"Smart" polymer enhances the efficacy of topical antimicrobial agents.

The delivery of antimicrobial agents to surface wounds has been shown to be of central importance to the wound healing process. In this work, we prepared film forming wound care formulations containing 3 polymers (FTP) that provide broad-spectrum antimicrobial protection for prolonged periods. FTP formulations comprises of a smart gel matrix comprising of pH-degradable and temperature responsive polyacetals (smart polymer) which allow for the FTP films to be hydrophobic at room temperature, preventing accidental rubbing off, and hydrophilic at lower temperatures, allowing for easy removal. Two FTP smart-antimicrobial films were evaluated in this work: FTP-AgSD (Silver sulfadiazine actives), and FTP-NP (Neosporin actives). The in vitro and ex vivo antimicrobial efficacy studies show that FTP-AgSD films are significantly more effective for longer durations against Staphylococcus aureus (3 days), Candida albicans (9 days) and Pseudomonas aeruginosa (4 days) when compared to the cream formulations containing antimicrobials. FTP-NP films showed significantly improved antimicrobial activity for a minimum of 3 days for all pathogens tested. Moreover, when tested ex vivo in porcine skin, FTP-AgSD and FTP-NP showed average improvements of 0.89 log10 and 1.66 log10 respectively over standard cream counterparts. Dermal toxicity studies were carried out in a rat skin excision model which showed a similar wound healing pattern to that in rats treated with standard cream formulations as represented by reduction in wound size, and increase in wound healing markers.

Evaluation of an alcohol-based surgical hand disinfectant containing a synergistic combination of farnesol and benzethonium chloride for immediate and persistent activity against resident hand flora of volunteers and with a novel in vitro pig skin model.

OBJECTIVE: To evaluate the immediate, persistent and sustained in vivo activity of an alcohol-based surgical hand disinfectant, consisting of a zinc gel and a preservative system containing a synergistic combination of farnesol and benzethonium chloride (ZBF disinfectant), and to develop a pig skin model for in vitro evaluation of the immediate and persistent efficacy of alcohol-based surgical hand disinfectants against resident hand flora. DESIGN: The in vivo immediate, persistent, and sustained activity of ZBF disinfectant was evaluated using human volunteers and the "glove-juice" method described in the US Food and Drug Administration's Tentative Final Monograph (FDA-TFM) for Healthcare Antiseptic Products. A novel in vitro pig skin model was developed to compare the immediate and persistent activity of alcohol-based surgical hand disinfectants against resident flora using Staphylococcus epidermidis as the test organism. Four alcohol-based surgical hand disinfectants were evaluated using this model. RESULTS: The results for the ZBF disinfectant exceed the FDA-TFM criteria for immediate, persistent, and sustained activity required for surgical hand disinfectants. The reduction factors for the 4 hand disinfectants obtained using the pig skin model show good agreement with the log(10) reductions in concentrations of hand flora obtained using human volunteers to test for immediate and persistent activity. CONCLUSION: The ZBF disinfectant we evaluated met the FDA-TFM criteria for surgical hand disinfectants. The immediate and persistent efficacy of the surgical hand disinfectants evaluated with the novel pig skin model described in this study shows good agreement with the results obtained in vivo.

Efficacy of an alcohol-based healthcare hand rub containing synergistic combination of farnesol and benzethonium chloride.

Healthcare workers are required to disinfect the hands several times a day using hand disinfectants, which leads to chronic hand exposure to high levels of antimicrobials contained in the disinfectants, which could compromise the skin integrity. This problem may be addressed by developing hand disinfectants containing synergistic combinations of small amounts of antimicrobials and other agents. The synergistic effect of farnesol and essential oils with several antimicrobials was studied in vitro to select an effective antimicrobial system in preservative concentration for use in healthcare hand rub. Farnesol and lemon oil showed synergistic activity against S. aureus, in combination with benzalkonium chloride and benzethonium chloride, but not with other antimicrobials studied. All essential oils studied showed synergy with benzethonium chloride against Staphylococcus aureus and Escherichia coli. An alcohol-based healthcare hand rub (ZBF hand rub) containing this unique synergistic combination of farnesol and benzethonium chloride was then developed and its efficacy as a healthcare hand rub was evaluated in human volunteers according to the US FDA-TFM protocol using Serratia marcescens as a marker organism. The ZBF hand rub showed a 3.22 log(10) reduction in the microbial count after the first application and a 5.49 log(10) reduction after the tenth application in vivo and exceeds the US FDA-TFM criteria for healthcare hand rub. The ZBF hand rub did not irritate the hands when tested on human volunteers when applied 10 times everyday for five consecutive days. The ZBF hand rub exhibits more than 5.5 log(10) reduction in the microbial count within 15s and more than 2.8 log(10) reduction in the two types of viruses tested within 30s in vitro. When evaluated in an in vitro pig skin model, the ZBF hand rub shows better prolonged activity (20-35 min post-application) against transient bacteria (S. aureus and E. coli) compared to other alcohol-based hand rubs. These findings suggest that the use of the ZBF hand rub amongst health care workers may lower the risk of chronic hand exposure to high levels of antimicrobials without compromising the efficacy.

Evaluation of the antimicrobial efficacy of urinary catheters impregnated with antiseptics in an in vitro urinary tract model.

OBJECTIVES: To evaluate the long-term efficacy of urinary Foley catheters (latex and silicone) impregnated with (1) chlorhexidine and silver sulfadiazine (CXS) and (2) chlorhexidine, silver sulfadiazine, and triclosan (CXST) in inhibiting extra-luminal bacterial adherence and to compare their efficacy with that of silver hydrogel latex (SH) and nitrofurazone-treated silicone (NF) catheters. DESIGN: The antimicrobial spectrum of these catheters was evaluated using a zone of inhibition assay. A novel in vitro urinary tract model was developed to study the potential in vivo efficacy of antimicrobial catheters in preventing extraluminal bacterial colonization. The "meatus" was inoculated daily with Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Enterococcus faecalis, Pseudomonas aerginosa, and Candida albicans. The "bladder" portion of the model was cultured daily to determine bacterial growth. RESULTS: Both CXS and CXST catheters had a broader antimicrobial spectrum than SH and NF catheters. In the in vitro model, CXST latex and silicone catheters exhibited significantly better efficacy (3 to 25days) against uropathogens, compared with CXS (1 to 14 days) and control (0 to 5 days) catheters (P = .01). CXST latex catheters exhibited significantly longer protection against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, and Pseudomonas aeruginosa, compared with SH catheters (P = .01). CXST silicone catheters resisted colonization with Staphylococcus aureus and Staphylococcus epidermidis for a significantly longer period (23 to 24 days) than did NF catheters (9 to 11 days) (P = .01). CONCLUSION: Catheters impregnated with synergistic combinations of chlorhexidine, silver sulfadiazine, and triclosan exhibited broad-spectrum, long-term resistance against microbial colonization on their outer surfaces.

The use of angiogenic-antimicrobial agents in experimental wounds in animals: problems and solutions.

A topical combination (silvathymosin) of natural proangiogeneic protein thymosin ß4 (Tß4) and antimicrobial silver sulfadiazine was hypothesized to promote the healing of large, full-thickness, clean or infected wounds in rats. Silvathymosin showed the fastest wound healing (85%) followed by silver sulfadiazine (84%) and Tß4 (72%). In the infected groups, the healing pattern was different, as Tß4 and silvathymosin groups did not show similar wound healing. Wound histopathology and VEGF and KI67 immunohistochemical assessment of angiogenesis was consistent and correlated well with the tempo of healing of the acute wounds. These preliminary data demonstrate the more rapid acute wound healing properties of the combination formulation of thymosin ß4 and silver sulfadiazine as compared to these agents alone. This novel agent could prove an effective treatment modality for debilitating chronic wounds and decubitus ulcers.

Rapid antibacterial activity of 2 novel hand soaps: evaluation of the risk of development of bacterial resistance to the antibacterial agents.

OBJECTIVE: To evaluate the antimicrobial efficacy of and risk of organisms developing resistance to 2 novel hand soaps: (1) a soap containing triclosan, polyhexamethylene biguanide, and benzethonium chloride added to a soap base (TPB soap); and (2) a soap containing farnesol, polyhexamethylene biguanide, and benzethonium chloride added to a soap base (FPB soap). Tests also included soaps containing only triclosan. DESIGN: The risk of emergence of resistant bacterial mutants was investigated by determining the susceptibility changes after repeated exposure of bacteria to the drugs and soaps in vitro. The effectiveness of the soaps was evaluated using an in vitro tube dilution method, a volunteer method (the ASTM standard), and 2 pig skin methods. RESULTS: The minimum inhibitory concentration and minimum bactericidal concentration of triclosan against Staphylococcus aureus increased 8- to 62.5-fold, whereas those of TPB and FPB (both alone and in soap) were unchanged. In vitro, TPB and FPB soaps produced higher log(10) reductions in colony-forming units of all tested organisms (4.95-8.58) than did soaps containing triclosan alone (0.29-4.86). In the test using the pig skin and volunteer methods, TPB soap produced a higher log(10) reduction in colony-forming units (3.1-3.3) than did the soap containing triclosan alone (2.6-2.8). CONCLUSION: The results indicate that TPB and FPB soaps may provide superior rapid and broad-spectrum efficacy with a lower risk of organisms developing resistance than do soaps containing triclosan alone. Pig skin methods may be used to predict the efficacy of antibacterial soaps in the rapid disinfection of contaminated hands. Hand washing with TPB and FPB soaps by healthcare workers and the general population may reduce the transmission of pathogens, with a lower risk of promoting the emergence of resistant organisms.

Comparison of microbial adherence to antiseptic and antibiotic central venous catheters using a novel agar subcutaneous infection model.

An agar subcutaneous infection model (agar model), which simulates the rat subcutaneous infection model (rat model), was developed to assess the ability of antimicrobial catheters to resist microbial colonization. The catheters were implanted in the agar and rat models and the insertion sites were infected immediately or on day 7, 14 or 21 post-implantation. The catheters implanted in the agar model were transferred to fresh media one day before infection on day 7, 14 or 21. The efficacy of chlorhexidine and silver sulfadiazine impregnated (CS) catheters, CS catheters with higher levels of chlorhexidine (CS+ catheters), minocycline-rifampicin (MR) catheters and silver catheters against Staphylococcus aureus and rifampicin-resistant Staphylococcus epidermidis RIF-r2 was compared in the agar and rat models. No significant difference in the adherence or the drug release was found between the in vitro and in vivo models. In both models, CS+ and MR catheters were effective against S. aureus even when infected on day 14, whereas CS catheters were colonized when challenged on day 7. CS+ catheters were effective against S. epidermidis RIF-r2, whereas MR catheters showed adherence when infected on day 7. CS+ catheters prevented colonization of all the organisms including, Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Candida albicans in the agar model, whereas MR catheters were effective only against S. aureus and S. epidermidis strains. Silver catheters were ineffective against all the organisms. The agar model may be used to predict the in vivo efficacy of antimicrobial catheters against various pathogens.