Evidence-Based Review of Antibiofilm Agents for Wound Care.

Significance: Biofilms in vivo are small densely packed aggregations of microbes that are highly resistant to host immune responses and treatment. They attach to each other and to nearby surfaces. Biofilms are difficult to study and identify in a clinical setting as their quantification necessitates the use of advanced microscopy techniques such as confocal laser scanning microscopy. Nonetheless, it is likely that biofilms contribute to the pathophysiology of chronic skin wounds. Reducing, removing, or preventing biofilms is thus a logical approach to help clinicians heal chronic wounds. Recent Advances: Wound care products have demonstrated varying degrees of efficacy in destroying biofilms in in vitro and preclinical models, as well as in some clinical studies. Critical Issues: Controlled studies exploring the beneficial role of biofilm eradication and its relationship to healing in patients with chronic wounds are limited. This review aims to discuss the mode of action and clinical significance of currently available antibiofilm products, including surfactants, dressings, and others, with a focus on levels of evidence for efficacy in disrupting biofilms and ability to improve wound healing outcomes. Future Directions: Few available products have good evidence to support antibiofilm activity and wound healing benefits. Novel therapeutic strategies are on the horizon. More high-quality clinical studies are needed. The development of noninvasive techniques to quantify biofilms will facilitate increased ease of research about biofilms in wounds and how to combat them.

Hyperosmotic Agents and Antibiotics Affect Dissolved Oxygen and pH Concentration Gradients in Staphylococcus aureus Biofilms.

Biofilms on wound surfaces are treated topically with hyperosmotic agents, such as medical-grade honey and cadexomer iodine; in some cases, these treatments are combined with antibiotics. Tissue repair requires oxygen, and a low pH is conducive to oxygen release from red blood cells and epithelialization. We investigated the variation of dissolved oxygen concentration and pH with biofilm depth and the variation in oxygen consumption rates when biofilms are challenged with medical-grade honey or cadexomer iodine combined with vancomycin or ciprofloxacin. Dissolved oxygen and pH depth profiles in Staphylococcus aureus biofilms were measured using microelectrodes. The presence of cadexomer iodine with vancomycin or ciprofloxacin on the surface of the biofilm permitted a measurable concentration of oxygen at greater biofilm depths (101.6 ± 27.3 µm, P = 0.02; and 155.5 ± 27.9 µm, P = 0.016, respectively) than in untreated controls (30.1 µm). Decreases in pH of ∼0.6 and ∼0.4 units were observed in biofilms challenged with medical-grade honey alone and combined with ciprofloxacin, respectively (P < 0.001 and 0.01, respectively); the number of bacteria recovered from biofilms was significantly reduced (1.26 log) by treatment with cadexomer iodine and ciprofloxacin (P = 0.002) compared to the untreated control. Combining cadexomer iodine and ciprofloxacin improved dissolved oxygen concentration and penetration depth into the biofilm, while medical-grade honey was associated with a lower pH; not all treatments established a bactericidal effect in the time frame used in the experiments.IMPORTANCE Reports about using hyperosmotic agents and antibiotics against wound biofilms focus mostly on killing bacteria, but the results of these treatments should additionally be considered in the context of how they affect physiologically important parameters, such as oxygen concentration and pH. We confirmed that the combination of a hyperosmotic agent and an antibiotic results in greater dissolved oxygen and reduced pH within an S. aureus biofilm.

Antibiotics and antiseptics for pressure ulcers.

BACKGROUND: Pressure ulcers, also known as bedsores, decubitus ulcers and pressure injuries, are localised areas of injury to the skin or the underlying tissue, or both. A range of treatments with antimicrobial properties, including impregnated dressings, are widely used in the treatment of pressure ulcers. A clear and current overview is required to facilitate decision making regarding use of antiseptic or antibiotic therapies in the treatment of pressure ulcers. This review is one of a suite of Cochrane reviews investigating the use of antiseptics and antibiotics in different types of wounds. It also forms part of a suite of reviews investigating the use of different types of dressings and topical treatments in the treatment of pressure ulcers. OBJECTIVES: To assess the effects of systemic and topical antibiotics, and topical antiseptics on the healing of infected and uninfected pressure ulcers being treated in any clinical setting. SEARCH METHODS: In October 2015 we searched: the Cochrane Wounds Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), Ovid MEDLINE, Ovid MEDLINE (In-Process & Other Non-Indexed Citations), Ovid EMBASE, and EBSCO CINAHL Plus. We also searched three clinical trials registries and the references of included studies and relevant systematic reviews. There were no restrictions based on language or date of publication or study setting. SELECTION CRITERIA: Randomised controlled trials which enrolled adults with pressure ulcers of stage II or above were included in the review. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, risk of bias assessment and data extraction. MAIN RESULTS: We included 12 trials (576 participants); 11 had two arms and one had three arms. All assessed topical agents, none looked at systemic antibiotics. The included trials assessed the following antimicrobial agents: povidone iodine, cadexomer iodine, gentian violet, lysozyme, silver dressings, honey, pine resin, polyhexanide, silver sulfadiazine, and nitrofurazone with ethoxy-diaminoacridine. Comparators included a range of other dressings and ointments without antimicrobial properties and alternative antimicrobials. Each comparison had only one trial, participant numbers were low and follow-up times short. The evidence varied from moderate to very low quality.Six trials reported the primary outcome of wound healing. All except one compared an antiseptic with a non-antimicrobial comparator. There was some moderate and low quality evidence that fewer ulcers may heal in the short term when treated with povidone iodine compared with non-antimicrobial alternatives (protease-modulating dressings (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.62 to 0.98) and hydrogel (RR 0.64, 95% CI 0.43 to 0.97)); and no clear difference between povidone iodine and a third non-antimicrobial treatment (hydrocolloid) (low quality evidence). Pine resin salve may heal more pressure ulcers than hydrocolloid (RR 2.83, 95% CI 1.14 to 7.05) (low quality evidence). There is no clear difference between cadexomer iodine and standard care, and between honey a combined antiseptic and antibiotic treatment (very low quality evidence).Six trials reported adverse events (primary safety outcome). Four reported no adverse events; there was very low quality evidence from one showing no clear evidence of a difference between cadexomer iodine and standard care; in one trial it was not clear whether data were appropriately reported.There was limited reporting of secondary outcomes. The five trials that reported change in wound size as a continuous outcome did not report any clear evidence favouring any particular antiseptic/anti-microbial treatments. For bacterial resistance, one trial found some evidence of more MRSA eradication in participants with ulcer treated with a polyhexanide dressing compared with a polyhexanide swab (RR 1.48, 95% CI 1.02 to 2.13); patients in the dressing group also reported less pain (MD -2.03, 95% CI -2.66 to -1.40). There was no clear evidence of a difference between interventions in infection resolution in three other comparisons. Evidence for secondary outcomes varied from moderate to very low quality; where no GRADE assessment was possible we identified substantial limitations which an assessment would have taken into account. AUTHORS' CONCLUSIONS: The relative effects of systemic and topical antimicrobial treatments on pressure ulcers are not clear. Where differences in wound healing were found, these sometimes favoured the comparator treatment without antimicrobial properties. The trials are small, clinically heterogenous, generally of short duration, and at high or unclear risk of bias. The quality of the evidence ranges from moderate to very low; evidence on all comparisons was subject to some limitations.

Extending the TIME concept: what have we learned in the past 10 years?(*).

The TIME acronym (tissue, infection/inflammation, moisture balance and edge of wound) was first developed more than 10 years ago, by an international group of wound healing experts, to provide a framework for a structured approach to wound bed preparation; a basis for optimising the management of open chronic wounds healing by secondary intention. However, it should be recognised that the TIME principles are only a part of the systematic and holistic evaluation of each patient at every wound assessment. This review, prepared by the International Wound Infection Institute, examines how new data and evidence generated in the intervening decade affects the original concepts of TIME, and how it is translated into current best practice. Four developments stand out: recognition of the importance of biofilms (and the need for a simple diagnostic), use of negative pressure wound therapy (NPWT), evolution of topical antiseptic therapy as dressings and for wound lavage (notably, silver and polyhexamethylene biguanide) and expanded insight of the role of molecular biological processes in chronic wounds (with emerging diagnostics and theranostics). Tissue: a major advance has been the recognition of the value of repetitive and maintenance debridement and wound cleansing, both in time-honoured and novel methods (notably using NPWT and hydrosurgery). Infection/inflammation: clinical recognition of infection (and non infective causes of persisting inflammation) is critical. The concept of a bacterial continuum through contamination, colonisation and infection is now widely accepted, together with the understanding of biofilm presence. There has been a return to topical antiseptics to control bioburden in wounds, emphasised by the awareness of increasing antibiotic resistance. Moisture: the relevance of excessive or insufficient wound exudate and its molecular components has led to the development and use of a wide range of dressings to regulate moisture balance, and to protect peri-wound skin, and optimise healing. Edge of wound: several treatment modalities are being investigated and introduced to improve epithelial advancement, which can be regarded as the clearest sign of wound healing. The TIME principle remains relevant 10 years on, with continuing important developments that incorporate new evidence for wound care.

Ameliorative effect of a microbial feed additive on infectious bronchitis virus antibody titer and stress index in broiler chicks fed deoxynivalenol.

Although acute mycotoxicoses are rare in poultry production, chronic exposure to low levels of mycotoxins is responsible for reduced productivity and increased susceptibility to infectious diseases. Deoxynivalenol (DON) is known to modulate immune function, but only a few studies have investigated the effect of DON on the vaccinal immune response. In addition, the effects of Mycofix select (Biomin GmbH, Herzogenburg, Austria) supplementation to DON-contaminated broiler diets have not yet been demonstrated. Therefore, an experiment with 1-d-old male broilers (Ross 308) was carried out to examine the effects of feeding DON-contaminated low-protein grower diets on performance, serum biochemical parameters, lymphoid organ weight, and antibody titers to infectious bronchitis vaccination in serum and to evaluate the effects of Mycofix select dietary supplementation in either the presence or absence of DON in broilers. In total, thirty-two 1-d-old broiler chicks were randomly assigned to 1 of the 4 dietary treatments for 5 wk. The dietary treatments were 1) control; 2) artificially contaminated diets with 10 mg of DON/kg of diet; 3) DON-contaminated diets supplemented with Mycofix select; and 4) control diet supplemented with Mycofix select. Feeding of contaminated diets decreased (P = 0.000) the feed intake, BW (P = 0.001), BW gain (P = 0.044), and feed efficiency during the grower phase. Deoxynivalenol affected the blood biochemistry, whereas plasma total protein and uric acid concentrations in birds fed contaminated grains were decreased compared with those of the controls. Moreover, in birds fed contaminated feeds, there was a tendency to reduce triglycerides in the plasma (P = 0.090), suggesting that DON in the diets affected protein and lipid metabolism in broiler chickens. The feeding of contaminated diets altered the immune response in broilers by reducing the total lymphocyte count. Similarly, the antibody response against infectious bronchitis vaccination antigens was decreased (P = 0.003) after feeding contaminated diets, compared with the controls. Moreover, contamination of the broiler diet with DON increased the heteropil:lymphocyte ratio (stress index), suggesting that DON elevated the physiological stress responses of broilers. However, feeding of DON-containing diets did not alter the other plasma constituents, including activities of enzymes. Mycofix select addition to the DON-contaminated feed led to normal immunological and physiological functions in broilers that were comparable with those of the control group, indicating that the addition of the additive to the DON-contaminated feed of the broilers effectively alleviated the alterations caused by DON. It was concluded that broiler performance and some blood and immunological parameters were adversely affected by feeding diets contaminated with the Fusarium mycotoxin DON. However, the dietary Mycofix select supplementation as a detoxifying agent was successful in overcoming the mycotoxin-related effects.

Evaluation of the efficacy of a feed additive to ameliorate the toxic effects of 4,15-diacetoxiscirpenol in growing chicks.

The possible protective effect of a feed additive (Mycofix) against the toxic effects of 4,15-diacetoxiscirpenol (DAS) in growing broiler chickens was investigated in a 21-d fully randomized trial consisting of seven dietary treatments (control with no DAS or Mycofix added, 1 ppm DAS alone, 1 ppm DAS supplemented with 0.75 g/kg Mycofix, 1 ppm DAS supplemented with 1.5 g/kg Mycofix, 2 ppm DAS alone, 2 ppm DAS supplemented with 0.75 g/kg Mycofix, and 2 ppm DAS supplemented with 1.5 g/kg Mycofix). When no feed additive was included, both levels of dietary DAS significantly decreased BW and feed intake and caused oral lesions, with the effect of 2 ppm DAS being more severe. When 1 ppm DAS was added to the diet, supplementation of Mycofix protected against the adverse effects of DAS on feed intake and BW at both levels of inclusion (0.75 and 1.5 g/kg); however, no protection against oral lesions was obtained by Mycofix supplementation. This finding suggests that the adverse effect of DAS on performance is not due to the oral lesions per se but it is likely the result of the systemic absorption of the mycotoxin. When 2 ppm dietary DAS was present in the diet, only partial protection on BW and feed intake was obtained by Mycofix supplementation. More studies are required to determine if a higher dose of Mycofix could be capable of counteracting the adverse effects of 2 ppm dietary DAS on chicken performance.

Antiseptic efficacy of disinfecting solutions in suspension test in vitro against methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli in pressure sore wounds after spinal cord injury.

In pressure sore wounds after spinal cord injury, methicillin-resistant Staphylococcus aureus can be detected in 2% of the cases. The elimination of the germ is the aim of the treatment. Pressure sore wounds are an often found complication after spinal cord injury. For local treatment five commercially available antiseptics for the skin and mucous membrane were tested in vitro. The method used is a modified qualitative and quantitative suspension test. The antiseptics were tested without and with addition of 5% albumin in order to simulate the conditions of the wound in vivo. The results show a superior efficacy of the povidone-iodine preparations. Betadine, probably due to the higher concentration, is more efficacious than Braunol; chlorhexidine is sufficiently efficacious without the addition of albumin. These results still have to be confirmed by in vivo studies.

New successful treatment with disinfectant for atopic dermatitis.

For the treatment of atopic dermatitis, a variety of therapies are used including folk medicine. At present, there is no single treatment which is effective to cure the symptoms of atopic dermatitis completely in all patients. We are drawing attention to the high isolation rate of Staphylococcus aureus when starting disinfectant treatment combined with topical steroid therapies for the purpose of killing S. aureus. As a result, we examined many patients in whom almost a complete remission was obtained even after short periods of therapy, though it had been difficult to obtain improvement by conventional treatments. In many patients, IgE values and reagin antibody titer decrease dramatically soon after starting treatment. As a disinfectant, 10% povidone-iodine solution was used. We investigated also the effect of iodine contained in the povidone-iodine solution on the thyroid gland.

[A comparison between "moist ointment" and 0.25% iodophor, silver sulfadiazine paste and 0.1% rivanol in the treatment of deep II degree burn wounds].

One hundred and fifteen patients suffering from deep II degree burn were randomly divided into four groups, and "Moist ointment," 0.25% iodophor, silver sulfadiazine paste and 0.1% rivanol were respectively used as topical agents. Their effects were observed and compared. The results showed that "Moist ointment" group was significantly inferior to other groups in respects of healing of wound surface, bacteriostatic property, cost of treatment and formation of hyperplastic scar. Therefore, we suggested that the use of moist ointment in the treatment of deep II degree burn wound should be prohibited.

[Fungicidal effect of iodophor preparations on dermatophyte arthrospores]. / Fungicydna aktywnosc preparatów jodoforowych na artrospory dermatofitów.

The purpose of the investigations was to determine antifungal activity of iodophores: Pollena-Jod K and Mycofix. In vitro studies 3 strains of Trichophyton mentagrophytes from Sabouraud liquid medium and arthrospores of this fungus in skin scrapings obtained from sick foxes were examined. The in vivo fungicidal effect of the iodophores was studied in foxes and in young bulls, where 5 and 10% solutions of the preparations were used three times. It was found that the exact inactivation of arthrospores is possible when 8-fold or even 10-fold higher concentrations of the preparations were used than that used for inactivation of vegetative cells. After 1 h exposition vegetative cells were destroyed by 0.4% solution of Pollena-Jod K or Mycofix, however, 5% solution of Pollena-Jod K and 3% solution of Mycofix destroyed arthrospores. In the field studies Mycofix revealed higher fungicidal effects. The index of isolation of the fungus from skin scrapings for animals treated with Mycofix was lower by 38% in comparison to that for animals treated with Pollena-Jod K. Despite three times application of 5% and 10% solutions of the examined iodophores on fungal foci in animals, a part of arthrospores survived. For the determination of fungicidal activity of antimycotic drugs used to prevent or control of dermatomycoses, arthrospores present in skin scrapings of sick animals may be used.