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hmacology eriesTopical Agents in Burn and Wound Care

With any open wound infection may occur. Many factors such as age andgeneral health status may increase the likelihood of infection but the size anddepth of the wound are critical factors in determining the chronicity of anywound. Infection greatly adds to the morbidity associated with open wounds.An infected wound not only heals more slowly there is also the risk of systemicinfection and even death. Infected wounds also scar more severely and areassociated with more prolonged rehabilitation. Topical therapeutic agents havebeen shown to be efective in the management of open skin wounds. meseagents may assist less complicated healing and decrease the conversiorz of apartial-thickness injury to a full-thickness injury and thereby reduce wound-related morbidity. Common topical agents with suggestions or application arediscussed in this review. [Ward RS SafleJR. Topical agents in burn andwound care. Phys mer. 1995; 75526-538.1Key Words: Bums Topical agents Wound care.

Physical therapists are often involvedwith direct treatment of open wounds,including the application of topicalagents and dressings. The severity of awound, its location, and its depth andsize can affect healing time and gener-ate problems of pain, malaise, anddisability. Knowledge of the status of awound, and its effect on the patient, isuseful in making decisions about theapplication of appropriate topicalagents. ~~14slG)Wound treatment protocols vary, andcompetent wound care requires anunderstanding of the rationale fornumerous treatment techniques thatinclude the application of topicalagents. Such treatments often usefixed protocols. The purpose of thisarticle is to provide information on

which sound judgment can be ren-dered in the selection of topical agentsin the care of bums and other skinwounds.Wound Assessment

Wounds are often described in termsof depth of injury. Bums and someother skin traumas, for example, areclassified as superficial (first degree),partial-thickness (second degree), orfull-thickness (third degree) i n j~r ies .~Superficial injury involves the epider-mis, and such wounds are erythema-tous and mildly painful.3 Partial-thickness injury involves some degreeof damage to the dermis and may befurther classified as superficial partial-

RS Ward. PhD. PT, is Staf Member. Intermountain Burn Center, an d Assistant Professor an d Co-Director, Division of Physical Therapy. University of Utah Health Sciences Center, Annex 1130,Salt Lake City, UT 84112 USA). Address all corresponde nce to Dr Ward .JR Saffle,MD. FACS, is Director. Intermountain Burn Center, and Associate Professor, Departmentof Surgery, University of Utah Health Sciences Center, 50 N Medical Dr, Salt Lake City, UT 84132.

R Scott WardJeffrey R at e

thickness or deep partial-thicknessinjury.3 Superficial partial-thicknessinjury, which disrupts the epidermisand the superficial portion of thedermis, is manifested as painful, red,blistered, and moist when the blistersare broken, whereas deep partial-thickness injury involves deeper layersof the dermis and can present as paleor red wounds that can also be palnfulor relatively anesthetic.' Full-thicknessinjury involves destruction of the en-tire dermis, which results in a rela-tively painless wound with a leathery,dry, and often tan or brown textureand appearance.3Depth of injury for skin or pressureulcers is commonly described by usinga staging system. A stage I ulcer (ornonblanching erythema) is character-ized by red, unbroken skin in whichthe erythema at the site does not fadewith elimination of pressure. A stage Iulcer exhibits disrupted epidermis,often with some invasion into thedermis. Stage ulcers demonstratedermal injury. Stage ulcers include

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exposed subcutaneous tissue and maypenetrate even deeper.SizeBum mounds, and other largewounds, are described according topercentage of body surface area in-~olvernent.~maller wounds, such aspressure ulcers, are characterized bymeasurements that often include thecircumference or the distances be-tween the borders of the wound.*,.The size of the wound is importantpartly because, in general, largewounds are at greater risk for infectionthan smaller wounds. Some topicalagents should not be used for ex-tended periods of time over largeopen wounds because of the risk oftoxicity secondary to systemicabsorption.7(ppH(~i-1GkLocationBecause skin responds to injury bycontracting, wounds that are locatedover joints may lead to limitation ofmovement and eventual contracture.Topical agents, and a dressing that isminimally restrictive, can be importantin allowing motion. Many topicalagents also are not recommended forthe face because of concerns that theagent may enter the eye or be unin-tentionally ingested.Reassessment of the WoundDocumentation of the depth and sizeof injury is important in measuring theprogress of wound healing. Depth,size, and location of injury will alsohelp in making a determination of anappropriate topical agent. Woundevaluation is necessary to make deci-sions about the efficacy of, or thepotential for mo ifying the choice of,a topical agent. If the chosen topicalagent does not appear to be success-ful, another topical agent may besubstituted. Table outlines conditionsrelated to wound care that shouldinvite medical consultation.Common InfectionsCommon bacterial skin infectionsinclude g~am-positive acteria (eg,

Table 1 ircumstances That Should Itzuolz~eMedical onsultationSuitable treatment has been unsuccessful delayed wound closure, infection)Signs of widespread infection or inflammation redness, warmth, pain, swelling, fever, malaise) are

present particularly outside the borders of the wound)The condition of the wound appears to be worsening signs of infection, increased size or depth)

predisposing rauma or illness or symptoms of an illness exist that have not been treated orfollowed by a physician

The lesions cover a large surface area and/or are deepLarge-area wounds have been treated with certain topical chemical agent for several daysThere is uncertainty as to what is the organism infecting the woundThe manifestation of symptoms that may indicate systemic infection eg, malaise, fever)

Streptococcus, Staphylococcussumand gram-negative bacteria (eg,Pseudornonas aeruginosa). Candidais a common source of fungal infec-tions in skin wounds.'3 Because thestratum corneum is normally too dryto support microbial growth, infectionson the skin rarely occur unless thesh n is broken. Topical wound therapyprovides treatment against severeinfection, and, if infection does occur,another topical agent should be se-lected. A wound that appears to beregressing (Tab. 1) should be culturedand the infecting agent should beidentified, and the wound should betreated with debridement and applica-tion of an appropriate topical agentand dressing.Techniques of Wound Care

ntisepticsThe use, or misuse, of antiseptics thatare used to cleanse and preparewounds for application of a topicalagent should be recognized. Antisep-tics are used to reduce bacterial con-tamination by inhibiting the growth ofmicroorganisms, and antisepticsshould be applied to intact skin andnot used directly on wounds as topicalagents.14Antiseptics may increase theintensity and duration of inflamma-tion,15J6and they have also beenshown to be toxic to human keratino-q.tes17 and fibrobla~ts'~J9nd to re-tard epitheli alizati~n .~~Iodine solutions and iodophors areoften used as antiseptics. Diluted io-

dine solutions (iodine solution USP[United States Ph ar rn acop a] [2%iodine, 2.5% sodium iodide] and io-dine tincture USP [2% iodine, 2.5%sodium iodide, 50% alcohol]), thoughbactericidal, may irritate tissue, stainthe skin, and cause sen~itization.~l(p~~~)Iodine solutions have a broad spec-trum and rapid germicidal action.Iodophors (such as povidone-iodine),which are compounds of iodine andcarriers or solubilizing agents, are notas problematic as other iodine solu-tions with regard to irritation, skinstaining, and se ns iti zat i~n. ~~s germi-cidal agents, however, iodophors arenot as effective as the sodium-iodines o l u t i o n ~ . ~ ~ ~ ~ 3Hydrogen peroxide is very commonlyused as an antiseptic on wounds;however, it has limited bactericidale f f e c t i v e n e ~s , ~~ . ~~s toxic to fibro-blasts,20 and impairs the rnicrocircula-tion of wounds.'7 The mechanicalcleansing effect of hydrogen peroxide,often attributed to the fizzing (whichis caused by its decomposition tooxygen and water wh en it comes incontact with blood and tissue fluids),is questionable. Given the concernsabout the detrimental effects of hydro-gen peroxide on tissue at the woundsite, it is not recommended as anantiseptic.I4Wound DressingsWounds require periodic washing,debridement, and observation. Be-cause the effectiveness of topicalagents is time limited,25(~~'37-139)hese

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Table 2. Common Topical AgentsUsed in Wound Care

Figure Dressing change with silver sulfadiazine. A) Patient with deep partial-thickness and full-thickness bums to the right arm, shoulder, and back removingdressings in preparation for washing. B) Patient washes the wounds in the hydrother-a y tank to remove old cream and to perform gentle debridement. C) The wounds aregently dried with a clean towel. D) Silver sulfadiazine is applied with a gloved hanu'.E) A consistent layer of silver sulfadiazine s placed over the entire wound; the cream

is applied thick1.y enough that the wound cannot be visualized through it. F) Drygauze is applied over the silver sulfadiazine. (G) The dressing is applied proximal todistal on the extremity. H) The gauze s held in place with elastic netting. (Repro-duced with permission from Sa@e JR, Schneb1.y W A . um wound care. In: Richard RLStalty MJ, ed-s.Burn Care and Rehabilitation: Principles and Practice. Philadelphia. Pa:FA Davis Co; 1994:13 7-139, 174.)agents must be reapplied to enhancetheir therapeutic effects. Washing thewound and reapplying the topicalagent before there is an Infection willreduce the risk of infection. After ithas been thoroughly cleansed to re-move any loose eschar or debris aswell as old topical medications (Fig-ure), the wound should be dried toafford better adherence before topicalagents are applied to the wound sur-face. Topical antibiotics are applied tothe wound site to the appropriatethickness and covered with a dressing.The dressing is applied to preventremoval of the topical agent by con-tact with objects and to maintain amoist wound environment. The com-fortable, moist covering for the woundthat is afforded by topical agents willincrease patient acceptance of thedressing application, and the moistenvironment may also enhance

wound healing and decrease the stiff-ness frequently associated with drywounds.

discussion of all of the dressingsthat are currently available to assistwith wound care is beyond the scopeof this article. Nevertheless, the propercombination of topical agents witheither biologic or synthetic woundcoverings can decrease the likelihoodof infection and enhance woundhealing.Topical AgentsThe term topical agent implies theuse of an antimicrobial applied to thesurface of the wound. The importanceof a topical application is particularlyapparent in ischemic wounds, inwhich dependable dispatch of a sys-temic (ie, bloodstream) antimicrobial

Type ofTopical Proprietary orAgent Nonproprietary Name

Ointments BacitracinPolymyxin B sulfateNeomycinPolysporinNeosporinPovidone-iodine 10

ointrnentaCreams Silver sulfadiazine 1 creama

Mafenide acetate 0.5 creamaNystatinaNitrofurazone 0.2compoundaGentarnicin 0.1 creama

Solutions Acetic acid 0.5 solutionSodium hypochlorite (Dakin's)

solutlonSilver nitrate 0.5 solutionaChlorhexidine gluconate 0.05

solution

aPhysician's prescription required

to the damaged tissue cannot beassured.25(~~137-139)urther, the loss ofthe stratum corneum decreases theresistance of percutaneous absorptionof the chemical agents.The following section provides infor-mation on currently used topicalagents, but is not exhaustive. list ofthe topical agents is provided inTable 2OintmentsTechniqueslindicationsor useOintments are water-in-oil prepara-tions in which the amount of oil ex-ceeds the amount of water in theemulsion.26 The ointment base ofthese topical agents is comfortable andsoothing, and although these agentscan be used successfully on bothpartial- and full-thickness wounds,they are most commonly applied onpartial-thickness injuries. Ointmentsare typically more occlusive and lubri-cating than other preparations. Oint-

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Figure continuedments should be applied just thickly because the antibacterial action of theenough to cover the wound and to ointments will last for only approxi-keep the around moist. petrolatum mately 12 hours. In addition, the oint-gauze is often placed over the ments eventually dry and the dressingsointment-covered wound. The dress- will then stick to the wound, leadinging should be changed routinely, to pain and damage of cells with re-

Figure cont inuedPhysical Therapy Volume 75, Number 6 /June 1995

moval. Because of the lubricatingproperties of ointments, they may beuseful as topical agents for woundssuch as exposed tendons.Though some hypersensitivity reac-tions (eg, itching, rashes, swelling)have been reported, these incidentsare uncommon and manly occur overareas of normal skin that have beenexposed to the agent for an extendedperiod of time.Bacitracin Bacitracin is a polypeptideantibiotic that is generally available ina white petrolatum base (ointment).This ointment is effective against gram-positive cocci and bacilli. The mecha-nism of action for bacitracin is inhibi-tion of cell-wall ~ynthesis.~l(p~~9)hedevelopment of bacitracin-resistantorganisms is rare. Bacitracin promoteswound healing indirectly by control-ling the level of infection on a woundsurface. Bacitracin may also enhancereepithelialization of the ~ o u n d , ~ 7 , ~ ~although bacitracin has been showneither to have no affect on keratino-q t e proliferation or to slightly de-crease it in vitr0.~9 he uncommonincidence of resistant strains is unllkelyto increase, because bacitracin acts onthe properties of the bacterial plasmamembrane and not on molecularsynthesis. Bacitracin augments theantimicrobial action of polymorphonu-clear leukocytes (PMNs).~'Althoughthis antimicrobial action may act toenhance the bactericidal properties ofbacitracin, the significance of this towound healing is not fully understood.Bacitracin has been shown to be safefor topical application in infants andchildren, as well as adults, with rareoccurrence of hypersensitivity reac-tions (itching, swelling, anaphylaxis),and is unlikely to result in contactder1natitis.3~ recent survey of bumcenters showed that bacitracin wasused in 43 of these facilities.33 Whentopically applied, the absorption ofbacitracin is minimal and systemictoxicity is unusual. Topical nonpre-scription bacitracin has a concentrationof 400 to 500 U/g of ointment. Bacitra-cin is typically applied one to threetimes daily. In bum and wound care,bacitracin is often used on superficial


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:igc.nt proniotc.\ woi~ncl ~caling e-cailse o its Ixictcricidril properties.

Figure continuedsoften it, thus increasing the dficultyand discomfort of wound debride-ment. This topical agent should not beduring pregnancy, on a newborn, onsmall children, or on patients withsuspected or known thyroid disease.41Povidone-iodine ointment should beapplied one or two tinies daily. Theointment may also temporarily stainskin or linens. Povidone-iodine maybe best suited, but may not be the firstchoice, for use on full-thickness tissueinjuries.CreamsTechnigueslindications for use. Anassortment of antibacterial agents areavailable in cream bases. Creams areoil-in-water emulsions in which theamount of water exceeds the amountof oil, and the term creams is mostcommonly used for water-misciblep r o d u c t ~ . * ~ ~ 3 ~ , ~ ~ach of the agentsis potent and useful for the appropri-ate wound and infective organisms.Creams are usually easy to apply, areoften soothing to the patient, and areuseful on varying depths of wound(Figure). Following removal of olddressings, creams from previous treat-ments are washed off and the woundis lightly debrided. The cream is then

applied to the gently dried wound. Acream should be applied so that thewound cannot be visualized throughit.25u37-'39)dry gauze wrap shouldthen be placed over the treatedwound. Regular dressing changes areencouraged to avoid the drying of thetopical agent and because the creamsare effective against organisms for only8 to 12 hours. The following top~calagents are commonly available incream form.Silver sulfadiazine cream. Silversulfadiazine is a topical sulfonamidecompound of silver nitrate and sodiumsulfadiazine introduced by Fox4%ndprepared in a 1% water misciblecream. Silver sulfadiazine is effectiveagainst a wide range of flora, particu-larly gram-negative bacteria (eg, E coli,Entembacter, Klehsiella species,P aen~ginosa), ut including gram-positive bacteria (eg, aureus) andCandida albicans.42.47 The fonnationof resistant organisms and superinfec-tion to silver sulfadiazine is rare.42Superinfection occurs when a neworganism, which is resistant to thecurrent treatment, infeczs the wound.Bactericidal effects are likely due tomodification of the cell membrane andalteration of the cell wall. This topical

Thcre is evidence that silver sulfadia-zinc is toxic to hu ~ i ~ a nerdtinocytesancl fibroblasts in ~ i t r o ? ~ . ~ ~ . ~he rateof reepithelialization in a porcinewouncl model, however, was en-hanced when the wound was treatedwith silver ~ulfadiazine.'~~~0ilversulfadiazine also appears to inhibit theefect o f PMNs in killing microorgan-isms as well as local lymphocyte func-tion, ~~'lthough whether this has aninfluence on wound healing is yetunknown.Silver sulfadiazine is currently the mostextensively used topical agent for bumcare in the United States. Althoughtransient leukopenia has txen re-ported after the first few days ofuse,52-izihe leukopenia is typically notsevere,52 emits even with continueduse of the d rugi2 occurs in only 5% to15% of pa ti en t~ ,~ jnd is not correlatedwith septic ep i~o de s.~ ~.~ Wle rg ie sothe sulfa in the cream are unusual,and very mild cutaneous sensitivity(typically a rash) occurs in less than5 of patients and seldom requiresdiscontinuance of topical therapy.4zBecause of the possibility of ker-nicterus (associated with sulfonamidetherapy), silver sulfadiazine should beavoided during pregnancy, on prenia-ture infants, or on infants youngerthan 2 months of age.55The creamitself causes no pain. This cream iseasy to apply, comfortable and sooth-ing for patients, and is readily re-moved with washing. Though thesilver may oxidize to a gray color, thiscream does not stain skin or linen.Silver sulfadiazine should be appliedone to two times daily. This agent isindicated for use with deep partial-thickness and full-thickness injuries. Itsuse on superficial partial-thicknessinjuries may be indicated if the woundis large and the patient is at risk forsystemic sepsis or for comfort andease of dressing a smaller wound.Some retardation of healing time islikely to be expected.Mafenide acetate 0.5 cream(Sulfamylon).Mafenide acetate 0.5%cream (mafenide) is a methylatedtopical sulfonamide compound.

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Mafenide was introcluced prior tosilver sulfadiazine and was ~viclelyused for the treatment o f bums.i0 Untilsilver su1f:icliazine was marketed.mafenide was the i~iostwidely ilsedtopical agent for burns. This drug hasa wide range of antibacterial activityagainst most gram-negative and gram-positive pathogens (its activity lnay belimited against some S a~rrezr.s).+'-~~The formation of resistant organisms israre, but superinfection with Candidamay occasionally cieve10p.~~hemechanism of n~afenides not fullyunderstood. Mafenide assists withwound healing by providing control ofsuperficial infection. This topical agenthas been shown to inhibit humankeratinocytes and fibroblasts invitro. 'x4'' McCau ley et alj%uggestthat the use of mafenide may be moreinhibitory ro reepithelialization thansilver sulfadiazine. Mafenide sup-presses PMN and lymphocyte,lctivity,31.ilAlthough rnafenide is available inmany bum centers in the UnitedStates, t is used with much less fre-quency than silver sulfadiazine.33Thednig is readily absorbed into the es-char and may therefore be a usefulalternative to silver sulfadiazine for aninvasive wound infection.*Thechance of sulfa allergy is higher withmafenide acetate than it is with silversillfadiazine. Rashes may be seen inabout 50 of patients receivingmafenicie treatment.42 n addition,secondary tachypnea and hyperventi-lation may result as a consequence ofa drug-induced metabolic acidosis(secondary to inhibition of carbonicanhydra~e) .~ 'etabolic acidosis in-duces the respiratory compensation,and elevated minute ventilation hasbeen reported to extend to 50 Umir~.*~When maf'enide is being used, respira-tory status. blood gases, and pH levelsshould be monitored regularly. Mon-criefll reported that toxicity may in-crease in correlation with the durationof treatment and size of area treated.The dn ~gs considerably painful uponapplication. Because of the risk oftoxicity and the associated pain, theagent is indicated for full-thicknesstissue injuiy, either on small woundsor for as short a time as possible on

hrge woiincls. Further, the topicalagent shoiild not be ;~pplit.clmoreoften than e\?ery12 hours hecru~se fthe absorption of the drug.Mafenide acetate may also be madeinto a solution from powder (5 con-centration) for use in wet-to-moistdressings. Its bactericidal activity iscomparable to that of the mafenidecream and causes less pain on appli-cation. i 6L The risk of toxicity-related acidosis may also be decreasedwith the use of the 5% mafenide501~1tion.6LNystatin. Nystatin is an effective fun-gicide against Candida. Candidaalbicans develops little resistance tothe drug, but other strains of Candidamay develop resistance. Increasedcell-wall permeability is thought to bethe mechanism for nystatin's fungicidalaction. If a fungal infection is presenton the wound surface, nystatin mayaid healing by containing the conta-gion. No reports could be found de-scribing the effect of nystatin on hu-man keratinocytes or fibroblasts.Dermal hypersensitivity reactions arerare even with extended use, and thecream does not stain skin or linen.Nystatin cream should be applied oneto three times each day on woundswith fungal invasion.Though often used in cream form,nystatin is also available as ointment.Nystatin can also be mixed into solu-tion from its powder form for use inwet-to-moist dressings. It rnay also

seem reasonable to combine nystatinin solution with other agents such asbacitracin, poly~nyxinB sulfate, neo-mycin, or mafenide acetate to increasethe spectrum of activity of the solu-tion. Though reasonably intimated,~llixturesmay not guarantee an in-crease in antibacterial efficacy. Kucanand Sn~ooto eported that addingnystatin powder (5,000,000 U/Lj to 5%mafenide solution did not adequatelycontrol fungal growth in studied bumwounds. Any of these solutions mustbe prescribed by a physician andmixed by a pham~acist.Nitmfumzone 0.2 compound.Nitrofurazone demonstrates a broad

antibacterial spectl-um, including beingefective against tirnLs, h t~tcjr-ohucirr, ancl E coli, but it is less effec-tive against P uemginosa than silversulfadiazine or ~nafenide cetate antihas no significant fungicidal activity.The formation of resistant organisms israre, but bacteria may develop a mildresistance with prolonged use. Themechanism of action appears to be byinhibition of bacterial enzymes.Wound healing is likely augmented bythe control of surface infection. Nitro-furazone has been shown to have adetrimental effect on the growth andmigration of keratinocytes in cult~lre.39Nitrofurazone is not frequently used inbum centers in the United States.33The cream causes no pain followingapplication. The development of usualsymptoms of contact dermatitis (rash,local edema, and pnlritus), thoughrare, have been reported. This topicalagent should be applied once dailyand is indicated more for use on full-thickness injuries.Nitrofurazone may also be mixed insolution for application with wet-to-dry dressings. Information about thebactericidal effects, wound healing,and hypersensitivity reactions of thecream applies equally to the solution.Gentamicin 0.1 cream. This drugis very effective against gram-negativeorganisms such as Entwobacter,Neb-siella, and P aerugino~a.'~1'16' 16J)The mechanism of action of this agentappears to be inhibition of proteinsynthesis and messenger ribonucleicacid t r a n ~ l a t i o n . ~ ( ~ ~ - ~ ~ ~ J )esistantorganisms can be expected, and thisresistance certainly limits the use ofthis medication. Gentamicin may notbe excessively toxic to keratinocytes,l9but has been shown to inhibit theactivity of PMNs.J1Skin hypersensitiv-ity has been reported with gentamicin.Ototoxicity and nephrotoxicity canoccur, particularly when the d n ~ gsused in large volumes or for an ex-tended period of time.7(ppN61-H6J1Gentamicin should be appliecl to srnallwounds or larger full-thickness injuriesonce a day.7(ppH61-l63) Because of thedevelopment of resistant bacterialstrains and the risk of toxicity, it issuggested that this topical agent be

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used only when treatment with othertopical medications has been unsuc-cessful, that it not e used prophylacti-cally, and that it be discontinued whenthe wound colonization is controlled.

SolutionsTechniques/indications for use.Topical agents in solution are useful ifthe choice of dressing is wet-to-m~ist . ~~(p~*Mlhe drug of choice isgenerally added in its powder form todistilled water or physiologic saline.Solutions are a useful form for topicalagents, especially when applied towounds with cavities or fissures, be-cause they can easily be cleansed byrinsing.44(p2B3B)The wound should bethoroughly rinsed following removalof old dressings to ensure removal ofpreviously applied agents. The woundmay then be gently debrided, and agauze that has been soaked in thesolution of choice is then placed onthe wound. If the gauze is beingplaced in a deep wound, care must betaken to not disrupt healing tissue byoveraggressive insertion of the dress-ing. All exposed parts of the woundshould be covered by the soakedg a ~ z e . ~ ~ ( p ~ ~ )his type of dressing isoften held in place by an elastic wrapbecause the occlusiveness of the wraphelps prevent leakage of the solution.Gauze soaked with the solution formof a topical agent is easily applied andremoved from most wound5 unlessthe gauze is allowed to dry out, atwhich time it can be damaging be-cause of the associated removal ofnewly forming tissue. (pZ8M' The solu-tions should be applied often enoughto keep the dressing from drying.Topical agents in solution generallyprovide safe and effective treatment ofInfected wounds, but the requirementthat dressings not be allowed to dryout undoubtedly increases the cost ofthe technique. These solutions arenecessarily unstable, and thereforethey must be mixed fresh. Topicalsolutions must be prescribed by aphysician and should be mixed by apharmacist to ensure appropriateconcentrations and antiseptic prepara-tion. The following topical solutions

are frequently used in the treatment ofcutaneous wounds.Acetic acid 0.5 . Acetic acid at thisconcentration is bactericidal to manygram-negative and gram-positive mi-croorganisms but is especially effectiveagainst aerugin~sa. -~~olutions of0.25% acetic acid have also been re-ported, but they appear to be lesseffective in reducing microorganismson ~ o u n d s . 3 ~his weak acid pene-trates the cell wall and disrupts thecell membrane to establish its bacteri-cidal effects. Any wound-healing assis-tance provided by this solution wouldbe in curbing growth of inhibitoryinfective organisms on the surface.Acetic acid has demonstrated toxicityto fibroblasts in cu lt ~r e. 3~educedepithelial cell proliferation in culture29and delayed healing of cultured epi-thelial autografts have been reportedat 0.25% strength.@ t may be that0.5% concentrations are more toxic toregenerating epithelium, but this hasnot been reported. Gn~be r t aP7described no adverse effect on reepi-thelialization of donor sites whencomparing 0.25% acetic acid withsaline. Acetic acid has been shown toreduce PMN function.3' Skin irritationmay occur if acetic acid is used at, orhigher than, the 0.5% concentration.Acidosis may result from protracteduse over large surface-area wounds.This solution should be applied fre-quently enough to keep the woundmoist, and it should be rinsed offthoroughly between applications. Thistopical agent in solution is a goodchoice for small infected wounds.

Sodium hypochlorite (Dakin'ssolution).This sodium hypochlorite(0.5% or 0.25% NaOC1) solution isconsidered a general bactericidal (eg,Staph l lo cocci and Streptococcz?,fungi-cidal, and virucidal agent. Concentra-tions as low as 0.025% have also dem-onstrated bactericidal effects.b8 Thebactericidal effects are the suggestedrationale for aiding wound healing.Sodium hypochlorite at 0.25%, how-ever, has displayed toxicity to fibro-blast~3~,39>~.~9nd keratinocytes29,3 nculture. Polymorphonuclear leukocyteviability is also inhibited by this topicalagen~31,~9odium hypochlorite solu-

tions of 0.5% would be expected todemonstrate at least these same levelsof toxicity. Tissue toxicity was notobserved at concentrations of0.025V0.~ elays in epithelializationand neovascularization might be ex-pe~ted.~ 3Vodiumypochlorite dis-solves blood clots and may also delayclotting. Bleeding may ensue, and thewound should be carefully monitoredwhen using this solution. Acidosis mayresult following continuous use overlarge-area wounds. This solution mayalso cause pain. A diluted sodiumhypochlorite solution is frequentlyused to irrigate wounds. In any dilu-tion, the solution should be thor-oughly rinsed off the site betweendressings, as prolonged exposure canlead to skin irritation. The soakeddressing should be changed oftenenough to avoid drying of the dress-ing. As with acetic acid, this sodiumhypochlorite might be considered asan alternative for treating small, in-fected wounds. Because of its level oftissue toxicity at typical concentrations,this solution may not be a suitablechoice for treatment of partial-thickness injuries that are sparselycolonized. Less concentrated solutionssuch as 0.025% should be consideredfor clinical use.@Silver nitrate 0.5 . Silver nitrate insolution provides bactericidal activityagainst a wide range of bacterial flora,but is probably more effective againstgram-positive bacteria (eg, S aureus).Silver nitrate solution has demon-strated invulnerability to resistant or-ga ni sm ~. '~ ound healing may beenhanced by control of local infectionwith this topical agent. There are con-flicting reports about the toxicity ofsilver nitrate solution to epitheliun1.3 xThe solution is extremely hypotonic,and electrolytes (eg, sodium and po-tassium) leach into the dressing. Thisleaching can lead to electrolyte imbal-ances, especially with prolonged useover large-area wounds. Use of silvernitrate on large wounds requires mon-itoring of ele~tro lytes.7~acterial re-duction of nitrate to nitrite may lead tomethemoglobinemia with use of thistopical agent.73This potential compli-cation, though rare, should be sus-pected if skin around the wound ap-

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pears gray or cyanotic, and thediagnosis can be confirmed withblood methemoglobinemia measure-ment.*l No reports of hypersensitivityreactions in the skin have occurredwith the use of silver nitrate solution.Because of potential toxicity, silvernitrate has been suggested to be moreeffective on smaller surface-areawounds. Although silver nitrate is areasonable choice as a topical agentfor smaller wounds, frequent soakingof the dressings (about every 2 hours)is required for the agent to remaineffective and application of the solu-tion may be slightly painful. Further,the solution stains skin, wounds,dressings, h e n , and clothing a darkbrown or black. The agent does notpenetrate eschar readily and thereforeshould not be the first choice for treat-ment of established infection^ ^^Tripe antibiotic solution Bacitracin(50,000 U), polymyxin B (200,000 U),and neomycin (40 mg) can be com-bined in 1 L of saline to produce atriple antibiotic (TAB) solution to useas a wet-to-moist dressing for in-fected wounds of several type~.~5(pl'-l)This solution shows at least a moder-ate level of activity against a variety ofgram-negat~ve nd gram-positive or-ganisms, with activity against aerugi-nosa being poor.'4 No data on resis-tant organisms were available. Thecomponents of the solution, when inointment form, showed limited toxicityto keratinocytes.39 Nystatin, in powderform, may be added to the solution ithere is a combined bacterial/fungalinfection. This TAB solution may beindicated for fresh, poorly colonizedwounds such as new skin grafts ordonor sites because of its potentiallylow level of' tissue toxicity.Chlohexidine gluconate solutionChlorhexidine gluconate solution(0.05% in distilled water) affords anti-bacterial activity against gram-positivebacteria, including ueruginosa andKlebsiellu, and against gram-positivebacteria such as S allreus and E c01i.~~Local infection control may assistwound healing. No data could befound that discussed the tissue toxicityof this solution, and systemic toxicityappears to be rare.42.75 his solution

rarely causes skin reactions; however,with prolonged, repeated use, contactdermatitis may d e ~ e l o p . ~ ~ ~he ap-parent low toxicity and high bacteri-cidal properties of this solution indi-cate that it may be a useful option as atopical therapeutic solution for differ-ent depths and sizes of injury. Thesolution should be used often enoughto keep the wound moist.MoisturizersAlthough moisturizers are not typicallydiscussed in the context of topicalagents, a brief discussion is war-ranted, particularly as it relates tosensitivity reactions and to antipruriticagents. Dryness, flakiness, and pruritusare typical in freshly epithelializedwounds and result from the loss ofproduction of skin oils. Superficialwounds and true partial-thicknesswounds will eventually recover theability to produce skin oils; however,deeper wounds will not. Topical mois-turizers, used as needed (often morefrequently than twice a day), willrelieve most complaints of flakinessand itching. Hypoallergenic moisturiz-ers that are not alcohol based, andcontain no perfumes, are preferred.Patients may develop sensitivity reac-tions to moisturizers that contain per-f u m e ~ . ~ ~hese reactions often occuras skin rashes or increased pruritus. Ifsuch a reaction occurs, the use of thatmoisturizer should be discontinued,the rash should be allowed to clear,and the patient should then exploreother moisturizers to find o ne that willnot produce an irritation. If the rashpersists following a change of topicalagent, a medical consultation shouldbe obtained.There are some mild antipruriticcreams that may be acquired withoutprescription, and these creams shouldbe applied as infrequently as willallow for control of itching. There arealso several choices of topical cortico-steroids that are used s anti-inflammatory and antipruritic agents.These corticosteroids, which requirephysician prescription, should beapplied as prescribed and seldomrequire prolonged use. Adverse reac-tions of burning, itching, erythema,

and skin and papular rashes havebeen reported, and topical corticoste-roids should be discontinued if any ofthese symptoms occur. Systemic effectsof topical corticosteroids are consid-ered reversible.

Other ConsiderationsGeneral contraindications Anyknown sensitivities, or the develop-ment of sensitivities to the pharmaceu-tical components of each of thesepreparations in ointment, cream, orsolution, should be considered astanding contraindication for a particu-lar topical agent.Resistant strains Although resistantstrains of organisms may developagainst some of the topical agentsdiscussed, this has not created a majorbarrier to treatment of wound infec-tion by the available choices of agentsprovided in this review. Methicillin-resistant Staphylococcusallreus(MRSA) is a reasonably commongram-positive species of bacteria thatcan cause a number of infections,including bacteremias, pneumonias,and soft tissue and bone infections.Because most cases are nosocornial,infection control and isolation precau-tions should be a part of any woundcare measures along with the use oftopical agents. In the case of MRSA,silver sulfadiazine, mafenide acetate,and nitrofurazone (as well as mupiro-cin, a topical agent not described inthis article) may be effective in treatingthis resistant ~train.~+- lmoot et alH1report that in their bum unit mafenideacetate has limited activity againstMRSA. This may be the result of theirfrequent use of this agent, which mayhave produced an MRSA resistance intheir particular center.R1f there is atopical agent of choice in a clinic anda resistance to a particular organismdevelops, the resistance may be clinicspecific and other topical agentsshould be used in attempts to subduethe resistant pathogen.Other Incorrect medication can resultin delayed healing, discomfort, in-creased scarring, progression of theinfection, or toxicity. For example,delayed healing may lead to prolifera-

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tion of fibroblasts and an increase inscarring. A large-area wound treatedwith the same topical agent for severaldays also has a potential for systemicto xi city. ^^ 51 m+ll A therapist whois aware of recurring wounds or infec-tions should refer the patient to aphysician.Patients should be taught the appro-priate application of topical agents anddressings, as well as the signs of infec-tion. Patients should also understandthat such drugs are n v r to be takeninternally.Topical gents and WoundHealingAny human tissue requires oxygen toremain viable. The importance ofblood supply to the skin can be easilyillustrated with the example of a pres-sure ulcer. Though there are othercontributing factors to the fomlation ofpressure ulcers, it is clear that localischemia caused by pressure-inducedconsuiction of capillaries leads todeath of the involved skin. Capillaryregrowth and associated wound re-modeling are hampered by decreasedoxygenation.H2-H dditionally, infec-tion is enhanced by an ischemic envi-ronment because bacteria require littleoxygen compared with the associatedcells.Hi Further, by consuming oxygen,bacteria decrease the amount of oxy-gen available to the ti s~ ue .~ 6nade-quate wound healing with concurrentinflammation and increased scarring isanother consequence of bacterialproliferation and related tissue hy-p ~ x i a . * ~diabetic ulcer is a classicexample of a poorly perfused woundthat demonstrates substandard woundhealing along with chronic inflarnma-t i ~ n . ~urn wounds are ischemic as aresult of the thrombosis caused by theinjury. Full-thickness bums display thisthrombosis through all layers of af-fected skin, whereas partial-thicknessbums demonstrate incomplete throm-bosis.*' Topical agents are used tofight wound infection related to de-creased tissue vascularity.Controlling infection in open woundswill enhance wound healing. Topicalagents reduce the number of germs

but do not obliterate them. Improvedwound healing decreases the pain andscarring that contribute to wound-related physical impairment.By removing bacteria and necroticdebris, debridement and cleansing areimportant components of any woundcare program to prevent infec-t i o n . p ~ ~ 5 ~ - l ~ ~ )ecrotic tissue presenton a wound surface promotes infec-tion by providing nutrients for bacte-ria. Besides fighting superficial infec-tion, most topical agents will helpsoften wound eschar, which will assistwith debridement of tissue. Removingpreviously applied creams and oint-ments from the wound allows forrepeated assessment of the wound.Superficial and partial-thicknesswounds heal by regeneration of epi-thelium from existing basal cells at thewound surface.H9 ome mild contrac-tion may be associated with the heal-ing of superficial wounds, but seldomis there scarring. In contrast, deepwounds usually heal by a combinationof reepithelialization and c0ntraction.~9Contraction serves to decrease thearea of the wound. Wounds are thenreepithelialized from the margins.Scarring and contraction of scar tissueare typically consequent problems tothe healing of deep partial-thicknessand full-thickness wounds.The rate of reepithelialization may beenhanced by the application of baci-t r a~ in ,~7 .~nd polymyxin B and Neo-sporin in an ointment or TAB solutionappear to either have no, or only aslight, inhibitory effect on keratinocytepr~liferation.~n contrast, povidone-i0dine,3~,3~ilver sulfadia~ine,' *~9mafenide acetate,3 4H,49,5%itrofun-zone,39acetic acid,29 nd sodium hy-pochlorite2 '9 will likely inhibit reepi-thel iali~ation .~~- bland ointment(bacitracin, polymyxin B sulfate, neo-mycin, and their combinations) andpossibly silver sulfadiazine are oftenthe topical agents of choice for reepi-thelializing wounds. Bland ointmentsare also generally less expensive thanthe sulfa-based topical agents andtherefore might be a more cost-effective choice for treatment of small,uncomplicated wounds.

Wound contraction is a natural pro-cess in which wounds heal by de-creasing their size. When a wound islocated over or near a joint surface,however, excessive contraction maycontribute to loss of joint motion.Further, when the wound encom-passes a large surface area, contractioncannot successfully close the wound.Little is known about the effects oftopical agents on the rate or amountof wound contraction. Bacitracin andsilver sulfadiazine have been shown toretard wound contraction in a pigmode1,Zs but the direct clinical applica-tion of these findings is not yet under-stood. Additionally, the appropriatechoices of topical treatment mayspeed wound coverage, thereby de-creasing the risk of scarring and asso-ciated scar contracture. A hypertrophicscar, which results from a poorlytreated wound or is the predictableresult of a healed full-thicknesswound, will continue to contract forseveral months, even followingwound healing.onclusion

Because of the availability of severaleffective topical agents, wound careprotocols may vary and still meet withsuccess. Observation of the wound,along with the appropriate selection ofa topical therapeutic agent, can im-prove the healing of wounds and leadto decreased patient morbidity. Thephysical therapist should be aware ofthe advantages and disadvantages ofvarying topical wound care agents.Collaboration with the physician indetermining infec~ive rganisms at awound site will assist with makingacceptable decisions about the topicalagents of choice. Future studies ofimportance to this clinical area shouldinclude controlled comparative clinicalstudies on the effects of various topicalagents on different types of wounds,the interaction of various dressingswith topical agents, the potential useof drug enhancers for these topicalagents, the effect of different topicalagents on wound and scar contraction,the rate of healing and its effect onscar formation, and the cost effective-ness of varying wound treatments.

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cknowledgmentWe thank Dr Jody Neuman, AssistantProfessor Clinical), College of Phar-macy, University of Utah Health Sci-ences Center, for her review of themanuscript.

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formed human keratinocytes. ,/ tzz~estDerma-tol. 1987;89:316-317.18 Viljanto J. Disinfection of surgical woundswithout inhibition of normal healing.ArchSurg. 1980;115:253-256.19 Lineaweaver W, Howard R Soucy D. Top-ical antimicrobial toxicity. Arch Sulg. 1985;120:267-270.20 Shelanski HA, Shelanski MV. PVP-iodine:History, toxicity and therapeutic uses.J IntCON Sulg. 1956;25:727-734.21 Jacobs MR, Zanowiak P. Topical anti-infective products. In: Feldman EG, ed. Hand-book of Nonprescriptive Drugs. 9th ed . Wash-ington, DC: American PharmaceuticalAssociation; 1990:779, 781.22 Gottardi W. Iodine and iod ine com-pounds. In: Block SS, ed. Disinfection, Steril-ization, and Preservation. Philadelphia, Pa:Lea Febiger; 1983:18+196.23 Craven DE, Moody B, Connolly MG, et al.Pseudobacteremia caused by povidone-iodinesolution contaminated with Pseudomonas ce-pacia. N Engl JM ed . 1981:305:621-623,24 Polk H, Finn M. Chemoprophylaxis ofwound infections. In: SimmonRL Howard RJ,eds. Surgical Infection Diseases. New York,NY Appleton Century Crofts; 1982:471.25 Same JR, Schnebly WA. Bum woun d care.In: Richard RL, Staley MJ, eds. B u m C are a n dRehabilitation: Principles an d Practice. Phila-delph ia, Pa: FA Davis Co; 1994:137-139, 174.26 Arndt KA. Formulary. In: Manual of Der-matologic Therapeutics. 3rd ed. Boston, Mass:Little, Brown and Company Inc; 1983:299.27 Eaglstein WH, Mertz PM, Alvarez OM. Ef-fect of topically applied agents on healingwounds. Clin Dermatol. 1984;2: 12-1 15.28 Watcher MA, Wheeland RG. The role oftopical agents in the healing of full-thicknesswounds. J Dermatol Surg Oncol. 1989;15:1188-1 195.29 Cooper ML, Boyce ST, Hansbrough JF,et al. Cytotoxicity to cultured human keratino-cytes of topical antimicrobial agents.J SurgRes. 1990;48:190-195,30 Saberwal G, Nagaraj R. Cell-lytic and anti-bacterial peptides that act by perturbing thebarrier function of membranes: facets of theirconformational features, structure-functioncorrelations and membrane perturbing abili-ties. Biochim Biophys Acta. 1994;1197:109-131.31 Hansbrough JF, Zapata-SirventRL CooperML. Effects of topical antimicrobial agents onthe human neutrophil resp~rato ry urst. ArchSulg. 1991;126:603-608.32 Gette MT, Marks JG Jr, Maloney ME. Fre-quency of postoperative allergic contact der-matitis to topical antibiotics. Arch Dermatol.1992;128:365-367.33 Taddonio TE, Thomson PD, Smith DJ Jr,Prasad JK. A survey of wound monitoring andtopical antimicrobial therapy practices in thetreatment of burn injury.J Bu m Care Rehabil.1990;11:423-427.34 Sande MA, Mandell GL. Antimicrobialagents: tetracyclines, chloramphenicol, eryth-romycin, and miscellaneous antibacterialagents. In: Gillman AG, Goodman LS, RallTW, Murad F, eds. The Pharmacologic Basiso f Therapeutics. New York. NY: MacmillanPut)lishing USA; 1985:1191-1192,

35 Brown MRW, Wood SM. Relation betweencation and lipid content of cell walls ofPseudomonas aen~g inosa, roteus ~ trlgaris.and KlebsieNa aerogenes and their sensitivityto polymyxin B and other antibacterial agents.JPharm Pharmacol. 1972;24:215-228.36 Kaiser W, von der Lieth H, Potel J Hey-mann H. Experimental study of the local ap-plication of silver sulfadiazine, cefsulodin andpovidone-iodine to burns. Infection. 1984;12:31-35.37 Robin AL, MacArthur JD, O'Connor N. Theinfluence of betadine ointment (povidone-iodine) on wound healing in rats. In: Geor-giade NG, Boswick JA, MacMillan BG, eds.Recent Antisepsis Techniques in the Manage-ment of Bum Wound. Norwalk, Conn: ThePurdue Frederick Co; 1974:12-14.38 Lineaweaver W, McMorris S, Soucy D,Howard R. Cellular and bacterial toxicities oftopical antimicrobials. Plast Reconstr Sulg.1985:75:394-j96.39 Smoot EC, Kucan JO, Roth A, et al. In vitrotoxicity testing for antibacterials against hu-man keratinocytes. Plast Reconstr Sulg. 1991;87:917-924.40 Mark JG. Allergic contact dermatitis topovidone-iodine. J Am Acad Dermatol. 1982;6473-475,41 Steen M. Review of the use of povidone-iodine (PVP-I) in the treatment of burns. Post-grad Med J. 1993;69:S84-S92.42 Monafo WW, West MA. Current treatmentrecommendations for topical bum therapy.Drugs. 1990;40:364-373.43 Kucan JO. Robson MC, Heggers JP. et al.Comparison of silver sulfadiazine, povidone-iodine and physiologic saline in the treatmentof chronic pressure ulcers.J Am Geria tr Soc.1981:29:232-235.44 Arndt KA Mendenhall PV, Sloan KB,Perrin JH. The pharmacology of topical ther-apy. In: Fitzgerald TB, Eisen AZ. Wolff K, etal, eds. Dermatology in General Medicine.New York, NY: McGraw-Hill Inc; 1993:2838,2839.45 Arndt KA. Treatment principles. In: Man-ual of Dermatologic Therapeutics.3rd ed.Boston, Mass: Little, Brown and Company Inc;1983229.46 Fox CL. Silver sulfadiazine: a new topicaltherapy. Arch SUT. 1968;96:184-188.47 Monafo WW, Ayvazian VH. Topical ther-apy. Sulg Clin North Am. 1978;58:1157-1171.48 Cooper ML. Laxer JA, Hansbrough JF. Thecytotoxic effects of commonly used topicalantimicrobial agents on human fibroblasts andkeratinocytes. J Trauma. 1991;31:775-784.49 McCauley RL Linares HA, Pelligrini V,et al. In vitro toxicity of topical antimicrobialagents to human fibroblasts.J SUT Res. 1989;46:267-274.50 Geronemus RG, Mertz PM, Eaglstein WH.Wound healing: the effects of topical antimi-crobial agents. Arch Dermatol. 1979;115:1311-1314.51 Zapara-SirventRL Hansbrough JF. Cyto-toxicity to human leukocytes by topical anti-microbial agents used for burn care.,/B u mCare Rehahil. 1993;14:132-140,52 Kiker RG, Cawajal JF, Mlcak RP. LarsonDL. A controlled study of the effects of silversulfadiazine on white blood cell counts inburned cllildren.J Trautna. 1977:17:835-836.

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1995; 75:526-538.PHYS THER.R Scott Ward and Jeffrey R SaffleTopical Agents in Burn and Wound Care

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PHYS THER-1995-Ward-526-38