Honey Combination Therapies for Skin and Wound Infections: A Systematic Review of the Literature

Figures & data

Table 1 Search Terms Used in the Study

Term (Group 1)	Term (Group 2)	Term (Group 3)
Honey	Antibiotic	Wound infection
	Rifampicin	Skin infection
	Oxacillin	Wound healing
	Tetracycline	Antibacterial
	Combination therapy	Antimicrobial
	Propolis
	Herbal extracts

Note: Combinations: group 1 terms AND group 2 terms AND group 3 terms until all combinations had been searched for.

Table 2 Table Created in Accordance with PRISMA Guidelines Showing Number of Articles Identified and Included in This Systematic Review

Search Strategy		No. of Articles
Identification	Records identified from PubMed database searching Records identified from other sources^T	397 11
Screening	Records after duplicated articles removed Records screened by abstract Records excluded	254 254 207
Eligibility	Full text articles assessed for eligibility Full text articles excluded	47 6
Included	Studies included in review	41

Note: ^TOther sources included articles sourced from the reference list of selected papers and articles recommended by experts in the field.

Figure 1 Possible mechanisms by which honey and antibiotics synergistically kill bacterial cells.

Table 3 Summary of the Key in vitro Findings of the Antimicrobial Activity of Honey and Antibiotic Combinations

Type of Honey	Antibiotic	Method	Micro-Organism	Key Findings	Reference
Manuka honey (5% w/v)	Oxacillin	Disc diffusion, E-test strip, broth dilution, chequerboards, growth curves.	MRSA	Synergistic antimicrobial activity against MRSA and reversal of oxacillin resistance.	^Citation23
Manuka honey (Manukacare, 18+, Comvita), (5% w/v)	15 antibiotics	Disc diffusion, E-test strip, broth dilution, chequerboards, growth curves.	MRSA P. aeruginosa	Synergistic antimicrobial activity against MRSA for manuka honey and tetracycline, imipenem and mupirocin combinations and additive activity against P. aeruginosa for manuka honey and tetracycline, rifampicin and colistin combinations.	^Citation26
Medihoney (Comvita Ltd) 5%, 7% w/v	Rifampicin	Disc diffusion assay, chequerboards, time kill curves.	MRSA, clinical isolates of S. aureus.	Synergistic antimicrobial activity of Medihoney and rifampicin combination against MRSA and clinical isolates of S. aureus.	^Citation25
Manuka honey (Comvita Ltd) (<8%)	Rifampicin, oxacillin, gentamicin, clindamycin	Disc diffusion assay, chequerboards	Strains of S. aureus (planktonic growth and biofilm formation)	Rifampicin and manuka honey considered to be most effective as demonstrated synergistic antimicrobial activity against all tested strains including planktonic bacteria and S. aureus biofilm formation. Clindamycin or oxacillin manuka honey combinations demonstrated synergistic antimicrobial activity against most strains (planktonic and biofilm formation) but not all. Gentamicin and manuka honey combinations demonstrated an additive antimicrobial effect.	^Citation24
Manuka honey (Medihoney, Comvita Ltd) (inhibitory and subinhibitory concentrations tested).	Rifampicin, fusidic acid, clindamycin, gentamicin, oxacillin.	Checkerboard microdilution assays, viability assays, MacSynergy II analysis.	S. aureus, established biofilm	Most effective combination against established S. aureus biofilms was rifampicin and Medihoney. Fusidic acid and Medihoney combination induced some synergistic antimicrobial effects. Clindamycin, gentamicin, and oxacillin Medihoney combinations induced antagonistic effects against S. aureus established biofilms when honey was used at sub-inhibitory concentrations but not at inhibitory concentrations.	^Citation30
Manuka honey (Manuka Health, NZ) (5%)	Linezolid	Disc diffusion assay	MRSA and MSSA strains of S. aureus	Manuka honey increases the sensitivity of MRSA and MSSA to linezolid.	^Citation27
Four medical grade honeys: 1. Comvita^® Manuka Medihoney^® 2. Comvita^® Medihoney^® Antibacterial Wound Gel™ 3. Revamil^® gel 4.Surgihoney™RO^®	Tetracycline, sulphatriad, streptomycin, penicillin G, chloramphenicol and ampicillin.	Broth culture assay	S. aureus P. aeruginosa	Surgihoney™RO^® and Comvita^® Medihoney^® Antibacterial Wound Gel™ increased the sensitivity of S. aureus to tetracycline and ampicillin. Comvita^® Manuka Medihoney^® did not enhance the sensitivity of S. aureus to any of the antibiotics tested. Comvita^® Medihoney^® Antibacterial Wound Gel™, Comvita^® Manuka Medihoney^® and Surgihoney™RO^® enhanced the sensitivity of P. aeruginosa to tetracycline. Whether the enhanced antimicrobial effects were synergistic, or additive was not determined in this study.	^Citation31

Table 4 Summary of the Key in vitro Findings of the Antimicrobial Activity of Honey and Natural Agent Combinations

Type of Honey	Natural Agent	Method	Micro-Organism	Key Findings	Reference
Ethiopian honey (50% v/v)	Ginger extracts (50% v/v) Prepared honey ginger mixture (50% v/v).	Agar well diffusion assay, broth assay.	S. aureus, MRSA, E. coli (sensitive and resistant strains). K. pneumoniae (resistant)	Honey and ginger combination induced higher mean zones of inhibition than honey or ginger alone or standard antibiotic discs (methicillin, penicillin, amoxicillin).	^Citation36
Algerian honey (orange blossom, eucalyptus)	Royal jelly (sub- MIC concentrations) (3% (v/v); 2% (v/v); 1% (v/v) added to honey).	MIC assay	P. aeruginosa	For each honey type there was > 90% decrease in the MIC when 3% (v/v) royal jelly was added; a 66.6% decrease when 2% (v/v) royal jelly was added and a 50% decrease in MIC when 1% (v/v) royal jelly was added.	^Citation37
Saudi Arabian sumra honey (Acacia tortilis)	Ethyl alcohol extract of propolis (Egyptian and Saudi Arabian) (sub MIC concentrations)	MIC assay	S. aureus, E. coli, C. albicans, polymicrobial cultures.	The MIC of honey and propolis combined was lower than honey or propolis alone.	^Citation38
Polish honey (lime) (75% w/w)	Ethanol extract of propolis (1%),	Agar well diffusion assay	E. coli	Larger zones of inhibition were seen when honey was enriched with 1% propolis.	^Citation39
Spanish honeys (heather, chestnut and multifloral)	Ethanol extracts of propolis (0.1, 0.3 or 0.5%) harvested from Spain.	Agar diffusion assay	Microorganisms including E. coli, S. aureus, P. aeruginosa.	In general, enhanced antimicrobial activity was observed when honey was supplemented with propolis. The increase varied depending on the type of honey, concentration of propolis and test micro-organism.	^Citation40
Iranian honey from Damavand district, Iran.	Cinnamaldehyde and carvacrol (sub-MIC concentrations)	Broth dilution method	P. aeruginosa	The MIC of the combination of honey, cinnamaldehyde and carvacrol was lower than honey alone (0.49µg/mL vs 114.2 μg/mL respectively). The antibacterial activity of the triple combination was reportedly greater than imipenem.	^Citation41
Iranian honey (25%) from Fasa, Iran	Gel composed of herbal extracts of Acacia catechu, Castanea sativa, Ephedra sinica and Momia combined with honey (25%), maple saps, Phoenix dactylifera (date), pomegranate extract and Azadirachta indica gum	Agar well diffusion assay	P. aeruginosa	Zone of inhibition induced by the herbal gel formulation was greater than honey alone (35.1 mm vs 13.1 mm respectively).	^Citation42
Slovakian honeys (sunflower, acacia and honeydew) UMF 15+ manuka honey (Natures Nectar, UK)	Vitamin C (Sub-inhibitory concentrations)	MIC assay Biofilm wound model	Planktonic bacteria including P. aeruginosa and S. aureus. Multispecies biofilms (P. aeruginosa, S. aureus, S. agalactiae, E. faecalis)	Supplementation of honey with vitamin C reduced the MIC of all honey types tested against planktonic P. aeruginosa. Supplementation of honeydew honey with vitamin C increased the MIC against planktonic S. aureus. Honeydew honey supplemented with vitamin C (100mg/g) had superior antibiofilm activity than honey alone.	^Citation43
Mexican yucatan honey (L-Mesitran)	Vitamins C and E (L-Mesitran contains 40% Mexican yucatan honey and vitamins C and E)	Antifungal MIC method for yeasts	C. albicans	L-Mesitran demonstrated antifungal activity against C. albicans (MIC 25%–50%), whereas 40% Mexican yucatan honey did not.	^Citation44
Mexican yucatan honey (L-Mesitran)	Vitamins C and E (L-Mesitran contains 40% Mexican yucatan honey and vitamins C and E)	Microbroth assay to determine MBC	Staphylococcus pseudintermedius, Malassezia pachydermatis	L-Mesitran had lower MBC in comparison to the honey component of L-Mesitran only.	^Citation45

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