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Tuberculosis (TB) continues to be a worldwide health problem despite available effective chemotherapy. In the past 2 decades, distribution of new TB cases in the U.S. has shifted to persons over the age of 65, who account for 12% of the U.S. population but 27% of the total TB morbidity. Residents of long-term care facilities are at greater risk of developing TB than are elderly persons living in private homes or in the community at large. Because this older age group continues to be the largest repository for TB and because the geriatric population in this country is growing, TB is an important medical issue.

Vancomycin has been considered first-line treatment for bacteremia caused by methicillin-resistant Staphylococcus aureus (MRSA) despite treatment failures in up to 20% of patients with MRSA bacteremia secondary to endocarditis. However, trimethoprim-sulfamethoxazole (TMP-SMX) is as effective as vancomycin for the management of MRSA bacteremia. secondary to endocarditis in injection drug users. We report the successful management of a left ventricular assist device-related MRSA infection with persistent MRSA bacteremia that failed to respond to vancomycin, linezolid, and quinupristin/dalfopristin but did respond to TMP-SMX.

Acinetobacter baumannii is an increasingly multidrug-resistant Gram-negative bacterial pathogen and contributes to many hospital-acquired infections. Discovering new treatments against Acinetobacter baumannii infections is necessary as the pathogen adapts to the antimicrobials prescribed by physicians. Cyclic di-GMP (c-di-GMP), a bacterial second messenger, can regulate various phenotypes including biofilm formation, desiccation tolerance, motility, etc.; many of these phenotypes may help A. baumannii better survive a hospital environment, such as dryness on hospital surfaces. Up to twelve c-di-GMP modulating enzymes (CMEs) and two c-di-GMP binding proteins are predicted to be encoded by this pathogen. Diguanylate cyclases (DGCs) produce c-di-GMP, whereas phosphodiesterases (PDEs) degrade c-di-GMP. More c-di-GMP that can bind to its binding proteins means more biofilm formation and less motility. Of the eleven CMEs, 7 are DGCs, 2 are PDEs, and 3 encode both domains (DGCs/PDEs). I hypothesized that biofilm formation, desiccation tolerance, and motility were controlled by c-di-GMP and that we could target these parts of the c-di-GMP signaling network for new treatments. If we disrupt these genes, then we should see a reduction in the regulatory effects of these phenotypes. In this investigation, we generated mutants with a single gene knockout or transposon mutagenesis in two different A. baumannii strains: 17978, a historical laboratory strain that exhibits swarming motility and AB5075, a recent clinical isolate that exhibits twitching motility. To test biofilm formation, we let the mutants grow to their maximum concentration in 96-well plates, stained the plates with crystal violet, and quantified the crystal violet that stained the biofilm. To test for motility, a LB agar plate was stabbed to the plastic surface or dropped on the agar surface with diluted culture to determine the presence of twitching or swarming motility, respectively. To test for desiccation tolerance, we washed the cultures in distilled water to rid the sample of any salt, serially diluted the samples in solution, and plated them out onto LB agar plates. Bacterial counts were quantified before and after desiccation to determine survival of each mutant. From these experiments, 6 DGCs, 1 PDE, and 2 DGCs/PDEs were shown to regulate biofilm formation in AB5075. Furthermore, a PDE and a DGC/PDE were shown to regulate twitching motility in AB5075, while a single DGC was required for tolerating dryness. In strain 17978, we have found a PDE and 4 DGCs that are necessary for swarming motility and are currently conducting biofilm and desiccation tolerance assays. So far, we’ve identified a role for c-di-GMP in A. baumannii biofilm formation, motility, and desiccation survival. Inhibiting the regulation of these pathways could produce novel mechanisms to combat this pathogen in the hospital environment.

Microbes compete for the same limited nutrients, space, and resources; therefore, they show competitive relationships. Our laboratory has previously shown that Alcaligenes inhibits the growth of Staphylococcus, a Gram-positive bacterium, and Candida, a fungi, which are both substantial causes of human infections. We are interested in determining the genetic factors in Alcaligenes that are responsible for killing these competitors. Transposon mutagenesis was used to interrupt gene segments by introducing a foreign piece of DNA into the Alcaligenes genome. By creating these mutants of Alcaligenes, we were able to screen these against Staphylococcus to find those that can no longer inhibit. The absence of zones of inhibition indicated that we successfully interrupted the genetic element in Alcaligenes that kills Staphylococcus. The genome of the mutants were isolated and the area disrupted was sequenced. In one mutant, we discovered that the gene being interrupted was a MFS transporter. This is an important transporter in bacteria for virulence, metabolism, and quorum sensing. Results from this study may help us find new targets for Staphylococcus aureus infections.

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This dissertation aims to explore the role of patient and family engagement in the context of two current health issues: catheter-associated urinary tract infections (CAUTI) and antibiotic resistance. Chapter One contains an introduction to patient and family engagement, CAUTI, and antibiotic resistance, followed by gaps in the science, a description of the theoretical framework, and specific aims addressed in this dissertation. Chapter Two is a systematic review of existing CAUTI prevention interventions that involve patient and family engagement. Chapter Three is a study designed to meet the learning needs of parents by developing a graphically-enhanced CAUTI-prevention educational resource using participatory design methods. Chapter Four is an environmental scan that summarizes the content and format of existing resources about antibiotic resistance and antibiotic use available from children’s hospital websites across the United States. Finally, Chapter Five contains an overall summary of the findings of this dissertation, a discussion of results within the guiding theoretical framework, practice and policy implications, and suggestions for future research.

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