotherapy to treat onychomycosis. TRIAL REGISTRATION NUMBER: WHO ICTRP NL8193.

Prospective and systematic screening for invasive aspergillosis in the ICU during the COVID-19 pandemic, a proof of principle for future pandemics.

The diagnostic performance of a prospective, systematic screening strategy for COVID-19 associated pulmonary aspergillosis (CAPA) during the COVID-19 pandemic was investigated. Patients with COVID-19 admitted to the ICU were screened for CAPA twice weekly by collection of tracheal aspirate (TA) for Aspergillus culture and PCR. Subsequently, bronchoalveolar lavage (BAL) sampling was performed in patients with positive screening results and clinical suspicion of infection. Patient data were collected from April 2020-February 2022. Patients were classified according to 2020 ECMM/ISHAM consensus criteria. In total, 126/370 (34%) patients were positive in screening and CAPA frequency was 52/370 (14%) (including 13 patients negative in screening). CAPA was confirmed in 32/43 (74%) screening positive patients who underwent BAL sampling. ICU mortality was 62% in patients with positive screening and confirmed CAPA, and 31% in CAPA cases who were screening negative. The sensitivity, specificity, positive and negative predictive value (PPV & NPV) of screening for CAPA were 0.71, 0.73, 0.27, and 0.95, respectively. The PPV was higher if screening was culture positive compared to PCR positive only, 0.42 and 0.12 respectively. CAPA was confirmed in 74% of screening positive patients, and culture of TA had a better diagnostic performance than PCR. Positive screening along with clinical manifestations appeared to be a good indication for BAL sampling since diagnosis of CAPA was confirmed in most of these patients. Prospective, systematic screening allowed to quickly gain insight into the epidemiology of fungal superinfections during the pandemic and could be applicable for future pandemics.

Diagnostic accuracy of urine biomarkers for urinary tract infection in older women: a case-control study.

OBJECTIVES: Urinary tract infection (UTI) is common among older women. However, diagnosis is challenging because of frequent chronic lower urinary tract symptoms, cognitive impairment, and a high prevalence of asymptomatic bacteriuria (ASB). Current urine diagnostics lack specificity, leading to unnecessary treatment and antimicrobial resistance. This study aimed to evaluate the diagnostic accuracy of 12 urine biomarkers for diagnosing UTI in older women. METHODS: In this case-control study, cases were women ≥65 years with ≥2 new-onset lower urinary tract symptoms, pyuria, and one uropathogen ≥104 CFU/mL. Controls were asymptomatic and classified as ASB (one uropathogen ≥105 CFU/mL), negative culture, or mixed flora. Urine biomarker concentrations were measured through liquid chromatography-mass spectrometry and ELISA. Diagnostic accuracy parameters of individual biomarkers and a biomarker model were derived from receiver operating characteristic curves. RESULTS: We included 162 community-dwelling and institutionalized older women. Five urine inflammatory biomarkers demonstrated high discriminative ability (area under the curve ≥0.80): interleukin 6, azurocidin, neutrophil gelatinase-associated lipocalin, tissue inhibitor of metalloproteinases 2, and C-X-C motif chemokine 9. Azurocidin exhibited the highest diagnostic accuracy (sensitivity 86% [95% CI 75%-93%] and specificity 89% [95% CI 82%-94%] at 16.7 ng/mmol creatinine). A combined biomarker and pyuria model showed improved diagnostic accuracy in patients with UTI and ASB, compared with pyuria alone. DISCUSSION: We identified several urine biomarkers that accurately differentiated older women with UTI from asymptomatic women, including ASB. These findings represent a potential advancement towards improved diagnostics for UTI in older women and warrant validation in a diverse population.

Improved Diagnostics in Bacterial Neonatal Meningitis Using a Next-Generation Sequencing Platform.

INTRODUCTION: Bacterial meningitis in infants is an infrequent but life-threatening condition. Empiric therapy should begin as soon as meningitis is thought likely. Consequently, the causative microorganisms may not always be detected using culturing techniques, as cerebrospinal fluid (CSF) cultures are influenced by antibiotics. Nucleic acid amplification tests, such as polymerase chain reaction (PCR) (multiplex panels), may overcome this limitation but require a priori knowledge of the likely pathogen present within the sample. With this in mind, we investigated to what extent a culture-free, broad-range 16S rRNA gene next-generation sequencing (NGS) platform (MYcrobiota) could add to the microbiological diagnosis of meningitis. METHODS: Retrospective cohort study at level III neonatal intensive care unit. Included were all infants with suspected meningitis admitted between 10 November 2017 and 31 December 2020. A comparison was made of the bacterial pathogen detection rate between MYcrobiota and conventional bacterial culture. RESULTS: In a 3-year period, 37 CSF samples (diagnostic and follow-up) from 35 infants with proven or possible meningitis were available for MYcrobiota testing. MYcrobiota detected the presence of bacterial pathogens in 11 samples (30%), in contrast with the conventional CSF culture, which detected bacteria in 2 of 36 samples (5.6%). CONCLUSION: Addition of 16S rRNA sequencing to conventional culturing greatly improved the identification of the aetiology of bacterial meningitis compared to culturing of CSF samples alone.

The accuracy of clinical diagnosis of onychomycosis in Dutch general practice: a diagnostic accuracy study.

BACKGROUND: Onychomycosis, the most common cause of nail dystrophy, is generally diagnosed by clinical examination. Current guidelines for Dutch general practice advise confirmatory testing only in cases of doubt or insufficient response to treatment. However, making a correct diagnosis can be challenging given the wide variety of clinical features and differential diagnosis. AIM: To establish accuracy of clinical diagnosis of onychomycosis by GPs. DESIGN & SETTING: A diagnostic accuracy study based on GPs' clinical diagnosis of primary care patients suspected of onychomycosis. METHOD: Using 137 complete datasets from the Onycho Trial, diagnostic accuracy of clinical diagnosis as the index test was compared with confirmatory testing as the reference test. A sensitivity analysis was performed to determine diagnostic values for different combinations of index and reference test. Logistical regression was used to assess which clinical characteristics were associated with the positive predictive value (PPV) of the index test. RESULTS: Clinical accuracy, that is the PPV of the index test, was 74.5%. Sensitivity analysis showed no significant difference in diagnostic values. Male sex and a history of any previous treatment significantly increased clinical accuracy with an odds ratio (OR) of 3.873 (95% confidence interval [CI] = 1.230 to 12.195, P = 0.021) and OR 4.022 (95% CI = 1.075 to 15.040, P = 0.039), respectively. CONCLUSION: The study demonstrated that the GPs' clinical diagnosis of onychomycosis was insufficiently accurate to initiate treatment without confirmatory testing. Further research is needed to investigate how to increase clinical accuracy and reduce potentially unnecessary exposure to treatment.

Clinical Impact of Polymerase Chain Reaction-Based Aspergillus and Azole Resistance Detection in Invasive Aspergillosis: A Prospective Multicenter Study.

BACKGROUND: Invasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of appropriate therapy. METHODS: In a prospective study, we evaluated the clinical value of the AsperGenius polymerase chain reaction (PCR) assay in hematology patients from 12 centers. This PCR assay detects the most frequent cyp51A mutations in A. fumigatus conferring azole resistance. Patients were included when a computed tomography scan showed a pulmonary infiltrate and bronchoalveolar fluid (BALf) sampling was performed. The primary end point was antifungal treatment failure in patients with azole-resistant IA. RESULTS: Of 323 patients enrolled, complete mycological and radiological information was available for 276 (94%), and probable IA was diagnosed in 99/276 (36%). Sufficient BALf for PCR testing was available for 293/323 (91%). Aspergillus DNA was detected in 116/293 (40%) and A. fumigatus DNA in 89/293 (30%). The resistance PCR was conclusive in 58/89 (65%) and resistance detected in 8/58 (14%). Two had a mixed azole-susceptible/azole-resistant infection. In the 6 remaining patients, treatment failure was observed in 1. Galactomannan positivity was associated with mortality (P = .004) while an isolated positive Aspergillus PCR was not (P = .83). CONCLUSIONS: Real-time PCR-based resistance testing may help to limit the clinical impact of triazole resistance. In contrast, the clinical impact of an isolated positive Aspergillus PCR on BALf seems limited. The interpretation of the EORTC/MSGERC PCR criterion for BALf may need further specification (eg, minimum cycle threshold value and/or PCR positive on >1 BALf sample).

Incidence, risk factors and pre-emptive screening for COVID-19 associated pulmonary aspergillosis in an era of immunomodulant therapy.

PURPOSE: COVID-19 associated pulmonary aspergillosis (CAPA) is associated with increased morbidity and mortality in ICU patients. We investigated the incidence of, risk factors for and potential benefit of a pre-emptive screening strategy for CAPA in ICUs in the Netherlands/Belgium during immunosuppressive COVID-19 treatment. MATERIALS AND METHODS: A retrospective, observational, multicentre study was performed from September 2020-April 2021 including patients admitted to the ICU who had undergone diagnostics for CAPA. Patients were classified based on 2020 ECMM/ISHAM consensus criteria. RESULTS: CAPA was diagnosed in 295/1977 (14.9%) patients. Corticosteroids were administered to 97.1% of patients and interleukin-6 inhibitors (anti-IL-6) to 23.5%. EORTC/MSGERC host factors or treatment with anti-IL-6 with or without corticosteroids were not risk factors for CAPA. Ninety-day mortality was 65.3% (145/222) in patients with CAPA compared to 53.7% (176/328) without CAPA (p = 0.008). Median time from ICU admission to CAPA diagnosis was 12 days. Pre-emptive screening for CAPA was not associated with earlier diagnosis or reduced mortality compared to a reactive diagnostic strategy. CONCLUSIONS: CAPA is an indicator of a protracted course of a COVID-19 infection. No benefit of pre-emptive screening was observed, but prospective studies comparing pre-defined strategies would be required to confirm this observation.

Effect of invasive aspergillosis on risk for different causes of death in older patients with acute myeloid leukaemia or high-risk myelodysplastic syndrome.

PURPOSE: Study objectives were to estimate the cumulative incidence of death due to different causes of death (CODs) and investigate the effect of invasive aspergillosis (IA) on each separate COD in a cohort of older patients with acute myeloid leukaemia (AML) or high-risk myelodysplastic syndrome (MDS) included in the Haemato-Oncology Foundation for Adults in the Netherlands (HOVON) 43 randomized controlled trial. METHODS: Pre-collected data from the trial was obtained from the HOVON data center and relevant clinical information was extracted. The cumulative incidence of death due to different CODs was estimated with a competing risk model and the association between each COD and prognostic factors, including IA, were investigated with a cause-specific hazard Cox regression model. RESULTS: In total 806 patients were included, mean age of 70 years and 55% were male. The cumulative incidences of death due to leukaemia or infection at 3, 6, 12 and 36 months were 0.06, 0.11, 0.23, 0.42 and 0.17, 0.19, 0.22, 0.25 respectively. Incidence of IA was 21% and diagnosis of IA up until the final chemotherapy cycle was associated with an increased risk of dying from leukaemia (cause-specific hazard ratio (CSHR): 1.75, 95% CI 1.34-2.28) and a trend was seen for infection (CSHR: 1.36, 95% CI 0.96-1.91). CONCLUSION: Leukaemia was the most likely cause of death over time, however in the first year after diagnosis of AML or high-risk MDS infection was the most likely cause of death. Patients with IA had a relatively increased risk of dying from leukaemia or infection.

Current Pyuria Cutoffs Promote Inappropriate Urinary Tract Infection Diagnosis in Older Women.

BACKGROUND: Pre-existing lower urinary tract symptoms (LUTS), cognitive impairment, and the high prevalence of asymptomatic bacteriuria (ASB) complicate the diagnosis of urinary tract infection (UTI) in older women. The presence of pyuria remains the cornerstone of UTI diagnosis. However, >90% of ASB patients have pyuria, prompting unnecessary treatment. We quantified pyuria by automated microscopy and flowcytometry to determine the diagnostic accuracy for UTI and to derive pyuria thresholds for UTI in older women. METHODS: Women ≥65 years with ≥2 new-onset LUTS and 1 uropathogen ≥104 colony-forming units (CFU)/mL were included in the UTI group. Controls were asymptomatic and classified as ASB (1 uropathogen ≥105 CFU/mL), negative culture, or mixed flora. Patients with an indwelling catheter or antimicrobial pretreatment were excluded. Leukocyte medians were compared and sensitivity-specificity pairs were derived from a receiver operating characteristic curve. RESULTS: We included 164 participants. UTI patients had higher median urinary leukocytes compared with control patients (microscopy: 900 vs 26 leukocytes/µL; flowcytometry: 1575 vs 23 leukocytes/µL; P < .001). Area under the curve was 0.93 for both methods. At a cutoff of 264 leukocytes/µL, sensitivity and specificity of microscopy were 88% (positive and negative likelihood ratio: 7.2 and 0.1, respectively). The commonly used cutoff of 10 leukocytes/µL had a poor specificity (36%) and a sensitivity of 100%. CONCLUSIONS: The degree of pyuria can help to distinguish UTI in older women from ASB and asymptomatic controls with pyuria. Current pyuria cutoffs are too low and promote inappropriate UTI diagnosis in older women. Clinical Trials Registration. International Clinical Trials Registry Platform: NL9477 (https://trialsearch.who.int/Trial2.aspx?TrialID=NL9477).

Predicting Neonatal Early Onset Sepsis: A 14-Year Cohort Study.

BACKGROUND: In many infants, treatment is started for suspicion of early onset sepsis (EOS), of whom the majority do not have an infection. Early prediction of the absence of a culture-proven sepsis (CPS) would significantly reduce the time of antibiotic treatment and hospitalization. Our objective was to analyze 3 criteria in infants with CPS: positive blood culture (BC) at 24 hours after the onset of suspicion of EOS (OSEOS), C-reactive protein (CRP) ≥10 mg/L and clinical signs of infection, so we can consequently consider to stop antibiotic treatment in infants without these criteria. METHODS: We included all infants with suspicion of EOS from 2007 until 2020. The proportion was calculated of (1) infants with CPS with, at 24 hours, a positive BC and/or CRP ≥10 mg/L and/or clinical signs of infection and (2) infants without CPS with CRP <10 mg/L between 12 and 24 hours after OSEOS. RESULTS: The BC showed growth of a pathogenic microorganism in 50 of 4120 included infants (1.2%). Time to positivity was ≥24 hours in 8 (16%) infants, of whom 7 infants had a raised CRP and/or clinical symptoms of infection within 24 hours. In 1095 (74%) of infants without CPS in whom CRP was measured between 12 and 24 hours after OSEOS, CRP was <10 mg/L. CONCLUSION: A combination of BC, CRP, and clinical signs of infection can diagnose 98% (49/50) of infants with CPS 24 hours after OSEOS. Based on normal CRP and the absence of a positive BC, the decision to stop antibiotics could have been brought forward to 24 hours in 74% of infants.

Implementation of a clinical decision rule for selecting empiric treatment for invasive aspergillosis in a setting with high triazole resistance.

World-wide, emerging triazole resistance increasingly complicates treatment of invasive aspergillosis (IA). In settings with substantial (>10%) prevalence of triazole resistance, empiric combination therapy with both a triazole and liposomal amphotericin B (LAmB) can be considered because of the low yields of susceptibility testing. To avoid toxicity while optimizing outcome, a strategy with monotherapy would be preferable. A newly designed treatment algorithm based on literature and expert consensus provided guidance for empiric monotherapy with either voriconazole or LAmB. Over a four and a half year period, all adult patients in our hospital treated for IA were included and patient data were collected. An independent committee reviewed the attributability of death to IA for each patient. Primary outcomes were 30- and 100-day crude mortality and attributable mortality. In total, 110 patients were treated according to the treatment algorithm. Fifty-six patients (51%) were initially treated with voriconazole and 54 patients (49%) with LAmB. Combined attributable and contributable mortality was 13% within 30 days and 20% within 100 days. Treatment switch to LAmB was made in 24/56 (43%) of patients who were initially treated with voriconazole. Combined contributable and attributable 100-day mortality in this subgroup was 21% and was not increased when compared with patients initially treated with LAmB (P = 0.38). By applying a comprehensive clinical decision algorithm, an antifungal-sparing regime was successfully introduced. Further research is warranted to explore antifungal treatment strategies that account for triazole-resistance. LAY SUMMARY: Due to resistance of Aspergillus against triazoles, combination therapy with liposomal amphotericin B (LAmB) is applied more often as primary therapy against invasive aspergillosis. This study presents the results of a decision tool which differentiated between triazole or LAmB monotherapy.

The road to zero nosocomial infections in neonates-a narrative review.

AIM: Nosocomial infections (NI) in neonates are associated with prolonged hospitalisation, adverse neurodevelopmental outcome and high mortality. Over the past decade, numerous prevention strategies have resulted in significant reductions in NI rates. In this review, we aim to provide an overview of current NI rates from large, geographically defined cohorts. METHODS: PubMed, Web of Science, EMBASE and Cochrane Library were searched for evidence regarding epidemiology and prevention of NI in neonates. Extracted studies were synthesised in a narrative form with experiential reflection. RESULTS: Despite the abundance of geographically defined incidence proportions, an epidemiological overview of NI is difficult to provide, given the lack of consensus definition for neonatal NI and different baseline populations being compared. Successful prevention efforts have focused on implementing evidence-based practices while eliminating outdated strategies. The most promising model for reduction in infection rates is based on quality improvement (QI) collaboratives and benchmarking, involving identification and implementation of best practices, selection of measurable outcomes and fostering a sense of community and transparency. CONCLUSION: The preventative rather than curative approach forms the new paradigm for reducing the burden of neonatal infections. Despite progress achieved, continued work towards improved prevention practices is required in the strive towards zero NIs.

Systematic screening for COVID-19 associated invasive aspergillosis in ICU patients by culture and PCR on tracheal aspirate.

BACKGROUND: A high prevalence of COVID-19 associated pulmonary aspergillosis (CAPA) has been reported, though histopathological evidence is frequently lacking. To assess the clinical significance of Aspergillus species in respiratory samples of mechanically ventilated COVID-19 patients, we implemented routine screening for Aspergillus in tracheal aspirate (TA). PATIENTS/METHODS: From all adult COVID-19 patients admitted to the intensive care unit (ICU), TA samples were collected twice a week for Aspergillus screening by PCR and or culture. Bronchoalveolar lavage (BAL) sampling was performed in patients with a positive screening result if possible. Clinical information was obtained from the electronic patient record and patients were categorised according to the recently published consensus case definition for CAPA. RESULTS: Our study population consisted of 63 predominantly (73%) male patients, with a median age of 62 years and total median ICU stay of 18 days. Aspergillus species were present in TA screening samples from 15 patients (24%), and probable CAPA was diagnosed in 11 (17%) patients. Triazole resistance was detected in one patient (14%). Concordance between TA and BAL was 86%, and all TA culture positives were confirmed in BAL. We were able to withhold treatment in three of fifteen patients with positive screening (20%) but negative BAL results. CONCLUSIONS: Positive culture, molecular detection and or antigen detection of Aspergillus species do not equal infection. Until we understand the clinical relevance of Aspergillus species detected in respiratory samples of COVID-19 patients, minimal-invasive screening by TA is a feasible method to monitor patients. Positive screening results should be an indication to perform a BAL to rule out upper airway colonisation.

A Randomized Controlled Trial to Investigate Safety and Variability of Egg Excretion After Repeated Controlled Human Hookworm Infection.

BACKGROUND: Controlled human hookworm infections could significantly contribute to the development of a hookworm vaccine. However, current models are hampered by low and unstable egg output, reducing generalizability and increasing sample sizes. This study aims to investigate the safety, tolerability, and egg output of repeated exposure to hookworm larvae. METHODS: Twenty-four healthy volunteers were randomized, double-blindly, to 1, 2, or 3 doses of 50 Necator americanus L3 larvae at 2-week intervals. Volunteers were monitored weekly and were treated with albendazole at week 20. RESULTS: There was no association between larval dose and number or severity of adverse events. Geometric mean egg loads stabilized at 697, 1668, and 1914 eggs per gram feces for the 1 × 50L3, 2 × 50L3, and 3 × 50L3 group, respectively. Bayesian statistical modeling showed that egg count variability relative to the mean was reduced with a second infectious dose; however, the third dose did not increase egg load or decrease variability. We therefore suggest 2 × 50L3 as an improved challenge dose. Model-based simulations indicates increased frequency of stool sampling optimizes the power of hypothetical vaccine trials. CONCLUSIONS: Repeated infection with hookworm larvae increased egg counts to levels comparable to the field and reduced relative variability in egg output without aggravating adverse events. CLINICAL TRIALS REGISTRATION: NCT03257072.

The Effect of Single-Room Care Versus Open-Bay Care on the Incidence of Bacterial Nosocomial Infections in Pre-Term Neonates: A Retrospective Cohort Study.

INTRODUCTION: Nosocomial infections (NIs) are a major source of iatrogenic harm in neonatal intensive care units (NICUs). The influence of the infrastructure of NICUs on NIs is not well documented. This study aims to examine the effect of single-room units (SRU) versus open-bay units (OBU) on the incidence of NIs, including central-line-associated bloodstream infections (CLABSI), in preterm neonates. METHODS: All preterm neonates (< 32 weeks gestational age) admitted to our NICU were included. Two study periods were compared: one prior to (May 2015-May 2017) and one following (May 2017-May 2019) transition from OBU to SRU. Incidence density (number of infections per 1000 patient-days) and cumulative incidence (number of infections per 100 neonates) for NIs were calculated. CLABSIs were calculated per 1000 central-line days. U chart analysis was performed to determine special-cause variation in quarterly CLABSI and NI rates. Multivariate competing risk regression was performed to identify independent NI risk factors. RESULTS: Of the 712 included infants, 164 (23%) infants acquired ≥ 1 NIs. No differences were found in incidence density (13.68 vs. 12.62, p = 0.62) or cumulative incidence of NI (23.97 vs. 22.02, p = 0.59) between OBU and SRU. CLABSIs showed a similar non-significant reduction after the move (14.00 vs. 10.59, p = 0.51). U chart analysis did not identify unit transition as a potential source of special-cause variation for CLABSI and NI. Competing risks regression analysis revealed longer duration of invasive mechanical ventilation as a significant risk factor for NI (subhazards ratio: 1.03 per day on ventilation, p = 0.01). CONCLUSION: Single-rooms are not associated with a significant reduction in NIs in the NICU. This study therefore does not add evidence that could support the transition to SRUs if based only on a large multimodal infection control strategy. Recommendations to build SRUs would require a wider justification, also taking into account other SRU benefits.

Benzylpenicillin Serum Concentrations in Neonates With Group B Streptococci Sepsis or Meningitis: A Descriptive Cohort Study.

BACKGROUND: Adequate dosage recommendations are imperative for successful treatment of invasive infections. We evaluated the occurrence of sub- and supratherapeutic serum and cerebrospinal fluid (CSF) concentrations of benzylpenicillin (BPEN) in neonates treated for a severe group B streptococci (GBS) sepsis and/or meningitis as well as discrepancies in dosing recommendations provided by pediatric reference sources. METHODS: Retrospective analysis of (pre)term infants treated with BPEN undergoing therapeutic drug monitoring (TDM) between May 2015 and May 2019. Outcomes included numbers of sub- and supratherapeutic concentrations, and dose adjustments, clinical evolution, and dosing recommendations from six pediatric reference sources. RESULTS: A total of 21 TDM samples from 8 neonates were evaluated. Among serum concentrations, 9/21 (43%) were below and 8/21 (38%) above the pre-specified therapeutic target range of 10-20 mg/L. Only 1 patient had BPEN determined in CSF whose concentration was below the lower limit of quantification. TDM identified a need for dose modification in 10/21 (48%) instances. Three of eight patients exhibited complete resolution of clinical, laboratory and radiologic signs of infection. Substantial variation in dosing recommendations (50,000-400,000 IE/kg/d) was present between reference sources. CONCLUSIONS: Our data reveal that under current dosage recommendations, the predefined target serum or CSF concentrations of BPEN are not achieved in all children. In case of clinical failure, serum and/or CSF BPEN concentrations should be determined. Given the wide variation in concentrations and subsequent dose requirements, further exploration of the clinical and pharmacologic characteristics of BPEN in (pre)term neonates is essential to optimize therapeutic efficacy.

The Effect of Single-Room Care Versus Open-Bay Care on the Incidence of Bacterial Nosocomial Infections in Pre-Term Neonates: A Retrospective Cohort Study.

INTRODUCTION: Nosocomial infections (NIs) are a major source of iatrogenic harm in neonatal intensive care units (NICUs). The influence of the infrastructure of NICUs on NIs is not well documented. This study aims to examine the effect of single-room units (SRU) versus open-bay units (OBU) on the incidence of NIs, including central-line-associated bloodstream infections (CLABSI), in preterm neonates. METHODS: All preterm neonates (< 32 weeks gestational age) admitted to our NICU were included. Two study periods were compared: one prior to (May 2015-May 2017) and one following (May 2017-May 2019) transition from OBU to SRU. Incidence density (number of infections per 1000 patient-days) and cumulative incidence (number of infections per 100 neonates) for NIs were calculated. CLABSIs were calculated per 1000 central-line days. U chart analysis was performed to determine special-cause variation in quarterly CLABSI and NI rates. Multivariate competing risk regression was performed to identify independent NI risk factors. RESULTS: Of the 712 included infants, 164 (23%) infants acquired ≥ 1 NIs. No differences were found in incidence density (13.68 vs. 12.62, p = 0.62) or cumulative incidence of NI (23.97 vs. 22.02, p = 0.59) between OBU and SRU. CLABSIs showed a similar non-significant reduction after the move (14.00 vs. 10.59, p = 0.51). U chart analysis did not identify unit transition as a potential source of special-cause variation for CLABSI and NI. Competing risks regression analysis revealed longer duration of invasive mechanical ventilation as a significant risk factor for NI (subhazards ratio: 1.03 per day on ventilation, p = 0.01). CONCLUSION: Single-rooms are not associated with a significant reduction in NIs in the NICU. This study therefore does not add evidence that could support the transition to SRUs if based only on a large multimodal infection control strategy. Recommendations to build SRUs would require a wider justification, also taking into account other SRU benefits. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40121-020-00380-9.

Paradoxal Trends in Azole-Resistant Aspergillus fumigatus in a National Multicenter Surveillance Program, the Netherlands, 2013-2018.

We investigated the prevalence of azole resistance of Aspergillus fumigatus isolates in the Netherlands by screening clinical A. fumigatus isolates for azole resistance during 2013-2018. We analyzed azole-resistant isolates phenotypically by in vitro susceptibility testing and for the presence of resistance mutations in the Cyp51A gene. Over the 6-year period, 508 (11%) of 4,496 culture-positive patients harbored an azole-resistant isolate. Resistance frequency increased from 7.6% (95% CI 5.9%-9.8%) in 2013 (58/760 patients) to 14.7% (95% CI 12.3%-17.4%) in 2018 (112/764 patients) (p = 0.0001). TR34/L98H (69%) and TR46/Y121F/T289A (17%) accounted for 86% of Cyp51A mutations. However, the mean voriconazole MIC of TR34/L98H isolates decreased from 8 mg/L (2013) to 2 mg/L (2018), and the voriconazole-resistance frequency was 34% lower in 2018 than in 2013 (p = 0.0001). Our survey showed changing azole phenotypes in TR34/L98H isolates, which hampers the use of current PCR-based resistance tests.

A controlled human Schistosoma mansoni infection model to advance novel drugs, vaccines and diagnostics.

Schistosomiasis treatment relies on the use of a single drug, praziquantel, which is insufficient to control transmission in highly endemic areas1. Novel medicines and vaccines are urgently needed2,3. An experimental human model for schistosomiasis could accelerate the development of these products. We performed a dose-escalating clinical safety trial in 17 volunteers with male Schistosoma mansoni cercariae, which do not produce eggs (clinicaltrials.gov NCT02755324), at the Leiden University Medical Center, the Netherlands. The primary endpoints were adverse events and infectivity. We found a dose-related increase in adverse events related to acute schistosomiasis syndrome, which occurred in 9 of 17 volunteers. Overall, 5 volunteers (all 3 of the high dose group and 2 of 11 of the medium dose group) reported severe adverse events. Worm-derived circulating anodic antigen, the biomarker of the primary infection endpoint, peaked in 82% of volunteers at 3-10 weeks following exposure. All volunteers showed IgM and IgG1 seroconversion and worm-specific cytokine production by CD4+ T cells. All volunteers were cured with praziquantel provided at 12 weeks after exposure. Infection with 20 Schistosoma mansoni cercariae led to severe adverse events in 18% of volunteers and high infection rates. This infection model paves the way for fast-track product development for treatment and prevention of schistosomiasis.