Consensus on Wound Antisepsis: Update 2018€¦ · Consensus on Wound Antisepsis: Update 2018 Kramer A Institute of Hygiene and Environmental Medicine University Medicine Greifswald

Consensus on Wound Antisepsis: Update 2018

Kramer A

Institute of Hygiene and Environmental Medicine

University Medicine Greifswald - Germany

Co-authorsJoachim Dissemond, Simon Kim, Roald Papke Christian Willy - Germany

Dieter Mayer – Switzerland

Felix Tuchmann, Ojan Assadian - Austria

Reviewed and formally approved by

Antiseptics Working Group, Int. Soc. Chemother. Infection and Cancer

German Society of Hospital Hygiene

Chronic Wound Initiative

Austrian Society of Infection Control

Organization of German-speaking Societies and Groups in Wound Management

Preliminary note

Since 323 references were evaluated in the Consensus Guideline, a correct citation is impossible in this lecture –instead I would like to refer to the publication in Skin Pharmacol Physiol 2018;31: 28–58 and some additionallyreferences

Indications of wound antisepsis

Premise

Strict indications are required for the application of antiseptics

because even highly tolerable antiseptics can have side

effects depending on the duration of use

Continuous observation of the therapeutic success

Treatment indications

Critically colonized chronic wounds

Infected acute and chronic wounds

Decolonization of wounds colonized with MRSA and other MDROs

Infection prevention

For acute wounds with increased risk of infection, such as traumatically contaminated wounds, bites, stabs/punctures and gunshot wounds, used after debridement, burn wounds >15% body surface

Pre-, intra- and postoperative application to prevent SSI

1.

Required antimicrobial spectrum of antiseptics

Al chron. diabetic ulcers (n=990) were colonized (unpubl.):

- P. aeruginosa (51%)

- K. pneumoniae (17%)

- E. cloacae (16%)

- E. coli (10%)

- 3% MD-GN, thereoff 95% P. aeruginosa, no MRSA, no VRE

- other: C. freundii and C. koseri, P. vulgaris, K. oxytoca, P.

multocida, E. aerogenes, S. liquefaciens and S. fronticola, M.

morganii and M. sibonii, Leclercia adecarboxylata, Raoul

ornithinolytica

MRE status is sign. associated with neuropathy, osteomyelitis, ulcer size> 4 cm² + more frequent surgical intervention, not with patient characteristics, ulcer type + duration of hospitalizationGadepalli R, et al. A clinico-microbiological study of diabetic foot ulcers in an Indian tertiary care hospital. Diabetes Care 2006;29(8):1727-32

2.

Development of chronic wound infection

1st step: Biofilm formation by skin commensals without host reaction

2nd step: Development of chronic infection by aggregation of so-called functionally equivalent pathogroup (FEP) (e.g., Cutibacterium + Corynebacterium + CNS)

Occurrence of toxin-forming ß-hemolytic streptococci or staphylococci with tissue destruction is more common in severe cases, non-toxicogenic strains more in deep structures and osteomyelitis

No association between occurrence of pathogens and polymicrobial microbiotics in non-healing diabetic ulcer

Oates A, et al. Molecular and culture-based assessment of the microbial diversity of diabetic chronic foot wounds and contralateral skin sites. J Clin Microbiol 2012; 50: 2263-71

Sequencing vs. culture: Anaerobes 87% vs. 23%, Gram-positive bacilli 78% vs. 4%

Mikrobiom of diabetic ulcer

Conclusion for desirable antimicrobial spectrum of

antiseptics

As broad as possible and microbicidal action, because the microbiological culture covers only a small part of the pathogens whose significance may be questionable in individual cases

Requirements for the choice of antiseptic active

compound

No local use of systemic antibiotics – high risk of resistance development and sensibilization

No risk for resistance development microbicidalinstead microbiostatic mode of action: true for PVP-iodine, hypochlorite, polihexanide (PHMB), octenidine(OCT), acetic acid; on the other hand chlorhexidinedigluconat (CHG) and silver ions induce efflux pumpsand silver bonding protein

Broad spectrum of activity and effectivity againstbiofilms

Assessment of the necessity of remanent efficacy

Tolerability – do not apply anything to chronic wounds which should not be applied to the eyes

3.

Requirements for efficacy

Phase 2, step 1: Suspension test (EN 13727)

Test organisms:

S. aureus, P. aeruginosa

E. faecium, C. albicans

Organic load:

Min. Ess. Medium (MEM) + FBS 10% (=

wound fluid)

30% defibrinated sheep blood

Requirement: > 3 lg within declared exposure time

Phase 2, step 2: Carrier test (EN 14561)

Requirement: > 3 lg within declared exposure time

Phase 3: Volunteers

Requirement: On donor site of mesh graft sign. more effective

against physiological flora as Ringer solution

4.

Requirements for tolerability

Wound-tolerability on the levels of Ringer's, saline solution or hydrogel, ideally promoting wound healing

No cytotoxic risk for other exposed tissues(e.g. cartilage, CNS, peritoneum)

No allergenic potential

No absorptive side effects

No risk for long term side effects(mutagenicity, carcinogenicity, teratogenicity)

5.

Irritative potency in hen’s egg test on

chorioallantoic membrane (HET CAM)

Irritiation score0 = no reaction (0.0 – 0.9) 1 = slight reaction (1.0 – 4.9)2 = moderate reaction (5.0 – 8.9)

3 = severe reaction (9 – 21)In WRR in print

Agents with no or low irritation potential on the CAM should be preferred to obtain optimal results

A highly valuable property - selective antiseptic action

Killing of bacteria, but survival of human cells in co-culture with bacteria

So far only proven for

PHMB

Acetic acid

NaOCl

Comparative evaluation of antiseptic

agents

Com-

pound

Remanence Wound

healing

Cartilage

tolerability

Sensibilization Systemic risk

PHMB + Supportive Yes <

0.005%

Yes (but rare),

anaphylaxis

(n = 3) No

OCT + No

inhibition

No No

PVP-

iodine

- Partial

inhibition

Yes (0.5%) Yes Yes

NaOCl /

HOCl

- Supportive No

No

No

Acetic acid - at 0.15%

supportive

?

Ag+ + Inhibition ? Yes

6.

Recommendations for the choice of

antiseptics

Octenidine (OCT)

0.1% for acute contaminated superficial traumatic wounds, including MRSA-colonization

Octenisept® (0.1 % OCT + phenoxyethanole)

For chronic wounds 0.05% OCT preferred

Octenilin®gel (0.05 % OCT without PE)

Cave! Use of OCT in combination with Vac Instill!

To avoid tissue damage, it is contraindicated to introduce the OCT preparation by syringe into the depth of the tissue. The product is only intended for superficial application by swab or spraying.

7.

Increased tolerance of P. aeruginosa to octenidine

with cross-resistance to other biocides

Laboratory and simulated clinical setting

7 clinical isolates exposed to increasing conc. over several days

OCT and CHG MICs of P. aeruginosa from hospital drain trap, exposed four times daily three months to a diluted OCT formul.

Results

Some planktonic cultures survived >50% of working conc. of in-use OCT formulation at the recommended exposure time

7 strains stably adapted following continuous exposure to increasing concentrations up to 32-fold

Increased MIC against amikacin, tobramycin (two-fold) and colistin (four-fold) + against didecyldimethylammoniumbromide, but not BAC

phenotypic changes

Conclusion

Continuous low-level exposure or inappropriate use of OCT can decrease efficacy against P. aeruginosa

Shepherd et al. Pseudomonas aeruginosa adapts to octenidine in the laboratory and a simulated clinical setting, leading to increased tolerance to chlorhexidine and other biocides, J Hosp Inf 2018; pii: S0195-6701(18)30188-9.

Decreased susceptibility of clinical isolates

MRSA isolates (n=31) 2013-2014 vs. 2002-2012 sign. increase of MIC (0.49 vs. 0.86 mg/L) and MBC (0.49 vs. 1.0 mg/L = 0.0001%; use conc. 0.05%)

Isolates with decreased susceptibility to OCT within the first year of its introduction into clinical practice

Phenotypic, not clonal

Warning

Strong indicated use

Water from antiseptic body wash not in sinks of patients room

Hardy et al. Increased usage of antiseptics is associated with reduced susceptibility in clinical isolates of Staphylococcus aureus. mBio 2018; 9:e00894-18.

Recommendation for the use of PHMB

Infection prevention of extensive traumatic contaminated injuries (0.04%) – at present no demonstrated for another antiseptic

First-line drug for infected chronic wounds and grade II/ III burns (0.02%) and in antiseptic dressings

Decolonization of MRSA

Prevention of surgical site infections (SSI):

- Single irrigation of traumatic soft tissue injuries (3 min)- PHMB dressing on entry point of external fixator- First and possibly second dressing after surgical

procedure- Poststernotomy sutures after cardiac surgery

Influence of betaine in combination with PHMB

(Prontosan®)

The surfactant betaine enhances

The antimicrobial efficacy

The cleaning effect - to improve the rinsing effect, sloughs can be soaked with Prontosan® soaked compresses; with a clear slough, soaking time of 10 to 15 minutes is suggested

On the other hand decreases

The cytotoxicity

Recommendation for the use of NaOCl/HOCl

Single or multiple antiseptic cleansings of contaminated traumatic wounds and for repeated antiseptic cleansing of chronic wounds until completion of the cleansing phase – but missing of remanentefficacy

Wounds at risk of contact with CNS structures or risk of drug retention after placement in enclosed cavities

Peritoneal lavage in septic peritonitis – only one trial; no pre-evaluatation in animal models, hopefulperspective is combination of PHMB with LipofundinSurg Inf 2018

For deep injuries in combination with Vac-Instill

Infection prevention for burn injuries

Decolonization of MRSA

Prevention of SSI – final rinsing before suture

Recommendation for the use of PVP-I

In combination with alcohol drug of first choice for stab, cut (with HBV, HCV or HIV infection risk) and bite injuries after induced bleeding

The required virucidal effect and intracellular action outweigh the risk of thyroid dangers

Final rinsing before wound closure to prevent SSI(0.35%)

Dispensable for chronic wounds, that does not apply to liposomal PVP-I

2nd line antiseptic for critically colonized or infected chronic wounds

In 28 of 39 controlled studies hinted at positive traits such as accelerated wound healing and bacterial reduction, but also improving quality of life or relief from pain were observed

On the basis of a expert recommendation, the use in wound treatment in critically colonized or infected wounds as well as decolonization of MRSA is recommended for a maximum of 14 d. Subsequently, a critical evaluation of the need for therapy should be assessed.

No large-scale, permanent and prophylactic use because of the risk of absorption toxicity

Recommendation for the use of silver compounds

Summary of clinical findings for

wound antisepticsCriteria NaOCl/HOCl OCT PHMB PVP-I

Antisepticeffective

yes

Peritoneal lavagein septicperitonitis

Possible,butneedsconfirmation

contraindicated

Applicability on CNS

possible contraindicated

Applicability on cartilage

contraindicated <0.005% 0.5%

Superior toAg+

PVP-I

Chlorhexidine

tend. better

sign. better

no studies

sign. bettertend. betternostudies

sign. bettersign. bettersign. better

tend. better

-

no studies

Prevention of SSI possible nostudies

effective tend. better

Suitable antiseptics for infection prevention by wound

irrigation

Acute wound, complex open contaminated fracture, severely injured patient, destroyed soft tissue architecture (also gunshot or explosion injury):

Rinsing with NaOCl/HOCl, short required exposure time; sufficient intraoperative exposure time of 1 min

Alternatively 1-3 min rinsing with PHMB with advantage of remanence

for both, no rinsing with saline solution or Ringer is effective

Suitable antiseptics for infection prevention by

wound irrigation

All intraoperative surgical sites are bacterially contaminated at operative closure

Surgery wound field at the end of "overlong" duration of surgery (> 75% as normal) to prevent SSI:

Rinsing with NaOCl/HOCl (hypothetic) or

PVP-iodine 0.35%Fournel I, Tiv M, Soulias M, et al. Meta-analysis of intraoperative povidone-iodine

application to prevent surgical-site infection. Br J Surg 2010;97:1603–13.

Meurs van SJ, Gawlitta D, Heemstra KA, Poolman RW, Vogely HC, Kruyt MC. Selection of an

optimal antiseptic solution for intraoperative irrigation: an in vitro study. J Bone Joint

Surg Am 2014; 96(4): 285-91.

Other benefits are the hydration of the wound bed + better examination of the area before closure.

Suitable antiseptics for therapeutic wound irrigation

Acute infected wound after debridement before wound closure or before NPWT (with or without instillation component):

Intraoperative irrigation with aqueous PHMB 0.04 %,

NaOCl/HOCl or undiluted aqueous PVP-iodine, if war deep

trauma

Continuous vacuum sealing therapy with instillation (NPWTi)

After abscess removal/ wound debridement NPWTi starts with PHMB 0.02 or NaOCl/ HOCl

In case of a knee joint infection due to cartilage contact PVP-iodine 0.5% suitable

In contact with neurogenic structures currently only NaOCl/HOCl

Perspectives

Further evaluation of

Combination of Negative Pressure Wound Therapy (NPWT) with antiseptic instillation (NPTWi)

Acetic acid-based antiseptics (0.25-1%)

Tissue tolerable cold physical plasma

8.

Conclusion

Substitution of CHG by

PHMB

Only for superficial application OCT

By solving the stability available as new option

NaOCl/HOCl

Indispensable for special indications

PVP-I

Dispensable

Chinolinols

Nitrofural

Obsolete

Local application of antibiotics

Dyes

Organomercury compounds

H2O2

Golden rule of antisepsis

Not the most effective antiseptic

is the most suitable one

but the most suitable antiseptic

is the best.

Axel Kramer

Take-home message:It is important to strike a balance between antiseptic efficacy, time-dependency of the antiseptic action and tolerability.

Responsibility of your inquiries

1st What properties of PHMB make this antiseptic

indicated as „antiseptic of choice” in treatment of

critically colonized and infected chronic wounds

including burns?

- Efficacy in vitro- Tolerability- Remanence- Superiority in clinical studies on chronic wounds

Efficacy in vitro - exposure time for RF > 3 log

Agent Bioburden S. aureus P. aeruginosa

Octenidine-Gel 0,1%

MEM +FBS (10%) 5 min 30 min

Blood (30%) 3 h 10 h

Octenidin-Gel 0,05%

MEM +FBS (10%) 5 min 30 min

Blood (30%) 3 h 10 h

PHMB-Gel0,04%

MEM +FBS (10%) 3 h 30 min

Blood (30%) 3 h 3 h

PHMB-Gel 0,02%

MEM +FBS (10%) 3 h 3 h

Schedler K, Assadian O, Brautferger U, Müller G, Koburger T, Classen S, Kramer A.. Proposed phase 2/

step 2 in-vitro test on basis of EN 14561 for standardised testing of the wound antiseptics PVP-iodine,

Chlorhexidine digluconate, Polihexanide and Octenidine dihydrochloride. BMC Inf. Dis. 2017; 17: 143.

Response1 after (n)

Substance Agent (%) 0.5 min 2 min 5 min

Lavasept 0.1 %

Polihexanide (0.02) 0 (13) 0 (13) 0 (13)

Dispaphenicol Chloramphenicol (0.5) 0 (1) 1a (8)

0 (1) 1a (8)

1a (3) 2a (6)

Floxal Ofloxacin (0.3) 0 (4) 1a (2)

0 (4) 1a (2)

0 (3) 1a (3)

Kanamytrex Kanamycin (0.62) 0 (2) 1a (6)

0 (2) 1a (6)

0 (2) 1a (6)

Posifenicol

Azidamfenicol (1)

0 (6) 1a (3)

0 (4) 1a (1)

1c (3) 2a (1)

0 (2) 1a (2)

1c (1) 2a (4)

Refobacin Gentamicin (0.5) 0 (3) 0 (1) 1a (2)

0 (1) 1a (2)

a b c Hyperemia = 1 low moderate strong

Hemorrhagy = 2 sporadic numerous copious

Kramer A, Behrens-Baumann W. Ophthalmologica 1997; 211 (Suppl 1):68-76.

Tolerability of antibiotic eye drops compared to

PHMB in HETCAM

Irritation score (IS) after 5 min (Harnoss et al. in rev.)

Agent IS Classification

LavaSurge® 0 No reaction(0-0,9)

Granudacyn (NaOCl/HOCl) 1,1slight reaction (1.0 – 4.9)

Prontosan® (PHMB + Betain)4,2

0.5% Chlorhexidine digluconate 9,4 severe reaction (9-21)

Octenilin (0.05% Octenidine) 10,2

Superiority of PHMB in clinical studies on

chronic wounds

Daeschlein G, Assadian O, Bruck JC, Meinl C, Kramer A, Koch S. Feasibility and clinicalapplicability of polihexanide for treatment of second-degree burn wounds. Skin

Pharmacol Physiol 2007; 20:292-6.

2nd: Mode of action of PHMB– does it acts efficiently

against Gram(-) pathogens also?

Broad spectrum of efficacy without gap due to the mode of action1 Interaction with anionic phospholipids of the plasma membrane PHMB interacts with anionic head groups of the outer layer of the plasma membrane via its cationic biguanide-groups and by simultaneously displacing surface-applied Ca2+.

• The hydrophobic hexamethylene units of PHMB are not very flexible and cannot be integrated into the hydrophobic membrane double layer.

• The attachment of PHMB creates a bridging of anionic head groups of adjacent anionic phospholipids which is followed by their rearrangement into anionic phospholipid clusters; neighboring anionic phospholipids repel each other and the hydrophobic clustering of phospholipid fatty acid tails of the membrane double layer is disintegrated. The membrane integrity is destabilized and its permeability is increased.

• Anionic glycerophospholipids are main component of plasma membrane of Gram-positive and Gram-negative bacteria, but not found in cell membrane of humans. This explains the high tolerance of eukaryotic cells to PHMB, since they mainly contain phosphatidylcholine (lecithin) in their cell membrane. PHMB reacts with phosphatidylcholine with improved tolerability

The probable main mode of action

2. PHMB forms nano-objects which interact with the phospholipid membrane similar to that observed for positively charged nanoparticles or cell penetrating peptides intracellularly producing an antimicrobial effect.

Cell entry of PHMB into a range of bacterial species; treated bacteria displayed cell division arrest and chromosome condensation, suggesting DNA binding as antimicrobial mechanism

The selective chromosome condensation in bacterial cells but not in mammal cells provides an unanticipated paradigm for antimicrobial action that may not succumb to resistance.

Chindera K et al. The antimicrobial polymer PHMB enters cells and selectively condenses

bacterial chromosomes. Sci Rep 2016 ;6:23121

Lin JQ, Alexander-Katz A. Cell membranes open “doors” for cationic nanoparticles/

biomolecules: Insights into uptake kinetics. ACS Nano 2013; 7(12): 10799- 808

Zorko M, Langel U. Cell-penetrating peptides: Mechanism and kinetics of cargo delivery. Adv

Drug Delivery Rev 2005; 57(4): 529-45

Required conc. (mg/L) Gram-pos./Gram-neg.

Exposure(min)

S. aureus P. aeruginosa

1 250 500

5 250 125

10 50 50

60 5 5

360 2.5 2.5

Koburger T, Hübner NO, Braun M, Siebert J, Kramer A. Standardized comparison of antiseptic efficacy of triclosan,

PVP-iodine, octenidine dihydrochloride, polyhexanide and chlorhexidine digluconate. JAC 2010;65(8):1712-9

3rd: Can microorganisms acquire resistance

against PHMB?

Acquired resistance to PHMB has not been reported

Due to the global no specific mode of action - membrane rupture + condense of bacterial chromosomes –development of resistance is unimaginable

4th: What does it means that PHMB displays

biocompatibility level >1?

Quotient from IC50/cell culture (L929) and

reduction factor for microbicidal efficacy > 3 lg

Agent BI [30 min]

L929/E. coli

L929/S. aureus

Octenidine

Polihexanide

PVP-I

Chlorhexidine digluconate

Triclosan

Ag(I)-Sulfadiazin,AgNO3

1.73

1.51

0.9

0.68

0.23

not calculable

2.11

1.36

1.0

0.68

0.46

not calculable

Müller G, Kramer A. Biocompatibility index of antiseptic agents by parallel assessment of antimicrobial activity and cellular cytotoxicity. J Antimicrob Chemother 2008; 61(6):1281-7.

5th: Does pH value is of impact on PHMB activity

in wounds? If so, what is this impact?

Bactericidal activity (S. aureus, P. aeruginosa) of chlorhexidine and octenidine was mainly pH independent in a pH range of 5.0–9.0.

Antimicrobial effect of PVP-I was strongly diminished with rising pH.

In contrast, PHMB showed significant efficacy increase at higher pH.

PHMB is advantageous for management of wound infections, as S. aureus and P. aeruginosa exhibited an increased susceptibility with rising pH.

Wiegand C et al. pH influence on antibacterial efficacy of common antiseptic substances. Skin Pharmacol Physiol 2015;28:147–58

6th: Is PHMB efficient against Acanthamoeba?

PHMB is the most effective drug for treatment of Acanthamoeba keratitis infection (cysts and trophozoites)

PHMB is effective against Acanthamoeba keratitis in concentrations as low as 0.025% as single substance as well as in combination with propamidine and neomycin.

PHMB acts cysticidal against Acanthamoeba at 0.009%, 0.006% and 0.0024% after 8, 24 or 48 h contact times

Lorenzo-Morales J et al. An update on Acanthamoeba keratitis: diagnosis, pathogenesis and treatment. Parasite 2015; 22: 10.

7th: Does application of PHMB during systemic

antibiotic therapy may lead to antagonistic effects?

Interaction of PHMB with ß-lactam-antibiotics

With CHG often antagonism or no influence

Hübinger L. Interaction of ß-lactam-antibiotics with the antiseptics octenidinedihydrochloride, polihexanide and Chlorhexidine digluconate. Diss Med Fak Univ Greifswald, 2010.

Germ Ampicillin Oxacillin Imipenem Ceftazidim Piperacillin/Tazobactam

S. aureus/MRSA

Synergism

Synergism

No tested

No tested

E. faecalis

no tested Synergism

synergism

E. faecium

P. aeruginosa synergism

E. coli

8th: Is PHMB clinically effective against multidrug

resistant cocci, incl. MRSA?

PHMB kills intracellular MRSA via direct interaction with pathogens inside keratinocytes and host cell entry is dynamin dependent.

Kamaruzzaman NF et al. Bactericidal effects of polyhexamethylene biguanide againstintracellular Staphylococcus aureus EMRSA-15 and USA 300. J Antimicrob Chemother2016;71(5):1252-9.

PHMB-treated gloves reduced surface-contaminationof carbapenem-resistant E. coli, MRSA and ESBL K. pneumoniae by ~4.5 lg within 10 min or ~2.5lg whenheavy-soiling or blood was present

Ali S er al. Effect of poly-hexamethylene biguanide hydrochloride (PHMB) treated non-sterile medical gloves upon the transmission of Streptococcuspyogenes, carbapenem-resistant E. coli, MRSA and Klebsiella pneumoniaefrom contact surfaces. BMC Infect Dis. 2017; 17: 574.

Effective against VREMoore K et al. Using PHMB antimicrobial to prevent wound infection. Wounds 2007; 3(2):96-102.

No gap is known for PHMB

21 MDR clinical strains of S. aureus, E. faecium, E. faecalis, E. coli, E. cloacae, K. pneumoniae, A. baumannii, and P. aeruginosa, including the multiresistant high-risk clones

Polyhexanide-betaine bactericidal against all MDR clinical isolates, including high-risk clones, at significantly lower concentrations and time of activity than those commercially used.

López-Rojas R et al. In vitro activity of a polyhexanide-betaine solution against high-risk clonesof multidrug-resistant nosocomial pathogens. Enferm Infecc Microbiol Clin 2017;35(1):12-9.

9th: Can PHMB be applied (according to

recommendations) in pregnant patients?

During the first four months of pregnancy use is contraindicated

At any time thereafter, a strict benefit/risk assessment has to be performed – in principle

from the 5th month no risk, because no

absorption from skin, mucous membranes and

wounds

10th: Can PHMB be applied together with negative

pressure wound therapy?

Results in porcine model suggestDavis K et al. Simultaneous irrigation and negative pressure wound therapy enhances

wound healing and reduces wound bioburden in a porcine model. Wound Repair

Regen 2013; 21: 869 – 75.

Phillips PL et al. The effect of negative pressure wound therapy with periodic

instillation using antimicrobial solutions on Pseudomonas aeruginosa biofilm on

porcine skin explants. Int Wound J 2013; 10 (suppl 1): 48 – 55

Clinical results underline results in porcine model

Osteomyelitis of pelvis and lower extremity: NPWT with PHMB was sign. superior to historic control

Timmers MS, et al. Negative pressure wound treatment with polyvinyl alcohol foamand polyhexanide antiseptic solution instillation in posttraumatic osteomyelitis. Wound Repair Regen 2009;17(2):278-86.

Multi-centre prospective, non-randomised observationalstudy: NPWTi/PHMB effective as adjunctive therapy to manage infected orthop. implants by removing infectious materials and helping to retain the implant, independent of acute or chronic infection

Lehner B. et al. First experiences with negative pressure wound therapy and instillation in the treatment of infected orthopaedic implants: a clinical observational study. Int Orthop 2011; 35(9): 1415–20.

Efficacy of NPWT with PHMB in clinical studies

Conv. PHMB-gauze vs. gauze-based NPWT (rand. cohortstudy): sign. better wound healing, shorter treatmentduration, and accelerated elimination of bacteria

Tuncel U et al. Clinical evaluation of gauze-based negative pressure wound therapy in challenging wounds. Int Wound J 2013 :10 (2): 152-8.

Prospective case control study (n = 16)

- Healing rate of secondary suturing of sc. wound

infections after median laparotomy/colorectal

surgery been conditioned

- conv. PHMB-gauze vs. NPTW gauze

- lowering treatment time and costs as well as

unnecessary usage of operating theaterMarquardt C. et al. Negative pressure wound therapy using PHMB

gauze for the management of postoperative subcutaneous surgical site infections. Coloproct 2014;· 36:364–9.

Efficacy of NPWT with PHMB in clinical studies

Retrospect. cohort study: NPWT/ PHMB sign. Superior to NPWT

Kim PJ, et al. The impact of negative-pressure wound therapy with instillation compared with standard negative-pressure wound therapy: a retrospective, historical, cohort, controlled study. Plast Reconstr Surg 2014, 133: 709-16

Further smaller studies partly without long-term follow-up: without exception favorable results

Kim PJ, et al. Negative pressure wound therapy with instillation: Review of evidence and recommendations. http://www.podiatrytoday.com/files/acelitysupp_wounds.pdf

NPWTi/ PHMB/Betain vs. NaCl - no differenceKim PJ, et al. Comparison of outcomes for normal saline and an antiseptic solution for negative-pressure wound therapy with instillation. Plast Reconstr Surg2015;136(5):657e-64e.

With proper use of PHMB for wound antisepsis,

carcinogenic risk can be ruled out

Two misinterpreted feeding animal studies with extremely high PHMB conc. above NO(A)EL of 400 ppm/rats and 600 ppm/mice.

At 4000 ppm after 103 weeks (162.3 mg/kg BW/rat/d 3 hemangiosarcoma + 1 carcinoma in the liver

Horner SA. Polyhexamethylene biguanide: two year feeding study in rats. Study performed by Zeneca Central

Toxicology Laboratory. Alderley Park, Macclesfield, Cheshire, UK. 1996; unpubl.

Feeding of 0, 400, 1200 and 4000 ppm PHMB/mice over 2 years, survival rates of male mice in all groups identical; in female, survival rate in 4000 ppm group was 12 % lower. Feeding of 4000 ppm PHMB (715 mg PHMB/kg BW/d male or 855 mg PHMB/kg BW/d female) only increased incidence of swelling at the anus and anal prolapse. In one male in 4000 ppm PHMB group 1 adenocarcinoma, which the author attributed to chronic inflammation of the colon. Similar to Horner’s findings, increasing incidence of hemangiosarcoma of liver: 0 ppm 4/110; 400 ppm 2/110; 1200 ppm 11/110; 4000 ppm 33/110).

Milburn GM. Polyhexamethylene biguanide: two year oncogenicity study in mice. Study performed by Zeneca Central Toxicology Laboratory. Alderley Park, Macclesfield, Cheshire, UK. 1996; unpubl.

With proper use of PHMB for wound antisepsis,

carcinogenic risk can be ruled out

Results can be explained by promoting fibroblast proliferation, which is desired at the wound but can become disadvantageous at the liver and colon at atypical exposure. With appropriate clinical use, this cannot occur due to absence of absorption.

By contrast, feeding in the NO(A)EL range resulted in no abnormal effects.

2nd argument: PHMB is no genotoxic. Therefor the only explanation for a carcinogenic effect is an epigenetic alteration of DNA, which cannot shown:

- No oxidative stress on DNA was induced

- No hydroxylation or hypermethylation of DNA

- No sign. production of mitogenic cytokines and transcription factor NF-KB (nuclear factor 'kappa-light-chain-enhancer' of activated B-cells)

- GAP junction not significantly affected.Creppy EE et al. Study of epigenetic properties of poly(HexaMethylene Biguanide) hydrochloride (PHMB). Int J Environ Res Public Health. 2014 8; 11(8):8069-92.

The study supports assessments of US Environmental Protection Agency and the Australian authorities, which interpreted the animal study data as no relevant health risk for humans.

Many thanks for the invitation and your attention

Caspar David Friedrich: Greifswald in the moonlight (Nationalmuseum Oslo)