Release Of Antibacterial Agents Research Articles

Bacterial anti-adhesive and pH-induced antibacterial agent releasing ultra-thin films of zwitterionic copolymer micelles

We report on preparation of substrates with dual function coatings, i.e. bacterial anti-adhesive and antibacterial agent releasing polymer films of zwitterionic block copolymer micelles (BCMs). BCMs were obtained by pH-induced self-assembly of poly[3-dimethyl (methacryloyloxyethyl) ammonium propane sulfonate-b-2-(diisopropylamino)ethyl methacrylate] (βPDMA-b-PDPA), resulting in BCMs with zwitterionic βPDMA-coronae and pH-responsive PDPA-core. These zwitterionic BCMs were then used as building blocks to construct mono- and multi-layer films. We found that the number of layers in the film was critical for the anti-adhesive property and 3-layer films were the most anti-adhesive against a model Gram-positive bacterium, Staphylococcus aureus. Antibacterial activity could be introduced to the films by loading Triclosan into βPDMA-b-PDPA micelles. Triclosan containing films were effective against Triclosan-sensitive Staphylococcus aureus specifically at moderately acidic conditions due to pH-induced disintegration of the micellar core blocks and release of Triclosan from the surface. Three-layer films also exhibited anti-adhesive property at physiological pH against a model Gram-negative bacterium, Escherichia coli. At moderately acidic pH, the coatings showed a contact antibacterial effect against an isolate of Escherichia coli with low sensitivity to Triclosan only when micellar cores were loaded with Triclosan. Such dual function films can be promising to combat biofouling at the non-homogeneous and/or defective parts of an anti-adhesive coating. Moreover, considering the moderately acidic conditions around an infection site, these multilayers can be advantageous due to their property of pH-induced antibacterial agent release. Statement of SignificanceThis study presents preparation of substrates with dual function ultra-thin coatings of zwitterionic block copolymer micelles which show bacterial anti-adhesive properties against a Gram-positive and a Gram-negative bacterium. Such coatings are also capable of releasing antibacterial compounds in response to pH changes. Films were prepared by self-assembly of polymers at the surface. Our findings showed that zwitterionic micellar coronae introduced bacterial anti-adhesive property to the films, whereas pH-responsive micellar cores enabled release of an antibacterial agent from the surface at acidic pH. Considering the moderately acidic conditions around an infection site, such multilayers can be promising for the coating of implants/medical devices.

Bacteria-responsive multilayer coatings comprising polycationic nanospheres for bacteria biofilm prevention on urinary catheters

This work reports on the development of infection-preventive coatings on silicone urinary catheters that contain in their structure and release on demand antibacterial polycationic nanospheres. Polycationic aminocellulose conjugate was first sonochemically processed into nanospheres to improve its antibacterial potential compared to the bulk conjugate in solution (ACSol). Afterward the processed aminocellulose nanospheres (ACNSs) were combined with the hyaluronic acid (HA) polyanion to build a layer-by-layer construct on silicone surfaces. Although the coating deposition was more effective when HA was coupled with ACSol than with ACNSs, the ACNSs-based coatings were thicker and displayed smoother surfaces due to the embedment of intact nanospheres. The antibacterial effect of ACNSs multilayers was 40% higher compared to ACSol coatings. This fact was further translated into more effective prevention of Pseudomonas aeruginosa biofilm formation. The coatings were stable in the absence of bacteria, whereas their disassembling occurred gradually during incubation with P. aeruginosa, and thus eradicate the biofilm upon release of antibacterial agents. Only 5 bilayers of HA/ACNSs were sufficient to prevent the biofilm formation, in contrast to the 10 bilayers of ACSol required to achieve the same effect. The antibiofilm efficiency of (HA/ACNSs)10 multilayer construct built on a Foley catheter was additionally validated under dynamic conditions using a model of the catheterized bladder in which the biofilm was grown during seven days. Statement of SignificanceAntibacterial layer-by-layer coatings were fabricated on silicone that efficiently prevents Pseudomonas aeruginosa biofilm formation during time beyond the useful lifetime of the currently employed urinary catheters in medical practice. The coatings are composed of intact, highly antibacterial polycationic nanospheres processed from aminated cellulose and bacteria-degrading glycosaminoglycan hyaluronic acid. The importance of incorporating nanoscale structures within bacteria-responsive surface coatings to impart durable antibacterial and self-defensive properties to the medical indwelling devices is highlighted.

In vitro and in vivo evaluation of xanthan gum-succinic anhydride hydrogels for the ionic strength-sensitive release of antibacterial agents.

In this work, we report a new approach to prepare high gel performance hydrogels which are used as ionic strength-sensitive drug release systems. Succinic anhydride (SA)-modified xanthan (XG-SA) derivatives were prepared and confirmed by Fourier transform-infrared spectroscopy and proton nuclear magnetic resonance spectroscopy. Rheological measurements showed that the storage moduli (G') and loss moduli (G'') of XG-SA were much higher than native XG suggesting a higher stability of the hydrogels. XG-SA could form stable hydrogels when the content of a dry gel was 1.4 wt%. Drug release studies showed the ionic strength-sensitive and sustained release of gentamicin (GS) for 9 days under aqueous physiological conditions. Biofilm inhibition assay revealed that the XG-SA/GS hydrogels were sufficient to inhibit biofilm formation. The Kirby-Bauer method showed that there was a zone of inhibition at around 8.2 mm indicating the excellent bactericidal function of the hydrogels. Cytocompatibility assessment against human lens epithelial cells revealed that the hydrogels supported cell adhesion, proliferation and migration when the loading dosage of GS was 1 mg g-1. XG-SA/GS hydrogels were compared to native XG-SA in the rabbit subcutaneous S. aureus infection model. XG-SA/GS hydrogels yielded a significantly lower degree of infection than XG-SA hydrogels at day 7. In this way, XG-SA hydrogels are promising drug delivery materials for antibacterial applications.

Sustained Release of Antibacterial Agents from Doped Halloysite Nanotubes.

The use of nanomaterials for improving drug delivery methods has been shown to be advantageous technically and viable economically. This study employed the use of halloysite nanotubes (HNTs) as nanocontainers, as well as enhancers of structural integrity in electrospun poly-e-caprolactone (PCL) scaffolds. HNTs were loaded with amoxicillin, Brilliant Green, chlorhexidine, doxycycline, gentamicin sulfate, iodine, and potassium calvulanate and release profiles assessed. Selected doped halloysite nanotubes (containing either Brilliant Green, amoxicillin and potassium calvulanate) were then mixed with poly-e-caprolactone (PLC) using the electrospinning method and woven into random and oriented-fibered nanocomposite mats. The rate of drug release from HNTs, HNTs/PCL nanocomposites, and their effect on inhibiting bacterial growth was investigated. Release profiles from nanocomposite mats showed a pattern of sustained release for all bacterial agents. Nanocomposites were able to inhibit bacterial growth for up to one-month with only a slight decrease in bacterial growth inhibition. We propose that halloysite doped nanotubes have the potential for use in a variety of medical applications including sutures and surgical dressings, without compromising material properties.

Electrostatic immobilization of cetylpyridinium chloride to poly(vinyl alcohol) hydrogels for the simple fabrication of wound dressings with the suppressed release of antibacterial agents

ABSTRACTPolymeric systems for antibacterial wound dressings require chemical reactions or syntheses for attaching or incorporating antibacterial moieties into polymer backbones. However, these materials often fail to satisfy the basic requirements, such as easy and inexpensive synthesis. We speculated that a positively charged organic antibacterial agent would be attracted to the polar groups of poly(vinyl alcohol) (PVA) hydrogels and would show suppressed release. PVA hydrogels containing cetylpyridinium chloride (CPC) were prepared by γ irradiation. CPC was barely released from the hydrogels, probably because of electrostatic interactions, and was stable upon γ irradiation. The suppressed release of CPC conferred antibacterial activity against Escherichia coli to the surface of the hydrogels, whereas no inhibition zone was observed around the hydrogels. The CPC‐containing PVA hydrogels were easy to prepare and contained known and safe materials. The simplicity and safety of this procedure for achieving the suppressed release of antibacterial agents were advantages of these CPC‐containing PVA hydrogels. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 40456.

Antibacterial properties of TiO2–Cu composite thin films grown by a one step DLICVD process

The correlations between microstructural features, chemical compositions and antibacterial properties of coatings containing metallic Cu particles embedded in a titanium dioxide matrix have been determined. A Direct Liquid Injection Chemical Vapor Deposition (DLICVD) process was used for the one step growth of TiO2–Cu composite coatings on various substrates. Titanium tetra-iso-propoxide (TTIP) and copper bis(2,2,6,6-tetramethyl-3,5-heptationate) (Cu(tmhd)2) were used as titanium and copper molecular sources, respectively. This growth process allows a good control of the quantity of metalorganic precursors injected into the CVD reactor and thus of the coating composition. The deposition occurs at 683K under low pressure (800Pa). The influence of the main features of the coatings on their antibacterial properties was investigated in order to produce bactericidal surfaces that are durable, non-toxic and containing a minimum amount of active agent. The antibacterial activity on Staphylococcus aureus without any photon activation was measured according to the JIS Z 2801:2000 standard method. An antibacterial activity was detected for a low metal content of ca. 1at.% Cu, and was found to increase with the Cu content. It was maximal for 3.5at.% Cu, i.e. TiO2–Cu composite coatings exhibit bactericidal behavior against S. aureus for this optimal composition (relative activity=100%). In order to better characterize the microbiological behavior of the coatings more discriminating methods derived from the literature were tested to assess the performances of these CVD coatings in terms of efficiency, release of antibacterial agent and accelerated aging.

Controlled release of metronidazole from composite poly-ε-caprolactone/alginate (PCL/alginate) rings for dental implants

ObjectiveDental implants provide support for dental crowns and bridges by serving as abutments for the replacement of missing teeth. To prevent bacterial accumulation and growth at the site of implantation, solutions such as systemic antibiotics and localized delivery of bactericidal agents are often employed. The objective of this study was to demonstrate a novel method of controlled localized delivery of antibacterial agents to an implant site using a biodegradable custom fabricated ring. MethodsThe study involved incorporating a model antibacterial agent (metronidazole) into custom designed poly-ε-caprolactone/alginate (PCL/alginate) composite rings to produce the intended controlled release profile. The rings can be designed to fit around the body of any root form dental implants of various diameters, shapes and sizes. ResultsIn vitro release studies indicate that pure (100%) alginate rings exhibited an expected burst release of metronidazole in the first few hours, whereas Alginate/PCL composite rings produced a medium burst release followed by a sustained release for a period greater than 4 weeks. By varying the PCL/alginate weight ratios, we have shown that we can control the amount of antibacterial agents released to provide the minimal inhibitory concentration (MIC) needed for adequate protection. The fabricated composite rings have achieved a 50% antibacterial agent release profile over the first 48h and the remaining amount slowly released over the remainder of the study period. The PCL/alginate agent release characteristic fits the Ritger–Peppas model indicating a diffusion-based mechanism during the 30-day study period. SignificanceThe developed system demonstrates a controllable drug release profile and the potential for the ring to inhibit bacterial biofilm growth for the prevention of diseases such as peri-implantitis resulting from bacterial infection at the implant site.

Evaluation of sealing ability of a root canal sealer with various antibiotic additives: An in vitro study

Introduction: One of the reasons for persistent endodontic infection is the retention of microorganism on root canal walls. Studies on endodontic prognosis have demonstrated that the addition of antibiotics to the root canal sealer is proven to be beneficial to prevent re-infection and impart antimicrobial property for a longer time. Aims and Objectives: The primary aim of this study is to determine and the secondary aim is to compare the sealing ability of Kerr Pulp Canal Sealer (extended working time) (PCS [EWT]) when used with or without various antibiotic additives viz.; amoxycillin, doxycycline and metronidazole using apical dye leakage method. Materials and Methods: An in vitro study was performed on extracted human teeth, obturated with sealer-antibiotic combinations and sealers alone. Rhodamine-B dye penetration was done for 10 days and the teeth were sectioned and viewed under light microscope; then linear dye penetration was measured and statistically analyzed. Results: Kerr PCS (EWT) showed mean apical leakage of 3.475 mm (P = 0.655, Z = 0.447), whereas PCS (EWT) combined with amoxycillin showed a mean apical leakage of 0.997 mm (P = 0.084, Z = 1.727) showing its clinical significance. PCS (EWT) + amoxycillin showed the best sealing ability with least apical leakage. Conclusion: Addition of antibiotics such as amoxycillin, doxycycline and metronidazole to Kerr PCS (EWT) sealer is recommended as it helps to improve the antibacterial property and the apical sealing ability.Clinical Relevance to Interdisciplinary DentistryBacteria and by-products in the dentinal tubules can cause reinfection of root canal treated teeth.The continuous release of antibacterial agent is desirable to prevent reinfection in root canal treated teeth.This original research hopes to prevent reinfection under the restorations of endodontically treated teeth by the action of additives in root canal sealers and by controlling the microleakage.

Cyclodextrin functionalization of several cellulosic substrates for prolonged release of antibacterial agents

AbstractSeveral cellulosic substrates have been surface‐functionalized with cyclomaltoheptaose (β‐cyclodextrin, β‐CD) using citric acid as a crosslinker agent to obtain new surface‐modified materials able to release antiseptic molecules over a prolonged period, in view of their use in medical domain. Three different commercial cellulosic substrates were used, namely: (i) an uncoated paper, (ii) a crepe paper, and (iii) a medical bandage. They were successfully grafted by a crosslinked polymer consisting on β‐CD molecules as assessed by scanning electron microscopy and Fourier transform infrared spectroscopy analysis. Several time–temperature kinetic cycles were performed to reach the optimum curing parameters. The grafted and nongrafted samples were loaded with chlorhexidine digluconate (digCHX), a widely used antiseptic agent. The drug‐delivery kinetics of the encapsulated digCHX was carried out by immersing the sample under investigation into an aqueous medium, and the quantity of the released digCHX was measured, as a function of time, by UV spectroscopy. The optimal grafting conditions were established on the basis of the highest weight gain. These samples did not give the best release performance. Nevertheless, several grafted substrates were able to uptake an appreciable amount of active molecules and release them over a prolonged time of about 20 days. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013

An innovative, easily fabricated, silver nanoparticle-based titanium implant coating: development and analytical characterization

Microbial colonization and biofilm formation on implanted devices represent an important complication in orthopaedic and dental surgery and may result in implant failure. Controlled release of antibacterial agents directly at the implant site may represent an effective approach to treat these chronic complications. Resistance to conventional antibiotics by pathogenic bacteria has emerged in recent years as a major problem of public health. In order to overcome this problem, non-conventional antimicrobial agents have been under investigation. In this study, polyacrylate-based hydrogel thin coatings have been electrosynthesised on titanium substrates starting from poly(ethylene glycol diacrylate)-co-acrylic acid. Silver nanoparticles (AgNPs) with a narrow size distribution have been synthesized using a "green" procedure and immobilized on Ti implant surfaces exploiting hydrogel coatings' swelling capabilities. The coatings have been characterized by XPS and SEM/EDX, while their silver release performances have been monitored by ICP-MS. The antibacterial activity of these AgNP-modified hydrogel coatings was tested evaluating in vitro inhibition growth of Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli, among the most common pathogens in orthopaedic infections. Moreover, a preliminary investigation of the biocompatibility of silver-loaded coatings versus MG63 human osteoblast-like cells has been performed. An important point of strength of this paper, in fact, is the concern about the effect of silver species on the surrounding cell system in implanted medical devices. Silver ion release has been properly tuned in order to assure antibacterial activity while preserving osteoblasts' response at the implant interface.

Polymer Multilayers with pH-Triggered Release of Antibacterial Agents

We report on the layer-by-layer design principles of poly(methacrylic acid) (PMAA) ultrathin hydrogel coatings that release antimicrobial agents (AmAs) in response to pH variations. The studied AmAs include gentamicin and an antibacterial cationic peptide L5. Adipic acid dihydrazide (AADH) is a cross-linker which, relative to ethylenediamine (EDA), increases the hydrogel hydrophobicity and introduces centers for hydrogen bonding to AmAs. AmA retention in AADH-cross-linked hydrogels in high-salt solutions was enhanced while AmA release at low pH was suppressed. L5 retains its antibacterial activity toward planktonic Staphylococcus epidermidis after release from PMAA hydrogels in response to pH decreases in the surrounding medium due to bacterial growth. Staphylococcus epidermidis adhesion and colonization was almost completely inhibited by L5 loading of hydrogels. The AmA-releasing and AmA-retaining properties of these hydrogel coatings provide new opportunities to study the fundamental mechanisms of AmA-coating-bacteria interactions and develop a new class of clinically relevant antibacterial coatings for medical devices.

Evaluation of the factors influencing stomach-specific delivery of antibacterial agents for Helicobacter pylori infection.

Because Helicobacter pylori infection is localized in the gastric mucus layer and at the mucus layer-epithelial cell interface, we have developed amoxycillin- and metronidazole-containing chitosan microspheres for stomach-specific drug delivery. Drug-loaded porous chitosan microspheres were prepared by simultaneous crosslinking and precipitation with sodium tripolyphosphate. The release of antibacterial agents into simulated gastric fluid (SGF, pH 1.2), and the stability and permeability through gastric mucin, were examined at 37 degrees C. Because of the high porosity of drug-loaded chitosan microspheres, all the amoxycillin and metronidazole were released in 2 h. High-performance liquid chromatography assays of the antibacterial agents in SGF at 37 degrees C indicated 40% degradation of amoxycillin after 10 h. Metronidazole was completely stable for up to 24 h in SGF. Amoxycillin and metronidazole were highly permeable through the gastric mucin gel layer. The results of this study show that acid-stable antibacterial agents, such as metronidazole, that rapidly permeate the gastric mucus layer would be very effective for the complete eradication of H. pylori infection when delivered specifically at the site of infection in the stomach.

In vitro comparison of antibacterial properties of plasma sprayed wollastonite coatings loading silver and gentamicin

To develop antibacterial coatings for orthopedic implants with a sustained release of drugs. Wollastonite coatings were deposited on the titanium substrates by an atmospheric plasma spray system. After soaking in weight percent of 5% AgNO(3) solution for 24 h, the wollastonite coatings loading silver were obtained. Gentamicin were loaded on the wollastonite coatings by collagen grafting process. The release rates of drugs from wollastonite coatings were investigated by the in vitro solution soaking test. One strain of S. aureus was used in zone of inhibition test to evaluate the antibacterial properties of drug loaded wollastonite coatings, and the cell culture test was used to evaluate their cytotoxicity. Silver and gentamicin loaded wollastonite coatings were successfully prepared. The release of silver ions from the silver loaded wollastonite coatings lasted 50 d in deionized water, effectively inhibiting the growth of S. aureus for 40 d. While an initial burst release of gentamicin was found during the in vitro solution soaking test. The gentamicin released from gentamicin loaded wollastonite coatings can inhibit the growth of S. aureus for 18 d. Both the two kinds of antibacterial wollastonite coatings showed no adverse effect on cellular adhesion, proliferation and alkaline phosphatase expression. Compared with gentamicin loaded wollastonite coatings, silver loaded wollastonite coatings may have more promising clinical applications due to the even and long-time antibacterial agent release.

Errata

In an article in the 1 May 2002 issue of the Journal (Mandell GL, Coleman EJ. Effect of antipyretic agents on uptake, transport, and release of antimicrobial agents by human polymorphonuclear leukocytes. J Infect Dis 2002;185:1314–9), there is an error in the fourth paragraph of the Results section. The last sentence should read as follows: “Nondirected transport and release of antibacterial agents by PMNL was not decreased by the antipyretics”.