Objectives: Voriconazole therapeutic drug monitoring (TDM) is recommended based on retrospective data and limited prospective studies. This study aimed to investigate whether TDM-guided... Show moreObjectives: Voriconazole therapeutic drug monitoring (TDM) is recommended based on retrospective data and limited prospective studies. This study aimed to investigate whether TDM-guided voriconazole treat-ment is superior to standard treatment for invasive aspergillosis.Methods: A multicentre ( n = 10), prospective, cluster randomised, crossover clinical trial was performed in haematological patients aged >= 18 years treated with voriconazole. All patients received standard voriconazole dose at the start of treatment. Blood/serum/plasma was periodically collected after treat-ment initiation of voriconazole and repeated during treatment in both groups. The TDM group had mea-sured voriconazole concentrations reported back, with dose adjustments made as appropriate, while the non-TDM group had voriconazole concentrations measured only after study completion. The composite primary endpoint included response to treatment and voriconazole treatment discontinuation due to an adverse drug reaction related to voriconazole within 28 days after treatment initiation. Results: In total, 189 patients were enrolled in the study. For the composite primary endpoint, 74 patients were included in the non-TDM group and 68 patients in the TDM group. Here, no significant difference was found between both groups ( P = 0.678). However, more trough concentrations were found within the generally accepted range of 1-6 mg/L for the TDM group (74.0%) compared with the non-TDM group (64.0%) ( P < 0.001). Conclusions: In this trial, TDM-guided dosing of voriconazole did not show improved treatment outcome compared with standard dosing. We believe that these findings should open up the discussion for an approach to voriconazole TDM that includes drug exposure, pathogen susceptibility and host defence. Clinical trial registration: ClinicalTrials.gov registration no. NCT00893555.(c) 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ ) Show less
Desikan, R.; Padmanabhan, P.; Kierzek, A.M.; Graag, P.H. van der 2022
The COVID-19 pandemic has severely impacted health systems and economies worldwide. Significant global efforts are therefore ongoing to improve vaccine efficacies, optimize vaccine deployment, and... Show moreThe COVID-19 pandemic has severely impacted health systems and economies worldwide. Significant global efforts are therefore ongoing to improve vaccine efficacies, optimize vaccine deployment, and develop new antiviral therapies to combat the pandemic. Mechanistic viral dynamics and quantitative systems pharmacology models of SARS-CoV-2 infection, vaccines, immunomodulatory agents, and antiviral therapeutics have played a key role in advancing our understanding of SARS-CoV-2 pathogenesis and transmission, the interplay between innate and adaptive immunity to influence the outcomes of infection, effectiveness of treatments, mechanisms and performance of COVID-19 vaccines, and the impact of emerging SARS-CoV-2 variants. Here, we review some of the critical insights provided by these models and discuss the challenges ahead. Show less
Introduction: Increasing resistance to beta-lactam antibiotics is an alarming development worldwide. Fecal carriership of TEM, SHV, CTX-M and CMY was studied in a community-dwelling population of... Show moreIntroduction: Increasing resistance to beta-lactam antibiotics is an alarming development worldwide. Fecal carriership of TEM, SHV, CTX-M and CMY was studied in a community-dwelling population of middle-aged and elderly individuals.Patients and methods: Feces was obtained from individuals of the Rotterdam Study. Carriership of the TEM, SHV, CTX-M and CMY genes was determined using real-time polymerase chain reaction (qPCR). Possible associations were investigated between carriership of these genes and several risk factors, such as the use of antimicrobial drugs, diabetes mellitus, protein pump inhibitor (PPI) use, travelling, the composition of the gut microbiota, and intake of certain foods.Results: The most prevalent gene was TEM (53.0%), followed by SHV (18.4%), CTX-M (5.4%) and CMY (3.6%). Use of penicillins with extended spectrum was associated with TEM carriership, whereas use of macrolides and lincosamides was associated with TEM and SHV carriership. Interestingly, use of PPIs was associated with a higher prevalence of carriership of TEM, SHV and CMY (TEM: odds ratio [OR] 1.34; 95% confidence interval [CI] 1.05-1.77; SHV: OR 2.17; 95%CI 1.55-2.87; CMY: OR 2.26; 95%CI 1.23-4.11). Furthermore, associations were found between the richness and composition of the gut microbiota and TEM and SHV carriership.Conclusions: The prevalence of carriership of TEM was substantial, but the prevalence of carriership of the extended-spectrum beta-lactamase gene, CTX-M and the AmpC beta-lactamase gene, CMY was relatively low in this community-dwelling, population-based cohort. The composition of the microbiota might play a role in the retention of resistance genes, but future studies are necessary to further elucidate this relationship. (C) 2021 Published by Elsevier Ltd. Show less
Objectives: The benefit of oseltamivir treatment in patients admitted with influenza virus infection and the design of studies addressing this issue have been questioned extensively. As the burden... Show moreObjectives: The benefit of oseltamivir treatment in patients admitted with influenza virus infection and the design of studies addressing this issue have been questioned extensively. As the burden of influenza disease is substantial and oseltamivir treatment is biologically plausible, this study assessed the clinical benefit of oseltamivir treatment in adult patients admitted with severe seasonal influenza virus infection in daily practice.Patients and methods: A multi-centre, retrospective cohort study was conducted to compare the effectiveness of treatment with and without oseltamivir <48 h after admission in patients admitted with laboratory-confirmed influenza virus infection in three large hospitals in the Netherlands. Propensity score matching was used to compare clinically relevant outcome variables.Results: In total, 390 patients were included in this study, of whom 80% had comorbidities. Thirty-day mortality, as well as the composite endpoint of 30-day mortality or intensive care unit admission >48 h after admission, were reduced by 9% (P = 0.04) and 11% (P = 0.02), respectively. Length of hospital stay and in-hospital mortality rates all showed a trend towards reduction. The median duration between symptom onset and initiation of treatment was 3 days.Conclusions: This study supports that, in daily practice, patients admitted with influenza virus infection should be treated with oseltamivir within 48 h of admission, even if they have had complaints for >48 h. (C) 2020 The Author(s). Published by Elsevier Ltd. Show less
Objectives: The benefit of oseltamivir treatment in patients admitted with influenza virus infection and the design of studies addressing this issue have been questioned extensively. As the burden... Show moreObjectives: The benefit of oseltamivir treatment in patients admitted with influenza virus infection and the design of studies addressing this issue have been questioned extensively. As the burden of influenza disease is substantial and oseltamivir treatment is biologically plausible, this study assessed the clinical benefit of oseltamivir treatment in adult patients admitted with severe seasonal influenza virus infection in daily practice.Patients and methods: A multi-centre, retrospective cohort study was conducted to compare the effectiveness of treatment with and without oseltamivir <48 h after admission in patients admitted with laboratory-confirmed influenza virus infection in three large hospitals in the Netherlands. Propensity score matching was used to compare clinically relevant outcome variables.Results: In total, 390 patients were included in this study, of whom 80% had comorbidities. Thirty-day mortality, as well as the composite endpoint of 30-day mortality or intensive care unit admission >48 h after admission, were reduced by 9% (P=0.04) and 11% (P=0.02), respectively. Length of hospital stay and in-hospital mortality rates all showed a trend towards reduction. The median duration between symptom onset and initiation of treatment was 3 days.Conclusions: This study supports that, in daily practice, patients admitted with influenza virus infection should be treated with oseltamivir within 48 h of admission, even if they have had complaints for >48 h. Show less
Skin bacterial colonization/infection is a frequent cause of morbidity in patients with chronic wounds and allergic/inflammatory skin diseases. This study aimed to develop a novel approach to... Show moreSkin bacterial colonization/infection is a frequent cause of morbidity in patients with chronic wounds and allergic/inflammatory skin diseases. This study aimed to develop a novel approach to eradicate meticillin-resistant Staphylococcus aureus (MRSA) from human skin. To achieve this, the stability and antibacterial activity of the novel LL-37-derived peptide P10 in four ointments was compared. Results indicate that P10 is chemically stable and antibacterial in hypromellose gel and Softisan-containing cream, but not in Cetomacrogol cream (with or without Vaseline), at 4 degrees C for 16 months. Reduction in MRSA counts on Leiden human epidermal models (LEMs) by P10 in hypromellose gel was greater than that of the peptide in Cetomacrogol cream or phosphate buffered saline. P10 did not show adverse effects on LEMs irrespective of the ointment used, while Cetomacrogol with Vaseline and Softisan cream, but not hypromellose gel or Cetomacrogol cream, destroyed MRSA-colonized LEMs. Taking all this into account, P10 in hypromellose gel dose-dependently reduced MRSA colonizing the stratum corneum of the epidermis as well as biofilms of this bacterial strain on LEMs. Moreover, P10 dose-dependently reduced MRSA counts on ex-vivo human skin, with P10 in hypromellose gel being more effective than P10 in Cetomacrogol and Softisan creams. P10 in hypromellose gel is a strong candidate for eradication of MRSA from human skin. (C) 2019 Elsevier B.V. and International Society of Chemotherapy. All rights reserved. Show less
Davido, B.; Batista, R.; Dinh, A.; Truchis, P. de; Terveer, E.M.; Roberts, B.; ... ; Caballero, S. 2019
Clean intermittent catheterisation (CIC) of the bladder is used to imitate normal bladder emptying in patients with bladder dysfunction. CIC is associated with urinary tract infection (UTI) that... Show moreClean intermittent catheterisation (CIC) of the bladder is used to imitate normal bladder emptying in patients with bladder dysfunction. CIC is associated with urinary tract infection (UTI) that may be difficult to treat in the case of antimicrobial resistance. The aim of this study was to establish the effect and safety of intravesical gentamicin treatment in such settings. In 2009, intravesical gentamicin treatment was started in selected patients. Here we describe our experience with two patients treated until March 2010. Two patients using CIC suffering recurrent UTI with multiresistant Escherichia coli were treated with daily administration of 80mg intravesical gentamicin. On treatment they appeared asymptomatic. During 8-and 9-month follow-up they were free of UTI, urine cultures were negative and there were no side effects. A systematic review was conducted through searches of PubMed and other databases. Clinical trials that met the eligibility criteria and displayed the efficacy or safety of intravesical aminoglycoside treatment in patients using CIC were studied. Study selection was performed by two independent reviewers. Eight studies were included for review. Owing to study heterogeneity, a meta-analysis could not be performed. Of four controlled studies using neomycin or kanamycin, two demonstrated a significant reduction in bacteriuria, whilst two other trials did not. One case series on neomycin/polymyxin showed that the majority of patients still developed bacteriuria. Three case series using gentamicin all pointed towards a significant reduction in bacteriuria and UTIs. There were no clinically relevant side effects reported but follow-up in all studies was limited. Although data are limited, intravesical treatment with gentamicin might be a reasonable treatment option in selected patients practicing CIC who suffer recurrent UTIs with highly resistant microorganisms. (C) 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Show less
