Browsing by Subject "Antibiotics"
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Item Antibiotic use for treatment of acute sinusitis(2012-04-10) Martinson, CarinItem Antibiotics for Acute Sinusitis(2012-07-26) Wong, Alexandra KuninItem Clinical Efficacy of Local Delivery Minocycline Gel for the Treatment of Moderate to Severe Periodontitis(2019-05) Shalev, AlonBackground: Local delivery of antimicrobial agents has been used for many years as an adjunct to treat periodontal disease. The gel form of minocycline local delivery application has an advantage in that it allows multiple sites to be treated with the same syringe loaded with minocycline gel when compared to other modalities on the market. However, the use of this gel form of minocycline has not been clinically proven effective or approved for clinical use in the United States. Objectives: The objective of this study was to determine the clinical efficacy of a 2.1% minocycline gel as an adjunct to scaling and root planning (SRP) for treating patients with moderate to severe periodontitis. The hypothesis for this study is that patients with moderate to severe periodontitis would have a statistically significant greater increase in clinical attachment (CAL) gain, reduced pocket depth (PD), and reduced bleeding on probing (BOP) when SRP with adjunctive minocycline gel were used when compared to patients treated with sham (SRP alone) and vehicle control (SRP+ vehicle without active ingredient). Material and Methods: Eligible patients (n=59) had at least ten remaining teeth and each subject had at least four teeth with pocket depths ≥5 - ≤9 mm with BOP at baseline. In addition to baseline, patients were evaluated at three, six and nine months. Enrolled subjects were randomly assigned to one of three groups: 1) root planing therapy only-sham; 2) root planing therapy and the vehicle control; 3) root planing and minocycline gel. The minocycline gel as well as the vehicle control were administered at 2 weeks and at the one, three and six-month visits. No mechanical debridement as supportive periodontal therapy was performed during this study. Results: It was found that in the overall study population the minocycline study group, when compared to the sham group, resulted in a greater significant decrease BOP (p=0.035) at 3-month, but not when compared to the vehicle control group (p=0.64). In sites presenting with the severe form of periodontitis (≥8 mm), there was a statistically significant difference between the minocycline gel group and the sham group with respect to % BOP reduction at 9-months (p=0.014). On the other hand, results failed to show any other statistically significant difference between the minocycline gel group and the sham group with respect to other clinical variables including PD and CAL (p>0.05). However, minocycline gel did present with statistically significant differences compared to the vehicle control group with respect to the clinical variables. Conclusion: The minocycline gel as an adjunct to non-surgical periodontal therapy provided a significant favorable clinical effect in decreasing BOP for all moderate to severe periodontitis sites following SRP at the 3-month evaluation. In the severe forms of periodontitis, minocycline gel had an adjunctive favorable effect at 9-months after SRP with respect to %BOP reduction. This study was supported in part by Sunstar Americas, Inc. and the clinical research center at the University of Minnesota.Item Design and Development of Antibiotics and Synthesis of Modified Nucleosides(2022-10) Hegde, PoojaTuberculosis (TB) remains a leading cause of infectious disease mortality and morbidity resulting in nearly 1.3 million deaths annually and infecting nearly one-quarter of the population. Chapter 1 discusses the epidemiology, control, and management of TB. Isoniazid (INH) is a cornerstone for the treatment of drug-susceptible TB, yet the quantitative structure-activity relationships for INH are not well documented in the literature. Chapter 2 evaluates a systematic series of INH analogs against contemporary Mycobacterium tuberculosis (Mtb) strains from different lineages and several key species of non-tuberculous mycobacteria (NTM). To assess the specific activity of this series of INH analogs against mycobacteria, we assayed them against a panel of gram-positive and gram-negative bacteria, as well as a number of fungi. Our findings provide an updated analysis of the structure-activity relationship of INH that will serve as a valuable resource for the development of a next generation antitubercular compounds. para-Aminosalicylic acid (PAS), is an important second-line agent for treating drug-resistant Mtb. PAS has a moderate bioavailability and rapid clearance that necessitate high doses in order to facilitate an effective treatment. Consequently, such high doses commonly results in gastrointestinal disturbances (presumably by disruption of gut microbiota and host epithelial cells). Chapter 3 discusses the design, synthesis and evaluation of PAS prodrugs and analogs with improved oral bioavailability, thereby preventing intestinal accumulation as well as undesirable bioactivation by the gut microbiome to cytotoxic folate species. The pivoxyl prodrug and fluorination at the 5- position address the primary limitations of PAS and have the potential to revitalize this second-line TB drug. Pyrazinamide (PZA) is a critical component of the first-line TB treatment regimen because of its sterilizing activity against non-replicating Mtb, but its mechanism of action has remained enigmatic. PZA is a prodrug converted to the active moiety- pyrazinoic acid (POA), by pyrazinamidase, an amidase within the nicotinamide adenine dinucleotide (NAD) salvage pathway encoded by pncA in Mtb. PZA resistance is most commonly induced via loss-of-function mutations within PncA. It has recently been demonstrated that POA induces targeted protein degradation of the enzyme PanD, a crucial component of the coenzyme A biosynthetic pathway, essential in Mtb. Chapter 4 describes the structure activity relationship (SAR) evaluation of various POA analogs. Further development and mechanistic analysis of these analogs may lead to a next generation POA analog for treating TB. The salicylic acid derived small molecule siderophores known as mycobactins are essential for mycobacterial iron acquisition and mycobactin biosynthesis has been biochemically and genetically validated as essential for survival in vivo. Sal-AMS, a modified nucleoside derivative that mimics an intermediate in the mycobactin biosynthetic pathway, is a potent Mtb inhibitor. Chapter 5 explores polyfluorinated salicylic acid derivatives as antimetabolites, designed to antagonize mycobactin synthesis. Enzymatic studies demonstrated that the tri- and tetra- fluorinated salicylic acid analogs were neither substrates nor inhibitors of MbtA, but the di-fluorinated compounds were readily activated by the bifunctional adenylating enzyme MbtA, responsible for processing salicylic acid moieties for synthesis of mycobactins. However further microbiological analysis revealed that the polyfluorinated derivatives have low potential as anti-TB agents and do not appear to operate by inhibiting mycobactin synthesis. Lastly, the chemical synthesis of nucleoside analogs, an important class of compounds with applications as anti-infective, anti-cancer, and diagnostic agents, is extremely challenging, typically requiring linear synthesis, multiple protection deprotection sequences, and stereoselective formation of the critical glycosidic linkage. Nucleoside phosphorylases (NPs) have tremendous biocatalytic potential and aid in the selective modification of nucleosides under green conditions. Chapter 6 focuses on the functional characterization of 15 thermostable purine NPs. Four of these were further selected for a comprehensive analysis of their substrate scope. Next, chemoenzymatic methods for the synthesis of modified nucleosides were extensively studied using various coupled systems, and 12 modified nucleosides were synthesized, isolated, and characterized.Item Design, Synthesis, and Evaluation of Pyrazinoic Acid-Derived Antituberculars for Drug-Resistant Mycobacterium tuberculosis(2022-01) Cole, MalcolmTuberculosis (TB), an infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb), is a major cause of suffering worldwide. The impact of this disease has been exacerbated by the ongoing coronavirus pandemic, reversing much recent progress that had increased diagnosis and treatment rates in the preceding decade. In addition to ongoing issues related to public health shortcomings and lack of access to treatment, the emergence and spread of resistant strains is an increasing cause for concern. While the antitubercular pipeline has produced a few new antibiotics in the 21st century, more novel treatments are urgently needed to keep abreast of resistant strains. This dissertation describes efforts to create new therapeutic options for resistant TB, centered around pyrazinoic acid (POA), the active form of pyrazinamide (PZA), an important first-line TB drug.Recently, a growing number of reports have highlighted the promise of β-lactam conjugates in selectively targeting resistant organisms. β-lactams are a widely-employed class of antibiotics that target cell wall biosynthesis. Bacteria can evade this activity through expression of β-lactamases, powerful enzymes that destroy the electrophilic β-lactam warhead. However, researchers have learned to take advantage of this resistance mechanism, designing β-lactam conjugates that release a molecular payload following β-lactamase cleavage. This strategy, referred to here as β-lactamase-mediated fragmentation, is explored in great detail in Chapter 1, including descriptions of its discovery and applications in a variety of fields, including diagnostics, cellular imaging, and antibiotic design. Chapter 2 describes our own work in this space, designing β-lactam conjugates bearing POA as a Mtb-selective warhead. This strategy circumvents the most common resistance mechanism against PZA, imparting activity in an Mtb macrophage infection model (where conventional β-lactams are typically ineffective). We also provide preliminary mechanistic evidence that our conjugates act as codrugs, achieving antibacterial activity through action of the β-lactam scaffold as well as the POA warhead. In Chapter 3, we remove the β-lactam scaffold and focus on POA itself, reporting a series of new analogues featuring substitutions on the pyrazine ring. We identify several analogues with improved activity over POA, and use biochemical techniques to demonstrate they are inhibitors of PanD, a putative target of POA. We use the structure of our most active lead and recent structural insights into PanD to design additional inhibitors with comparable antimycobacterial activity, providing proof-of-concept for future structure-based design of new PanD inhibitors.Item Determination of the antibiotic and antibiotic resistance footprint in surface water environment of a metropolitan area: Effects of anthropogenic activities(2022-09-26) He, Huan; Bueno, Irene; Kim, Taegyu; Wammer, Kristine H.; LaPara, Timothy M.; Singer, Randall S.; Beaudoin, Amanda; Arnold, William A.; heh@umn.edu; He, Huan; University of Minnesota Department of Civil, Environmental, and Geo- Engineering; University of Minnesota Department of Veterinary and Biomedical Sciences; University of St Thomas Department of Chemistry; Minnesota Department of HealthThis study investigated geospatial distributions of antibiotics and antibiotic resistance genes (ARGs) in surface waters and their associations with anthropogenic activities. During July‒October 2020, the concentrations of antibiotics (water and sediment) and ARGs (sediment) were measured at 39 sites in the Twin Cities metropolitan area (Minnesota) that experience a gradient of impacts related to human activities. For water samples, the number of antibiotics detected and the concentrations of certain antibiotics (e.g., sulfonamides) positively correlated with urbanization indicators (e.g., urban percentage, population density, number of wastewater discharge points; ρ =0.32‒0.46, p =0.003‒0.04) and negatively correlated with undeveloped land indicators (e.g., forest; ρ =-0.34‒-0.62, p =<0.00001‒0.04). Antibiotics in sediments exhibited geospatial distribution different from that in corresponding water samples and exhibited no associations with anthropogenic factors. Relative abundances of ARGs were not associated with anthropogenic factors, but several ARGs (e.g., blaoxa, mexB, and sul2) were inversely related to the organic content of sediments (ρ =-0.38‒-0.44, p =0.01‒0.04). Strong correlations were found among relative abundances of various ARGs and intI1 (ρ ≥ 0.67, p < 0.05), highlighting their co-occurrence in (sub)urban surface waters. These results identified promising anthropogenic/environmental factors for predicting antibiotic geospatial distributions and useful gene markers to monitor ARGs in surface waters.Item Do you have strep throat?(2012-04-09) Smith, AndreaItem Ear Infections: How long does my child need to be treated?(2012-04-09) Scrafford, JonathanItem Examining immune responses in a mouse model of Salmonella infection(2010-09) Griffin, Amanda JillSalmonella infections are responsible for significant morbidity and mortality throughout the world. Although extensive research has elucidated the mechanisms of protective immunity following vaccination with live vaccine strains (LVS) of Salmonella, very little work has been done to examine immune responses during and following antibiotic treatment of virulent Salmonella infections. We have developed a murine model of naturally acquired immunity to Salmonella, where susceptible mice are orally infected with virulent S. typhimurium and treated with antibiotics for an extended period of time. These mice demonstrate weak protective immunity to rechallenge with virulent Salmonella, which is due to Th1 and antibody responses and can be augmented by the administration of a TLR5 agonist. We have also used antibiotic treatment to examine the development of Th1 responses to LVS Salmonella, which are vital for mediating protective immunity to this pathogen. We show that Th1 cells develop after sustained exposure to Salmonella antigens. Eradication of the bacteria by antibiotic intervention within one week of primary infection has profound effects on the ability of mice to survive rechallenge with virulent Salmonella. We also establish that full effector/memory function of Th1 cells, as determined by robust production of Th1 cytokines, requires two weeks of exposure to Salmonella antigens. Finally, we use short-term antibiotic treatment to establish a model of relapsing virulent Salmonella infection where mice appear to have cleared the bacteria soon after they begin treatment but suffer recurrent and fatal Salmonella infection upon withdrawal. We demonstrate that Salmonella harbored in CD11b+Gr1- resident monocytes in mouse mesenteric lymph nodes (MLNs) are the source of relapsing infection. In addition, the MLNs appear to act as a filter prohibiting the dissemination of Salmonella to systemic tissues. By using antibiotic treatment to examine immune responses to Salmonella, this thesis work may contribute to future research in the development of efficacious therapeutic and/or preventative typhoid vaccines. Moreover, these studies may stimulate future studies using these same tools in other infectious disease models.Item Fate and impact of antibiotics in slow-rate biofiltration processes.(2010-12) Wunder, David BarnesAntibiotics have been detected in surface waters worldwide at concentrations up to 1.9 micrograms/L, but are typically detected at low nanogram/L concentrations. The potential health effects of exposure to low levels of these compounds via tap water are not known, but there is significant concern among water consumers regarding the occurrence of antibiotics and other pharmaceutical compounds in water supplies. Thus, a significant amount of research has been performed recently to investigate the removal of pharmaceuticals via conventional and advanced water treatment processes. While conventional treatment processes (i.e., coagulation, flocculation, sedimentation, and filtration) are generally not effective, oxidation processes (e.g., chlorination, ozonation) and granular activated carbon exhibit some effectiveness at removing pharmaceuticals. As expected, removals are highly dependent on compound structure. Furthermore, some oxidants, such as chloramines, are not effective at oxidizing pharmaceuticals. Slow-rate biofiltration processes (SRBF), such as slow sand filtration (SSF) and riverbank filtration (RBF), are drinking water treatmeant systems comprised of two stages in sequence: 1) a relatively shallow biotic region where media (i.e., filter sand or aquifer material) is colonized by biofilm bacteria, followed by 2) an deeper abiotic filtration zone. These processes are extensively used in Europe and developing global regions and are seeing increased usage in the United States. There is evidence in the literature that SRBFs can remove a wide variety of trace organic pollutants including: pesticides, disinfection byproducts, and some pharmaceuticals. Little is known regarding the ability of SRBF processes to remove antibiotics from water supplies nor has any work been done to investigate the potential adverse effects of antibiotics on the biofilm bacteria that are critical to SRBF system performance. Thus, this research was performed to determine the extent and mechanisms (i.e., sorption versus biodegradation) of antibiotic removal in SRBF processes and the effects of antibiotics on biofilm bacteria (i.e., activity and community composition). The effect of antibiotics on bacterial activity and community structure was investigated by growing biofilm in the presence and absence of a mixture of antibiotics in a continuous-flow rotating annular bioreactor (CFRAB) with acetate as substrate. Three representative compounds were selected for use in this research: sulfamethoxazole (SMX), erythromycin (ERY), and ciprofloxacin (CIP). These antibiotics were selected because they: 1) represent three prominent classes of antibiotics with differing mechanisms of action against bacteria, 2) have been detected in surface water, 3) exhibit different chemical characteristics, and 4) have differing levels of biodegradability. Areal acetate utilization rates for a constant feed of antibiotics were similar to the control experiments, and utilization rates did not change during an antibiotic shock loading experiment. Attached biomass levels were greater for experiments involving a high CIP concentration (3.33 micrograms/L), however, yielding comparatively lower steady-state biomass-normalized substrate utilization rates. Microbial community analyses via automated ribosomal intergenic spacer analysis (ARISA) revealed shifts in community structure for the high dose CIP experiments. A CFRAB was also used to investigate antibiotic sorption to bacterial biofilm. The extent of sorption, as indicated by the organic carbon partition coefficient (Koc), was 15 to 23 times greater for CIP compared to ERY and SMX. The Koc values did not correlate with experimentally-determined Kow values, suggesting that the sorption of relatively hydrophilic (i.e. Kow < 1.7) and charged antibiotics to typically negatively charged biofilm is driven by ionic interactions (i.e. ion exchange) rather than hydrophobic interactions. The attenuation and impact of antibiotics in SRBF systems was investigated by conducting bench-scale filter column experiments with mixtures of SMX, ERY, and CIP at high (3.33 micrograms/L, each) and low (0.33 microgram/L, each) antibiotic feed conditions. Consistent with the CFRAB experiments, antibiotic breakthrough times were greatest for CIP, with very little uptake of SMX or ERY. Biodegradation was not observed for any antibiotic during 6-weeks of filter column operation or in complementary batch experiments. A one-dimensional advection-dispersion equation (with linear sorption) model was validated against experimental results and used to compare antibiotic retardation in SSF, RBF, and rapid gravity biofiltration (RGBF) systems. Of the modeled systems, antibiotic retardation was greatest in RBF, with little antibiotic removal expected for SSF. Based on analysis of ARISA data, the community structure of bacterial biofilm was not affected in filters exposed to antibiotics at low concentrations (i.e. 0.33 microgram/L, each) similar to those found in surface waters, with a few species impacted under high concentration conditions (3.33 microgram/L, each). The results of this work will help those interested in understanding and predicting antibiotic fate in engineered and natural systems where biofilm is present. The results indicate that antibiotic removal in SRBF processes will be dictated by compound properties such as charge and hydrophobicity, and that limited removal of antibiotics in SRBF processes can be expected. Finally, the results suggest that that mixtures of antibiotics at concentrations typically observed in surface waters are unlikely to adversely affect SRBF biofilm bacteria or process performance.Item Genomic analysis of regulatory mechanisms involved in secondary metabolite production.(2010-09) Castro-Melchor, MarleneMany secondary metabolites have beneficial uses for humans. In addition to their use as antibacterial and antifungal agents, secondary metabolites have been used as immunosuppressants, anti-tumor agents, and antiparasitics. Most of the secondary metabolites known today are produced by filamentous fungi or by members of the Streptomyces genus. Production of secondary metabolites by microorganisms involves a complex, dynamic system, with interconnected elements acting at different levels. Diverse tools were used in this work to explore regulation of secondary metabolite production, mostly in Streptomyces. The tools have a common characteristic: they either generate large amounts of data, or require large amounts of data. Regulation of secondary metabolite production in Streptomyces coelicolor was analyzed at the genome level, by using network modules inferred from a large transcriptome dataset. The upstream sequence of the elements in the network modules was searched for the presence of consensus sequences, and these results combined with information on known interactions, binding sites, and functional relatedness. The combination of this information resulted in a set of twenty networks that have a high likelihood of representing true interactions and represent a starting point for further experimental studies. The characteristics of high productivity were analyzed by comparing the genomes of two strains of the clavulanic acid producer Streptomyces clavuligerus. One of the strains is a high producer of clavulanic acid. Next generation sequence data was used to perform a genome-wide screening to identify all the differences between the two genomes. In addition to mutations in genes involved in β-lactam antibiotic production or their upstream region, structural differences were detected between the two strains. Next generation sequencing technologies were also used to assemble a draft genome for the curdlan producer Agrobacterium sp. ATCC 31749. Curdlan production mimics that of secondary metabolites, it is triggered under starvation conditions. These varied approaches exemplify some of the paths that can lead to a better understanding of secondary metabolism and its regulation.Item Procalcitonin: a blood test that can help the doctor know if your cough can be treated with antibiotics.(2012-07-26) Dijkstal, JohannaItem Procalcitonin: A clinical tool for determining etiology and necessity of antibiotics in community acquired pneumonia(2012-04-10) VanSickle, RyanItem Sinus Infections: To treat or not to treat?(2012-07-26) Hennen, ErinItem Sore throat and antibiotics: How much do they really help us as adults?(2011-08-03) Rogers, KatelynItem Sore throat in children and antibiotics(2012-07-24) Vang, CheeItem Strep Throat in Children(2009-09-18) Gieselman, KathrynStrep throat is a common illness in children that is easily treated with antibiotic therapy. This flyer provides a basic overview of strep throat, its treatment, and prevention. This would be a useful resource for a parent who is unfamiliar with the illness to read when their child is diagnosed with strep throat for the first time.Item Strep Throat: Do you really need to take medication to cure it?(2012-07-23) Vogelaar, JessicaItem Treatment of bacterial skin abscesses: Antibiotics are usually not needed.(2012-07-23) Melling, David