Dendrimer-mediated permeation enhancement of chlorhexidine digluconate: Determination of in vitro skin permeability and visualisation of dermal distribution.

Chlorhexidine digluconate (CHG) is a cationic bisbiguanide used in the UK as the first-line skin antiseptic prior to surgery in the UK due to its favourable efficacy and safety profile, high affinity for skin binding and minimal reports of resistance. Despite this, bacteria remain within deeper skin layers, furrows and appendages that are considered inaccessible to CHG, due to its poor dermal penetration. In this study a third generation, polyamidoamine dendrimer (G3 PAMAM-NH2) was utilised to improve dermal penetration of CHG. A topical gel formulation was optimised to maximise CHG delivery (containing 0.5% gelling agent and 4% drug), followed by drug and dendrimer co-formulation into a commercially viable gel. The gel containing 4% CHG and 1 mM PAMAM dendrimer significantly increased the depth permeation of CHG compared to the commercial benchmark (Hibiscrub®, containing 4% w/v CHG) (p < 0.05). The optimised formulation was further characterised using Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS), which indicated that the depth of dermal penetration achieved was sufficient to reach the skin strata that typically harbours pathogenic bacteria, which is currently inaccessible by commercial CHG formulations. This study therefore indicates that a G3 PAMAM-NH2 dendrimer gel may be viable as a permeation enhancer of CHG, for improved skin antisepsis in those at risk of a skin or soft tissue infection as a result of surgical intervention.

Biomarkers for the toxicity of sublethal concentrations of triclosan to the early life stages of carps.

Accumulation, contents of protein, non-enzymatic antioxidant glutathione (GSH and GSSG), lipid peroxidation product (melondialdehyde-MDA) and organic acids (fumarate, succinate, malate and citrate), and activities of neurological (acetylcholinesterase-AChE), detoxification (glutathione S-transferase-GST) and metabolic (lactate dehydrogenase-LDH, aspartate transaminase-AST and alanine transaminase-ALT) enzymes were recorded in the hatchlings of Cyprinus carpio, Ctenopharyngodon idella, Labeo rohita and Cirrhinus mrigala after 7 and 14 days exposure and 10 days post exposure (recovery period) to sublethal concentrations (0.005, 0.01, 0.02 and 0.05 mg/L) of triclosan, a highly toxic and persistent biocide used in personal care products. Accumulation was maximum between 7-14 days at 0.01 mg/L for C. carpio and L. rohita but at 0.005 mg/L for C. idella and C. mrigala. No triclosan was observed at 0.005 mg/L in C. carpio and C. mrigala after recovery. Significant decline in protein, glutathione and acetylcholinesterase but increase in glutathione S-transferase, lactate dehydrogenase, aspartate transaminase, alanine transaminase, melondialdehyde and organic acids over control during exposure continued till the end of recovery period. Integrated biomarker response (IBR) analysis depicted higher star plot area for glutathione and glutathione S-transferase during initial 7 days of exposure, thereafter, during 7-14 days of exposure and the recovery period, higher star plot area was observed for acetylcholinesterase, aspartate transaminase, alanine transaminase and organic acids. Higher star plot area was observed for protein in all the species throughout the study. The study shows that L. rohita is most sensitive and glutathione, acetylcholinesterase, aspartate transaminase and alanine transaminase are the biomarkers for the toxicity of sublethal concentrations of TCS.

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.

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.

Sensitivity Analysis of a Pharmacokinetic Model of Vaginal Anti-HIV Microbicide Drug Delivery.

Uncertainties in parameter values in microbicide pharmacokinetics (PK) models confound the models' use in understanding the determinants of drug delivery and in designing and interpreting dosing and sampling in PK studies. A global sensitivity analysis (Sobol' indices) was performed for a compartmental model of the pharmacokinetics of gel delivery of tenofovir to the vaginal mucosa. The model's parameter space was explored to quantify model output sensitivities to parameters characterizing properties for the gel-drug product (volume, drug transport, initial loading) and host environment (thicknesses of the mucosal epithelium and stroma and the role of ambient vaginal fluid in diluting gel). Greatest sensitivities overall were to the initial drug concentration in gel, gel-epithelium partition coefficient for drug, and rate constant for gel dilution by vaginal fluid. Sensitivities for 3 PK measures of drug concentration values were somewhat different than those for the kinetic PK measure. Sensitivities in the stromal compartment (where tenofovir acts against host cells) and a simulated biopsy also depended on thicknesses of epithelium and stroma. This methodology and results here contribute an approach to help interpret uncertainties in measures of vaginal microbicide gel properties and their host environment. In turn, this will inform rational gel design and optimization.

Minimal effective dose of povidone-iodine in abdominal surgery Our clinical experience.

UNLABELLED: The aim of this study is to evaluate the thyroid function tests in order to examine whether 10 % of Povidone-Iodine(PI), the medication we applied in 1/5 ratio diluted with 0.9 %NaCl, joins the systemic circulation during clean contaminated, contaminated and dirty operations for solid organ hydatid cysts in abdominal area to avoid abscess formation and spreading. 7 men and 6 women were included to the present study, prospectively. The mean age was 33.69(± 13.49). TSH, free T3 (fT3) and free T4 (fT4) hormone levels were measured before the operation and at the third day of postoperative period. Amount of used povidone-iodine for patients was recorded. As a result of statistical analysis applied, the preoperative and post operative values were not significantly different regarding with the measured hormone levels (preTSH vs postTSH: p= 0.984; prefT3 vs postfT3: p= 0.101; prefT4 vs postfT4: p=0.146). Thus, it has been shown that the dose we used is effective, and it does not enters at all or at quite low levels into the systemic circulation. Patients whom this application performed, abscess and intestinal adhesions have not been observed in our clinical experience. We recommend the use of suggested doses of Povidone-Iodine in the presence of intraabdominal perforation and abscess or in cases such as carrying a risk of cyst spreading to intraabdominal area in hydatid cysts. KEY WORDS: Povidone-iodine, Surgical adhesions, Surgical wound infections, Thyroid function tests.

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.

In vitro CPC retention and VSC adsorption by IPM oil droplets: possible mechanisms of action of a two phase mouthwash.

Two phase oil-water mouthwash has been previously shown to efficiently bind oral microorganisms, relying on their cell surface hydrophobicity. The aim of the present in vitro study was to test the cetylpyridinium chloride (CPC) retention and volatile sulfide compounds (VSCs) adsorption abilities of the oil droplets created by mixing of a two phase oil-water solution. VSC adsorption was assayed using a salivary incubation assay and garlic powder solutions, and demonstrated using microscopic sulfide assay. CPC retention was assayed by kinetic and endpoint measurement of Streptococcus salivarius outgrowth using microplate (ELISA) reader. Results showed that the isopropyl myristate (IPM) oil droplets in the two phase solutions were able to adsorb 68-80% of VSCs. CPC at a concentration of 0.05% was most affectively retained by the oil droplets showing a significantly increase in residual antibacterial activity against Streptococcus salivarius. These results taken together, suggests that VSC adsorption and CPC retention by IPM oil droplets may be two additional mechanisms in the activity of the two phase mouthwash formulation.

Cytotoxicity of rigid gas-permeable lens care solutions.

PURPOSE: Reports on cytotoxic effects of rigid gas-permeable lens multipurpose solutions, which remain important because of increasing popularity of orthokeratology, are limited. This study determined cytotoxic effects of rigid gas-permeable lens multipurpose solutions on human corneal epithelial cells and assessed the proliferation rate at different levels of cell membrane damage. METHODS: The human corneal epithelial cells were exposed to multipurpose solutions containing chlorhexidine gluconate (0.003%) and polyaminopropyl biguanide (PHMB) (0.0005%) (MPS-A), PHMB (0.0005%) (MPS-B) and PHMB (0.0001%) (MPS-C) for one, five and 10 minutes. Following staining with Annexin V-FITC/7-AAD, cell viability and membrane integrity were assessed by flow cytometry. Effects of exposure to concentrations of 10 to 40 per cent multipurpose solutions for 12 hours on the metabolic rate of human corneal epithelial cells were assessed by 3-(4-,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell proliferation assay. Recovery rates were assessed after re-culture for 96 hours at 37°C. RESULTS: MPS-A exposure caused the highest percentage of early and late necrotic cells for all exposure times and was significantly higher than other multipurpose solutions (p < 0.0001). After 10 minutes exposure, almost 40 per cent of cells in MPS-A but less than five per cent in MPS-B or MPS-C, were in late necrotic stage. After 12 hours of exposure, cell activity was significantly reduced in a dose-response manner for MPS-A treated cells only (p > 0.05). After 96 hours of re-culture, all exposed cells showed some reduction in viability but the effects of exposure to 30 and 40 per cent MPS-A resulted in loss of viability. CONCLUSION: The presence of chlorhexidine appeared to increase cytotoxicity of multipurpose solutions for rigid gas-permeable lenses. This was apparent in both increased levels of necrotic cells on initial exposure and reductions in viability after prolonged exposures at lower dilutions. Multipurpose solutions containing PHMB as a preservative, while not causing acute cytotoxicity, did affect cell viability following exposure to diluted solutions. This indicated it is inadvisable to expose the cornea to multipurpose solutions but rather to rinse lenses with saline before insertion and use artificial tears for rewetting.

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.

Local antimicrobial administration for prophylaxis of surgical site infections.

Despite a lack of consensus guidelines, local antibiotic administration for prophylaxis of surgical site infections is used during many surgical procedures. The rationale behind this practice is to provide high antibiotic concentrations at the site of surgery while minimizing systemic exposure and adverse effects. Local antibiotic administration for surgical site prophylaxis has inherent limitations in that antibiotics are applied after the incision is made, rather than the current standard for surgical site prophylaxis that recommends providing adequate antibiotic concentrations at the site before the incision. The efficacy and safety of local application of antibiotics for surgical site prophylaxis have been assessed in different types of surgery with a variety of antibiotic agents and methods of application. We identified 22 prospective, randomized, controlled trials that evaluated local application of antibiotics for surgical site prophylaxis. These trials were subsequently divided and analyzed based on the type of surgical procedure: dermatologic, orthopedic, abdominal, colorectal, and cardiothoracic. Methods of local application analyzed included irrigations, powders, ointments, pastes, beads, sponges, and fleeces. Overall, there is a significant lack of level I evidence supporting this practice for any of the surgical genres evaluated. In addition, the literature spans several decades, and changes in surgical procedures, systemic antibiotic prophylaxis, and microbial flora make conclusions difficult to determine. Based on available data, the efficacy of local antibiotic administration for the prophylaxis of surgical site infections remains uncertain, and recommendations supporting this practice for surgical site prophylaxis cannot be made.

Formulation, pharmacokinetics and pharmacodynamics of topical microbicides.

The development of safe topical microbicides that effectively prevent human immunodeficiency virus (HIV) infection is a major goal in curbing the human immunodeficiency virus pandemic. A number of past failures resulting from mucosal toxicity or lack of efficacy have informed the field. Products that caused toxicity to the female genital tract mucosa, and thereby increased the likelihood of HIV acquisition, included nonoxynol 9, cellulose sulfate, and C31 G vaginal gel Savvy. Topical products that were ineffective in preventing HIV infection include BufferGel, Carraguard, and PRO 2000. Antiretroviral drugs such as tenofovir and dapivirine formulated into microbicide products have shown promise, but there is much to learn about ideal product formulation and acceptability, and drug distribution and disposition (pharmacokinetics). Current formulations for water-soluble molecules include vaginally or rectally applied gels, vaginal rings, films and tablets. Dosing strategies (e.g. coitally dependent or independent) will be based on the pharmacokinetics of the active ingredient and the tolerance for less than perfect adherence.

Transdermal absorption of ethanol- and 1-propanol-containing hand disinfectants.

BACKGROUND AND AIMS: Ethanol- or 1-propanol-containing hand disinfectants are widely used as surgical hand antisepsis. The primary objective of this study was to investigate transdermal absorption of ethanol and 1-propanol from combination of 45% ethanol and 18% 1-propanol with skin protecting ingredients (Softa-Man®) within 1 h after application in comparison to the absorption of these alcohols from the product in the absence of the cosmetic additives. The secondary objective was to evaluate the dermal tolerability. MATERIALS AND METHODS: Following the double-blind, randomized cross-over design for this clinical trial, 20 ml of two different alcohol-containing disinfectants was applied with a 200-cm(2) gauze swab on a skin area, identical in size and location, of 14 healthy volunteers for 10 min to investigate the absorption rate of ethanol and 1-propanol. Local dermal tolerability was evaluated using a four-point erythema scale. RESULTS: No clinically relevant dermal absorption, with respect to ethanol and 1-propanol, could be observed within 1 h after application. Disinfectant-related mild local skin erythema was observed in three cases. CONCLUSION: The use of the tested formulations containing ethanol and 1-propanol can be considered as safe. The tested formulation containing skin protecting additives (Softa-Man®) does not result in more alcoholic absorption than the formulation without protective additives.

Conservative management of exomphalos major with silver dressings: are they safe?

Historically, some dressings used in exomphalos major were associated with toxicity. These have been abandoned in favor of safer dressings. Silver toxicity has not been described following the use of silver dressings in infants. We, however, found disconcerting serum silver levels in 2 consecutive patients during treatment with silver salt containing dressings.

Clinical evaluation of microbicide formulations.

The clinical evaluation of microbicide formulations presents variable and interacting challenges. Specific domains of acceptability, pharmacokinetics, and toxicity interact with each other to potentially inhibit or enhance a microbicide's efficacy. Each of these is further influenced by application and use parameters in the relative presence (or absence) of vaginal and/or seminal fluids, ultimately impacting effectiveness. Historically, acceptability of formulation and use parameters, and their concomitant behavioral influences, have been considered separately from pharmacokinetics and toxicity. While independent evaluation of these elements is necessary in some respects, we must acknowledge that this approach is not sufficient for the successful development of microbicides. Each needs to be considered in an integrated clinical evaluation strategy. This article presents the rationale for such an approach. This article forms part of a special supplement covering two presentations on clinical evaluation of microbicides from the symposium on "Recent Trends in Microbicide Formulations" held on 25 and 26 January 2010, Arlington, VA.

Enhanced chlorhexidine skin penetration with eucalyptus oil.

BACKGROUND: Chlorhexidine digluconate (CHG) is a widely used skin antiseptic, however it poorly penetrates the skin, limiting its efficacy against microorganisms residing beneath the surface layers of skin. The aim of the current study was to improve the delivery of chlorhexidine digluconate (CHG) when used as a skin antiseptic. METHOD: Chlorhexidine was applied to the surface of donor skin and its penetration and retention under different conditions was evaluated. Skin penetration studies were performed on full-thickness donor human skin using a Franz diffusion cell system. Skin was exposed to 2% (w/v) CHG in various concentrations of eucalyptus oil (EO) and 70% (v/v) isopropyl alcohol (IPA). The concentration of CHG (µg/mg of skin) was determined to a skin depth of 1500 µm by high performance liquid chromatography (HPLC). RESULTS: The 2% (w/v) CHG penetration into the lower layers of skin was significantly enhanced in the presence of EO. Ten percent (v/v) EO in combination with 2% (w/v) CHG in 70% (v/v) IPA significantly increased the amount of CHG which penetrated into the skin within 2 min. CONCLUSION: The delivery of CHG into the epidermis and dermis can be enhanced by combination with EO, which in turn may improve biocide contact with additional microorganisms present in the skin, thereby enhancing antisepsis.

Characterization of a polyurethane-based controlled release system for local delivery of chlorhexidine diacetate.

Conventional formulations of chlorhexidine usually provide short-term efficiency, requiring repeated applications to maintain antibacterial activity. Therefore, appropriate release system of chlorhexidine controlling local drug delivery would reduce the number of applications and enhance patient compliance. The aim of this study was to develop a controlled release system based on medical polyurethane for the local delivery of chlorhexidine diacetate (CDA). CDA-loaded polyurethane films (CDA-Films) and CDA-loaded polyurethane sandwiches (CDA-Sandwiches) were obtained by casting and solvent evaporation. The physico-chemical aspects of CDA-loaded polyurethane systems were investigated, and the crystalline state of CDA in the polymeric system was highlighted. CDA-Films exhibited appropriate mechanical properties for further applications. Drug release was measured in two different media: (i) distilled water and (ii) physiological saline solution to mimic in vivo conditions. Drug release studies were performed up to 11days on CDA-Films and 29days for CDA-Sandwiches. Release of CDA depended on drug loading and the structure of the system. In particular, release of CDA from the sandwich system followed zero-order kinetic. The release rate was significantly lower in physiological solution. Antibacterial studies were carried out on CDA-Films against Staphylococcus aureus and Staphylococcus epidermidis showing 35days persisting antibacterial activity. In conclusion, the polyurethane-based system developed in this study is potentially useful as a local delivery system for CDA and could be used not only in surgery but also in dental and clinical applications.