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Mupirocin is a bacteriostatic antibiotic that is used to decolonize people who carry methicillin-resistant staphylococci, primarily methicillin-resistant Staphylococcus aureus (MRSA). Mupirocin reversibly binds to bacterial isoleucyl tRNA synthetase to disrupt protein synthesis. Resistance to mupirocin is due either to a point mutation to the ileS gene that encodes the isoleucyl tRNA synthetase, classified as low-level mupirocin resistance; or, bacteria may obtain a plasmid that carries the ileS2 gene encoding an alternate isoleucyl tRNA synthetase, conferring high-level resistance. Mupirocin resistance plasmids contain insertion sequence (IS) 257 repeats, into which the ileS2 gene is inserted. Such plasmids have been characterized by their IS257-ileS2 junctions in both S. aureus and, recently, in Staphylococcus pseudintermedius in a dog from Croatia. The primary goals of this study were to determine the prevalence of mupirocin resistance in isolates of S. pseudintermedius in Texas, to determine whether resistance was due to point mutations in the native ileS or due to carriage of mupirocin resistance plasmids, and to characterize the structure of the mupirocin resistance genes carried on plasmids. In this study, 572 S. pseudintermedius isolates, collected from veterinary patients from across Texas were screened for their susceptibility to low levels of mupirocin. Of these isolates, only one out of 572 (0.17%) tested positive for mupirocin resistance and was found by polymerase chain reaction (PCR), using previously published primers mupA and mupB, to have a 458 bp fragment and, with primers M1 and M2 to have a 237 bp fragment, indicating the presence of the high-level mupirocin resistance gene, ileS2. The arrangement of the IS257-ileS2 junctions was then analyzed by PCR and the products, bands at 1816 bp for primers ileS2-5’ and IS257R and at 1127 bp for primers ileS2-3’ and IS257F, which are consistent with the amplification pattern for an S2 plasmid, were cloned into a plasmid, pT7Blue, and sequenced for comparison to published sequences in GenBank. BLAST analyses in NCBI, comparing the isolate to recently published sequences for mupirocin-resistant S. pseudintermedius isolated from a dog with pyoderma in Croatia, indicate a 100% similarity to the upstream junction, JX186508, and 97% to the downstream junction, JX186509.

The CDC estimates that one in 20 patients admitted to the hospital is a carrier of methicillin-resistant Staphylococcus aureus (MRSA). Staphylococci are commonly found on the skin and mucous membranes within the anterior nares, which provides the principle reservoir for this organism. These organisms can go on to cause surgical site infections in hospitalized patients. Mupirocin is an effective topical medication used to eliminate nasal carriage of Staphylococcus aureus (S. aureus). Based on Level A evidence, the 2007 Society of Thoracic Surgeons has made a Class I recommendation for the use of mupirocin for all patients undergoing cardiac surgery in the absence of documentation of a negative culture for staphylococcal colonization. The purpose of this before-and-after study is to examine the rates of surgical site infections (SSI) for cardiac surgery patients who came through the pre-admission testing unit prior to same-day admission (SDA) for surgery before and after providing 2% mupirocin nasal ointment. Specific aims: 1. To examine the relationship between providing mupirocin to the SDA cardiac surgery patient and the prevalence of SSI. 2. To examine the cost-effectiveness of providing mupirocin to the SDA cardiac surgery patient and SSI. 3. To examine the adherence of SDA preoperative cardiac surgery patients and the use of mupirocin preoperatively, if the medication is provided at no cost to the patient. Retrospective chart reviews were completed on 330 patients: 175 patients in the pre-provision of mupirocin and 150 in the mupirocin provided group. Chi Square and students' t-tests were used to analyze the data. There were five SSIs in the pre-provision of mupirocin group and no SSIs in the mupirocin provided group. This was a significantly statistical difference between the groups (X2 = 4.497, p > 0.5) Continued provision of 2% nasal mupirocin to prevent SSI in the cardiac surgery patients is recommended.

This dissertation is comprised of four distinct formulation sections, which are described below: A novel solid dosage formulation was investigated for achieving zero-order drug release profile by combining tablet shape design and tablet membrane film coating. Verapmail (model drug) was compressed into hydrophilic matrix tablet cores of flat-faced and bi-convex shape, which were encapsulated with membrane controlling film. The hydrophilic tablet core contained hydroxypropyl methylcellulose (HPMC) 15 LV, pectin, and Avecil��. The membrane film coating solution was comprised of deionized water, Opadry��, Surelease�� and talc. The combination of membrane film coating and tablet shape design was found to influence in vitro verapamil release profile towards the zero-order release demonstrated by the commercial Covera HS�� (Pharmacia). An alternative formulation for the commercial Bactroban�� (Smithkline Beacham) ointment 2% was developed. Both the texture and consistency of the new ointment were comparable to the Bactroban�� ointment. The new and the commercial formulations were found to be equivalent in drug release by the Bauer-Kirby test. Mupirocin remained unstable in the new formulation. Mg����� was added to help stabilize mupirocin and was shown to complex with mupirocin by nuclear magnetic resonance (NMR). The modified formulation including Mg����� however failed to stabilize mupirocin. The stability assay results showed an average of 67.2% mupirocin recovery along with 25.2% degradation products. A generic omeprazole formulation was developed, which was comprised of nonpareil core, omeprazole matrix layer, and an enteric locating layer of ammoniated hydroxypropyl methylcellulose phthalate (HPMCP) 55S. The new formulation was gastro-resistant in protecting against omeprazole degradation for up to 2 h, but failed to dissolve as rapidly as the commercial Prilosec�� (Astra Merk) in simulated intestinal fluid. The addition of expotab�� to the enteric coating layer failed to improve omeprazole dissolution rate. A novel hot-melt coating methodology utilizing direct blending technique has been developed. The processing steps for the direct blending hot-melt coating are: (a) Hot-melt system preparation; (b) Dispersion/dissolution of the active ingredient(s) in the hot-melt system; (c) Pre-heating of the coating substrate; and (d) Cooling and congealing of the hot-melt on substrate surface. Immunogenic effect was observed in mice administered with enteric-coated ragweed pollen extract (RPE) alpha fraction by the hot-melt coating encapsulation with direct blending method. The effect was not shown to be statistically significant. / Graduation date: 2003

Control of antibiotic resistance in bacteria is based on the concept that resistance incurs a fitness cost in non-selective conditions. Fitness costs were assessed for low- and high-level mupirocin resistance in locally-derived Staphylococcus aureus and S. epidermidis. Costs of resistance were assessed in pure cultures by comparing growth curve characteristics and in mixed culture as the proportion of resistant cells surviving. Costs were not present in comparisons of growth rates among groups of naturally-occurring isolates from the different resistance categories. However, in S. aureus, growth rates within resistance categories differed by approximately 30 – 90%. Among near-isogenic pairs of strains, fitness costs ≥10% were present in three of eleven pairs under pure culture and in six of eleven pairs under competition in mixed culture. Differences in intrinsic growth rates could easily mask fitness costs of the magnitudes observed. Thus, clinical outcomes also depend on whether there is a mixed infection and if so, on the growth rates of strains present.

To combat widespread infections caused by Staphylococcus aureus, mupirocin was introduced at the Veterans Affairs Medical Center, Mountain Home, Tennessee. Soon after introduction, high-level mupirocin-resistance emerged. The rapid emergence was hypothesized to be due to conjugative transfer of the mupA resistance gene from S. epidermidis to S. aureus. Results have shown that transfer of high-level mupirocin-resistance from S. aureus donors commonly occurs. However, transfer from naturally-occurring S. epidermidis donors was not attainable. Staphylococcus epidermidis transconjugants, however, were capable of serving as donors. Further examination of non-transmissibility included PCR analysis of conjugative transfer genes (tra genes) in capable and non-capable donors. Results confirmed that capable donors possess full-length copies of selected transfer genes. Non-capable donors varied in the presence/absence of full-length copies of transfer genes, but none had all three genes. The genetic differences among non-capable donors suggest that non-transmissibility has arisen independently in different strains via gene deletions and recombinations.

Objectives This research project focused on the inhibitory effectiveness of a novel antimicrobial gel (AMG) towards a panel of common microbes involved in wound infections. Methods A novel antimicrobial topical gel consisting of vitamin E TPGS (tocopherol polyethylene glycol succinate), ascorbyl palmitate, zinc aspartate, lavender oil and deionized distilled water was developed in our laboratory. Various in vitro techniques were used to determine the effectiveness of AMG on prokaryotic and eukaryotic microbes. Results In vitro experiments show that while AMG had varying inhibitory effects on both prokaryotic and eukaryotic microbes, there was a predilection for AMG to inhibit planktonic growth and biofilm formation of Staphylococcus species, most notably Methicillin Resistant Staphylococcus aureus (MRSA). The inhibitory effect of the AMK on planktonic growth was immediate with a four-fold reduction in growth, compared to controls, within 4 to 6 hrs of induction. Within 24 hrs S. aureus growth was minimal and complete inhibition of growth was achieved within 48 hrs. In an in vitro biofilm model, the AMG inhibited Staphylococcus biofilm attachment by 67% (density), 82% (mass) and 95% (viability). On pre-formed established biofilms, the AMG was able to inhibit 47% (density), 47% (mass) and 44% (viability) Staphylococcus biofilms. Antibiotic comparison experiments demonstrated that the MIC (minimum inhibitory concentration) of Mupirocin was Conclusions AMG is nontoxic to humans and canines and demonstrates potential for use in wound infections as an alternative to commonly prescribed antibiotics without the unintended drug resistance seen with antibiotics. AMG is an effective treatment option, this far in vitro, for Staphylococcus infections that are particularly prone to biofilm growth.