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15 pages, 2436 KiB

Open AccessArticle

Correlation between Antimicrobial Resistance and the Hospital-Wide Diverse Use of Broad-Spectrum Antibiotics by the Antimicrobial Stewardship Program in Japan

by Takashi Ueda, Yoshio Takesue, Kazuhiko Nakajima, Kaoru Ichiki, Kaori Ishikawa, Kumiko Yamada, Toshie Tsuchida, Naruhito Otani, Yoshiko Takahashi, Mika Ishihara, Shingo Takubo, Kosuke Iijima, Hiroki Ikeuchi, Motoi Uchino and Takeshi Kimura

Pharmaceutics 2023, 15(2), 518; https://doi.org/10.3390/pharmaceutics15020518 - 03 Feb 2023

Cited by 9 | Viewed by 1444

Abstract

Increased antibiotic use and antibiotic homogeneity cause selective pressure. This study investigated the correlation between antibiotic diversity and antimicrobial resistance (AMR) in Gram-negative organisms. The days of therapy/100 patient-days (DOT) for four broad-spectrum antibiotic classes were evaluated for 2015–2022. The antibiotic heterogeneity index [...] Read more.

Increased antibiotic use and antibiotic homogeneity cause selective pressure. This study investigated the correlation between antibiotic diversity and antimicrobial resistance (AMR) in Gram-negative organisms. The days of therapy/100 patient-days (DOT) for four broad-spectrum antibiotic classes were evaluated for 2015–2022. The antibiotic heterogeneity index (AHI) for the equal use of four classes (25%) and the modified AHI for the equal use of three classes (30%), excluding fluoroquinolones (10%), were measured (target: 1.0). Quarterly antibiotic use markers and the resistance rates against ≥2 anti-Pseudomonas antibiotics were compared. The DOT value was 9.94, and the relative DOT were 34.8% for carbapenems, 32.1% for piperacillin/tazobactam, 24.3% for fourth generation cephalosporins/ceftazidime/aztreonam, and 8.9% for fluoroquinolones. Although no correlation was found between the total DOT and the resistance rate for any bacterium, a significant negative correlation was found between the heterogeneity indices and resistance rates for Pseudomonas aeruginosa and Klebsiella pneumoniae. The significant cutoffs that discriminate the risk of resistance were 0.756 for the AHI and 0.889 for the modified AHI for K. pneumoniae. Antibiotic diversity is more important in preventing AMR than overall antibiotic use. The ideal ratio of broad-spectrum antibiotics should be studied for diversified use to prevent AMR. Full article

(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)

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19 pages, 4448 KiB

Open AccessArticle

Polyenes in Medium Chain Length Polyhydroxyalkanoate (mcl-PHA) Biopolymer Microspheres with Reduced Toxicity and Improved Therapeutic Effect against Candida Infection in Zebrafish Model

by Aleksandar Pavic, Zoran Stojanovic, Marina Pekmezovic, Đorđe Veljović, Kevin O’Connor, Ivana Malagurski and Jasmina Nikodinovic-Runic

Pharmaceutics 2022, 14(4), 696; https://doi.org/10.3390/pharmaceutics14040696 - 24 Mar 2022

Cited by 5 | Viewed by 2592

Abstract

Immobilizing antifungal polyenes such as nystatin (Nys) and amphotericin B (AmB) into biodegradable formulations is advantageous compared to free drug administration providing sustained release, reduced dosing due to localized targeting and overall reduced systemic drug toxicity. In this study, we encapsulated Nys and [...] Read more.

Immobilizing antifungal polyenes such as nystatin (Nys) and amphotericin B (AmB) into biodegradable formulations is advantageous compared to free drug administration providing sustained release, reduced dosing due to localized targeting and overall reduced systemic drug toxicity. In this study, we encapsulated Nys and AmB in medium chain length polyhydroxyalkanoates (mcl-PHA) microspheres (7–8 µm in diameter). The obtained formulations have been validated for antifungal activity in vitro against a panel of pathogenic fungi including species of Candida, Aspergillus, Microsporum and Trichophyton genera and toxicity and efficacy in vivo using the zebrafish model of disseminated candidiasis. While free polyenes, especially AmB, were highly toxic to zebrafish embryos at the effective (MIC) doses, after their loading into mcl-PHA microspheres, inner organ toxicity and teratogenicity associated with both drugs were not observed, even at 100 × MIC doses. The obtained mcl-PHA/polyene formulations have successfully eradicated C. albicans infection and showed an improved therapeutic profile in zebrafish by enhancing infected embryos survival. This approach is contributing to the antifungal arsenal as polyenes, although the first broad-spectrum antifungals on the market are still the gold standard for treatment of fungal infections. Full article

(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)

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22 pages, 4502 KiB

Open AccessArticle

Electrospun Amphiphilic Nanofibers as Templates for In Situ Preparation of Chloramphenicol-Loaded Liposomes

by Ivo Laidmäe, Andres Meos, Irja Alainezhad Kjærvik, Sveinung G. Ingebrigtsen, Nataša Škalko-Basnet, Kalle Kirsimäe, Tavo Romann, Urmas Joost, Vambola Kisand and Karin Kogermann

Pharmaceutics 2021, 13(11), 1742; https://doi.org/10.3390/pharmaceutics13111742 - 20 Oct 2021

Cited by 5 | Viewed by 2380

Abstract

The hydration of phospholipids, electrospun into polymeric nanofibers and used as templates for liposome formation, offers pharmaceutical advantages as it avoids the storage of liposomes as aqueous dispersions. The objective of the present study was to electrospin and characterize amphiphilic nanofibers as templates [...] Read more.

The hydration of phospholipids, electrospun into polymeric nanofibers and used as templates for liposome formation, offers pharmaceutical advantages as it avoids the storage of liposomes as aqueous dispersions. The objective of the present study was to electrospin and characterize amphiphilic nanofibers as templates for the preparation of antibiotic-loaded liposomes and compare this method with the conventional film-hydration method followed by extrusion. The comparison was based on particle size, encapsulation efficiency and drug-release behavior. Chloramphenicol (CAM) was used at different concentrations as a model antibacterial drug. Phosphatidylcoline (PC) with polyvinylpyrrolidone (PVP), using ethanol as a solvent, was found to be successful in fabricating the amphiphilic composite drug-loaded nanofibers as well as liposomes with both methods. The characterization of the nanofiber templates revealed that fiber diameter did not affect the liposome size. According to the optical microscopy results, the immediate hydration of phospholipids deposited on the amphiphilic nanofibers occurred within a few seconds, resulting in the formation of liposomes in water dispersions. The liposomes appeared to aggregate more readily in the concentrated than in the diluted solutions. The drug encapsulation efficiency for the fiber-hydrated liposomes varied between 14.9 and 28.1% and, for film-hydrated liposomes, between 22.0 and 77.1%, depending on the CAM concentrations and additional extrusion steps. The nanofiber hydration method was faster, as less steps were required for the in-situ liposome preparation than in the film-hydration method. The liposomes obtained using nanofiber hydration were smaller and more homogeneous than the conventional liposomes, but less drug was encapsulated. Full article

(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)

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15 pages, 6083 KiB

Open AccessArticle

Evaluation of the Influence of a Hydrogel Containing AMPD on the Stability of Tetracycline Hydrochloride

by Agnieszka Kostrzębska, Adrianna Złocińska and Witold Musiał

Pharmaceutics 2021, 13(9), 1381; https://doi.org/10.3390/pharmaceutics13091381 - 01 Sep 2021

Cited by 3 | Viewed by 1975

Abstract

Tetracyclines, as beneficial antimicrobial factors in both local and systemic therapy, are characterized by high instability. The aim of the study was the development of the influence of hydrogel formulation on the tetracycline hydrochloride (TC) level under varying storage conditions. The HPLC, XPRD [...] Read more.

Tetracyclines, as beneficial antimicrobial factors in both local and systemic therapy, are characterized by high instability. The aim of the study was the development of the influence of hydrogel formulation on the tetracycline hydrochloride (TC) level under varying storage conditions. The HPLC, XPRD as well as SEM and macroscopic observations were involved in the study. The TC concentration decreased within ca. two months from 9.37 µg/mL to 4.41 µg/mL in the case of the photoprotected TC solution stored at 23 °C, whereas the decrease in storage temperature did not improve the final level of TC. In the presence of AMPD, the TC level in aqueous solution decreased drastically to ca. 1 µg/mL. Application of a polyacrylic acid derivative enabled conservation of the TC level through the ca. two months. Thus, the use of alcoholamine in the preparation of the TC hydrogel may result in the development of a therapeutic product with a dual action against acne, including antimicrobial activity and saponification of free fatty acids deposited in the follicles. Full article

(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)

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17 pages, 2465 KiB

Open AccessArticle

Staphylococcus aureus Specific Electrospun Wound Dressings: Influence of Immobilization Technique on Antibacterial Efficiency of Novel Enzybiotic

by Olga Urbanek, Alicja Wysocka, Paweł Nakielski, Filippo Pierini, Elżbieta Jagielska and Izabela Sabała

Pharmaceutics 2021, 13(5), 711; https://doi.org/10.3390/pharmaceutics13050711 - 13 May 2021

Cited by 7 | Viewed by 2322

Abstract

The spread of antimicrobial resistance requires the development of novel strategies to combat superbugs. Bacteriolytic enzymes (enzybiotics) that selectively eliminate pathogenic bacteria, including resistant strains and biofilms, are attractive alternatives to antibiotics, also as a component of a new generation of antimicrobial wound [...] Read more.

The spread of antimicrobial resistance requires the development of novel strategies to combat superbugs. Bacteriolytic enzymes (enzybiotics) that selectively eliminate pathogenic bacteria, including resistant strains and biofilms, are attractive alternatives to antibiotics, also as a component of a new generation of antimicrobial wound dressings. AuresinePlus is a novel, engineered enzybiotic effective against Staphylococcus aureus—one of the most common pathogenic bacteria, found in infected wounds with a very high prevalence of antibiotic resistance. We took advantage of its potent lytic activity, selectivity, and safety to prepare a set of biodegradable PLGA/chitosan fibers generated by electrospinning. Our aim was to produce antimicrobial nonwovens to deliver enzybiotics directly to the infected wound and better control its release and activity. Three different methods of enzyme immobilization were tested: physical adsorption on the previously hydrolyzed surface, and covalent bonding formation using N-hydroxysuccinimide/N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide (NHS/EDC) or glutaraldehyde (GA). The supramolecular structure and functional properties analysis revealed that the selected methods resulted in significant development of nanofibers surface topography resulting in an efficient enzybiotic attachment. Both physically adsorbed and covalently bound enzymes (by NHS/EDC method) exhibited prominent antibacterial activity. Here, we present the extensive comparison between methods for the effective attachment of the enzybiotic to the electrospun nonwovens to generate biomaterials effective against antibiotic-resistant strains. Our intention was to present a comprehensive proof-of-concept study for future antimicrobial wound dressing development. Full article

(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)

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20 pages, 4750 KiB

Open AccessArticle

Development of Cephradine-Loaded Gelatin/Polyvinyl Alcohol Electrospun Nanofibers for Effective Diabetic Wound Healing: In-Vitro and In-Vivo Assessments

by Anam Razzaq, Zaheer Ullah Khan, Aasim Saeed, Kiramat Ali Shah, Naveed Ullah Khan, Bouzid Menaa, Haroon Iqbal and Farid Menaa

Pharmaceutics 2021, 13(3), 349; https://doi.org/10.3390/pharmaceutics13030349 - 07 Mar 2021

Cited by 46 | Viewed by 3875

Abstract

Diabetic wound infections caused by conventional antibiotic-resistant Staphylococcus aureus strains are fast emerging, leading to life-threatening situations (e.g., high costs, morbidity, and mortality) associated with delayed healing and chronic inflammation. Electrospinning is one of the most widely used techniques for the fabrication of [...] Read more.

Diabetic wound infections caused by conventional antibiotic-resistant Staphylococcus aureus strains are fast emerging, leading to life-threatening situations (e.g., high costs, morbidity, and mortality) associated with delayed healing and chronic inflammation. Electrospinning is one of the most widely used techniques for the fabrication of nanofibers (NFs), induced by a high voltage applied to a drug-loaded polymer solution. Particular attention is given to electrospun NFs for pharmaceutical applications (e.g., original drug delivery systems) and tissue regeneration (e.g., as tissue scaffolds). However, there is a paucity of reports related to their application in diabetic wound infections. Therefore, we prepared eco-friendly, biodegradable, low-immunogenic, and biocompatible gelatin (GEL)/polyvinyl alcohol (PVA) electrospun NFs (BNFs), in which we loaded the broad-spectrum antibiotic cephradine (Ceph). The resulting drug-loaded NFs (LNFs) were characterized physically using ultraviolet-visible (UV-Vis) spectrophotometry (for drug loading capacity (LC), drug encapsulation efficiency (EE), and drug release kinetics determination), thermogravimetric analysis (TGA) (for thermostability evaluation), scanning electron microscopy (SEM) (for surface morphology analysis), and Fourier-transform infrared spectroscopy (FTIR) (for functional group identification). LNFs were further characterized biologically by in-vitro assessment of their potency against S. aureus clinical strains (N = 16) using the Kirby–Bauer test and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, by ex-vivo assessment to evaluate their cytotoxicity against primary human epidermal keratinocytes using MTT assay, and by in-vivo assessment to estimate their diabetic chronic wound-healing efficiency using NcZ10 diabetic/obese mice (N = 18). Thin and uniform NFs with a smooth surface and standard size (<400 nm) were observed by SEM at the optimized 5:5 (GEL:PVA) volumetric ratio. FTIR analyses confirmed the drug loading into BNFs. Compared to free Ceph, LNFs were significantly more thermostable and exhibited sustained/controlled Ceph release. LNFs also exerted a significantly stronger antibacterial activity both in-vitro and in-vivo. LNFs were significantly safer and more efficient for bacterial clearance-induced faster chronic wound healing. LNF-based therapy could be employed as a valuable dressing material to heal S. aureus-induced chronic wounds in diabetic subjects. Full article

(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)

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20 pages, 5725 KiB

Open AccessArticle

Assessment of Antimicrobic, Antivirotic and Cytotoxic Potential of Alginate Beads Cross-Linked by Bivalent Ions for Vaginal Administration

by Miroslava Pavelková, Jakub Vysloužil, Kateřina Kubová, Sylvie Pavloková, Dobromila Molinková, Vladimír Celer, Alena Pechová, Josef Mašek and David Vetchý

Pharmaceutics 2021, 13(2), 165; https://doi.org/10.3390/pharmaceutics13020165 - 27 Jan 2021

Cited by 4 | Viewed by 2254

Abstract

Antimicrobial agent abuse poses a serious threat for future pharmacotherapy, including vaginal administration. The solution can be found in simple polymeric systems with inherent antimicrobial properties without the need to incorporate drugs, for instance alginate beads cross-linked by bivalent ions. The main goal [...] Read more.

Antimicrobial agent abuse poses a serious threat for future pharmacotherapy, including vaginal administration. The solution can be found in simple polymeric systems with inherent antimicrobial properties without the need to incorporate drugs, for instance alginate beads cross-linked by bivalent ions. The main goal of the presented study was to provide improvement on the well-documented cytotoxicity of Cu²⁺ cross-linked alginate. Alginate beads were prepared by external ionotropic gelation by cross-linking with Cu²⁺, Ca²⁺ and Zn²⁺ ions, separately and in mixtures. Morphological properties, swelling capacity, ion release and efficacy against the most common vaginal pathogens (C. albicans, E. coli, E. faecalis and virus strain—human herpesvirus type 1) were evaluated. The prepared particles (particle size 1455.68 ± 18.71–1756.31 ± 16.58 µm) had very good sphericity (0.86 ± 0.04–0.97 ± 0.06). In mixture samples, Cu²⁺ hampered second ion loading, and was also released incompletely (18.75–44.8%) compared to the single ion Cu²⁺ sample (71.4%). Efficacy against the selected pathogens was confirmed in almost all samples. Although anticipating otherwise, ion mixture samples did not show betterment over a Cu²⁺ cross-linked sample in cytotoxicity–pathogen efficacy relation. However, the desired improvement was found in a single ion Zn²⁺ sample whose minimal inhibition concentrations against the pathogens (0.6–6.12 mM) were close to, or in the same mathematical order as, its toxic concentration of 50 (1.891 mM). In summary, these findings combined with alginate’s biocompatibility and biodegradability give the combination solid potential in antimicrobial use. Full article

(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)

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14 pages, 32376 KiB

Open AccessArticle

Au–ZnO Conjugated Black Phosphorus as a Near-Infrared Light-Triggering and Recurrence-Suppressing Nanoantibiotic Platform against Staphylococcus aureus

by Atanu Naskar, Sohee Lee and Kwang-sun Kim

Pharmaceutics 2021, 13(1), 52; https://doi.org/10.3390/pharmaceutics13010052 - 02 Jan 2021

Cited by 23 | Viewed by 2653

Abstract

Antibiotic therapy is the gold standard for bacterial infections treatment. However, the rapid increase in multidrug-resistant (MDR) bacterial infections and its recent use for secondary bacterial infections in many COVID-19 patients has considerably weakened its treatment efficacy. These shortcomings motivated researchers to develop [...] Read more.

Antibiotic therapy is the gold standard for bacterial infections treatment. However, the rapid increase in multidrug-resistant (MDR) bacterial infections and its recent use for secondary bacterial infections in many COVID-19 patients has considerably weakened its treatment efficacy. These shortcomings motivated researchers to develop new antibacterial materials, such as nanoparticle-based antibacterial platform with the ability to increase the chances of killing MDR strains and prevent their drug resistance. Herein, we report a new black phosphorus (BP)-based non-damaging near-infrared light-responsive platform conjugated with ZnO and Au nanoparticles as a synergistic antibacterial agent against Staphylococcus aureus species. First, BP nanosheets containing Au nanoparticles were assembled in situ with the ZnO nanoparticles prepared by a low-temperature solution synthesis method. Subsequently, the antibacterial activities of the resulting Au–ZnO–BP nanocomposite against the non-resistant, methicillin-resistant, and erythromycin-resistant S. aureus species were determined, after its photothermal efficacy was assessed. The synthesized nanocomposite exhibited excellent anti-S. aureus activity and good photothermal characteristics. The non-resistant S. aureus species did not produce drug-resistant bacteria after the treatment of multiple consecutive passages under the pressure of the proposed nanoantibiotic, but rapidly developed resistance to erythromycin. This work clearly demonstrates the excellent photothermal antibacterial properties of Au–ZnO–BP nanocomposite against the MDR S. aureus species. Full article

(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)

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14 pages, 2505 KiB

Open AccessArticle

Liposomes-In-Hydrogel Delivery System Enhances the Potential of Resveratrol in Combating Vaginal Chlamydia Infection

by May Wenche Jøraholmen, Mona Johannessen, Kirsten Gravningen, Mirja Puolakkainen, Ganesh Acharya, Purusotam Basnet and Nataša Škalko-Basnet

Pharmaceutics 2020, 12(12), 1203; https://doi.org/10.3390/pharmaceutics12121203 - 11 Dec 2020

Cited by 26 | Viewed by 3242

Abstract

Chlamydia trachomatis is the most common cause of bacterial sexually transmitted infections and causes serious reproductive tract complications among women. The limitations of existing oral antibiotics and treatment of antimicrobial resistance require alternative treatment options. We are proposing, for the first time, the [...] Read more.

Chlamydia trachomatis is the most common cause of bacterial sexually transmitted infections and causes serious reproductive tract complications among women. The limitations of existing oral antibiotics and treatment of antimicrobial resistance require alternative treatment options. We are proposing, for the first time, the natural polyphenol resveratrol (RES) in an advanced delivery system comprising liposomes incorporated in chitosan hydrogel, for the localized treatment of C. trachomatis infection. Both free RES and RES liposomes-in-hydrogel inhibited the propagation of C. trachomatis in a concentration-dependent manner, assessed by the commonly used in vitro model comprising McCoy cells. However, for lower concentrations, the anti-chlamydial effect of RES was enhanced when incorporated into a liposomes-in-hydrogel delivery system, with inhibition of 78% and 94% for 1.5 and 3 µg/mL RES, respectively for RES liposomes-in-hydrogel, compared to 43% and 72%, respectively, for free RES. Furthermore, RES liposomes-in-hydrogel exhibited strong anti-inflammatory activity in vitro, in a concentration-dependent inhibition of nitric oxide production in the LPS-induced macrophages (RAW 264.7). The combination of a natural substance exhibiting multi-targeted pharmacological properties, and a delivery system that provides enhanced activity as well as applicability for vaginal administration, could be a promising option for the localized treatment of C. trachomatis infection. Full article

(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)

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13 pages, 3289 KiB

Open AccessArticle

Efficacy of Local Minocycline Agents in Treating Peri-Implantitis: An Experimental In Vivo Study in Beagle Dogs

by Sung-Wook Yoon, Myong-Ji Kim, Kyeong-Won Paeng, Kyeong Ae Yu, Chong-Kil Lee, Young Woo Song, Jae-Kook Cha and Ui-Won Jung

Pharmaceutics 2020, 12(11), 1016; https://doi.org/10.3390/pharmaceutics12111016 - 23 Oct 2020

Cited by 9 | Viewed by 2333

Abstract

Background: Local delivery agents (LDA) have the advantage of delivering the antibiotics at high concentrations to the targeted sites. However, the constant flow of gingival crevicular fluids and saliva may restrict their efficacy. Therefore, the drug sustainability and pharmacodynamic properties of any proposed [...] Read more.

Background: Local delivery agents (LDA) have the advantage of delivering the antibiotics at high concentrations to the targeted sites. However, the constant flow of gingival crevicular fluids and saliva may restrict their efficacy. Therefore, the drug sustainability and pharmacodynamic properties of any proposed LDA should be evaluated. Methods: Four dental implants were placed unilaterally in the edentulous mandible of six beagle dogs. Peri-implantitis were experimentally induced using silk-ligatures. Each implant was randomly allocated to receive one of the following four treatments: (i) MC (Chitosan-alginate (CA) minocycline), (ii) MP (CA-without minocycline), (iii) PG (Polyacrylate-glycerin minocycline), and (iv) Control (mechanical debridement only). Mechanical therapies and LDAs were administered into the gingival sulcus two times at a 4-week interval. Drug sustainability as well as clinical, radiographical, and immunohistochemical (IHC) analyses were conducted to evaluate the efficacies of treatments. Results: Reduced mean probing depth was observed in all of the test groups after the second delivery. A minimal marginal bone level change was observed during the treatment period (MP (−0.06 ± 0.53 mm) to PG (−0.25 ± 0.42 mm)). The distribution of IHC cell marker analysis of all targeted antibodies ranged from 6.34% to 11.33%. All treatment outcomes between the test groups were comparable. A prolonged retention of LDA was observed from CA microspheres (MC and MP) at both administrations (p < 0.017) and prolonged sustainability of bacteriostatic effect was observed from MC compared to PG after the second administration (p < 0.05). Conclusions: Prolonged retention of CA microspheres was observed and the longer bacteriostatic effect was observed from the MC group. Mechanical debridement with adjunct LDA therapy may impede peri-implantitis progression, however, prolonged drug action did not lead to improved treatment outcome. Full article

(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)

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17 pages, 2616 KiB

Open AccessArticle

Poly(Aspartic Acid) Functionalized Poly(ϵ-Caprolactone) Microspheres with Enhanced Hydroxyapatite Affinity as Bone Targeting Antibiotic Carriers

by Stijn G. Rotman, Thomas F. Moriarty, Benjamin Nottelet, Dirk W. Grijpma, David Eglin and Olivier Guillaume

Pharmaceutics 2020, 12(9), 885; https://doi.org/10.3390/pharmaceutics12090885 - 17 Sep 2020

Cited by 17 | Viewed by 3275

Abstract

Bone infection is a feared complication for patients with surgically fixed bone fractures and local antibiotic delivery is important in prophylaxis and treatment of these infections. Recent studies indicated that Staphylococcus aureus can penetrate bone tissue through micron-sized canaliculi and evade systemic and [...] Read more.

Bone infection is a feared complication for patients with surgically fixed bone fractures and local antibiotic delivery is important in prophylaxis and treatment of these infections. Recent studies indicated that Staphylococcus aureus can penetrate bone tissue through micron-sized canaliculi and evade systemic and currently available local antibiotic treatments. Targeting bacteria within the bone requires highly efficient delivery of antimicrobials to the infected bone tissue. In this work, a biodegradable microsphere carrier loaded with antibiotics and with specific affinity to bone mineral was developed. Two widely used antibiotics, i.e., Gentamicin-dioctyl sulfosuccinate (GM-AOT) and Ciprofloxacin (CF) were embedded in poly(ϵ-caprolactone) (PCL) microspheres fabricated by oil-in-water emulsion techniques with carboxylated poly(vinyl alcohol) (cPVA) as surfactant. The carboxylic acid groups present at the Poly(ϵ-caprolactone)/cPVA (PCL-cPVA) microsphere surface were functionalized with aspartic acid oligomers (ASP) granting bone targeting properties. We report on cPVA synthesis, microsphere formulation, and antibiotic loading of PCL/cPVA-ASP microspheres. Antibiotic loaded PCL/cPVA-ASP microspheres show sustained release of its antibiotic load and can inhibit bacterial growth in vitro for up to 6 days. PCL/cPVA-ASP microspheres show enhanced affinity to mineralized substrates compared to non-functionalized PCL/cPVA microspheres. These findings support further development of these bone targeting antibiotic carriers for potential treatment of persistent bone infections. Full article

(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)

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23 pages, 5530 KiB

Open AccessArticle

Saturated Fatty Acid-Based In Situ Forming Matrices for Localized Antimicrobial Delivery

by Takron Chantadee, Wichai Santimaleeworagun, Yaowaruk Phorom and Thawatchai Phaechamud

Pharmaceutics 2020, 12(9), 808; https://doi.org/10.3390/pharmaceutics12090808 - 25 Aug 2020

Cited by 22 | Viewed by 2590

Abstract

In recent years, the world has faced the issue of antibiotic resistance. Methicillin-resistant Staphylococcus aureus (MRSA) is a significant problem in various treatments and control of infections. Biocompatible materials with saturated fatty acids of different chain lengths (C₈–C₁₈) were [...] Read more.

In recent years, the world has faced the issue of antibiotic resistance. Methicillin-resistant Staphylococcus aureus (MRSA) is a significant problem in various treatments and control of infections. Biocompatible materials with saturated fatty acids of different chain lengths (C₈–C₁₈) were studied as matrix formers of localized injectable vancomycin HCl (VCM)-loaded antisolvent-induced in situ forming matrices. The series of fatty acid-based in situ forming matrices showed a low viscosity (5.47–13.97 cPs) and pH value in the range of 5.16–6.78, with high injectability through a 27-G needle (1.55–3.12 N). The preparations exhibited low tolerance to high concentrations of KH₂PO₄ solution (1.88–5.42% v/v) and depicted an electrical potential change during phase transformation. Their phase transition and matrix formation at the microscopic and macroscopic levels depended on the chain length of fatty acids and solvent characteristics. The VCM release pattern depended on the nucleation/crystallization and solvent exchange behaviors of the delivery system. The 35% w/v of C₁₂–C₁₆ fatty acid-based in situ forming matrix prolonged the VCM release over seven days in which C₁₂, C₁₄, C₁₆ –based formulation reached 56, 84, and 85% cumulative drug release at 7th day. The release data fitted well with Higuchi’s model. The developed formulations presented efficient antimicrobial activities against standard S. aureus, MRSA, Escherichia coli, and Candida albicans. Hence, VCM-loaded antisolvent-induced fatty acid-based in situ forming matrix is a potential local delivery system for the treatment of local Gram-positive infection sites, such as joints, eyes, dermis of surgery sites, etc., in the future. Full article

(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)

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18 pages, 5928 KiB

Open AccessArticle

Biogenic Silver Nanoparticles Decorated with Methylene Blue Potentiated the Photodynamic Inactivation of Pseudomonas aeruginosa and Staphylococcus aureus

by Paramanantham Parasuraman, Thamanna R. Y, Chitra Shaji, Alok Sharan, Ali H. Bahkali, Helal F. Al-Harthi, Asad Syed, V.T. Anju, Madhu Dyavaiah and Busi Siddhardha

Pharmaceutics 2020, 12(8), 709; https://doi.org/10.3390/pharmaceutics12080709 - 29 Jul 2020

Cited by 26 | Viewed by 3729

Abstract

The persistence of multidrug resistance among microorganisms has directed a mandate towards a hunt for the development of alternative therapeutic modalities. In this context, antimicrobial photodynamic therapy (aPDT) is sprouted as a novel strategy to mitigate biofilms and planktonic cells of pathogens. Nanoparticles [...] Read more.

The persistence of multidrug resistance among microorganisms has directed a mandate towards a hunt for the development of alternative therapeutic modalities. In this context, antimicrobial photodynamic therapy (aPDT) is sprouted as a novel strategy to mitigate biofilms and planktonic cells of pathogens. Nanoparticles (NPs) are reported with unique intrinsic and antimicrobial properties. Therefore, silver NPs (AgNPs) were investigated in this study to determine their ability to potentiate the aPDT of photosensitizer against Staphylococcus aureus and Pseudomonas aeruginosa. Biologically synthesized AgNPs were surface coated with methylene blue (MB) and studied for their aPDT against planktonic cells and biofilms of bacteria. The nano-conjugates (MB-AgNPs) were characterized for their size, shape and coated materials. MB-AgNPs showed significant phototoxicity against both forms of test bacteria and no toxicity was observed in the dark. Moreover, activity of MB-AgNPs was comparatively higher than that of the free MB, which concludes that MB-AgNPs could be an excellent alternative to combat antibiotic resistant bacteria. Full article

(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)

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18 pages, 2788 KiB

Open AccessArticle

Polymeric Nanoparticle Associated with Ceftriaxone and Extract of Schinopsis Brasiliensis Engler against Multiresistant Enterobacteria

by Maísa Soares de Oliveira, João Augusto Oshiro-Junior, Mariana Rillo Sato, Marta Maria Conceição and Ana Cláudia Dantas Medeiros

Pharmaceutics 2020, 12(8), 695; https://doi.org/10.3390/pharmaceutics12080695 - 23 Jul 2020

Cited by 11 | Viewed by 2410

Abstract

Bacterial resistance has become an important public health problem. Bacteria have been acquiring mechanisms to resist the action of antimicrobial active pharmaceutical ingredients (API). Based on this, a promising alternative is the use of nanotechnology, since when the systems are presented in nanometric [...] Read more.

Bacterial resistance has become an important public health problem. Bacteria have been acquiring mechanisms to resist the action of antimicrobial active pharmaceutical ingredients (API). Based on this, a promising alternative is the use of nanotechnology, since when the systems are presented in nanometric size, there is an increase in the interaction and concentration of the action at the target site improving the activity. Thus, this study aims to develop a polymeric nanoparticle (PN) composed of chitosan and hydroxypropylmethylcellulose, as an innovative strategy for the administration of an association between ceftriaxone and extract of S. brasiliensis, for the treatment of Enterobacteriaceae. From a Box–Behnken design, nanoparticles were obtained and evaluated using the DLS technique, obtaining the particle size between 440 and 1660 nm, IPD from 0.42 to 0.92, and positive charges. Morphological characteristics of PN by SEM revealed spherical morphology and sizes similar to DLS. Infrared spectroscopy showed no chemical interaction between the components of the formulation. The broth microdilution technique evaluated their antimicrobial activity, and a considerable improvement in the activity of the extract and the API compared to the free compounds was found, reaching an improvement of 133 times in the minimum inhibitory activity CRO. Full article

(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)

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36 pages, 7905 KiB

Open AccessArticle

“Smart” Antimicrobial Nanocomplexes with Potential to Decrease Surgical Site Infections (SSI)

by Zehra Edis, Samir Haj Bloukh, May Reda Ibrahim and Hamed Abu Sara

Pharmaceutics 2020, 12(4), 361; https://doi.org/10.3390/pharmaceutics12040361 - 15 Apr 2020

Cited by 35 | Viewed by 3916

Abstract

The emergence of resistant pathogens is a burden on mankind and threatens the existence of our species. Natural and plant-derived antimicrobial agents need to be developed in the race against antibiotic resistance. Nanotechnology is a promising approach with a variety of products. Biosynthesized [...] Read more.

The emergence of resistant pathogens is a burden on mankind and threatens the existence of our species. Natural and plant-derived antimicrobial agents need to be developed in the race against antibiotic resistance. Nanotechnology is a promising approach with a variety of products. Biosynthesized silver nanoparticles (AgNP) have good antimicrobial activity. We prepared AgNPs with trans-cinnamic acid (TCA) and povidone–iodine (PI) with increased antimicrobial activity. We synthesized also AgNPs with natural cinnamon bark extract (Cinn) in combination with PI and coated biodegradable Polyglycolic Acid (PGA) sutures with the new materials separately. These compounds (TCA-AgNP, TCA-AgNP-PI, Cinn-AgNP, and Cinn-AgNP-PI) and their dip-coated PGA sutures were tested against 10 reference strains of microorganisms and five antibiotics by zone inhibition with disc- and agar-well-diffusion methods. The new compounds TCA-AgNP-PI and Cinn-AgNP-PI are broad spectrum microbicidal agents and therefore potential coating materials for sutures to prevent Surgical Site Infections (SSI). TCA-AgNP-PI inhibits the studied pathogens stronger than Cinn-AgNP-PI in-vitro and on coated sutures. Dynamic light scattering (DLS), ultraviolet-visible spectroscopy (UV-Vis), Fourier Transform infrared spectroscopy (FT-IR), Raman, X-ray diffraction (XRD), microstructural analysis by scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS) confirmed the composition of TCA-AgNP-PI and Cinn-AgNP-PI. Smart solutions involving hybrid materials based on synergistic antimicrobial action have promising future perspectives to combat resistant microorganisms. Full article

(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)

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27 pages, 8711 KiB

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Electrospun Antimicrobial Drug Delivery Systems and Hydrogels Used for Wound Dressings

by Zahra Moazzami Goudarzi, Angelika Zaszczyńska, Tomasz Kowalczyk and Paweł Sajkiewicz

Pharmaceutics 2024, 16(1), 93; https://doi.org/10.3390/pharmaceutics16010093 - 10 Jan 2024

Viewed by 1315

Abstract

Wounds and chronic wounds can be caused by bacterial infections and lead to discomfort in patients. To solve this problem, scientists are working to create modern wound dressings with antibacterial additives, mainly because traditional materials cannot meet the general requirements for complex wounds [...] Read more.

Wounds and chronic wounds can be caused by bacterial infections and lead to discomfort in patients. To solve this problem, scientists are working to create modern wound dressings with antibacterial additives, mainly because traditional materials cannot meet the general requirements for complex wounds and cannot promote wound healing. This demand is met by material engineering, through which we can create electrospun wound dressings. Electrospun wound dressings, as well as those based on hydrogels with incorporated antibacterial compounds, can meet these requirements. This manuscript reviews recent materials used as wound dressings, discussing their formation, application, and functionalization. The focus is on presenting dressings based on electrospun materials and hydrogels. In contrast, recent advancements in wound care have highlighted the potential of thermoresponsive hydrogels as dynamic and antibacterial wound dressings. These hydrogels contain adaptable polymers that offer targeted drug delivery and show promise in managing various wound types while addressing bacterial infections. In this way, the article is intended to serve as a compendium of knowledge for researchers, medical practitioners, and biomaterials engineers, providing up-to-date information on the state of the art, possibilities of innovative solutions, and potential challenges in the area of materials used in dressings. Full article

(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)

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22 pages, 1207 KiB

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Topical Probiotics: More Than a Skin Deep

by Mohammed Habeebuddin, Ranjith Kumar Karnati, Predeepkumar Narayanappa Shiroorkar, Sreeharsha Nagaraja, Syed Mohammed Basheeruddin Asdaq, Md. Khalid Anwer and Santosh Fattepur

Pharmaceutics 2022, 14(3), 557; https://doi.org/10.3390/pharmaceutics14030557 - 03 Mar 2022

Cited by 36 | Viewed by 13128

Abstract

Skin, an exterior interface of the human body is home to commensal microbiota and also acts a physical barrier that protects from invasion of foreign pathogenic microorganisms. In recent years, interest has significantly expanded beyond the gut microbiome to include the skin microbiome [...] Read more.

Skin, an exterior interface of the human body is home to commensal microbiota and also acts a physical barrier that protects from invasion of foreign pathogenic microorganisms. In recent years, interest has significantly expanded beyond the gut microbiome to include the skin microbiome and its influence in managing several skin disorders. Probiotics play a major role in maintaining human health and disease prevention. Topical probiotics have demonstrated beneficial effects for the treatment of certain inflammatory skin diseases such as acne, rosacea, psoriasis etc., and also found to have a promising role in wound healing. In this review, we discuss recent insights into applications of topical probiotics and their influence on health and diseases of the skin. Patents, commercially available topical probiotics, and novel probiotic impregnated fabrics have been emphasized. A thorough understanding of the relationship between probiotics and the skin microbiome is important for designing novel therapeutic approaches in using topical probiotics. Full article

(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)

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23 pages, 2876 KiB

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Antibacterial Layer-by-Layer Coatings for Medical Implants

by Ane Escobar, Nicolas Muzzio and Sergio Enrique Moya

Pharmaceutics 2021, 13(1), 16; https://doi.org/10.3390/pharmaceutics13010016 - 24 Dec 2020

Cited by 52 | Viewed by 6158

Abstract

The widespread occurrence of nosocomial infections and the emergence of new bacterial strands calls for the development of antibacterial coatings with localized antibacterial action that are capable of facing the challenges posed by increasing bacterial resistance to antibiotics. The Layer-by-Layer (LbL) technique, based [...] Read more.

The widespread occurrence of nosocomial infections and the emergence of new bacterial strands calls for the development of antibacterial coatings with localized antibacterial action that are capable of facing the challenges posed by increasing bacterial resistance to antibiotics. The Layer-by-Layer (LbL) technique, based on the alternating assembly of oppositely charged polyelectrolytes, can be applied for the non-covalent modification of multiple substrates, including medical implants. Polyelectrolyte multilayers fabricated by the LbL technique have been extensively researched for the development of antibacterial coatings as they can be loaded with antibiotics, antibacterial peptides, nanoparticles with bactericide action, in addition to being capable of restricting adhesion of bacteria to surfaces. In this review, the different approaches that apply LbL for antibacterial coatings, emphasizing those that can be applied for implant modification are presented. Full article

(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)

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22 pages, 2259 KiB

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Electrospinning Proteins for Wound Healing Purposes: Opportunities and Challenges

by Alma Akhmetova and Andrea Heinz

Pharmaceutics 2021, 13(1), 4; https://doi.org/10.3390/pharmaceutics13010004 - 22 Dec 2020

Cited by 66 | Viewed by 7323

Abstract

With the growth of the aging population worldwide, chronic wounds represent an increasing burden to healthcare systems. Wound healing is complex and not only affected by the patient’s physiological conditions, but also by bacterial infections and inflammation, which delay wound closure and re-epithelialization. [...] Read more.

With the growth of the aging population worldwide, chronic wounds represent an increasing burden to healthcare systems. Wound healing is complex and not only affected by the patient’s physiological conditions, but also by bacterial infections and inflammation, which delay wound closure and re-epithelialization. In recent years, there has been a growing interest for electrospun polymeric wound dressings with fiber diameters in the nano- and micrometer range. Such wound dressings display a number of properties, which support and accelerate wound healing. For instance, they provide physical and mechanical protection, exhibit a high surface area, allow gas exchange, are cytocompatible and biodegradable, resemble the structure of the native extracellular matrix, and deliver antibacterial agents locally into the wound. This review paper gives an overview on cytocompatible and biodegradable fibrous wound dressings obtained by electrospinning proteins and peptides of animal and plant origin in recent years. Focus is placed on the requirements for the fabrication of such drug delivery systems by electrospinning as well as their wound healing properties and therapeutic potential. Moreover, the incorporation of antimicrobial agents into the fibers or their attachment onto the fiber surface as well as their antimicrobial activity are discussed. Full article

(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)

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21 pages, 4475 KiB

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Clinical Efficacy of Single Application Local Drug Delivery and Adjunctive Agents in Nonsurgical Periodontal Therapy: A Systematic Review and Network Meta-Analysis

by Oi Leng Tan, Syarida Hasnur Safii and Masfueh Razali

Pharmaceutics 2020, 12(11), 1086; https://doi.org/10.3390/pharmaceutics12111086 - 12 Nov 2020

Cited by 9 | Viewed by 2615

Abstract

This review aimed to rank the clinical efficacy of commercially available single-application local drug delivery and adjunctive agents (LDAs) compared with subgingival mechanical debridement (SMD) in nonsurgical periodontal therapy (NSPT). Randomized controlled clinical trials that compared LDAs against SMD alone or with placebo [...] Read more.

This review aimed to rank the clinical efficacy of commercially available single-application local drug delivery and adjunctive agents (LDAs) compared with subgingival mechanical debridement (SMD) in nonsurgical periodontal therapy (NSPT). Randomized controlled clinical trials that compared LDAs against SMD alone or with placebo in adults (aged at least 18 years) diagnosed with periodontitis with a minimum of 6 months follow-up were included. A frequentist approach to random-effects network meta-analysis was implemented. The efficacies of the LDAs measured by probing pocket depth (PPD) reduction and clinical attachment level (CAL) gain were reported as mean difference (MD) with 95% confidence intervals (CIs). The treatments were ranked according to their P-score. Four network meta-analyses suggested that sulfonic/sulfuric acid gel (PPD MD −1.13 mm, 95% CI −1.74 to −0.53, P-score 0.91; CAL MD −1.09 mm, 95% CI −1.58 to −0.61, P-score 0.95) and doxycycline hyclate gel (PPD MD −0.90 mm, 95% CI −1.50 to −0.30, P-score 0.93; CAL MD −0.84 mm, 95% CI −1.40 to −0.28, P-score 0.92) were the most effective in reducing PPD and gaining CAL in split-mouth and parallel studies, respectively (moderate certainty of evidence). LDAs have differing efficacies, but they present with possible clinical significance over SMD alone in NSPT. Full article

(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)

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19 pages, 5957 KiB

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Bactericidal Antibacterial Mechanism of Plant Synthesized Silver, Gold and Bimetallic Nanoparticles

by Olufunto T. Fanoro and Oluwatobi S. Oluwafemi

Pharmaceutics 2020, 12(11), 1044; https://doi.org/10.3390/pharmaceutics12111044 - 30 Oct 2020

Cited by 34 | Viewed by 4315

Abstract

As the field of nanomedicine develops and tackles the recent surge in antibiotic resistance, there is a need to have an in-depth understanding and a synergistic view of research on the effectiveness of a metal nanoparticle (NP) as an antibacterial agent especially their [...] Read more.

As the field of nanomedicine develops and tackles the recent surge in antibiotic resistance, there is a need to have an in-depth understanding and a synergistic view of research on the effectiveness of a metal nanoparticle (NP) as an antibacterial agent especially their mechanisms of action. The constant development of bacterial resistance has led scientists to develop novel antibiotic agents. Silver, gold and its bimetallic combination are one of the most promising metal NPs because they show strong antibacterial activity. In this review we discuss the mode of synthesis and the proposed mechanism of biocidal antibacterial activity of metal NPs. These mechanisms include DNA degradation, protein oxidation, generation of reactive oxygen species, lipid peroxidation, ATP depletion, damage of biomolecules and membrane interaction. Full article

(This article belongs to the Special Issue Local Antibacterial and Antimicrobial Drug Delivery Systems)

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