Formulations Of Vancomycin Research Articles

P-210. Real-World Utilization and Cost of Fidaxomicin versus Oral Vancomycin: A Comparative Analysis of Outpatient Medicaid Prescription Reimbursements

Abstract Background Clostridioides Difficile Infection (CDI) is a leading cause of infectious diarrhea in the United States. In 2017, the Infectious Diseases Society of America (IDSA) and Society of Healthcare Epidemiology of America (SHEA) joint guidelines added fidaxomicin (FX) as a first line therapy for initial and first recurrence of non-fulminant CDI alongside oral vancomycin (OV). Under a 2021 guideline revision FX became the preferred therapy based on lower CDI recurrence among those treated with FX. Multiple analyses have attempted to predict the economic impact of increased FX use but have yielded conflicting results. The use of real-world data on actual cost and utilization has been limited.Figure 1:Total Annual Outpatient Medicaid CDI Therapy Prescription CountCDI: Clostridioides Difficile Infection Methods We conducted a retrospective analysis of utilization and cost of FX and OV between January 1st, 2013 and December 31st, 2022 in the Medicaid State Drug Utilization Database (SDUD). The SDUD contains covered outpatient medications excluding those reimbursed under bundled services. Prescriptions for OV were distinguished from other vancomycin formulations using national drug codes. Utilization was estimated by the number of prescriptions reimbursed. Total cost was calculated as the sum of Medicaid and non-Medicaid reimbursement. We approximated the annual per prescription cost (APPC) as the quotient of total cost and prescription count.Figure 2:Total Annual Outpatient Medicaid CDI Therapy Prescription CostCDI: Clostridioides Difficile Infection Results Following the 2017 guidelines the average annual FX prescription count (Figure 1) increased by 32% compared to a 2013-2016 baseline. After the 2021 guideline revision, average annual FX prescription count grew by 113% as compared to a 2017-2020 baseline. The total annual cost of FX (Figure 2) surpassed the total annual cost of OV in 2019 with FX reaching $17,984,998 in 2022 as compared to $3,135,523 for OV. Throughout the study period the FX APPC (Figure 3) was substantially greater ($2,614-$3,956) than the OV APPC ($134-$1,579).Figure 3:Annual Per Prescription Cost of Outpatient Medicaid CDI TherapyCDI: Clostridioides Difficile Infection Conclusion Among Medicaid beneficiaries, outpatient FX use increased in time periods following the 2017 and 2021 guideline changes. While FX use was significantly lower than OV from 2013-2022, FX total cost and APPC far outweighed that of OV. Further analysis is necessary to determine the real-world cost effectiveness of FX, but our results highlight the budgetary impact associated with these IDSA/SHEA guideline changes. Disclosures All Authors: No reported disclosures

Suspensions of antibiotics in self-emulsifying oils as a novel approach to formulate eye drops with substances which undergo hydrolysis in aqueous environment

The aim of this study was to develop eye-drops with cefuroxime (CEF) sodium or vancomycin (VAN) hydrochloride, antibiotics that are instable in water. Anhydrous self-emulsifying oils (SEO) are proposed as a carrier and antibiotics are suspended. In the contact with tear fluid, the formulation should transform into emulsion, with fast dissolution of an antibiotic. CEF or VAN (5% w/w) was suspended in SEO carriers prepared by dissolving surfactants (Tween 20 or Span 80 5% w/w) in Miglyol, castor oil, or olive oil. Formulations with or without sodium citrate (2% w/w) were compared. Six-months or 1-year stability tests were carried out at 40 °C. The content of CEF and VAN was evaluated using HPLC and the potency of the antibiotic was assessed with agar diffusion method. In contact with water, drug particles suspended in SEO dissolved rapidly and o/w emulsion was formed. After 1-year at 40 °C, the content of degradation products was at most 0.5% in CEF and 4.0% in VAN formulations. The agar diffusion assay has shown that CEF and VAN loaded into SEO retained its potency against the sensitive microorganisms comparable to an aqueous solution. Therefore, SEO can be used as a novel carrier for the active substances which may not require improved solubility or absorption but need to be protected from moisture. This is a formulation that can be produced on industrial scale, with no limitation of stability or drug concentration.

Best Practices in the Management of Clostridioides difficile Infection in Developing Nations.

Clostridioides difficile infection (CDI) is a well-known cause of hospital-acquired infectious diarrhea in developed countries, though it has not been a top priority in the healthcare policies of developing countries. In the last decade, several studies have reported a wide range of CDI rates between 1.3% and 96% in developing nations, raising the concern that this could represent a healthcare threat for these nations. This review defines developing countries as those with a human development index (HDI) below 0.8. We aim to report the available literature on CDI epidemiology, diagnostics, management, and prevention in developing countries. We identify limitations for CDI diagnosis and management, such as limited access to CDI tests and unavailable oral vancomycin formulation, and identify opportunities to enhance CDI care, such as increased molecular test capabilities and creative solutions for CDI. We also discuss infection prevention strategies, including antimicrobial stewardship programs and opportunities emerging from the COVID-19 pandemic, which could impact CDI care.

Preparation Times and Estimated Costs for Vancomycin Formulations: Does the Difference Matter?

Objective Infections from methicillin-resistant Staphylococcus aureus are increasingly treated in longterm care facilities, but long-term care pharmacies face high costs in the provision of sterile vancomycin for intravenous administration. This study compares pharmaceutical costs of outsourced, compounded, and room temperature premixed vancomycin formulations in a long-term care pharmacy. Design This retrospective observational study reviewed 124 orders of vancomycin. Means for total pharmacy preparation time, pharmacist labor time, and extrapolated time over complete course of treatment were compared for three vancomycin preparations: outsourced, compounded by pharmacy, and room temperature premixed vancomycin formulations. Cost calculations were generated using ingredient costs as reported by the pharmacy and median pharmacist labor costs as published from national sources. Results Mean total preparation times and pharmacist preparation times were shortest for premixed vancomycin. Over full courses of treatment, mean pharmacy preparation time for compounded was 5 hours 3 minutes (mean of 28 treatments) and 2 hours 8 minutes for premixed (mean of 54 treatments). Data on pharmacist time in outsourced orders were not available. Total pharmacy costs were $993.94 for compounded vancomycin, $2220.34 for outsourced, and $809.36 for room temperature premixed vancomycin. Conclusion There were reduced preparation times for room temperature premixed vancomycin compared with compounded and outsourced formulations for skilled nursing facilities. As multiple drug-resistant organism infections are increasingly treated in long-term care, finding cost-effective approaches to medication provision from pharmacies is critical.

Evaluation of an Oral Vancomycin Capsule for the Treatment of Clostridioides difficile Infections in an Academic Medical Center in Thailand

Background: The oral capsule formulation of vancomycin (Vancin-S) recently became available in Thailand; therefore, information on its effectiveness and safety in treating Clostridioides difficile infection (CDI) has not been available. Objective: To evaluate CDI outcomes and to access safety at the HRH Princess Maha Chakri Sirindhorn Medical Center (MSMC) following recommended oral vancomycin capsule treatment. Materials and Methods: Retrospective review of MSMC patients prescribed oral vancomycin capsule between December 1, 2022 and August 31, 2023. Inclusion and exclusion criteria were applied, analyzing CDI outcomes post- oral vancomycin capsule treatment and within 90 days thereafter. Safety of oral vancomycin capsule usage was also assessed. Results: Of the 41 patients prescribed oral vancomycin capsule, 13 met inclusion criteria and did not meet with exclusion criteria. There were eight definite and five probable CDI cases, with 12 initial treatments and one initial fulminant treatment. The incidence of CDI in the MSMC was 21.33 person-year. Clinical improvements were observed by the tenth day, with one patient experiencing residual symptoms, subsequently testing negative for CDI. All patients were cured. The oral vancomycin capsule treatments were well-tolerated without significant adverse effects. No CDI recurrence was detected among 12 cases followed up within 90 days post-treatment. Conclusion: The oral vancomycin capsule demonstrates safety and potential efficacy for CDI treatment in Thailand. Keywords: Oral vancomycin; Clostridioides difficile infection; Thailand

Simultaneous determination of amphotericin B, tobramycin and vancomycin in rabbit ocular biofluids and tissues by LC-MS/MS: An antimicrobial therapy for keratitis and its PK-PD application

A rationale poly-microbial keratitis (PMK) therapy requires quick identification of pathogen (bacteria and fungi) and their efficient treatment. However, majority of healthcare providers are still having trouble finding an effective medicine to treat PMK due to constraints such as antimicrobial resistance, dose and dosing schedule. Thus, a broad spectrum anti-fungal and antibacterial having less resistance in community involving combination therapy such as amphotericin B (AmB), tobramycin (TBR) and vancomycin (VCM) is required. Hence, to characterize the pharmacokinetic (PK) and PK-pharmacodynamic (PD) indices, a rapid and sensitive simultaneous LC-MS/MS bioanalytical method was developed and validated for the quantification of AmB, TBR and VCM in rabbit ocular biofluids and tissues. Chromatographic resolution was achieved on a Zorbax C18 column with a mobile phase composed of acetonitrile and 0.4 % formic acid in deionized water using a gradient mode of elution. The calibration curves showed good linearity over the concentration range of 1.95–500 ng/mL for AmB and TBR, 3.9–800 ng/mL for VCM, respectively. The lower limit of quantification (LLOQ) was found to be 1.95 ng/mL for AmB and TBR, and 4.5 ng/mL for VCM. Analyte extraction was performed by simple protein precipitation method with minimal sample volume of 10 µL. Finally, the developed method was validated for selectivity, linearity (r2 > 0.99), precision, accuracy, matrix effects, and stability. The ocular pharmacokinetic profile of commercial AmB, TBR, and VCM formulations was further assessed using the validated method and the PK-PD indices along with dosing frequency was predicted by PK-PD modelling using Phoenix WinNonlin Software.

Design and development of reinforced antibiotic eye drops in a community pharmacy

Objective: Develop sterile vancomycin-amikacin reinforced antibiotics in smaller batches of finished products than those produced at the industrial level and under different working conditions. In this work, critical aspects concerning the elaboration process such as equipment and process evaluation, protocol development, physicochemical characterization, and microbiological tests were analyzed. In the first stage, the preparation of the formulations was carried out in the Department of Pharmaceutical Sciences of the Faculty of Chemical Sciences of the National University of Cordoba. In the second stage, the eye drops were prepared in the laboratory of Farmacia Vilarrubi, an office pharmacy authorized by the health authority and dedicated to the preparation of non-sterile compounding formulations. Both samples prepared at different manufacturing sites were subjected to the same physicochemical and microbiological tests. Methods and results: The sample compounding formulations of Vancomycin, Amikacin or their combination, at a dose of 30 mg/mL, were developed and subjected to physicochemical essays such as macroscopic observation, measurement of pH, osmolality, particle size, and quantification of drug concentration, during 7 days stored under adequate conditions of light and temperature. In addition, microbiological assays were carried out to verify their sterility and procedure under aseptic conditions. All the formulations made of reinforced antibiotic eye drops demonstrated high physicochemical and microbiological stability during the evaluated period. Conclusion: The reinforced antibiotic eye drops and the container used for their conservation showed correct sterility and microbiological stability during the time of use for the patient. It is possible to transfer small batch production of this type of quality sterile formulations to a pharmacy. For this, the training and education of the pharmaceutical professional is imperative.

Preparation and evaluation of vancomycin spray-dried powders for pulmonary delivery

The aim of the current study was to achieve a dry powder formulation of vancomycin by spray drying whilst evaluating the effect of pH and excipient type and percentage used in formulation on particle characteristics and aerosolization performance. A D-optimal design was applied to optimize the formulation comprising vancomycin and two main excipient groups; a carbohydrate bulking agent (lactose, mannitol or trehalose) and a second excipient (hydroxypropyl beta-cyclodextrin or L-leucine) at pH 4 and 7. The physicochemical properties of particles (size, morphology, crystallinity state, residual moisture content), stability, and aerosolization characteristics were investigated. Using the combination of two excipients increased the fine particle fraction of powder emitted from an Aerolizer® device at a flow rate of 60 L/min. Hydroxypropyl beta-cyclodextrin showed more potential than L-leucine in aerosolization capabilities. Stability studies over 3 months of storage in 40 °C and 75% relative humidity suggested a good physical stability of the optimized formulation containing 17.39% hydroxypropyl beta-cyclodextrin along with 29.61% trehalose relative to the amount of drug at pH 4. Use of two excipients including trehalose and hydroxypropyl beta-cyclodextrin with a total weight ratio of 47% relative to the amount of drug is appropriate for the preparation of vancomycin dry powder formulation for inhalation.

Stability Evaluation of Extemporaneously Compounded Vancomycin Ophthalmic Drops: Effect of Solvents and Storage Conditions.

Vancomycin is the drug of choice for methicillin-resistant Staphylococcus aureus keratitis and other ocular infections. Vancomycin ophthalmic drops are not commercially available and require compounding. The present study was designed to investigate the stability of vancomycin ophthalmic drops in normal saline, phosphate-buffered saline (PBS), and balanced salt solution (BSS) while stored at room temperature or under refrigeration. Vancomycin ophthalmic drops (50 mg/mL) were aseptically prepared from commercially available intravenous powder using PBS, BSS, and saline. Solutions were stored at room temperature and in a refrigerator for 28 days. The vancomycin stability was tested by a microbiology assay and high-performance liquid chromatography HPLC analysis immediately after formulation and at days 7, 14, and 28 after storage at room temperature or under refrigeration. The pH, turbidity was also tested. Vancomycin formulations in PBS, BSS and normal saline had initial pH of 5; 5.5; 3 respectively. The formulation in PBS developed turbidity and a slight decrease in pH upon storage. Microbiological assay did not show any change in zone of inhibition with any of the formulation upon storage either at room temperature or under refrigeration. HPLC analysis did not detect any decrease in vancomycin concentration or the accumulation of degraded products in any of the formulations upon storage either at room temperature or under refrigeration. Vancomycin ophthalmic drops prepared using PBS, BSS, and normal saline were stable up to the tested time point of 28 days, irrespective of their storage temperature.

Potency of vancomycin against Mycobacterium tuberculosis in the hollow fiber system model

ObjectivesTo determine whether an inhaled vancomycin formulation resulting in high intrapulmonary 24-h area under the concentration–time curve (AUC0–24) could be optimised for tuberculosis treatment. We also explored vancomycin synergy and antagonism with d-cycloserine and benzylpenicillin. MethodsWe determined MICs of two Mycobacterium tuberculosis (Mtb) laboratory strains (H37Ra and H37Rv) and two drug-susceptible and nine multidrug resistant clinical strains. Second, in the hollow fiber system model of TB [HFS-TB] using Mtb H37Ra strain, we recapitulated vancomycin intrapulmonary pharmacokinetics of eight doses administered twice daily over 28 days, mimicking a 6-h half-life. Using the HFS-TB, vancomycin was tested in combination with d-cycloserine and benzylpenicillin to determine synergy or antagonism between drugs targeting the same pathway. ResultsVancomycin MICs were 12 and 48 mg/L in drug-susceptible clinical isolates but >96 mg/L in all MDR isolates.In the HFS-TB, vancomycin killed 3.9 ± 0.6 log10 CFU/mL Mtb. The EC50 was calculated as AUC0–24/MIC of 184.6 ± 106.5. Compared with day 0, 1.0 and 2.0 log10 CFU/mL kill was achieved by AUC0–24/MIC of 168 and 685, respectively. Acquired vancomycin resistance developed to all vancomycin doses tested in the HFS-TB. In the HFS-TB, vancomycin was antagonistic to benzylpenicillin, which works downstream to glycopeptides in peptidoglycan synthesis, but synergistic with d-cycloserine, which inhibits upstream d-Ala-d-Ala ligase and alanine racemase. ConclusionOur proof-of-concept studies show that vancomycin optimal exposure target for Mtb kill could be achieved via inhalational drug delivery. Addition of drugs synergistic with vancomycin, e.g. d-cycloserine, may lower the vancomycin concentrations required to kill Mtb.

Development of mucoadhesive thiomeric chitosan nanoparticles for the targeted ocular delivery of vancomycin against Staphylococcus aureus resistant strains

Abstract This study aims to formulate mucoadhesive vancomycin loaded thiolated chitosan (TCS) nanoparticles. These nanoparticles are mucoadhesive and enhance the retention of the drug at the ocular site. For this purpose, TCS loaded vancomycin nanoparticles were prepared by the ion-gelation method and were characterized for their size, shape, polydispersity index, mucoadhesion, cellular uptake and anti-inflammatory activity. The average size of the synthesized nanoparticles was found to be 288 nm with positive zeta potential. Moreover, 85% vancomycin was successfully encapsulated in TCS nanoparticles by using this method. A 2-fold increase in mucoadhesion was found as compared to non-thiolated vancomycin formulation (p < 0.05). Zone of inhibition of vancomycin loaded TCS was also significantly improved compared to non-thiolated chitosan nanoparticles and vancomycin alone. In-vivo anti-inflammatory evaluation via histopathology resulted in ocular healing. Based on the results, it is inferred that TCS nanoparticles are a promising drug delivery carrier system for ocular delivery of vancomycin.

Stability of 4 Intravenous Drug Formulations in Prefilled Syringes Stored Frozen for Up to 60 Days.

Purpose: Prefilled drug syringe use may reduce the cost of routine antibiotic drug delivery. Storage of prefilled syringes frozen (-20°C) or refrigerated (4°C-5°C), can optimize the use of robotic syringe filling systems if acceptable stability data is gathered per USP 797 standards. Methods: Four intravenous (IV) drug formulations were prepared from bulk standard solutions and filled into 10 mL syringes using an Intellifill© IV Robot. Formulations were Piperacillin (2.0 g) and Tazobactam (0.25 g) as 2.25 g in 10 mL; Piperacillin (3.0 g) and Tazobactam (0.375 g) as 3.375 g in 10 mL; Cefuroxime as 1.5 g in 11 mL; and Vancomycin as 1.0 g in 10 mL. Concentrations were assayed at "zero time," and after 21, 45, and 60 days frozen. Syringes were warmed to room temperature (RT) by gently rolling in hands. Three syringes of each formulation were assayed by stability-indicating HPLC per USP procedures. Assay results are the average of 5 injections of samples from each syringe upon return to RT and repeated for 3 separate syringes maintained at RT for 24 hours. Results: All formulations were stable out to 60 days frozen. Both of the piperacillin/tazobactam formulations were also stable when kept at refrigerated temperature for 9 days. Conclusion: Piperacillin/Tazobactam formulations can be stored frozen (-20°C) for up to 60 days with no appreciable loss. Cefuroxime and Vancomycin formulations can be stored frozen for up to 60 days. Both Piperacillin/Tazobactam formulations can be refrigerated for up to 9 days. Implementation of larger batch compounding coupled with frozen syringe storage and delivery could result in enhanced uniformity of composition and significant manpower savings.

Dual Antibiotic and Diffusible Signal Factor Combination Nanoliposomes for Combating Staphylococcus epidermidis Biofilm.

Purpose: Microbial biofilms are one of the main causes of persistent human infections. Encapsulation of an antibiotic and a biofilm dispersal agent within a nano-carrier has been recognized as a novel approach to combat the problem of biofilm-related infections. Here, we develop the nanoliposomal formulation for delivery of vancomycin in combination with cis-2- decenoic acid (C2DA), to Staphylococcus epidermidis biofilm. The effects of the formulations were studied at two stages: biofilm growth inhabitation and biofilm eradication. Methods: Liposomal formulations were prepared by the solvent evaporation dehydration-rehydration method and were evaluated for size, zeta potential, and encapsulation efficacy. The ability of different agents in free and encapsulated forms were assessed to evaluate the anti-biofilm activities. Results: Vancomycin and C2DA were successfully co-encapsulated in the same nanoliposome (liposomal combination). The zeta potential values of the liposomal formulations of vancomycin, C2DA, and the liposomal combination were 37.2, 40.2, 51.5 mV, and the mean sizes of these liposomal formulations were 167.8±1.5, 215.5±8.8, 235.5±0.01, respectively. Encapsulation efficacy of C2DA was 65% and about 40% for vancomycin. The results indicated that liposomal combination exerted strong anti-biofilm activities, slightly exceeding those observed by the free form of a combination of vancomycin and C2DA, but higher than either agent used alone in their free forms. The anti-biofilm activity of formulations followed concentration and time-dependent manner. Conclusion: The combination of vancomycin and C2DA could inhibit biofilm formation. Employing the liposomal combination is a considerable method to remove bacterial biofilm.

Preparation and in vivo evaluation of nanoliposomes containing vancomycin after intravitreal injection in albino rabbits.

Objective(s):The in vivo efficacy of nanoliposomal formulation of vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) assessed.Materials and Methods:Nanoliposomal formulations were prepared and characterized. The in vivo study was carried out on rabbits which received liquid culture medium containing MRSA under anesthesia. After 48 hr, the eyes treated with the liposomal and free form of vancomycin. The rabbits were euthanized at predesignate intervals at 12, 24, 48, 96, 144 hr intervals injection. The antibacterial activity of different vancomycin formulations was assayed by the time killing method. Results:The zeta potential, mean sizes and encapsulation efficacy of liposomal vancomycin were 29.7 mV, 381.93±30.13 nm and 47%, respectively. The results of time–killing studies indicated that the liposomal formula was more effective than the free form of vancomycin.Conclusion:The results of this study revealed that liposomal vancomycin formulation is a powerful nano-antibacterial agent to combat infectious endophthalmitis.

Activity of pulmonary vancomycin exposures versus planktonic and biofilm isolates of methicillin-resistant Staphylococcus aureus from cystic fibrosis sputum

Vancomycin is commonly used to treat methicillin-resistant Staphylococcus aureus (MRSA) infections in patients with cystic fibrosis (CF) lung disease. However, there are limited data to support the in vitro activity of this agent against MRSA isolated from CF sputum. The primary objective of this study was to evaluate the activity of vancomycin at pulmonary concentrations (intravenous and inhaled) against four clinical MRSA CF sputum isolates in planktonic and biofilm time-kill (TK) experiments. Vancomycin minimum inhibitory concentrations (MICs) were determined for these isolates at standard inoculum (SI) (~106 CFU/mL) and high inoculum (HI) (~108 CFU/mL) as well as in biofilms cultivated using physiological medium representing the microenvironment of the CF lung. Vancomycin concentrations of 10, 25, 100 and 275 µg/mL were evaluated in TK experiments against planktonic MRSA at varying inocula and versus biofilm MRSA. Vancomycin MICs increased from 0.5 µg/mL when tested at SI to 8-16 µg/mL at HI. Vancomycin MICs were further increased to 16-32 µg/mL in biofilm studies. In TK experiments, vancomycin displayed bactericidal activity (≥3 log10 killing at 24 h) against 1/4 and 0/4 planktonic MRSA isolates at SI and HI, respectively, whereas vancomycin was bactericidal against 0/4 isolates against MRSA biofilms. Based on these findings, vancomycin monotherapy appears unlikely to eradicate MRSA from the respiratory tract of patients with CF, even at high concentrations similar to those observed with inhaled therapy. Novel vancomycin formulations with enhanced biofilm penetration or combination therapy with other potentially synergistic agents should be explored.

Quality of Vancomycin for Injection Formulations in Brazil

Background: The presence of impurities in vancomycin compromised the safety and contributed to decrease of its use for years. In Brazil, vancomycin generic drug represents an option to reduce hospital costs. However, the controversy over the quality of these formulations and their relationship to effectiveness and safety raised concerns. Objective and Methods: To assess in vitro quality of vancomycin injections through uniformity of weight, pH, clarity of solution, microbiological assay and impurities determination by High Performance Liquid Chromatography (HPLC). Results: The samples were approved in the tests. Conclusion: The injectable formulations of vancomycin proved to be safe for use in hospital environment. This work contributes to increase health professionals’ confidence on generic vancomycin.

Antibiotic elution and compressive strength of gentamicin/vancomycin loaded bone cements are considerably influenced by immersion fluid volume.

The effect of doubling the immersion fluid (eluate) volume on antibiotic concentrations and on mechanical stability from vancomycin and gentamicin loaded bone cements was investigated in vitro. Antibiotic loaded bone cements containing premixed 1.34% gentamicin antibiotic concentration in the cement powder (wt), premixed 1.19% gentamicin wt and 4.76% vancomycin wt and premixed 1.17% wt gentamicin additionally manually blended with 4.68% wt vancomycin were tested. Six specimens per group were immersed in 4 ml and 8 ml for 6 weeks while the eluate was exchanged every 24 h. The antibiotic concentrations were repeatedly measured. Then the specimens were tested for compressive strength. Doubling the eluate volume significantly decreased gentamicin and vancomycin concentrations from 6 h and 24 h on, except for the gentamicin concentration of the additionally manually blended formulation after 3 weeks. The additionally manually blended vancomycin formulation produced significantly higher gentamicin concentrations in 8 ml compared to the other formulations. The reduction ratios of the vancomycin concentrations were significantly smaller than the reduction ratios of the gentamicin concentrations for the manually blended vancomycin formulation. Vancomycin containing formulations showed significantly lower compressive strengths than the vancomycin free formulation after immersion. Doubling the eluate volume lead to significant compressive strength reduction of the vancomycin containing formulations. Eluate volume change influences antibiotic elution dependent on the antibiotic combination and loading technique. The reducing effect is higher on vancomycin than on gentamicin elution. Compressive strength of gentamicin/vancomycin loaded bone cements after immersion is eluate volume dependent.

Different formulations of vancomycin: In vitro antimicrobial activity against clinical isolates of methicillin-resistant Staphylococcus aureus

We compared in vitro antimicrobial activity of four vancomycin formulations used clinically against clinical isolates of Staphylococcus aureus, including methicillin-resistant and -susceptible (MRSA and MSSA, respectively), using different susceptibility assays. The minimal inhibitory concentrations (MICs) against MRSA clinical isolates were significantly different for some vancomycin formulations by the broth microdilution and agar dilution methods. However, these variations would not compromise their clinical use, since the MICs were within the range recommended by the Clinical and Laboratory Standards Institute. Furthermore, 26.9% of MRSA clinical isolates showed a vancomycin MIC ≥1.5 μg/mL according to the Etest® method but none by broth microdilution. Regarding quality, all formulations were in accordance with United States Pharmacopeia criteria. Our results showed that all vancomycin formulations tested showed similar in vitro antimicrobial activity, making them suitable for clinical use, and that the evaluation method chosen to determine sensitivity to this antimicrobial should be carefully performed, particularly for MRSA.

Identification and treatment of the Staphylococcus aureus reservoir in vivo.

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is reaching epidemic proportions causing morbidity, mortality, and chronic disease due to relapses, suggesting an intracellular reservoir. Using spinning-disk confocal intravital microscopy to track MRSA-GFP in vivo, we identified that within minutes after intravenous infection MRSA is primarily sequestered and killed by intravascular Kupffer cells (KCs) in the liver. However, a minority of the Staphylococci overcome the KC's antimicrobial defenses. These bacteria survive and proliferate for many days within this intracellular niche, where they remain undetected by recruited neutrophils. Over time, the KCs lyse, releasing bacteria into the circulation, enabling dissemination to other organs such as the kidneys. Vancomycin, the antibiotic of choice to treat MRSA bacteremia, could not penetrate the KCs to eradicate intracellular MRSA. However, based on the intravascular location of these specific macrophages, we designed a liposomal formulation of vancomycin that is efficiently taken up by KCs and diminished the intracellular MRSA. Targeting the source of the reservoir dramatically protected the liver but also dissemination to other organs, and prevented mortality. This vancomycin formulation strategy could help treat patients with Staphylococcal bacteremia without a need for novel antibiotics by targeting the previously inaccessible intracellular reservoir in KCs.

Identification of risk factors for nephrotoxicity in patients receiving extended-duration, high-trough vancomycin therapy.

In the past, impurities in vancomycin formulations were thought to contribute to nephrotoxicity. In contrast, when current, purer formulations are dosed at conventional trough levels (i.e., 5-15 mg/L), the incidence of nephrotoxicity is relatively low. Recent guidelines have recommended targeting higher vancomycin trough levels in treatment of complicated methicillin-resistant Staphylococcus aureus infections. Dosing based on these higher trough levels may be associated with nephrotoxicity, so the potential risk factors for vancomycin-associated nephrotoxicity require clearer definition. To determine the occurrence of nephrotoxicity in patients receiving more than 7 days of vancomycin therapy with high trough levels (15-20 mg/L) and to identify and evaluate specific risk factors related to development of vancomycin-associated nephrotoxicity (i.e., serum creatinine ≥ 44.2 μmol/L or increase ≥ 50% [i.e., ≥ 26.2 μmol/L] from baseline on 2 consecutive days). Health care records were reviewed for patients seen at 2 major teaching hospitals between January 2008 and March 2011. Patients who had attained high trough levels of vancomycin were screened for eligibility. Patients with unstable renal function, those undergoing hemodialysis, and those for whom dosage and/or sampling times were unclear were excluded. Univariate and multivariate analyses were performed to identify risk factors associated with nephrotoxicity. Univariate variables with p < 0.1 were included in the logistic regression model. Of the 176 patients with high trough levels included in the analysis, 24 (14%) experienced nephrotoxicity. In univariate analysis, admission to a general medicine unit (the setting of care for 16 [67%] of the 24 patients with nephrotoxicity) and extended duration of vancomycin treatment were identified as risk factors for nephrotoxicity (p < 0.1). Other risk factors included gastrointestinal comorbidity (p = 0.056), malignancy (p = 0.044), and febrile neutropenia (p = 0.032). Multivariate analysis identified treatment on general medicine units and treatment courses longer than 7 days as independent predictors of vancomycin-associated nephrotoxicity. Patients being treated on general medicine units and those receiving vancomycin for more than 7 days had an increased likelihood of experiencing nephrotoxicity. The increased risk for patients on general medicine units is likely multifactorial. The relationship between treatment duration and risk of nephrotoxicity appeared to be linear. When using extended-duration, high-trough vancomycin therapy, clinicians should be vigilant in monitoring for nephrotoxicity.