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"Davis, Stephen C"
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Interactions of methicillin resistant Staphylococcus aureus USA300 and Pseudomonas aeruginosa in polymicrobial wound infection
Understanding the pathology resulting from Staphylococcus aureus and Pseudomonas aeruginosa polymicrobial wound infections is of great importance due to their ubiquitous nature, increasing prevalence, growing resistance to antimicrobial agents, and ability to delay healing. Methicillin-resistant S. aureus USA300 is the leading cause of community-associated bacterial infections resulting in increased morbidity and mortality. We utilized a well-established porcine partial thickness wound healing model to study the synergistic effects of USA300 and P. aeruginosa on wound healing. Wound re-epithelialization was significantly delayed by mixed-species biofilms through suppression of keratinocyte growth factor 1. Pseudomonas showed an inhibitory effect on USA300 growth in vitro while both species co-existed in cutaneous wounds in vivo. Polymicrobial wound infection in the presence of P. aeruginosa resulted in induced expression of USA300 virulence factors Panton-Valentine leukocidin and α-hemolysin. These results provide evidence for the interaction of bacterial species within mixed-species biofilms in vivo and for the first time, the contribution of virulence factors to the severity of polymicrobial wound infections.
Journal Article
Candida albicans Infections: a novel porcine wound model to evaluate treatment efficacy
Candida albicans
is a common cause of opportunistic mycoses worldwide and a major contributor in wound infections. The purpose of this study was to establish a fungal wound model and analyze the effects of a common antifungal agent against the proliferation of three
C. albicans
strains. Second degree burns were created, and then inoculated with one of three different
C. albicans
ATCC strains: 10261 reference strain, 64550 fluconazole resistant and 26310 fluconazole sensitive. After fungal inoculation, every wound was covered with dressings for 4 h to allow fungal colonization on every wound bed. After 4 h, the dressings were removed, and each wound was treated either once or twice daily with a topical terbinafine hydrochloride or left untreated. On days 2, 4 and 7 post inoculation, three wounds from each treatment group were scrub cultured and quantified. On day 2, wounds infected with the sensitive strains 26310 and 10261 and treated twice showed a significant reduction when compared against those infected wounds receiving once daily treatment. On day 4, wounds which were infected with
C. albicans
fluconazole sensitive (ATCC 26310) showed a significant reduction in fungal cell counts with treatment applied twice daily. A significant reduction in the colony counts was exhibited in all three strains at the seventh day with active as compared to the non-treated wounds. Twice daily treatment resulted in a lower fungal count than once daily treatment. Neither treatment was able to entirely eradicate
C. albicans
during the duration of this study. Establishing a reliable fungal wound model will help in the translational goal of identifying new antifungal that could be used clinically by wound care providers.
Journal Article
The efficacy of a nitric oxide-releasing formulation on nares isolated Methicillin-Resistant Staphylococcus aureus in porcine wound infection model
The colonization of
(SA) acquired in nosocomial infections may develop acute and chronic infections such as Methicillin-Resistant
(MRSA) in the nose. As a commensal microorganism with the ability to form a biofilm, SA can dwell on the skin, nostrils, throat, perineum, and axillae of healthy humans. Nitric oxide (NO) is an unstable gas with various molecular functions and has antimicrobial properties which are converted into many potential treatments.
Methicillin-Resistant
MRSA BAA1686 isolated from nasal infection was used in a porcine wound infection model. Deep partial-thickness wounds (10mm x 7mm x 0.5mm) were made on three animals using a specialized electrokeratome. All wounds were inoculated and then covered with polyurethane film dressings for biofilm formation. After 48 hours, three wounds were recovered from each animal for baseline enumeration. The remaining wounds were randomly assigned to six treatment groups and treated once daily. The treatment groups are as follows: NO topical ointments concentrations of 0.3, 0.9 and 1.8%, Vehicle Ointment, Mupirocin 2%, and Untreated Control. Microbiological recoveries were conducted on day 4 and day 7.
The greatest efficacy observed from the NO formulations against MRSA BAA1686 was the 1.8% concentration. This agent was able to reduce more than 99% of bacterial counts when compared to Baseline, Vehicle Ointment, and Untreated Control wounds on both assessment days. Mupirocin 2% was the overall best treatment against MRSA BAA1686 on both assessment days, with a significant reduction (p ≤ 0.05) of 4.70 ± 0.13 Log CFU/mL from day 4 to day 7.
Overall, the positive control Mupirocin 2% was the most effective in eliminating MRSA BAA1686 throughout the study. This experiment demonstrated a downward trend from the highest concentration of NO topical ointment formulations to the lowest concentrations on both assessment days (0.3% - 1.8%). Out of all NO topical ointments, the highest concentration (1.8%) was the most effective with the potential to be an alternative treatment against a MRSA nasal strain biofilm.
Journal Article
Scaffolds with spatiotemporally controlled growth factor delivery and cyclodextrin-enabled antagonism of growth factor receptor sequestration promote cutaneous wound healing
Chronic wounds present a major burden to patients, health care professionals, and health care systems worldwide, yet treatment options remain limited and often ineffective. Although initially promising, growth factor-based therapies displayed limited and underwhelming effectiveness largely due to poor bioavailabilbioity and impaired receptor function within the chronic wound microenvironment. Here we demonstrate that chronic wounds exhibit elevated cholesterol synthesis, which disrupts growth factor signaling by sequestering receptors within lipid rafts. To address this, we developed a novel therapy combining growth factors with cyclodextrin in an ECM-mimetic scaffold, enabling localized cholesterol modulation and improved receptor accessibility. We demonstrate that this approach enhances growth factor bioavailability and functionality, creating a regenerative environment. In both human ex vivo and diabetic mouse wound models, this targeted co-delivery strategy significantly improved healing outcomes by stimulating angiogenesis and re-epithelialization, supporting a promising new direction for chronic wound therapy through localized metabolic modulation of the wound niche.
Journal Article
Antimicrobial effects of a multimodal wound matrix against methicillin‐resistant Staphylococcus aureus and Pseudomonas aeruginosa in an in vitro and an in vivo porcine wound model
Chronic non‐healing wounds pose significant challenges due to an elevated inflammatory response caused in part by bacterial contamination (Physiol Rev. 2019;99:665). These wounds lead to billions being spent in the health care system worldwide (N Engl J Med. 2017;376:2367, Int J Pharm. 2014;463:119). We studied the in‐vitro and in‐vivo antimicrobial effects of a multimodal wound matrix (MWM) against two common wound pathogens, Methicillin‐Resistant Staphylococcus aureus (MRSA USA300) and Pseudomonas aeruginosa ATCC 27312 (PA27312) (Int Wound J. 2019;16:634). The in‐vitro study conducted was a zone of inhibition test with the two microbes at 104 Log CFU/mL inoculated on Tryptic soy agar with 5% sheep blood (TSAII) plates. Treatments used were MWM, Mupirocin (Positive control for MRSA), Silver Sulfadiazine (Positive Control for PA), Petrolatum and Sterile Saline (both serving as Negative Controls). Treatments were allowed to diffuse into the agar for 3 h and then were incubated for 24 h at 37°C. The in‐vivo study utilized a deep dermal porcine wound model (22 × 22 × 3 mm) created on six animals. Three animals were inoculated with MRSA USA300 and the other three with PA27312 with each allowing a 72‐h biofilm formation. After 72 h, baseline wounds were assessed for bacterial concentration and all remaining wounds were treated with either MWM alone, Silver Treatment or Untreated Control. Wounds were assessed on days 4, 8 and 12 after treatment application for microbiological analysis. In‐vitro, MWM exhibited significant inhibition of MRSA USA300 and PA27312 growth when compared to negative controls (p ≤ 0.05). Likewise, in‐vivo, the MWM‐treated wounds exhibited a significant (p ≤ 0.05) bacterial reduction compared to all other treatment groups, especially on days 8 and 12 for both pathogens. MWM demonstrated promise in addressing colonized wounds with biofilms. Additional studies on MWM's benefits and comparisons with existing treatments are warranted to optimize wound care strategies (Adv Wound Care. 2021;10:281).
Journal Article
Wound Healing Property of a Novel Thermo‐Reversible Wound Gel With Lasting Antimicrobial and Antibiofilm Activity
This study investigated the efficacy and safety of a novel thermo‐reversible antimicrobial wound gel (TRG, revyve Antimicrobial Wound Gel) designed to combat biofilm‐related infections in wounds. The TRG was evaluated for its ability to disrupt biofilms, sustain antimicrobial activity and promote wound healing. The gel exhibited thermo‐reversible properties, transitioning from a less viscous liquid ≤ 18°C to a highly viscous solid gel at wound temperature which would facilitate easy application and removal. Antimicrobial testing demonstrated that TRG effectively inactivated a broad range of wound‐related pathogens, including Staphylococcus aureus and Pseudomonas aeruginosa, with a 99.99%–99.9999% reduction in bacterial counts within 30 min. The TRG also maintained its antimicrobial efficacy after multiple inoculations with high microbial load (107 CFU/mL) over 7 days. In vitro biofilm assays showed effectiveness against biofilm bacteria with a reduction of ≥ 99.99% bacterial counts with one application over the course of 7 days. Biocompatibility testing confirmed that TRG was safe, with no signs of tissue necrosis or signs of tissue damage and no impact on wound healing in a porcine wound model. TRG's ability to reduce both planktonic and biofilm‐based bacteria without compromising wound healing makes it a promising candidate for treating both chronic and acute wounds. Key Messages Thermo‐reversible properties of wound gel, transitioning from a low‐viscosity form at low temperature to a high‐viscosity gel at wound temperature, make the gel form‐fitting to the wound upon application and remain in place during treatment, while its lower viscosity upon cooling facilitated painless removal without damaging healing tissue. TRG was effective against both planktonic and biofilm forms of wound‐related pathogens and this effectiveness can be sustained over 7 days, minimising the need for frequent dressing changes. Safety and potential cytotoxic effect on wound healing of TRG was confirmed using biocompatibility and porcine wound study.
Journal Article
Antimicrobial effectiveness of wound matrices containing native extracellular matrix with polyhexamethylene biguanide
A variety of wound matrix materials that are designed to help heal both acute and chronic wounds are currently available. Because wounds often encounter opportunistic microbes that can delay healing, the effectiveness of these materials is often suboptimal, resulting in delayed or compromised wound healing. The importance of reducing and controlling wound microbes is well recognised and there are several antimicrobial options available to address this unmet clinical need. This study compares the antimicrobial and wound healing capabilities, both in vivo and in vitro against methicillin‐resistant Staphylococcus aureus (MRSA) USA 300, for the following compounds: Collagen Wound Matrix‐Anti Microbial (CWM‐AM); Collagen Wound Matrix‐Anti Microbial XT (CWM‐AM XT); Antimicrobial Hydrofiber Wound Dressing (AHWD); Dermal Scaffold with Silver (DRSAg); Collagen Extracellular Matrix (CEM); Collagen Wound Matrix (CWM); Matrix Wound Dressing with Silver (MWDAg); Cadexomer Iodine Gel (CIG); Triple Antibiotic Ointment (TAO); and Antimicrobial Wound Gel (AWG). For the in vitro zone of inhibition assay, AWG and CIG had the largest diffused areas, followed by CWM‐AM and CWM‐AM XT. Furthermore, CWM‐AM, CWM‐AM XT, AWG, and CIG exhibited a persistent antimicrobial activity for up to 10 days after incubation. However, in the cytotoxicity studies performed using human fibroblasts, CWM‐AM and CWM‐AM XT had no detrimental effects in cell proliferation and viability, while AWG and CIG were cytotoxic and prohibitive for cell proliferation. Treatments were then assessed for microbiology and wound healing efficacy using an in vivo porcine deep reticular dermal wound model. CWM‐AM XT displayed the greatest in vivo antimicrobial activity against MRSA USA300 and expedited the reepithelialisation at a faster rate than other treatment groups. This study shows that a novel collagen matrix containing an antimicrobial agent can reduce the bacterial load and support healing.
Journal Article
In vitro analysis of interactions between Pseudomonas aeruginosa and Candida albicans treated with silver sulfadiazine in wound infections
Abstract
Background
Microorganisms tend to rely on close relationships with other species to survive. Consequently, biofilms formed by interactions of different species have been shown to delay the wound healing process. Studies suggest these mixed-population infections contribute to the development of drug resistance and inhibition of host immune response. Silver sulfadiazine (SSD) has been shown to effectively decrease the risk of infection in an open wound. Typically, these are bacterial wound infections; however, the role of fungal species needs further attention.
Objectives
The purpose of this in vitro study was to determine the effect of SSD on interactions between Pseudomonas aeruginosa 09-009 (PA1) or P. aeruginosa 09-010 (PA2) and Candida albicans ATTC 64550 (CA).
Methods
A mixture of 4 mL of tryptic soy broth (TSB) and 100 µL of CA and/or PA1 or PA2 (∼106 log cfu/mL) inoculums were deposited into either wells or vials. The wells or vials were then sonicated (50 W for 10 s) to separate microorganisms attached to the walls. After incubation, cell counts were performed at 24 and 48 h for each microorganism using specific media.
Results
Our results show that without SSD treatment, P. aeruginosa exhibits an inhibitory effect on C. albicans. Treatment with SSD demonstrated significant reduction of P. aeruginosa; however, C. albicans persisted. This experiment demonstrates that SSD was effective in reducing the bioburden of both P. aeruginosa strains after 24 and 48 h; however, it was not as effective in reducing C. albicans.
Conclusions
The data suggest that for polymicrobial mixed infections containing Pseudomonas spp. and C. albicans, treatment with SSD may be beneficial but does not provide adequate microorganism eradication. As such, added treatments that provide coverage for Candida infection are necessary. Additional in vivo studies are needed to obtain a better understanding of the complex interactions between these organisms.
Journal Article
Preliminary evidence supporting a new enzymatic debridement product for use in chronic wounds
A new recombinant proteolytic enzyme, isolated from maggot saliva, with fibrinolytic action has been investigated through a series of non‐clinical toxicology and in‐vitro/in‐vivo pharmacology studies to explore its potential safety and efficacy as an enzymatic debridement agent for use in chronic wounds. Studies indicate that the enzyme has a good safety profile. When locally administered, it is not detrimental to wound healing, is non‐sensitising and is rapidly inactivated in the systemic circulation. Adverse effects are limited, at very high concentrations, to transient erythema at the site of application. In‐vitro testing indicates that the enzyme, whilst selective for fibrin, has additional proteolytic action against collagen and elastin, with enzymatic action for all three substrates being dose dependent. In‐vivo, we used an established MRSA biofilm model, in which microbiological counts were used as a surrogate for debridement efficacy. Here, we showed that higher concentrations of the enzyme in a formulated proprietary gel, significantly reduced MRSA counts over a period of 2 to 14 days, and significantly improved the vascularity of the wound at 14 days. Together, these data support the potential for this maggot‐derived proteolytic enzyme as a clinically effective debriding agent.
Journal Article