Cost containment measures within hospital systems push for earlier discharges on stable patients. Due to patient placement difficulties and costs associated with skilled facilities, antibiotic use in home health care settings is becoming a common occurrence. This trend will likely increase as care continues to shift to outpatient areas. Lack of sufficient serum drug concentrations needed in severe infections and increasing resistance to many of the oral options often necessitates the use of the intravenous (IV) route. Home health care practitioners may have minimal information on patients or limited experience with IV antibiotics that may impact quality of care. This review summarizes key points relevant to IV antibiotics routinely used by home health prescribers, nurses, technicians, and care managers. This review will focus on antibacterial agents including vancomycin, aminoglycosides, beta-lactams, daptomycin, tigecycline, and telavancin. Appropriate dosing, indications, adverse events, monitoring parameters, and feasibility of using IV antibiotics are discussed.

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Purpose: Oral vancomycin is a first-line treatment for Clostridium difficile-associated diarrhea. Preparation of oral vancomycin solutions historically has been facilitated by extemporaneous compounding, using various formulas or compounding kits, such as FIRST® - Vancomycin. More recently, FIRVANQ™ (vancomycin HCl) for oral solution was approved by the FDA, replacing the FIRST® compounding kits. Preparation and storage of unit-doses of oral solutions can expedite delivery of the medication to the patient and reduce opportunity for dosing errors. In this study, we evaluated the stored stability of two preparations of vancomycin HCl oral solution (FIRST® – Vancomycin and FIRVANQ™), stored in oral syringes and dosing cups at refrigerated and room temperatures. Methods: Triplicate batches of vancomycin HCl oral solution (50 mg/mL) were prepared using FIRST® - Vancomycin and FIRVANQ™, aliquoted into plastic oral syringes and sealed dosing cups, and stored at refrigerated and room temperatures for a total of six batches. Additionally, remaining samples from FIRVANQ™ batches were unit-dosed in clear Luer-Lok™ syringes and stored under refrigeration as a seventh batch. Samples were removed and analyzed for vancomycin recovery using a previously validated high-performance liquid chromatography with ultraviolet detection (HPLC-UV) method over a 30-day period. Recovery was quantitatively assessed by comparing to a freshly prepared United States Pharmacopoeia (USP) reference standard on each day of sampling. Results: Stability was defined as recovery of 90 - 110% of labeled amount. For all tested samples, the chemical potency remained within the therapeutically acceptable window for the entire study period of 30 days. At room temperature, the FIRST® syringes and cups both retained 95% potency after 30 days. Under refrigeration, this product retained 100% potency and 91% potency in syringes and cups, respectively. Similarly, the FIRVANQ™ room temperature syringes were at 99% recovery and the room temperature cups at 95% recovery after 30 days. Refrigerated FIRVANQ™ retained a potency of 102% potency in the dosing cups after 30 days, and the both syringes types (clear and amber) were 97% and 101%, respectively, recovery during the study period. Conclusion: The percent recovery of vancomycin in each test group remains within 90 – 110% of the labeled amount throughout duration of study (0 – 30 days). Based on this study, unit-dosing has been shown to have a 30-day chemical stability. In this case, unit-dosing not only may be used to improve workflow and reduce dosing errors, but may also have an impact of reducing drug waste due to avoidance of discarding appropriately potent drug product. Additionally, stability within the study period was independent of storage container and condition. Finally, this unit-dosing practice for FIRVANQ™ is equally acceptable in the classic luer-slip amber plastic syringes, and the newer Luer-Lok™ clear plastic syringes.

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Acute kidney injury (AKI) is a significant adverse effect of many medications that leads to increased morbidity, cost, and mortality among hospitalized patients. Recent literature supports a strong link between empiric combination antimicrobial therapy and increased AKI risk. As briefly summarized below, the following chapters describe my research conducted in this area. Chapter 1 presents and summarizes the published literature connecting combination antimicrobial therapy with increased AKI incidence. This chapter sets the specific aims I aim to achieve during my dissertation project. Chapter 2 describes a study in which patients receiving vancomycin (VAN) in combination with piperacillin-tazobactam (TZP) or cefepime (CFP). I matched over 1,600 patients receiving both combinations and found a significantly lower incidence of AKI among patient receiving the CFP+VAN combination when controlling for confounders. The conclusion of this study is that VAN+TZP has significantly increased risk of AKI compared to CFP+VAN, confirming the results of previous literature. Chapter 3 presents a study of patients receiving VAN in combination with meropenem (MEM) or TZP. This study included over 10,000 patients and used inverse probability of treatment weighting to conserve data for this population. After controlling for confounders, VAN+TZP was associated with significantly more AKI than VAN+MEM. This study demonstrates that MEM is clinically viable alternative to TZP in empiric antimicrobial therapy. Chapter 4 describes a study in which patients receiving TZP or ampicillin-sulbactam (SAM) with or without VAN were analyzed for AKI incidence. The purpose of this study was to identify whether the addition of a beta-lactamase inhibitor to a beta-lactam increased the risk of AKI. This study included more than 2,400 patients receiving either agent and found that there were no differences in AKI among patients receiving SAM or TZP; however, AKI was significantly more common in the TZP group when stratified by VAN exposure. This study shows that comparisons of TZP to other beta-lactams without beta-lactamase inhibitors are valid. Chapter 5 presents a study of almost 30,000 patients who received combination antimicrobial therapy over an 8-year period. This study demonstrates similar AKI incidence to previous literature and the studies presented in the previous chapters. Additionally, the results of the predictive models suggest that further work in this research area is needed. The studies conducted present a clear message that patients receiving VAN+TZP are at significantly greater risk of AKI than alternative regimens for empiric coverage of infection.

Prior work by our research group showed that the total Western diet (TWD), a rodent diet which models the typical American diet, promoted the development of colon tumors when fed to mice. Other researchers previously showed that vancomycin, an antibiotic that changes the gut microbiome composition, causes differential changes in the severity of colon inflammation and CRC. Our goal was to determine the combined effects of feeding the TWD and vancomycin treatment on colitis and CRC, and if these factors interact. We hypothesized that vancomycin treatment would mitigate colitis and CRC in mice fed the TWD. To this end, mice were fed either a healthy diet or the TWD. Mice were also given either vancomycin in their drinking water, or plain water. Colon inflammation and tumor development was induced in mice by treating them with a gut irritant and a chemical carcinogen. Contrary to our hypothesis, mice fed the TWD and treated with vancomycin experienced more severe intestinal inflammation and had greater tumor burden compared to mice fed a standard diet. Furthermore, vancomycin treatment decreased the number of bacteria l species present in the fecal microbiome and altered the relative abundance of the taxa that were present. Rather than the diet consumed, vancomycin was the driving force in determining the bacterial community composition. Overall, these results suggest that vancomycin-induced changes to the gut microbiome may be associated with increased development of colon tumors, particularly in the context of a Western dietary pattern.

<p>The goal of this work is to develop novel molecular systems, functionalization techniques, and data collection routines with which to study the binding of immobilized cognate binding partners. Our ultimate goal is the routine evaluation of thermodynamic parameters for immobilized systems through interpretation of the variation of the binary probability of binding as a function of soluble ligand concentration. The development of both data collection routines that minimize non-specific binding and functionalization techniques that produce stable ordered molecular systems on surfaces are of paramount importance towards achievement of this goal. Methodologies developed here will be applied to investigating the thermodynamics of multivalent systems.</p><p>In the first part of this work, the effect of contact force on molecular recognition force microscopy experiments was investigated. Increased contact forces (>250 pN) resulted in increased probabilities of binding and decreased blocking efficiencies for the cognate ligand-receptor pair lactose-G3. Increased contact force applied to two control systems with no known affinity, mannose-G3 and lactose-KDPG aldolase resulted in non-specific ruptures that were indistinguishable from those of specific lactose-G3 interactions. Thus, it is essential to design data collections routines that minimize contact forces to ensure that ruptures originate from specific, blockable interactions.</p><p>In the second part of this work we report the first example of the preparation of stable self assembled monolayers through hydrosilylation of a protected aminoalkene onto hydrogen-terminated silicon nitride AFM probes and subsequent conjugation with biomolecules for force microscopy studies. Our technique can be used as a general attachment technique for other molecular systems.</p><p>In the third part of this work we develop novel molecular systems for tethering oriented vancomycin and its cognate binding partner L-Lys-D-Ala-D-Ala to surfaces and AFM tips. Unbinding experiments demonstrated that traditional methods for forming low surface density amine layers (silanization with APTMS and etherification with ethanolamine) provided molecular constructs which displayed probabilities of binding that were too low and showed overall variability too high to use for probabilistic evaluation of thermodynamics parameters. Instability and heat-induced polymerization of APTMS layers on tips and surfaces also prohibited their utility. Formation of Alkyl SAMs on silicon provides a more reliable, stable molecular system anchored by Si-C bonds that facilitates attachment of vancomycin and is capable of withstanding prolonged exposure to heated organic and aqueous environments. It follows that covalent immobilization of KDADA to silicon nitride AFM tips via Si-C bonds using hydrosilylation chemistry will be similarly advantageous. These methods offer great promise for probabilistic evaluation of thermodynamic parameters characterizing immobilized binding partners and will permit unambiguous determination of the role of multivalency in ligand binding, using an experimental configuration in which intermolecular binding and aggregation are precluded.</p> / Dissertation

Three Streptococcal strains: S. milleri P213, S. milleri P35 and S. milleri B200 and three enterococcal strains: E. faecalis 123, E. faecalis 126 and E. faecium were used to test for vancomycin resistance. Two strains were used as reference strains that were already characterized as vancomycin resistant. E. faecium BM4147 was used as a VanA control and E. faecalis ATCC was used as a VanB control. Susceptibility of each strain to this antibiotic was tested by disk-diffusion assay and the MIC values for the strains were found to be between 5 - 10 ug/ml and for the VanA control, the MIC was > 64 ug/ml and for the VanB control was 32 ug/ml. These MIC values indicate that S. milleri P213, S. milleri P35, S. milleri B200, E. faecalis 123, E. faecalis 126, and E. faecium are all of the VanC phenotype. All strains were tested for lysis by means of addition of vancomycin (10 ug/ml) to the bacterial cultures. Lytic curves were constructed and the VanB control was found to be most autolytic upon addition of vancomycin and E. faecalis 123 was the least autolytic. However, under normal conditions in phosphate buffer, lytic curves showed that S. milleri P213 was the most autolytic and the VanA control, the least autolytic. PCR assays were performed to detect specific antibiotic resistant genes. Primers were selected from Dukta-Malen et al., 1995. The VanA primer yielded amplification of 732 bp for only the VanA control DNA and the VanB primer set yielded products for the VanB control DNA. S. milleri P213, P35, B200 and E. faecalis 123 and 126, and E. faecium DNA were amplified with the VanC primers. This supports the results obtained in MIC that these strains are possibly VanC resistant strains. Amplified VanA control and that of E. faecalis 126 were thereafter sequenced. VanA control amplicon was correctly amplified since it showed homology to E. faecium BM4147 as well as the VanB amplicons which was found to be homologous to the transposon Tn1549 found on the well-characterized E. faecalis strain which is known to harbour the VanB vancomycin-resistant genes. Whilst E. faecalis 126 which represented the VanC phenotype showed 96% homology to E. gallinarum BM4147 which is a well-characterized glycopeptide-resistant enterococci belonging to the VanC phenotype. Southern blots were performed using specific primers as a probe to verify whether the gene sequences for the specific genotype were present in these strains and results confirmed those found in the PCR assays and in DNA sequencing. The peptidoglycan precursors of each strain were arrested in vancomycin (20 ug/ml) to block transpeptidation and transglycosylation steps of peptidoglycan synthesis and bacitracin (100 ug/ml) was used to amplify precursors at the transglycosylation step. Precursors were extracted and analysed by reverse-phase HPLC. UDP-MurNAc-tetrapeptides cell wall precursors, which are found abundantly in vancomycin-resistant strains, were found in large proportions in all strains, except in E. faecalis 123 when arrested with vancomycin. This precursor has a noticeably decreased affinity for vancomycin, hence contributing to its resistance. The precursor accumulated when arrested with bacitracin, was, UDPMurNAc-tetrapeptide in all strains except in E. faecalis 126. UDP-MurNAc-pentapeptides were also found in moderate amounts in most strains. The molecular masses of the peptidoglycan precursors obtained from mass spectrometry correctly identified them. This confirmed that the bacterial strains investigated were in fact resistant to the antibiotic vancomycin and this study shows that results obtained from conventional phenotypical screening methods reliably correlated with the genotypes classified using more advanced techniques such as PCR, southern blot/hybridisation and DNA sequencing. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2005.

Antibiotic use is a vital method for the treatment of most diseases involving bacterial infections. Unfortunately, in certain cases these agents are not effective in treatments against diseases for either some limitation in antibiotic usage because of the side effects or some distribution problems caused by physiological or pathological barriers in the body. Such problems are thought to be minimized by development of controlled release systems which involve implantation of antibiotic loaded polymeric systems directly to the site of infection. Present study involves Vancomycin, a very strong antibiotic with a wide spectrum of activity, and two biocompatible and biodegradable polymers, poly(3-hydroxybutyrate-co-3-valerate) PHBV and poly(L-lactide-co-glycolide) PLGA, in the construction of rod shaped controlled release systems designed for the aim of local treatment of osteomyelitis. Vancomycin carrying rods of either PHBV 8 or PLGA (50:50) polymers were prepared by the use of cold paste and hot extrusion methods in two different loading ratios (2:1 and 1:1 P:V). In situ release kinetics of each type of rod was determined by spectrophotometric measurement of vancomycin concentration. For determination of drug content of the controlled release rods initially and at the end of the release experiments, extraction and IR (infrared) studies were carried out. The efficacy of the system was measured in vitro on the bacterial strain, B. subtilis. Characterization of the rods was made by the use of stereomicroscopy and SEM (scanning electron microscopy). In situ release results of the controlled Vancomycin release formulations revealed that for both polymer types, hot extrusion process enabled the formation of a more compact system that provided slower release of the agent compared to the cold paste method. With the combined effect of variable loading proportion and polymer type the most prolonged release was obtained by PHBV rods having 2:1, P:V, ratio (prepared by hot extrusion method). In general, the release kinetics from the rods obeyed the Fickian diffusion kinetics except for PLGA rods prepared by cold paste method with 1:1 and 2:1 (P:V) loading ratios, which had a first order rate of drug release. According to in vitro bioactivity assays, all the groups effectively inhibited bacterial growth with the first day release samples. On the seventh day, however, only two cold paste samples, PHBV:Vancomycin 1:1 and PLGA:Vancomycin 1:1 had drug content barely sufficient for MEC while the others were in the ineffective range. The IR and grinding-extraction studies proved that Vancomycin was still present within the rods after a ten day release period. The PHBV rods with 2:1 (P:V) ratio prepared by hot extrusion method seem to be the most promising drug delivery system in terms of providing prolonged release as an implantable drug delivery system for the treatment of bacterial infections of the bone, namely osteomyelitis.