The downside of antimicrobial agents for wound healing.

Background Burn injuries are an important health problem. They occur frequently in the head and neck region - the area central to a person's identity, that provides our most expressive means of communication. Topical interventions are currently the cornerstone of treatment of partial-thickness burns to the face. Objectives To assess the effects of topical interventions on wound healing in people with facial burns of any depth. Search methods We searched the Cochrane Wounds Group Specialised Register (searched 12 November 2012); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 10); Ovid MEDLINE (1950 to November Week 1 2012); Ovid MEDLINE - In-process & Other Non-Indexed Citations (searched November 12, 2012); Ovid EMBASE (1980 to 2012 Week 45); and EBSCO CINAHL (1982 to 9 November 2012) for relevant trials. We did not apply date or language restrictions. Selection criteria Randomised controlled trials (RCTs) that evaluated the effects of topical treatment for facial burns were eligible for inclusion in this review. Data collection and analysis Two review authors independently assessed and included the references identified by the search strategy. Included trials were assessed using a risk of bias form, and data were extracted using a standardised data extraction sheet. For dichotomous and continuous outcomes, we calculated risk ratios and mean differences, respectively, both with 95% confidence intervals (CI). Main results We included five RCTs, comprising a total of 119 participants. Two studies compared two different antimicrobial agents and three compared a biological or bioengineered skin substitute with an antimicrobial agent. All studies had small sample sizes and were at high risk of bias. Heterogeneity of interventions and outcomes prevented pooling of data. In three studies time to complete wound healing was significantly shorter for those using a skin substitute than for those using an antibacterial agent, but the quality of the evidence was low. Pain was significantly reduced with the use of skin substitutes in both studies that reported this outcome in all groups, range mean differences -2.00 (95% CI -3.82 to -0.18) to -4.00 (95% CI -5.05 to -2.95) on a 10-point scale. Authors' conclusions There is insufficient high quality research and evidence to enable conclusions to be drawn about the effects of topical interventions on wound healing in people with facial burns.

Silver sulfadiazine (SSD), a topical antimicrobial agent, has been widely used for the prophylaxis and treatment of burn infections during the past 30 years. We determined the antimicrobial activity of SSD, alone and in combination with cerium nitrate (CN), gentamicin and amikacin against 130 recent clinical isolates, including multiresistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa. The overall activity of SSD was good against all the tested strains and it was particularly high against MRSA (MIC90 100 μg/ml). CN showed no inhibitory effect, even up to 800 μg/ml, on bacterial strains tested. The combination of SSD and CN was as active as SSD alone. In conclusion, SSD has a broad spectrum of activity at concentrations lower than those commonly used in clinical preparations. All strains were inhibited by less then one-fiftieth of the SSD “in use” concentration (10 mg/ml). Our data confirm the efficacy of this topical agent in the prevention and treatment of infections in burns or other surgical wounds and suggest its possible use in clearing staphylococcal carriage as an alternative to mupirocin.

The emergence of bacterial strains resistant to topical antimicrobials in both human and veterinary medicine has raised concerns over retaining the efficacy of these preparations. Yet, little information is available regarding the use of topical antimicrobials in either sector for planning targeted interventions. This study aims to quantify the use of topical antimicrobials in 44 Dutch companion animal clinics before and during their participation in an antimicrobial stewardship programme (ASP), to explore the effect of the intervention on topical antimicrobial use (AMU). Hence, prescription and clinic animal population data, collected from July 2012 until June 2018 were used. Specifically, the period from July 2012 until June 2015 was defined as pre-intervention period, whereas clinics started to participate in the ASP from March 2016 onwards. As quantification metric, the Defined Daily Dose for Animals (DDDA) was used and a mixed effect times series model with auto-regression was applied to monthly topical AMU data. The intervention effect was modelled using a step function with a change in (linear) time trend and clinic characteristics, as potential determinants of topical AMU, were assessed using a multivariable regression model. A seasonal pattern was identified, in the pre-intervention period, where topical AMU was highest in July-August and lowest in February-March. In addition, total topical AMU appeared to significantly decrease over time in the pre-intervention period and the proportion of dogs in the clinic was positively associated with topical AMU. The intervention effect was significant only for second line and for skin product AMU. This study demonstrates that during participation in an ASP, second line and skin product AMU decreased in Dutch companion animal clinics. Additionally, this study demonstrates the existence of a seasonal effect and a decrease in topical AMU over time already before introduction of a targeted intervention.

Topical antimicrobials may complement traditional infection control measures and hasten the control of an outbreak. When a suitable nonabsorbable antimicrobial regimen can be found, its use during outbreaks caused by Enterobacteriaceae colonizing the digestive tract appears especially attractive, whether the infection occurs via primary endogenous colonization or exogenous colonization. In the latter circumstance, however, topical antimicrobials are not a substitute for isolation precautions and careful handwashing, which remain insufficiently adhered to in ICUs. Topical antimicrobials should be used as part of a global strategy in which isolation precautions remain of primary importance. It is likely, but unproven by well-designed studies, that nasal decontamination of patient carriers during outbreaks due to methicillin-resistant Staphylococcus aureus can be useful to control the outbreak. In this instance, however, skin and wound disinfection appears as an essential complementary measure, and careful attention should be given to extranasal sites of colonization with MRSA, where resistance to the topical agent can emerge. Whatever the circumstances and setting, prolonged use of topical antimicrobials during protracted outbreaks is less effective and carries a major risk of resistance to the topical agent(s) used against the outbreak strains. In such circumstances, careful microbiologic monitoring of colonization is mandatory.

One percent silver sulfadiazine has been commonly used as a topical antimicrobial agent after a burn injury. Incidence of burn wound colonization by Staphylococcus aureus in patients treated with silver sulfadiazine has spurred research for other agents. A topical preparation that contains zinc and sulfadiazine (Zad-G) was evaluated for in vitro antibacterial spectrum and in vivo efficacy. Muscle biopsy specimens of rats treated with Zad-G appear to have fewer colonies of S. aureus than groups treated with silver sulfadiazine. Topical therapy with Zad-G for patients with burns was comfortable, reduced wound infection, and was comparable to therapy with silver sulfadiazine. A topical Zad-G preparation that contains zinc sulfadiazine appears to be an effective alternative to silver sulfadiazine in the treatment of burn wounds.

IntroductionSilver sulfadiazine cream 1% is a sulfa derivative topical antimicrobial commonly used in burn care, in part due to its wide spectrum of activity, particularly against Pseudomonas aeruginosa. Contact dermatitis due to sulfadiazine component is a known but rare complication of silver sulfadiazine. In contrast, systemic sulfonamide antimicrobials are a commonly reported allergy and have been implicated in multiple hypersensitivity reactions. Some authors recommend avoidance of all sulfonamide antimicrobials regardless of route of administration for a patient with a known allergy to a sulfonamide antimicrobial due to structural similarities between all drugs in the class, resulting in a high risk of cross-reactivity. Clinical reports are lacking, however, and the few reports that do exist implicate silver as the culprit rather than the sulfadiazine component. Therefore, while the theoretical risk of reactivity to a topical application of sulfadiazine exists, there is no data to support this in practice.MethodsA retrospective review of 42 patients with a sulfa allergy who were admitted to the burn unit of an academic medical center between June 2016 and June 2021 were reviewed. Inclusion criteria were age > 18, burn requiring admission, sulfa allergy, and receiving topical sulfa antimicrobial therapy. Data on the reported allergen, reaction, and any adverse reaction from the use of topical sulfa agents were recorded.ResultsForty-two patients were identified. Of these, 32 (76%) reported a non-specific “sulfa” allergy, while 10 (24%) reported a specific allergy to trimethoprim-sulfamethoxazole. The reactions were reported as unknown (20, 48%), rash (9, 21%), hives (6, 14%), gastrointestinal (4, 9%), or other (3, 7%). One patient had a history of respiratory distress with trimethoprim-sulfamethoxazole administration. All 42 patients received treatment with topical silver sulfadiazine and 10 also were treated with topical mafenide acetate solution. There were no reported adverse events and no patients discontinued therapy. Two patients were identified with no previous sulfa allergy but who discontinued topical silver sulfadiazine due to burning sensation, a rare but previously reported side effect of this medication.ConclusionsSilver sulfadiazine remains one of the most commonly used topical antimicrobials in burn care due to its broad spectrum of activity, low cost, and ease of use. Adverse reactions to topical silver sulfadiazine and mafenide acetate are rare, even in those with reported sulfa allergies. Topical sulfa anti-microbials can likely be used safely in most patients with allergies to systemic sulfa antibiotics, and the rate of cross-reactivity appears to be low. A test patch is recommended prior to application over a large area.

Topical antiseptics in wound care: time for reflection

Topical antimicrobial agents for treating foot ulcers in people with diabetes.

Acetic acid solution is effective in healing of chronic wounds by its ability to eradicate biofilms. One percent silver sulfadiazine (SSD) cream is the commonly used topical antimicrobial agent in burn wound care. In our study, we compared the efficacy and safety of 1% acetic acid gel with 1% SSD in partial-thickness burn wound with <20% total body surface area. Context: Bacterial colonization of burn wounds results in delayed wound healing. SSD is commonly used as a topical antibiotic in the second degree and third-degree burn wounds. The acetic acid solution is found to be clinically effective against the eradication of mature or chronic biofilm.[6] We have used 1% acetic acid gel as an anti-microbial dressing for acute burn wounds and compared it with 1% SSD. Aims: To evaluate the efficacy and safety of acetic acid gel with SSD cream in patients with second-degree burn wounds involving up to 20% of total body surface area. Outcome parameters evaluated were Wound healing (BWAT score and status as on Day 21), Pain (VAS score), Healing quality (VSS score at 1 and 3 months) and adverse effects if any. Settings and Design: The study was conducted in the burn department affiliated with a tertiary care centre. It is a prospective randomized, investigator-initiated open-label case-control study. Inclusion criteria 1. Males and females between the ages of 18 and 65 years 2. Second-degree burn involving total body surface area up to 20% at 48 h of burn injury. Exclusion criteria1.Patients with pre-existing comorbidities. Uncontrolled diabetes Mellitus. Renal insufficiency.2. Patients with known keloid tendency3.Patients with electrical burn4. Patients with inhalation burn. Patients were included in the study in accordance with mentioned inclusion and exclusion criteria. Informed consent was obtained from all patients. All procedures contributing to this work comply with the ethical standards of the relevant national and institutional guidelines on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. The study group received 1% Acetic acid gel while the control group received 1% SSD cream for antimicrobial dressings. Simple randomization was followed for the allocation of patients. Outcome parameters were assessed, compiled, and were statistically analyzed. Subjects and Methods: Eighty cases were included in the study, forty in each group. Each group patient underwent dressing with respective allotted topical antimicrobial agent, and outcome parameters were compared. In both groups, Bates-Jensen Wound Assessment Tool (BWAT), Visual Analog Scale (VAS), and Vancouver Scar Scale (VSS) scores were documented. Parameters compared were wound healing, patient acceptability, any adverse events, and quality of the healed scar. Statistical Analysis Used: The data was compiled and analyzed statistically for Outcome parameters will be analyzed for distribution, central tendency, and variability by calculating Mean, SD and p-value using Microsoft excel software (2007). Results: At 21 days, the acetic acid group showed complete reepithelialization in 45% of the cases and complete granulation in 7.5% of the cases, whereas the SSD group showed complete reepithelialization in 32.5% of the cases. The remaining cases in both groups healed after 21 days. BWAT scores were reduced in both groups. Mean VAS and mean VSS scores were comparable in both groups. No adverse event was noted in any group due to respective agent. Conclusions: In our study, we found that 1% acetic acid gel was comparable to 1% SSD in terms of efficacy and is safe to use in partial-thickness burn wounds <20% total body surface area (TBSA) with good clinical outcomes.

Silver ions and silver-containing compounds have been used as topical antimicrobial agents in a variety of clinical situations. We have previously shown that the enzyme phosphomannose isomerase (PMI) is essential for the biosynthesis of Candida albicans cell walls. In this study, we find that PMI can be inhibited by silver ions. This process is shown to be irreversible, and is a two-step process, involving an intermediate complex with a dissociation constant, Ki, of 59 +/- 8 microM, and a maximum rate of inactivation of 0.25 +/- 0.04 min-1 in 50 mM Hepes buffer, pH 8.0 at 37 degrees C. The enzyme can be protected against this inactivation by the substrate mannose 6-phosphate, with a dissociation constant of 0.31 +/- 0.04 mM, close to its Km value. Flamazine (silver sulfadiazine) is a silver-containing antibiotic which is used clinically as a topical antimicrobial and antifungal agent. We compared the ability of silver sulfadiazine and two other silver-containing compounds to irreversibly inactivate C. albicans PMI. The addition of the organic moiety increased the affinity of the compounds, with silver sulfadiazine showing a Ki of 190 +/- 30 nM. In all cases, the maximum inhibition rate was similar, implying a similar rate-determining step. Silver sulfadiazine does not inhibit Escherichia coli PMI, and this suggests a role of the only free cysteine, Cys-150, in the inactivation process. To confirm this, we mutated this residue to alanine in C. albicans PMI. The resultant Cys150 --> Ala mutant protein showed similar Vm and Km values to the wild-type enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)

Using electronic data from a large population-based network of Family Paediatricians (Pedianet), we aimed to describe the use of topical antimicrobials, including ozenoxacin 1% cream, in impetigo in children in Italy. We included 2929 children aged 6 months–14 years from 2016 to 2019 with at least one episode of impetigo treated with topical antimicrobials. Overall, 3051 cases of impetigo were included in the analysis. Treatment started in most cases on the same day as the impetigo diagnosis and lasted around eight days. In about 8% of the cases, a systemic antibiotic was prescribed after the topical antimicrobial, usually after 4–14 days. In this study, ozenoxacin was used in 8% of the cases. Treatment duration was significantly shorter for patients prescribed ozenoxacin compared to the whole study population (median of six vs. seven days, respectively). In contrast, the rate of treatment failure was similar. Very few adverse reactions were identified.

Over 440 000 children receive medical attention for burn injuries each year in the US. Burn wound infections are a major source of morbidity and mortality in these patients. Infected wounds not only heal more slowly, but also may lead to systemic infections. The factors that contribute to wound complications are both the size and depth of the wound. Burn depth is usually categorized into first-degree (superficial, involving only the epidermis), second-degree (partial thickness, involving both epidermis and dermis), and third-degree (full thickness, through the epidermis, dermis, and into fat). Burns that will not heal within 2 weeks are at least second-degree and should generally be referred to a burn surgeon for possible excision and grafting, due to the increased risk of infection and scarring. The burn wound is dynamic. Proper treatment minimizes the extent of the burn injury, whereas improper treatment (lack of proper wound-care, edema formation, lack of resuscitation) may actually increase the size and/or depth of the wound. Topical antimicrobial agents have been shown to decrease wound-related infections and morbidity in burn wounds when used appropriately. The goal of topical antimicrobial therapy is to control microbial colonization, thus preventing development of invasive infections. A wide variety of agents are available for treatment of burn wounds, including ointments, creams, biological and nonbiological dressings. Topical antimicrobials of choice include bacitracin, neomycin, silver sulfadiazine and mafenide.

Postoperative Topical Antimicrobial Use

Treatment of infected burn wounds remains a challenge in burn units. Silver-sulfadiazine (SSD) is the most commonly used topical antimicrobial agent in managing these wounds. We aimed to accelerate the healing of burn wounds by combined application of ovine acellular peritoneal matrix (OAPM), honey (H), and ovine fetal skin extract (OFSE). Sixty-four standardized burn wounds were created on the dorsum of 16 rats and were subsequently inoculated with Staphyloccocus aureus and Pseudomonas aeruginosa. After 48 hr, the wounds were surgically debrided and received either physiologic saline (control group) or SSD, OAPM+SSD, OAPM+H+SSD, and OAPM+H+OFSE+SSD. The healing wounds were evaluated for size, bacterial counts, histopathology, and biomechanical properties on days 3, 7, 14, 21, and 28 after surgery. All treatments had effectively reduced the level of S. aureus and P. aeruginosa on wounds compared to the control group by day 3 and 7. The wounds treated with combined application of OAPM+H+OFSE+SSD demonstrated considerable inflammation reduction, fibroplasia, complete re-epithelialization, and wound contraction together with significantly lesser scar tissue formation. Treatment with OAPM+H+OFSE+SSD showed superior biomechanical properties of the healing wounds. The findings suggested that the synergistic effect of dressing the wounds with OAPM, H, and OFSE was a very effective approach in accelerating the healing process of the experimentally induced infected full-thickness burn wounds in rats.

Introduction Topical antimicrobials are key to prevention of infection and mortality in the acute burn patient population. The purpose of this study was to determine the effectiveness of commercially available and in-house compounded topical preparations. Methods One hundred isolates from 15 different microorganisms were used to evaluate topical antimicrobial effectiveness. The isolates included 40 Gram-positive and 60 Gram-negative microorganisms. Sixteen multidrug-resistant organisms were included in the study. The study was conducted using the Nathan Topical Well Assay method to assess in-vitro activity. Twenty-two various irrigation solutions and ointments were tested. Since there are no standardized zones to determine susceptibility for topical antimicrobials, any zone of inhibition (>8 mm) was considered to show effectiveness. Results The compounds 1:1:1 + DAB (1 part bacitracin: 1 part silver sulfadiazine: 100,000 units per gram nystatin + 5mg/gram neomycin sulfate + 500 units/gram polymyxin B) and 3:1 + DAB (3 part bacitracin: 1 part silver sulfadiazine + 5mg/gram neomycin sulfate + 500 units/gram polymyxin B) in both irrigation and ointment dosage form demonstrated 100% effectiveness against all isolates. Sodium hypochlorite 0.5% solution appeared to be very effective against gram-negative organisms, but moderately effective against gram-positive organisms. Double antibiotic solution was highly effective against all gram-negative bacteria. 3:1 ointment and 1:1:1 ointment were highly effective against gram-positive organisms and moderately effective against gram-negative organisms. The data indicates that many of the topical antimicrobials target certain bacteria more readily than others. Besides 1:1:1 + DAB and 3:1 + DAB, it shows that more than one drug product is necessary to demonstrate adequate killing ability of a broad spectrum of organisms. Multidrug resistant organisms also indicate more resistance against topical antimicrobials. The only compounds that showed a high degree of effectiveness against MDROs were sodium hypochlorite 0.5% solution, 1:1:1 + DAB ointment and solution, and 3:1 + DAB ointment and solution. Conclusions The bacitracin and silver sulfadiazine component of 3:1 and 1:1:1 has a high degree of effectiveness against Gram-positive organisms. Double antibiotic ointment was moderately effective against Gram-negative organisms. However, when the two were combined into one ointment it created a synergistic effect, which killed all the organisms tested. Applicability of Research to Practice Antimicrobial effectiveness and adverse effects must be considered when selecting the appropriate topical agent to be used on wounds. Further research is needed to determine the production of resistant bacteria and topical antimicrobials and the clinical usefulness of topical antimicrobial susceptibilities.