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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 3  |  Issue : 1  |  Page : 28-41

Role of systemic antibiotic prophylaxis and burn dressings in preventing invasive burn infections – A systematic review


Department of Burns and Plastic Surgery, AIIMS, Rishikesh, Uttarakhand, India

Date of Submission07-Jun-2020
Date of Decision16-Aug-2021
Date of Acceptance23-Oct-2021
Date of Web Publication28-Apr-2022

Correspondence Address:
Dr. Akshay Kapoor
Department of Burns and Plastic Surgery, AIIMS, Virbhadra Road, Rishikesh - 249 203, Uttarakhand
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JME.JME_9_20

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  Abstract 


Background: Burn dressings and systemic antibiotics are used to combat invasive burn wound infections. With emergence of antibiotic resistance and a emergence of a large variety of dressings, it becomes important to work out a strategy to use systemic antibiotics and burn dressings effectively. Materials and Methods: A systematic database search to include PubMed/Medline, EMBASE, COCHRANE, SCOPUS was performed from January 2000 to January 2021 and reviewed to define invasive burn infection, and the topical antimicrobial therapy for clinical use. For the section on antimicrobials, MESH terms used were 'Antimicrobial Prophylaxis' AND 'burn Infection' and randomised controlled trial studies were alone selected. For the section on Burn dressings, another search was carried out with search words 'Dressings' AND 'Burn Infections'. Since the Search revealed several systematic reviews, the analysis was restricted to only those studies. Results: Systemic antibiotic prophylaxis does not seem to offer advantage in preventing burn wound infection, septic episodes or mortality. Although there is some benefit in decreasing mortality in patients of inhalation burn injury who would require mechanical ventilation. It can be given pre-operatively before skin grafting as there is improved graft survival in patients getting prophylaxis. Honey and hydrogel were found to promote wound healing while honey and skin substitutes prevented infection better than conventional dressings including silver sulphadiazine. For wound cover, though the permanent method of choice is still autologous skin grafts, with the advent of cell culture technologies, cultured autografts may hold a promising future. Conclusion: Systemic antibiotic prophylaxis can be given to patients of inhalational burn injury and as a pre-operative prophylaxis but not for preventing invasive burn wound infections. The ideals strategy for preventing invasive burn infection is isolation of the patient, wound cover (surgical/artificial) and frequent wound tissue sampling.

Keywords: Burns, skin substitutes, topical antimicrobials, wound infection


How to cite this article:
Vathulya M, Kapoor A, Chattopadhyay D, Rao N. Role of systemic antibiotic prophylaxis and burn dressings in preventing invasive burn infections – A systematic review. J Med Evid 2022;3:28-41

How to cite this URL:
Vathulya M, Kapoor A, Chattopadhyay D, Rao N. Role of systemic antibiotic prophylaxis and burn dressings in preventing invasive burn infections – A systematic review. J Med Evid [serial online] 2022 [cited 2022 Nov 30];3:28-41. Available from: http://www.journaljme.org/text.asp?2022/3/1/28/344302




  Introduction Top


Burn injuries are devastating to the patient because they result not only in mortality but significant morbidity which affects not only the ability to seek meaningful employment but also the activities of daily life. Central Asia has the highest age-standardised burn incidence of about 298 cases per 100,000 population.[1] Around 50%–75% of burn injuries result in sepsis making it the most lethal complication in burns patients.[2] The destruction of skin, which is the first line of defence, along with an altered host immune response leave the patient susceptible to microbial invasion leading to Invasive burn wound infection which later results in sepsis.

The American Burn Association has defined invasive burn wound infection as 'the presence of pathogens in a burn wound at concentrations sufficient in conjunction with depth, surface area involved and age of patient to cause suppurative separation of eschar or graft loss, invasion of adjacent unburned tissue or cause the systemic response of sepsis syndrome'.[3]


  Materials and Methods Top


In order to explore the role of systemic antimicrobial prophylaxis in burns we searched articles in PubMed, EMBASE and SCOPUS with the keywords 'Antibiotic Prophylaxis' AND 'Burns' AND 'Infections'. Our search revealed 1,868 articles published between 2000 and 2021. We only included randomised controlled trial (RCT) and cohort studies. This narrowed the number of studies to 304. On searching through the abstracts we excluded studies not giving data on the use of systemic antimicrobial prophylaxis and those dealing with burns <25%. We finally analysed 17 studies out of which 6 results were of significance and are summarised in [Table 1] and [Figure 1]. Our other objective was to look into the current evidence available regarding ideal dressing materials for tackling infection in burn wounds. We performed a search of articles in PUBMED, EMBASE and SCOPUS with key words 'Dressings' AND 'Burns' AND “Infection'. We found 1366 articles relating to our key words. From this, we removed case reports, series, letter to editor, narrative reviews and expert opinions. We found 391 articles whose abstracts we studied. We excluded all articles not documenting the presence of infection confirmed by culture reports, microscopy or gene sequencing. Studies dealing with healing of wound as the endpoint were also excluded. We found 20 articles. Since the search yielded a fair number of systematic reviews, we preferred to retain them and discard the rest of the study types finally arriving at eight studies are summarised in [Table 2] and [Figure 2].
Table 1: Evidence regarding systemic antibiotic prophylaxis in burns

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Table 2: Evidence regarding use of dressings for management of infection in burn wound

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Figure 1: Article selection for systemic antibiotic prophylaxis in burns

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Figure 2: Article selection for evaluating dressings in burn wounds

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The abstracts were screened by two of the authors (AK, DC) and the third author (MV) was referred to opine on articles where there was a disparity in the selection criteria amidst the other two authors.

Quality assessment

Quality assessment for RCT studies considered for review under antibiotics section was analysed using NEW Ottawa castle tool while for the review of Burn dressings, the quality was analysed using Glenny's scale as it considered only systematic review studies. Only good and fair-quality studies were selected for analysis.


  Pathogenesis of Burn Infection Top


Bacteria, which are endogenous to the skin, have the same degree of heat resistance as the skin cells. It is considered that if the skin cells are destroyed in burn injury then the temperatures must be high enough to destroy the endogenous bacterial flora as well. If the extent of injury is not deep enough then bacteria in the hair follicles and sebaceous glands may survive. Usually, the quantitative counts from this region are 103 bacteria per gram.[4] If these bacteria get optimum conditions then a single bacterial cell can increase in numbers to over 10 billion within a 24-h period as the mean cell generation time is only 20 min.[5] Once these levels increase to >105 per gram tissue, the bacteria will emerge from hair follicle and sebaceous gland region and migrate to the injury zone and infiltrate the dermal-subcutaneous tissue boundary. Besides endogenous bacteria, other possible sources of infection at this stage are unsterile blankets and dressings used to cover the burn wound and nosocomial spread when these patients are kept in the general ward. The bacteria coming from other sources tend to be more resistant to antimicrobial agents than those from patient's endogenous flora.[6]

If the microorganism growth is not tackled, then they will gradually invade the vessels supplying the skin leading to thrombosis and subsequent necrosis of the skin. Such a change would increase the severity of burn injury, as it would convert a partial thickness burn injury into a full-thickness one.

Besides change in grade of burn, other signs of invasion can be the presence of hemorrhage or necrosis in unburned tissue and detection of dense bacterial growth in the sub-eschar space.

Another important aspect to consider while managing wound infections is the gradual change in the character of microbial flora from Gram-positive to Gram-negative to an extent that by the 21st day of admission it is common to find the burn wound colonised by Pseudomonas which is resistant to extended-spectrum β-lactamase [Table 3].
Table 3: Common pathogens responsible for burn infections

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  Management Strategy Top


The prevention of Invasive infection by restoration of healthy epithelial lining is the main focus when treating burns. In order to make this possible the modern strategy of burn care recommends early debridement of necrotic tissue (usually within 48 h) followed by autologous skin graft cover 7. In order to remove necrotic debris, and films formed between wound exudates and topical dressing materials the patients are given shower baths. Most centres have replaced immersion baths with shower baths because of the fear of risk of nosocomial infections. However, at present, the risk of nosocomial infection appears to be equal in both forms of hydrotherapy.[7]

But shower baths have an additional use when treating chemical burns where copious irrigation is required and all the water should drain to the floor.[8]

For patients with extensive burns, it is preferable to give temporary coverage, as there are insufficient donor sites. The options available for temporary coverage are allograft, xenograft, dermal analogues and biological dressings. All of these options promote re-epithelialisation and prepare the wound bed faster than traditional dressings for autografting.[9] The major drawback with biological dressings and skin substitutes is the high cost and lack of availability thus making traditional dressings such as paraffin gauze the only viable option.

While using such traditional dressings it is best to use them with some topical antibiotic to prevent invasive infection. The only problem while using topical antibiotics is that along with microbial killing they also hinder regeneration of skin by inhibiting keratinocyte and fibroblast proliferation.[10]

Once invasive infection is suspected the culture samples from the wound will help in choosing the appropriate systemic and topical antimicrobial. Wound tissue sampling, which is the acquisition of deep tissue biopsy after cleansing of the superficial debris, is the most effective sampling method. It is performed like slit skin method. At the wound site, two parallel incisions of 1–2 cm length are given about 1.5 cm apart. The depth is such that the underlying fat becomes visible through the incisions. Wound swabs and blister fluid may also be sent for culture but they lack the specificity of tissue culture samples.

The issue of biofilm-forming bacteria causing sepsis gains important in our setup where the time to cover the wound is often delayed by lack of appropriate skin substitutes and tissue culture techniques.[11] Once these organisms colonise the wound the chances of emergence of antimicrobial resistance increases as the biofilm provide protection against antibiotics. Some newer technologies to tackle this problem are the use of agents which interfere in quorum sensing and the use of engineered enzymatic bacteriophages.[12],[13]

Another issue that is sometimes missed is the incidence of toxic shock syndrome in burns patient. This can even occur in burns as small as 10%. So the clinician must always have a high index of suspicion for diagnosing this condition. Its incidence is 2.6% with a mean age of 2 years. Clinically, the patient has a prodromal phase of fever, diarrhoea and vomiting lasting for 1–2 days with rapid deterioration to shock and mortality on the 3rd to 4th day. It may be associated with rash but the character of the burn remains unchanged which differentiates it from invasive burn infection. The causative agent is toxic shock syndrome toxin 1 released from staph aureus. The treatment is to empirically start antibiotics against methicillin-resistant staph aureus (MRSA) along with fresh frozen plasma and intravenous immunoglobulin to provide passive immunity against the toxin.[14]

The issue of using systemic prophylaxis to prevent infections in burns still remains controversial and at present the only time we use systemic prophylaxis is in the perioperative stage to prevent graft site infection. Following is the evidence from recent RCT and Cohort studies, which have considered clinical trial data from 2000 to 2020 that support our observation[15],[16],[17],[18],[19],[20] [Table 1]. Another conclusion that we found is a grade 3 evidence in favour of giving antibiotic prophylaxis to patients who would require mechanical ventilation. A retrospective study by Tagami et al. with propensity matching pair studied the effect of systemic prophylaxis on mortality in mechanically ventilated patient. They found lower mortality rates in patients who were given systemic prophylaxis as compared to those who needed ventilators but had not received prophylaxis.[20]

At present, our protocol is to wait for culture and sensitivity reports from the burn wound before starting antibiotics. If there are signs and symptoms of sepsis we start with piperacillin and tazobactam with vancomycin.[21] The other case when we use antibiotics is preoperatively before debridement and grafting where our departmental and institutional protocol is to use 1 g of Intravenous ceftriaxone.


  Topical Antimicrobials Top


The topical system of delivery of antimicrobials is more effective in cases of burns as it is able to penetrate eschars and biofilms making it more effective against colonisation and wound infection than systemic antimicrobials.

The following properties that should be considered when selecting a topical antimicrobial are as follows.

  1. Should have a broad spectrum of coverage but not stimulate the development of resistance
  2. Ability to penetrate burn eschar
  3. Painless application on the wound
  4. Should be effective for prolonged periods so that numbers of dressing change are reduced
  5. Should not be systemically absorbed to prevent systemic side effects
  6. Not inhibit wound healing.


At present, we do not have any antimicrobial, which can fulfill all the above-mentioned criteria.

Even though the development of resistance to topical antimicrobials is rare, still it is best to rotate the various topical antimicrobials being used and also to find out the microorganisms, which are endemic to the burn ward. Based on these data, an antimicrobial best suited for a particular ward can be started even before the culture reports have arrived.

Following are the commonly used topical antimicrobials.

Silver-based topical therapy

Silver cation has bactericidal properties and high reactivity at relatively low concentrations. Silver ions act through a variety of pathways such as inhibition of enzymes necessary for metabolism, respiration, DNA and RNA replication of the microorganism. They also disrupt cell wall and cell membrane synthesis. The presence of multiple mechanisms of actions makes it highly unlikely that resistance to silver would emerge. Despite this, there has been some evidence of resistance when there has been chronic exposure to low dose of silver, which is why it is preferable to use dressings or agents that release high levels of silver.[22]

The disadvantage of ionic silver is the inability to penetrate eschar and deep burns. This is primarily due to its high reactivity because of which it readily combines with proteins and exudates on the wound surface causing it to become inactivated.

Another problem is that Silver can delay wound healing because in vitro studies have found it to be toxic to keratinocytes and fibroblasts. A study by Warriner et al. has demonstrated that silver ion can delay healing of second-degree burns in vivo.[23]

Therefore, it is best to avoid the use of silver ions in partial-thickness wounds, which are expected to heal spontaneously and are not heavily colonised.

Silver sulphadiazine

It is available as a water-soluble cream containing 1% silver sulphadiazine (SSD). Silver ion has a bactericidal action while the sulphadiazine has a bacteriostatic action. Along with abroad spectrum which included Gram-positive and negative bacteria, it is also effective against Candida albicans.[24]

Amongst the disadvantages of using SSD is its ability to inhibit epithelialisation and the formation of a pseudoeschar on the wound surface, which is a yellowish-white paste formed on the wound surface due to an amalgamation of surface proteins and SSD. It prevents accurate wound examination and may be mistaken for a deep burn.

Its use is contraindicated in facial burns due to the risk of ocular irritation and in those patients who have a history of allergy to sulfonamides. It should not be used in infants <2 months of age and in pregnant females because of risk of kernicterus from the sulfonamide component.

Silver nitrate

It is available as 0.5% silver nitrate (AgNO3) solution. This concentration is not toxic to regenerating epithelium and at the same time is bacteriostatic against both Gram-positive and negative bacteria. It has also been used with 2% miconazole powder as prophylaxis against fungal growth in the wounds.

Among the side effects at the local application site, it causes blackening due to combination of the light sensitive solution with chloride containing compounds. If the area of application is large then it can even lead to hyperpyrexia because the solution tends to dry and when covered by an impervious dressing it prevents heat loss.

Amongst systemic side effects, it may cause methemoglobenemia as nitrate positive organisms (such as Enterobacter cloacae) can convert the nitrate into nitrite which can get absorbed.[25] Its tendency to cause hyponatremia and hypochloremia as the solution is hypotonic and can cause osmolar dilution on systemic absorption is also

Nanosilver ointments and dressings

A single silver nanocrystal is <20 nm in diameter and contains 30–50 silver atoms. Once the nanocrystal comes in contact with water it releases the silver atoms into the surroundings. Therefore, dressings impregnated with silver nanocrystals have the ability to slowly release silver cations into the wound for a prolonged period (about 5–7 days). The advantage of this property is that these dressings can be left in place for at least 5 days leading to reduced number of dressings and reduction in pain to the patient because of dressing changes.

Nanosilver has several advantages compared with other traditional silver-based ointments. First, it has a larger contact area compared with the conventional silver formulation, thus, the requisite amount of silver ions is greatly reduced for the equal amount of bacteria. This is of great significance in improving the efficacy and safety of silver therapies. Second, Nanosilver dressing has the superior permeability and is advantageous for the drainage of wound, which significantly reduces the risk of cellulitis.[26] Third, Nanosilver greatly facilitates the wound healing through inhibiting the secretion of matrix metalloproteinase in the local site of wound.[27] More importantly, nanosilver dressings are less likely to spur the development of drug-resistant bacteria than traditional antibiotics and SSD.[28]

Mafenide acetate

It is available as an 11% cream and a 5% aqueous solution and the active component is sulphonamide. Its use is mostly reserved for cases where a thick eschar is present at the wound site and where deep penetration is needed. In facial burns with the involvement of ear cartilage, it is an agent of choice to prevent suppurative chondritis of the ear cartilage.[29]

Its lack of antifungal activity can be compensated by the addition of nystatin. For superficial burns, it is better to use the 5 and 2.5% solutions as they are less painful to apply.[30]

Its side effect at the wound site is its ability to delay wound healing as it inhibits fibroblasts and keratinocytes.

Amongst systemic side effects, it inhibits carbonic anhydrase which can lead to severe metabolic acidemia with compensatory hyperventilation. Therefore, it should not be used repetitively for large surface areas. Instead, it can be alternated with silver ointments for large burns.

Antibiotic ointments

These ointments have a consistency of water in oil emulsion because of which they produce a moist environment in the wound, which is conducive to healing. Because of this, they are used for superficial burns where no grafting would be needed. Along with a layer of ointment, a non-adherent dressing like paraffin gauze should be applied.

Bacitracin

Its use is mostly limited by its narrow spectrum that includes only Gram-positive bacteria. It is important to terminate its use once re-epithelialisation has occurred as it may lead to a rash due to yeast overgrowth.[30] It is normally recommended for superficial facial burns.

Mupirocin

Effectiveness against Staphylococcus aureus. It is the only topical ointment that can suppress MRSA therefore is one of the most widely used topical antimicrobials in burn wards.[31]

Polymyxin B sulphate

It provides good coverage against Gram-negative bacteria including pseudomonas. Repeated application on limited areas of burn is not associated with many side effects but nephrotoxicity and neurotoxicity have been reported when it has been used repeatedly over large burn areas.[31]

Neomycin

Like all aminoglycosides, it gives good coverage against Gram-negative bacilli such as E. coli and Enterobacter, along with some Gram-positive species. Even though it has a good spectrum but when compared to other topical antimicrobials, its use is limited by the observation that resistance tends to develop against it. Repeated application on a large surface area can cause systemic absorption to a degree that may lead to nephrotoxicity and ototoxicity.[31]

Antiseptic solutions

The advantage of using these solutions is that they are effective against a broad spectrum of microorganisms, which include bacteria, virus and even fungi. Their ability to act disrupt biofilms makes them useful in pseudomonas infections as well.[32] Resistance to these chemicals is uncommon but the downside is that they are cytotoxic to keratinocytes and fibroblasts because of which they delay wound healing.

Sodium hypochlorite

It is commonly available as 0.5% buffered solution known as Daikin's solution. The problem with this concentration is that it impedes wound healing so studies with 0.025% concentration were done. At this concentration, there was no significant cytotoxicity and it was effective against both Gram-positive and negative bacteria.[33]

Acetic acid

It is available at concentrations of 1-3% and is the mainstay of dressing when there is heavy pseudomonas colonisation in the wound. It is effective against all biofilm-producing organisms. Acetic acid solution is mainly effective against organisms that produce biofilms.[34] Like all agents that belong in this class, it tends to delay wound healing due to toxicity to keratinocytes and fibroblasts. Even solutions of 0.25% are found to be toxic to keratinocytes in vitro therefore its use is best reserved for cases where skin grafting will be required and the grafting bed has to be treated for pseudomonas infection.

Povidone iodine

It is available as a 10% ointment and solution. It is an effective antimicrobial having activity against bacteria, fungi and virus because of which it is effective in controlling bacterial colonisation. Its use is quite limited in burn patients because it is painful to apply and has cytotoxic effects on fibroblasts and keratinocytes. Concerns about systemic absorption leading to iodine toxicity, renal failure and acidosis have limited its use and are usually contraindicated in extensive burns.[35]


  Burn Wound Cover Top


One of the most vital components in combating infections in burns is the ability to provide some type of cover to the burn wound. The following are the options that we have [Figure 3].
Figure 3: Types of burn wound cover

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  Skin Grafts Top


Autologous skin grafts are the ideal choice for providing burn wound cover. However, in cases with burns over a large surface area (>45% TBSA) the donor sites become very limited. Furthermore, we must avoid wasting precious autologous skin grafts over necrotic and unhealthy wound beds, as they will not take up the autologous skin grafts. Our goal in such cases is to provide some temporary cover over the unhealthy wound bed to prevent further infection and allow the formation of healthy granulation over which autologous grafts can finally be placed.

Allograft is the ideal temporary cover for a burn wound. It is available in fresh form and in the cryopreserved state. The rates of vascularisation of the fresh graft over healthy wound are much better than the cryopreserved form. Therefore, while the donor sites of the patient recover these grafts will provide cover over the wound until they get rejected in 3–4 weeks. Although immunosuppressants will allow these grafts to survive longer it is generally not practiced, as these drugs would increase the chance of infection.

Xenografts are the next best option when allografts are not available.[36] Their primary disadvantage being they do not get vascularised and have to be changed more frequently (2–3 days). Porcine skin is the most commonly available xenograft and consists of homogenised porcine dermis which is fashioned into sheets and meshed. They provide a good cover over superficial burn wounds as they decrease pain and decrease the frequency of dressing changes. They have also been used to cover donor sites. In infected wounds, they have been combined with SSD to control wound colonisation.


  Biological Materials Top


With a better understanding of the microbial flora contaminating burn wounds and the added advantage of nutritional support, a decreasing trend in the sepsis and multisystem organ failure due to burns has been observed.[37] However, this has led to the added burden of temporary or permanent wound cover in these survivors.

About 17% of burn mortality occurs in patients with TBSA of more than 20% (Total burn surface area) according to national burn repository data 2005.[38] The LA50 (Lethal area 50 Index which denotes the TBSA leading to 50% mortality in adults is 81%.[39]

Although split-thickness skin graft (STSG) harvested from the patient (autograft) is the ideal treatment for these patients there is seldom any available adequately. In addition, the wound bed might not be sufficient to accept them at that point of time. Hence is the need for biological dressings to help in wound coverage.

Biological materials depending on their function, form and duration of action can be broadly categorised as:

  • Biological dressing
  • Skin substitutes
  • Biomembranes
  • Scaffolds.


Advantages of these materials

  1. Haemostasis
  2. Provision of a water barrier to reduce water loss
  3. Moist environment to promote cell survival and growth in turn promoting rapid epithelialisation
  4. Reduces pain
  5. Barrier to microbes from environment entering the wound surface and hence to check infections
  6. Prevents loss of protein exudate and blood cells
  7. Can help in testing the graft bed.


Disadvantages

  • These materials have allogenic and xenogeneic antigens can elicit immunologic reaction.



  Biologic Dressings Top


Therapies based on re-establishing the homeostasis milieu conducive for wound healing can be included under this category. They may include active biologic agents characterised by:

  1. Prevention of evaporative water and heat loss
  2. Prevention loss of electrolytes and protein
  3. Aid autolytic debridement which helps in the formation of granulation tissue in wound bed and also prevent contamination.


E.g.,: Monoterpenoids: Terpene-based chemicals present in essential oils. They contain anti-inflammatory, antioxidant and antimicrobial properties.

They include thymol, borneol, genepin, sericin, etc.

Thymol has many properties aiding in wound healing. The anti-myeloperoxidase activity decreased leucocyte influx, prevention of lipid peroxidation and influence on collagen synthesis are few of its characteristics attributed to its wound healing properties.

Sulbogin[32] is a compound comprised of borneol, bismuth subgallate and vaseline.

Believed to help in wound healing by inducing growth factor secretion from macrophages and inducing re-epithelialisation and granulation tissue formation.

Sericin,[33],[34] a protein derived from cocoon of silkworm has shown to have anti-inflammatory properties, collagen formation and re-epithelialisation and thus promote wound healing.

Honey

The wound healing property of honey is long known. The source of honey can be broadly classified as Apiary and Forest Honey. Apiary honey is obtained for the Indian Hive bee, Apis cerana indica and the European bee, Apis mellifera using the modern extraction method while the forest honey is extracted by the crude squeezing of comb of rock bee, Apis dorsata, or from wild nests of Apis cerana indica in forests. The honey can also be classified as unifloral or multifloral based on whether honey from flowers of the same plant or different plants are pooled together. Irrespective of the source all these extractions have been found to have beneficial effects on burn wounds.[40] The antimicrobial action is due to flavinoids, phenols and hydrogen peroxide present.[41],[42] It has also shown the added mechanical advantage due to high viscosity and Ph. The peroxide action is activated after honey comes in contact with moisture. In addition, honey also helps in healing by providing a moist environment.


  Skin Substitutes Top


They are substances designed by tissue engineering and used to temporarily or permanently replace skin in form and function.[43]

These substitutes can be classified based on their length of usage or their components.

On the basis of usage, they can be categorised into temporary or permanent substitutes

Temporary impervious substitutes

Single layer

  1. Natural/Biological: For example, Amnion, potato peel
  2. Synthetic: For example, synthetic polymer sheet (opsite, tegaderm), polymer spray or foam.


Bilayer (tissue engineered)

  1. Transcyte.


Durable single layer

  1. Epidermal substitutes: Cultured epithelial autografts (CEA), apligraf
  2. Dermal Substitutes: Bovine and porcine collagen sheets, bovine dermal matrix and human dermal matrix.


Composite skin substitutes

  1. Skin grafts: Allograft, xenograft
  2. Tissue-engineered skin: Dermal regeneration template (DRT) (integra), Biobrane.


Based on their form, they can be grouped under cellular and acellular substitutes

  1. Human cadaveric dermis deprived of its cellular components are considered as acellular substitute while the addition of fibroblasts or keratinocytes which are antigens serve as cellular substitutes. e.g.,: Transcyte, integra, alloderm
  2. Cellular skin substitutes: They comprise of cellular components that actively stimulate wound healing.


They can be either allogenic or autogenous:

  1. Allogenic


  2. E.g.,: Transcyte, apligraf, dermagraft.

  3. Autologous: CEA, cellular skin substitutes.


Depending on the component they substitute for these are further classified in to epidermal, dermal and dermal-epidermal replacement 3).

Epidermal skin substitute

Permanent type

Epicel

CEA, this is a unique technique where keratinocytes are obtained from the patient and made to grow in a culture which contains murine fibroblasts. This leads to formation of epidermal autografts which can then be processed into long sheets and then applied on to the patient from whom the keratinocytes were harvested in which autologous keratinocytes with murine fibroblasts are cultured to form epidermal autografts.

Shortcomings: Long time to culture, blistering, contracture and infection.

Laser skin

In this technique, keratinocytes and fibroblasts derived from a skin biopsy from the patient making both these components autologous. Both these cellular components are then cultured on a laser micro perforated biodegradable matrix consisting of benzyl esterified hyaluronic acid. The microperforations allow the exudates to drain out while the proliferation and migration of cells through the matrix occurs forming a layer of cultured graft that can be used for transfer.

Shortcomings: Expensive technique and cultured graft has a short shelf life of only 2 days.

Dermal skin substitutes

Temporary type

Transcyte

It is a dermal substitute which is prepared by ex vivo culture of allogenic human fibroblasts onto a bio absorbable nylon mesh scaffold. The scaffold has a silicone layer covering and the fibroblasts are derived from neonatal foreskin. Culture takes 4-6 weeks and requires local growth factors and secretory components of extracellular matrix.

Shortcoming: Expensive.

Biobrane

This an acellular dermal substitute which is made of type I Porcine collagen, porous nylon mesh covered by a silicone membrane. The membrane is semi permeable in nature so it prevents evaporative water loss but at the same time allows entry of topical antimicrobials and drainage of wound exudate. The silicone membrane facilitates adherence to wound surface.

Shortcoming: It does not have any component which promote debridement of dead tissue. When applied on partial thickness wounds it can induce permanent scarring.

Permanent or temporary type

Dermagraft - it is a cryopreserved allogenic human fibroblast dermal substitute. It is made by culture of neonatal dermal fibroblasts in a bio-absorbable polyglactin mesh scaffold. The fibroblasts proliferate and secrete collagen, extracellular matrix proteins, growth factors and cytokines whilch fill up the interstices of the polyglactin mesh.

Contraindications: Unsuitable for those with allergy to bovine products.

Permanent type

  1. AlloDerm-It is made from donated human cadaver skin, which is lyophilised. The acellular dermis obtained after processing serves as a scaffold for tissue remodelling


  2. Shortcoming: Infection. Requires two procedures for completion of treatment.

  3. Integra DRT– It is an acellular dermal substitute made up of a matrix containing bovine type 1 collagen and chondroitin-6-suphate glycosaminoglycan. The matrix is covered by a layer of silicone that acts as a temporary epidermis and functions like a semi permeable membrane. Once applied on the wound bed it tends to stimulate the ingrowth of fibroblasts and macrophages into the matrix, which leads to angiogenesis, and formation of healthy granulation tissue. Once the granulation appears healthy enough to graft, the silicone layer is removed and autologous STSG placed.


Shortcoming: It requires complete excision of the wound prior to application.

It is an avascular structure so can get infected secondarily in which case the graft applied over it also becomes susceptible to infection and necrosis.

Combined epidermal and dermal skin replacements

  1. Apligraf - It as also marketed as Living Cell Therapy. It is composed of a bilayer where the epidermal component consists of allogenic keratinocytes cultured from neonatal foreskin and the dermal component has allogenic neonatal fibroblasts. Both components are present in a gel of type 1 bovine collagen to form a composite bilayer that can be readily applied on the wound bed. Like other skin substitutes in its category they promote wound healing by release of various growth factors and in case of deep burns prepare the wound bed for grafting


  2. Contraindications: Contraindicated in those allergic to bovine collagen and in those patients where the wound bed is heavily infected. Short shelf life of 5 days.

  3. OrCel - Similar to Apligraf as it also contains allogenic keratinocytes and fibroblasts but they are cultured in different layers at a liquid-air interface. Furthermore, the matrix is made of porous bovine type 1 collagen into which the cells grow. During healing the autologous cells can also proliferate and grow into the matrix to replace the allogenic cells


  4. Shortcoming: Contraindicated in those allergic to bovine collagen and in those patients where the wound bed is heavily infected. Short half-life.

  5. Graft Jacket - This is a regenerative tissue matrix developed from human cadaveric skin. The matrix is devoid of any cellular component but has an intact basement membrane into which new vessels from the wound bed can grow into.


Shortcoming: Requires cryopreservation for storage. Despite vigilant screening process there may be a risk of disease transmission, which is usually associated with allogenic transplantation.


  Biomembranes Top


They are made up of compatible biological membranes of vegetal materials including rubber, poly D lactic acid. Polyurethane and amnion also come under this subset.

  1. Amnion: Commercially available biomembrane[44] consists of skin like foetal ectoderm. They have angiogenic properties. They are freeze-dried and gamma irradiated before put to use. They decrease pain, reduce scar formation, provide protection from infection and control electrolyte and protein loss
  2. Polyurethane film (tegaderm)[45] has gas semipermeability action and this helps in increasing epithelialisation. They also help to retain moisture and contribute in wound healing as already established. It also regulates TGF beta by regulating transepidermal water loss and stimulates keratinocytes thus helping in wound healing
  3. Hevea brasiliensis[46] derived from rubber tree known to increase angiogenesis and epithelialisation also has a role in wound dressing.



  Bioengineered Scaffolds Top


They are polymeric substrates coated with bioactive materials such as fibrin, collagen, silk or tissue-engineered substrate impregnated with endothelial progenitor cells and nanoscaffold substrate.


  Mechanism of Action Top


Collagen 1[47] scaffold can provide medium to transfer circulating angiogenic cells and hence enhance healing.

The scaffolds can be modified by coating with porous polyethylene (CCPE)[48] and bio-inert poly (2-methacryloyloxyethyl phosphoryl choline-co-n-butyl methacrylate)-coated polyethylene. Upregulation of angiogenesis and interleukin beta characterstics of these materials help in wound healing.

Fibroblast propagation electrospun core,[49] gelatin/poly(L-lactic acid)-co-poly-(ε-caprolactone) nanofibers, with a core of photosensitive polymer poly (3-hexylthiophene), and epidermal growth factor has found a role in wound healing.

Microbial cellulose[50] helps in skin tissue rejuvenation and wound healing due to its additional hydrophilic, elastic and wound exudate-absorbing properties.


  Results of the Review of Antibiotics Top


Systemic antibiotic prophylaxis does not seem to offer advantage in preventing burn wound infection, septic episodes or mortality. It does seem to offer some benefit as decreased mortality in patients of inhalation burn injury who would require mechanical ventilation. Antibiotic prophylaxis can be given pre operatively before grafting as there is improved graft survival in patients of acute burns taken up for skin grafting. However, skin grafting is normally attempted only on sterile wound beds.


  Results of Systematic Review of Burn Dressings Top


About eight systematic reviews have been analysed for the efficacy of skin substitutes and dressings in preventing infections and promoting wound healing[51],[52],[53],[54],[55],[56],[57] [Table 3]. Honey and hydrogel were found to promote wound healing while honey and skin substitutes prevented infection better than conventional dressings including SSD. Since cost and availability of bioengineered skin substitutes are a limiting factor, there is still a paucity of large trials, which aim at exploring their superiority over allografts.

Three-dimensional bioprinting

Irrespective of the type of skin substitutes, the major pitfall of the majority of these applications is the existence of allogenicity and hence the complications related to it. Though the conventional tissue engineering technologies show promises to build skin scaffolds, the complexity of adult skin can never be duplicated in the form of the skin appendages such as hair, sweat and sebum. The newer three-dimensional (3D) bioprinting involves the bonding of thin layers sequentially introduced using a scaffold generated from a computer-aided manufacture and design, to replicate all the properties of a complex structure such as skin.[58]

Stem cell-based scaffolds

Research integrating embryonic stem cells and adipose-derived stem cells with 3D scaffolds for regenerating dermis recently have achieved varying degree of success.[59]


  Future in Managing Burn Infections Top


As technology advances, efforts to replicate a living skin model through 3D printing and culture will continue. But in cases where infection is already established in the wound, antimicrobials have often been ineffective, especially against biofilm-forming bacteria. Now, efforts are on to use a cocktail of bacteriophages to treat burn wound formed by biofilm forming bacteria such as pseudomonas. The strategy would be to use these bacteriophages as a topical application. The ideal concentration of the phages still needs to be determined.[60]

Another plan to combat this infection and prevent emergence of antibiotic resistance is to use recombinant vaccines targeted at the outer membrane proteins of this bacteria.[61]


  Summary Top


The management strategy in combating burn infections primarily depends on preventive strategies like isolation and sterile environment for care. The role of dressings and skin substitutes in preventing infections and promoting the rates of healing adds to the armamentarium to tackle burn infections. Therefore along with the following the established infection control guidelines, the stress should be on providing a suitable cover to the burn wound to prevent invasive burn infection. Whenever a burn wound infection is detected, the choice of subsequent management would depend upon the requirement of skin grafting and the choice of antibiotics on the wound culture. Prophylactic systemic antibiotics have been valued only in patients on mechanical ventilation and those requiring grafting. The final determinant of local wound applications would rest upon the objective of treatment– whether infection control or promotion of wound healing. As the majority of extensive burn wounds requiring grafting procedures seldom have adequate donor sites it is imperative to cover these wounds temporarily with skin substitutes which can help both in wound healing and infection control until a suitable donor site is available.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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  In this article
Abstract
Introduction
Materials and Me...
Pathogenesis of ...
Management Strategy
Topical Antimicr...
Burn Wound Cover
Skin Grafts
Biological Materials
Biologic Dressings
Skin Substitutes
Biomembranes
Bioengineered Sc...
Mechanism of Action
Results of the R...
Results of Syste...
Future in Managi...
Summary
References
Article Figures
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