Browsing by Subject "MRSA"

Now showing 1 - 7 of 7
  • Thumbnail Image
    Item
    Characterization of Staphylococcus aureus at the Human-Swine interface
    (2016-11) Sun, Jisun
    The goal of this thesis was to advance understanding of the epidemiology of Staphylococcus aureus in the US swine industry, particularly in relation to potential human health risks from this animal reservoir. The studies were conducted to investigate the prevalence of S.aureus in swine and swine veterinarians in the USA. A total of 720 nasal swabs (20 swabs per herd) were collected from 36 herds and self-nasal samples from 66 swine veterinarians were submitted every month for 18 months. The patterns of S.aureus colonization were determined based on molecular epidemiological methods (MLST and spa typing). Antimicrobial susceptibility testing, enterotoxin genes, immune evasion cluster genes testing were performed to identify their characterizations. Later, a subset of 76 isolates purposely selected was submitted for whole genome sequencing analysis. In swine study, MRSA was not detected in any of the 35 herds except a positive control herd. S.aureus was detected from 76% of pigs sampled. In case of swine veterinarians, the prevalence of S.aureus (avg 65%, monthly range from 58-82%) and MRSA (avg 9%, monthly range from 6-15%) were confirmed suggesting elevated risk of nasal colonization. Similar distribution of genotypes between swine and swine veterinarians were observed. The patterns of phenotypic antibiotic resistance, the absence of enterotoxin genes and IEC genes also showed relatively similar regardless of host species. In addition, WGS data supported that there were unique traits of putative virulence genes and antibiotic resistance genes by each genotype. All the data generated in this dissertation provide a comprehensive assessment of swine associated S.aureus giving a crucial insight into the phenomenon of interspecies dissemination.
  • Thumbnail Image
    Item
    Demonstration of pharmacometric applications to anti-infective chemotherapy.
    (2010-06) Salem, Ahmed Hamed Ahmed
    We developed a population pharmacokinetic model for efavirenz in pediatric HIV patients to guide dosing and decrease incidence of subtherapeutic levels. Data comprised of 3172 plasma concentrations collected over 4 years from 96 HIV-1 infected children who participated in the Pediatric AIDS Clinical Trials Group 382 (PACTG382) study. A one compartment model adequately described the data and the allometric size model accounted for the effect of body size on oral clearance and apparent volume of distribution. A sigmoid Emax maturation model demonstrated an increase in oral clearance by age to reach 90% of its mature level by the age of 9 months. The bioavailability of oral liquid formulations relative to the capsule formulation was also found to increase by age to reach 90% of its mature value of 0.79 by the age of 8 years. CYP2B6-G516T polymorphism was associated with a 51% decrease in oral clearance while MDR1-C3435T polymorphism has shown no effect. The final model showed good predictability performance and its application to improve dosing in pediatrics warrants further investigation. Appropriate initial treatment choices for methicillin resistant Staphylococcus aureus (MRSA) infections are very critical especially in the intensive care units (ICU) settings. We compared the ability of ceftobiprole, dalbavancin, daptomycin, tigecycline, linezolid and vancomycin to achieve their requisite PK/PD targets against MRSA isolates collected from ICU settings. Ceftobiprole and dalbavancin were found to have the highest probability of achieving favorable outcome against MRSA infections in the ICU. The susceptibility results suggested a further reduction of the vancomycin breakpoint to 1 μg/ml. We also employed a recently developed quantitative methodology to characterize the killing effect of vancomycin and rifampin combination against MRSA biofilm. The results suggest antagonism between vancomycin and rifampin against MRSA biofilm. The quantitative approach used provides a scientific rationale for further in vivo investigations which should allow a better understanding of the therapeutic potential of this combination in biofilm-associated MRSA infections. Finally, we compared the activities of moxifloxacin and vancomycin against MRSA and MRSE biofilms. Moxifloxacin exhibited a superior anti-biofilm activity suggesting potential benefit in treatment of MRSA and MRSE biofilm associated infections.
  • Thumbnail Image
    Item
    Development of Antibacterial Compounds to Target Drug Resistant Bacteria
    (2021-05) Schultz, John
    Nosocomial infections caused by resistant Gram-positive organisms are on the rise, presumably due to a combination of factors including prolonged hospital exposure, increased use of invasive procedures and pervasive antibiotic therapy. Compounding the problem is the emergence of multidrug-resistant (MDR) Gram-positive bacteria [e.g. methicillin resistant Staphylococcus aureus (MRSA), Streptococcus pneumoniae and Enterococcus spp.], which render treatment extremely difficult. As a result, last resort antibiotics (e.g. vancomycin, linezolid and daptomycin) are frequently deployed as treatment for these infections, which have the unintended consequence of selecting resistance to these agents. Although antibiotic stewardship and infection control measures are helpful, newer agents against MDR Gram-positive bacteria are urgently needed. Here we describe our efforts that lead to the identification of 5-aminoquinolone 111 with exceptionally potent Gram-positive activity with MICs ≤ 0.06 µg/mL against numerous clinical MRSA isolates. Preliminary mechanism of action and resistance studies demonstrate the 5-aminoquinolones are bacteriostatic but become cidal with 4-8 times MIC, do not select for resistance, and selectively disrupt bacterial membranes over eukaryotic membranes. While the precise molecular mechanism has not been elucidated, the lead compound is non-toxic displaying a therapeutic index of greater than 1000, is devoid of hemolytic activity and has attractive physicochemical properties (clogP = 3.8, MW = 441) that warrant further investigation of this promising antibacterial scaffold for treatment of Gram-positive infections.Another infectious disease that has a massive burden upon the global society and shares the same concern of drug resistance is Tuberculosis (TB). Mycobacterium tuberculosis (Mtb), the causative infectious agent of TB, contains many essential biosynthetic pathways necessary for the survival and virulence of Mtb, but are absent in humans making these pathways prime candidates for antimicrobial compounds. Chorismate biosynthesis is one such essential pathway that has been exploited as a route to TB chemotherapy. Chorismate is also a metabolic hub towards the biosynthesis of a wide array of aromatic small molecules such as folates, mycobactins, aromatic amino acids, and menaquinone in Mtb. Herein, we describe the synthesis of the epimers of 6-fluoroshikimate and methyl-6-fluoroshikimate, known inhibitors of chorismate-utilizing pathways, and biological evaluation of methyl (6S)-6-fluoroshikimate (125) in Mycobacterium. Initial supplementation studies indicate that methyl (6S)-6-fluoroshikimate may act upon unexpected chorismate-utilizing pathways.
  • Thumbnail Image
    Item
    Hospital Policies and Hospital-onset Methicillin-resistant Staphylococcus aureus Infections: A Mixed Method Evaluation
    (2022-03) Lesher Erickson, Lindsey
    MRSA continues to spread in hospitals, despite modest recent success. Gaps exist regarding how hospital policies impact MRSA transmission in hospitals. Characterization of the policy environment has been useful in approaching other public health issues including alcohol control. Our goals were to develop a tool to identify measurable and modifiable hospital policy components designed to prevent MRSA, then utilize this tool to evaluate policies to examine the relationship between policies and MRSA incidence. We developed a tool to systematically evaluate hospital policies that included instructional and implementation elements. Each policy element was evaluated for its presence and thoroughness. Four hospital policy types were evaluated from five hospitals in Minnesota: hand hygiene, multidrug-resistant organism (MDRO)/isolation, influenza vaccination, and whistleblower (corporate compliance). Results demonstrated that the policies varied in comprehensiveness and thoroughness across hospitals and topics. Most policies included purpose and policy statements. Most policies lacked consequences for noncompliance, accountability, responsibility, monitoring and enforcement of policy expectations; when included, components scored low for thoroughness. Of the policies, influenza vaccination was the most complete while hand hygiene policies scored highest for thoroughness, followed by MDRO/Isolation. Upon evaluation of policy scores and MRSA incidence rates, we found an indication of a negative correlation between the MDRO/Isolation policy score and MRSA incidence: the higher the mean score of the MDRO/Isolation policy, the lower the MRSA rate. We found a similar indication of a negative correlation between the mean hand hygiene policy score and MRSA incidence. As we begin to characterize policy, endogenous in nature, as a potential exposure it is important that we develop rigorous measurement; we provided a first step in developing such an approach. The work of this dissertation will contribute to the field of epidemiology by gaining insight into organizational policy – including how we measure, analyze, and draw inferences with the results.
  • Thumbnail Image
    Item
    A pilot study of the epidemiology of Staphylococcus aureus in multiple site swine production
    (2013-08) Linhares, Leticia Caldas Monteiro
    Staphylococcus aureus (S. aureus) is a common colonizer of both humans and pigs (Lowy, 1998; Frana, 2012). The ability of S. aureus to acquire genes that confer resistance to multiple drugs has further elevated its importance to public health (Cuny and Witte, 2008a). In particular, clones of S. aureus that are resistant to methicillin and other beta-lactam antimicrobials (MRSA) are a major clinical problem, and the discovery of MRSA in livestock populations has raised concerns about the potential importance of livestock as reservoirs of MRSA (Voss et al., 2005).However, the importance of pigs in S. aureus transmission to humans and clinical disease is yet to be determined (Cuny and Witte, 2008b). Most recent studies of pigs have focused on MRSA, and there have been no comprehensive studies of the epidemiology of S. aureus (MSSA and MRSA) in pigs. Despite being considered ubiquitous in production animal facilities (Frana, 2012), S. aureus ecology in livestock production farms is poorly documented. Most recent research has used selective enrichment methods to study MRSA in swine populations, rather than generic S. aureus. S. aureus can be isolated from several anatomic sites of pigs, as well as from air, environmental samples and persons having contact with pigs. In fact, isolation of S. aureus in air samples from swine barns suggests this is likely an important route of exposure for people working in livestock facilities (Gibbs et al., 2006; Oppliger et al., 2012). Overall, the limited information on the ecology of S. aureus in the pork production chain limits the ability of the swine industry to understand and communicate the risks to public health in an informed manner.The core rationale for this thesis was that there has been no prior systematic effort to describe the occurrence of S. aureus in swine production systems. The vast majority of studies have focused on MRSA strains using selective culture methods, and/or focused on a limited number of matrices. The objective was therefore to obtain preliminary data on the occurrence of S. aureus in pigs, people, environmental and air samples on pig farms and some insight into the distribution of the organism in the swine farm milieu. Thus, a pilot study of the epidemiology of S. aureus in multiple site swine production was conducted.
  • Thumbnail Image
    Item
    Use of Small Molecule Potentiators to Enhance Activity of Beta-Lactams Against Gram+ Bacteria
    (2019) Hammerstad, Travis, A
    An initial screening of 45,000 small molecules was conducted at the ICCB-Longwood Screening Facility at Harvard to find molecules which could "reactivate" older generations of antibiotics against MRSA. This approach indicates that both the antibiotic and the potentiator have no activity against MRSA, but together they do. The molecular hits were resynthesized in the lab along with analogs to increase the potency and solubility.
  • Thumbnail Image
    Item
    What is Community Acquired MRSA?
    (2009-05-04) Chhabra, Manik
    Community Acquired Methicillin Resistant Staphylococcus aureus (CA-MRSA) has become a common cause of skin and soft tissue infections in the outpatient setting. This education tool is designed to inform patients about common presentations of MRSA, treatments, and prevention methods.