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Wound antisepsis

Prof. Ojan Assadian, MD, DTMH Institute of Skin Integrity and Infection Prevention School of Human & Health Sciences Wound infection in chronic wounds

DMII, PAVK IIb, TASC B/C – 22.11.2014 Final treatment – 24.01.2015 soft tissue infection 7 Sessions, Methacrylate dressing + Suspected osteomyelitis metatarsal II Octenidine Wound infection in acute wounds 1928 – Fleming noted Penicillium notatum to inhibit Stapylococcus aureus

Consequence  For the past 6 decades, we have relied on the availability and efficacy of antibiotics for prevention and control of infections in our health-care systems.

Prevalence of MRSA in Europa – 2010 N

Central

S

Eur Antimicrobial Resistance Surveillance Network (EARS-Net) Prevalence of E. coli in Europa – 2010 E. coli Fluorquinolon-resistance (R+I)

N

S

Eur Antimicrobial Resistance Surveillance Network (EARS-Net) Only 10% of the annual global antibiotic production is used in human medicine …

e.g. Chile 2008: per annum 400,000 t Salmon 380,000 t antibiotics = 1 kg antibiotic / kg salmon

90% , 8% sulfonamides

Raschi E at al. Bj J Clin Pharmacol 2009;67:88-98. Commercially available chicken breast in Germany 399 samples from 9 supermarkets in Berlin  44% ESBL-positive – E. coli SHV-12 (n=82) – E. coli CTX-M-1 (n=77) – E. coli TEM-52 (n=16) Bacterial Resistance – Selection and Transmission

Antibiotic

Omnimax Forte® Bacterial Resistance – Selection and Transmission Today‘s clinical reality

Male Pat. DOB:. 1970 Burns ICU; Blood culture Isolate: 01 Acinetobacter baumannii-Komplex 02 Stenotrophomonas maltophilia Relaying on Antibiotics alone is like driving a car with no breaks and no seat belt but only with an Airbag! What did physicians do before 1941?

No antibiotics, but a wealth of knowledge on ! Classification of antimicrobial compounds

Antimicrobials

Anti-infective Antibiotics Biocides Biologics

Antiseptics

Skin Antiseptics Surface Disinfectants

Mucous membrane Instrument Antiseptics Disinfectants

Wound Antiseptics Hand Disinfectants Antiseptics/ Disinfectants

Alkohols Aldehydes Oxidants Phenoles QAVs* Guanidines

Ethanol Formaldehyde Ozone

Isopropanol Glutardialdehyd Peroxides Pentachlorphenol Benzethonium e chloride N-propanol Glyoxal Peroxicarbon Cresol Mecetronium Alexidine acid ethylsulfate Methanol Methenamine Hydrogen Chlorocresol Cetremide Pyridines peroxide Butanol Propenal Sodium Tymol Cetylpyridinum Octenidine perborate chloride Chlorbutanol Piperonal Hypochlorous Dipyrithione acid Glycerol Dimethylol- Benzoyl Biphenyl Tetradonium chloride Na-Pyrion hydantoin peroxid Benzyl alcohol Hexamethyl- Halogens Bisphenoles Zinc enetramin pyrithione 2-Phenoxyethanol Chloro- Chlorine, , Clorophene Pyrimidines allylchloride Bromium Hypochlorites Hexachlorophen e *QACs = quaternary ammonium compounds

Antimicrobial activity of antiseptics Log RF (ATCC 6538) – 1% mucin

Established standardized Test protocol; Phase 1, Phase 2/ Step 1 Tests, Pitten FA et al. J Hosp Infect 2003; 55: 108-115. Preventive or therapeutic application of antiseptics

Octenidine Polyhexanide confirmed Povidone-Iodine S. aureus?

(, S. aureus Chlorhexidine) K. oxytoca? Therapeutic Preventive Benefit (Antimicrobial) – Risk (Cytotoxicity)

Benefit: Risk Killing of Delayed wound micoorganisms healing: cytotoxicity Recommended Antiseptics for wound antisepsis in Central Europe

• German Consensus Recommendation • Octenidine dihydrochloride (OCT) • Polyhexanide (PHMB) • PolyVinylPyrrolidone-Iodine (PVP-I)

Kramer A et al. Zschr. Wundheilung 2004; 3:110-120 Biocompatibility-Index (BCI)

Aim: to assess antimicrobial efficacy and cytotoxicity at the same time.

• BCI = quotient of IC50 and CRF >log 3

– IC50 = concentration, which kills 50% of cells (fibroblasts). – CRF >log 3 = concentration to achieve min. 3 log reduction of test microorganism

Müller G et al. J Antimicrob Chemother 2008; 61: 1281-7. Interpretation of BCI

• BI > 1 – Low cytotoxicity / high antimicrobial efficacy – [high conc. needed/ low conc. needed]

• BI < 1 – High cytotoxicity / low antimicrobial efficacy – [low conc. needed/ high conc. needed] Biocompatibility-Index (BCI)

Compound BCI [30 min]

[L929/E. coli] [L929/ S. aureus]

Octenidine-dihydrochloride 1.8 1.51 Polihexanide 1.5 1.33 PVP-I 1.0 0.95 Chlorhexidin-digluconate 0.8 0.73 0.23 0.46 Ag-Protein 0.13 - Ag(I)-sulfadiazine**) << 0.004 - **) AgNO3 << 0.002 -

Müller G et al. J Antimicrob Chemother 2008; 61: 1281-7. Use of Antiseptics

Therapeutic Prophylactic

Rapid action Slower action

PVP-Iodine Polihexanide

Therapeutic Prophylactic Octenidine Taurolidine

Kramer A. et al. Zeitschrift für Wundheilung 2004;3:110-120 Octenidine – Antimicrobial spectrum

Gram - positive bacteria Yeasts

• S. aureus • C. albicans • S. pyogenes Fungi • α-haem. Streptocci • T. mentagrophytes • E. faecium • T. rubrum • E. faecalis • M. gypseum Gram - negative bacteria • Epidermophyton • E. coli floccosum

• P. mirabilis Protozoa • (P. aeruginosa) • T. vaginalis • G. vaginalis • T. gallinae • N. gonorrhoeae • Chlamydia trachomatis Virus • M. hominis Herpes simplex • U. urelyticum HBV, HCV, HIV Octenidine – Antimicrobial efficacy

MIC (µg/mL) to achieve > 5 log RF at 5 min contact time

• C. albicans, M. gypseum, E. floccosum 0.001 • S. aureus, E. coli 1 • K. pneumoniae, P. mirabilis 2 • P. aeruginosa 4

MMC (µg/mL) to achieve > 5 log RF at 5 min contact time

• C. albicans 100 • S. aureus 250 • E. coli, P. mirabilis, P. aeruginosa 250 MIC (µg/mL) OCT / CHG 5 min contact time

Test organisms Octenidine Chlorhexidine Polyhexanide Triclosa n S. aureus 1 0.2 0.1 0.1

E. coli 1 0.5 5 0.3

K. pneumoniae 2 3.9 5 0.5

P. mirabilis 2 15.6 10 5

P. aeruginosa 4 15.6 25 1,000 How to apply antiseptics on wounds?

• Flushing

• Irrigation

• Spraying

• Antimicrobial wound dressings Currently available antimicrobial wound dressings (only Germany and Austria, 2014)

Silver (49) Honey(13) Physical/ mechanical Iodine (5) H2O2 (1) Decontamination (3)

Chlorhexidin (1) Chitosan (1) due to bacterial adherence to charged dressings Polihexanide (6) Maggots (1) Recommended Antiseptics / Available antimicrobial dressings

• German Consensus Recommendation • Polyhexanide (PHMB) • Octenidine dihydrochloride (OCT) • PVP-Iodine Kramer A et al. Zschr. Wundheilung 2004; 3:110-120

• Available antimicrobial wound dressings • Mostly silver-based (>49)

• PHMB = 6 • OCT = 0  Misbalance between • PVP-Iodine = 5 recommendations & availability

Combination of antiseptics and a novel methacrylate dressing Methacrylate Dressings

• Powder made of biocompatible Polymers (e.g. contact lenses) • 84.9 % poly-2 hydroxyethyl-methacrylate (pHEMA), • 14.9% poly-2 hydroxypropyl-methacrylate (pHPMA)

• The particles are microscopic in size and will form 4-7 nm wide capillary structures in-between. • Once poured into a wound, the particles absorb exudate from the wound site, hydrate and aggregate to form a flexible dressing. Application

Apply from sterile pouch to wound directly, then use gloved finger, gauze, or spatula, … to tap dressing into place. Combination with antiseptics In-vitro experiment: Altrazeal in combination with antiseptics Antimicrobial efficacy against S. aureus (ATCC 33591) Time-Kill Study, S. aureus (ATCC 33591)

1.00E+09

1.00E+08

1.00E+07

1.00E+06

Negative Control Altrazeal alone 1.00E+05 0.02% PHMB (Cosmocil) Prontosan C 1.00E+04 Prophylactic application Lavasept Braunol Octenisept 1.00E+03

1.00E+02 Therapeutic application

1.00E+01

Forstner C, et al. Int J Mol Sci 2013; 14:10582-90. 1.00E+00 0 h 24 h 48 h 72 h 96 h 120 h II° Burn injury, 40% TBSA C. albicans; complete eradication with Methacrylate + Octenidine after 8 days Cutaneous Leishmaniasis June 6, 2013 - pentavalent antimony Cutaneous Leishmaniasis June 13, 2013 – Methacrylate + OCl-/HCLO (Hypochlorite/ Hypochlorous acid, Microdacyn) Stahl et al. BMC Infectious Diseases 2014, 14:619 Cutaneous Leishmaniasis June 21, 2013 – Methacrylate + OCl-/HCLO (Hypochlorite/ Hypochlorous acid, Microdacyn) Summary

ResistantPathogen Pathogen

Prevent Prevent Transmission Infection Infection Resistance

Effective Use of Therapy & antiseptics Diagnosis

Antibiotics