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| 12. |
- 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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- Berglund, Björn, et al.
(författare)
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Insertion sequence transpositions and point mutations in mgrB causing colistin resistance in a clinical strain of carbapenem-resistant Klebsiella pneumoniae from Vietnam
- 2018
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Ingår i: International Journal of Antimicrobial Agents. - : ELSEVIER SCIENCE BV. - 0924-8579 .- 1872-7913. ; 51:5, s. 789-793
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Tidskriftsartikel (refereegranskat)abstract
- Resistance among Klebsiella pneumoniae to the last-resort antibiotics carbapenems and colistin is increasing worldwide. In this study, whole-genome sequencing was used to determine the colistin resistance mechanisms in clinical isolates of carbapenem-and colistin-resistant K. pneumoniae from Vietnam. Alterations in the regulatory gene mgrB, via mutations and insertion sequence transpositions, were found in 30 of 31 isolates, emphasising the importance of this resistance mechanism in colistin-resistant K. pneumoniae. (c) 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
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| 21. |
- Bi, Zhenwang, et al.
(författare)
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Prevalence of the mcr-1 colistin resistance gene in extended-spectrum beta-lactamase-producing Escherichia coli from human faecal samples collected in 2012 in rural villages in Shandong Province, China
- 2017
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Ingår i: International Journal of Antimicrobial Agents. - : ELSEVIER SCIENCE BV. - 0924-8579 .- 1872-7913. ; 49:4, s. 493-497
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Tidskriftsartikel (refereegranskat)abstract
- Since its initial discovery in China in 2015, the plasmid-mediated colistin resistance gene mcr-1 has been reported in Escherichia coli isolated from clinical samples, animals and meat worldwide. In this study, 706 extended-spectrum beta-lactamase (ESBL)-producing E. coli from 411 persons were detected in a collection of faecal samples from 1000 rural residents in three counties in Shandong Province, China. These isolates were screened for mcr-1 and phenotypic colistin resistance. The gene was found in 3.5% of the isolates (from 4.9% of persons) from all three counties. All isolates with phenotypic colistin resistance carried mcr-1. These data indicate that commensal carriage of ESBL-producing E. coli with mcr-1 among persons in rural China was already present in 2012 and that mcr-1 was the most important colistin resistance mechanism. Interventions are necessary to minimise further dissemination of mcr-1, which would limit the future usefulness of colistin as a last-resort antibiotic. (C) 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
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| 24. |
- Björn, Camilla, et al.
(författare)
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Efficacy and safety profile of the novel antimicrobial peptide PXL150 in a mouse model of infected burn wounds
- 2015
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier BV. - 0924-8579 .- 1872-7913. ; 45:5, s. 519-524
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Tidskriftsartikel (refereegranskat)abstract
- The urgent need to develop novel antimicrobial therapies has stimulated interest in antimicrobial peptides as therapeutic candidates for the treatment of infectious diseases. The aim of this study was to evaluate the anti-infectious effect of the synthetic antimicrobial peptide PXL150, formulated in hydroxypropyl cellulose (HPC) gel, on Pseudomonas aeruginosa in vitro and in an in vivo mouse model of infected burn wounds as well as to assess the in vivo safety profile of PXL150 in rats and rabbits. Minimal microbicidal concentration analysis showed prominent efficacy of PXL150 against P. aeruginosa in vitro, which was further enhanced in formulating the peptide in HPC gel. Application of 1.25, 2.5, 5, 10 and 20 mg/g PXL150 in HPC gel twice daily for four consecutive days significantly reduced bacterial counts in the burn wounds compared with non-treated or placebo-treated controls. Continuous bioluminescence measurements of the bacteria revealed a pronounced anti-infective effect already at the first day post infection by PXL150 in concentrations of >= 2.5 mg/g. In the non-clinical safety studies, PXL150 showed a favourable safety profile following repeated administration systemically and locally in rats and rabbits, respectively. In conclusion, these data support that PXL150 has the potential to be an effective and safe drug candidate for the treatment of infected burn wounds. The findings encourage the progression of PXL150 as a novel topical treatment of microbial infections.
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| 25. |
- Brazier, J, et al.
(författare)
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European surveillance study on antimicrobial susceptibility of Gram-positive anaerobic cocci
- 2008
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Ingår i: International Journal of Antimicrobial Agents. - Amsterdam : Elsevier. - 0924-8579 .- 1872-7913. ; 31:4, s. 316-320
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Tidskriftsartikel (refereegranskat)abstract
- Gram-positive anaerobic cocci (GPAC) are a heterogeneous group of microorganisms frequently isolated from local and systemic infections. In this study, the antimicrobial susceptibilities of clinical strains isolated in 10 European countries were investigated. After identification of 299 GPAC to species level, the minimum inhibitory concentrations of penicillin, imipenem, clindamycin, metronidazole, vancomycin and linezolid were determined by the agar dilution method according to the Clinical and Laboratory Standards Institute. The majority of isolates were identified as Finegoldia magna and Parvimonas micra (formerly Peptostreptococcus micros), isolated from skin and soft tissue infections. All isolates were susceptible to imipenem, metronidazole, vancomycin and linezolid. Twenty-one isolates (7%) were resistant to penicillin (n=13) and/or to clindamycin (n=12). Four isolates were resistant to both agents. The majority of resistant isolates were identified as F. magna and originated from blood, abscesses and soft tissue infections.
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| 26. |
- Brill, Margreke JE, et al.
(författare)
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Confirming model-predicted pharmacokinetic interactions between bedaquiline and lopinavir/ritonavir or nevirapine in patients with HIV and drug resistant tuberculosis
- 2017
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier BV. - 0924-8579 .- 1872-7913. ; 49, s. 212-217
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Tidskriftsartikel (refereegranskat)abstract
- Bedaquiline and its metabolite M2 are metabolised by CYP3A4. The antiretrovirals ritonavir-boosted lopinavir (LPV/r) and nevirapine inhibit and induce CYP3A4, respectively. Here we aimed to quantify nevirapine and LPV/r drug–drug interaction effects on bedaquiline and M2 in patients co-infected with HIV and multidrug-resistant tuberculosis (MDR-TB) using population pharmacokinetic (PK) analysis and compare these with model-based predictions from single-dose studies in subjects without TB. An observational PK study was performed in three groups of MDR-TB patients during bedaquiline maintenance dosing: HIV-seronegative patients (n = 17); and HIV-infected patients using antiretroviral therapy including nevirapine (n = 17) or LPV/r (n = 14). Bedaquiline and M2 samples were collected over 48 h post-dose. A previously developed PK model of MDR-TB patients was used as prior information to inform parameter estimation using NONMEM. The model was able to describe bedaquiline and M2 concentrations well, with estimates close to their priors and earlier model-based interaction effects from single-dose studies. Nevirapine changed bedaquiline clearance to 82% (95% CI 67–99%) and M2 clearance to 119% (92–156%) of their original values, indicating no clinically significant interaction. LPV/r substantially reduced bedaquiline clearance to 25% (17–35%) and M2 clearance to 59% (44–69%) of original values. This work confirms earlier model-based predictions of nevirapine and LPV/r interaction effects on bedaquiline and M2 clearance from subjects without TB in single-dose studies, in MDR-TB/HIV co-infected patients studied here. To normalise bedaquiline exposure in patients with concomitant LPV/r therapy, an adjusted bedaquiline dosing regimen is proposed for further study.
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| 27. |
- 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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| 28. |
- 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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| 29. |
- 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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| 30. |
- Chu, Hencelyn, et al.
(författare)
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Candidate vaginal microbicides with activity against Chlamydia trachomatis and Neisseria gonorrhoeae
- 2010
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier BV. - 0924-8579 .- 1872-7913. ; 36:2, s. 145-150
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Tidskriftsartikel (refereegranskat)abstract
- Vaginal microbicides with activity towards organisms that cause sexually transmitted infections have been proposed as a strategy to reduce transmission. Small-molecule inhibitors of Chlamydia trachomatis serovar D belonging to the class of salicylidene acylhydrazides (INPs) have been shown to work through a mechanism that involves iron restriction. Expanding on this work, ten INPs were tested against a lymphogranuloma venereum strain of C. trachomatis (serovar L2), Neisseria gonorrhoeae, and hydrogen peroxide-producing Lactobacillus crispatus and Lactobacillus jensenii. Seven INPs had minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations of <50 microM towards C. trachomatis L2. Three INPs had a MIC <12.5 microM against N. gonorrhoeae. Inhibition was reversed by iron, holo-transferrin and holo-lactoferrin but not by the iron-poor forms of these compounds. The compounds exhibited no bactericidal activity toward Lactobacillus. The INPs were not cytotoxic to HeLa 229 cells. When INP 0341 was tested in a mouse model of a Chlamydia vaginal infection there was a significant reduction in the number of mice shedding C. trachomatis up to 4 days after infection (P<0.01). In summary, select INPs are promising vaginal microbicide candidates as they inhibit the growth of two common sexually transmitted organisms in vitro, are active in a mouse model against C. trachomatis, are not cytotoxic and do not inhibit organisms that compose the normal vaginal flora.
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| 31. |
- Dhanani, Jayesh, et al.
(författare)
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Antimicrobial chemotherapy and lung microdialysis: a review
- 2010
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier BV. - 1872-7913 .- 0924-8579. ; 36:6, s. 491-500
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Forskningsöversikt (refereegranskat)abstract
- Pneumonia is a form of lung infection that may be caused by various micro-organisms. The predominant site of infection in pneumonia is debatable. Advances in the fields of diagnostic and therapeutic medicine have had a less than optimal effect on the outcome of pneumonia and one of the many causes is likely to be inadequate antimicrobial concentrations at the site of infection in lung tissue. Traditional antimicrobial therapy guidelines are based on indirect modelling from blood antimicrobial levels. However, studies both in humans and animals have shown the fallacy of this concept in various tissues. Many different methods have been employed to study lung tissue antimicrobial levels with limited success, and each has limitations that diminish their utility. An emerging technique being used to study the pharmacokinetics of antimicrobial agents in lung tissue is microdialysis. Development of microdialysis catheters, along with improvement in analytical techniques, has improved the accuracy of the data. Unfortunately, very few studies have reported the use of microdialysis in lung tissue, and even fewer antimicrobial classes have been studied. These studies generally suggest that this technique is a safe and effective way of assessing the pharmacokinetics of antimicrobial agents in lung tissue. Further descriptive studies need to be conducted to study the pharmacokinetics and pharmacodynamics of different antimicrobial classes in lung tissue. Data emanating from these studies could inform decisions for appropriate dosing schedules of antimicrobial agents in pneumonia. (C) 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
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| 32. |
- Di Paolo, Antonello, et al.
(författare)
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Population pharmacokinetics of daptomycin in patients affected by severe Gram-positive infections
- 2013
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier BV. - 0924-8579 .- 1872-7913. ; 42:3, s. 250-255
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Tidskriftsartikel (refereegranskat)abstract
- A population pharmacokinetic analysis of daptomycin was performed based on therapeutic drug monitoring (TDM) data from 58 patients receiving doses of 4–12 mg/kg for the treatment of severe Gram-positive infections. At a daily dose of 8 mg/kg, daptomycin plasma concentrations (mean ± S.D.) were 76.9 ± 9.8 mg/L at the end of infusion and 52.7 ± 15.4 mg/L and 11.4 ± 5.4 mg/L at 0.5 h and 23 h after drug administration, respectively. The final model was a one-compartmental model with first-order elimination, with estimated clearance (CL) of 0.80 ± 0.14 L/h and a volume of distribution (Vd) of 0.19 ± 0.05 L/kg. Creatinine clearance (CLCr) was identified as having a significant influence on daptomycin CL, and a decrease in CLCr of 30 mL/min from the median value (80 mL/min) was associated with a reduction of daptomycin CL from 0.80 L/h to 0.73 L/h. These results confirm that the presence of severe infection may be associated with an altered disposition of daptomycin, with an increased Vd. MICs were available in 41 patients and results showed that 38 and 31 subjects achieved AUC/MIC values associated with bacteriostatic (>400) and bactericidal effects (>800), respectively. Of note, 31 of these 41 subjects experienced a clinical improvement or were cured. Although daptomycin pharmacokinetics may be influenced by infections, effective AUC/MIC values were achieved in the majority of patients. The present model may be applied in clinical settings for a TDM routine on the basis of a sparse blood sampling protocol.
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| 34. |
- Ebmeyer, Stefan, et al.
(författare)
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PER extended-spectrum β-lactamases originate from Pararheinheimera spp
- 2019
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier BV. - 1872-7913 .- 0924-8579. ; 53:2, s. 158-164
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the origin of PER extended-spectrum β-lactamases, publicly available sequence databases were searched for bla PER-like genes. Three genomes from Pararheinheimera, a genus associated with water and soil environments, were found to carry bla PER-like genes but lacked the ISCR1/ISPa12/ISPa13 insertion sequences commonly associated with bla PER in clinical isolates. Sequence analysis revealed 78–96% nucleotide identity and conserved synteny between the clinical mobile genetic elements (MGEs) encoding bla PER-1 and the bla PER locus in the Pararheinheimera genomes. Notably, bla PER genes were only identified in 3 of 21 Pararheinheimera and Rheinheimera genomes, whereas the genetic environment of bla PER genes as found in clinical MGEs was conserved in all Pararheinheimera and Rheinheimera genomes. These findings indicate that bla PER genes were likely acquired by a branch of the Pararheinheimera genus long before the antibiotic era. Later, bla PER genes were mobilised, likely through the involvement of insertion sequences, from one or several Pararheinheimera species, allowing their dissemination into human pathogens.
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| 35. |
- Ebmeyer, Stefan, 1990, et al.
(författare)
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The mobile FOX AmpC beta-lactamases originated in Aeromonas allosaccharophila
- 2019
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier BV. - 1872-7913 .- 0924-8579. ; 54:6, s. 798-802
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Tidskriftsartikel (refereegranskat)abstract
- Objective: It is important to understand the origins of antibiotic resistance genes so that risks associated with the emergence of novel resistance genes can be assessed and managed. The chromosomal ampC gene (CAV-1) of Aeromonas caviae (A. caviae) has been reported as the origin of mobile FOX cephalosporinases. The recent identification of A. caviae as the origin of MOX-2 cephalosporinases and the comparably great sequence divergence between FOX and MOX genes makes it unlikely that both genes arose from the same species. Therefore, this study investigated the origin of FOX cephalosporinases using large-scale genomics. Methods: Publicly available genomes and plasmids were searched for FOX-like genes. Synteny and nucleotide identities of the identified FOX-like genes and their genetic environments were compared and a phylogenetic tree was generated. Results: FOX-like genes were identified in > 230 Aeromonas genomes and in 46 Enterobacteriaceae isolates. Analysis of the genomic context of CAV-1 revealed a truncated insertion sequence directly upstream of the ampC gene. The chromosomal ampCs of A. caviae (n = 31) were 75–78% identical to CAV-1. In contrast, CAV-1, mobile FOX genes and their context were 95–98% similar to the chromosomal ampC-locus of Aeromonas allosaccharophila (A. allosaccharophila) (n = 6). The A. allosaccharophila ampCs formed a monophyletic branch with mobile FOX genes, whereas the A. caviae ampCs clustered with mobile MOX genes. Conclusions: These findings show that FOX cephalosporinases originate not in A. caviae, as previously reported, but in A. allosaccharophila, which is a fish pathogen. This finding agrees with the hypothesis that antibiotic use in aquaculture could have contributed to the emergence of FOX genes in human pathogens.
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| 36. |
- Ebmeyer, Stefan, 1990, et al.
(författare)
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The PER extended-spectrum beta-lactamases originate from Pararheinheimera sp.
- 2019
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Ingår i: International journal of antimicrobial agents. - : Elsevier BV. - 1872-7913 .- 0924-8579. ; 53:2, s. 158-64
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the origin of the PER extended-spectrum beta-lactamase, publicly available sequence databases were searched for PER-like genes. Three genomes from Pararheinheimera, a genus associated with water and soil environments, were found to carry PER-like genes, but lacked the ISCR1/ISPa12/ISPa13 insertion sequences (IS) commonly associated with PER in clinical isolates. Sequence analysis revealed 78-96% nucleotide identity and conserved synteny between the clinical mobile genetic elements (MGEs) encoding PER-1 and the PER locus in the Pararheinheimera genomes. Notably, PER genes were only identified in 3 of 21 Pararheinheimera and Rheinheimera genomes, whereas the genetic environment of PER genes as found in clinical MGEs was conserved in all Pararheinheimera and Rheinheimera genomes. These findings indicate that PER genes were likely acquired by a branch of the Pararheinheimera genus long before the antibiotic era. Later, PER genes were mobilized, likely through involvement of IS, from one or several Pararheinheimera species, allowing their dissemination into human pathogens.
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| 37. |
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| 39. |
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| 40. |
- Forthal, Donald N, et al.
(författare)
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In vitro anti-HIV-1 activity of salicylidene acylhydrazide compounds
- 2012
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier BV. - 0924-8579 .- 1872-7913. ; 40:4, s. 354-360
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Tidskriftsartikel (refereegranskat)abstract
- Salicylidene acylhydrazide compounds have been shown to inhibit bacterial pathogens, including Chlamydia and Neisseria gonorrhoeae. If such compounds could also target HIV-1, their potential use as topical microbicides to prevent sexually transmitted infections would be considerable. In this study, the in vitro anti-HIV-1 activity, cytotoxicity and mechanism of action of several salicylidene acylhydrazides were determined. Inhibitory activity was assessed using TZM-bl cells and primary peripheral blood mononuclear cells (PBMCs) as targets for HIV-1 infection. Antiviral activity was measured against cell-free and cell-associated virus and in vaginal fluid and semen simulants. Since the antibacterial activity of salicylidene acylhydrazides is reversible by Fe(2+), the ability of Fe(2+) and other cations to reverse the anti-HIV-1 activity of the compounds was determined. Real-time PCR was also employed to determine the stage affected in the HIV-1 replication cycle. Four compounds with 50% inhibitory concentrations against HIV-1 of 1-7μM were identified. In vitro toxicity varied but was generally limited. Activity was similar against three R5 clade B primary isolates and whether the target for virus replication was TZM-bl cells or PBMCs. Compounds inhibited cell-free and cell-associated virus and were active in vaginal fluid and semen simulants. Fe(2+), but not other cations, reversed the anti-HIV-1 effect. Finally, the inhibitory effect of the compounds occurred at a post-integration step. In conclusion, salicylidene acylhydrazides were identified with in vitro anti-HIV-1 activity in the micromolar range. The activity of these compounds against other sexually transmitted pathogens makes them potential candidates to formulate for use as a broad-spectrum topical genital microbicide.
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| 41. |
- 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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| 42. |
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| 43. |
- Gharizadeh, Baback, et al.
(författare)
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Detection of gyrA mutations associated with ciprofloxacin resistance in Neisseria gonorrhoeae by rapid and reliable pre-programmed short DNA sequencing
- 2005
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier BV. - 0924-8579 .- 1872-7913. ; 26:6, s. 486-490
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Tidskriftsartikel (refereegranskat)abstract
- Quinolone resistance is rapidly increasing in Neisseria gonorrhoeae and is posing a significant public health threat that requires constant surveillance. A rapid and reliable mutation detection assay has been developed. The assay is based on pre-programmed short DNA sequencing and is designed to detect point mutations in the gyrA gene that are highly related to ciprofloxacin resistance, i.e. in codons 91 and 95. By developing an assay based on pyrosequencing and exploiting the pre-programmed nucleotide dispensation capability of this technology, the sequence comprising the mutations will be analysed and promptly reveal whether the N. gonorrhoeae pathogen carries resistance to ciprofloxacin. A panel of 40 N. gonorrhoeae clinical isolates, of which 27 phenotypically displayed decreased susceptibility or resistance to ciprofloxacin, was used in the present study. All point mutations in the short stretch of the N. gonorrhoeae gyrA gene were easily discriminated, and the genotypic results obtained by pre-programmed sequencing were mainly in agreement with the phenotypically identified decreased susceptibility or resistance to ciprofloxacin. The new method used in the present study has the potential for rapid and reliable identification of known as well as previously unknown drug resistance mutations.
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| 44. |
- 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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| 45. |
- Grabe, Magnus
(författare)
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Antibiotic prophylaxis in urological surgery, a European viewpoint.
- 2011
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier BV. - 1872-7913 .- 0924-8579. ; 38, s. 58-63
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Tidskriftsartikel (refereegranskat)abstract
- Surgical site infections (SSI) including urinary tract infections (UTI) cause a significant morbidity in urological surgery. Antibiotic prophylaxis is one of several factors impacting on infection rates. Antibiotic prophylaxis is relevant only for clean and clean-contaminated operations and in the absence of bacterial growth in the urine. Strict classification of urological procedures is lacking, but a proposal is presented elsewhere. Only TURP and transrectal core prostate biopsy are well documented. The present review confirms that there is a lack of hard data, insufficient consistency in classification and definitions, and that new well-powered RCT and large multicentre quality cohort studies including risk factor analysis are necessary to improve recommendations for antibiotic prophylaxis in urologic surgery.
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| 46. |
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| 47. |
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| 48. |
- Hagstrand Aldman, Malin, et al.
(författare)
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Treatment outcome with pencillin G or cloxacillin in penicillin susceptible Staphylococcus aureus bactearemi
- 2022
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier BV. - 0924-8579. ; 59:4
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Tidskriftsartikel (refereegranskat)abstract
- An increasing proportion of penicillin-susceptible Staphylococcus aureus (PSSA) has been reported over the last years. The aim of this retrospective study was to compare penicillin G with cloxacillin in the treatment of PSSA bloodstream infections. The primary outcome was the mortality rate after 90 days and the secondary outcome was the development of treatment complications of varying severity. Medical records from patients with PSSA bacteraemia during 2018–2020 were reviewed. Patient outcome was ranked on an ordinal scale according to severity: (i) alive at 90 days without any complications; (ii) adverse events not requiring treatment; (iii) change or addition of antibiotics owing to treatment failure or adverse events; (iv) relapse within 90 days; and (v) death within 90 days. The outcome ranking scale was dichotomised at every level and was analysed by logistic regression and a propensity score-weighted analysis. A total of 316 patients received cloxacillin and 68 patients received penicillin G as final treatment. Mortality rates did not differ significantly between the treatment groups (cloxacillin 19% vs. penicillin G 13%; P = 0.24), but patients treated with cloxacillin had an increased odds of having any complication compared with patients treated with penicillin G (odds ratio = 2.43, 95% confidence interval 1.30–4.53; P = 0.005). A propensity score analysis confirmed the results. Mortality rates in PSSA bacteraemia did not differ between treatment groups but cloxacillin treatment increased the overall odds of treatment complications.
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| 49. |
- Hanberger, Håkan, et al.
(författare)
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Increased mortality associated with meticillin-resistant Staphylococcus aureus (MRSA) infection in the Intensive Care Unit: results from the EPIC II study
- 2011
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier. - 0924-8579 .- 1872-7913. ; 38:4, s. 331-335
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Tidskriftsartikel (refereegranskat)abstract
- Controversy continues regarding whether the presence of meticillin resistance increases mortality risk in Staphylococcus aureus infections. In this study, we assessed the role of meticillin resistance in survival of patients with S. aureus infection included in the EPIC II point-prevalence study of infection in critically ill patients performed on 8 May 2007. Demographic, physiological, bacteriological and therapeutic data were collected for 13 796 adult patients in 1265 participating Intensive Care Units (ICUs) from 75 countries on the study day. ICU and hospital outcomes were recorded. Characteristics of patients with meticillin-sensitive S. aureus (MSSA) and meticillin-resistant S. aureus (MRSA) infections were compared. Co-morbidities, age, Simplified Acute Physiology Score (SAPS) II, site of infection, geographical region and MRSA/MSSA were entered into a multivariate model, and adjusted odds ratios (ORs) [95% confidence interval (CI)] for ICU and hospital mortality rates were calculated. On the study day, 7087 (51%) of the 13 796 patients were classified as infected. There were 494 patients with MRSA infections and 505 patients with MSSA infections. There were no significant differences between the two groups in use of mechanical ventilation or haemofiltration/haemodialysis. Cancer and chronic renal failure were more prevalent in MRSA than in MSSA patients. ICU mortality rates were 29.1% and 20.5%, respectively (P andlt; 0.01) and corresponding hospital mortality rates were 36.4% and 27.0% (P andlt; 0.01). Multivariate analysis of hospital mortality for MRSA infection showed an adjusted OR of 1.46 (95% CI 1.03-2.06) (P = 0.03). In ICU patients, MRSA infection is therefore independently associated with an almost 50% higher likelihood of hospital death compared with MSSA infection.
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| 50. |
- Holmberg, Anna, et al.
(författare)
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Antibiotic regimens with rifampicin for treatment of Enterococcus faecium in biofilms.
- 2014
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier BV. - 1872-7913 .- 0924-8579. ; 44:1, s. 78-80
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Tidskriftsartikel (refereegranskat)abstract
- Enterococcus faecium is an important pathogen that is resistant to many antibiotics and is able to form biofilms on implanted medical devices. In this study, the efficacy of rifampicin-containing antibiotic regimens against biofilms of E. faecium in vitro was investigated by determination of the minimum biofilm eradication concentration and by time-kill experiments of bacteria in biofilms formed on beads of bone cement. Rifampicin combined with tigecycline, daptomycin or linezolid was more efficient in reducing bacterial numbers and halting the development of rifampicin resistance than the combination of rifampicin and vancomycin.
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