Dissertations / Theses on the topic 'Antimicrobial infections'
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1
Baelo, Álvarez Aida. "New antimicrobial strategies against bacterial infections." Doctoral thesis, Universitat de Barcelona, 2021. http://hdl.handle.net/10803/673587.
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Bacterial infections are a major health concern worldwide due to the mortality and comorbidity associated levels. Besides the development of drug-resistance mechanisms, most recalcitrant infections are caused by bacteria forming biofilms, which are bacterial communities that grow within an extracellular polymeric substance (EPS) matrix that protects bacterial cells from the action of antimicrobials and immune mechanisms. The frequent appearance and spreading of bacterial drug-resistant strains, together with the recalcitrance of infections caused by biofilms, has pointed out the urgent need to develop novel antibacterial agents that target essential bacterial processes and biofilm-forming bacteria. This thesis investigated the development of new antibacterial strategies by both targeting bacterial essential processes and biofilm-forming bacteria. Ribonucleotide reductase (RNR) are essential enzymes required by any cellular organism, since they catalyze the synthesis of deoxyribonucleotides, critical for both DNA synthesis and repair processes. Due to its key role in DNA replication, several RNR inhibitors have been developed as antiproliferative drugs in cancer and infectious diseases. Amongst RNR inhibitors, radical scavenger molecules have proved for long its inhibitory activity against the RNR enzyme, including some cytotoxic hydroxylamine derivatives such as hydroxyurea (HU). Here, the use of hydroxylamine derivative compounds as antibacterial agents specifically targeting the bacterial RNR enzyme was investigated. The results provided show that N-methyl-hydroxylamine (M-HA) molecule and some newly synthesized Nhydroxylamine derivative molecules (N-HA) inhibit bacterial RNR, displaying a wide range of antibacterial activity against different bacterial pathogens, together with low cytotoxicity to eukaryotic cells. Also, M-HA molecule shows intracellular antimycobacterial activity during macrophages infection, together with Pseudomonas aeruginosa in vitro antibiofilm activity. Several of the N-HA molecules display antibiofilm activity against P. aeruginosa, Staphylococcus aureus, and Escherichia coli biofilms, and we demonstrate the ability of such molecules to inhibit bacterial growth by radical scavenging of the RNR enzyme. Further, this thesis explores the use of a drug delivery system based on poly(lactic-co-glycolic) (PLGA) nanoparticles (NPs) to remove P. aeruginosa biofilms by combining the action of the antibiotic ciprofloxacin and the DNA-hydrolytic activity of the deoxyribonuclease I enzyme (DNase I). The synthesized biodegradable PLGA NPs, loaded with ciprofloxacin and functionalized with DNase I through poly(lysine) (PL) coating, synergistically improve the ciprofloxacin antibacterial efficacy by disassembling the extracellular DNA, one of the main components of the EPS matrix.
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Irom, Sara Julie. "High Dose Antimicrobial Protocols for Canine Urinary Tract Infections." The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1274464691.
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Braithwaite, M., Vuuren SF Van, and AM Viljoen. "Validation of smoke inhalation therapy to treat microbial infections." Elsevier, 2008. http://encore.tut.ac.za/iii/cpro/DigitalItemViewPage.external?sp=1000386.
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Aim of the study: In traditional healing, the burning of selected indigenous medicinal plants and the
inhalation of the liberated smoke are widely accepted and a practiced route of administration. This
study elucidated the rationale behind this commonly practiced treatment by examining the antimicrobial
activity for five indigenous South African medicinal plants commonly administered through inhalation
(Artemisia afra, Heteropyxis natalensis, Myrothamnus flabellifolius, Pellaea calomelanos and Tarchonanthus
camphoratus).
Material and Methods: An apparatus was designed to simulate the burning process that occurs in a traditional
setting and the smoke fraction was captured for analysis and bioassay. Methanol and acetone
extracts as well as the essential oil (for the aromatic species) were prepared and assayed in parallel with
the smoke fraction.
Results: Antimicrobial data revealed that in most cases, the ‘smoke-extract’ obtained after burning had
lower minimum inhibitory concentration (MIC) values than the corresponding solvent extracts and essential
oils. The combustion, acetone and methanol extracts produced different chromatographic profiles as
demonstrated for Pellaea calomelanos where several compounds noted in the smoke fraction were not
present in the other extracts.
Conclusion: These results suggest that the combustion process produces an ‘extract’ with superior antimicrobial
activity and provides in vitro evidence for inhalation of medicinal smoke as an efficient mode of
administration in traditional healing.
4
Trienekens, Theodora Antoinetta Maria. "Urinary tract infections and antimicrobial agents A study into factors influencing the efficacy of antimicrobial agents /." Maastricht : Maastricht : Rijksuniversiteit Limburg ; University Library, Maastricht University [Host], 1993. http://arno.unimaas.nl/show.cgi?fid=5757.
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Smith, Sharon Phillips. "Community-acquired Urinary Tract Infections| Treatment, Outcomes, and Antimicrobial Resistance." Thesis, University of California, Berkeley, 2014. http://pqdtopen.proquest.com/#viewpdf?dispub=3616604.
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Community-acquired urinary tract infections (CA-UTI) are common in young women. Reports of increasing resistance to the antimicrobial drugs commonly prescribed to treat CA-UTI, evidence of wide-spread dissemination of strains of multi-drug resistant i that can cause community outbreaks and expanding appreciation of the importance of the rational use of antibiotics are challenging the traditional management of this disease.
Two population-based studies were performed to investigate the epidemiological features of CA-UTI with an emphasis on the antimicrobial resistance of causative bacteria. An eight-year retrospective cohort study was conducted in a large health maintenance organization to identify changes in uropathogen etiology and antimicrobial resistance and in empirical antimicrobial treatment practices and outcomes. A cross-sectional study was performed in a university population to investigate the relationship between changes in the prevalence of genotype-based clonal groups of uropathogen E. coli and the prevalence of antimicrobial resistance.
From 1998 through 2005, less than 20% of the Escherichia coli causing uncomplicated CA-UTI (UCA-UTI) were resistant to the first line empirical treatment antimicrobial, trimethoprim/sulfamethoxazole (TMP/SMX). No trends were detected in the proportions of Escherichia coli that were resistant to TMP/SMX or to nitrofurantoin. In contrast, a small but steady increase in the proportion of Escherichia coli that were resistant to ciprofloxacin was observed. Over the same period of time, the use of ciprofloxacin as empirical treatment for UCA-UTI steadily increased while the use of TMP/SMX decreased. No sustained decreases in treatment failure or in microbiologically incompatible treatment were detected. Thus TMP/SMX remains a viable empirical treatment for women with UCA- UTI in these populations. Molecular typing of Escherichia coli causing CA-UTI revealed that the prevalence of antimicrobial resistance was influenced by a small number of Escherichia coli clonal groups. This suggests that the prevalence of antimicrobial resistant UTI in a community is not only the result of community prescribing practices and individual antimicrobial use but can be significantly impacted by the introduction and circulation of strains of uropathogens that are already drug resistant. Thus, strategies developed to maintain the usefulness of empirical treatment options for CA-UTI must include interventions that target sources of antimicrobial resistant uropathogens.
6
Fasugba, Oyebola. "Antimicrobial resistance in urinary tract infections caused by Escherichia coli." Thesis, Australian Catholic University, 2017. https://acuresearchbank.acu.edu.au/download/67ce6b272ae23ebc1ea1e8727d748f9cc7a61a59c3d5c0c98d2d1d0350c55a51/5885672/Fasugba_2017_Antimicrobial_resistance_in_urinary_tract_infections.pdf.
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Urinary tract infections (UTI) are one of the most common bacterial infections in hospital and community settings requiring antimicrobial treatment. Escherichia coli (E. coli), a bacterium frequently implicated in UTI, is becoming increasingly resistant to antimicrobials. Antimicrobial resistance (AMR) reduces the effectiveness of antimicrobial agents, leading to difficulty in treatment of patients, with the potential to prolong the duration of illness and increase mortality in patients. To date in Australia, there is a paucity of data comparing resistance patterns over time for hospital- and community-acquired E. coli UTI with no published data on incidence and risk of urinary E. coli resistance in Australia. Ciprofloxacin, a high priority critically important antimicrobial, is not recommended for empirical therapy of UTI yet resistance to this antimicrobial agent is increasing. There are no systematic reviews of studies investigating ciprofloxacin resistance in hospital- and community-acquired E. coli UTI. Therefore, the research program sought to address these knowledge gaps in three separate but interrelated studies. The research described in this thesis is the first of its kind in Australia.
7
Bendall, J. B. "Bacterial resistance to antimicrobial agents in geriatric medical wards." Thesis, University of Nottingham, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.381441.
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Powis, Samantha. "Chlorine Dioxide for the Prevention of Biomaterial-Associated Infections." Diss., Tucson, Arizona : University of Arizona, 2005. http://etd.library.arizona.edu/etd/GetFileServlet?file=file:///data1/pdf/etd/azu%5Fetd%5F1307%5F1%5Fm.pdf&type=application/pdf.
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Tassev, Dimiter V. "Antimicrobial susceptibility testing of novel anticancer derivatives against infectious bacteria for the potential minimization of nosocomial infections." Connect to resource, 2006. http://hdl.handle.net/1811/6457.
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Thesis (Honors)--Ohio State University, 2006.Title from first page of PDF file. Document formatted into pages: contains 27 p.; also includes graphics. Includes bibliographical references (p. 24-27). Available online via Ohio State University's Knowledge Bank.
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More, G. K. (Garland Kgosi). "Antimicrobial constituents of Artemisia afra Jacq. ex Willd. against periodontal pathogens." Diss., University of Pretoria, 2012. http://hdl.handle.net/2263/24659.
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The phytochemical investigation of an ethanol extract of Artemisia afra, led to the isolation of six known compounds, Acacetin (1) 12α,4α-dihydroxybishopsolicepolide (2), Scopoletin (3) α-amyrin (4), Phytol (5) and a pentacyclic tri-terpenoid Betulinic acid (6). The isolated compounds were evaluated for their anti-microbial activity against Gram positive (Actinomyces naeslundii, Actinomyces israelii and Streptococcus mutans), Gram negative bacteria (Privotella intermedia, Porphyromonus gingivalis and Aggregatibacter actinomycetemcomitans previously known as Actinobacillus actinomycetemcomitans) and Candida albicans. The crude extract of A. afra inhibited the growth of all tested microbial species at concentration range of 1.6 mg/ml to 25.0 mg/ml. The compounds 1-6 also showed activity range at 1.0 mg/ml to 0.25 mg/ml. Three best compounds which showed good activity were selected for further studies. Cytotoxicity of the extract and compounds was determined using the XTT (Sodium 3’-[1-(phenyl amino-carbonyl)-3,4-tetrazolium]-bis-[4-methoxy-6-nitro] benzene sulfonic acid hydrate) cell proliferation kit. The antioxidant activity of the extract and compounds was done using the DPPH scavenging method. The extract showed good antioxidant activity with an IC50 value of 22.2 μg/ml. Scopoletin had a strong transformation of the DPPH radical into its reduced form, with an IC50 value of 1.24 μg/ml which was significant to that of vitamin C (1.22 μg/ml). Acacetin and Betulinic acid exhibited a decreased scavenging activity with the IC50 of 2.39 and 2.42 _g/ml, respectively. The extract and compounds showed moderate toxicity on McCoy fibroblast cell line and the extract influenced the release of cytokine against Hep2 cells. Scopoletin was relatively non-toxic with an IC50 value of 132.5 μg/ml. Acacetin and betulinic acid also showed a smooth trend of non-toxic effects at lower concentrations and toxic at higher concentrations with IC50 values of 35.44 and 30.96 μg/ml. The obtained results in this confirmed the use of A. afra in the treatment of microbial infections.Dissertation (MSc)--University of Pretoria, 2012.
Plant Science
unrestricted
11
Lo, Joey Chor Yee. "Novel antimicrobial peptide coating to prevent catheter-associated urinary tract infections." Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/56262.
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Introduction: Urinary catheters provide ideal surfaces for bacterial biofilm formation, being a major factor for hospital-acquired infections. With increased antibiotic resistance, there is a push for non-antibiotic-based measures to prevent catheter-associated urinary tract infections (CAUTI). I pursue the use of polymer-linked, broad-spectrum, host-defense-based antimicrobial peptides (AMPs) as novel catheter coatings. Here, I present the efficacy of tethered AMPs against common uropathogens both in vitro and in vivo.
Materials and Methods: Peptides E6, Tet20, Tet26, and Kai13 were linked to surfaces using polymer brushes PDMA, PMPC, and PMPDSAH. All peptides were chosen based on their antimicrobial activity and biocompatibility as suggested by previously published papers. Antimicrobial activity of each coating was determined in vitro via colony counts 6 hours post-exposure to uropathogens. The in vivo efficacy of AMP coatings was also tested using a clinically relevant CAUTI mouse model; bladders of mice were catheterized percutaneously under ultrasound guidance, and 50 μL of 5E+5 CFU/mL P. aeruginosa was instilled. Indwelling polyurethane catheters and urine were collected after 7 days for examination of bacterial adherence and growth.
Results: The most effective peptide-brush combination was E6-PDMA, decreasing bacterial adhesion and planktonic growth by up to 94.1% and 63.8%, respectively based on in vitro data. In vivo results look even more promising; the coating decreased bacterial adhesion by up to 99.9958% and planktonic growth by 99.8660% in comparison to untreated mice.
Conclusions: Based on our in vitro and in vivo data, E6-PDMA coatings may effectively prevent CAUTI. Further testing of these novel coatings against more common uropathogens as well as tests to confirm the safety of such coatings will be important.Medicine, Faculty of
Medicine, Department of
Experimental Medicine, Division of
Graduate
12
Halstead, Fenella. "Developing novel topical antimicrobial agents for the treatment of biofilm infections." Thesis, University of Warwick, 2017. http://wrap.warwick.ac.uk/101063/.
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Background Bacterial wound infections (especially those involving biofilms) represent a major challenge to healthcare, and are responsible for significant morbidity and mortality. Owing to the rise in antimicrobial resistance, there is renewed interest in alternative antimicrobial agents for treatment of wound infections, where prevention of colonisation largely relies on topically applied biocides. Objectives The aim was to investigate the antibacterial activity of acetic acid (AA), following on from preliminary testing, and small-scale use on burns patients. This led on to the testing of additional products (SurgihoneyRO (SH1) and blue light (BL)), for which no prior evaluation (against biofilms) had been performed. Methods In vitro experiments were performed to test the antimicrobial activity of the agents against bacteria growing planktonically and as biofilms. Comparisons were also made to a range of commercially-available antimicrobial dressings (AMDs) and medical honeys. Results were assessed through measurement of biofilm biomass, and biofilm seeding using a crystal violet assay. Results All agents were effective against biofilms of a large panel of clinically important nosocomial wound pathogens. AA could prevent biofilm formation at concentrations of ≤0.31%, and eradication of mature biofilms was observed after 3 hours of exposure. SH1 prevented biofilm formation of 16 bacterial isolates at dilutions (from neat) of 1:2 to 1:128. Mature biofilms were highly susceptible to BL, with significant reduction in seeding observed for all isolates. Conclusions All of the test antimicrobial agents have shown promise in vitro for the treatment and eradication of biofilm infections caused by a range of important wound pathogens. However, there are still some unanswered questions. Clinical trials are planned, and it remains to be seen whether the in vitro findings will translate to the in vivo setting, where there is a complex interplay between host and pathogen, and many other factors that influence biofilm presence and persistence.
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Bezruk, Т. О., and V. V. Bezruk. "Etiological structure and antimicrobial resistance in pathogens causing urinary tract infections." Thesis, Sumy State University, 2016. http://essuir.sumdu.edu.ua/handle/123456789/47823.
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There is an increase of the number of patients with urinary tract infections in Ukraine. The objective is the definition of the range of sensitivity to the antibiotics of major groups of pathogens of the urinary system among the population of the Chernivtsi region. In order to conduct an accurate bacteriological study 2828 urine samples of patients of medical institutions in the Chernivtsi region were analyzed during 2009 – 2013. Our aim was the verification of the diagnosis «urinary tract infections» (UTI).
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Phee, Lynette. "Unorthodox antimicrobial combination therapies for the treatment of multi-drug resistant Gram-negative infections." Thesis, Queen Mary, University of London, 2018. http://qmro.qmul.ac.uk/xmlui/handle/123456789/44695.
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The rise of antimicrobial resistance (AMR) has culminated in the most pressing problem in modern medicine. The situation is most acute with regards to the management of multi- drug resistant Gram-negative infections (MDRGNB) with common infections increasingly untreatable due to rapidly dwindling therapeutic options. A solution to the problem of AMR is unlikely to be easily found, but revisiting and re-purposing existing antimicrobials is a viable approach in the medium term. This study investigated the use of unorthodox antimicrobial combination therapies for the treatment of MDRGNB, with particular focus on agents of last resort. A systematic review of clinical studies highlighted the potential for polymyxin (colistin) combination therapies (e.g. colistin-rifampicin, colistin-carbapenems), although this could not be supported in a formal meta-analysis. A systematic approach for screening MDRAB for susceptibility to novel colistin combinations using multiple methods was employed and uncovered a number that were more potent than those previously identfied. The most potent combination that was consistently identified was colistin when combined with fusidic acid, despite this drug having no useful activity against MDRGNB on its own. The combination was further evaluated in static time-kill assays against a range of Gram-negative pathogens with defined resistance mechanisms, including to polymyxins and using invertebrate (Galleria mellonella) and murine models of MDRGNB infection. Colistin and fusidic acid combination therapy was subsequently used to successfully treat a case of ventilator-associated pneumonia due to MDR A. baumannii. This work highlights how older drugs can be re-purposed to tackle the problem of AMR using a precision medicine approach. Further studies to elucidate the mechanism of action of the colistin- fusidic acid combination and a formal clinical trial are warranted to investigate the potential utility of this combination in the treatment of MDRGNB with the expressed goal of bridging the current antimicrobial development gap.
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Ironmonger, Dean. "An investigation into the relationship between antimicrobial prescribing and antimicrobial resistance in urinary tract infections at a population level." Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/8531/.
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The inappropriate use of antibiotics is a key factor in the development of antimicrobial resistance (AMR). UK national guidance has been ineffective in standardising the management of infections in the community. Many prescribers in the community are sceptical that their actions have an effect on AMR in their locality. As part of this study, routine surveillance of AMR in a large regional population was established. To help interpret surveillance data, two surveys were undertaken: a survey of laboratory methods, and a survey of GP sampling and prescribing protocols. Using these survey results, surveillance tools were developed to provide hospital and community prescribers with data on antibiotic resistance in bacteria within their locality; and enable laboratories to compare methods for determining antibiotic susceptibility. This thesis demonstrated that routine AMR surveillance can be used to monitor key antibiotic resistance, detect emergence of new or unusual resistance mechanisms, and enable the bench-marking of laboratory methods. This study was also able to demonstrate that small increases in antibiotic prescribing by individual GPs increases the number of non-susceptible bacteria isolated from specimens taken from their practice population. The results of this thesis provides supporting evidence to those developing strategies to combat AMR in the community.
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Mottola, Carla. "Virulence characterization and antimicrobial resistance of major bacterial genera from diabetic foot infections." Doctoral thesis, Universidade de Lisboa, Faculdade de Medicina Veterinária, 2017. http://hdl.handle.net/10400.5/14119.
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Tese de Doutoramento em Ciências Veterinárias na especialidade de Ciências Biológicas e BiomédicasDiabetes mellitus is a major chronic disease that continues to increase significantly. One of the most important and costly complications of diabetes is the development of foot ulcers, colonized by pathogenic and antimicrobial resistant bacteria, which may be responsible for impairing its successful treatment. Diabetic foot ulcer (DFU) bacterial communities can be organized in polymicrobial biofilms, which may be responsible for its chronicity. The ability of these communities to produce biofilm was evaluated and was higher when compared to biofilm formation by individual species. Staphylococcus aureus is one of the most prevalent species in diabetic foot infections (DFI). Staphylococci isolated from DFU in patients from the Lisbon area were identified, genotyped and screened for virulence and antimicrobial resistance traits. The isolates showed high genomic diversity, were resistant to important clinically antibiotics and expressed relevant virulence determinants. As biofilm formation is one of the most important virulence traits of S. aureus, the antimicrobial susceptibility patterns of biofilm-producing S. aureus strains were also analysed. The minimum biofilm inhibitory and eradication concentrations were determined for ten antimicrobial compounds. Staphylococci biofilms were resistant to antibiotic concentrations ten to thousand times higher than those effective for planktonic cells. Furthermore, the enterococci frequently isolated from DFI, were also identified and characterized, showing high antimicrobial resistance and important virulence traits. Since DFI are often caused by resistant bacteria, it is necessary to find alternatives to antibiotic therapy, such as phage therapy. The inhibitory potential of five bacteriophages, previously characterized, was evaluated against established biofilms formed by S. aureus, P. aeruginosa and A. baumannii. A significant cell reduction after phage exposure was observed, mainly after multiple treatments. DFI are very complex and studies on this topic are scarce. It is necessary to intensify research in order to develop more adequate therapeutic protocols for this type of infection.
RESUMO - Caracterização da virulência e resistência a antimicrobianos dos principais géneros bacterianos envolvidos em infeções de pé diabético - Diabetes mellitus é uma doença crónica com grande impacto em saúde pública e cuja incidência continua a aumentar significativamente em todo o mundo, atingindo atualmente mais de 400 milhões de pessoas. Uma das complicações mais importantes da diabetes e associada a gastos económicos significativos são as úlceras de pé diabético. Uma vez que a camada protetora de pele é danificada, os tecidos profundos ficam expostos à infeção bacteriana, a qual pode evoluir rapidamente. As infeções das úlceras de pé diabético são a causa mais comum de internamento hospitalar de pacientes diabéticos e uma importante causa de morbilidade, levando frequentemente à amputação dos membros inferiores. Estas infeções podem ser promovidas por bactérias potencialmente patogénicas e resistentes aos compostos antimicrobianos, prejudicando assim o sucesso do tratamento. As comunidades bacterianas presentes nas úlceras podem estar organizadas em biofilmes polimicrobianos, que contribuem para que as infeções se tornem crónicas e muito difíceis de resolver. Foi avaliada a capacidade de produção de biofilme por comunidades polimicrobianas de isolados bacterianos de pé diabético, utilizando um ensaio de microtitulação em placa com “Alamar Blue” (AB) e uma técnica de Hibridação In Situ Fluorescente Múltipla (MFISH). Esta avaliação foi realizada em três períodos de incubação distintos (24, 48 e 72 horas), depois da determinação da capacidade de formação de biofilme por 95 isolados de úlceras de pé diabético pertencentes a vários géneros bacterianos (Staphylococcus, Corynebacterium, Enterococcus, Pseudomonas e Acinetobacter). Todos os isolados apresentaram a capacidade de produzir biofilme às 24 horas, sendo que a quantidade de biofilme produzido aumentou com o tempo de incubação. Pseudomonas apresentou a capacidade mais elevada de produção de biofilme, seguida de Corynebacterium, Acinetobacter, Staphylococcus e por fim, Enterococcus. Foram encontradas diferenças estatisticamente significativas na capacidade de formação de biofilme entre os três períodos de incubação. As comunidades polimicrobianas produziram mais biofilme do que as espécies individualmente. As comunidades formadas por Pseudomonas + Enterococcus, Staphylococcus + Acinetobacter e Corynebacterium + Staphylococcus formaram mais biofilme do que as comunidades formadas por Enterococcus + Staphylococcus e por Enterococcus + Corynebacterium. O comportamento biológico das diferentes espécies bacterianas nos biofilmes polimicrobianos tem implicações clínicas muito importantes para o sucesso do tratamento deste tipo de infeções. A sinergia entre as bactérias presentes em biofilmes multiespécies foi descrita previamente, sendo que este trabalho representa o primeiro estudo sobre a evolução temporal da formação de biofilme por parte de comunidades polimicrobianas isoladas de úlceras de pé diabético, incluindo várias espécies. [...]
Centro de Investigação Interdisciplinar em Sanidade Animal” (CIISA) of Faculty of Veterinary Medicine, University of Lisbon, Portugal
N/A
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Chu, Pui-shan, and 朱佩珊. "Antimicrobial resistant escherichia coli and sequence type 131 in urinary tract infections." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/206499.
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Background
A pandemic clone, Escherichia coli sequence type 131 (ST131), has been disseminated worldwide and represents an important cause of antimicrobial resistant infections. The spread of this resistant clone has become a great public health concern.
Objectives
The aims of this study were to investigate the prevalence of ST131 in Escherichia coli isolates from human urinary cultures in Hong Kong and study the antimicrobial phenotypes of ST131.
Methodology
This study included 340 E. coli clinical urinary isolates obtained from patients in four district hospitals between May 2013 and July 2013 in Hong Kong. Antimicrobial susceptibilities were assessed by disk diffusion method with reference to CLSI. The isolates were investigated by phylogroup-specific and ST131-specific PCR assays. ST131 strains were further assessed for subclone distribution, antimicrobial resistance and extended-spectrum β-lactamase (ESBL) type.
Results
A total of 18.5% (63/340) of the E. coli population was identified as ST131. ST131 isolates were significantly more likely than non-ST131 isolates to be ciprofloxacin resistant (69.8%, 44/63 versus 31.0%, 86/277; P <0.001), gentamicin resistant (38.1%, 24/63 versus 24.9%, 69/277; P=0.03) and ESBL producers (41.3%, 26/63 versus 18.8%, 52/277; P <0.001). Among the ST131 E. coli isolates, 68.3% (43/63) belonged to the H30 subclone. Most H30 isolates were ST131-O25b (97.7%, 42/43). Also, the ST131-H30 E. coli subclone was statistically associated with ciprofloxacin resistance compared with the non-H30 ST131 isolates (P <0.001). Additionally, strains which were co-resistant to ciprofloxacin, co-trimoxazole and gentamicin were overwhelmingly associated with the H30 subclone than non-H30 (23.3%, 10/43 versus 0%, 0/20; P=0.02).
Conclusion
This study showed that ST131 isolates were widespread among human E. coli urinary isolates in Hong Kong. The increase in antimicrobial resistance phenotypes are highlighted with ST131, especially the H30 subclone isolates. The dissemination of the ST131 resistant clonal group has aroused clinical attention and limited the choice of empirical treatment.published_or_final_version
Medical Sciences
Master
Master of Medical Sciences
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Raja, Farah. "Development and characterisation of novel antimicrobial phosphate glasses for urinary tract infections." Thesis, Aston University, 2018. http://publications.aston.ac.uk/37661/.
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Urinary tract infections (UTIs) affect significant proportions of the population, particularly prevalent in elderly patients. Up to 40 % of healthcare associated infections are UTIs and 80% of those are associated with catheter use. CA-UTIs significantly effect patient’s health and are frequently associated with substantial morbidity and mortality. Furthermore, the financial implications are enormous as the high complication rate arising from catheterisation requires significant time and cost. In the UK, more than a million cases are reported each year accounting for annual economic burden of approximately £125 million. The aim of this study was to develop novel antimicrobial bioactive glasses that can be used to prevent and treat catheter associated urinary tract infections. This was achieved by assessing the antimicrobial efficacy of increasing cobalt or zinc content (1, 3, 5 and 10 mol %) in phosphate based glass system (P2O5-Na2O-CaO). Glass compositions with two metal oxides (cobalt, copper or zinc) were also studied to determine synergistic combinations against a panel of clinically relevant microorganisms. A decrease in the dissolution rates of cobalt glasses was seen with increasing cobalt content, however an increase in dissolution rate was observed with higher zinc content (5% and 10%). A strong antimicrobial activity was exhibited by 5 and 10 mol % cobalt or zinc doped glasses which was not only time dependent but also strain specific. Moreover, combinations such as Co/Cu, Co/Zn and Cu/Zn showed synergism against E. coli and S. aureus. Whilst a strong antimicrobial activity was seen, the cytotoxic studies demonstrated decrease in cell viability of mammalian cells when exposed to glasses directly and their dissolution products. Nevertheless, cobalt and/or zinc doped phosphate based glasses could potentially be used as a cartridge in drainage bags or to coat catheters with a decreasing amount to prevent cytotoxic effects.
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Czuban, Magdalena Anna [Verfasser]. "Antimicrobial biomaterials for treatment of bone and implant infections / Magdalena Anna Czuban." Berlin : Freie Universität Berlin, 2020. http://d-nb.info/1215572069/34.
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Carzoli, Joshua, and Cody Thompson. "A systematic review of pharmacotherapy for diabetic foot infections." The University of Arizona, 2010. http://hdl.handle.net/10150/623762.
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Class of 2010 AbstractOBJECTIVES:The main purpose of this study was to review recent and good quality studies of the antimicrobial therapy of for moderate to severe (“limb threatening”) DFI. The analysis of these studies was to conclude with one or two “standard” approach to the routine management of this clinical entity. METHODS: This literature review study consisted of an evaluation of clinical trials that compare two or more active systemic antimicrobial regimens for the treatment of moderate to severe (i.e., “limb-threatening”) diabetic foot infections in human patients. Literature sources were identified primarily from OVID MEDLINE, but also included additional tertiary sources. The primary criteria for the clinical studies were: prospective, controlled, randomized and investigator blinded. Studies had to be published after the year 2003, and be available in full-text in English. RESULTS: Ultimately, only four studies were found that met the criteria for consideration. Trials differed in numerous features. All four studies were sponsored by the manufacturer of one of the comparator drugs. Three of the four were non-inferiority design. Evidence is lacking that any of the suggested regimens are superior. CONCLUSIONS: Instead of meeting our original goal of concluding that one or two regimens could be the “standard” management of DFI, we were limited to commentary on the quality and applicability of the current literature on this clinical entity. Numerous suggestions for improvement in the clinical information provided by DFI studies were offered. We eagerly anticipate the publication of the updated IDSA guideline document on DFI.
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Gharse, Sachin. "Antibacterial strategies for improved eradication of Pseudomonas aeruginosa infections." Diss., University of Iowa, 2018. https://ir.uiowa.edu/etd/6110.
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Cystic fibrosis (CF) is a hereditary multi-organ disorder characterized by formation of thick, viscous mucus in the lungs, leading to decreased fluid clearance and significant bacterial colonization. The bacteria form colonies, called biofilms, that are attached to the mucosal surface and produce a protective polymeric matrix. The matrix helps the biofilms form stable structures in the lungs while also protecting the embedded bacterial colonies from the host defense system and antimicrobials. Pseudomonas aeruginosa are opportunistic bacteria that commonly infect CF airways in the biofilm form. Current antibiotic treatment regimens fail to completely eradicate these biofilms, leading to chronic, persistent infections that over time lead to patient death. Therefore, there is a need to investigate antibacterial strategies that would completely eradicate these infections at reasonable doses and improve quality of patients’ lives.
In this thesis, two strategies are investigated to better eradicate bacterial colonies – (1) the use of nutrient dispersion compounds for increasing the susceptibility of biofilm bacteria to the co-administered antibiotics, and (2) PEGylation of antimicrobial peptides to increase peptide retention in the lung airways.
Clinical strains of P. aeruginosa isolated from lungs of CF patients were used in this research to better mimic the greater robustness of clinical biofilms compared to biofilms of laboratory bacterial strains. Growth curve studies were carried out to characterize the growth patterns of the bacterial strains. Antibiotic susceptibility of the planktonic (free-flowing) bacteria was studied using the minimum inhibitory concentration (MIC) assay. A method to grow and characterize 1-day and 4-day old biofilms in the minimum biofilm eradication concentration (MBEC) assay apparatus was developed and characterized. The MBECs of combination formulations consisting of an antibiotic and a nutrient dispersion compound for different treatment durations were measured against biofilms of the clinical isolates using four commonly used antibiotics, and sodium citrate as the nutrient dispersion compound.
The growth curve studies allowed for better understanding of the clinical isolates’ growth rates in vitro, which could play an important role on their susceptibility to antibiotics. All bacterial strains displayed susceptibility to tobramycin sulfate and ciprofloxacin hydrochloride. Uniform bacterial growth was observed for 1-day old biofilms of both clinical isolates across all pegs. Growing 4-day old biofilms using 100% MHB without refreshing the bacterial suspension over 4 days gave uniform biofilm bacterial growth across the pegs. Four-day old biofilms displayed greater biomass than 1-day old biofilms for 2 out of 3 bacterial strains. Combination formulations eradicated 1-day and 4-day old biofilms at lower antibiotic concentrations than the antibiotic alone, with further improvement in eradication after increasing the duration of treatment. Sodium citrate did not enhance the metabolic activity of the biofilm bacteria.
The antimicrobial peptide CaLL was conjugated with different MW polyethylene glycol (PEG) molecules using disulfide and maleimide linkages, and the effect of PEGylation on its antibacterial activity against P. aeruginosa laboratory strain PAO1 was evaluated. PEGylation was observed to reduce bacterial growth inhibition by CaLL, with the disulfide-linked CaLL-PEG less efficacious than the maleimide-linked CaLL-PEG. Time-kill assays demonstrated the longer duration of action of PEGylated peptides compared to non-PEGylated peptides, probably due to prevention of enzymatic degradation of the peptide by the PEG molecule.
This research will shed light on antibacterial strategies for complete and rapid eradication of bacterial biofilms, thereby reducing development of antibiotic resistance and prevent recurrence of infection, reducing progressive lung damage caused in people with CF, and improve their quality of life.
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Pegg, Elaine. "Eimeria species as novel antimicrobial vaccine delivery vectors." Thesis, Royal Veterinary College (University of London), 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.701658.
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Beaumont, Paula Elizabeth. "Cathelicidin and its role in defence against bacterial infections of epithelial cells." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/15847.
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Cathelicidins are antimicrobial peptides (AMPs) that were first discovered to have microbicidal properties but more recently to be multifunctional immunomodulators and thus important in influencing host defence against infectious disease. Whilst roles in various organs have been demonstrated, their expression patterns in health and disease in other organs are less clear and their key immunomodulatory functions remain undefined, particularly with regard to the balance of immunomodulatory properties and microbicidal activity in their ability to promote defence against infection. I therefore set out to describe LL-37 expression (human cathelicidin) in the female reproductive tract (across the menstrual cycle) and in the lung (during specific lung diseases), to define the effects on the function of airway epithelial cells during bacterial infection and to evaluate the key in vivo roles of endogenous cathelicidin (using a knockout mouse model) as well as the effect of therapeutic administration of LL-37 in a pulmonary Pseudomonas aeruginosa infection model. I demonstrated that cathelicidin protein and transcription shows a cyclical pattern of expression in female reproductive tissues which is maintained at high levels in decidua. LL- 37 protein was also detected in hTERT endometrial epithelial cells but despite the suggestion that cathelicidin may be regulated by steroid hormones there was no direct effect of progesterone on transcription. LL-37 is barely detected in healthy airways however is well known to increase during infection or inflammation. I observed that sputum from patients with bronchiectasis showed a correlation between the level of LL-37, TNF, MPO and chronic colonisation of Pseudomonas aeruginosa. Patients with lung cancer expressed much less LL- 37 than the bronchiectasis patients but there was a trend towards increased production postsurgery compared to pre-surgery. LL-37 was previously shown by our lab to selectively promote BAX and caspase-dependant death of infected epithelial cells. I went on to show that this appears to be a partially caspase- 1 dependent mechanism and that human bronchial epithelial (HBE) cells and A549 cell lines both express several of the components required to form inflammasomes, a caspase-1 dependant form of inflammatory cell death. Finally, I showed using murine models that cathelicidin enhances bacterial clearance during pulmonary infection in vivo, a response which is defective in mice lacking endogenous cathelicidin and that administration of exogenous, synthetic LL-37 at the time of infection can promote an early protective neutrophil influx in the absence of endogenous cathelicidin production.
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Huh, Youchin, and Tina Wang. "Appropriateness of Antimicrobial Therapy for Bloodstream Infection based on Reporting Conditions with a Rapid Species Identification Assay." The University of Arizona, 2012. http://hdl.handle.net/10150/623644.
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Class of 2012Specific Aims: The primary aim of this study was to determine the time to appropriate therapy for all patients with candidemia and/or bacteriemia (due to either Enterococcus or Streptococcus species) during a one year period in relation to time of blood culture, time of Gram-stain result, time of PNA FISH species result, and time of final species determination result. The secondary and third aims were to compare the time to appropriate therapy based on clinician group that was notified of Gram-stain result and PNA FISH result and compare the time to appropriate therapy based on PNA FISH assay results reported during the day and night microbiology laboratory shifts. Methods: This Institutional Review Board approved project is a retrospective, chart review evaluation of the 24 hour/ 7 days a week use of PNA FISH assays with therapeutic interventions by infectious diseases pharmacists and physicians on patient outcome measures and time to appropriate therapy. All patients admitted to an academic medical center during a one year period (April 2010-March 2011) with either Enterococcus, Streptococcus, or Candida species isolated from blood were included. Main Results: A total of 168 subjects were identified with Candida species isolated from 31 subjects and Enterococcus/Streptococcus species isolated from blood in 137 subjects. Conclusions: While reporting conditions can affect interpretation and intervention rates, rapid species identification assays such as PNA FISH can be used by pharmacists to provide antimicrobial therapy recommendations based on the species identification and to decrease the time to appropriate antimicrobial therapy.
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Sartelli, Massimo, Francesco M. Labricciosa, Pamela Barbadoro, Leonardo Pagani, Luca Ansaloni, Adrian J. Brink, Jean Carlet, et al. "The Global Alliance for Infections in Surgery: defining a model for antimicrobial stewardship—results from an international cross-sectional survey." BIOMED CENTRAL LTD, 2017. http://hdl.handle.net/10150/625526.
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Background: Antimicrobial Stewardship Programs (ASPs) have been promoted to optimize antimicrobial usage and patient outcomes, and to reduce the emergence of antimicrobial-resistant organisms. However, the best strategies for an ASP are not definitively established and are likely to vary based on local culture, policy, and routine clinical practice, and probably limited resources in middle-income countries. The aim of this study is to evaluate structures and resources of antimicrobial stewardship teams (ASTs) in surgical departments from different regions of the world. Methods: A cross-sectional web-based survey was conducted in 2016 on 173 physicians who participated in the AGORA (Antimicrobials: A Global Alliance for Optimizing their Rational Use in Intra-Abdominal Infections) project and on 658 international experts in the fields of ASPs, infection control, and infections in surgery. Results: The response rate was 19.4%. One hundred fifty-six (98.7%) participants stated their hospital had a multidisciplinary AST. The median number of physicians working inside the team was five [interquartile range 4-6]. An infectious disease specialist, a microbiologist and an infection control specialist were, respectively, present in 80.1, 76.3, and 67.9% of the ASTs. A surgeon was a component in 59.0% of cases and was significantly more likely to be present in university hospitals (89.5%, p < 0.05) compared to community teaching (83.3%) and community hospitals (66.7%). Protocols for pre-operative prophylaxis and for antimicrobial treatment of surgical infections were respectively implemented in 96.2 and 82.3% of the hospitals. The majority of the surgical departments implemented both persuasive and restrictive interventions (72.8%). The most common types of interventions in surgical departments were dissemination of educational materials (62.5%), expert approval (61.0%), audit and feedback (55.1%), educational outreach (53.7%), and compulsory order forms (51.5%). Conclusion: The survey showed a heterogeneous organization of ASPs worldwide, demonstrating the necessity of a multidisciplinary and collaborative approach in the battle against antimicrobial resistance in surgical infections, and the importance of educational efforts towards this goal.
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Cassin, Margaret Emily. "The Design of Antimicrobial Detachable Thin Films for the Study of Hepatic Infections." Thesis, Virginia Tech, 2015. http://hdl.handle.net/10919/77426.
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Microbial infections are a global problem. Due to the over and misuse of antibiotics, drug-resistant pathogens are becoming more common. It is imperative to explore broad spectrum antimicrobial approaches. In this work, we modified collagen/hyaluronic acid polyelectrolyte multilayers (PEMs) with the natural antimicrobial peptide, LL-37 to study hepatic infections. LL-37 was physisorbed and covalently linked to the surface of the PEMs. Escherichia coli DH10B were cultured in the presence of LL-37modified PEMs in bacterial adhesion and contact killing models. Physisorbed LL-37 PEMs prevented bacterial adhesion and could also kill pathogens in the surrounding environment due to the release of LL-37 from the film. Immobilized LL-37 PEMs resulted in less bacterial adhesion on the surface due to the presence of the peptide. Films were then placed in contact with primary rat hepatocytes as well as in hepatocyte/bacteria co-cultures. LL-37 input concentrations up to of 16μM did not exhibit cytotoxic effects on hepatocytes. The LL-37 modified PEMs exhibited a hepatoprotective effect on albumin and urea secretion functions in co-cultures. The hepatoprotective effects were dependent on the ratio of hepatocytes and bacteria as well as the concentration of LL-37. These findings are encouraging and demonstrate that LL-37 modified PEMs can be used to investigate hepatic infections caused by bacteria.Master of Science
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Omar, G. S. M. "Killing of organisms responsible for wound infections using a light-activated antimicrobial agent." Thesis, University College London (University of London), 2010. http://discovery.ucl.ac.uk/19414/.
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Infected wounds are a major cause of hospital-acquired infections and these are difficult to treat due to the emergence of antibiotic-resistant bacteria. This project is concerned with evaluating a novel antimicrobial approach involving the photosensitizer indocyanine green (ICG) which generates reactive oxygen species when irradiated with near-infrared (NIR) light which enables good tissue penetration. The photo-susceptibility of common wound-infecting organisms to ICG coupled with NIR-light was investigated. All species were susceptible to killing. ICG at a concentration of 25 μg/mL enabled the killing of the Gram-positive species (Staphylococcus aureus and Streptococcus pyogenes), higher concentrations (100-200μg/mL) were necessary to achieve substantial kills of the Gram-negative species (Pseudomonas aeruginosa and Escherichia coli). Both high and low fluences were able to kill 99.999% of the Gram-positive bacteria. High fluence irradiation was necessary to kill 99.99% of the Gram-negative bacteria. The pulsed-mode of irradiation was as effective as the continuous-mode for killing the Gram-positive species. Yet only the continuous-mode of irradiation was able to kill P. aeruginosa. Biofilms of Staph. aureus and P. aeruginosa were susceptible to disruption and killing by ICG-photosensitization. A significant enhancement of lethal photosensitization of Staph. aureus was achievable using gold-nanoparticles and antioxidants. Significant kills (>99%) were achieved in the presence of serum and 100 μg/mL ICG. A low oxygen concentration reduced the kills to 96.77% and 71.62% for Staph. aureus and Strep. pyogenes respectively. Mechanistic studies revealed that killing was mediated mainly by reactive-oxygen species. In vivo studies in mice showed that ICG and continuous-NIR light could achieve kills of 96%, 93% and 78-91% for P. aeruginosa, Strep. pyogenes and Staph. aureus respectively. The results of these in vitro and in vivo studies imply that ICG-PDT could be an effective means of decreasing the microbial burden in wounds.
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Adukwu, Emmanuel. "Investigating physiological and genetic characteristics of community acquired infections and potential antimicrobial interventions." Thesis, University of Northampton, 2013. http://nectar.northampton.ac.uk/8842/.
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Vuori-Holopainen, Elina. "Etiology and antimicrobial treatment of pneumonia and other common childhood infections warranting hospitalization." Helsinki : University of Helsinki, 2001. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/vuori-holopainen/.
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Matougui, Nada. "Development and characterization of antimicrobial peptides loaded lipid nanocapsules to treat bacterial infections." Thesis, Angers, 2017. http://www.theses.fr/2017ANGE0069.
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La multiplication des résistances aux antibiotiques constitue une grave menace qui nécessite de nouvelles stratégies antimicrobiennes. Le but de ce travail est d'étudier le potentiel des nanocapsules lipidiques (NCLs) pour l'administration de peptides antimicrobiens (PAMs). Les premiers travaux ont porté sur le développement et l'optimisation de NCLs chargées en PAMs. Différentes stratégies d’association ont été testé (adsorption à la surface ou encapsulation dans le coeur de NCLs). Les résultats ont démontré une efficacité d'association comprise entre 20 et 40%, lorsque les peptides sont adsorbés à la surface et plus de 80%,lorsqu’ils sont encapsulés. La deuxième partie s’est concentrée sur l'évaluation de l’activité des complexes PAMs et NCLs ainsi que leur stabilité vis-à-vis des protéases. Les résultats ont montré que l'adsorption entraîne une potentialisation de l'activité antimicrobienne des PAMs, associée à une protection partielle contre la dégradation enzymatique. Inversement, l’encapsulation des PAMs montre une meilleure stabilité aux enzymes, corrélée à une efficacité d'encapsulation supérieure sans amélioration de l'activité antimicrobienne in vitro. Dans une troisième partie, les mécanismes impliqués dans les interactions LNC/PAM ainsi que l'interaction du complexe avec un modèle de membrane bactérienne ont été étudiés. Il a été montré que la structure et la flexibilité des PAMs aux interfaces solide-liquide gouverneraient l'adsorption des peptides à la surface des NCLs, entrainant un changement de leur comportement avec les membranes bactériennes. L’ensemble de ces résultats démontre le potentiel prometteur des NCLs en tant que vecteur de PAMsThe rapid increase in drug-resistant infections presents an acute problem in the healthcare sector, generating interest in novel antimicrobial strategies. The aim of this work is to explore the potential of lipid nanocapsules (LNCs) for Antimicrobial peptides (AMPs) delivery. Firstly, the experiments were focused on the development and optimization of AMP-loaded LNCs. Different strategies were investigated to deliver AA230,LL37 and DPK060 using LNCs (peptides adsorption atthe surface or encapsulated in the core of modified LNCs). The results demonstrated an association efficiency of 20 to 40%, when peptide is adsorbed, and over 80% encapsulation efficiency, when peptides are encapsulated. The second part concerned the study ofthe influence of peptides loading on their activity and stability against proteases. The results showed that peptides adsorption induced a potentiation of the antimicrobial activity of the native peptides, with a partial protection against proteolytic degradation. Conversely, peptides encapsulation allowed better peptide stability, correlated with higher encapsulation efficiencies and a preservation of the in vitro antimicrobial activity. In a third part, the mechanisms involved in LNC/AMP interactions and the complex interaction with model bacterial membrane have been evaluated. It has shown that structure and flexibility at solid-liquid interfaces govern peptide adsorption on the surface of the LNCs, which in turn is expected to change LNCs properties and interaction with bacterial membranes. Taken together, these results demonstrate the potential of LNCto deliver AMPs as an alternative anti-infective therapy
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Ma, Menghan. "Local delivery of antimicrobial peptides using self-organized TiO₂ nanotubes for implant-related infections." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/30508.
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Among the various complications that lead to the failure of orthopaedic implants, prosthetic-related infections have been reported as one of the major causes. Local delivery of antimicrobial agents through the implants surface is an ideal solution to the peri-implant infection problem.
Due to the increasing resistance of pathogens to the current therapy utilizing antibiotics, developing novel antimicrobial agents has received much attention recently. Among the potential alternatives are the antimicrobial peptides (AMPs). Because of their broad-spectrum bactericidal ability, low toxicity and immunogenicity, as well as complex killing mechanisms, AMPs have much lower possibility of developing resistance than traditional antibiotics.
In the past decade, fabrication of TiO₂ nanotubular structures by anodization method has attracted great interests because of its controllable, reproducible results as well as the simple process. In light of their high surface-to-volume ratio, controllable dimensions, excellent biocompatibility, adjustable wettability and other promising properties, TiO₂ nanotubes are considered as an ideal carrier for drugs.
In the current study, self-organized, vertically-oriented TiO₂ nanotubes were successfully prepared by anodization method in both water based electrolytes (phosphoric acid based and ammonium sulphate based electrolytes) and organic based electrolytes (Glycerol based and Ethylene glycol based electrolytes). The nanotube coatings prepared in ethylene glycol based electrolytes, with ~80nm diameter and ~7 μm thickness, were selected for the drug delivery purpose. HHC-36, one of the most potent broad-spectrum AMPs with the sequence of (KRWWKWWRR) was loaded onto the titanium dioxide nanotubes via a simple vacuum assisted physical adsorption method. Antimicrobial activity test against Gram-positive bacteria (Staphylococcus aureus) demonstrated that this novel AMP-loaded nanotube surface significantly inhibited bacteria proliferation and effectively reduced bacterial adhesion on the surface. It was also found that the antimicrobial activities of the samples were highly dependent on the drug loading conditions. By changing the loading conditions, the bacteria killing rate after 4 hour incubation increased dramatically from 90% to 99.9%. In vitro study showed that the AMP-loaded nanotube samples are not cytotoxic for MG-63 osteoblast-like cells.
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Sakko, M. (Marjut). "Antimicrobial activity and suitability of 2-hydroxyisocaproic acid for the treatment of root canal infections." Doctoral thesis, Oulun yliopisto, 2016. http://urn.fi/urn:isbn:9789526211046.
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Abstract Microbial infection in dental root canal induces an inflammatory reaction called apical periodontitis. In post-treament disease, Enterococcus faecalis is the most commonly found organism, which may survive well in root canal despite calcium hydroxide paste medication. In these cases, effective irrigation or repeated chlorhexidine medication are recommended. New medications with long-lasting antimicrobial activity are needed for the treatment of persistent root canal infections. 2-hydroxyisocaproic acid (HICA) is a protein fermentation product of lactobacilli and few other bacterial or fungal species express enzymes required for its metabolism. However, mammalian cells can metabolise it and use it for protein production. It is known to be well-tolerated by humans and have anti-inflammatory properties as well. Therefore, the hypothesis was that it affects microbe-specific metabolic pathways and have potential as a novel antimicrobial agent. The aim of this study was to evaluate the antibacterial and antifungal spectrum of HICA using in vitro microdilution methods for susceptibility testing and an ex vivo extracted tooth root canal infection-model. The impact of dentine on the antimicrobial activity of HICA was also evaluated. The results showed that HICA has broad-spectrum bactericidal activity for gram-positive and gram-negative organisms. It is also fungicidal for several fungal species and it is only marginally inactivated by clinically-relevant concentrations of dentine. It is at least as active against E. faecalis as presently-used interappointment medications in infected root canals after a seven-day incubation ex vivo. Since HICA has a broad-spectrum and long-term antimicrobial activity as well as an anti-inflammatory effect, it may be a useful new agent for clinical endodontology. However, controlled clinical studies are needed for evaluation of the efficacy of HICA in clinical conditionsTiivistelmä Hampaan juurikanavan mikrobi-infektio aiheuttaa apikaalisen parodontiitin eli tulehdusreaktion juuren kärjen läheisyydessä oleviin kudoksiin. Silloin, kun infektio ei parane hoidon jälkeen, Enterococcus faecalis on yleisin löydös. Jos kalsiumhydroksidilääkitys ei ole tehokas, hoitoon suositellaan huolellista desinfektiohuuhtelua ja uusittavaa lyhytkestoista klooriheksidiinilääkitystä. Juurikanavainfektioiden hoitoon tarvitaan uusia antimikrobiaineita, joilla on pitkäaikainen vaikutus. Lactobacillus-bakteerit tuottavat proteiiniaineenvaihdunnassa 2-hydroksi-isokapronihappoa eli HICAa, jonka metaboloimiseen tarvittavia entsyymejä tunnetaan vain muutamilla muilla bakteereilla. Ihmissolut metaboloivat ja käyttävät sitä proteiinituotantoon. Se on hyvin siedetty aine ja se lieventää tulehdusreaktiota. Tutkimuksen hypoteesina oli, että HICA vaikuttaa mikrobien aineenvaihduntaan ja se voisi olla mahdollinen uusi antimikrobiaine. Tässä tutkimuksessa HICAn antimikrobitehoa tutkittiin bakteereita ja sienilajeja vastaan pienerälaimennusmenetelmällä tehdyissä herkkyystesteissä. Sen soveltuvuutta hampaiden juurikanavainfektioiden hoitoon arvioitiin dentiinin läsnäollessa sekä potilailta poistetuissa ja kokeellisesti infektoiduissa hampaissa. Tulokset osoittavat, että HICA tappaa laajakirjoisesti gram-positiivisia ja gram-negatiivisia bakteereita sekä hiivoja ja muita sienilajeja. Dentiinin vaikutus HICAn antimikrobitehoon on vähäinen. Sen vaikutus E. faecalista vastaan poistettujen hampaiden juurikanavissa on viikon jälkeen yhtä hyvä tai parempi kuin nykyisten lääkeaineiden vaikutus. Laajakirjoisen, pitkäkestoisen antimikrobitehon ja anti-inflammatorisuuden vuoksi HICA voisi olla uusi vaihtoehto juurikanavainfektioiden hoitoon. HICAn kliinisen tehokkuuden arviointiin tarvitaan kontrolloituja kliinisiä tutkimuksia
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Kazemzadeh-Narbat, Mehdi. "Local delivery of antimicrobial peptides from titanium surface for the prevention of implant-associated infections." Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/44017.
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Titanium (Ti) is a key biomedical material extensively used in orthopaedic implants. Prevention of implant-associated infections has been one of the main challenges in orthopaedic surgery. This challenge is further complicated by the concern over the development of antibiotic resistance as a result of using traditional antibiotics for infection prophylaxis. One of the promising alternatives is the family of antimicrobial peptides (AMPs). The present dissertation develops progressive approaches that enable the loading and local delivery of a unique group of cationic antimicrobial peptides through titanium implant surfaces.
In the first technique, a thin layer of micro-porous calcium phosphate (CaP) coating was processed by electrolytic deposition onto the surface of titanium as the drug carrier. The AMP-loaded CaP coating was not cytotoxic for MG-63 osteoblast-like cells, and the implants showed high antimicrobial activity against both Gram-positive (Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa) bacteria with 10⁶-fold reductions of both bacterial strains within 30 min and ∼92% and ∼77% inhibition of luminescence at 4 h and 24 h, respectively.
Second study investigated the in vitro AMP release, antimicrobial performance, and cytotoxicity of a modified Tet213 (HHC36), as well as the in vivo bone growth of AMP loaded into calcium phosphate coated Ti implants in a rabbit model. Burst release during the first few hours followed by a slow and steady release for 7 days was observed. In vivo bone growth study showed that loading of AMP did not impair bone growth onto the implants.
In the last study multilayer thin films of titania nanotubes (NT) and CaP coatings were formulated with AMP and were topped with a thin phospholipid film similar to cell membrane. The films were shown to be non-cytotoxic, hydrophilic, with the potential of tuning loading and release kinetics of AMP. The best model describing the AMP release was first-order model.
The first two approaches demonstrated a promising method for an early stage peri-implant infection treatment. The last study proposed a technique to improve the kinetics of AMP release and total loaded AMP quantity, and to increase the Ti interfacial strength while maintain the osteconductivity by applying CaP coating.
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Ravensdale, Joshua Thomas. "Investigations into the therapeutic potential of antimicrobial peptides: applications for treating topical Staphylococcus aureus infections." Thesis, Curtin University, 2015. http://hdl.handle.net/20.500.11937/870.
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In this study, resistance towards antimicrobial peptides developed rapidly in MRSA, but resistance was mitigated by controlling the environment in which the cells are treated. Resistance was not stable in a population and seemed to sensitise some cells to certain antibiotics. Antibacterial peptides enhanced the bactericidal effectiveness of an antibacterial gauze when used in tandem with a wetting agent and lysozyme. Results from this study suggest antibacterial peptides may have clinical applications as topical therapeutics.
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Trinkle, Mara. "The Inhibitory Effects of an Antimicrobial Gel on the Staphylococcus Species." Digital Commons @ East Tennessee State University, 2020. https://dc.etsu.edu/honors/540.
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The prevalence of antibiotic resistant bacteria has made the choices for topical treatments for patients who experience burns wounds extremely limited. The Staphylococcus genus is naturally occurring in and on the human body but can become harmful once it enters the bloodstream. A novel antimicrobial gel has been shown by our laboratory to inhibit both the planktonic growth and biofilm formation of Staphylococcus aureus in previous studies. The antimicrobial gel is made of seven natural compounds including antioxidants (vitamin C and E). We wanted to examine the effects of the antimicrobial gel on numerous other Staphylococcal species because it is prevalent on the body and becomes harmful when the immune system is compromised. The species tested were Staphylococcus capitis, Staphylococcus epidermidis, and Staphylococcus saprophyticus. A planktonic broth challenge test, biofilm attachment test, and biofilm maturation test were all performed in order to test this hypothesis. These tests showed a significant inhibition of the Staphylococcus species as a result of the effects of the antimicrobial gel. The antimicrobial gel inhibited the attachment, maturation, and growth of Staphylococcus colonies in a 10% antimicrobial gel solution. The antimicrobial gel shows promise as an option in treating burn patients and should be considered in further testing for its uses in other areas of medicine.
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Phathekile, Bonke. "Synthesis of peptide-loaded chitosan nanoparticles for the treatment of sexually transmitted infections (STI’s)." University of Western Cape, 2019. http://hdl.handle.net/11394/7726.
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>Magister Scientiae - MScPeptides are among the main drugs which attract much attention because of their great potential in treating sexually transmitted diseases and other chronic diseases. There has been a major challenge of delivering these drugs in mucosal sites with low pH environment. The aim of this study is to synthesize acidic pH stable peptide loaded chitosan nanoparticles gels that could penetrate mucus layers covering the epithelial cells and kill HIV virus. Chitosan nanoparticles were synthesized by crosslinking method called Ionic gelation with Sodium tripolyphosphateTPP.
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Jooste, Marius Johannes. "The in vitro antimicrobial activity of amikacin and ceftazidime against multiple resistant gram-negative bacilli in nosocomial infections." Thesis, Cape Town : Cape Technikon, 1988. http://dk.cput.ac.za/cgi/viewcontent.cgi?article=1018&context=td_ctech.
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Ramos, Martín V. "Optimization of antimicrobial therapy for Gram-positive bacterial infections in children using a translational pharmacological approach." Thesis, University of Liverpool, 2017. http://livrepository.liverpool.ac.uk/3008292/.
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Nosocomial bloodstream infection (BSI) is the most common type of hospital-acquired infection in paediatric patients and a major cause of morbidity and mortality worldwide. Methicillin-resistant staphylococci (CoNS and MRSA) are a leading cause of hospital-acquired neonatal sepsis and BSI. Glycopeptides (vancomycin and teicoplanin) constitute the current mainstay of therapy. There is limited antimicrobial PK-PD data available for neonates and children and optimal drug exposures resulting in maximal efficacy and suppression of resistance are not known. A translational pharmacological approach can be used to build the evidence required to optimize the current use of antimicrobial therapy in children. Pre-clinical experimental (in vitro and in vivo) and clinical PK-PD work was conducted throughout this thesis to improve our understanding of the PK-PD relationships of vancomycin and teicoplanin against CoNS and MRSA. The in vitro HFIM defined the relevant PD indexes and free drug exposures associated with maximal bacterial killing and suppression of resistance. The in vivo models (a rabbit central-line associated BSI and a mouse neutropenic thigh infection model) validated the in vitro findings. CRP concentrations were incorporated as an in vivo PD input. A clinical PK study of teicoplanin in 57 patients (neonates, infants and older children) was conducted and the population PK parameters estimated. PK-PD modelling techniques were used to analyse the PK-PD data and bridge the experimental results to human patients by means of Monte Carlo (MC) simulations. Vancomycin and teicoplanin displayed a concentration-dependent pattern of activity. An AUC:MIC ratio was associated with maximal antibacterial activity and suppression of resistance. Based on MC simulations, the probability of the in vivo target attainment with currently used teicoplanin dosage regimens results insufficient to treat a majority of patients with MRSA infection. High teicoplanin PK variability was identified in children. Weight, age and renal function were the best explanatory covariates of PK variability. Wider drug exposure distribution is observed in the paediatric population with respect to adults. A patient-tailored TDM approach with the aid of a Bayesian feedback adaptive control tool is required to ensure individual patients achieve optimal drug exposures in a precise and safe manner. The defined pre-clinical optimal targets of exposure for vancomycin-CoNS and teicoplanin-MRSA now need to be prospectively evaluated in patients. Currently used teicoplanin dosage regimens in both, adults and children, may be insufficient to treat a high proportion of patients with serious MRSA infection. Current EUCAST clinical breakpoint may need to be revised for teicoplanin against MRSA. The current strategy of using teicoplanin fixed population-based antibiotic regimens results in a wide range of drug exposures in neonates and children. An individualised dosing and TDM approach can ensure optimal target attainment at the individual level and in real-time.
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Lieberman, Mia Tova Rock. "Characterization of polymicrobial infections in macaques with chronic cranial implants and evaluation of alternative antimicrobial strategies." Thesis, Massachusetts Institute of Technology, 2018. http://hdl.handle.net/1721.1/120910.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2018.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 221-242).
Macaques are the most commonly used non-human primate in cognitive neuroscience research due to similarities between the macaque and human brain. Cephalic recording chambers (CRCs) are often surgically implanted to obtain neuronal recordings. CRCs represent a persistent source of microbial contamination, which can occasionally progress to clinical sequelae of meningitis and brain abscesses. In this thesis, we first examined aerobic and anaerobic bacterial species colonizing CRCs using both traditional culture-dependent methods and 16S microbiota culture-independent methods. We evaluated the most prevalent species, and compared CRC bacterial communities to skin, oral and fecal bacterial communities. Our results indicated that CRC bacterial communities are predominantly composed of anaerobic flora and are relatively unique between individual macaques. Additionally CRC bacterial communities are more similar to skin and oral bacterial communities than fecal bacterial communities, indicating that fecal contamination of CRCs is a less likely source of contamination. Aerobic culture and sensitivity data from samples collected in 2011 identified Staphylococcus aureus, Enterococcus faecalis and Proteus spp. as the most prevalent species isolated, and that E.faecalis isolates displayed marked resistance to multiple antimicrobial classes. Routine CRC sanitization procedures were revised in September 2014 to prohibit antimicrobial use within CRCs, and we evaluated how E.faecalis lineages persisted and evolved between 2011 and 2017. We identified a shift in sequence type (ST) from ST4 and ST55, predominating in 2011, to ST48 predominating in macaques implanted after 2013. ST48 lineages were less resistant to antimicrobials and stronger biofilm producers as compared to ST4 and ST55 lineages. We concluded that loss of selective pressure from antimicrobial use within CRCs permitted ST48 to emerge as the predominant lineage due to its strong biofilm-forming abilities. Finally, we evaluated alternative E.faecalis biofilm treatment strategies. We isolated lytic bacteriophages with activity against ST55 E.faecalis and evaluated the use of phages and antimicrobial peptides LL-37 and PR-39 against E. faecalis biofilm, alone, and in combination with antimicrobials. Our results identified that bacteriophages successfully decreased biofilm produced by ST55 and ST4 E. faecalis isolates and should be evaluated further for treatment of animal and human enterococcal-associated biofilm infections.
by Mia Tova Rock Lieberman.
Ph. D.
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Santos, Tânia Raquel Martins dos. "Novel therapeutic strategies for the management of diabetic foot infections : the evaluation of selected antimicrobial peptides against clinically isolated bacterial pathogens." Doctoral thesis, Universidade de Lisboa, Faculdade de Medicina Veterinária, 2020. http://hdl.handle.net/10400.5/20150.
Full textAbstract:
Tese de Doutoramento em Ciências Veterinárias na Especialidade de Ciências Biológicas e BiomédicasDiabetic foot infections (DFIs) are a frequent complication of Diabetes mellitus. These ulcers are prone to be colonized by Staphylococcus aureus and Pseudomonas aeruginosa, including multidrug resistant and biofilm-producing strains, possibly leading to DFI chronicity and amputation. New therapeutic strategies for DFI management are urgent and the antimicrobial peptides (AMPs) nisin and pexiganan are potential candidates. This project aimed to evaluate the activity of these AMPs, incorporated in a guar gum biogel, against selected DFI clinical isolates. Firstly, nisin’s activity against a collection of S. aureus DFI clinical isolates was determined. Results showed that nisin was able to inhibit and eradicate S. aureus planktonic and biofilm cells at concentrations below its acceptable daily intake. When incorporated in the biogel, nisin kept its antimicrobial activity. This work also evaluated the potential of nisin to complement the activity of conventional antiseptics and antibiotics against established biofilms formed by these isolates. An in vitro antimicrobial schematic protocol was developed to mimetize DFI management guidelines. Fifteen antimicrobial combinations, including nisin-biogel, chlorhexidine, clindamycin, gentamicin and vancomycin, were tested. Results showed that the higher levels of biofilm inhibitory effects were presented by therapeutic combinations that included the nisin-biogel formulation. Nisin-biogel ideal storage conditions and cytotoxicity were also evaluated. Results demonstrate that if stored at temperatures between -20 and 22ºC, nisin-biogel is able to maintain its antimicrobial activity up to 24 months. Moreover, after 24 h of exposition, the nisin-biogel presented no significant levels of toxicity regarding the human keratinocytes under study. Lastly, to cover the complex microbiota present in DFIs, a combination of AMPs with different action spectra was developed, based on the simultaneous incorporation of nisin and pexiganan in the biogel. The activity of this dual-AMPs formulation was tested against two S. aureus and P. aeruginosa strains isolated from the same DFI. Acting together, these AMPs were able to diffuse from the biogel and inhibit and eradicate biofilms formed by these DFI isolates. The effectiveness of AMPs, particularly nisin and pexiganan, as novel antimicrobial strategies for the management of DFIs is still an unknown territory that merits investigation. In vitro biofilm models are the basis of preliminary research; however, they underrepresent the complex microbiota present in DFIs and their interaction with the immune system and skin cells constituents. Further research is necessary to understand the AMPs full potential regarding the clinical management of biofilm-related diseases, such as DFIs.
RESUMO - As infecções do pé diabético (IPDs) são uma complicação frequente da Diabetes mellitus. Estas úlceras tendem a ser colonizadas por Staphylococcus aureus e Pseudomonas aeruginosa, incluindo estirpes multirresistentes e produtoras de biofilme, possivelmente causando cronicidade da IPD e amputação. É urgente criar novas estratégias para o tratamento das IPD e os péptidos antimicrobianos (PAMs) nisina e pexiganan são potenciais candidatos. Este projecto avaliou a actividade destes PAM, incorporados num biogel de goma de guar, contra isolados de IPD. Primariamente, foi determinada a actividade da nisina contra uma colecção de S. aureus isolados de IPD. Os resultados mostraram que a nisina é capaz de inibir e erradicar S. aureus na forma planctónica e de biofilme a concentrações abaixo da dose diária recomendada. Quando incorporada no biogel, a nisina manteve a sua actividade. Foi ainda avaliado o potencial da nisina para complementar a actividade de antissépticos e antibióticos convencionais contra biofilmes formados por estes isolados. Foi criado um protocolo que simula in vitro o tratamento convencional das IPDs. Foram testadas 15 combinações de antimicrobianos, incluindo biogel de nisina, clorohexidina, clindamicina, gentamicina e vancomicina. Os resultados mostraram que o maior efeito inibidor de biofilmes pertencia a combinações que incluam o biogel de nisina. Foram também avaliadas as condições de armazenamento ideais para o biogel de nisina e a sua citotoxicidade. Quando armazenado a temperaturas entre -20 e 22ºC, o biogel de nisina manteve a sua actividade antimicrobiana durante pelo menos 24 meses. Adicionalmente, após exposição durante 24 horas, o biogel de nisina não apresentou níveis significativos de toxicidade relativamente aos queratinócitos humanos em estudo. Por último, para abranger a complexa microbiota presente nas IPDs, foi avaliada uma combinação de PAMs com diferentes espectros de acção, baseada na incorporação simultânea de nisina e pexiganan no biogel. A actividade desta formulação foi testada contra duas estirpes de S. aureus e P. aeruginosa isoladas da mesma IPD. Conjuntamente, estes PAMs foram capazes de se difundir do biogel e inibir e erradicar biofilmes formados por estes isolados. A eficácia dos PAMs como novas estratégias para o tratamento das IPD é ainda uma área desconhecida. Os modelos in vitro de biofilmes são a base da investigação; contudo, não representam a microbiota presente nas IPD nem a sua interacção com o sistema imunitário e outros constituintes celulares. É essencial continuar a investigar para compreender o potencial dos PAMs na terapêutica de doenças onde haja formação de biofilmes, como é o caso das IPDs.
N/A
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Guimond-Peron, Gabriel. "The ecology and evolution of antimicrobial resistance in asymptomatic Salmonella enterica /." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=99182.
Full textAbstract:
Infections caused by resistant pathogens fail to respond to treatment, resulting in increased costs due to prolonged illness and hospitalization. Determining the extent of resistance in animal populations is thus of great importance to public health. In this work, we first showed that asymptomatic populations of Salmonella in pigs present greater genotypic and phenotypic diversity than disease-associated populations. Second, we identified a clonal population structure associated with asymptomatic Salmonella found in the Canadian swine industry and we confirmed that food-producing pigs are a significant reservoir of Salmonella enterica, more particularly the clinically important serotype Typhimurium DT104. Finally, we identified the possible independent evolution of multidrug-resistance in serotypes Typhimurium, Derby and Heidelberg. Our work on asymptomatic Salmonella enterica stresses the importance of linking ecology and evolutionary biology to public health in order to understand and predict the response of pathogenic bacteria to selective pressure imposed by host immunity, whether naturally or artificially induced.
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Singh, Shalini. "Amphiphilic Peptide Interactions with Complex Biological Membranes : Effect of peptide properties on antimicrobial and anti-inflammatory effects." Doctoral thesis, Uppsala universitet, Institutionen för farmaci, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-282781.
Full textAbstract:
With increasing problem of resistance development in bacteria against conventional antibiotics, as well as problems associated with diseases either triggered or enhanced by infection, there is an urgent need to identify new types of effective therapeutics for the treatment of infectious diseases and its consequences. Antimicrobial and anti-inflammatory peptides have attracted considerable interest as potential new antibiotics in this context. While antimicrobial function of such peptides is being increasingly understood demonstrated to be due to bacterial membrane disruption, the mechanisms of their anti-inflammatory function are poorly understood. Since bacterial membrane component lipopolysaccharide triggers inflammation, this thesis aims at clarifying importance of lipopolysaccharide (LPS)-peptide interactions while investigating possible modes of action of peptides exhibiting anti-inflammatory effect. Furthermore, effect of poly(ethylene)glycol (PEG)-conjugation was investigated to increase performance of such peptides. Results presented in this thesis demonstrate that peptide-induced LPS- and lipid A binding/scavenging is necessary but not sufficient criterium for anti-inflammatory effects of peptides. Furthermore, preferential binding to LPS over lipid membrane, as well as higher binding affinity to the lipid A moiety within LPS, are seen for these peptides. In addition, results demonstrate that apart from direct LPS scavenging, membrane-localized peptide-induced LPS scavenging seem to contribute partially to anti-inflammatory effect. Furthermore, fragmentation and densification of LPS aggregates, in turn dependent on the peptide secondary structure on LPS binding, as well as aromatic packing interactions, correlate to the anti-inflammatory effect, thus promoting peptide-induced packing transition in LPS aggregates as key for anti-inflammatory functionality. Thus, peptide-induced LPS aggregate disruption together with reduction of the negative charge of LPS suggests the importance of phagocytosis as an alternative to the inflammatory pathway, which needs to be further investigated. Furthermore, PEG conjugation of peptide results in strongly reduced toxicity at a cost of reduced antimicrobial activity but markedly retained anti-inflammatory effect. Taken together, the results obtained in this work have demonstrated several key issues which need to be taken into consideration in the development of effective and selective anti-inflammatory peptide therapeutics for the treatment of severe Gram-negative bacterial infections.
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Ribera, Puig Alba. "Orthopaedic device-related infections: some thoughts on management and antimicrobial efficacy from a clinical and experimental perspective." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/587107.
Full textAbstract:
Orthopaedic device-related infections represent a health care problem of first magnitude due to the increasing incidence, complexity of management, and elevated cost. These device related infections have etio-pathogenic features that involve the participation of bacteria in the stationary growth phase as well as mature biofilms, which makes their diagnosis and treatment more challenging. Several studies have been performed to ameliorate the present guidelines. Nevertheless, there are still many points of uncertainty and many relevant clinical questions remain unanswered. This thesis explores some of these unanswered questions in the field of orthopaedic device related infections from the perspective of an infectious diseases specialist.
A. On the management of orthopaedic device-related infections
A.1. Diagnostic aspects of PJI
• Aim 1: to analyse the microbiological and clinical findings in patients with suspected prosthetic joint aseptic loosening, and to compare them to patients with chronic PJI
Conclusions:
1.1 Several patients with suspected prosthetic aseptic loosening have misdiagnosed PJI or some microorganisms in their samples.
1.2 Sonication samples provide additional microbiological information that should help clinicians with the diagnosis of delayed low-grade infections that mimic natural aseptic failure.
1.3 Clinical parameters that determine the final prosthesis removal are correlated with the number of positive peri-prosthetic samples.
A.2. Surgical management of PJI
• Aim 2: to evaluate the risk of re-infection following one-stage and to-stage surgical revision with hip PJI
Conclusions:
2.1 The one-stage revision strategy may be as effective as the two-stage revision strategy.
B. On the assessment of antimicrobial efficacy for the treatment of orthopaedic devicerelated infections
B.1. Infections by Streptococcus spp
• Aim 3: to assess the efficacy of adding rifampicin to β-lactams for the treatment of streptococcal PJI managed with implant retention, and its impact on the prognosis
Conclusions:
3.1 For the largest case series of stretopcoccal PJI managed with DAIR, this pathology showed a not-so-good prognosis as expected.
3.2 The treatment with β-lactams seems ideal for fighting the planktonic component of streptococcal PJI; the addition of rifampin some days or weeks after debridement could have a role in the antibiofilm profile to improve the current modest outcomes.
3.3 A concomitant and optimal surgical procedure is advised, following IDSA criteria and ensuring the exchange of removal components during the debridement. Similar prognosis results were observed when the IDSA criteria for DAIR were cutoff at the third month of revision.
B.2. Infections by MDR Gram-negative bacilli
B.2.1 The use of β-lactams in continuous infusion
• Aim 4: to standardize a measurement procedure based on UHPLC-MS/MS for the simultaneous determination of multiple β-lactam concentrations in human plasma
Conclusions:
4.1 The development of a single UHPLC-MS/MS method for the simultaneous measurement of multiple β-lactam concentrations in human plasma enable the applicability of this method to routine clinical practice and the validation of an easy-to use equation for clinical use.
• Aim 5: to evaluate the efficacy and safety of β-lactams in continuous infusion for difficult-to-treat osteoarticular infections caused by Gram-negative bacilli, and to validate an easy method for clinical use
Conclusions:
5.1 The use of β-lactams in continuous infusion is safe and effective, and may recover previously resistant strains that became susceptible in terms of their pharmacodynamic parameters. Lower doses could be used by BL-CI for susceptible strains.
5.2 A simple equation could help clinicians to estimate the β-lactams continuous infusion dosage and its plasma levels in the early hours of treatment.
B.2.2 The use of antibiotic combinations with colistin
• Aim 6: to evaluate the benefits of the combination of colistin and β-lactams when treating patients with MDR Pseudomonas aeruginosa infections
Conclusions:
6.1 Current recommendations should consider the combination of low-dose colistin with β-lactams as an optimized treatment for osteoarticular infections caused by MDR P.aeruginosa.
6.2 This antibiotic combination is essential for achieving positive outcomes for these difficult-to-treat infections.
• Aim 7: to study the effect of adding colistin to β-lactams against ESBL-producing klebsiella pneumoniae biofilm in an in vitro experimental model
Conclusions
7.1 As expected, colistin in monotherapy was ineffective against biofilm-embedded bacteria and resulted in the emergence of colistin resistant strains.
7.2 Meropenem in monotherapy and its combination with colistin achieved rapid killing rates that were maintained until the end of treatment. However, only the combination showed bactericidal activity in one of the tested strains of ESBL-producing Klebsiella pneumoniae and its effect was more pronounced under conditions that produced a greater biofilm. The combined therapy avoided the emergence of colistin-resistant strains.
7.3 Our preliminary results may indicate a slight overall superiority in vitro of adding colistin to β-lactams against carbapenem-susceptible ESBL-producing K. pneumoniae.Les infeccions osteoarticulars relacionades amb implants ortopèdics són un problema de salut de primera magnitud: per la seva incidència creixent, la seva complexitat i l’alt cost sanitari. Suposen un gran repte per l’especialista en malalties infeccioses, principalment per les seves particularitats etio-patogènicas amb participació de bacteris en fase estacionària de creixement i la formació de biofilm. Els objectius d’aquesta tesi pretenen explorar alguns aspectes no resolts sobre el maneig i la eficàcia antimicrobiana en el marc de la infecció osteoarticular relacionada amb l’implant. Al través de 7 treballs s’han desenvolupat els següents punts: • Estudi de les característiques clíniques i microbiològiques dels casos d’afluixament asèptic protèsic sotmesos a revisió, amb l’objectiu d’entendre millor aquesta entitat (interpretació dels cultius positius aïllats). • Estudi comparatiu del maneig quirúrgic de la infecció protèsica crònica: recanvi en un o dos temps. • Estudi de la infecció protèsica estreptocòccica manejada amb desbridament, antibiòtics i retenció de l’implant (DAIR); amb l’objectiu d’avaluar el pronòstic d’aquesta entitat i els factors que poden millorar la seva taxa de curació. • Estudi sobre l’ús de betalactàmics en infusió continua en les infeccions osteoarticulars relacionades amb implants causades per BGN, amb els objectius: 1) estandarditzar un procediment basat en UHPLC-MS/MS para la determinació dels nivells plasmàtics de betalactàmics, 2) validar una equació senzilla per estimar la dosis de betalactàmics òptima en perfusió continua i els nivells plasmàtics. 3) avaluar la seguretat i eficàcia antimicrobiana de l’ús de betalactàmics en infusió continua. • Estudis sobre l’eficàcia d’afegir colistina al tractament amb betalactàmics en el maneig d’infeccions gram-negatives multiresistents: 1) estudi clínic , 2) model in vitro per la formació de biofilm. Les principals troballes: • Alguns casos amb sospita d’afluixament protèsic asèptic són realment infeccions o presenten microorganismes aïllats sobre la superfície de l’implant. • L`estratègia de revisió protèsica pel tractament de les infeccions de pròtesis articulars en un temps pot ser (en general) tan efectiva com la revisió en dos temps. • La infecció protèsica estreptocòccica manejada amb DAIR va mostrar un pitjor pronòstic del descrit prèviament a la literatura. Un bon maneig de les guies IDSA, el recanvi dels components mòbils i la potencial eficàcia del tractament combinat amb rifampicina podrien millorar aquest modest pronòstic. • L’estandardització d’un mètode UHLPC-MS/MS per la determinació de betalactàmics permet la monitorització de nivells en pacients tractats amb perfusió contínua. • Mitjançant la comparació amb els resultats UHLPC-MS/MS s’ha pogut validar una equació simple per una estimació individualitzada de la dosi òptima de betalactàmics en perfusió continua i de nivells en plasma . • L’ús clínic de betalactàmics en perfusió continua és segur y eficaç. • Afegir colistina als betalactàmics en el tractament de les infeccions osteoarticulars produïdes per BGN multiresistents mostra millors resultats que el tractament en monoteràpia amb betalactàmic. • En el model in vitro per la formació de biofilm, també hem objectivat el benefici de la teràpia combinada amb colistina.
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Gómez, Junyent Joan. "Osteoarticular infections: insights on bacteremic clinical forms and antimicrobial alternatives against Pseudomonas aeruginosa from a translational perspective." Doctoral thesis, Universitat de Barcelona, 2020. http://hdl.handle.net/10803/670664.
Full textAbstract:
Osteoarticular infections are frequent in the clinical practice and have a high impact on patients and health systems. These infections may be associated with concomitant bacteremia and a characteristic feature is the presence of bacterial biofilm, which limits the efficacy of antimicrobial therapy. In recent years, the emergence of multidrug-resistant microorganisms has resulted in the need of new antimicrobial alternatives to improve patients’ outcomes. In this line, translational research plays a key role in providing therapeutic alternatives for the global management of osteoarticular infections. This thesis included clinical and experimental studies to deepen on the available knowledge of bacteremic osteoarticular infections (BOAs) and antimicrobial alternatives for these infections by Pseudomonas aeruginosa.
The first part of the thesis included four observational studies on bacteremic osteoarticular infections, performed at Hospital Universitari de Bellvitge (1985-2014). We observed that the incidence of BOAs increased during the study period, at the expense of nosocomial and healthcare-related infections, vertebral osteomyelitis (VO) and those affecting devices. Cases by methicillin-resistant Staphylococcus aureus (MRSA), Streptococci, Enterococci and Gram-negative bacilli (GNB) also increased. We then analyzed the association between BOAs and infective endocarditis (70 cases, 11.5% of endocarditis, 15% of OAs); there was an association between BOAs of the axial skeleton (arthritis or VO) and the presence of infective endocarditis. VO was mainly caused by low-virulent microorganisms (viridans and bovis Streptococci, Enterococci and coagulase-negative Staphylococci), whereas arthritis of the axial skeleton was mainly caused by S. aureus. The third study compared the characteristics of bacteremic septic arthritis according to the site acquisition. Nosocomial and healthcare-related cases affected more frequently older patients and with comorbidities and caused by MRSA and P. aeruginosa. Infections affecting the axial skeleton were more frequent in community-acquired and healthcare-related cases, whereas prosthetic joint infection was more common in nosocomial cases. Finally, 30-day mortality of BOAs was 12.2%, which was higher in peripheral septic arthritis and cases by MRSA. Mortality was lower in patients with peripheral septic arthritis managed with surgical debridement.
The second part of the thesis evaluated the role of therapeutic alternatives in OAs by P. aeruginosa. The first study was an observational study, which analysed the efficacy and therapeutic drug monitoring of continuous beta-lactam infusion in OAs by fluoroquinolone-resistant P. aeruginosa at Hospital Universitari de Bellvitge (2016-2018). 52 patients were included, 19 with fluoroquinolone-resistant strains (13; 68.4% MDR/XDR). Most patients had beta-lactam concentrations between 3-10xMIC and higher concentrations occurred in patients with renal impairment. There were no differences in failure rates between patients with fluoroquinolone-susceptible or resistant strains. The last two studies were experimental and used a dynamic in vitro biofilm model, the CDC Biofilm Reactor. The first evaluated the activity of ceftolozane-tazobactam, with/without colistin, against three MDR/XDR P. aeruginosa strains. Ceftolozane-tazobactam in monotherapy was ineffective and meropenem monotherapy was bactericidal against carbapenem-susceptible strains. Colistin was intitially effective, but regrowth occurred at the end of the experiments. Beta-lactam plus colistin combinations were more effective than monotherapies and prevented the emergence of colistin-resistant strains. Ceftolozane-tazobactam plus colistin was the most effective combination againts carbapenem-resistant strains, whereas meropenem plus colistin was for carbapenem-susceptible strains. The second study evaluated the pharmacokinetics/pharmacodynamics of continuous ceftazidime infusion, with/without colistin, against two susceptible strains (PAO1 and HUB8); growing clinically-achievable concentrations of ceftazidime (4-10-20-40 mg/L) were used. Higher ceftazidime concentrations (20-40) in monotherapy had higher anti-biofilm activity against PAO1, but not against HUB8. Ceftazidime resistance emerged with lower concentrations. Combinations of ceftazidime plus colistin increased the activity of monotherapies and prevented the emergence of colistin and ceftazidime resistance. With combinations against both strains, 40mg/L ceftazidime plus colistin had higher efficacy than 4mg/L ceftazidime plus colistin.Los estudios clínicos y experimentales de esta tesis pretenden ampliar la información existente sobre las infecciones osteoarticulares bacteriémicas así como evaluar alternativas terapéuticas para estas infecciones por P. aeruginosa. La primera parte de la tesis aborda la problemática de las infecciones osteoarticulares bacteriémicas e incluye 4 estudios realizados en el Hospital Universitari de Bellvitge (1985-2014). La incidencia de infecciones osteoarticulares aumentó a lo largo de los años, con incremento de las infecciones nosocomiales y asociadas al ámbito sanitario, además de las infecciones asociadas a material ortopédico y la osteomielitis vertebral. Los casos por S. aureus meticilin-resistente (SARM), estreptococos, enterococos y bacilos gram-negativos aumentaron. La infección osteoarticular bacteriémica con afectación del esqueleto axial (artritis o espondilitis) se asoció independientemente a la presencia de endocarditis infecciosa. Los casos nosocomiales y asociados al ámbito sanitario se presentaron más frecuentemente en individuos mayores y con más comorbilidades y fueron causados por SARM y P. aeruginosa. La mortalidad fue del 12.2%, mayor en la artritis séptica periférica y en infecciones por SARM. La mortalidad fue menor en los pacientes con artritis séptica periférica tratados con desbridamiento quirúrgico. La segunda parte de la tesis pretende encontrar alternativas terapéuticas para la infección osteoarticular por P. aeruginosa. El primer estudio analiza infecciones osteoarticulares por P. aeruginosa tratados con beta-lactámicos en perfusión continua y monitorización plasmática de concentraciones. 52 pacientes incluidos, 19 con cepas resistentes a fluoroquinolonas (13;68.4% cepas MDR/XDR). La mayoría tenían concentraciones de 3-10xMIC, concentraciones superiores frecuntes en insuficiencia renal. No hubo diferencias en el fracaso entre aquellos con infecciones por cepas resistentes o sensible a fluoroquinolonas. Se realizaron dos estudios experimentales con un modelo in vitro dinámico de biofilm. El primero evalúa la actividad de ceftolozano-tazobactam, con/sin colistina, frente a P. aeruginosa multiresistente. Ceftolozano-tazobactam con colistina fue el tratamiento más eficaz ante la cepa resistente a meropenem, mientras que meropenem con colistina lo fue frente a cepas sensibles a carbapenems. El segundo analiza las características farmacocinéticas/farmacodinámicas de ceftazidima en infusión continua, con/sin colistina, frente P. aeruginosa sensible. Frente PAO1, se observó una actividad anti-biofilm ligeramente superior con concentraciones de ceftazidima de 20-40mg/L, además de mayor actividad anti-biofilm frente ambas cepas con combinaciones de colistina y ceftazidima a concentraciones de 40mg/L que con 4mg/L.
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Martin, Siseko. "In Vitro antimicrobial synergy testing of Acinetobachter Baumannii." Thesis, Stellenbosch : University of Stellenbosch, 2010. http://hdl.handle.net/10019.1/5228.
Full textAbstract:
BibliographyThesis (MMed (Pathology. Medical Microbiology))--University of Stellenbosch, 2011.
ENGLISH ABSTRACT: Acinetobacter baumannii has emerged as one of the most troublesome nosocomial pathogens globally. This organism causes infections that are often extremely difficult to treat because of the widespread resistance to the major antibiotic groups. Colonization or infection with multidrugresistant A. baumannii is associated with the following risk factors: prolonged hospital stay, admission to an intensive care unit (ICU), mechanical ventilation, and exposure to broad spectrum antibiotics, recent surgery, invasive procedures, and severe underlying disease. A. baumannii has been isolated as part of the skin flora, mostly in moist regions such as axillae, groin and toe webs. It has also been isolated from the oral cavity and respiratory tract of healthy adults. Debilitated hospitalized patients have a high rate of colonization, especially during nosocomial Acinetobacter outbreaks. This organism is an opportunistic pathogen as it contains few virulence factors. Clinical manifestations of A. baumannii include nosocomial pneumonia, nosocomial bloodstream infections, traumatic battlefield and other wound infections, urinary tract infections, and post-neurological surgery meningitis. Fulminant community-acquired pneumonia has recently been reported, indicating that this organism can be highly pathogenic. The number of multidrug-resistant A. baumannii strains has been increasing worldwide in the past few years. Therefore the selection of empirical antibiotic treatment is very challenging. Antibiotic combinations are used mostly as empirical therapy in critically ill patients. One rationale for the use of combination therapy is to achieve synergy between agents. The checkerboard and time-kill methods are two traditional methods that have been used for synergy testing. These methods are labor intensive, cumbersome, costly, and time consuming. The E-test overlay method is a modification of the E-test method to determine synergy between the different antibiotics. This method is easy to perform, flexible and time efficient. The aim of this study was to assess the in vitro activity of different combinations of colistin, rifampicin, imipenem, and tobramycin against selected clinical strains of A. baumannii using the checkerboard and the E-test synergy methods. The MICs obtained with the E-test and broth microdilution method were compared. The results of the disk diffusion for imipenem and tobramycin as tested in the routine microbiology laboratory were presented for comparison. Overall good reproducibility was obtained with all three methods of sensitivity testing. The agreement of MICs between the broth dilution and E-test methods was good with not more than two dilution differences in MIC values for all isolates, except one in which the rifampicin E-test MIC differed with three dilutions from the MIC obtained with the microdilution method. However, the categorical agreement between the methods for rifampicin was poor. Although MICs did not differ with more than two dilutions in most cases, many major errors occurred because the MICs clustered around the breakpoints. The combinations of colistin + rifampicin, colistin + imipenem, colistin + tobramycin, rifampicin + tobramycin, and imipenem + tobramycin all showed indifferent or additive results by the E-test method. No results indicating synergy were obtained for all the above-mentioned combinations. There was one result indicating antagonistic effect for the combination of colistin + tobramycin. The results of the checkerboard method showed results indicating synergy in four of the six isolates for which the combination of colistin and rifampicin was tested. The other two isolates showed indifferent/additive results. All the other combinations showed indifferent/additive results for all isolates except isolate 30 (col + tob) and isolate 25 (rif + tob) which showed synergism. No antagonistic results were observed by the checkerboard method. When the results obtained with the E-test and checkerboard methods were compared, it was noted that for most antibiotic combinations an indifferent/additive result was obtained. However, for the colistin + rifampicin combination, the checkerboard method showed synergism for 4 of 6 isolates, whereas the E-test method showed indifference and an additive result in one. For the rifampicin + tobramycin, and colistin + tobramycin combinations, synergism was also shown with the checkerboard method in one isolate for each combination. The E-test method however showed an indifferent and additive result respectively. . The E-test method was found to be a rapid, reproducible, easy-to-perform, and flexible method to determine synergistic antibiotic activity. This study was however limited by low numbers of isolates. This might explain why no synergistic results were obtained with the E-test method and few synergistic results with the checkerboard method. Genotypic analysis using pulse-field gel electrophoresis (PFGE) may be considered in future studies to determine relatedness of the isolates which will facilitate the selection of different strains for synergy testing. Furthermore, clinical studies are needed to establish whether in vitro synergy testing is useful in the clinical setting and whether the results of synergy testing will have any bearing on the clinical outcome of patients infected with multidrug resistant A. baumannii.
AFRIKAANSE OPSOMMING: Acinetobacter baumannii het wêreldwyd as een van die mees problematiese nosokomiale patogene verskyn. Hierdie organisme veroorsaak infeksies wat dikwels baie moeilik is om te behandel weens wydverspreide weerstandigheid teen major antibiotikagroepe. Kolonisasie of infeksie met multi-weerstandige A. baumannii word geassosieer met die volgende riskofaktore: verlengde hospitaalverblyf, toelating tot ‘n intensiewe sorgeenheid (ICU), meganiese ventilasie, blootstelling aan breëspektrum antibiotika, onlangse chirurgie, indringende prosedures en ernstige onderliggende siekte. A. baumannii kan deel vorm van die normale velflora, veral in die axillae, inguinale area en tussen die tone. Dit is ook al vanuit die mondholte en die respiratoriese traktus van gesonde volwassenes geïsoleer. Verswakte gehospitaliseerde pasiënte word veral gekoloniseer gedurende nosokomiale Acinetobacter uitbrake. Hierdie organisme is ‘n opportunistiese patogeen en bevat min virulensie faktore. Kliniese manifestasies van A. baumannii sluit nosokomiale pneumonie, nosokomiale bloedstroom infeksies, troumatiese slagveld- en ander wondinfeksies, urienweginfeksies en meningitis wat volg op neurologiese chirurgie in. Fulminerende gemeenskapsverworwe pneumonie is onlangs beskryf en dui aan dat hierdie organisme hoogs patogenies kan wees. Die aantal multi-weerstandige A. baumannii stamme het wêreldwyd toegeneem oor die laaste paar jare. Daarom is die seleksie van empiriese antibiotiese behandeling ‘n uitdaging. Antibiotika kombinasies word meestal as empiriese behandeling in ernstige siek pasiënte gebruik. Die beginsel hiervan is om sinergistiese werking tussen agente te verkry. Die “checkerboard” en “time-kill” metodes is twee tradisionele metodes van sinergisme toetsing. Hierdie metodes is werksintensief, duur en tydrowend. Die E-toets sinergisme metode is gebaseer op die E-toets metode. Hierdie metode is maklik, buigbaar en tydseffektief. Die doel van hierdie studie was om die in vitro aktiwiteit tussen verskillende antibiotika kombinasies van colistin, rifampisien, imipenem, en tobramisien teen geselekteerde kliniese A. baumannii isolate te toets met die “checkerboard” en E-toets sinergisme toetsing metodes. Die minimum inhibitoriese konsentrasies (MIKs) verkry met die E-toets en “broth microdilution” metode is ook vergelyk. Die resultate van die skyfie diffusie metode (die metode wat in die roetiene mikrobiologie laboratorium gebruik word) vir imipenem en tobramisien word ook verskaf vir vergelyking van die resultate van verskillende sensitiwiteitsmetodes. In oorsig is goeie herhaalbaarheid van resultate verkry met al drie metodes van sensitiwiteitstoetsing. Die ooreenstemming van MIKs tussen die “broth dilution” en E-toets metodes was goed en resultate het met nie meer as twee verdunnings in MIK waardes verskil nie. Daar is een uitsondering waar die rifampisien E-toets MIK waarde met drie verdunnings van die MIK waarde verkry met die “microdilution” metode verskil. Die ooreenstemming tussen die sensitiwiteitskategorie resultate tussen die twee metodes was egter swak vir rifampisien. Alhoewel die MIKs in die meeste gevalle met nie meer as twee verdunnings in waarde verskil het nie, was daar baie major foute aangetoon omdat die MIKs rondom die breekpunte geval het. Die kombinasies van colistin + rifampisien, colistin + imipenem, colistin + tobramisien, rifampisien + tobramisien, en imipenem + tobramisien het oorwegend slegs matige interaksie met die E-toets metode getoon. Geen sinergisme is verkry met enige van die antibiotika kombinasies met hierdie metode nie. Daar was egter een resultaat wat antagonisme getoon het vir die kombinasie van colistin + tobramycin. Die resultate van die “checkerboard” metode het sinergisme getoon in vier van die ses isolate wat vir die kombinasie van colistin en rifampisien getoets was. Die ander twee isolate het slegs matige interaksie getoon. Al die ander kombinasies het ook slegs matige interaksie getoon, behalwe in isolaat 30 (col + tob) en isolaat 25 (rif + tob) waar die spesifieke kombinasies sinergisme getoon het. Geen antagonisme is waargeneem met die “checkerboard” metode nie. Met vergelyking van die E-toets en “checkerboard” metodes, is dit opmerklik dat vir die meeste van die antibiotika kombinasies slegs matige interaksie verkry is. Vir die colistin + rifampisien kombinasie toon die “checkerboard” metode egter sinergisme vir 4 uit 6 isolate, terwyl die E-toets metode slegs matige interaksie toon. Vir rifampisien + tobramisien, en colistin + tobramisien kombinasies is sinergisme getoon met die “checkerboard” metode in een isolaat vir elke kombinasie. Die E-toets metode het slegs matige interaksie getoon. Die E-toets sinergisme metode was vinnig, herhaalbaar en maklik om uit te voer. Hierdie studie word egter beperk deur lae getalle van isolate. Dit mag verklaar waarom geen sinergistiese resultate met die E-toets metode verkry is nie en die min sinergistiese resultate met die “checkerboard” metode. Genotipiese analiese met “pulse-field gel electrophoresis” mag in aanmerking geneem word in toekomstige studies om die verwantskap tussen isolate te bepaal wat die seleksie van verskillende stamme vir sinergisme toetsing sal vergemaklik. Verder, kliniese studies is nodig om te bepaal of in vitro sinergisme toetsing van waarde is en of die resultate van sinergisme toetsing ‘n rol speel in die kliniese uitkoms van pasënte geïnfekteer met multiweerstandige A. baumannii.
The National Health Laboratory Serivice
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Knoetze, Hendriette. "Characterization of a broad-spectrum antimicrobial peptide from Enterococcus mundtii active against bacteria associated with middle ear infections." Thesis, Stellenbosch : University of Stellenbosch, 2006. http://hdl.handle.net/10019.1/17373.
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Thesis (MSc)--University of Stellenbosch, 2006.ENGLISH ABSTRACT: Strain ST4SA, isolated from soya beans, was identified as Enterococcus mundtii. BacST4SA, a bacteriocin produced by strain ST4SA inhibited the growth of Acinetobacter baumannii, Bacillus cereus, Clostridium tyrobutyricum, Enterococcus faecalis, Enterococcus faecium, Lactobacillus sakei, Propionibacterium spp., Streptococcus caprinus, Pediococcus sp., Listeria monocytogenes, Staphylococcus aureus, Streptococcus pneumoniae, and unidentified middle ear isolates A, BW, DW, F, G, and H. BacST4SA was active against Pseudomonas aeruginosa G, BG, I, J, B and E, although variable degrees of resistance were observed for some strains. BacST4SA is positively charged, hydrophobic, contains the YGNGV sequence in the N-terminal, a double-glycine processing site and a disulphide bridge, all of which is typical of a class IIa bacteriocin. The operon, which contains a structural-, ATP-dependent transporter- and immunity gene, is located on a 50-kb plasmid. The 58-amino acid prepeptide is homologous to mundticin KS, mundticin AT06 and bacteriocin QU 2, and differs from enterocin CRL35 by only two amino acids. The 674-amino acid ATP-dependent transporter, consisting of a peptidase C39B domain, an ABC-transporter and an ABC-DLP family domain, displayed 98.9% homology to mundticin KS and 99.25% to enterocin CRL35. The 98-amino acid immunity gene of bacST4SA is completely homologous to enterocin CRL35 and 96.9% to mundticin KS. BacST4SA is 3.950 kDa in size, based on electron spray mass spectrometry. The peptide was isolated from the cell-free supernatant, precipitated with 80% saturated ammonium sulphate, dialysed and freeze-dried to 1 638 400 AU (arbitrary units) per ml. No change in antimicrobial activity was recorded when bacST4SA was incubated in buffer ranging from pH 2 to 12, heated to 100 °C for 90 min and 121 °C for 20 min, and when incubated in the presence of Tween 20, Tween 80, Triton X-100, SDS, urea, EDTA, middle ear fluid and blood. Optimal levels of bacST4SA production (51 200 AU/ml) was recorded after 14 h of growth in MRS broth at 30°C. Maximum production (102 400 AU/ml) was recorded in modified MRS media supplemented with tryptone, yeast extract, a combination of tryptone and yeast extract, K2HPO4 (10.0 or 20.0 g/l), or with the addition of DL-6,8-thoictic acid, L-ascorbic acid, and thiamine, respectively. BacST4SA is bactericidal towards E. faecium HKLHS and bacteriostatic towards S. pneumoniae 40 and middle ear isolates F, BW and H. The peptide adsorbed maximal (94%) to S. pneumoniae 40, P. aeruginosa 25 and E. faecium HKLHS. BacST4SA forms pores in the cytoplasmic membrane of sensitive cells, leading to dissipation of the cell membrane and leakage of cytoplasmic material. BacST4SA was compared with various other antimicrobial treatment agents, and revealed similar to a higher activity towards a number of these agents. BacST4SA revealed a similar level of activity against E. faecium HKLHS and middle ear pathogens P. aeruginosa J and S. pneumoniae 27 when compared with tetracycline (30μg). However, bacST4SA revealed much higher activity when compared to nasal sprays, aminoglycosides, cephalosporins, fluoroquinolones, lincosamides, macrolides, nitroimidazole, penicillin, quinolones, sulfonamides, chloramphenicol, furanzolidone, fusidic acid, rifampicin, trimethoprim, trimethoprim-sulfamethoxazole and vancomycin when tested in vitro.
AFRIKAANSE OPSOMMING: Stam ST4SA, geïsoleer uit sojabone, is as Enterococcus mundtii geidentifiseer. BacST4SA, ‘n bakteriosien geproduseer deur stam ST4SA het die groei van Acinetobacter baumannii, Bacillus cereus, Clostridium tyrobutyricum, Enterococcus faecalis, Enterococcus faecium, Lactobacillus sakei, Propionibacterium spp., Streptococcus caprinus, Pediococcus sp., Listeria monocytogenes, Staphylococcus aureus, Streptococcus pneumoniae en ongeïdentifiseerde middeloor isolate A, BW, DW, F, G, en H geinhibeer. BacST4SA is aktief teen Pseudomonas aeruginosa stamme G, BG, I, J, B en E, alhoewel effense weerstand soms waargeneem is. BacST4SA het ‘n netto positiewe lading, is hidrofobies, bevat die YGNGV-volgorde in die N-terminaal, ‘n dubbel-glisien prosesserings setel en ‘n disulfied brug, kenmerkend van klas IIa bakteriosiene. Die operon, wat bestaan uit ‘n strukturele geen, ‘n ATP-afhanklike transport sisteem geen en ‘n immuniteits-geen, is op ‘n 50 kb plasmied gelokaliseer. Die voorloper peptied (58 aminosure lank), is homoloog aan mundticin KS, mundticin AT06 en bakteriosien QU 2 en verskil van enterocin CRL35 met slegs twee aminosure. Die ATP-afhanklike transporter (674 aminosure lank) bestaan uit ‘n peptidase C39B domein, ‘n ABC-transporter en ‘n ABC-DLP tipe domein en is 98.9% homoloog aan mundticin KS and 99.25% aan enterocin CRL35. Die immuniteits-geen (98 aminosure lank) van bacST4SA is ten volle homoloog aan enterocin CRL35 en 96.9% homoloog aan mundticin KS. BacST4SA is 3.950 kDa groot, gebaseer op elektrosproei-massa spektrometrie. Die peptied is uit selvrye supernatant geïsoleer, met 80% versadigde ammonium sulfaat gepresipiteer, gedialiseer en gevriesdroog tot ’n finale konsentrasie van 1 638 400 AE (arbitrêre eenhede) per ml. Geen verandering in antimikrobiese aktiwiteit is waargeneem tydens inkubasie van bacST4SA in buffer van pH 2 tot 12, tydens verhitting (100 °C vir 90 min en 121 °C vir 20 min) en tydens inkubasie in die teenwoordigheid van Tween 20, Tween 80, Triton X-100, SDS, ureum, EDTA, middeloor vloeistof en bloed. Optimale vlakke van bacST4SA produksie (51 200 AE/ml) is na 14 h groei in MRS media by 30°C waargeneem. Maksimale vlakke van die peptied (102 400 AE/ml) is geproduseer in gemodifiseerde MRS medium, aangevul met triptoon, gisekstrak, ‘n kombinasie van triptoon en gisekstrak, K2HPO4 (10.0 of 20.0 g/l), of met byvoeging van DL-6,8-thioktiensuur, L-askorbiensuur, en tiamien onderskeidelik. BacST4SA is bakteriosidies teenoor E. faecium HKLHS en bakteristaties teenoor S. pneumoniae 40 en middeloor isolate F, BW en H. Die peptied adsorbeer optimaal (94%) aan S. pneumoniae 40, P. aeruginosa 25 en E. faecium HKLHS. BacST4SA vorm porieë in die selmembraan van sensitiewe selle en lei tot vernietiging van die selmembraan en lekkasie van die sitoplasma inhoud. In vergelykende studies het bacST4SA ‘n soortgelyke en selfs hoër antimikrobiese aktiwiteit teenoor ‘n aantal bekende antimikrobiese middels getoon. Die aktiwiteit van bacST4SA is soortgelyk aan dié van tetrasiklien (30μg) in toetse teen E. faecium HKLHS en middeloor patogene P. aeruginosa J en S. pneumoniae 27. BacST4SA het egter in ’n in vitro vergelyking met neussproeie, aminoglisiedes, cephalosporiene, fluoroquinolone, lincosamides, makroliede, nitroimidazole, penisilien, quinolone, sulfonamide, chloramphenicol, furanzolidone, fusiensuur, rifampisien, trimethoprim, trimethoprim-sulfamethoxazool en vankomisien ‘n baie hoër aktiwiteit teen patogene getoon.
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Bergman, Peter. "Antimicrobial peptides and pathogenic Neisseria : experimental studies in mouse, man and rat /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-428-7/.
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Gibson, Roger L. "Primary prevention of acute respiratory infection among United States Air Force recruits through the use of antimicrobial handwipes : a randomized clinical trial /." Thesis, Connect to this title online; UW restricted, 1996. http://hdl.handle.net/1773/10905.
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Schlusselhuber, Margot. "Therapeutic potential of equine antimicrobial peptides against Rhodococcus equi and other major horse pathogens." Caen, 2012. http://www.theses.fr/2012CAEN3135.
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Au cours de la dernière décennie, la sensibilité des bactéries aux antibiotiques conventionnels a considérablement diminué et nous assistons à l'émergence de microbes multirésistants en médecine humaine et équine. Les peptides antimicrobiens (AMPs) sont de petites molécules qui participent à la réponse immunitaire innée chez l’ensemble des organismes vivants. Ils ont montré un grand intérêt en tant que nouvelle classe d’agents antimicrobiens au coté des antibiotiques pour bon nombre de raisons. En effet, ils sont reconnus pour avoir un mode d'action rapide et bactéricide, un large spectre d'action et un faible risque de sélection de résistance. Dans ce travail, le potentiel thérapeutique d’AMPs équin a été évalué pour divers agents pathogènes du cheval avec un accent particulier sur Rhodococcus equi, une cause majeure de mortalité chez les poulains. Le peptide le plus prometteur, eCATH1, a montré une activité antibactérienne à de faibles concentrations contre R. Equi ainsi que Pseudomonas spp. , Escherichia coli, Salmonella enterica Typhimurium, Streptococcus zooepidemicus et Klebsiella pneumoniae indépendamment de la résistance aux antibiotiques des souches. En outre, le peptide s'est avéré efficace contre R. Equi intramacrophage in vitro ainsi que dans un modèle souris de l'infection sans induire de toxicité et a présenté une interaction positive avec la rifampicine. Malgré le fort potentiel thérapeutique de eCATH1 contre rhodococcose, il reste à mettre en place une méthode de production en grande quantité et à faibles coûts afin de prouver son efficacité chez les poulains infectés, ainsi que de rendre son utilisation viable pour l'industrie pharmaceutiqueOver the last decade, the susceptibility of bacteria for conventional antibiotics decreased substantially and we are witnessing to the emergence of multidrug-resistant microbes in both human and equine medicine. Antimicrobial peptides (AMPs) are small molecules that participate in the innate immune response in almost all living organisms. They have been attracting greater interest as new class of antimicrobial drugs besides to antibiotics for number of reasons. Indeed, they are recognized to have a rapid and bactericidal mode of action, a broad spectrum of action and a low frequency in selecting resistance. In this work, the therapeutic potential of equine AMPs was assessed against various pathogens of the horse with a special focus on Rhodococcus equi, a major cause of death in foals. The most promising peptide, eCATH1, was shown to exert an antibacterial activity at low micromolar concentrations against R. Equi as well as Pseudomonas spp. , Escherchia coli, Salmonella enterica Typhimurium, Streptococcus zooepidemicus and Klebsiella pneumoniae independently of the antibiotic resistance of the strains. Moreover, the peptide proved to kill efficiently intramacrophage R. Equi in vitro as well as in mice model of infection without inducing toxicity and presented a positive interaction with rifampicin. Despite the high therapeutic potential of eCATH1 against rhodococcosis, it remains to set up a method of production in high amount and low costs in order to prove its efficacy in infected foals as well as to make its use viable for pharmaceutical industry
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Jamieson, William David. "Nano-scale systems for the detection and treatment of bacterial infections in burn wounds : modes of action and efficacy." Thesis, University of Bath, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.642025.
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Bacterial infections are and likely always will be a serious and costly complication to treatment in a healthcare environment. However consistent rises in the number of both healthcare associated and antibiotic resistant infections over the last of decades has the potential to turn a serious problem into a catastrophe. Control of infections in hospital wards has improved over the last five years but data from the European Centre for Disease Prevention and Control suggests a stale mate. While the numerical rise in drug resistant organisms has slowed, the severity of drug resistance appears to be on the increase with the prolific emergence of multiple drug resistant isolates. On the front lines of the threat that these organisms represent are some of the most susceptible. In hospitals those who are already sick are more vulnerable, those with co-morbidities, those with surgical or other wounds, the very old and the very young. Children especially show high susceptibility as they are often incapable of communicating clinical complications in the way an adult might. This coupled with higher commonality of specific aetiologies in children such as scalds, open wounds that are prone to infection without proper treatment, creates population in need. Antibiotics are often thought to be part of the problem in drug resistance, indeed to an extent they are. However their real downfall may be improper use. In order to improve treatment outcomes and simultaneously decrease antimicrobial resistance a combination of rapid diagnosis and prophylaxis can be utilised to decrease selection of resistance. As such, this study focuses on the development of a novel vesicle based sensor system for the detection of bacterial infections in burn wounds. Additionally an organometallic antimicrobial system has been developed with the potential for surface attachment. Work with the vesicle based biosensor demonstrates high sensitivity to both Staphylococcus aureus and Pseudomonas aeruginosa. The toxins involved in activation of the sensor have been determined in both cases and an in-depth study into the activity of the staphylococcal agents of lysis (Phenol Soluble Modulins and delta haemolysin), shows a high degree of plasticity and tunability in the sensors function. Work with the zinc based antimicrobial reveals a highly complex system which demonstrates possible functions as a not only an antimicrobial but as a sensor system in its own right.