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Topical antimicrobial agents for preventing and treating foot infections in people with diabetes

  1. Benjamin A Lipsky1,
  2. Christopher Hoey2,
  3. Mario Cruciani3,
  4. Carlo Mengoli4,*

Editorial Group: Cochrane Wounds Group

Published Online: 22 MAR 2014

DOI: 10.1002/14651858.CD011038


How to Cite

Lipsky BA, Hoey C, Cruciani M, Mengoli C. Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol). Cochrane Database of Systematic Reviews 2014, Issue 3. Art. No.: CD011038. DOI: 10.1002/14651858.CD011038.

Author Information

  1. 1

    University of Washington, Medicine, Seattle, Washington, USA

  2. 2

    VA Puget Sound, Pharmacy Service, Seattle, WA, USA

  3. 3

    ULSS 20 Verona, Center of Community Medicine and Infectious Diseases Service, Verona, Italy

  4. 4

    Università di Padova, Department of Histology, Microbiology and Medical Biotechnology, PADOVA, Italy

*Carlo Mengoli, Department of Histology, Microbiology and Medical Biotechnology, Università di Padova, Via Aristide Gabelli, 63, PADOVA, 35121, Italy. carlo.mengoli@unipd.it.

Publication History

  1. Publication Status: New
  2. Published Online: 22 MAR 2014

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Table 1. Infectious Diseases Society of America and International Working Group on the Diabetic Foot classification of diabetic foot infection

Clinical Manifestation of Infection PEDIS GradeIDSA Infection
Severity

No symptoms or signs of infection1Uninfected

Infection present, as defined by the presence of at least 2 of the following items:
• local swelling or induration
• erythema
• local tenderness or pain
• local warmth
• purulent discharge (thick, opaque to white or sanguineous secretion)

Local infection involving only the skin and the subcutaneous tissue (without involvement of deeper tissues and without systemic signs as described below). If erythema, must be > 0.5 cm to ≤ 2 cm around the ulcer
Exclude other causes of an inflammatory response of the skin (e.g. trauma, gout, acute Charcot neuro-osteoarthropathy, fracture, thrombosis, venous stasis)
2Mild

Local infection (as described above) with erythema > 2 cm, or involving structures deeper than skin and subcutaneous tissues (e.g. abscess, osteomyelitis, septic arthritis, fasciitis), and no systemic inflammatory response signs (as described below)3Moderate

Local infection (as described above) with the signs of SIRS, as manifested by ≥ 2 of the following:
• temperature >38°C or < 36°C
• heart rate > 90 beats/min
• respiratory rate > 20 breaths/min or PaCO2 < 32 mmHg
• white blood cell count > 12 000 or < 4000 cells/μL or ≥ 10% immature (band) forms
4Severe*

 Abbreviations: IDSA, Infectious Diseases Society of America; PaCO2, partial pressure of arterial carbon dioxide; PEDIS, perfusion, extent/size, depth/tissue loss, infection, and sensation; SIRS, systemic inflammatory response syndrome
* Ischemia may increase the severity of any infection, and the presence of critical ischemia often makes the infection severe. Systemic infection may sometimes manifest with other clinical findings, such as hypotension, confusion, vomiting, or evidence of metabolic disturbances, such as acidosis, severe hyperglycemia, and new-onset azotemia
 
Table 2. Topical antiseptic products available for treating chronic wounds

Product and formulationsFormulationsBacterial spectrumAdvantagesDisadvantagesCostaIndicationsb and comments

Acetic acid0.25%, 0.5%, and 1% solutionsBactericidal against most Gram-positive and Gram-negative organisms, including Pseudomonas aeruginosaInexpensive: shown to eliminate P aeruginosa colonization from burnCytotoxic in vitro although maybe not in vivo; limited activity against biofilm$No longer as widely used as it was in the past

Cadexomer iodineGel,c ointment, and dressingPolysaccharide starch lattice; active agent is slowly-released free iodine; broad spectrum of activity (same as iodine)Reduced local toxicity compared to iodine; elemental iodine released on exposure to exudateApplication may cause stinging and erythema, but less tissue damage than other iodine products; effect may not persist, and efficacy may be reduced in body fluids$$Indicated for use in cleaning wet ulcers and wounds and reducing microbial load in the wound environment

CetrimideSolution, 40%Active against bacteria and fungi; not active against P aeruginosaMay be less toxic to wound tissues than other antisepticsMay be corrosive and is potentially harmful if swallowedNot available in the United States

Chlorhexidine

gluconate
Solution, 2% and 4%; liquid, 2% and 4%; hand rinse, 0.5%; wipes, 0.5%; sponge/brush, 4%; and foam, 4%Active against Gram-positive bacteria (e.g. Staphylococcus aureus) and Gram-negative bacteria, including P aeruginosaPersistent activity up to 6 h after application; few adverse effectsHypersensitivity, including anaphylaxis, generalized

urticaria, bronchospasm, cough, dyspnoea, wheezing, and malaise; may cause serious injury to the eye and middle ear; avoid contact with face or head; some resistance reported
$2% chlorhexidine indicated as surgical hand scrub, hand wash, preoperative skin, skin wound cleanser, and skin cleaner; polyhexanide is a similar newer biguanide

HexachloropheneLiquid, 3%; foam, 0.23% with 56% alcoholBiguanide that is bacteriostatic against Staphylococcus species and other Gram-positive bacteriaMay retain residual effect on skin for several daysRapidly absorbed and may result in toxic blood levels; application to burns has resulted in neurotoxicity and death; may cause central nervous system stimulation and convulsions, dermatitis, and photosensitivity reactions$$$Not recommended for routine use on wounds because of potential toxicity

Iodine compounds and iodine tincturecSolution (aqueous) 2% and 2.4%; and Tincture (44-50% alcohol) 2% and 2.4%.Microbicidal against bacteria, fungi, viruses, spores, protozoa, and yeastsBroad spectrumHighly toxic if ingested or significantly absorbed; do not use with occlusive dressings; causes pain and stains skin and clothing; use cautiously in patients with thyroid disorders$Iodine compounds are now rarely used for wound management; cadexomer iodine and povidone iodine products are less toxic

Povidone iodinecOintment, 1%, 4.7%, 10%; solution, 1% and 10%; also wash, scrub, cleanser, gel, aerosol, gauze pad, swab, and other forms.Broad spectrum includes S aureus and enterococci; active ingredient is liberated free iodine; shares spectrum but is less potent than iodineLess irritating to skin and allergenic than iodine. Can be covered with dressings. Clinically significant resistance very rareAntibacterial action requires at least 2 min contact; may cause stinging and erythema; effect may not persist, and efficacy may be reduced in body fluids; prolonged use may cause metabolic acidosis; stains skin and clothing; possible interaction with starches in dressings$Indicated for perioperative skin cleansing and for cleansing and prevention of infection in superficial burns, incisions, and other superficial wounds

Sodium hypochlorite

(Dakin’s solution

and EUSOL)
Solution, 0.0125%, 0.125%, 0.25%, and 0.5%Vegetative bacteria, viruses, and some spores and fungiInexpensiveNo known systemic toxicity. May require prolonged contact for antibacterial action; inactivated by pus; toxic to fibroblasts and keratinocytes, and may cause pain or lyse blood clots$A concentration of 0.025% is both bactericidal and nontoxic to tissues (Heggers 1991).

Hydrogen peroxidecSolution, 1% and 3%; and cream, 1%Oxidizing agent active against many Gram-positive and Gram-negative bacteriaBroad-spectrum, bactericidal, inexpensive; no known resistanceMay cause some discomfort$Commonly used, but few clinical studies

Silver nitrateSolution 0.5%, 10%, 25%, and 50%; ointment, 10%; and swabs, 25%–50%Silver ions are bactericidal against a broad spectrum of Gram-positive and Gram-negative bacteriaLow cost; easily appliedPainful on application; stains tissues; may delay healing; concentrations 10.5% cause cauterization; inactivated by wound exudates and chlorine$Previously widely used, but now largely replaced by other compounds, including newer silver dressings

Sliver dressingsAt least 6 approved products with different propertiesSlowly released silver ions have broad-spectrum, including MRSA and VREProvide sustained levels of active silver ions; microbial resistance is rare; less painful and few adverse effects than silver nitrate; variety of products adaptable to different types of wounds; infrequent application requiredLevels of silver ions at wound interface not well defined; may cause silver staining of tissues; may delay epithelialization; relatively expensive; few published comparative trials$$Should not substitute for non medicated dressings for uninfected wounds; may be useful for subclinically infected, highly colonized wounds or for wounds being prepared for skin grafting

 EUSOL, Edinburgh University Solution of Lime; MRSA, methicillin-resistant S aureus; VRE, vancomycin-resistant enterococci. a Costs are approximate in USD per day for treating 100-cm2 wound, as follows: $, < USD 3; $$, USD 3–15; and $$$, > UDS 15. b US Food and Drug Administration–approved indications. c Available without prescription. Modified from Lipsky 2009
 
Table 3. Topical antibiotic products available for treating chronic wounds

Product and
formulations
FormulationsBacterial spectrumAdvantagesDisadvantagesCostaIndicationsb and comments

Bacitracin cOintment, 500 units/g; and powder combinations with neomycin, polymixin B, and zincMany Gram-positive organisms, including aerobic staphylococci and streptococci, corynebacteria, anaerobic cocci, and clostridia; inactive against most Gram-negative organismsActivity not impaired by blood, pus, necrotic tissue, or large bacterial inocula; resistance is rare but increasing among staphylococci; no cross-resistance with other antibiotics; minimal absorptionMay cause allergic reactions, contact dermatitis, and (rarely) anaphylactic reactions; may lead to overgrowth of drug-resistant organisms, including fungi$Widely used for many years; indicated for prevention of infection in minor skin

Fusidic acidCream, 2%; ointment, 2%; and gel, 2%Staphylococcus aureus, streptococci (in topical concentrations), corynebacteria, and clostridiaPenetrates intact and damaged skin as well as crust and cellular debrisOccasional hypersensitive reactions; resistance among staphylococci is emerging; must apply 3 times daily$$Not available in the United States

GentamicinCream, 0.1%; and ointment, 0.1%Streptococci, staphylococci, Pseudomonas aeruginosa, Enterobacter aerogenes, Escherichia coli, Proteus vulgaris, and Klebsiella pneumoniaeBroad spectrum; inexpensiveMust be applied 3–4 times daily; may drive resistance to an agent used systemically$Indicated for primary skin infections (pyodermas) and for secondary skin infections, including infected excoriations, and for bacterial superinfections

Mafenide acetateSolution, 5%; and cream, 85 mg/gA sulfonamide that is bacteriostatic against many Gram-negative organisms, including P aeruginosa, and some Gram-positive organisms, but minimal activity against staphylococci and some obligate anaerobesRemains active in the presence of pus and serum, and its activity is not affected by acidity of environmentSystemic absorption may occur; dug and metabolites may inhibit carbonic anhydrase, potentially causing metabolic acidosis; use cautiously in patients with renal impairment; pain on application; hypersensitive reactions$$$Indicated as adjunctive therapy in second and third-degree burns; may be used in rapidly progressing bacterial necrotizing fasciitis; limited use in other wounds

MetronidazoleCream, 0.75%; gel, 1%; lotion, 0.75%Many clinically important anaerobic bacteriaMay reduce odor associated with anaerobic infections; application only 1–2 times dailyRelatively expensive; systemic formulations available; could drive resistance to these$–$$Indicated for inflammatory papules and pustules of rosacea

Mupirocin and mupirocin calciumOintment, 2%; for mupirocin calcium, cream, 2.15%; and nasal ointment,
2.15%; (equivalent to 2% mupirocin)
Gram-positive aerobes, including S aureus (most MRSA), Staphylococcus epidermidis, Staphylococcus saprophyticus, and streptococci (groups A, B, C, and G) but not enterococci, some Gram-negative aerobes (not P aeruginosa), corynebacteria, and obligate anaerobesMinimal potential for allergic reactionsRare local burning and irritation; applying ointment to large wounds in azotemic patients can cause accumulation of polyethylene glycol; long-term use can lead to resistance among staphylococci, which is increasing$$Indicated for topical treatment of impetigo and eradication of nasal colonization with S aureus

Neomycin sulfatecPowder; cream, 0.5%, combinations with polymixin B and pramoxine; and ointment, 0.5%, combinations with bacitracin, polymixin B, lidocaine, and pramoxineGood for Gram-negative organisms but not P aeruginosa; active against some Gram-positive
bacteria, including S aureus, but
streptococci are generally resistant; inactive
against obligate anaerobes
Low cost; applied only 1–3 times daily; may
enhance reepithelialization
Topical powder in wound irrigating solution
may cause systemic toxicity (FDA banned); use other formulations cautiously on large wounds, especially with azotemia; hypersensitive reaction in 1%–6%, often with chronic use or history of allergies
$Use of topical powder alone or in solution is not recommended; cream and ointment, in combination with other agents are indicated for prevention of infection in minor skin injuries

NitrofurazoneSolution, 0.2%; ointment, 0.2%; and cream, 0.2%Broad Gram-positive and Gram-negative activity,
including S aureus and streptococci, but not P aeruginosa
Used mainly for burn woundsHypersensitive reactions; polyethylene glycols (in some formulations) may be absorbed and can cause problems in azotemic patients$$Indicated as adjunctive to prevent infections in patients with second- and third-degree
burns

Polymixin BcCream, 5000 units/g or
10,000 units/g, in combination
with other agents
Bactericidal against many Gram-negative organisms,
including P aeruginosa; minimal activity against Gram-positive bacteria; activity may be neutralized by divalent cations
InexpensiveSome hypersensitive and neurological or
renal adverse reactions reported; may show cross-reaction with bacitracin
$Only available in combination with other agents, including bacitracin and neomycin;
indicated for prevention

RetapamulinOintment, 1%Active against staphylococci (but uncertain
for MRSA) and streptococci and some obligate
anaerobes
May be active against some mupirocin-resistant S aureus strains; broader activity than mupirocinNot evaluated for use on mucosal surfaces; may cause local irritation$$$Indicated for impetigo, due to S aureus methicillin-susceptible only) or Streptococcus pyogenes

Silver sulfadiazineCream, 1%A sulfonamide; the released silver ions are the primary active ingredient; active against many Gram-positive and Gram-negative organisms, including P aeruginosa
.
Applied only once or twice daily; soothing
application; low rate of hypersensitive reaction
Potential cross-reaction with other sulfonamides; may rarely cause skin staining$Indicated as adjunctive treatment to prevent
infections in patients with second- and third-degree burns

Sulfacetamide Na+Lotion, 10%Bacteriostatic against many Gram-positive and Gram-negative pathogensBroad spectrum; can be combined with sulphurSystemic absorption and rarely severe side
effects occur with application to large, denuded areas; hypersensitive reactions
may occur
$$$Indicated for secondary bacterial skin infections
due to susceptible organisms and for acne vulgaris in adults

 There are no published studies supporting the use of topical erythromycin, clindamycin, aminoglycosides other than neomycin, gramicidin, or tetracyclines for treating chronically infected wounds.
FDA, US Food and Drug Administration; MRSA, methicillin-resistant S aureus.
a Costs are approximate in USD per day for treating 100-cm2 wound, as follows: $, < USD 3; $$, USD 3–15; and $$$, > USD 15.
b FDA-approved indications.
c Available without prescription.