| 1. |
- Ancillotti, Mirko, 1981-, et al.
(författare)
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Preferences regarding antibiotic treatment and the role of antibiotic resistance : a discrete choice experiment
- 2020
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier BV. - 0924-8579 .- 1872-7913. ; 56:6
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To identify preferences of the Swedish public regarding antibiotic treatment characteristics and the relative weight of antibiotic resistance in their treatment choices.Methods: A questionnaire including a discrete choice experiment questionnaire was answered by 378 Swedish participants. Preferences of the general public regarding five treatment characteristics (attributes) were measured: contribution to antibiotic resistance, cost, side effects, failure rate and treatment duration. Latent class analysis models were used to determine attribute-level estimates and heterogeneity in preferences. Relative importance of the attributes and willingness to pay for antibiotics with a lower contribution to antibiotic resistance were calculated from the estimates.Results: All attributes influenced participants’ preferences for antibiotic treatment. For the majority of participants, contribution to antibiotic resistance was the most important attribute. Younger respondents found contribution to antibiotic resistance more important in their choice of antibiotic treatments. Choices of respondents with lower numeracy, higher health literacy and higher financial vulnerability were influenced more by the cost of the antibiotic treatment. Older respondents with lower financial vulnerability and health literacy, and higher numeracy found side effects to be most important.Conclusions: All attributes can be considered as potential drivers of antibiotic use by lay people. Findings also suggest that the behaviour of lay people may be influenced by concerns over the rise of antibiotic resistance. Therefore, stressing individual responsibility for antibiotic resistance in clinical and societal communication has the potential to affect personal decision making.
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| 2. |
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| 4. |
- Cena-Diez, Rafael, et al.
(författare)
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Naturally occurring dipeptide from elite controllers with dual anti-HIV-1 mechanism
- 2023
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier BV. - 0924-8579 .- 1872-7913. ; 61:5, s. 106792-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Enhanced levels of a dipeptide, WC-am, have been reported among elite controllers - patients who spontaneously control their HIV-1 infection. This study aimed to evaluate anti-HIV-1 activity and mechanism of action of WC-am.Methods: Drug sensitivity assays in TZM.bl cells, PBMCs and ACH-2 cells using WT and mutated HIV-1 strains were performed to evaluate the antiviral mechanism of WC-am. Mass spectrometry-based proteomics and Real-time PCR analysis of reverse transcription steps were performed to unravel the second anti-HIV-1 mechanism of WC-am.Results: The data suggest that WC-am binds to the CD4 binding pocket of HIV-1 gp120 and blocks its binding to the host cell receptors. Additionally, the time course assay showed that WC-am also inhibited HIV-1 at 4-6 hours post-infection, suggesting a second antiviral mechanism. Drug sensitivity assays under acidic wash conditions confirmed the ability of WC-am to internalise into the host cell in an HIV independent manner. Proteomic studies showed a clustering of all samples treated with WC-am independent of the number of doses or presence or absence of HIV-1. Differentially expressed proteins due to the WC-am treatment indicated an effect on HIV-1 reverse transcription, which was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR).Conclusion: Naturally occurring in HIV-1 elite controllers, WC-am stands out as a new kind of antiviral compound with two independent inhibitory mechanisms of action on HIV-1 replication. WC-am halts HIV-1 entry to the host cell by binding to HIV-1 gp120, thereby blocking the binding of HIV-1 to the host cell. WC-am also exerts a post-entry but pre-integration antiviral effect related to RT-activity.
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| 5. |
- Chen, Ricky Hao, et al.
(författare)
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Is there a need to optimise pyrazinamide doses in patients with tuberculosis? A systematic review
- 2023
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Ingår i: International Journal of Antimicrobial Agents. - : ELSEVIER. - 0924-8579 .- 1872-7913. ; 62:3
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Forskningsöversikt (refereegranskat)abstract
- Pyrazinamide (PZA) is a first-line antituberculosis drug with potent sterilising activity. Variability in drug exposure may translate into suboptimal treatment responses. This systematic review, conducted according to PRISMA guidelines, aimed to evaluate the concentration-effect relationship. In vitro/in vivo studies had to contain information on the infection model, PZA dose and concentration, and microbiological outcome. Human studies had to present information on PZA dose, measures of drug exposure and maximum concentration, and microbiological response parameter or overall treatment outcome. A total of 34 studies were assessed, including in vitro (n = 2), in vivo (n = 3) and clinical studies (n = 29). Intracellular and extracellular models demonstrated a direct correlation between PZA dose of 15-50 mg/kg/day and reduction in bacterial count between 0.50-27.7 log(10) CFU/mL. Consistent with this, higher PZA doses (>150 mg/kg) were associated with a greater reduction in bacterial burden in BALB/c mice models. Human pharmacokinetic studies displayed a linear positive correlation between PZA dose (i.e. 21.4-35.7 mg/kg/day) and drug exposure (AUC range 220.6-514.5 mg center dot h/L). Additionally, human studies confirmed a dose-effect relationship, with an increased 2-month sputum culture conversion rate at AUC/MIC targets of 8.4-11.3 with higher exposure/susceptibility ratios leading to greater efficacy. A 5-fold variability in AUC was observed at PZA dose of 25 mg/kg. A direct concentration-effect relationship and increased treatment efficacy with higher PZA exposure to susceptibility ratios was observed. Taking into account variability in drug exposure and treatment response, further studies on dose optimisation are justified.
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| 6. |
- Cheng, Anying, et al.
(författare)
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Diagnostic performance of initial blood urea nitrogen combined with D-dimer levels for predicting in-hospital mortality in COVID-19 patients
- 2020
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Ingår i: International Journal of Antimicrobial Agents. - : ELSEVIER. - 0924-8579 .- 1872-7913. ; 56:3
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Tidskriftsartikel (refereegranskat)abstract
- The crude mortality rate in critical pneumonia cases with coronavirus disease 2019 (COVID-19) reaches 49%. This study aimed to test whether levels of blood urea nitrogen (BUN) in combination with D-dimer were predictors of in-hospital mortality in COVID-19 patients. The clinical characteristics of 305 COVID19 patients were analysed and were compared between the survivor and non-survivor groups. Of the 305 patients, 85 (27.9%) died and 220 (72.1%) were discharged from hospital. Compared with discharged cases, non-survivor cases were older and their BUN and D-dimer levels were significantly higher ( P < 0.0 0 01). Least absolute shrinkage and selection operator (LASSO) and multivariable Cox regression analyses identified BUN and D-dimer levels as independent risk factors for poor prognosis. Kaplan-Meier analysis showed that elevated levels of BUN and D-dimer were associated with increased mortality (logrank, P 0.0 0 01). The area under the curve for BUN combined with D-dimer was 0.94 (95% CI 0.90-0.97), with a sensitivity of 85% and specificity of 91%. Based on BUN and D-dimer levels on admission, a nomogram model was developed that showed good discrimination, with a concordance index of 0.94. Together, initial BUN and D-dimer levels were associated with mortality in COVID-19 patients. The combination of BUN 4.6 mmol/L and D-dimer > 0.845 mu g/mL appears to identify patients at high risk of in-hospital mortality, therefore it may prove to be a powerful risk assessment tool for severe COVID-19 patients. (c) 2020 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
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| 7. |
- Frimodt-Møller, Niels, et al.
(författare)
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Apramycin efficacy against carbapenem- and aminoglycoside-resistant Escherichia coli and Klebsiella pneumoniae in murine bloodstream infection models
- 2024
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier. - 0924-8579 .- 1872-7913. ; 64:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe aminoglycoside apramycin has been proposed as a drug candidate for the treatment of critical Gram-negative systemic infections. However, the potential of apramycin in the treatment of drug-resistant bloodstream infections (BSIs) has not yet been assessed.MethodsThe resistance gene annotations of 40 888 blood-culture isolates were analysed. In vitro profiling of apramycin comprised cell-free translation assays, broth microdilution, and frequency of resistance determination. The efficacy of apramycin was studied in a mouse peritonitis model for a total of nine Escherichia coli and Klebsiella pneumoniae isolates.ResultsGenotypic aminoglycoside resistance was identified in 87.8% of all 6973 carbapenem-resistant Enterobacterales blood-culture isolates, colistin resistance was shown in 46.4% and apramycin in 2.1%. Apramycin activity against methylated ribosomes was > 100-fold higher than that for other aminoglycosides. Frequencies of resistance were < 10-9 at 8 × minimum inhibitory concentration (MIC). Tentative epidemiological cut-offs (TECOFFs) were determined as 8 µg/mL for E. coli and 4 µg/mL for K. pneumoniae. A single dose of 5 to 13 mg/kg resulted in a 1-log colony-forming unit (CFU) reduction in the blood and peritoneum. Two doses of 80 mg/kg resulted in an exposure that resembles the AUC observed for a single 30 mg/kg dose in humans and led to complete eradication of carbapenem- and aminoglycoside-resistant bacteraemia.ConclusionEncouraging coverage and potent in vivo efficacy against a selection of highly drug-resistant Enterobacterales isolates in the mouse peritonitis model warrants the conduct of clinical studies to validate apramycin as a drug candidate for the prophylaxis and treatment of BSI.
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| 8. |
- Gkoufa, Aikaterini, et al.
(författare)
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Pulmonary and systemic pharmacokinetics of colistin methanesulfonate (CMS) and formed colistin following nebulisation of CMS among patients with ventilator-associated pneumonia
- 2022
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier. - 0924-8579 .- 1872-7913. ; 59:6
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Tidskriftsartikel (refereegranskat)abstract
- There has been accumulating interest in nebulised colistin methanesulfonate (CMS) for the treatment of ventilator-associated pneumonia (VAP). In this study, pulmonary and systemic pharmacokinetics following nebulisation of CMS at a dose of 3 MIU and 5 MIU, using a vibrating mesh nebuliser, for VAP caused by extensively drug-resistant Gram-negative pathogens was assessed. Blood samples and minibronchoalveolar lavage (mini-BAL) was performed post-dose at 1, 4 and 8 h. Concentrations of CMS and formed colistin in mini-BAL and plasma were determined by liquid chromatography-tandem mass spectrometry, and pharmacokinetic analysis was conducted using a population approach. The study population included three groups ( n = 10 per group): (A) intravenous CMS and concomitantly nebulised CMS at a dose of 3 MIU (30 min duration); (B) nebulised CMS at a dose of 3 MIU (30 min duration) as monotherapy; and (C) nebulised CMS 5 MIU (45 min duration) as monotherapy. Mean plasma formed colistin concentrations were < 1 mg/L following CMS nebulisation as monotherapy (groups B and C). Predicted trough concentrations of formed colistin in the epithelial lining fluid (ELF) following 24-h dosing of 3 MIU and 5 MIU nebulised CMS were 120.4 mg/L and 200.7 mg/L, respectively. The model predicted that concomitant intravenous CMS (group A) had minimal impact on the formed colistin concentration in ELF. This study demonstrated high ELF formed colistin concentrations following nebulised CMS (constantly above colistin MICs), while plasma concentrations were lower than those associated with nephrotoxicity. Our results provide important information for optimisation of nebulised colistin therapy. (c) 2022 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.
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| 9. |
- Kesarimangalam, Sriram, 1983, et al.
(författare)
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High diversity of bla NDM-1 -encoding plasmids in Klebsiella pneumoniae isolated from neonates in a Vietnamese hospital
- 2022
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier BV. - 1872-7913 .- 0924-8579. ; 59:2
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The carbapenemase-encoding gene blaNDM-1 has been reported in Vietnam during the last 10 years, and blaNDM-producing Enterobacteriaceae are now silently and rapidly spreading. A key factor behind dissemination of blaNDM-1 is plasmids, mobile genetic elements that commonly carry antibiotic resistance genes and spread via conjugation. The diversity of blaNDM-1-encoding plasmids from neonates at a large Vietnamese hospital was characterized in this study. Methods: 18 fecal Klebsiella pneumoniae and Klebsiella quasipneumoniae isolates collected from 16 neonates at a large pediatric hospital in Vietnam were studied using optical DNA mapping (ODM) and next-generation sequencing (NGS). Plasmids carrying the blaNDM-1 gene were identified by combining ODM with Cas9 restriction. The plasmids in the isolates were compared to investigate whether the same plasmid was present in different patients. Results: Although the same plasmid was found in some isolates, ODM confirmed that there were at least 10 different plasmids encoding blaNDM-1 among the 18 isolates, thus indicating wide plasmid diversity. The ODM results concur with the NGS data. Interestingly, some isolates had two distinct plasmids encoding blaNDM-1 that could be readily identified with ODM. The coexistence of different plasmids carrying the same blaNDM-1 gene in a single isolate has rarely been reported, probably because of limitations in plasmid characterization techniques. Conclusions: The plasmids encoding the blaNDM-1 gene in this study cohort were diverse and may represent a similar picture in Vietnamese society. The study highlights important aspects of the usefulness of ODM for plasmid analysis.
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| 10. |
- Koele, Simon E., et al.
(författare)
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Early bactericidal activity studies for pulmonary tuberculosis : A systematic review of methodological aspects
- 2023
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier. - 0924-8579 .- 1872-7913. ; 61:5
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Forskningsöversikt (refereegranskat)abstract
- A milestone in the development of novel antituberculosis drugs is the demonstration of early bactericidal activity (EBA) in a phase IIa clinical trial. The significant variability in measurements of bacterial load complicates data analysis in these trials.A systematic review and evaluation of methods for determination of EBA in pulmonary tuberculosis studies was undertaken. Bacterial load quantification biomarkers, reporting intervals, calculation methods, statistical testing, and handling of negative culture results were extracted. In total, 79 studies were identi-fied in which EBA was determined. Colony-forming units on solid culture media and/or time-to-positivity in liquid media were the biomarkers used most often, reported in 72 (91%) and 34 (43%) studies, respec-tively. Twenty-two different reporting intervals were presented, and 12 different calculation methods for EBA were identified. Statistical testing for a significant EBA compared with no change was performed in 54 (68%) studies, and between-group testing was performed in 32 (41%) studies. Negative culture result handling was discussed in 34 (43%) studies.Notable variation was found in the analysis methods and reporting of EBA studies. A standardized and clearly reported analysis method, accounting for different levels of variability in the data, could aid the generalization of study results and facilitate comparison between drugs/regimens.
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