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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 log 10 and 1.66 log 10 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., (Copyright © 2019 Elsevier Ltd and ISBI. All rights reserved.)

A topical combination (silvathymosin) of natural proangiogeneic protein thymosin β4 (Tβ4) 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 Tβ4 (72%). In the infected groups, the healing pattern was different, as Tβ4 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 β4 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., (© 2012 New York Academy of Sciences.)

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.

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.

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.

Alcohol-based surgical hand disinfectants are widely available in healthcare settings. Some currently marketed alcohol-based products use active concentrations of antimicrobials to achieve the required efficacy, raising the risk for exposure to potentially irritating levels of antimicrobials. This study compares the in vitro and in vivo efficacy of an alcohol-based surgical hand preparation containing 70% ethanol and preservative levels of chlorhexidine gluconate (CHG) and benzalkonium chloride (BZK) in synergistic combination with ethylhexylglycerin (Surgicept) with a surgical hand disinfectant containing 61% ethanol and 1% CHG (Avagard). The in vivo efficacy of Surgicept and Avagard was evaluated in volunteers using the Tentative Final Monograph method of the Food and Drug Administration (FDA), and their prolonged effect against transient pathogens was compared using a pig skin model. Surgicept exceeded the FDA requirements for surgical hand antiseptic with mean log(10) reductions of 2.36, 3.3 and 3.54 in resident flora 1 min after initial application, and showed a persistent effect with mean log(10) reductions of 2.23, 2.73 and 3.3, 6h post application on days 1, 2 and 5, respectively. Surgicept showed a superior prolonged effect against transient bacteria compared with Avagard. Surgicept (70% alcohol and preservative levels of CHG and BZK) may provide similar in vivo efficacy as Avagard (61% ethanol and 1% CHG).

A new alcohol-based hand antiseptic (Octoxy hand rub) containing a synergistic combination of an emollient (Octoxyglycerine) and preservatives was developed and evaluated for immediate and prolonged activity against transient bacteria. The in vitro and in vivo antimicrobial efficacy was compared with other alcohol hand rubs containing preservative/antimicrobial (Prevacare and Avagard). In vitro evaluation was carried out using a tube-dilution method and a pig-skin model. Rapid and prolonged efficacy in vivo was evaluated against Staphylococcus epidermidis on the hands of volunteers. Octoxy hand rub was 100% effective in rapidly killing pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium in vitro. In volunteers, all three hand rubs gave a significant reduction in microbial count within 15s. Octoxy hand rub showed significantly higher efficacy against S. aureus and Escherichia coli than Avagard and Prevacare 15 min after application to the pig-skin model, and against S. epidermidis in both the pig-skin model and in volunteers. Use of Octoxy hand rub with broad-spectrum immediate and prolonged antimicrobial activity may be a very effective way of improving hand hygiene without exposing the hands to higher concentrations of antimicrobials.

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.

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.

Objective: To compare the efficacy of a new antiseptic catheter containing silver sulfadiazine and chlorhexidine on the external surface and chlorhexidine in the lumens to an antibiotic catheter impregnated with minocycline and rifampin on its external and luminal surfaces., Design: Experimental trial., Methods: Antimicrobial spectrum of catheters was determined by zones of inhibition. Resistance to luminal colonization was tested in vitro by locking catheter lumens with Staphylococcus epidermidis or Staphylococcus aureus culture after 7 days of perfusion. In vitro development of resistance to the antiseptic or antibiotic combination used in catheters was investigated. In vivo efficacy was tested (rat subcutaneous model) by challenge with sensitive or antibiotic-resistant bacteria., Results: Antiseptic and antibiotic catheters exhibited broad-spectrum action. However, antibiotic catheters were not effective against Candida species and Pseudomonas aeruginosa. Both catheters prevented luminal colonization. Compared to controls, both test catheters resisted colonization when challenged with S aureus 7 and 14 days' postimplant (P<.05). Repeated in vitro exposure of S epidermidis culture to the antibiotic and antiseptic combinations led to small increases in the minimum inhibitory concentration (15 times and 2 times, respectively). Unlike the antibiotic catheter, the in vitro and in vivo activity of the antiseptic catheter was unaffected by the resistance profile of the test organism. Antiseptic catheters were more effective than antibiotic catheters in preventing colonization by rifampin-resistant S epidermidis in vivo (P<.05)., Conclusions: Antiseptic and antibiotic catheters exhibit similar efficacy; however, when challenged with a rifampin-resistant strain, the antibiotic catheter appeared to be more susceptible to colonization than the antiseptic device.

The risk of development of resistance in Staphylococcus epidermidis to the antibiotics and antiseptics impregnated in central venous catheters was evaluated. The culture was passaged 10-20 times through subinhibitory concentrations of different antimicrobials, singly and in combination, and the MIC of each antimicrobial before and after passage was compared. There was a 10- to 16-fold increase in the MIC of the combination of minocycline and rifampicin, while no significant increase in the MIC of minocycline alone was seen. The MIC of rifampicin was 25,000-fold higher against strains passaged through rifampicin alone (as compared with that for the original strain), while the increase was only 80-fold when it was combined with minocycline for passage. There was no substantial change in susceptibility to the antiseptic chlorhexidine when used alone or in combination with either silver sulphadiazine or triclosan (the MIC of triclosan alone increased eight-fold). In time-kill studies, synergy was observed between chlorhexidine and both triclosan and silver sulphadiazine. Zone of inhibition tests of catheters impregnated with minocycline and rifampicin showed that their activity against rifampicin-resistant strains was lower than that against the susceptible strain. On the other hand, the activity of the antiseptic (chlorhexidine and silver sulphadiazine) catheters against the rifampicin-resistant and -susceptible strains was similar. Although this study indicates that antibiotic catheters may be at a higher risk of being colonized by antibiotic-resistant bacteria, the implications of these results in clinical settings need to be determined.

Background: Infection remains the single most important challenge to extended left ventricular assist device (LVAD) use and often arises from the percutaneous driveline exit site. We evaluated the ability of an LVAD driveline prototype impregnated with chlorhexidine, triclosan, and silver sulfadiazine to resist bacterial and fungal colonization., Methods: The spectrum and duration of antimicrobial activity were evaluated in vitro by daily transfer of driveline segments embedded on agar plates inoculated with 10(8) colony-forming units (CFU) of Staphylococcus aureus (S. aureus), Staphlococcus epidermidis, Enterobacter aerogenes, Psuedomonas aeruginosa, and Candida albicans, and then measuring zones of inhibition around the sample subsequent to 24 hours of incubation at 37 degrees C. Antimicrobial activity was demonstrated against all organisms for greater than 14 days, and for over 21 days for gram-positive bacteria. To demonstrate in vivo efficacy of the treated driveline, 3-cm segments of driveline were implanted in the dorsal and ventral surface of rats. The exit site was inoculated with 10(6) CFU of S. aureus. After 7 days, driveline segments were aseptically explanted and assayed for bacterial colonization and retention of antimicrobial activity. One hundred percent of control segments were colonized (10(5) CFU S. aureus/cm) as against 13% of the test explants (< or = 330 CFU/cm; p < 0.0001)., Results: Subcultures of the insertion site and driveline pocket tissue resulted in 10(3) to 10(5) CFU per swab culture for control rats and 0 to 10(2) CFU/swab for test animals. Test drivelines retained 80% of anti-S. aureus activity. Gross and histological examination of the driveline and surrounding pocket revealed minimal tissue reactivity with positive signs of tissue ingrowth., Conclusion: An antimicrobial driveline may prevent early infections and facilitate ingrowth of tissue to provide long-term stability and protection against late infection.

It has been suggested that the invasion of microbes into the catheter tract occurs mainly at the time of catheter insertion. To investigate whether the presence of an antimicrobial environment during the initial period after insertion is sufficient to reduce the risk of subsequent catheter colonization and infection, we evaluated the use of benzalkonium chloride-heparin bonded (BZK-hep) central venous catheters, which exhibit short-lived surface antimicrobial activity, using a rat subcutaneous model. Bacterial adherence on these catheters was determined, seven days after challenging the insertion site with 10(6) cfu of Staphylococcus aureus. A chlorhexidine-silver sulphadiazine impregnated catheter (Arrowg+ard), with longer lasting surface antimicrobial activity, and a hydrophilic coated catheter ('Hydrocath'), were evaluated simultaneously for comparison. Unlike Arrowg+ard antiseptic catheters, BZK-hep 'Hydrocath' and control catheters had significant bacterial adherence on their surface. Arrowg+ard catheters were colonized in 19% of the animals compared with 100% in all the other groups (P < 0.05; mean cfu cm-2: control = 1.3 x 10(6), BZK-hep = 4.3 x 10(5), Hydrocath = 2 x 10(5), Arrowg+ard = 71). Our results indicate that catheters with short-lived surface antimicrobial activity are unlikely to provide long-term protection against catheter-related infection. The efficacy of Arrowg+ard catheters may be due to the initial high rate of kill and prolonged antimicrobial activity.

A procedure for the bonding of antibacterial agents directly to prosthetic vascular grafts has been developed. This method does not involve the use of carriers or surfactants which may cause local toxicity or thrombogenesis. Using this procedure, antibiotics can be bonded to the graft alone or in combination with a metal, such as silver. Incorporation of silver along with the antibiotic enhances the antibacterial activity and prolongs retention of the antibiotics in the prosthetic grafts. Silver mediated bonding appears to release the antibiotic biphasically. In the initial phase (40 to 50 per cent), the drug is rapidly released and, in the second phase, the rest is diffused gradually enabling the graft to retain antibacterial activity for a longer period of time.

Zinc sulfadiazine is a new compound which is effective in vitro and in vivo against Pseudomonas aeruginosa infections in burned mice and rats. It contains an important body constituent, zinc, and appears to expedite wound healing, diminish weight loss after infected burns and improve food intake. Like silver sulfadiazine, it prevents the postburn changes in plasma proteins. After topical application, the uptake of the radioactively labeled zinc is significant in the zone of injury and negligible in organs and body fluids. The binding to deoxyribonucleic acid by zinc is similar to, but less than, that by silver. The data indicate that zinc sulfadiazine may be a valuable addition to the therapeutic armamentarium for the control of burn wound sepsis.

The role of silver and sulfadiazine in the mechanism of action of silver sulfadiazine on burn wound infections was investigated. Silver, but not sulfadiazine, was bound by bacteria. Sulfadiazine did not act as an antibacterial agent in low concentrations, but exhibited specific synergism in combination with subinhibitory levels of silver sulfadiazine. The efficacy of silver sulfadiazine is thought to result from its slow and steady reactions with serum and other sodium chloride-containing body fluids, which permits the slow and sustained delivery of silver ions into the wound environs. In this circumstance, a relatively minute amount of sulfadiazine appears active.

Norfloxacin is a new synthetic antibiotic with a broad spectrum of activity against gram-positive and gram-negative bacteria, and is more effective than the aminoglycosides against P aeruginosa. In this study norfloxacin was particularly effective in treatment of P aeruginosa infection of the rabbit cornea, and caused no toxicity in normal rabbit eyes after prolonged administration. The addition of silver to norfloxacin enhances its antipseudomonal activity, and broadens its spectrum to include antifungal activity. In this study, silver norfloxacin appears to be the most effective antibiotic against P aeruginosa corneal ulcer in the rabbit. Because of its broad antibacterial spectrum, silver norfloxacin may be useful in the initial treatment of bacterial corneal ulcer before the identity of the bacteria is known. Because of its low toxicity in topical administration, and its antifungal and antibacterial activity, silver norfloxacin may be helpful in prophylaxis against infection in chronic corneal ulcers.

The superior efficacy of quinolones (norfloxacin, pefloxacin, and enoxacin) in controlling burn wound infections signals the discovery of new topical agents. However, there are a few reports on the emergence of resistant mutants to quinolones. Since attempts to develop AgSD resistant strains in vitro were unsuccessful and the emergence of AgSD resistance in vivo is a rare occurrence, we decided to investigate if the combined use of AgSD with other effective antibiotics, especially quinolones, would minimize the development of resistant bacteria. Our in vitro results indicate that when Ps. aeruginosa cultures were serially transferred 10 times through subinhibitory concentrations of norfloxacin, pefloxacin, etc., the MIC increased 40 times while when the cultures were passed through a combination of AgSD and these quinolones, the MIC of quinolones increased only tenfold. In vivo, when burned mice infected with either AgSD sensitive or resistant Ps. aeruginosa strains were treated with a topical cream containing 10mM silver sulfadiazine and 5mM norfloxacin or 5mM pefloxacin, the mortality was much lower than that of 10mM silver sulfadiazine alone or 5mM quinolones alone. Thus, combined use of silver sulfadiazine and quinolones appears to diminish the ability of Ps. aeruginosa strains to form resistant mutants. Furthermore, when the combination is used as a topical agent in burn wounds, lesser amounts of the individual drug are needed to control infection thereby reducing the toxic effects, if any, associated with these drugs. This combination does not in any way interfere with the antifungal or antibacterial properties of these individual drugs.

Sulfadiazine silver-resistant strains of Pseudomonas aeruginosa isolated from burned patients from several countries are sensitive to sulfadiazine silver in vitro, but in burned mice and rats resist topical therapy with sulfadiazine silver. In searching for an effective topical agent against these resistant organisms, we found that FPQC (1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7[1-piperazinyl]-quinoline-carboxylic acid) and its silver salt are effective both in vitro and in vivo. In vitro, their minimal inhibitory concentrations are ten to 20 times lower than that of sulfadiazine silver. In burned mice infected with resistant Pseudomonas strains, mortality in groups receiving topical therapy with FPQC or FPQC silver is 0%, but 80% to 100% with sulfadiazine silver and 100% without treatment. Similar results were obtained in burned rats. The efficacy of FPQC and FPQC silver in vivo may represent discovery of new agents of known low toxicity that are useful in topical burn therapy.