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Antibacterial activity of honey against ESBL -producing strains
E. E. Stobberingh, PhD Deputy Head of Dept. of Medical Microbiology Academic Hospital Maastricht (azM), The Netherlands, December 2010 Antibiotic resistance in Gram-positive as well as Gram- All experiments were performed in duplo. negative microorganisms is a growing problem world-wide. The prevalence of Methicillin resistant Staphyloco- For the semi-quantitative assessment the blood agar ccus aureus (MRSA) and Gram negatives producing an plates were inoculated according to the “four streak” Extended Spectrum beta-lactamase (ESBL) is steadily method: growth in the fi rst streak only was recorded as increasing during the past decades. Antibiotic use is 1, in the second streak as 2, in the third streak as 3 and generally considered the main risk factor for antibiotic growth up to the last streak as 4.
resistance. Eff orts to reduce the use of antimicrobial agents are therefore warranted.
One of the possibilities to reduce the use of antimicrobi- Characteristics of the clinical isolates: al agents is the use of non-antibiotic compounds for the The antibiotic susceptibility of the tested E. treatment of infections. Examples of these non-antibi- sented in table 1. All isolates had diff erent susceptibility otic agents are the use of cranberries to prevent urinary to the antibiotics tested.
tract infections or the use of honey in case of wound infections. The antibiotic susceptibility of the tested K. pneumoniaeis depicted in table 2. All isolates had diff erent suscepti- In this report, we describe the in-vitro antibacterial ac- tivity of medical grade honey against clinical isolates of ESBL producing Escherichia coli The characteristics of the reference strains are given in Eff ect of L-Mesitran Ointment on clinical isolates Clinical isolates of ESBL producing E. Using an inoculum of ~10e5cfu/ml eight out of ten iso- niae, nine and eight of each species respectively were lates were completely inhibited (=bactericidal) in the used as well as the following reference strains: E. presence of honey ointment. No eff ect was observed in ducing CTX-M1, K. pneumonaie producing SHV1 and K two isolates, i.e. A02 and A06 in the fi rst experiment and pneumoniae producing CTXM15/SHV11/TEM1. The production of ESBL was determined according to At an higher inoculum ( ~ 10e7/ml) three to four out of the method as described by the NVMM. The production ten were completely inhibited. A 100-1000 fold reduc-of ESBL of the reference strains was genetically charac- tion in cfu/ml were observed with the other isolates.( Solutions of L-Mesitran Ointment and L-Mesitran Soft Using an inoculum of ~10e5 cfu/ml a reduction in cfu/gel were tested as follows: one gram of each product ml was observed for strain B05 and B08, whereas the was added to Mueller Hinton Broth in 50% w/w result- other isolates were completely inhibited in the pres- ing in a fi nal concentration of honey in the solutions of ence of honey ointment. In the duplo experiment the 24%w/w and 20% w/w respectively. At an inoculum of ~10e7 cfu/ml mostly only a reduc- Tubes containing the solution of the L-Mesitran oint- tion in cfu/ml were observed. In the fi rst experiment a ment and L-Mesitran Soft gel were inoculated with 100µ reduction was found in all isolates tested, in the second litre of a diluted ( 10e-1 and 10-3) overnight culture of experiment four out of 10 strains were completely in-the E. oli and K. pneumoniae isolates, incubated over- hibited, the others showed a reduction in cfu/ml.
night at 37 C and plated onto blood agar plates. The plates were overnight incubated at 37C and the results The eff ect of the ointment on the reference strains were (semi)-quantitatively assessed. Tubes without honey comparable with those obtained with the clinical iso-solutions inoculated with the same bacterial dilutions lates (table 5a and b)were used as control. Antibacterial activity of L-Mesitran Ointment and L-Mesitran Soft, December 2010 Table 1. Antibiotic susceptibility of the clinical isolates of Escherichia coli
Table 2. Antibiotic susceptibility of the clinical isolates of Klebsiella pneumoniae
Table 3. Characteristics of the reference strains
Table 4a. Antibacterial eff ect of L-Mesitran ointment Table 4b. Antibacterial eff ect of L-Mesitran ointment
Escherichia coli
Sample strain#
Initial Inocu-
Bacterial count (log after overnight
Sample strain#
Initial Inocu-
Bacterial count (log after overnight
incubation with honey ointment
incubation with honey ointment
Antibacterial activity of L-Mesitran Ointment and L-Mesitran Soft, December 2010 Table 5a. Antibacterial eff ect of L-Mesitran Ointment
Table 5b. Antibacterial eff ect of L-Mesitran Ointment
Sample strain#
Initial Inocu-
Bacterial count (log after overnight
Sample strain#
Initial Inocu-
Bacterial count (log after overnight
incubation with honey ointment
incubation with honey ointment
Eff ect of L-Mesitran Soft gel on clinical isolates c and K. pneumoniae isolates were completely inhibited in the presence of honey gel, irrespective of the inoculum size. After incubation of the E. coli and K. pneumoniae strains with solutions of the honey gel no growth at all was observed. The eff ect of honey gel on the reference strains were similar as those obtained with the clinical isolates. The reference stains were completely inhibited.
The antibacterial activity of the L-Mesitran Soft gel against ESBL producing strains (E. coli and K. pneumo-niae) was better than that of the L-Mesitran Ointment. Similar results were also obtained in previous experi-ments (Stobberingh, Vandersanden: December 2010).
The variable results obtained with the Ointment are probably due to diffi culties to obtain a homogenous solution of the Ointment in the broth, a problem which we did not encounter with the Soft gel. This study was partly sponsored by Triticum Exploitatie BV, manufacturer of L-Mesitran Ointment and L-Mesi-tran Soft.
Antibacterial activity of L-Mesitran Ointment and L-Mesitran Soft, December 2010 The anti-bacterial activity of honey-based ointments against
antibiotic resistant Staph. aureus
and Ps. aeruginosa
(in-vitro, clinical isolates)
E. E. Stobberingh, PhD1, Geert Vandersanden BSc2(1) Deputy head Dept. of Medical Microbiology Academic Hospital Maastricht (azM), The Netherlands (2) Dept. of Medical Microbiology Academic Hospital Maastricht (azM), The Netherlands , December 2010 wound care, because honey may contain pesticides, herbicides, heavy metals, antibiotics (used for the treat- Wound infections, antibiotics, burns, Staphylococcus au- ment of diseases in bees) and spores of Clostridium reus, Pseudomonas aeruginosa, honey, dilution method, botulinum which can lead to wound botulism. Killing of medical microbiology, post-operative surgical wounds these spores without aff ecting the antibacterial activity of the honey is only possible using gamma irradiation (8). The other pollutants are absent in honeys harvested in careful selected areas without e.g. industrial pollution. Four commercial available honey based products and Honey free from all these pollutants is called a medical irradiated honey were in-vitro compared for antibacte- rial activity against clinical isolates and reference strains of Staphylococcus aureus and Pseudomonas aeruginosa In recent years MGH products have been approved by with known antibiotic resistance. Diff erent amounts the EU for the use in wound care. These products are were diluted with Mueller Hinton Broth (MHB) or NaCl used with success in wound care management and are and incubated at 37°C for 18-24hours on a mixing plate. considered to have antibacterial activity. They all use After incubation 100 μl was plated on to a blood agar diff erent types of MGH and are either 100% MGH or con-plate and after incubation for another 18-24 hours at tain added (natural) ingredients.
37°C the bacterial growth was semi-quantitative as-sessed. As a control 80μl MHB + 20μl overnight culture Aimof S. aureus and P. aeruginosa was used.
The aim of this in-vitro study was to determine the an- L-Mesitran Soft showed the highest anti-bacterial prop- tibacterial activity of commercially available MGH and erties after 24hrs at the lowest dilution. Honey has as an MGH-based products against clinical isolates and refer-added benefi t that it can speed up wound healing and ence strains of antibiotic resistant and susceptible Sta-therefore (apart from lower material costs) can provide phylococcus aureus and Pseudomonas aeruginosa. These a cost eff ective therapy. The tested products provide an species were selected because of their important role attractive alternative for the use of (topical) antibiotics in in dermal infections (Staphylococcus aureus) and burns the management of wound infections, L-Mesitran Soft (Pseudomonas aeruginosa). A test method was devel-in particular.
oped that could provide comparable results of all the tested products.
The golden standard for treatment of infected wounds is still the use of systemic or topical antibiotics (1). There Nine clinical isolates of Staphylococcus aureus, (num-is however a growing concern worldwide about the bered 1-9), 6 methicillin susceptible and 3 methicillin rise in antibiotic resistance (2, 3). Data collected by the resistant were selected with diff erent characteristics i.e European Antimicrobial Resistance Surveillance Sys- Panton Valentine Leucocidine (PVL), and Toxic Shock tem (EARSS) reported “an unpleasant, but important Staphylococcal Toxine (TSST), positive and negative message: antimicrobial resistance is becoming a larger strains were selected from diff erent genetic background. public health problem” (4). This European concern is The PVL and TSST positive strains were chosen because shared worldwide (5). Finding eff ective alternatives for these are commonly found in severe wound infections, antibiotics to reduce the use and therefore reduce the including MRSA-strains. emerging antibiotic resistance is therefore of the utmost importance.
Five clinical isolates of Pseudomonas aeruginosa (n=5), numbered A-E also varied in susceptibility to antibiot- Recently Cooper et al. described the antibacterial ef- ics. The antibiotic susceptibility of the isolates have been fi cacy of diff erent types of honey, varying from table described previously: reference strains Pseudomonas honey to specifi c fl oral types of honey (6). All in vitro aeruginosa ATCC 27853 and Staphylococcus aureus ATCC research shows that most honeys do have an antibacte- rial eff ect, albeit with a variation in eff ectivity (7). How-ever, not all pure unprocessed honey can be used for Antibacterial activity of L-Mesitran Ointment and L-Mesitran Soft, December 2010 80μl MHB + 20μl overnight culture of S. aureus and P. aeruginosa was used.
Compared to ‘Regular Honey’, Manuka honey proved to be more eff ective against Staphylococcus aureus. Manu- ka was more eff ective against the clinical isolates than against the reference strain ATCC29213, i.e. clinical iso- lates were killed at 24% w/w, the reference strain need-ed at least 40% w/w. No diff erence in activity of both products were observed against the diff erent MRSA Manuka honey was more eff ective against Pseudomonas aeruginosa than ‘Regular Honey’. This eff ect is less than the diff erence between the two for Staphylococcus au-reus. The reference strain of Pseudomonas aeruginosa was more inhibited in the presence of honey than the a. ‘’Regular Honey’’: this pure honey, it is the main ingre- clinical isolates, this eff ect is similar for Manuka honey dient of products C + D, listed here under. This honey and ‘Regular honey’. The clinical isolates of Pseudomonas was gamma irradiated; aeruginosa were completely killed at concentrations of b. pure honey, Revamil® (B-factory, NL); 32 % w/w Manuka honey. The ‘Regular honey’ showed d. L-Mesitran® Soft (Tricum, NL): this gel contains 40% “Regular Honey” (see a.), hypoallergenic medical Revamil is bactericidal against Pseudomonas aeruginosa, grade lanolin (Medilan®), propylene glycol, PEG 4000 but not eff ective against Staphylococcus aureus. At an in-and vitamin C & E.
oculum of 10e7 CFU/ml of the diff erent Staphylococcus e. L-Mesitran® Ointment (Triticum, NL): this ointment aureus strains, bacterial growth was rather inhibited. contains 48% “Regular Honey” (see a.), hypoallergenic medical grade lanolin (Medilan®), sunfl ower oil, cod L-Mesitran Ointment is bactericidal against the refer-liver oil, Calendula Offi cinalis, Aloe Barbadensis, zinc ence strain of Staphylococcus aureus, the antibacterial oxide and vitamin C & E.
eff ect against the other isolates showed varying results. Against Pseudomonas aeruginosa the product was bac- tericidal at concentrations of 10e7 CFU/ml. However, at higher bacterial concentrations (10e9 CFU/ml) no Diff erent amounts of “Regular Honey” and Manuka were growth inhibition was observed, both for the reference diluted with 0,9 % NaCl to obtain the following concen- trations i.e. 96%, 80%, 64%, 48%, 32% . One ml of each concentration was added to 1 ml of Mueller Hinton L-Mesitran Soft was bactericidal at a honey concentra-Broth (MHB) resulting in fi nal concentrations of honey tion of 20% w/w against all Staphylococcus aureus and of 48%, 40%, 32%, 24%, 16% (w/w). Pseudomonas aeruginosa strains tested.
L-Mesitran Ointment and Soft contain fatty elements The tested honey products also have an antimicrobial and dilution with 0,9 % NaCl to obtain diff erent con- eff ect, but their effi cacy was variable. (table 2). centrations was not possible. Therefore these products, as well as Revamil, were tested in one dilution only: L- L-Mesitran Soft was by far the most eff ective product Mesitran Ointment 24% w/w/ honey equivalent, L-Mesi- against Staphylococcus aureus isolates both methicillin tran Soft 20% w/w honey equivalent and Revamil 50% susceptible and resistant, and Pseudomonas aeruginosa. w/w honey. Moreover, the least amount of the product was needed for optimal antibacterial eff ectivity. To obtain a similar All tubes were inoculated with diff erent inoculum sizes level of antibacterial activity one would need relatively of the strains of Staphylococcus aureus from 1.5X10e6- more material of the other honey products, with the ex- 1.5x10e8 cfu/ml and Pseudomonas aeruginosa 1.5X10e6- ception of the Revamil product, which does not seem 1.5x10e8 cfu/ml. The tubes were incubated at 37°C for to have any signifi cant activity against Staphylococcus 18-24hours on a mixing plate. After incubation 100 μl was plated on to a blood agar plate( OXOID CM) and after incubation for another 18-24 hours at 37C the bacterial growth were semi-quan-titative assessed as +,++,+++ and ++++. As a control Antibacterial activity of L-Mesitran Ointment and L-Mesitran Soft, December 2010 ing the wounds were found to be resistant to ampicil- General interpretation of the results of antibacterial ef- lin, oxytetracycline, gentamicin, chloramphenicol and fectivity against two bacteria and their clinical isolates Honey was used on nine infants with large infected surgical wounds that failed to heal with intravenous antibiotics, cleaning the wound with aqueous 0.05% chlorhexidine solution and application of fusidic acid ointment. Marked clinical improvement was seen in all cases after fi ve days of treatment with honey, and all wounds were closed, clean and free of infection after 21 The use of honey was compared with gentamicin, ofl ax- ocin, chloramphenicol in animal models (10). Honey <-----------------------------------> had a comparable result to that of local antibiotics for infections of surgical wounds and conjunctiva. A randomized controlled trial (101 patients) demon-strated that regular, thrice-weekly, topical exit-site ap- This in vitro study shows that medical grade honey prod- plication of standardized antibacterial honey was safe ucts have the potential to kill bacteria commonly found and cost-eff ective and resulted in a comparable rate as causative agents such as Staphylococcus aureus and of catheter-associated infection to that obtained with Pseudomonas aeruginosa within 24 hours. L-Mesitran topical mupirocin exit-site application in patients with Soft was the most eff ective compound tested in terms tunnelled, cuff ed hemodialysis catheters (15).
of antibacterial activity against Staphylococcus aureusand Pseudomonas aeruginosa i.e. antibacterial (killing) In a study with 102 patients with infected open fracture activity was observed at the lowest concentration com- wounds and unresponsive to conventional antibiotic treatment (cephalexin and cefazolin), honey treatment caused wound discharge to end and promoted healthy It was not the aim of the study to (re)defi ne the mode granulation tissue within two weeks of treatment (16). of action of the products. The antimicrobial activity has A non-insulin-dependent diabetic female patient with been described in literature as being primarily caused an MRSA infected post-operative surgical wound in the by the high osmolarity of honey (due to the high sugar groin was successfully debrided and cleansed within content), the production of hydrogen peroxide and its nine days of treatment with honey ointment. Wound low acidity (typically between 3-4) and the presence of malodour was eliminated and a swab culture for MRSA other components such as antioxidants (9).
The in-vitro antibacterial activity of honey has also been The same ointment was used to treat a male patient demonstrated in the study of Noori: Gram-positive bac- with pathogenic obesity (BMI 96.5) with a Pseudomonas teria were killed after 1 hour of exposure to 50% honey, aeruginosa infected excised wound on his right leg. The with complete elimination after 3-24 hours. Killing of infection and the malodour were cleared within three Gram-negative bacteria started after 4-6 hours, and days without the use of any additional considered an-were completed after 48 hours (10). Concentrations tibiotics (18).
needed for an optimal eff ect were as low as 5%, but the highest inhibition was seen at 20% (7). In a large number of randomized controlled clinical tri-als with (acute and chronic) infected wounds, honey The worldwide growing antibiotic resistance against treatment has been successfully used in comparison to Staphylococcus aureus (3) and Pseudomonas aeruginosa conventional therapies such as povidone iodine treat- (2) is a cause for concern, taken into account the con- ment, silver sulfadiazine, saline, eusol, sugar, ampicillin tinued use of antibiotics. To date no resistance against ointment and antibiotics (19).
honey has been reported (11, 12) and the fi ndings in this study support the clinical use of honey for the treat- For the management of infections the clinician might ment of infected wounds caused by Staphylococcus also choose an appropriate silver impregnated dressing. aureus and/or Pseudomonas aeruginosa. Several clinical Silver dressings have been used with success in clinical studies described promising results. practice to reduce infection. In-vitro results confi rm the capability of these dressings to eff ectively kill bacteriae In patients with wounds infected with antibiotic-resist- in 24hrs (20). However, research shows that silver can be ant strains of bacteria, not responding to antibiotic ther- cytotoxic to fi broblasts and keratinocytes and therefore apy, good results have been achieved within a couple inhibitory for wound healing (21). In an evaluation of the of weeks after application of honey. The bacteria infect- epidermal cell proliferation, silver dressings signifi cantly Antibacterial activity of L-Mesitran Ointment and L-Mesitran Soft, December 2010 delayed re-epithelialization (22) and a recent study iden- tifi ed two silver-resistant bacteria (23). Medical grade honey based products are antibacte- Moreover: in a direct comparison in vitro of honey and rial, but vary in activity. From the in-vitro tested honey silver dressings it was demonstrated that the silver in- products available on the European market, L-Mesitran terfered with epidermal cell proliferation and migra- Soft showed the highest anti-bacterial properties when tion, implying that it contains cytotoxic material. On the tested against clinical isolates and reference strains of other hand honey signifi cantly stimulates the growth Staphylococcus aureus and Pseudomonas aeruginosaof new cells (keratinocytes and fi broblasts), results in a with known antibiotic resistance. good new cell structure without abundant scar forma-tion and is not cytotoxic (24).
Compared to antibiotics or the use of silver, the use of honey is safe and without adverse eff ects for the Although eff ective, the use of silver as an alternative treatment of infected wounds. The tested honeys can to antibiotic therapy for the management of infected achieve the same goal as antibiotics and silver: reduc-wounds is obviously not without drawbacks.
ing the bacterial burden. Honey has as an added benefi t that it can speed up wound healing and therefore (apart This in-vitro research did not focus on toxicity or the in- from lower material costs) can provide a cost eff ective fl uence of the tested honey products on cell prolifera- therapy. Honey, and in particular the tested products, tion and therefore wound healing. However, no reports does therefore provide an attractive alternative for the of toxicity of honey have been reported to date. On the use of (topical) antibiotics in the management of wound contrary, honey has been shown to stimulate wound infections.
healing as discussed here above. Honey also can provide a cost eff ective solution. In a comparison study between honey and hydrogel for Nonethe healing of shallow wounds and abrasions, honey was extremely cost eff ective in material use, 24 times Referencescheaper (25). Honey speeds up the healing of wounds signifi cantly compared to sugar (26) and e.g. silver sul- 1. Diehr S, Hamp A, Jamieson B (2007) Do topical antibi- phadiazine, povidone iodine, eusol and paraffi n gauze/ otics improve wound healing? J Fam Pract. 56(2):140- hydrocolloid (19). This resulted in reduced hospital stay and nursing time, therefore reducing signifi cantly costs 2. Oudhuis GJ, Verbon A, Hoogkamp-Korstanje JAA, related to wound care, not forgetting the patient com- Stobberingh EE (2008) Antimicrobial resistance in fort realized with the fast and effi cient recovery from a Escherichia coli and Pseudomonas aeruginosa from Intensive Care Units in The Netherlands, 1998–2005. International Journal of Antimicrobial Agent vol All these studies strongly support the use of honey in the clinical setting. However, without standardized prod- 3. Rijnders M, Deurenberg RH, Boumans M, Hoogkamp- ucts certifi ed for clinical use in hospital and home care Korstanje M, Beisser P and Stobberingh EE (2009) setting they are somewhat fl awed from a practical point Antibiotic resistance of Staphylococcus aureus from of view. European (CE), American (FDA), Australian (TGA) ICUs in the Netherlands 1996 to 2006. Critical Care and other government authorities, have broken ground by allowing certain products to be sold and prescribed 4. EARSS Annual Report 2007, by physicians, but only after rigorous investigations earss/Images/EARSS%202007_FINAL_tcm61-55933.
into product safety and reproducible quality. Clinicians would be placing their patients and their own careers 5. Davey P, Brown E, Fenelon L,Finch R, Gould I, Holmes at risk, by using non authorised honey products. This in- A, Ramsay C, Taylor E, Wiff en P, Wilcox M (2006) Sys- vitro study should be followed up by in-vivo research on tematic review of antimicrobial drug prescribing L-Mesitran Soft, because it tested as the best choice as in hospitals. Emerging Infectious Diseases www.cdc.
an antibacterial agent in-vitro. The AZM academic hos- pital in Maastricht is currently devising a randomized in- 6. Cooper RA, Jenkins L (2009) A comparison between vivo comparison model with topical antibiotics to that medical grade honey and table honeys in relation to antimicrobial effi cacy. Feb 12, 2009: http://www. cacy accessed on March 11, 2010 7. Lusby PE, Coombes AL, Wilkinson JM (2005) Bacteri- cidal activity of diff erent honeys against pathogenic bacteria. Arch Med Res. 36(5):464-7 Antibacterial activity of L-Mesitran Ointment and L-Mesitran Soft, December 2010 8. Postmes T, Van den Boogaard A, Hazen M. (1993) Hon- 24. Du Toit DF, Page BJ (2009) An in vitro evaluation of ey for wounds,ulcers and skin graft preservation. The the cell toxicity of honey and silver dressings. Journal 9. Molan P (1992) The antibacterial activity of honey. 2. 25. Ingle R, Levin J, Polinder K. (2006) Wound healing Variation in the potency of the antibacterial activity. with honey – a randomised controlled trial. SAMJ 10. Noori S. Al-Waili (2004) Investigating the antimicro- 26. Mphande A, Killowe C, Phalira S, Wynn Jones H, Har- bial activity of natural honey and its eff ects on the rison W (2007) Eff ects of honey and sugar dress- pathogenic bacteria infections of surgical wounds ings on wound healing. Journal of Wound Care Vol. 11. Bonn D (2003) Sweet solution to superbug infec- tions? The Lancet Infectious Diseases Vol 3:608 12. Pieper B (2009) Honey-based dressings and wound care. J Wound Ostomy Continence Nurs. 36(1):60-66 13. Molan PC (2001) Honey as a topical antibacterial agent for treatment of infected wounds. World Wide Wounds 14. Vardi A, Barzilay Z, Linder N, Cohen HA, Paret G, Barzi- lai A. (1998) Local application of honey for treatment of neonatal postoperative wound infection. Acta Paediatr 15. Johnson DW, Eps van C, Mudge DW, Wiggins KJ, Armstrong K, Hawley CM, Campbell SB, Isbel NM, Nimmo GR, Gibbs H (2005) Randomized, controlled trial of topical exit-site application of honey (Medi-honey) versus mupirocin for the prevention of cath-eter-associated infections in hemodialysis patients. J Am Soc Nephrol 16. Fakoor M, Pipelzadeh MH (2007) A study on the healing eff ect of honey on infected open fracture wounds. Pak J Med Sci Vol. 23(3):327-329 17. Owen G (2005) Successful debridement and cleans- ing of a surgical wound infected with MRSA using Mesitran Ointment and Mesitran Mesh. Poster pre-sented at Wounds UK, Harrogate, 2005 18. Milias K , Nikolaidis D, Karamanlidis A, Anastasiadis H, Vakalis I, Anemoulis P (2008) Extended wound, Ps.aeruginosa. NOVW Practicum October 2008:17 19. Molan PC (2006) The evidence supporting the use of honey as a wound dressing. Lower Extremity Wounds5(1):40–54 (20) Ip M,1 Lui SL,Poon V, Lung I, Burd A (2006) Antimicro- bial activities of silver dressings: an in vitro compari-son. Journal of Medical M 21. Trop M, Novak M, Rodl S, Hellbom B, Kroell W, Goessler W. (2006) Silver-coated dressing Acticoat caused raised liver enzymes and argyria-like symptoms in burn patient. J Trauma Vol. 60(3):648-52 22. Burd A et al. (2007) A comparative study of the cyto- toxicity of silver-based dressings in monolayer cell, tissue explant, and animal models. Wound repair and regeneration Vol. 15(1):94-104 23. Percival SL, Woods E, Nutekpor M, Bowler P, Radford A, Cochrane C (2008) Prevalence of silver resistance in bacteria isolated from diabetic foot ulcers and ef-fi cacy of silver-containing wound dressings. Ostomy Wound Manage. 54(3):30-40 Antibacterial activity of L-Mesitran Ointment and L-Mesitran Soft, December 2010
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