Background: Meropenem plasma concentration above a pathogen's MIC over the whole dosing interval (100% ƒT .MIC ) is a determinant of outcome in severe infections. Significant variability of meropenem pharmacokinetics is reported in ICU patients.Objectives: To characterize meropenem pharmacokinetics in variable CL CR or renal replacement therapy and assess the appropriateness of recommended regimens for MIC coverage.Methods: A pharmacokinetic analysis (NONMEM) was conducted with external model validation. Patient characteristics were tested on meropenem clearance estimates, differentiated according to the presence/absence of continuous renal replacement therapy (CRRT, CL CRRT or CL no-CRRT ). Simulations evaluated the appropriateness of recommended dosing for achieving 100% fT .MIC in 90% of patients.Results: A total of 101 patients were studied: median 63 years (range 49-70), 56% male, . 32% had a CL CR .60 mL/min, 49% underwent CRRT and 32% presented severe sepsis or septic shock. A total of 127 pathogens were documented: 76% Gram-negatives, 24% Gram-positives (meropenem MIC 90 2 mg/L, corresponding to EUCAST susceptibility breakpoint). Three hundred and eighty plasma and 129 filtrate-dialysate meropenem concentrations were analysed: two-compartment modelling best described the data. Predicted meropenem CL no-CRRT was 59% lower in impaired (CL CR 30 mL/min) compared to normal (CL CR 100 mL/min) renal function. Simulations showed that recommended regimens appropriately cover MIC 90 in patients with CL CR ,60 mL/min. Patients with CL CR of 60 to ,90 mL/min need 6 g/day to achieve appropriate coverage. In patients with CL CR !90 mL/min, appropriate exposure is achieved with increased dose, frequency of administration and infusion duration, or continuous infusion.Conclusions: Recommended meropenem regimens are suboptimal in ICU patients with normal or augmented renal clearance. Modified dosing or infusion modalities achieve appropriate MIC coverage for optimized antibacterial efficacy in meropenem-susceptible life-threatening infections.

Gene expression-based prediction of genomic copy number aberrations in the chromosomal region 12q13 to 12q15 that is flanked by MDM2 and CDK4 identified Wnt inhibitory factor 1 (WIF1) as a candidate tumor suppressor gene in glioblastoma. WIF1 encodes a secreted Wnt antagonist and was strongly downregulated in most glioblastomas as compared with normal brain, implying deregulation of Wnt signaling, which is associated with cancer. WIF1 silencing was mediated by deletion (7/69, 10%) or epigenetic silencing by promoter hypermethylation (29/110, 26%). Co-amplification of MDM2 and CDK4 that is present in 10% of glioblastomas was associated in most cases with deletion of the whole genomic region enclosed, including the WIF1 locus. This interesting pathogenetic constellation targets the RB and p53 tumor suppressor pathways in tandem, while simultaneously activating oncogenic Wnt signaling. Ectopic expression of WIF1 in glioblastoma cell lines revealed a dose-dependent decrease of Wnt pathway activity. Furthermore, WIF1 expression inhibited cell proliferation in vitro, reduced anchorage-independent growth in soft agar, and completely abolished tumorigenicity in vivo. Interestingly, WIF1 overexpression in glioblastoma cells induced a senescence-like phenotype that was dose dependent. These results provide evidence that WIF1 has tumor suppressing properties. Downregulation of WIF1 in 75% of glioblastomas indicates frequent involvement of aberrant Wnt signaling and, hence, may render glioblastomas sensitive to inhibitors of Wnt signaling, potentially by diverting the tumor cells into a senescence-like state.

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Background Coronavirus disease 2019 (COVID-19) is now a global pandemic with Europe and the USA at its epicenter. Little is known about risk factors for progression to severe disease in Europe. This study aims to describe the epidemiology of COVID-19 patients in a Swiss university hospital. Methods This retrospective observational study included all adult patients hospitalized with a laboratory confirmed SARS-CoV-2 infection from March 1 to March 25, 2020. We extracted data from electronic health records. The primary outcome was the need to mechanical ventilation at day 14. We used multivariate logistic regression to identify risk factors for mechanical ventilation. Follow-up was of at least 14 days. Results 200 patients were included, of whom 37 (18.5%) needed mechanical ventilation at 14 days. The median time from symptoms onset to mechanical ventilation was 9.5 days (IQR 7.00, 12.75). Multivariable regression showed increased odds of mechanical ventilation in males (3.26, 1.21-9.8; p=0.025), in patients who presented with a qSOFA score ≥2 (6.02, 2.09-18.82; p=0.001), with bilateral infiltrate (5.75, 1.91-21.06; p=0.004) or with a CRP of 40 mg/l or greater (4.73, 1.51-18.58; p=0.013). Conclusions This study gives some insight in the epidemiology and clinical course of patients admitted in a European tertiary hospital with SARS-CoV-2 infection. Male sex, high qSOFA score, CRP of 40 mg/l or greater and a bilateral radiological infiltrate could help clinicians identify patients at high risk for mechanical ventilation.

Background This study aims to describe the epidemiology of COVID-19 patients in a Swiss university hospital. Methods This retrospective observational study included all adult patients hospitalized with a laboratory confirmed SARS-CoV-2 infection from March 1 to March 25, 2020. We extracted data from electronic health records. The primary outcome was the need to mechanical ventilation at day 14. We used multivariate logistic regression to identify risk factors for mechanical ventilation. Follow-up was of at least 14 days. Results 145 patients were included in the multivariate model, of whom 36 (24.8%) needed mechanical ventilation at 14 days. The median time from symptoms onset to mechanical ventilation was 9·5 days (IQR 7.00, 12.75). Multivariable regression showed increased odds of mechanical ventilation with age (OR 1.09 per year, 95% CI 1.03–1.16, p = 0.002), in males (OR 6.99, 95% CI 1.68–29.03, p = 0.007), in patients who presented with a qSOFA score ≥2 (OR 7.24, 95% CI 1.64–32.03, p = 0.009), with bilateral infiltrate (OR 18.92, 3.94–98.23, p<0.001) or with a CRP of 40 mg/l or greater (OR 5.44, 1.18–25.25; p = 0.030) on admission. Patients with more than seven days of symptoms on admission had decreased odds of mechanical ventilation (0.087, 95% CI 0.02–0.38, p = 0.001). Conclusions This study gives some insight in the epidemiology and clinical course of patients admitted in a European tertiary hospital with SARS-CoV-2 infection. Age, male sex, high qSOFA score, CRP of 40 mg/l or greater and a bilateral radiological infiltrate could help clinicians identify patients at high risk for mechanical ventilation.

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Background Conidiobolus spp. (mainly C. coronatus ) are the causal agents of rhino-facial conidiobolomycosis, a limited soft tissue infection, which is essentially observed in immunocompetent individuals from tropical areas. Rare cases of invasive conidiobolomycosis due to C. coronatus or other species ( C.incongruus, C.lamprauges ) have been reported in immunocompromised patients. We report here the first case of invasive pulmonary fungal infection due to Conidiobolus pachyzygosporus in a Swiss patient with onco-haematologic malignancy. Case presentation A 71 year-old female was admitted in a Swiss hospital for induction chemotherapy of acute myeloid leukemia. A chest CT performed during the neutropenic phase identified three well-circumscribed lung lesions consistent with invasive fungal infection, along with a positive 1,3-beta-d-glucan assay in serum. A transbronchial biopsy of the lung lesions revealed large occasionally septate hyphae. A Conidiobolus spp. was detected by direct 18S rDNA in the tissue biopsy and subsequently identified at species level as C. pachyzygosporus by 28S rDNA sequencing. The infection was cured after isavuconazole therapy, recovery of the immune system and surgical resection of lung lesions. Conclusions This is the first description of C. pachyzygosporus as human pathogen and second case report of invasive conidiobolomycosis from a European country.

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