Povidone-iodine pharmacokinetics and study design.

Dr. Gnanasekaran et al. reported the bactericidal activity of various concentrations of povidone iodine (PI) solution in an agar plate experiment of respiratory flora. The study design and the pharmacokinetic properties of PI solution ensured that dilute PI would not be effective in this study. These results may not replicate the typical clinical situation and are significantly different than a previously reported agar plate experiment, again owing to subtle but very significant differences in methodology.

Peritoneal lavage with povidone-iodine solution in colorectal cancer-induced rats.

BACKGROUND: Although peritoneal lavage with povidone-iodine (PVPI) is frequently performed after surgery on the gastrointestinal tract, the effects of PVPI on the intestinal epithelial barrier are unknown. The purpose of this study was to investigate the effects of abdominal irrigation with PVPI on the intestinal epithelial barrier in a colorectal cancer (CRC)-induced rat model. MATERIALS AND METHODS: The CRC model was induced in rats with azoxymethane and dextran sodium sulfate. Next, a total of 24 male CRC-induced rats were randomly divided into three groups (n = 8): (1) a sham-operated group, (2) an NS group (peritoneal lavage 0.9% NaCl), and (3) a PVPI group (peritoneal lavage with 0.45%-0.55% PVPI). The mean arterial pressure was continuously monitored throughout the experiment. The levels of plasma endotoxin and D-lactate, blood gases, and protein concentration were measured. The ultrastructural changes of the epithelial tight junctions were observed by transmission electron microscopy. RESULTS: The mean arterial pressure after peritoneal lavage was lower in the PVPI group than that in the NS group. The protein concentration and levels of endotoxin and D-lactate were higher in the PVPI group than they were in the PVPI group. In addition, PVPI treatment resulted in a markedly severe metabolic acidosis and intestinal mucosal injury compared with NS rats. CONCLUSIONS: Peritoneal lavage with PVPI dramatically compromises the integrity of the intestinal mucosa barrier and causes endotoxin shock in CRC rats. It is unsafe for clinical applications to include peritoneal lavage with PVPI in colorectal operations.

Solid lipid nanoparticles for targeted delivery of triclosan into skin for infection prevention.

Healthcare-associated infections (HAIs) are a concern for health service providers, exacerbated by poor delivery of antimicrobials to target sites within the skin. The dermal route is attractive for local and systemic delivery of drugs, however; permeation, penetration, and access to deeper skin layers are restricted due to the barrier function of the stratum corneum (SC). Solid lipid nanoparticles present several benefits for topical delivery for therapeutic applications, especially via the follicular route. Hair follicles, surrounded by a close network of blood capillaries and dendritic cells, are an important target for delivery of antimicrobials and present a unique microbial nidus for endogenous infections in situations where the barrier is disrupted, such as after surgery, for example, triclosan, a broad-spectrum antimicrobial agent, was encapsulated into nanoparticles using glyceryl behenate and glyceryl palmitostearate (GP) solid lipids, and incorporating Transcutol P, a known permeation enhancer at different ratios. Optimised formulation was stable over 90 d and in vitro permeation studies using full thickness porcine ear skin showed that the lipid-based nanoparticles enhanced delivery of triclosan into the skin and could direct the agent towards hair follicles, indicating their potential as a carrier system for antiseptic dermal delivery.

Efflux Pumps Might Not Be the Major Drivers of QAC Resistance in Methicillin-Resistant Staphylococcus aureus.

Quaternary ammonium compounds (QACs) are commonly used antiseptics that are now known to be subject to bacterial resistance. The prevalence and mechanisms of such resistance, however, remain underexplored. We investigated a variety of QACs, including those with multicationic structures (multiQACs), and the resistance displayed by a variety of Staphylococcus aureus strains with and without genes encoding efflux pumps, the purported main driver of bacterial resistance in MRSA. Through minimum inhibitory concentration (MIC)-, kinetic-, and efflux-based assays, we found that neither the qacR/qacA system present in S. aureus nor another efflux pump system is the main reason for bacterial resistance to QACs. Our findings suggest that membrane composition could be the predominant driver that allows CA-MRSA to withstand the assault of conventional QAC antiseptics.

Intranasal Delivery of Topically-Acting Levofloxacin to Rats: a Proof-of-Concept Pharmacokinetic Study.

PURPOSE: To evaluate the potential of levofloxacin intranasal administration as a promising alternative approach to treat local infections such as chronic rhinosinusitis, by delivering drug concentrations directly to the site of infection. METHODS: Drug concentrations were measured in plasma, olfactory bulb and nasal mucosa of anterior (ANM) and posterior regions after intranasal (0.24 mg/kg) and intravenous (10 mg/kg) administration to rats, and pharmacokinetic parameters were compared between routes. For intranasal administration a thermoreversible in-situ gel was used. RESULTS: Plasma and olfactory bulb exposure to levofloxacin was minimal following intranasal dose, preventing systemic and central nervous system adverse effects. Levofloxacin concentration-time profile in ANM revealed higher concentrations during the first 60 min of the study following intranasal administration than the corresponding ones obtained after intravenous administration. A rapid and continuous decay of levofloxacin concentration in this nasal region was observed after intranasal delivery, resulting in much lower values at the last sampling time-points. CONCLUSION: The higher dose-normalized concentrations and pharmacokinetic exposure parameters of levofloxacin in ANM after intranasal administration, demonstrates that intranasal delivery of the formulated gel is, by itself, advantageous for delivering levofloxacin to biophase and thus an attractive approach in management of chronic rhinosinusitis.

Enhanced chlorhexidine skin penetration with 1,8-cineole.

BACKGROUND: Chlorhexidine (CHG) penetrates poorly into skin. The purpose of this study was to compare the depth of CHG skin permeation from solutions containing either 2% (w/v) CHG and 70% (v/v) isopropyl alcohol (IPA) or 2% (w/v) CHG, 70% (v/v) IPA and 2% (v/v) 1,8-cineole. METHODS: An ex-vivo study using Franz diffusion cells was carried out. Full thickness human skin was mounted onto the cells and a CHG solution, with or without 2% (v/v) 1,8-cineole was applied to the skin surface. After twenty-four hours the skin was sectioned horizontally in 100 µm slices to a depth of 2000 µm and the concentration of CHG in each section quantified using high performance liquid chromatography (HPLC). The data were analysed with repeated measures analysis of variance. RESULTS: The concentration of CHG in the skin on average was significantly higher (33.3% [95%, CI 1.5% - 74.9%]) when a CHG solution which contained 1,8-cineole was applied to the skin compared to a CHG solution which did not contain this terpene (P = 0.042). CONCLUSIONS: Enhanced delivery of CHG can be achieved in the presence of 1,8-cineole, which is the major component of eucalyptus oil. This may reduce the numbers of microorganisms located in the deeper layers of the skin which potentially could decrease the risk of surgical site infection.

Effect of chitosan coating on microemulsion for effective dermal clotrimazole delivery.

Clotrimazole (CTZ) is a broad spectrum antimycotic agent known to be very effective locally for the treatment of fungal skin infections. The aim of this study was to study the effect of chitosan-coated microemulsion (CME) for topical delivery of CTZ and also evaluate its in vitro antifungal efficacy, ex vivo permeation and retention ability on the skin surface. The pseudo-ternary phase diagrams were developed using clove oil as oil phase, Tween 80 and propylene glycol as surfactant and co-surfactant, respectively, and distilled water as aqueous phase. CME was prepared by the drop wise addition of chitosan solution to the optimized microemulsion. Physicochemical parameters (globule size, zeta potential, drug content, viscosity and pH) and in vitro release of CME were studied. The in vitro antifungal efficacy of CME and ME was studied by cup-plate method against Candida albicans. Ex vivo drug permeation study was also carried out in a modified diffusion cell, using rat skin. The developed CME displayed an average globule size less than 50 nm and a positive surface charge, acceptable physico-chemical behavior, and exhibited sustained drug release in in vitro study. In in vitro anti-fungal study, CME showed greater values of zone of inhibition as compared to ME due to its prolonged action as well as fungistatic nature of chitosan. In ex vivo study, CME showed better retention and sustained permeation property than ME due to the mucoadhesive property of chitosan. These results suggest that positively charged CMEs could be used as novel topical formulation for its ability to retain on the skin and its ability to sustain the release of the drug.

Mucoadhesive in situ gel formulation for vaginal delivery of clotrimazole: formulation, preparation, and in vitro/in vivo evaluation.

The purpose of this study was to develop a suitable mucoadhesive in situ gel formulation of clotrimazole (CLO) for the treatment of vaginal candidiasis. For this aim, the mixture of poloxamer (PLX) 407 and 188 were used to prepare in situ gels. Hydroxypropyl methylcellulose (HPMC) K100M or E50 was added to in situ gels in 0.5% ratio to improve the mucoadhesive and mechanical properties of formulations and to prolong the residence time in vaginal cavity. After the preparation of mucoadhesive in situ gels; gelation temperature/time, viscosity, mechanical, mucoadhesive, syringeability, spreadibility and rheological properties, in vitro release behavior, and anticandidal activities were determined. Moreover vaginal retention of mucoadhesive in situ gels was investigated with in vivo distribution studies in rats. Based on the obtained results, it was found that gels prepared with 20% PLX 407, 10% PLX 188 and 0.5% HPMC K100M/E50 might be suitable for vaginal administration of CLO. In addition, the results of in vivo distribution studies showed that gel formulations remained on the vaginal mucosa even 24 h after application. In conclusion, the mucoadhesive in situ gels of CLO would be alternative candidate for treatment of vaginal candidiasis since it has suitable gel properties with good vaginal retention.

The Compatibility of Chlorhexidine and a Skin Care Product Line: A Real-World Analysis of Hospital-Acquired Infection Rates.

Chlorhexidine gluconate (CHG) use helps reduce hospital-acquired infections (HAIs). Chlorhexidine gluconate effectiveness can be reduced by use of skin care products. Although laboratory work can be performed to prove compatibility, such work has limitations. The purpose of this study was to compare HAI rates when CHG antiseptic wipes were used in conjunction with a silicone- and micronutrient-based skin care product line (SMSP) and when CHG wipes were used without the SMSP. Using commercial distribution data, 17 hospitals that purchased both CHG wipes and SMSP were identified. Hospital-acquired infection rates from this group were compared with HAI rates from 18 hospitals that used CHG wipes, but not SMSP. Hospital-acquired infection information was obtained from the Leapfrog Group (www.hospitalsafetyscore.org/). Four infection rates were compared: (1) infection in the blood during an intensive care unit stay, (2) infection in the urinary tract during an intensive care unit stay, (3) surgical site infection after colon surgery, and (4) average infection rate from 1 to 3. There was no significant difference between the infection rates of the two groups (Ps ranged from .285 to .983). There was also no statistically significant association between hospital grade and product use (P = .194). When considering publicly available data on HAI, there was no measurable difference in HAI rates between facilities that use CHG wipes with or without an SMSP. The SMSP does not impact the efficacy of CHG wipes.

Ocular delivery systems for topical application of anti-infective agents.

For the treatment of anterior eye segment infections using anti-infective agents, topical ocular application is the most convenient route of administration. However, topical delivery of anti-infective agents is associated with a number of problems and challenges owing to the unique structure of the eye and the physicochemical properties of these compounds. Topical ocular drug delivery systems can be classified into two forms: conventional and non-conventional. The efficacy of conventional ocular formulations is limited by poor corneal retention and permeation resulting in low ocular bioavailability. Recently, attention has been focused on improving topical ocular delivery of anti-infective agents using advanced drug delivery systems. This review will focus on the challenges of efficient topical ocular delivery of anti-infective agents and will discuss the various types of delivery systems used to improve the treatment anterior segment infections.

Temocillin: a new candidate antibiotic for local antimicrobial delivery in orthopaedic surgery?

OBJECTIVES: To assess the performance of the Gram-negative-specific antibiotic temocillin in polymethylmethacrylate bone cement pre-loaded with gentamicin, as a strategy for local antibiotic delivery. METHODS: Temocillin was added at varying concentrations to commercial gentamicin-loaded bone cement. The elution of the antibiotic from cement samples over a 2 week period was quantified by LC-MS. The eluted temocillin was purified by fast protein liquid chromatography and the MICs for a number of antibiotic-resistant Escherichia coli were determined. The impact strength of antibiotic-loaded samples was determined using a Charpy-type impact testing apparatus. RESULTS: LC-MS data showed temocillin eluted to clinically significant concentrations within 1 h in this laboratory system and the eluted temocillin retained antimicrobial activity against all organisms tested. Impact strength analysis showed no significant difference between cement samples with or without temocillin. CONCLUSIONS: Temocillin can be added to bone cement and retains its antimicrobial activity after elution. The addition of up to 10% temocillin did not affect the impact strength of the cement. The results show that temocillin is a promising candidate for use in antibiotic-loaded bone cement.

Antimicrobial functionalization of bacterial nanocellulose by loading with polihexanide and povidone-iodine.

Bacterial nanocellulose (BNC) is chemically identical with plant cellulose but free of byproducts like lignin, pectin, and hemicelluloses, featuring a unique reticulate network of fine fibers. BNC sheets are mostly obtained by static cultivation. Now, a Horizontal Lift Reactor may provide a cost efficient method for mass production. This is of particular interest as BNC features several properties of an ideal wound dressing although it exhibits no bactericidal activity. Therefore, BNC was functionalized with the antiseptics povidone-iodine (PI) and polihexanide (PHMB). Drug loading and release, mechanical characteristics, biocompatibility, and antimicrobial efficacy were investigated. Antiseptics release was based on diffusion and swelling according to Ritger-Peppas equation. PI-loaded BNC demonstrated a delayed release compared to PHMB due to a high molar drug mass and structural changes induced by PI insertion into BNC that also increased the compressive strength of BNC samples. Biological assays demonstrated high biocompatibility of PI-loaded BNC in human keratinocytes but a distinctly lower antimicrobial activity against Staphylococcus aureus compared to PHMB-loaded BNC. Overall, BNC loaded with PHMB demonstrated a better therapeutic window. Moreover, compressive and tensile strength were not changed by incorporation of PHMB into BNC, and solidity during loading and release could be confirmed.

Design and construction of a silver(I)-loaded cellulose-based wound dressing: trackable and sustained release of silver for controlled therapeutic delivery to wound sites.

Although application of silver nitrate and silver sulfadiazine have been shown to be effective in thwarting infections at burn sites, optimization of the delivery of bioactive silver (Ag(+)) remains as an obstacle due to rapid precipitation and/or insolubility of the silver sources. To circumvent these shortcomings, we have designed a silver(I) complex [Ag(ImD)2]ClO4 (ImD = dansyl imidazole) that effectively increases the bioavailability of Ag(+) and exhibits MIC values of 2.3 and 4.7 µg/mL against E. coli and S. aureus, respectively. This fluorescent silver complex has been incorporated within a robust hydrogel derived from carboxymethyl cellulose that allows slow release of silver. A complete occlusive dressing has finally been constructed with the Ag(ImD)CMC (1% Ag loaded) pad sealed between a sterile mesh gauze (as bottom layer) and a rayon-based surgical tape (as the top layer). Such construction has afforded a dressing that displays sustained delivery of silver onto a skin and soft tissue infection model and causes effective eradication of bacterial loads within 24 h. The transfer of the bioactive silver complex is readily visualized by the observed fluorescence that overlays precisely with the kill zone. The latter feature introduces a unique feature of therapeutic trackability to this silver-donating occlusive dressing.

The biological fate of silver ions following the use of silver-containing wound care products - a review.

Ionic silver has a long history as an antimicrobial in human health care. This article is a review of the published literature on how ionic silver may enter the body from exposure to silver-containing wound care products and its eventual metabolic fates, in an assessment of the safety during normal use of these products in wound care. Following the application to breached skin, there appears to be little evidence of localised or systemic toxicity, and this is borne out by the continuous use of silver sulfadiazine formulations for more than 50 years. Consequently, following normal use, the risk of silver ion toxicity locally and systemically is considered to be low or negligible.

[The treatment of acute inflammation of the middle ear].

The authors propose the differential approach to the treatment of acute inflammation of otitis media and otitis externa taking into consideration etiology of the disease. Its clinical form and stage. Special attention is given to the method of local treatment including the use of various eardrops. The results of their comparative assessment are presented.

Phase 1 study of the iodine absorption, safety, and tolerability of a 0.5% povidone-iodine nasal spray (Nasodine).

KEY POINTS: PVP-I is a widely used antiseptic but only recently proposed for intranasal use. The extent of iodine absorption from available PVP-I nasal products is unknown. Iodine absorption from use of Nasodine (0.5% PVP-I nasal spray) is not clinically significant.

Distribution and visualisation of chlorhexidine within the skin using ToF-SIMS: a potential platform for the design of more efficacious skin antiseptic formulations.

PURPOSE: In order to increase the efficacy of a topically applied antimicrobial compound the permeation profile, localisation and mechanism of action within the skin must first be investigated. METHODS: Time-of-flight secondary ion mass spectrometry (ToF-SIMS) was used to visualise the distribution of a conventional antimicrobial compound, chlorhexidine digluconate, within porcine skin without the need for laborious preparation, radio-labels or fluorescent tags. RESULTS: High mass resolution and high spatial resolution mass spectra and chemical images were achieved when analysing chlorhexidine digluconate treated cryo-sectioned porcine skin sections by ToF-SIMS. The distribution of chlorhexidine digluconate was mapped throughout the skin sections and our studies indicate that the compound appears to be localised within the stratum corneum. In parallel, tape strips taken from chlorhexidine digluconate treated porcine skin were analysed by ToF-SIMS to support the distribution profile obtained from the skin sections. CONCLUSIONS: ToF-SIMS can act as a powerful complementary technique to map the distribution of topically applied compounds within the skin.

Systemic iodine absorption associated with the use of preoperative ophthalmic antiseptics containing iodine.

BACKGROUND: Polyvinylpyrrolidone-Iodine (PVP-I) is routinely used as preoperative antiseptic during ophthalmic surgery. Iodine absorption from iodine-containing antiseptics can lead to the development of thyroid disorders. Therefore, a quantitative measurement of iodine absorption from these antiseptics was performed in patients undergoing elective cataract surgery. METHODS: This study enrolled 241 patients to evaluate systemic iodine absorption after exposure to conjunctival and/or periorbital 1.25% and 10% PVP-I compared to an iodine-free antiseptic. RESULTS: All patients who received the 10% PVP-I regardless of the application site showed a 1.2-1.5-fold increase in urinary iodine excretion after 24 h (p = 0.01). In 17 out of 110 (15.5%) patients in whom 10% PVP-I was used, the critical threshold of urinary iodine excretion as defined by WHO (>300 µg/L) was exceeded. In contrast, no significant ioduria was observed with the use of 1.25% PVP-I except in patients after 48 h (p = 0.01) and with a concurrent conjunctival and periorbital application. The proportion of the excreted iodine in urine ranged from 0.24% to 1.77%. No correlation was found between the total applied concentration of iodine and the amount excreted in urine. CONCLUSION: Based on our findings, we believe that the use of 10% PVP-I as preoperative ophthalmic antiseptic should undergo further clinical evaluation in regard to its impact on thyroid function. Conjunctival or periorbital application of 1.25% PVP-I does not result in significant ioduria.

In vivo evaluation of a metronidazole-containing gel for the adjuvant treatment of chronic periodontitis: preliminary results.

The present study developed an experimental metronidazole-based gel and evaluated its efficacy for the adjuvant treatment of chronic periodontitis. Sixteen patients were randomly allocated into two groups of eight subjects according to the following proposed treatments: (1) scaling and root planing (active control) or (2) scaling and root planing and direct periodontal intrapocket application of 15% metronidazole-based gel in two sites (≥5 mm in depth) (experimental group). Potential changes in the subgingival microbiota were assessed using a DNA Checkerboard method at three proposed times: baseline and following 7 or 30 days of drug administration. High-performance liquid chromatography (HPLC) monitored metronidazole concentrations in the crevicular fluid during treatment. The metronidazole experimental group presented lower bacterial counts than the control group at the three evaluated times (p<0.01 for baseline, p<0.001 for 7 or 30 days) when the target species were analyzed as a pool of bacteria. Samples revealed significantly lower counts 7 days after drug administration compared with baseline or after 30 days (p<0.05). HPLC analysis detected gel 1 h after application. The metronidazole-based gel significantly decreased the total bacterial count at the three evaluated times. Periodontopathogenic species were not different after gel administration.

Metabolization of the bacteriostatic agent triclosan in edible plants and its consequences for plant uptake assessment.

Persistent environmental contaminants may enter agricultural fields via the application of sewage sludge, by irrigation with treated municipal wastewater or by manuring. It has been shown that such contaminants can be incorporated into crop plants. The metabolism of the bacteriostatic agents triclocarban, triclosan, and its transformation product methyl triclosan was investigated after their uptake into carrot cell cultures. A fast metabolization of triclosan was observed and eight so far unknown phase II metabolites, conjugates with saccharides, disaccharides, malonic acid, and sulfate, were identified by liquid chromatography-mass spectrometry. Triclocarban and methyl triclosan lack a phenolic group and remained unaltered in the cell cultures. Phase I metabolization was not observed for any of the compounds. All eight triclosan conjugates identified in the cell cultures were also detected in extracts of intact carrot plants cultivated on triclosan contaminated soils. Their total amount in the plants was assessed to exceed the amount of the triclosan itself by a factor of 5. This study shows that a disregard of conjugates in studies on plant uptake of environmental contaminants may severely underestimates the extent of uptake into plants and, eventually, the potential human exposure to contaminants via food of plant origin.