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Wound infection implies replication of organisms within a wound having a detrimental effect on host. They may have an enormous impact on patients quality of life and contribute substantially to the financial cost of patient care as it prolongs the hospital stay (Haley RW 1981; MC Gowan 1991). Skin normally is a strong physical barrier and provides primary protection against infections. When this barrier is damaged, pathogens directly infiltrate the body resulting in infection (Clinton Muray 2011). Patients having wound show the potential to became colonized and infected more readily than other patients, because of the deprivation of mechanical barrier provide by the skin and mucous membranes besides the depression of immunological response. Disruption of the local or systemic steady state existing between the wound and organism may result in more severe complications such as sepsis which is a leading cause of morbidity and mortality (Kinsner Robert S 2009). Clinical features regarding wound infections include redness, warmth and tenderness in wound and surrounding area. Fever and a foul smelling, yellowish-white fluid coming from the wound may be present (Janet M Torpy 2005).
Wound infections are one of the most common hospital acquired infections particularly in surgical setups (Sohail ahmed khan 2006.)The major causes known from the old times to be considered under the discussion of wound infections are pressure ulcers, bite wounds, burns, trauma, amputation and postoperative wounds (Akhtar S 2001; Lab Tests Online 2011). Amongst all of the above mentioned, burns and surgical site wound infections are the most commonly observed types of wound infections. Infections are the major contributing factor for morbidity and mortality in burn units (Clinton Murray 2011). Surgical site infections accounts for 14% to 16% deaths of 2 million nosocomial infections resulting from the surgical sites in US (Singhal 2002).The general factors that play a major role in wound infection are age, obesity, malnutrition, poor hygiene, smoking, hypoxia, anaemia, endocrine and metabolic disorders, malignancies and immunosupression. Characteristics of wounds that are directly involved in infections are nonviable tissue in wounds, any foreign body, tissue ischeamia and haematoma formation (Vanessa Ngan 2011) Wound infections are considered to be the most important factor for postoperative morbidity in patients leading to general complications like patient's discomfort, prolonged stay in hospital, financial crises (Steven M and John J 2002). Complications related to treatment are more severe as it is one of the commonest and troublesome disorder of wound healing (Nicholas RL 1992). These include wound dehiscence, gangrene (John Riefler 2010), tissue death of surroundings which may lead to local debridement or amputation of some part of body, bacteremia which may end up in septic shock related death (Janet M Torpy 2005).
1.2 COMMON ORGANISMS RESPONSIBLE FOR WOUND INFECTIONS
Pathogens those infect wounds can be a part of normal flora or can be acquired from the hospital environment; other infected patients (V.Singh 2012).The predominant organisms isolated from infected wounds are (a) Gram-positive Staphylococcus aureus and coagulase-negative Staphylococcus (Mordi R.M et al. 2008). (b) Gram-negative facultative anaerobes which include Escherichia.coli, Klebsiella species, Enterobacter species and Proteus species (Mehta M et al. 2007). (c) Non-fermenters which includes Pseudomonas species and Acinetobacter species and anaerobes (Mumtaz S ET AL. 2004). Staphylococcus aureus is one of the commonest causes of wound infections, being the normal microbial flora of the skin. MRSA( Methicillin-resistant Staphylococcus aureus) is a potential and significant cause of morbidity and mortality in cases of wound infections. MRSA has shown high prevalence in wounds in a study in India (V.Singh 2012)
Wound infections are one of the most important components of hospital acquired infections According to WHO, there is 3-21% prevalence rate of hospital acquired infections with wound infections at the rate of 5-34%of the total (Singhal H et al. 2009). According to one survey in United States, around one million patients got wound infections postoperatively, every year (Haley RW 1981; Wenzel RP 1992).
Situation in Pakistan:
In Pakistan, population based data are lacking; however, several hospital based studies from different parts of the country have consistently indicated a very high incidence of wound infections. A study performed in Aga Khan University, Karachi showed rates of surgical site wound infections higher than the NNIS standards. Overall the SSI rates for the NNIS risk categories 0, 1, 2 and 3 were 1.9%, 3.7%, 6.7% and 5.1% (Pishori T et al. 2003). According to a study in 2007, the overall rate of wound infections in a surgical setup was 13%. Out of which 5.3% infections were in clean operations, 12.4% in clean contaminated, 36.3% in contaminated and 40% in dirt-infected cases (Sangrasi A K et al. 2008). Another study in regard of infections in post burn wounds revealed that the 49.3%total patients were infected (M.Ahmed 2006), which is more higher than a similar study in 2004, Nigeria (Kehinde A.O 2004). In another study related to SSI, the rate of infections were 9.3% in a tertiary care hospital of Nawabshah, Pakistan (Mohd Sharif Awan et al. 2011).
1.4 GENERAL TREATMENT MEASURES
Management of wound infections is a fundamental part of wound care practice. Treatment of the wound infections specifically depends on the nature of wound, degree of infection, and the bacterial colonization responsible for infection. Generally all wounds with infections should be cleaned ,all foreign materials must be removed (if present), pus must be drained, before starting with the specific treatment (Janet M Torpy 2005).
1.5 SPECIFIC TREATMENT MEASURES :
Tissue repair is extremely complex and often unpredictable relying upon the controlled response to trauma and the intrinsic ability of the body to heal. Before 1980's, it was relatively easy to categorize the management options for wound infections due to their less number. Now a days, multiple treatment options are available in different clinical platforms including local topical dressings like locally acting antimicrobials (silver sulfadiazine) creams and honey, local debridement therapy, maggot treatment and use of topical negative pressure/ vaccum assisted wound closure dressings and systemic antimicrobial therapy (Khan F.R et al. 2007; Visvadia B.G et al. 2008).
1.5.1 Antimicrobial therapies
Amongst all of the above therapies, antimicrobial therapy is most commonly used for preventing and treating wound infections along with a local dressing like silver sulfadiazine. The use of antibiotics was a milestone in the effort to prevent and treat wound infections. In 1960s, the concept of prophylactic use of antibiotics was established (Burke JF 1961; Barchitta M et al.2011). Advantages of antibiotics depends on certain factors like its activity against the particular bacterial infection for which it has to be used, its power of tissue penetration to reach the involved wound, its cost effectiveness and its minimal disturbance to intrinsic body flora e.g gut etc (Woodfield JC et al.2009). It is thought that approximately one in four patients with a chronic wound infections is being treated with antibiotics at any one time, while 60%will have received systemic antibiotics within the previous 6 months period. Expert opinion guides the use of topical antibiotics, but clear indications and durations of usage in an infected wound are still unclear. As there are limited trial data available concerning the effectiveness of topical antibiotics to reduce bacterial burden, current treatment protocols tend to be based on an empirical approach (Landis SJ 2008). The selection of the specific antibiotic treatment used depends very much on the preferences and previous experiences of the clinician involved (Bates-Jenson BM 2007).
But with time, the power of most effective antimicrobial treatment against the bacterial wound infection is weakened particularly correlated to the development of bacterial resistance against these drugs. Bacterial resistance is directly associated with the increase in morbidity and mortality rates (Khan A.J et al. 2008). Presently, MRSA in cases of gram positive aerobes and ESBL producing E.coli and Klebsiella etc are frequently isolated in wound infections (Tao C et al. 2009). Along with the above bacteria, Multi Drug Resistant bacteria are one of the important causes of non-healing wounds. In 2007, a study reveals the rate of MDR bacteria as high as 18% of total cultures of infected wounds (Seybold U et al. 2007). When resistance to three or more classes of antibiotics is demonstrated, Acinetobacter baumannii is referred to as multidrug resistant (Peleg et al. 2008).
The situation has become complicated due to the organisms capability to acquire diverse resistance mechanisms. This has resulted in the emergence of pan drug resistant strains and there is deficiency of new antimicrobial agents in development.(Talbot et al., 2006; Lolans et al., 2006).
1.5.2 Silver Sulfadiazine and other Silver compounds
From thousands of years, Silver has been used as a medicine (Thomas S and Mc Cubbin 2003). Since 1996, the topical use of Silver compounds as dressing have been strongly marketed and used in medical setups (Michaels JA et al. 2009). Silver has shown to be effective against many antibiotic-resistant bacteria like MRSA and vancomycin -resistant Enterococci (Jones SA et al.2004). The mechanism of action of silver has been explained as it is due to the ability of silver to form ionic salts (Ag+) in the presence of acid. These positively charged ions(Ag+) got attracted and bind to negatively charged cell membrane structures of the bacteria and enter the bacteria (Michaels JA et al. 2009). Inside bacterial cell it acts on the multiple pathways. It blocks the key pathways such as cellular respiration structural changes of bacterial membranes. It also blocks the enzymes and transport system of bacteria (Asavavisthchai S et al. 2009). It may also inhibit transcription and replication of bacterial RNA or DNA (Fong J and Wood F 2006). The multi-system affects of Silver compounds help their antibacterial activity. This mechanism also inhibit the development of resistance of bacteria to silver, as multiple random mutations are required. However, if the exposure of low level concentration of silver is continued; resistance development is possible (Leaper DJ 2006).
Silver was formulated as the salt of the sulphanomide antibiotic, sulfadiazine, in 1960s by Fox (Fox 1968). Since the introduction of silver sulfadiazine into clinical setups, it has been used extensively in topical treatment of infected burns, infected chronic wounds and recently also for the prevention of wound infections. Although Silver containing dressings or topical agents play role in the treatment of wound infections but their activity in preventing wound infections or provoking wound healing is not confirmed even till now(Storm-Versloot MN 2010). In treating wound infections, it is probable that silver sulfadiazine functions by delivering sustained, low concentration of silver into the wound environment, and that this interferes with, or modulates, multiple cellular processes. There are multiple delirious effects in microorganisms rather than a single, specific inhibitory mechanism (Fox and Modak 1974). Initially, gram negative and gram positive species were found to be susceptible in regard of silver sulfadiazine (Carr et al.1973). But later in 1993, another study revealed the details that coagulase-negative staphylococcus, Streptococcus pyogenes, Enterococci, Candida albicans, E.coli, Klebsiella pnumoniae, Enterobacter spp, Proteus mirabilis, indole- positive Proteus spp, Providencia struartii and Pseudomonas aeruginosa along with the multi-resistant bacteria such as MRSA and Acinetobacter spp all are susceptible for silver sulfadiazine irrespective of their sensitivity to sulphonamides (Hamilton-Miller et al.1993).
For silver, the bacterial resistance is developed through plasmid-based genes (Silver 2003). In 1974, some silver sulfadiazine resistant and some sulphonamide resistant strains of Staphylococcus aureus, Acinetobacter spp, Klebsiella spp, E.coli, Enterobacter spp, Proteus spp were detected (Lowbury et al 1976). Similarly, some in vitro studies have proven that silver sulfadiazine resistant strains of Pseudomonas aeuroginosa also exists (Modak and Fox 1981). Silver sulfadiazine has been associated with many cytotoxic effects in human body as it induces agranulocytosis (Willoughby 1977), allergic contact dermatitis ( Fisher 2003; Agarwal and Gawkrodger 2002). Increased serum level of silver has been seen to cause renal dysfunctions, liver and nerve toxicity due to prolonged use of topical silver sulfadiazine (Maitre et al. 2002). cytotoxicity in vitro has been explained and postulated as a cause of delayed wound healing (Poon and Burd 2004).
1.6 REASONS OF TREATMENT FAILURE
Management of wound infections is very critical as the medical personnel may accompany many problems on their way for treating the wound infections. The three major key factors or reasons that lead to treatment failure or increased morbidity and mortality in wound infections are poly-microbial nature of infected wounds, microbial synergy and development of antimicrobial resistance (Stephan J .Landis 2008).
1.6.1 Poly-microbial nature of infected wounds
All infected wounds, especially chronic wounds have a complex microbiological environment with mixed flora, which changes over time. Initially, in most of the cases the infected wound is found to be populated with gram-positive cocci like Staphylococcus aureus, coagulase-negative Staphylococci or Streptococcus spp. Later on, facultative anaerobic or aerobic gram-negative bacilli such as E.coli, Klebsiella or Pseudomonas spp etc take up residence in few days or weeks (Bowler PG and Davies BJ 1999a). This presentation of infected wounds with multiple bacteria is one of the important factors for treatment failure.
1.6.2 Microbial synergy
Microbial synergy is another major reason that plays a vital role in failure of successful infective wounds management. Many bacteria work together in microbial synergy (Bowler PG and Davies BJ 1999b). The net pathogenic effect of bacteria is greater than if these same organisms worked independently of each other. In mixed aerobic / anaerobic infections, microbial synergy frequently exists (Bowler PG 1998).
1.6.3 Development of antimicrobial resistance
Development of antimicrobial resistance is another key feature of treatment failure. With increasing frequency, infected chronic wounds are seen colonized with many MDR bacteria including both gram-positive and gram-negative bacteria (Fridkin SK et al. 2005). MRSA is also an important and commonly seen in cases of infected wounds (Boucher HW and Corey GR, 2008). These resistant strains of different bacteria are a constant threat to the health care environments.
1.7 TRADITIONAL MEDICINE
The escalation of resistance mechanisms in bacteria and cost of antimicrobial therapies has countered the initial and seemingly guaranteed success of antimicrobial therapy. Hence, WHO recommends use of traditional medicine in developing countries to accelerate the struggle for primary health care establishment (Elujoba AA et al. 2005). According to WHO estimates about 80%of people living in developing countries rely on harvested wild plants for some part of their primary health care (E.Elisabetsky et al.1996).Due to the expenses, side effects and the resistance that pathogenic microorganisms have developed against antibiotics, recently much attention has been paid to extracts and biologically active compounds isolated from natural species used in herbal medicine. These traditional methods are affordable, readily available, and most importantly acceptable to local people. In order to achieve the goal of health for all, adaptation and integration of traditional medicine along with modern medicine is very important (Elujoba AA et al. 2005). This context motivated us to determine the antibacterial activity of honey (one of the commonly used traditional medicine) in treating infected wounds in comparison of silver sulfadiazine.
By making honey, bees have served humanity since very ancient times. beekeeping goes as far back as 3500 BCE (Encyclopedia Americana 1993). Originally used by the ancient Egyptians and Greeks, honey is a viscous, saturated sugar solutions now widely used in healthcare setups (Simon A et al.2009). Since the beginning of human history across a broad and diverse array of cultures, honey has been used as a therapeutic agent on a very large scale(White JW Jr 1966). Many evidences for its use as a multi-purpose medicine are available from ancient scrolls, tablets and books. Sumarian clay tablets estimated to be 6200 BC, Egyptian papryri dated from 1900-1250BC, Veda (Hindu Holy Scripture) about 5000 years old (Board).(the national honey board 2008).
1.8.1 Honey and Islam
Almost in all Holy Scriptures including Holy Quran, Holy Bible and Holy Torah, the miraculous healing properties are mentioned (Namias N 2003). Honey's healing property has been mentioned in the Holy Quran and the Hadith. The Almighty Allah says in Quran,
"And thy Lord taught the Bee to build its cells in hills, on trees and in (men's) habitations. Then to eat of all the produce (of the earth)and find with skill the spacious paths of its Lord. There issues from within their bodies a drink of varying colour, wherein is healing for men .Verily in this is a sign for those who give thought." (Abdullah Yusuf Ali 1999)
Our Greatest prophet Muhammad (peace and blessings of Allah be upon Him) says:
"Make use of the two cure: honey and the Quran."(Qayyim II 1999)
1.8.2 Antibacterial properties of honey
In 1882, the antimicrobial activity of honey was first reported (Robson V et al. 2008). The antibacterial properties of honey were first reported by Van Ketel in 1892 and were mentioned by Dustmann in 1979 (Dustmann JH 1979). In 1937, Dold revealed that inhibine is hydrogen peroxide generated by an enzyme hydrogen peroxide from bee gland (Okeke et al. 2005). The antibacterial activity discovery leads to many other studies in the due course of time which confirmed the antibacterial potential of honey (Efem et al. 1992 ; French et al. 2005). The important components of honey that are the key factor in antimicrobial activity are its acidity, high osmolarity, hydrogen peroxide generated by glucose oxidase (bee origin) and non-peroxide factors (plant origin) (Dustmann 1979, Molan 1999; Franchini et al. 2007). The methylglyoxal (MGO) is explained as an active component of honey, responsible for non-peroxide antibacterial activity in Manuka honey which was previously labeled as, Unique Manuka Factor (UMF) (Mavric et al. 2008). Honey, amazingly inhibits more than sixty different species of pathogenic bacteria (Olofsson T et al. 2008). Honey is also capable to disrupt the biofilm produced by different bacteria and interfere with the potential of pathogenic organisms to attach on host surfaces (Irish J et al. 2006; Okhiria O et al. 2004). Honey resistant bacteria have been not reported till now (S.E. Maddocks 2012).
1.8.3 Immunity enhancing properties of honey
Along with the antibacterial properties, honey enhances the immune system by stimulating cytokine (TNF-a, IL-6) production from human monocytes via TLR4 as highlighted by Tonkes et al in 2007 (Tonks AJ 2007). Honey has been proved to improve the growth of normal flora of gastrointestinal tract (Olofsson T et al. 2008). A variety of non-digestible carbohydrates (prebiotics) have been identified in honey. The prebiotics seems to promotes beneficial bacteria like bifidofacteria and lactobacilli (Shin and Ustunol 2005).
1.8.4 Role of honey in management of wounds
Honey has been used for the treatment of wound infections for the past 4000 years (Jull AB et al. 2008).Hippocrates, the Greek physician (460-377 BC) prescribed honey for clinical conditions including wounds and gastritis. (Cooper RA et al. 2000; George MN and Cutting KF 2007). The viscosity of honey provides a protective barrier, osmolarity draws fluid from underlying tissues, dressings do not adhere to wound surface because the viscous nature of honey provides an interface between wound bed and dressing, removes malodor as bacteria prefer for sugar instead of proteins (amino acids) and lactic acid is produced in place of malodorous compounds, promotes autolytic debridement (Bogdanov S 2009). Honey helps in the formation of a protective layer on the wound by absorbing moisture and lowering pH, which results in the prevention of wound penetration and colonization of bacteria (Lofti A 2008). It stimulates healing due to its bio-active effect and also acts as an anti-inflammatory. Honey is also found to be effective against a wide range of microbes including clinical isolates of MRSA, VRE, and other MDR gram-negative organisms including P.aeruginosa (George N.M and Cutting K.F 2009). Honey is also useful in the management of wound infections with coagulase-negative Staphylococci (French M et al. 2005). Honey is also capable to disrupt the biofilm produced by different bacteria mostly found in infected wound like Pseudomonas aeruginosa and Staphylococcus aureus etc and interfere with the potential of pathogenic organisms to attach on host surfaces (Irish J et al. 2006; Okhiria O et al. 2004). In one recent study, revealed that honey can disrupt the interaction between Streptococcus pyogenes and human fibronectin which result in inhibition of biofilm production in this bacteria (S.E. Maddocks 2012).
1.8.5 Honey products
Honey is regaining popularity in medicine. Its re-introduction depended upon the development of wound care products that achieved approval by regulatory authorities, and its acceptance rested on evidence of clinical efficacy (Naef et al. 2004). It has been approved by FDA as therapeutic agent for leg ulcers, diabetic foot ulcers, burns, skin graft donor sites and surgical wounds. It is also effective when the conventional treatment fails (Bonn 2003). The first modern product to gain regulatory status was Medi-honey. It was licensed as a complementary therapy by the Australian Therapeutic Groups Administration in 1999 and has since become CE marked and is being used in Europe. In the United Kingdom the first CE marked wound dressing to gain drug tariff status in 2004 was impregnated with active Manuka honey (Naef et al. 2004). A range of honey wound care products are now available throughout Europe, Australia and New Zealand and some are expected to be introduced into North America (Lusby et al. 2005) .
1.9 DIVERSITY IN HONEY FLORA:
In Pakistan, there is diversity in honey flora due to abundance of flowering plants including Beri, Citrus, Acacia, Clover and Brassica etc. The antibacterial component of honey depends upon the nectar of the flora used by particular honey bees. This property imparts great variation in antibacterial activity of honey as there is variation in honey flora throughout the world. The different aspects of honeys antibacterial potential have been extensively reviewed by Molan in 1992 (Molan 1992a; Molan 1992b). Another research from Bangladesh reported that unifloral honeys available in the region were significantly active against the wound infecting pathogenic bacteria (Khalil et al. 2001). More than one hundred botanical species from which European unifloral honeys can be produced are identified and surprisingly no two honey are completely the same and hence the antibacterial potential also varies (Persano Oddo and Bogdanov 2004) .
1.10 BERRY HONEY
Pakistan produces some of the best varieties of natural honey in the world, Pakistan's Beri (Zizyphus jujuba) honey is regarded as the most valuable in the world being dark in colour (Hannan A et al. 2009). Beri honey is unifloral; a honey is considered unifloral if the pollen grain proportion of that is above 45%. Beri honey has dark colour, as the dark colour honeys are considered to have high level of antioxidant as well as antibacterial property among all Pakistani flora.
Recently a study conducted at University of Health Sciences, Lahore, Pakistan revealed that the antibacterial activity of Pakistani Beri-honey is compareable to the FDA approved Manuka honey (Hannan A et al. 2009). It has been thought that non-gamma irradiated honey might contain spores of Clostridium botulinum, so should be sterile with gamma irradiation before using it topically. However, as a matter of fact not a single case of clostridium botulinum associated with wound infection has ever been reported so far. On the other hand it has been reported recently that raw/non-gamma irradiated honey harbor lactobacilli and bifidobacteria (Olosson T and Vasquez A 2008) which are beneficial flora and enhance the process of wound healing (Halper.J et al. 2003). These interesting linkages motivate us to compare both gamma irradiated and non-gamma irradiated Pakistani Beri honey with silver sulfadiazine as a topical antibacterial agent in infected wounds management. A recently study conducted at the Department of Microbiology, University of Health Sciences Lahore, Pakistan revealed that out of one hundred sample of Beri honey, collected from Karak district has more antibacterial activity against MDR S. typhi.
1.11 Rational of the study
Due to the problems of resistance and side effects of modern treatment, honey is re-establishing as a valuable agent in modern wound care management. Silver sulfadiazine is commonly used dressing, for the management of simple and critically colonized wound infections as well as for prophylaxis. Emergence of resistant strains of microbial species, retardation of wound healing and cytotoxicity are the undesirable characteristics that result in the treatment failure with topical silver sulfadiazine. The aim of the present study was to determine the antibacterial activity of Pakistani Beri honey in comparison with silver sulfadiazine in infected wounds. In this prospective, controlled trial, we will determine the efficacious therapeutic aspects of Pakistani Beri-Honey versus silver sulfadiazine dressings for treating infected wounds. Another aspect of our study will be to compare the efficacy of gamma irradiated Beri honey with non-gamma irradiated Beri honey. Inshallah, our research will help in optimizing the efficacy of Pakistani Beri honey in wound management.
1.12 AIMS & OBJECTIVES:
The objective of the study was:
To evaluate the antibacterial activity of Pakistani Beri-honey compared to silver sulfadiazine in infected wounds.
To find out the susceptibility pattern of isolates from infected wounds before and after the application of different dressings.