Delivery Of Vancomycin Research Articles

Outcomes of Continuous Enteral Vancomycin Infusion in Intensive Care Unit Patients: A Novel Treatment Modality for Severe Clostridium Difficile Colitis.

Background and objectiveSevere Clostridium difficile (C. difficile) infection (CDI)-related colitis is associated with high morbidity and mortality. Current guidelines recommend oral vancomycin plus intravenous metronidazole as the first-line treatment and early total colectomy in case of medication failure. In critically ill patients at high surgical risk and with multiple comorbidities, loop ileostomy creation and enteral vancomycin infusion have been employed albeit with limited success. We hypothesized that continuous enteral vancomycin (CEV) infusion via a postpyloric feeding tube would provide a less invasive, efficacious, and safer route to treat high surgical risk patients.MethodsAll adult (>18 years) non-pregnant patients admitted to the ICU for severe CDI from October 2012 to October 2016 and received CEV after the failure of conventional therapy were included. Vancomycin was prepared as a 1-2-mg/ml enteral solution and run continuously through a feeding pump at 42 ml/hour via a post-pyloric feeding tube. The primary efficacy endpoint was clinical improvement defined as (a) decrease in stool output, (b) decreased vasopressor requirement, or (c) improved leukocytosis, and the secondary endpoint was treatment failure defined as the need for total colectomy or death due to severe CDI.ResultsOur cohort comprised 11 patients in total. The median age of the participants was 64 years, and there were more females (67%) than males (36%). Clinical improvement was seen in seven patients (63%); treatment failure documented as the need for total colectomy was observed in two patients (18%), and death attributable to CDI occurred in three patients (27%).ConclusionCEV resulted in clinical improvement in most patients with severe CDI who were at high surgical risk. Sustained intestinal vancomycin delivery may increase luminal concentration and bactericidal effect. The use of a feeding tube and pump provides an effective and less invasive route of vancomycin delivery in critically ill patients.

Injectable Peg-Induced Silk Nanofiber Hydrogel for Vancomycin Delivery

Injectable Peg-Induced Silk Nanofiber Hydrogel for Vancomycin Delivery

Biofilm Responsive Zwitterionic Antimicrobial Nanoparticles to Treat Cutaneous Infection.

To avert the poor bioavailability of antibiotics during S. aureus biofilm infections, a series of zwitterionic nanoparticles containing nucleic acid nanostructures were fabricated for the delivery of vancomycin. The nanoparticles were prepared with three main lipids: (i) neutral (soy phosphatidylcholine; P), (ii) positively charged ionizable (1,2-dioleyloxy-3-dimethylaminopropane; D), and (iii) anionic (1,2-dipalmitoyl-sn-glycero-3-phospho((ethyl-1′,2′,3′-triazole) triethylene glycolmannose; M) or (cholesteryl hemisuccinate; C) lipids. The ratio of the anionic lipid was tuned between 0 and 10 mol %, and its impact on surface charge, size, stability, toxicity, and biofilm sensitivity was evaluated. Under biofilm mimicking conditions, the enzyme degradability (via dynamic light scattering (DLS)), antitoxin (via DLS and spectrophotometry), and antibiotic release profile was assessed. Additionally, biofilm penetration, prevention (in vitro), and eradication (ex vivo) of the vancomycin loaded formulation was investigated. Compared with the unmodified nanoparticles which exhibited the smallest size (188 nm), all three surface modified formulations showed significantly larger sizes (i.e., 222–277 nm). Under simulations of biofilm pH conditions, the mannose modified nanoparticle (PDM 90/5/5) displayed ideal charge reversal from a neutral (+1.69 ± 1.83 mV) to a cationic surface potential (+17.18 ± 2.16 mV) to improve bacteria binding and biofilm penetration. In the presence of relevant bacterial enzymes, the carrier rapidly released the DNA nanoparticles to function as an antitoxin against α-hemolysin. Controlled release of vancomycin prevented biofilm attachment and significantly reduced early stage biofilm formations within 24 h. Enhanced biocompatibility and significant ex vivo potency of the PDM 90/5/5 formulation was also observed. Taken together, these results emphasize the benefit of these nanocarriers as potential therapies against biofilm infections and fills the gap for multifunctional nanocarriers that prevent biofilm infections.

Preclinical assessment of nanostructured liquid crystalline particles for the management of bacterial keratitis: in vivo and pharmacokinetics study.

The research work was driven to develop, optimize, and characterize novel nanostructured liquid crystalline particles as carriers for the ocular delivery of vancomycin. The formulations were developed by fragmenting the cubic crystalline phase of glycerol monooleate, water, and poloxamer 407. A four-factor, three-level Taguchi statistical experimental design was constructed to optimize the formulation. Formulations exhibited internal-cubic structure of the vesicles with particle size in the range of 51.11 ± 0.96nm to 158.73 ± 0.46nm and negative zeta potential. Ex vivo transcorneal permeation studies demonstrated that the optimized cubosomes had a 2.4-fold increase in apparent permeability co-efficient as compared to vancomycin solution, whereas in vivo studies in rabbits demonstrated that the severity of keratitis was considerably lowered on day 3 with optimized cubosomes. Ocular pharmacokinetic studies evaluated the level of drug in aqueous humor, and results revealed that the time to peak concentration (Tmax) of vancomycin-loaded cubosomal formulation was about 1.9-fold higher and mean residence time was 2.2-fold greater than vancomycin solution. Furthermore, histological examination revealed that the corneal layers displayed well-maintained morphology without any stromal swelling, consequently indicating the safety of formulation. It could be concluded that the developed nanostructured liquid crystalline particles of vancomycin demonstrated improved pre-ocular residence time, increased permeability, reduced dosing frequency, controlled drug release, and reduced systemic side-effects. Results manifested that the developed vancomycin-loaded cubosomes could be a promising novel ocular carrier and an ideal substitute for conventional eye drops for the management of bacterial-keratitis.

Topical ocular delivery of vancomycin loaded cationic lipid nanocarriers as a promising and non-invasive alternative approach to intravitreal injection for enhanced bacterial endophthalmitis management

Vancomycin (VCM) is a drug of choice for treating infections caused by Staphylococcus species, reported being the most causative agent of bacterial endophthalmitis. However, the ocular bioavailability of topically applied VCM is low due to its high molecular weight and hydrophilicity. The current study sought to explore whether the nanostructured lipid carriers (NLCs) fabricated via cold homogenization technique could improve ocular penetration and prolong the ophthalmic residence of VCM. A 23 full factorial design was adopted to evaluate the influence of different process and formulation variables on VCM-loaded NLC formulae. The optimized formula with the particle size of 96.4 ± 0.71 nm and narrow size distribution showed spherical morphology obtained by AFM and represented sustained drug release up to 67% in 48 h fitted to the Korsmeyer-Peppas model with probably non-Fickian diffusion kinetic. FTIR studies visualized the drug-carrier interactions in great detail. High encapsulation of VCM (74.8 ± 4.3% w/w) in NLC has been established in DSC and PXRD analysis. The optimal positively charged (+ 29.7 ± 0.47 mV) colloidal dispersion was also stable for 12 weeks at both 4 °C and 25 °C. According to in vivo studies, incorporation of VCM in NLC resulted in a nearly 3-fold increase in the intravitreal concentration of VCM after eye-drop instillation over control groups. Besides, microbiological evaluation admitted its therapeutic effect within five days is comparable to intravitreal injection of VCM. Further, the optimized formula was found to be nonirritant and safe for ophthalmic administration in RBC hemolytic assay. Also, fluorescent tracking of NLCs on rabbit's cornea showed an increase in corneal penetration of nanoparticles. Thus, it is possible to infer that the evolved NLCs are promising drug delivery systems with superior attainments for enhanced Vancomycin ophthalmic delivery to the eye's posterior segment and improved bacterial endophthalmitis management.

Production of bioactive glass/chitosan scaffolds by freeze-gelation for optimized vancomycin delivery: Effectiveness of glass presence on controlling the drug release kinetics

The major objective of this work was the creation of vancomycin loaded composite scaffolds designed for bone treatment from inexpensive and biocompatible materials such as chitosan. Bioactive glass was chosen as filler due to its outstanding bioactivity and ability for bone regeneration. The scaffolds were prepared using the freeze-gelation method, which was efficient and cost-effective. They included different glass contents (0, 25, and 50 wt %) and symbolized as C, C25, and C50, respectively. The SEM/EDXA, TGA and the FTIR were used to characterize the scaffolds. The degradation properties of the scaffolds were controlled through modifying their glass contents. Furthermore, the kinetics of the released drug was improved as the glass content increased. The final cumulative percentages of released drug from scaffolds C, C25, and C50 reached 52.49, 70.82 and 98.22%, respectively. The Higuchi model proved that the drug was released through a diffusion-controlled mechanism. For neat polymer scaffold, the drug was released in two following stages. In contrast, for composite scaffolds, the release pattern was modulated and differentiated into four stages. That modulation was attributed to glass presence and deposition of apatite layer on their surfaces. Additionally, cell viability was enhanced by the presence of glass. In brief, glass presence was highly effective in controlling degradation properties and improving the drug release kinetics of the scaffolds. Therefore, the scaffolds made of chitosan and bioactive glass could be a good candidate for localized bone treatment.

Impacts of compacting methods on the delivery of erythromycin and vancomycin from calcium polyphosphate hydrogel matrices.

Designing hydrogels for controlled drug delivery remains a big challenge. We developed a calcium polyphosphate hydrogel (CPP) as matrix for delivery of vancomycin (VCM) and erythromycin (EM) by unique ionic binding and physical wrapping. In this continuing study, we investigated if gel discs prepared by mechanical compaction (at 3000 psi pressure, C-discs) is superior to that of discs prepared by regular manual compaction (M-discs) for the release of VCM and EM (10wt.%). Data demonstrated a significant reduction of burst release of VCM and EM in C-discs (1.8% and 5%, respectively) as compared to that from M-discs within 72 hr (55% and 60%, respectively, p< 0.05). In addition, C-discs significantly extended the VCM release (1500 hr) and EM (800 hr) as compared to M-discs (160 and 96 hr, respectively, p< 0.05). The VCM released from C-discs retained its bactericidal activity much longer (1500 hr) than that from M-discs (700 hr, p< 0.05). Raman Spectroscopy indicated an ionic bond of both VCM and EM with fully hydrated polyphosphate chains of CPP hydrogel matrix for both M-discs and C-discs. Micro CT showed that C-discs had much denser microstructures and less number/depth of microcracks as a result of high pressure. We propose that CPP hydrogel represents an excellent tool for the controllable and sustained delivery of VCM and EM. Extensive experiments are currently underway to evaluate the potential impacts of the modification of compaction techniques, other antibiotics, gel concentrations on the drug release, degradation behavior and infection control both in vitro and in vivo.

Development of Vancomycin Delivery Systems Based on Autologous 3D Platelet-Rich Fibrin Matrices for Bone Tissue Engineering.

Autologous platelet-rich fibrin (PRF) is derived from the blood and its use in the bone tissue engineering has emerged as an effective strategy for novel drug and growth factor delivery systems. Studies have approved that combined therapy with PRF ensures higher biological outcomes, but patients still undergo additional treatment with antibiotic drugs before, during, and even after the implantation of biomaterials with PRF. These systematically used drugs spread throughout the blood and lead not only to positive effects but may also induce adverse side effects on healthy tissues. Vancomycin hydrochloride (VANKA) is used to treat severe Staphylococcal infections but its absorption in the target tissue after oral administration is low; therefore, in this study, we have developed and analyzed two kinds of VANKA carriers—liposomes and microparticles in 3D PRF matrices. The adjustment, characterization, and analysis of VANKA carriers in 3D PRF scaffolds is carried out in terms of encapsulation efficiency, drug release kinetics and antibacterial activity; furthermore, we have studied the micro- and macrostructure of the scaffolds with microtomography.

Mucoadhesive and mucopenetrating chitosan nanoparticles for glycopeptide antibiotic administration

The use of nanoparticles (NPs) represents a useful strategy for peptide antibiotic delivery to mucosal membranes by either prolonging drug residence time at the target site (mucoadhesive NPs) or by enhancing diffusion across mucus layer to reach the underlying epithelium (mucopenetrating NPs). The purpose of this study was to design chitosan (CH) NPs and to evaluate their employment as mucoadhesive and/or mucopenetrating systems for vancomycin (VM) delivery. NPs were prepared by ionic gelation of CH with sodium carboxymethylcellulose (CMC), sodium alginate (ALG), sodium tripolyphosphate (TPP) or phytic acid (PA) and characterized in terms of size, zeta-potential, morphology, drug encapsulation efficiency, mucoadhesion and mucopenetrating ability. Moreover, in vitro tests were conducted to evaluate VM release and the antibacterial activity against Staphylococcus aureus and Bacillus subtilis. NPs showed sizes ranged from 150 nm to 350 nm with good polydispersity index and positive zeta-potential. The selection of the suitable crosslinker allowed to modulate the mucoadhesive/mucopenetrating properties: CH/TPP NPs showed the best mucoadhesive ability, while CH/PA and CH/CMC NPs were characterized by an improved diffusion across the mucus layer. Further, NPs allowed a fast and complete release of VM, maintaining the antibacterial activity against the tested bacteria species.

Effect of Local Delivery of Vancomycin and Tobramycin on Bone Regeneration.

ObjectiveA bone defect rat model was established to investigate the osteogenic effect of local delivery two antibiotics (vancomycin and tobramycin powder) on bone regeneration.MethodsTwenty‐four Sprague–Dawley (SD) male rats (6 to 8 weeks, 200 to 250 g) were used in this study. All these rats were randomly divided into four groups. Based on dose conversion between rat and human via body surface area, the rat dose of two antibiotics was 88μg/g and 176 μg/g for vancomycin and tobramycin, respectively. Con group (no antibiotic), Van group (vancomycin, 88 μg/g), Tob group (tobramycin 176 μg/g), and Van+Tob group (vancomycin 88μg/g combined with tobramycin 176 μg/g). A 5.0‐mm full‐thickness standardized mandibular bone defect was performed with a drill in each rat and different antibiotic powders were placed over the bone defect space, respectively. All these animals were sacrificed after 12 weeks post‐operation. The mandible bones were harvested for further radiographic and histologic analysis. The bone volume/total volume (BV/TV) ratio, bone volume (BV), and bone fractional area (BFA) in the defect area via micro‐computed tomography (μCT scanning) were further analyzed. Then, we performed a histological assessment via hematoxylin and eosin (H&E) and Masson's trichrome staining to analyze bone regeneration and also analyze the number of osteoblasts per filed.ResultsThere were no postoperative deaths, signs of vancomycin‐related or tobramycin‐related toxicity, or signs of systemic illness in any of the four groups. All wounds healed well, and no complications or surgical site infection were observed in all rats. From the μCT scans analyses, there was less bone regeneration in the Van group than in the Con group (BV/TV: F = 64.29, R 2 = 0.9602; P = 0.0052; BFA: F = 76.17, R 2 = 0.9662, P = 0.0007; BV: F = 194.4, R 2 = 0.9865, P = 0.0022). However, when the tobramycin and vancomycin were combined, an increase in bone defect re‐ossification was found in the Van+Tob group than in the Van group (BV/TV: F = 64.29, R 2 = 0.9602, P = 0.0033; BFA: F = 76.17, R 2 = 0.9662, P = 0.0006; BV: F = 194.4, R 2 = 0.9865, P = 0.0033). Routine H&E and Masson staining supported the finding of μCT scanning. Quantitative indices confirmed that both the bone regeneration and the number of osteoblasts per filed in the defect area was higher in the Van+Tob group than in the Van group (percentage of bone tissue: F = 145.7, R 2 = 0.9562, P = 0.0008; number of osteoblasts per file; F = 67.3, R 2 = 0.9098, P < 0.0001). There was no significant difference between the Con group and the Van+Tob group on the number of osteoblasts each field (F = 145.7, R 2 = 0.9562, P > 0.9999).ConclusionFor bone defect, local application of vancomycin combined with tobramycin was recommended over vancomycin alone. This animal study presents data suggesting that the use of local delivery of vancomycin and tobramycin should be investigated further in clinical studies.

2021 Chitranjan S. Ranawat Award: Intraosseous vancomycin reduces periprosthetic joint infection in primary total knee arthroplasty at 90-day follow-up.

Infection complicating primary total knee arthroplasty (TKA) is a common reason for revision surgery, hospital readmission, patient morbidity, and mortality. Increasing incidence of methicillin-resistant Staphylococcus aureus (MRSA) is a particular concern. The use of vancomycin as prophylactic agent alone or in combination with cephalosporin has not demonstrated lower periprosthetic joint infection (PJI) rates, partly due to timing and dosing of intravenous (IV) vancomycin administration, which have proven important factors in effectiveness. This is a retrospective review of a consecutive series of primary TKAs examining incidence of PJI, adverse reactions, and complications using IV versus intraosseous (IO) vancomycin at 30-day, 90-day, and one-year follow-up. A retrospective review of 1,060 patients who underwent TKA between May 2016 to July 2020 was performed. There were 572 patients in the IV group and 488 in the IO group, with minimal 30 days of follow-up. Patients were followed up at regularly scheduled intervals (two, six, and 12 weeks). No differences between groups for age, sex, BMI, or baseline comorbidities existed. The IV group received an IV dose of 15 mg/kg vancomycin given over an hour preceding skin incision. The IO group received a 500 mg dose of vancomycin mixed in 150 ml of normal saline, injected into proximal tibia after tourniquet inflation, before skin incision. All patients received an additional dose of first generation cephalosporin. Evaluation included preoperative and postoperative serum creatinine values, tourniquet time, and adverse reactions attributable to vancomycin. Incidence of PJI with minimum 90-day follow-up was 1.4% (eight knees) in the IV group and 0.22% (one knee) in IO group (p = 0.047). This preliminary report demonstrated an reduction in the incidence of infection in TKA using IO vancomycin combined with a first-generation cephalosporin. While the study suffers from limitations of a retrospective, multi-surgeon investigation, early findings are encouraging. IO delivery of vancomycin after tourniquet inflation is a safe and effective alternative to IV administration, eliminating the logistical challenges of timely dosing. Cite this article: Bone Joint J2021;103-B(6 Supple A):13-17.

Vancomycin-Loaded Microneedle Arrays against Methicillin-Resistant Staphylococcus Aureus Skin Infections.

Skin and soft tissue infections (SSTIs) caused by methicillin‐resistant Staphylococcus aureus (MRSA) are a major healthcare burden, often treated with intravenous injection of the glycopeptide antibiotic vancomycin (VAN). However, low local drug concentration in the skin limits its treatment efficiency, while systemic exposure promotes the development of resistant bacterial strains. Topical administration of VAN on skin is ineffective as its high molecular weight prohibits transdermal penetration. In order to implement a local VAN delivery, microneedle (MN) arrays with a water‐insoluble support layer for the controlled administration of VAN into the skin are developed. The utilization of such a support layer results in water‐insoluble needle shafts surrounded by drug‐loaded water‐soluble tips with high drug encapsulation. The developed MN arrays can penetrate the dermal barriers of both porcine and fresh human skin. Permeation studies on porcine skin reveal that the majority of the delivered VAN is retained within the skin. It is shown that the VAN‐MN array reduces MRSA growth both in vitro and ex vivo on skin. The developed VAN‐MN arrays may be extended to several drugs and may facilitate localized treatment of MRSA‐caused skin infections while minimizing adverse systemic effects.

Sequential drug delivery of vancomycin and rhBMP-2 via pore-closed PLGA microparticles embedded photo-crosslinked chitosan hydrogel for enhanced osteointegration

As generally accepted, inhibiting the bacterial invasion at initial stage and promoting the behavior of related osteogenesis cells afterwards is crucial to achieve favorable osteointegration after dental implantation. In this study, a novel combined structured hydrogel composed of chitosan and pore-closed poly(lactic-co-glycolic acid) microparticles was prepared and characterized. In vitro and in-vivo studies have identified that this biocompatible material can rapidly release vancomycin at initial 2 days and then sustainedly release recombinant human bone morphogenetic protein-2 for about 12 days, thus respectively accomplish antibacterial and osteogenesis functions. This sequential drug release system can be used as a promising coating material to improve the surface conditions of dental implant to enhance the osteointegration after surgery.

Dual drug delivery of vancomycin and imipenem/cilastatin by coaxial nanofibers for treatment of diabetic foot ulcer infections

Diabetic foot ulcer infections are the main causes of hospitalization in diabetics. The present study aimed to develop vancomycin and imipenem/cilastatin loaded core-shell nanofibers to facilitate the treatment of diabetic foot ulcers. Therefore, novel core-shell nanofibers composed of polyethylene oxide, chitosan, and vancomycin in shell and polyvinylpyrrolidone, gelatin, and imipenem/cilastatin in core compartments were prepared using the electrospinning technique. The nanofibers were characterized using scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, tensile test, and drug release. The antibacterial activity of drug-loaded nanofibers in different drugs concentrations was evaluated against Methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, and Pseudomonas aeruginosa by disk diffusion method. Furthermore, the cytotoxicity of fibers was investigated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. The obtained results showed that the prepared nanofibers were smooth having a core-shell structure with almost no cytotoxicity. The nanofibrous mats exhibited significant antibacterial activity against S. aureus and MRSA with the inhibition zones of 2.9 and 2.5 cm and gram-negative bacteria species of E. coli and P. aeruginosa with the inhibition zones of 1.9 and 2.8 cm, respectively. With respect to the significant antibacterial activities of these nanofibrous mats, they might be used as suitable drug delivery devices not only for diabetic foot ulcer infections but also for other chronic wounds.

Engineering mesoporous silica nanoparticles towards oral delivery of vancomycin.

Vancomycin (Van) is a key antibiotic of choice for the treatment of systemic methicillin resistant Staphylococcus aureus (MRSA) infections. However, due to its poor membrane permeability, it is administered parenterally, adding to the cost and effort of treatment. The poor oral bioavailability of Van is mainly due to its physico-chemical properties that limit its paracellular and transcellular transport across gastrointestinal (GI) epithelium. Herein we report the development of silica nanoparticles (SNPs)-based formulations that are able to enhance the epithelial permeability of Van. We synthesized SNPs of different pore sizes (2 nm and 9 nm) and modified their surface charge and polarity by attaching different functional groups (-NH2, -PO3, and -CH3). Van was loaded within these SNPs at a loading capacity in the range of ca. 18-29 wt%. The Van-loaded SNPs exhibited a controlled release behaviour when compared to un-encapsulated Van which showed rapid release due to its hydrophilic nature. Among Van-loaded SNPs, SNPs with large pores showed a prolonged release compared to SNPs with small pores while SNPs functionalised with -CH3 groups exhibited a slowest release among the functionalised SNPs. Importantly, Van-loaded SNPs, especially the large pore SNPs with negative charge, enhanced the permeability of Van across an epithelial cell monolayer (Caco-2 cell model) by up to 6-fold, with Papp values up to 1.716 × 10-5 cm s-1 (vs. 0.304 × 10-5 cm s-1 for un-encapsulated Van) after 3 h. The enhancement was dependent on both the type of SNPs and their surface functionalisation. The permeation enhancing effect of SNPs was due to its ability to transiently open the tight junctions measured by decrease in transepithelial resistance (TEER) which was reversible after 3 h. All in all, our data highlights the potential of SNPs (especially SNPs with large pores) for oral delivery of Van or other antimicrobial peptides.

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 &lt; 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.

Eradicating intracellular MRSA via targeted delivery of lysostaphin and vancomycin with mannose-modified exosomes

Intracellular methicillin-resistant Staphylococcus aureus (MRSA) is extremely difficult to remove by common antibiotics, leading to infection recurrence and resistance. Herein we report a novel exosome-based antibiotic delivery platform for eradicating intracellular MRSA, where mannosylated exosome (MExos) is employed as the drug carrier and preferentially taken up by macrophages, delivering lysostaphin (MExoL) and vancomycin (MExoV) to intracellular pathogens. Combination of MExoL and MExoV eradicated intracellular quiescent MRSA. Moreover, MExos rapidly accumulated in mouse liver and spleen, the target organs of intracellular MRSA, after intravenous (IV) administration. Thus, the MExos antibiotic delivery platform is a promising strategy for combating intracellular infection.

Mapping the potential of thiolated pluronic based nanomicelles for the safe and targeted delivery of vancomycin against staphylococcal blepharitis

The present study was performed to develop mucoadhesive vancomycin loaded thiolated pluronic F68 polymeric nanomicelles against staphylococcal blepharitis. The polymeric micelles were intended to be mucoadhesive in nature with prolonged retention at site of infection to address the barriers in topical delivery to eyelids. The mucoadhesive and enhanced retention of polymeric micelles was investigated by synthesis of vancomycin loaded thiolated polymeric micelles of tri block copolymer Pluronic F68. The drug loaded thiolated polymeric micelles were characterized for their zeta potential, particle size, PDI, release profile, animal studies and stability. The FTIR analysis of the thiolated polymeric nanomicelles confirmed successful synthesis of vancomycin loaded thiolated polymeric nanomicelles (Vnc-PF68-Cys) with no interaction between vancomycin and polymer. X-Ray diffraction studies (XRD) showed crystalline nature of vancomycin in the thiolated polymeric nanomicelles. The surface roughness of the developed polymeric nanomicelles was evident from results of AFM (Atomic force microscopy) images. TEM (Tranmission electron microscopy) confirmed spherical shape and unilamelar nature of nanomicelles. Furthermore, Vnc-PF68-Cys nanomicelles were found to be stable regarding particle size, zeta potential and polydispersity index with nanosize, low polydispersity index and negative zeta potential. Thermal stability of the formulation was confirmed by DSC (Differential scanning calorimetry). Visual inspection of the nanoformulation showed particles-free clear solution. Mucoadhesive property was evaluated by rheological behaviour of formulation when mixed with freshly prepared mucin solution in terms of viscosity that showed 2 folds increase in viscosity upon thiolation of formulation due to thiols group in polymer backbone forming disulfide linkage with cysteine groups of mucins. Release profile showed sustained drug release up to 48 h for thiolated formulation with 98% drug released under sink conditions. The prepared thiolated nanomicelles were found non-toxic towards mice. Based on the results, the developed Vnc-PF68-cys polymeric nanomicelles formulation seems to be promising mucoadhesive formulation for ocular deliveryagainst staphylococcal blepharitis.

Formulation of pH-Responsive Quatsomes from Quaternary Bicephalic Surfactants and Cholesterol for Enhanced Delivery of Vancomycin against Methicillin Resistant Staphylococcus aureus.

Globally, human beings continue to be at high risk of infectious diseases caused by methicillin-resistant Staphylococcus aureus (MRSA); and current treatments are being depleted due to antimicrobial resistance. Therefore, the synthesis and formulation of novel materials is essential for combating antimicrobial resistance. The study aimed to synthesize a quaternary bicephalic surfactant (StBAclm) and thereof to formulate pH-responsive vancomycin (VCM)-loaded quatsomes to enhance the activity of the antibiotic against MRSA. The surfactant structure was confirmed using 1H, 13C nuclear magnetic resonance (NMR), Fourier-transform infrared spectroscopy (FT-IR), and high-resolution mass spectrometry (HRMS). The quatsomes were prepared using a sonication/dispersion method and were characterized using various in vitro, in vivo, and in silico techniques. The in vitro cell biocompatibility studies of the surfactant and pH-responsive vancomycin-loaded quatsomes (VCM-StBAclm-Qt1) revealed that they are biosafe. The prepared quatsomes had a mean hydrodynamic diameter (MHD), polydispersity index (PDI), and drug encapsulation efficiency (DEE) of 122.9 ± 3.78 nm, 0.169 ± 0.02 mV, and 52.22 ± 8.4%, respectively, with surface charge switching from negative to positive at pH 7.4 and pH 6.0, respectively. High-resolution transmission electron microscopy (HR-TEM) characterization of the quatsomes showed spherical vesicles with MHD similar to the one obtained from the zeta-sizer. The in vitro drug release of VCM from the quatsomes was faster at pH 6.0 compared to pH 7.4. The minimum inhibitory concentration (MIC) of the drug loaded quatsomes against MRSA was 32-fold and 8-fold lower at pH 6.0 and pH 7.4, respectively, compared to bare VCM, demonstrating the pH-responsiveness of the quatsomes and the enhanced activity of VCM at acidic pH. The drug-loaded quatsomes demonstrated higher electrical conductivity and a decrease in protein and deoxyribonucleic acid (DNA) concentrations as compared to the bare drug. This confirmed greater MRSA membrane damage, compared to treatment with bare VCM. The flow cytometry study showed that the drug-loaded quatsomes had a similar bactericidal killing effect on MRSA despite a lower (8-fold) VCM concentration when compared to the bare VCM. Fluorescence microscopy revealed the ability of the drug-loaded quatsomes to eradicate MRSA biofilms. The in vivo studies in a skin infection mice model showed that groups treated with VCM-loaded quatsomes had a 13-fold decrease in MRSA CFUs when compared to the bare VCM treated groups. This study confirmed the potential of pH-responsive VCM-StBAclm quatsomes as an effective delivery system for targeted delivery and for enhancing the activity of antibiotics.

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.