Medical Education The Use of Collagen as an Antibiotic ... · system for occular application,...

NOVEMBER/DECEMBER 2001 • PODIATRY MANAGEMENTwww.podiatrymgt.com 97

(Fibracol), bovine collagen (HyCure), acommonly-known hemostatic agent(Avetene); another type 1 bovine colla-gen material (Heletene); and anothertype 1 bovine collagen material derivedfrom tendon rather than cowhide(Hemacol). Similar types of overall re-sults have been obtained with these dif-

ferent types of collagen agents. As timeprogressed I attempted additional caseswith varying degrees of infection, and atlast count I had approximately 160cases attempted with only 12 BK ampu-tations and 38 partial amputations oftoes or to the midfoot.

Continued on page 98

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Following this article, an answer sheet and full set of instructions are provided (p. 116).—Editor

Author’s Note: This article was orig-inally prepared and presented in 1997.In the ensuing years I expanded the pro-tocols included here to include the useof several other collagen-based materi-als, including: collagen/alginate sheets

By Lawrence O. Kollenberg, D.P.M.

Objectives

Upon completion of this articlethe participant should better un-derstand:

1) The components of collagenand how it works in wound man-agement.

2) The diverse nature of manag-ing the diabetic foot.

3) How collagen can be used asa drug delivery system for topicaluse of potent antibiotics.

4) The need for multiple materi-als management of wounds andhow no single agent can functionto cure wounds.

5) The use and application ofcollagen impregnated antibioticsand how it can improve the out-come in certain patients.

Continuing

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The Use ofCollagen as anAntibioticDelivery SystemA new method of fighting infection in chronic wounds.

DIABETES:Building onthe Basics

DIABETES:Building onthe Basics

SummarySerious pedal infections in people

with diabetes can easily lead to ampu-tation. Tissue concentration of antibi-otic is dependent upon the ability toget high enough blood levels toachieve tissue concentration greaterthan MIC for extended time frame. Re-view of the literature shows that type Ibovine collagen allows for a sustainedlinear zero order kinetic release ofdrugs.

Clinical evidence is used to illus-trate how three commonly utilized an-tibiotics can be impregnated into col-lagen in order to assist with achievingresolution of infection in deep soft tis-sue or osteomyelitis infections of thefeet.

IntroductionToday’s health care practitioner

has the burden of providing cost-effec-tive care. Treatment of infections is noexception. Todaywe all try to man-age our patientswith a minimalnumber of hospitalstays. This case re-port shows a possi-ble new method ofdrug delivery of an-tibiotics in serious,significant infec-tions includingdeep space soft tis-sue or osteomyeli-tis infections of thefeet that may lead to minimizing needfor inpatient care.

As clinicians treat infections thereexist certain basic concerns on all pa-tients. These include such problems asgeneral health status (e.g., diabetes, pe-ripheral vascular disease, collagen vas-cular disorders). In arterial ischemicdiseases, the lack of blood flow to tis-sue results in compromise of deliveryof macrophages and nutrients to allowcells to fight infections. Similarly, an-tibiotic delivery in the bloodstreamand thus to the tissues is compro-mised.

The protocols listed in this articleare designed for clinicians to test theseresults on their own patients. The goalis to see if in fact this new drug deliv-ery system can assist in resolving theenigma of amputation, and perhaps

result in shorter length of stay in thesecases.

The LiteratureVirtually all human organs and tis-

sues contain connective tissue. Con-nective tissue macro molecules arecomposed of at least 19 known formsof collagen.1 This article will focus onType I collagen as a drug delivery vehi-cle. Type I collagen, the most abun-dant form of collagen in humans, isfound in all connective tissues excepthyaline cartilage and basement mem-branes.2

The collagen molecule is com-posed of two alpha and one alpha2chains wrapped in a triple helix withthree left-handed helical alpha chainstwisted into a right-handed super helixstructure.3,4 The alpha chains are simi-lar in structure and contain approxi-mately 1,000 amino acid residueswhere commonly every thirdmolecule is glycine. The other aminoacids are either leucine and proline, or

hydroxyleucineand hydroxypro-line.4 To maintainthis structure, hy-drogen bonds anddisulfide bondsmust remain intactor it results in anon-functionalprotein.5 This triplehelix arranged col-lagen is known asfibrillar collagen.1

Collagen hasbeen reported as a

well-tolerated and completelybiodegradable material. In addition,collagen has been utilized as a carriersystem for occular application, involv-ing pilocarpine and macrolide antibi-otics.6,7,8 Collagen has been shown tobe a drug carrier vehicle for lipophillicdrugs including tretinoin and lido-caine.4 Collagen, when combined withchitosan, has acted as a transdermaldelivery system for delivering calciumchannel blocker and beta blockerdrugs.9 The releasing system of collagenhas been shown to be sustained overtime (approximately 2.5 days) in a lin-ear fashion.10 Collagen sheets with im-pregnated gentamycin have been usedto treat chronic osteomyelitis.11 Duringthe course of this study, the systemicabsorption of gentamycin after the col-

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98 www.podiatrymgt.comPODIATRY MANAGEMENT • NOVEMBER/DECEMBER 2001

Serial plain radiographs were utilized

to follow osteomyelitiscases until clinical andradiographic resolution

of osteomyelitis wasdetermined.

monitored patient compliance for diabetes checks,antibiotics being administered, etc.

All the patients were initially treated with oral antibi-otics. Empirical choice was based upon patient history, du-ration of infection, and type of infection (i.e., soft tissue or

bone). Oral agentsi n c l u d e dCephalexin 2grams (split dos-ing four timesdaily) or Clin-damycin 900mg(split dosing threetimes daily).

At the initialclinic visit, all in-fected areas werecarefully evaluat-ed and preppedwith chlorox-ylenol 3.0 percent,cocamidopropylP G - d i m o n i u mchloride phos-phate 3.0 percent(PCMX 3.0 percent) for two minutes, following Universityof Minnesota transplant pre-operative surgical prep proto-col.15 When open and draining with apparent deep portalulceration, wounds were probed to determine if infectiontraveled to the bone.

The physician should probe gently with blunt instru-mentation until resistance is met and then feel the tissue

Continuing

Medical Educationlagen sponge was implanted into patients, was found to beminimal (if present at all). The mechanism elucidated forthis process shows that the collagen triple helix contains

about 17 percent charged amino acid residues which areuniformly distributed over its entire length.10 Under physio-logical conditions, the overall net charge is neutral. Withspecific chemical reactions, the collagen molecule can bemodified to yield a net negative or a net positive charge.This results in an enhanced retention of the oppositelycharged drugs by binding interactions.10

When collagen sponge is combined with liposome en-capsulated antibiotics, the duration of time for release ofthe antibiotic has been reported to be up to three timesgreater than that of collagen sponge alone.12 Polymixin Band Amikacin have been shown in other laboratory experi-ments to have significant sustained release action againstPseudomonas Aeruginosa when attached to type I colla-gen.13 There exists significant data that collagen when ap-plied topically to open wounds may accelerate the healingcapacity of wounds.14 Furthermore, this study demonstrat-ed that gentamycin impregnated collagen sponge showsup to 600 times MIC as compared to methyl methacrylatebeads at 300 times MIC. Methyl methacrylate beads are re-ported to be sporadic in their release rate, whereas therehas been significant evidence brought to bear that theremay exist a constant linear diffusion rate of collagen givinga sustained release of many drugs6-13

The literature suggests that type I collagen, in a triplehelix arrangement, may give a steady sustained release ofantimicrobial agents in infectious disease. This report willreview the clinical application of this in 12 patients withactive, clinically significant infections involving deep softtissues or bone.

MethodsA total of 12 patients were evaluated by the same phy-

sician. Initial evaluation included history and physical ex-amination (See Table 1), plain radiographs, blood laborato-ry analysis (See Table 2), debridement of infected tissue,deep tissue biopsy of soft tissue or bone for culture and sen-sitivity. Eight of the patients had diminished palpable puls-es or delayed capillary return time, and outside vascularlaboratory analysis, including bidirectional doppler withtoe pressures, were obtained. (No patients had vascular by-pass surgery during this course of care.)

There were no patient admissions or IV administrationof antibiotics during the course of care. Outside homehealth agency nurses were trained in this protocol to assistwith patient home bound care on a daily basis. Nurses also

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TABLE 1: INITIAL EVALUATION

soft tissue No. Age Range ABI<.7 NIDDM IDDM osteomyelitis infection only

Male 5 68-82 3 2 2 3 2

Female 7 63-98 5 2 3 5 2

TABLE 2: BLOOD ANALYSIS

• CBC with differential • Random Blood Sugar• Hemoglobin A1C• Serum Creatinine B.U.N• E.S.R.-Westergren• Albumin• Globulin• A/G Ratio• Total Proteins• C-Reactive Protein

sistent instructions at the first clinic at-tendance, as follows:

1) Minimal walking2) Wear special shoe at all times

that you are out of bed3) Warm, moist compress to hind

foot and leg two hours on and twohours off while awake

4) Sponge bathing only5) Continue regular or special diet6) Start vitamins; multivitamins

(Centrum) three times daily (x 30days), then continue twice daily; vita-min C, 1 gram twice daily (untilhealed)

7) Diabetic patients to monitorfasting blood sugar in a.m. and p.m.unless otherwise directed by primarycare physician

8) If fasting blood sugar >200mgpercent call primary care physician

9) Take antibiotic on prescribedcourse

10) Change dressing once daily11) Check oral temperature three

times daily. Begin acetaminophen(Tylenol) if oral temperature greaterthan 101˚ F

12) Take pain pills as prescribed ifneeded

13) Do not follow friends’ or otheroutside individuals’ advice withoutchecking with clinic nurse first

14) Keep all follow-up appoint-ments

15) Notify doctor if any red streakson leg or increase in swelling to foot,ankle or leg

16) Keep collagen mixture awayfrom moist areas, i.e., bathroom. Storein cabinet

All patients attended clinic at leasttwice the first week and then weeklyfor serial evaluations until the infec-tion was resolved and wounds wereclosed. All laboratory reports were re-evaluated at the second visit. Whenbacterial organisms were determinedto be resistant to gentamycin or theoral agent, then a change in antibi-otics was made (Table 3).

Three of the patients received Clin-damycin impregnated into type Ibovine collagen and three of the pa-tients received Vancomycin impreg-nated into type I bovine collagen. If re-sistance was reported to initial oral

agents, selected pa-tients’ oral agentswere changedbased upon sensi-tivity results fromthe culture report.Patients remainedon the oral agentuntil the infectionwas localized.

All patientshad repeat of CBCwith differential,ESR, CRP, everytwo weeks until re-sults returned tonormal. Serial plainradiographs wereutilized to followosteomyelitis casesuntil clinical andradiographic resolu-tion of osteomyeli-tis was determined.In the event of pre-

with the instrument. This minimizestrauma to surrounding tissue.

If the lesion had not been probedprior to debridement, the sites weresurgically traced at the time of initialsurgical debridement, to determine ifinfection was in bone. Plain radio-graph, bone, and soft tissue changeswere used to aid diagnosis.

Deep soft tissue specimen or bonespecimen was obtained for culture andsensitivity analysis. Upon completionof surgical debridement, wounds werepacked with type I bovine collagenmixed with gentamycin followed bysecondary sterile dressing. Packing theinfected tissue should be done withlight packing, as collagen expandswhen fluid is applied to it.

Initially, if the lesion involved dis-tal toes, then 5cm x 5cm gauze wasrolled and placed into sulcus of toe atthe initial dressing to assist with de-pressurizing the digit. All 12 patientswere placed into a surgical shoe,which was modified for depressuriza-tion of the affected area and to allowimmediate limited ambulation (mealtable and bathroom). Application of a2 x 2 gauze pad incorporated intodressing functioned as a buttress padfor depressurizing the distal os-teomyelitic digit.

Patients were given clear and con-

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TABLE 3: ORGANISMS FROM CULTURE

Organisms isolated Number of Isolates Gentamycin Resistant

Staphylococcus Aureus 6 2

M.R.S.A. 4 3

Staphylococcus Epidermidis 5 2

Enterococcus 3 3

Pseudomonas Aureginosa 3 0

Klebsiella Pneumonia 2 0

Escherechia Coli 1 0

Proteus Miralbis 2 0

5 patients had 1 isolate3 patients had 2 isolates2 patients had 3 isolates1 patient had 4 isolates1 patient had 5 isolates


This article illustrates the

treatment and care ofsignificant infections

involving eight differentorganisms and three

different drugs.

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• Apply pad (specialty absorptive orfoam) over wound area and secure withtransparent adhesive covering.

• Cover the affected area with withgauze and secure with netting.

• Change dressing once daily.The gauze cover was applied be-

cause many patients found that the filmdressing would roll or stick to clothing;

the gauze reduced the incidence of in-terference. Dressings were applied daily,because patients were unwilling to ac-cept alternate-day dressings.

MaterialsAll 12 patients had initially re-

ceived the same or very similar materi-als (Table 4). As the cases progressedclinically, modifications in materialsutilized were made based upon a com-bination of patients’ clinical courselaboratory reports and surgeons’judgement. The type I bovine collagenand antibiotic mixture were providedto each patient from the clinic and pa-tients were required to bring their mix-ture for each clinic visit.

The combination of antibiotic im-pregnated into the collagen is generical-ly described below and specifically list-ed in Table 5 for individual antibiotics

mature closure, then the infectionsite was re-opened.

All patients were followed until 30days after clinical complete resolutionof the infection process. After the ini-tial infection was brought under con-trol, surgical shoes were modified toinclude pads to allow for depressuriza-tion of plantar or digital lesions. Longterm care included prophylactic sur-gery to improve biomechanical forcesor biomechanically correct orthotics.

Patients or home health nurseswere instructed on dressings applica-tion as follows:

• Wash area with PCMX 3.0 percent(Technicare) saturated gauze pad.

• Rinse with sterile saline until allsoap residue is washed off.

• Apply collagen antibiotic mixture toinfected location until about 2/3 full.

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TABLE 4: PRODUCTS AND MANUFACTURERS

Generic Name Proprietary Name Manufacturer

Gentamycin Garamycin Schering Plough

Clindamycin Cleocin Upjohn

Vancomycin Vancocin Eli Lilly

PCMX 3.0% Technicare Care Tech Labs

Surgical Shoe Darco Shoe Darco, Inc.

Crest Pads N/A Stein’s Foot Specialties

Cut-out Pads N/A Stein’s Foot Specialties

Type I Bovine Collagen Medifil BioCore, Inc.

Cephalexin Keflex Eli Lilly

Ofloxacin Floxin McNeil

Doxycycline Vibramycin Pfizer

Sulfamethoxazole Bactrim DS Roche Labs

Trimethoprim

Gauze Kling Johnson & Johnson

Foam Hydrosorb Convatec

Adhesive Film Dressing Opsite Smith and Nephew

Gauze Netting Spandage Medi-Tech International

Sterile Saline for irrigation N/A Baxter Healthcare

This limited anecdotalreport does show

that there is potential forcost effective outpatientcare even when serious

limb threateninginfections are treated.

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a light, air tight container. (Note: theauthor is unaware of any shelf life dataof this mixture.) The patients were in-structed to store the mixture in a dark,non-humid cabinet/closet, such as alinen closet at home.

At the initial visit, patients were fit-ted for their surgical shoes, which werelater modified with additional pads ortoe crests to depressurize the infectedlocation. After the initial debridement

(see Figures E-F), infected wounds wereintentionally left open to drain. Foamsand specialty absorptive pads were ap-plied to keep external contaminationto a minimum (see Figures G-I).

Oral agents utilized were changedContinued on page 105

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(see Figures A-D at right). A total of15cc of type I bovine particles werepoured into a sterile container. The an-tibiotic was then measured in a sterilesyringe and squirted slowly directly onthe particles in the container. With asterile tongue depressor blade, the mix-ture was stirred until non-lumpy pastewas achieved. The container utilized is

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Figure A shows the instrument set upneeded for this process in the operat-ing room. Note the collagen flakes arein a separate sterile container to beadmixed during the course of the case.

Figure B shows the addition of the an-tibiotic solution to the collagen flakesin preparation to being applied intothe osteomyelitic area.

Figure C shows the mixing of the an-tibiotic with the collagen flakes priorto impregnation.

Figure D shows the addition of thecollagen antibiotic mixture directly toa gauze pad to pack a large volumearea of osteomyelitis.

term use, change was made when culture allowed,to limit the risk of pseudomembranous colitis.

The oral agents utilized in all cases were discontinuedafter three weeks. The standard of care in osteomyelitis is aminimum of six weeks; the remainder of the infectious dis-ease resolution was thus the topical treatment of the antibi-otic impregnated into the type I bovine collagen.

Of the 12 patients initially started on gentamycin intype I collagen, six remained with this form of topical ther-apy until all appearance of infection was resolved clinicallyand the wound areas were 100 percent re-epithelialized. Se-rial radiographic evidence was followed clinically withplain x-rays obtained every three weeks for all osteomyelitispatients. Of the six patients to which culture biopsy re-vealed resistance to gentamycin, three of the patients were

started onto Clin-damycin impregnatedinto type I bovine colla-gen and three patientswere started on Van-comycin impregnatedinto type I bovine colla-gen. (Table 5)

Patient resolutionto complete healingranged from 35 to 162days.

Continuing

Medical Educationbased upon the sensitivity results of tissue cultures. Addi-tional antibiotics selected included Ofloxacin, sul-famethoxazole trimethoprim, doxycycline. Oral agentswere continued until infectious disease was localized.

ResultsIn this report, all 12 patients were initially treated with

gentamycin impregnated into type I bovine collagen. Inaddition, with generalized cellulitis being present, all pa-

tients were told toremain in bed oron a couch athome. They wereall treated withwarm moist com-presses from theknee to theankle/mid foot.The intention wasto keep the warmcompress off theinfected area anddressing. In addi-tion, five patientswere givencephelexin 500mg(2g per day, splitdosing QID) andc l i n d a m y c i n300mg, (900mgper day, split dos-ing TID). No pa-tients were hospi-talized or receivedinjection adminis-tration of antibi-otics.

Oral agentswere continued,discontinued, orchanged basedupon the follow-ing criteria:

1) Tissuebiopsy culture re-sults and sensitivi-ty.

2) Clinical lo-calization of infec-tion, with generalresolution of cel-lulitis; clinicallythe drainage nolonger appearedpurulent.

3) Due to po-tential of adversedrug reaction re-ported for clin-damycin in long

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Figure E Curretage biopsy of bone forInitial C & S identification of organism.

Figure F Open resection of os-teomyelitic bone after culture resultsreceived getting ready for impregna-tion of collagen antibiotic mixture.

Figure G 24 hours post op bone resectionfor chronic osteomyelitis with externalspecialty absorptive dressing intact.

Figure H Wound as collagen antibioticmixture is being removed.

Figure I Irrigation of the re-maining mixture during redressvisit prior to primary closuretwo weeks post bone resection.

Case Report: Patient VAPatient VA was referred as an alternative to amputation by his primary care physician. His

ABI was reported as 0.41 with toe pressures of 60mm of Hg. His initial care consisted of avul-sion of his second toenail, debridement of necrotic tissue, curretage of osteomyelitic bone withbone specimen for tissue culture report. He had a polymicrobial infection. He was changed tocollagen/clindamycin on the 4th day and the wound had completely resolved in approximate-ly 90 days (Figures 1-16). Figure 1 shows the initial presentation of a 74 year old male with aninfected ulcer of the second toe, right foot.

The patient had been treated at a local diabetes treatment center without success. Recom-mendation from orthopedic specialist in foot and ankle was to admit to hospital for IV antibi-otics and schedule for amputation. ABI had been reported to be 0.41 with toe pressure reportedas approximately 60mm Hg. It can be seen in Figure 1 that the toenail looks non-viable. There ismild generalized edema, without gross severe systemic cellulitis. Figure 2 shows the toenailavulsed. Superficial skin has been debrided, plantar view. In Figure 3, we see the curettage of thebone, which was performed for culture and sensitivity purposes. Toe isshown post curettage. Figure 4: The toe after packing with gentamycin im-pregnated into collagen. Figure 5: Presentation of second toe 48 hours postbiopsy. Figure 6: Presentation of toe at Day 6 post biopsy.

Home health nurses had been asked to change from gentamycin to clin-damycin in collagen, 48 hours prior to this visit. Necrotic tissue was debrid-ed at this visit; clindamycin in collagen and other orders to be continued.

On day 13 (see Figure 7), minimal necrotic tissue is noted. Perimeter ofwound shows good granular bed that is present. Collagen lattice is presentin mid-central portion of wound bed.

On day 18 (see Figure 8), the digit showed minimal edema and erythema.There was still a dusky appearance to the toe, but the wound continued toshow improvement in size, shape, and appearance. The toe is shown post de-bridement. The granular tissue continues to develop. Margin depth was gettingnarrower. Appearance of keratin development to perimeter as wound getssmaller and contracts inward.

Day 25 (Figure 9), the wound has developed a hyperkeratotic. There isminimal maceration with collagen lattice in the central portion of woundbed.

After debridement (Figure 10), it can be seen that the bed is now virtual-ly 100 percent granulated across. The wound continues to get smaller andshallower.

Figure 11 shows the wound on day 32, pre-debridement. The antibioticcollagen mixture has liquified but has not been absorbed by the externalsecondary dressing. Hyperkeratosis build-up, as seen in previous pictures, issignificantly lessened this time.

After debridement on the same day (Figure 12), erythema is minimized.Digit shows minimal bulby aspects to it. No local edema is visible. Changein position of shoe buttress pad was made this visit.

Figure 13 on day 39 shows the wound pre-debridement. The hyperkeratoticrim is significant in spite of attempts to depressurize digit. A change in positionof the shoe buttress pad was made at this visit.

It can be seen in Figure 14, from day 53, that the toe shows no erythe-ma, edema, undermining or tunneling. The wound is continuing to shrink.

On day 74, (Figure 15), the wound is epithelialized. The digit shows com-plete resolution of infectious process.

At a follow-up visit 10 weeks later (Figure 16), the wound site is 100 per-cent epithelialized. The toe shows minimal scarification and the skin is soft,supple, pliable.

Postscript:Patient VA is now one year post ulcer with osteomyelitis. The digit re-

mains pink, clean, clear and closed without any signs or symptoms or othersequella of potential breakdown being present.


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Case Report: Patient JP

Patient JP sus-tained digital injuryto three differenttoes when heslipped and fell andabraded his third,fourth and fifthtoes. His endocri-nologist initiallytreated these lesionswith Bactroban andoral Cephalexin.When he was re-ferred, the orthope-dist had recom-mended an AK am-putation due to hissevere peripheralvascular disease. Hisendocrinologist wasaware of the au-thor’s current treat-ment protocol andmade the referral in-stead of the ampu-tation.

This patient hadABI of 0.31 with atoe pressure of40mm Hg and noknown run off onhis angiogram. Histissue biopsy culturereport revealedMRSA and S. Epider-midis, both resistantto Clindamycin andGentamycin. Theorganisms were iso-lated as sensitiveonly to Van-comycin and sul-famethoxazole andtrimethoprim. Al-though slow toheal, his infectedsoft tissue lesionsdid resolve: the firstone in 97 days, thesecond one in 111days and the thirdone in 140 days. Noamputation wasperformed.

JP10 Close up where bonebiopsy of the medial DIPJ5th toe had been performedfor C & S purposes. Note theclinical appearance of thetoe being almost closed.

JP1 Initial presentation asdescribed in text.

JP2 Removal of crust to de-termine if viable tissue ex-isted underneath the crustysurface.

JP3 Clinical appearance ofdigits after 7 days of care.

JP4 Using the foams tomaintain the collagen im-pregnated antibiotic mate-rial on the digits. This wasable to assist with the need-ed moist environment thatgood wound managementtechniques demand.

JP5 Digits with necrosis sec-ondary to the MRSA thatwas present here.

JP6 With the ischemic na-ture of the process it wasfelt that this patient wouldbe best served by allowingthe collagen material to actas its own debriding agentby stimulating phagocyto-sis of the necrotic tissue.

JP7 The necrotic tissue be-gins to convert slowly withthe collagen antibiotic ma-terial with the early devel-opment of some capillarybudding tissues.

JP8 All digits continue to im-prove in their appearance.

JP9 Close up clinical appear-ance of the granular basethat has developed to theformerly necrotic 3rd toe.

J11 Shows the 3rd toe 2weeks later. The 4th toewas closed this visit.

JP12 The 3rd toe has nowclosed completely.

JP13, JP14, JP15 Clinicalappearance of the toes 1year after the injury. Continued on page 109

Individual Summaries

Patient WSPatient WS suffers from morbid obe-

sity. His soft tissue infection was tracedfrom the plantar surface of his foot to

Collagen... agents were continued. Her ABIwas determined to be greater than1.0. It was determined that she doessuffer from Mockinberg’s sclerosis andthus was maximally vasodilated. Aboutthe 30th day, her skin was superficiallyclosed, yet clinically she remainedbulby erythematous and it was felt thatshe was still infected. Thus her toe wasreopened and she continued treatmentwith Vancomycin in collagen until res-olution of the osteomyelitis. Her toewas closed about the 60th day frominitial presentation.

Patient TDPatient TD had an initial history of

a neurotrophic diabetic ulcer whichwas non-healing. Her status post CVAhad precluded any clearance for vascu-lar reconstruction. She had been in-fected approximately two monthsprior to her initial presentation. Herulcer was 11 months old.

Prior antibiotic usage had includedCiprofloxacin. Her culture report forthe gram negative organisms was ex-

the dorsal tendon sheath of his foot. HisABI was reported at 0.69. His area wascompletely resolved on the 67th day.

Patient GWPatient GW is on renal dialysis. Her

MRSA was determined to be sensitiveonly to vancomycin. Thus no oral

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TABLE 5: MIXING TABLE

Gentamycin: Mix 4cc (160mg) of gentamycin with 15cc mature lyophilized type I bovine collagen particles. Yields 10mg of gentamycin/cc of collagen particles.

Clindamycin: Mix 4cc (600mg) of clindamycin phosphate with 10cc of mature lyophilized type I bovine collagen particles.Yields 60mg of clindamycin/cc of collagen particles.

Vancomycin: Dissolve 1 g of vancomycin powder with 10cc of a local anesthetic (lidocaine). Then mix the solution with 15cc of mature lyophilized type I bovine collagen particles.Yields 66mg of vancomycin/cc of collagen particles.

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tended out to specifically test for theClindamycin she was started on. Al-though the polymicrobial infectionwas sensitive to it, she developed diar-rhea after five days on oral Clin-damycin. Thus she was changed tooral doxycycline BID for three weeks.Her infection was found to travelthrough the flexor hallucis longus ten-don sheath. Her course of care was un-eventful and this lesion was complete-ly healed in 49 days.

Patient GNPatient GN had applied topical

corn medicine to her toes and alsowas recalcitrant to staying out of thegarden. Both organisms grown frombone culture were reported as sensi-tive to all antibiotics except peni-cillin. Her infection location wascompletely healed in 56 days.

Patient GWPatient GW is a 98 year old, long

term care facility resident, who had a

Collagen... her primary care physician. Hertissue biopsy was reported as sensi-tive to all antibiotics except penicillinand tetracyclines. The initial injury lo-cation of her fifth metatarsal was ini-tially necrotic to bone. Her woundhealed in approximately 70 days.

Patient PBPatient PB utilized the theory of ‘a

little is good, a lot is better’ and con-tinuously applied corn medicine toher baby toe. The resulting lesion wasa soft tissue infection to her 5th toe.Her status of being post CVA onCoumadin did not affect her healing.Her ABI was reported at 0.63 and toepressures were reported to be 90mmHg. Her cellulitis was evident withpalpable inguinal and poplitealnodes. Based upon her soft tissuebiopsy culture of the necrotic tissuedeep to the burn she self inflicted,she was well maintained with sulfamethoxazole/trimethoprim orally forher cellulitis. Her toe healed unevent-fully in about 35 days. She did have

distal lesion of her third toe. Al-though communicative, she wasmildly hostile to the shoe gearchanges that were ordered for her.Her staphylococcal organism was re-ported as resistant to cephalosporins.Her clinical course was initially verystormy due to her lack of coopera-tion involving the shoe gear duringthe first two weeks.

After she realized the need to keepdressings intact and appropriate shoegear in place, her toe healed unevent-fully. Total duration from the incep-tion of her case was approximately 90days. Her vascular status was surpris-ingly quite good with an ABI of 0.96and toe pressures of 110mm Hg.

Patient PMPatient PM was injured by a horse.

She developed an active charcot footwith bounding pulses. Initially herhemoglobin A1C was reported as 11.3with a random blood sugar of 334mgper 100ml. She was brought undercontrol by tight, four times daily fin-ger sticks and close cooperation with

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Case Report: Patient OG

Patient OG was a woman withdecent circulation who therefore wasnot one of the twelve patients in thestudy. An overview of her treatmentis included here, however, because itprovides an excellent photographicdepiction of the “collagen-as-antibi-otic-delivery-system” process.

OG10 Wound is very super-ficial and progressing verywell.

OG1 Initial debridement ofthe soft tissues for cultureand sensitivity purposes.

OG2 One week later notethe beginning of the capil-lary rim to the perimeter ofthe ulcer.

OG3 Days after initial pre-sentation wound is nowabout 50% granular andbulby erythema to the cel-lulites is resolving. Fibrousslough remains in the mid-central section. Since thereis viable vascularity, de-bridement of the slough toaugment the healing pro-cess was performed.

OG4 Post debridement onthe same day as in OG3.Note the depth of the mid-central portion of the ulcerwhere the granular tissuehas not developed as yet.

OG5 6 days since the lastdebridement, the leadingedge of the complete ep-ithelialization to the entireperimeter is well shown. Inthis slide the mid-centralportion shows collagen se-cretion of the wound. It isnot wise from here on tocontinue with surgical de-bridement as the collagenmaterial forms a latticewith crosslinking to the un-derlying tissues.

OG6 5 Days since the lastpicture. Wound continuesto heal. Note how the pres-sure of walking even withthe offloading devices is be-ginning to shift the focalpoint of the ulcer. Epithe-lialization continues toprogress relatively rapidly.

OG7 Serial progression ofthe wound continuing tocontract and fill in.

OG8 The wound has crustedover and is superficiallyclosing. This MUST be de-brided to prevent the smol-dering potential of thisproblem to exacerbate it-self as a recurring ulcer.

OG9 The cap and crust havebeen excised from the sur-face allowing for the ulcerto be fully exposed again.

OG11 Wound closed.

OG12 9 month follow up.Note that there is minimalscar tissue present. The useof an orthotic with healingand immediate post heal-ing phases will allow for adecrease in the potentialfor recurrence.


prophylactic hammertoe surgery forher toe after the infection was re-solved and the toe completely healed.

Patient RSPatient RS was initially dancing

with her husband and someonestepped on her ingrown toenail.When she presented a week later, herentire left hallux was erythematous,bulby and edematous. Upon avulsionof her toenail, a surprising sinus tractwas traced directly to her distal pha-lanx of her hallux. Her bone biopsytissue culture was positive for Staph.Aureus, which was sensitive to bothcephalexin and gentamycin. In twoweeks, her digital cellulitis was re-solved and the cephalexin was discon-tinued. She was healed in 42 days un-eventfully.

Patient BRPatient B had a distal segment by-

pass to her left dorsalis pedis artery sixmonths prior to her injury of her fifthmetatarsal. She suffered from a dis-placed fracture of her fifth metatarsalshaft. Open reduction with internalfixation was performed and she wasput in a Cad-Cam walker for healingthe fracture site and to minimize po-tential for atrophy to muscle in herleg. She decided to put a high heelshoe in her foot and go to church onEaster Sunday. She removed all dress-ings to the surgical location due to hertight shoe.

The location became infected andshe failed to keep follow-up appoint-ments for 10 days. Her daughterfound her at home with a raging cel-lulitis and her HMO refused her ad-mission to hospital. Her distal seg-mental by-pass did clot off during hercellulitic episode. The hardware andfractured bone was removed surgicallyon an outpatient basis. She achievedcomplete closure without amputationin 162 days. Of significance, her cul-ture report showed no oral agentwhich would treat her MRSA or ente-rococcus.

Patient FMPatient FM was referred by his pri-

mary care physician for a neutrophicdiabetic ulcer which he sustainedwhile driving his automobile for 15hours with minimal stopping. His per-

Collagen... tions involving eight differentorganisms and three differentdrugs. The numbers presented hereare too small for any scientific conclu-sions to be drawn from this.

The author is well aware that fur-ther laboratory and clinical work isneeded to provide the scientific evi-dence required to create specific out-come results associated with differentinfections like those presented here.As a rural practitioner, this limits theauthor from obtaining the large popu-lation base needed to really expandthis out further.

ConclusionsThis limited anecdotal report does

show that there is potential for costeffective outpatient care even whenserious limb threatening infections aretreated. The author admits that a sig-nificant amount of work remains tobe performed before any real conclu-sions about safety, efficacy, and carestatements could be made.

AcknowledgementThe author gratefully acknowl-

edges the home health division of theGarland County Health Departmentand its nurses, for their due diligencein patient care without which thiscase report probably would not havebeen able to be made.

Thanks to Bill Danzeisen D.P.M.,for scanning the photographs.

sonal hygiene was quite poor. Hewore no socks and cheap, old, torngym shoes. He had an ABI of 0.66with toe pressures of 100mm Hg. Hishealing was uneventful in about 60days.

DiscussionIn today’s healthcare world, we

are all being forced to look for alter-native venues with changes in deliv-ery of healthcare. Cost effectivehealthcare has been forced on allphysicians. This limited anecdotalcase report may be a methodthrough which all physicians candeliver cost effective care withoutneed for lengthy hospital stay.

The literature shows good evi-dence of why triple helix arrangedtype I collagen can act as a sustainedrelease vehicle and that many drugscan apparently be delivered on a lin-ear zero order release kinetic basis.

It was not possible, in this study,to measure tissue antibiotic levels.However, previous research11 hasshown how there is minimal, if any,of the toxic drug absorbed into theblood stream. This is despite evidenceof achieving tissue levels that cannotbe achieved through systemic admin-istration of potent drugs like gen-tamycin (due to the ototoxicity andnephrotoxicity associated with thisdrug).

This article illustrates the treat-ment and care of significant infec-

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maceutical Research 1995, 12:8, pp. 1205-1210.[PubMed Abstract]

11 Ipsen, T., Jorgenson, P., Damholt, V.& Torholm, G.: Gentamycin-collagensponge for local applications, Acta OrthoScand 1991; 62(6):592-594.[PubMed Ab-stract]

12 Trafny, E.A., Grzybowski, J., Ol-szowska-Golec, M., Antos, M., Struzyna, J.:Antipseudomonal Activity of CollagenSponge with Liposomal Polymixin B, Phar-macological Research 1996, 33:1, pp. 63-65.[PubMed Abstract]

13 Trafny, E.A., Stepinska, M., Antos,M., Grzybowski, J.: Effects of Free and Lipo-some Encapsulated Antibiotics on Adher-ence of Pseudomonal Aeruginosa to Colla-gen Type I, Antimicrobial Agents andChemistry 1995, 39:12; pp.2645-2649.[PubMed Abstract]

14 Kollenberg, L.: Type I Bovine Colla-gen and Wound Care; A Study on 1000 Pa-tients, Poster Presentation, InternationalBurn and Wound Federation, February1997, Maui, Hawaii.

15 Statz, C., Johnson, E., Ukins, M.,Dunn, D.: A Retrospective Review of 30Consecutive Patients with Open WoundsTreated With Techni-Care, University ofMinnesota, Department of Surgery, Min-neapolis, Minnestota.

Appendix—Protocol for InfectedWounds of Lower Extremity

1) Historya) general medical historyb) nutrition historyc) infection history

2) Laboratory Analysisa) CBC with differentialb) CRPc) ESRd) total proteinse) albuminsf) globulinsg) serum creatinineh) BUNi) random glucosej) hemoglobin A1C, if diabetick) deep tissue biopsy for culture

3) Physical Examinationa) determine gross vasculature—if diminished, obtain vascular consultationb) evaluate neurological status

i) two point discriminatoryii) vibratoryiii) Semmes Weinstein

c) infection evaluationi) palpation of infected area and supportive structures

ii) plain x-rayiii) bluntly probe open lesion for depth structures

d) evaluate pathomechanical causes, if any

4) Surgical Treatmenta) excise necrotic tissueb) curretage aggressively infected bonec) obtain specimen of deep tissues indicated i.soft ii.bone

5) Apply antibiotic paste to affected area until 2/3 to 3/4 filled

a) cover with secondary dressing

6) Home bound instructions as listed inarticle

7) Start oral agent of choice until culturereport received

8) Re-evaluate patient in 24-72 hours de-pendent upon severity of condition

Of significance, since the publi-cation of this article the author hasfound that using a multitude of col-lagen-based products leads to simi-lar results in the treatment of infec-tions. It is the author’s hope thatone of the major pharmaceuticalcompanies will sponsor additionalresearch to develop a topical deliv-ery system which allows for thepenetration of infections with amultitude of antibiotics and othermaterials. The opinions listed hereare those of the author. They arenot intended to endorse or implythat any specific product should beutilized over another product. �

Reprinted with permission All materialscopyright © 1992-1999 by the Surgical Ma-terials Testing Lab. unless otherwise stated.URL: http://www.smtl.co.uk/World-Wide-Wounds/1998/july/Topical-Antibiotic-De-livery-System/topical-antibiotic-delivery-system.html

For more information about theproducts mentioned in the precedingarticle, circle the corresponding num-ber on the reader service card in thismagazine.

Fibracol (Johnson & Johnson): cir-cle #154

HyCure (Southwest Technolo-gies): circle #155

Avetene (Bard): circle #156Heletene (Integra): circle #157

References1 Prockop, D.J., Kivirikko, K. I.: Colla-

gens, Molecular biology, diseases and po-tentials for therapy. Annual Review of Bio-chemistry, 1995;64: 403-434. [PubMed Ab-stract]

2 Miller, E.J., Gay, S.: Collagen struc-ture and function. Wound Healing: Bio-chemical and Clinical Aspects, Ch. 8,Cohen, I., Diegelmann, R.I., Lindblad,W.J., editors, W.B. Saunders 1992: 132.

3 Prockop, D.J., Kivirikko, K.I., Tuder-man, L., Guzman, N.A.: The Biosynthesisof Collagen and its disorders. New EnglandJournal of Medicine, 1979; 301: 13-23. [NoAbstract]

4 Rossler, B., Kreuter, J., Scherer, D.:Collagen microparticles preparation andproperties, Journal of Microencapsulation,1995: 12;1 pp. 49-57 [No Abstract]

5 Prockop, D.J., Berg, R.A., Kivirikko,K.I.: Intracellular steps in the biosynthesisof collagen. Ramachadren, G.N., Redd,A.H., editors, Biochemistry of Collagen,Plenum Press, N.Y., 1976: pp. 163-273.

6 Vasantha, R., Sehgal, P.K., Pandura-nia, Ra.OK.: Collagen ophthalmic insertsfor pilocarpine drug delivery system, Inter-national Journal of Pharmaceutics, 1988:47; 95-102. [No Abstract]

7 Phinney, R.B., Schwartz, S.D., Lee,D.A., Mondino, B.J.: Collagen shield deliv-ery of gentamycin and vancomycin.Archives of Ophthalmology, 1988. 106 pp.1599-1604. [PubMed Abstract]

8 O’Brien, T.P., Sawusch, M.R., Dick,J.D., Hamburg, T.R., Gottsch, J.D.: Use ofcollagen cornea shields vs. soft contactlenses to enhance penetration of topicaltobramycin. Journal of Cataract and Re-fractive Surgery, 1988: 14 pp: 505-507.[PubMed Abstract]

9 Thacharidi, D., Panduranga, Ra,O.K.: Collagen—chitosan composite mem-branes controlled transdermal delivery ofnifedipine and propranalol hydrochloride,International Journal of Pharmaceutics1996: 34, pp: 239-241.

10 Singh, M.P., Stefko, J., Lumpkin,J.A., Rosenblatt, J.: The effect of electrostat-ic charge interactions on release rates ofgentamycin from collagen matrices. Phar-

Collagen...Con

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The author has15 years ofwound manage-ment and clinicalexperience andcurrently residesin Jacksonville,FL. Dr. Kollenbergcan be contactedat [email protected].

bolic ProfileB) CBC with DiffC) Liver Function testsD) All of the above

7) How many patients had 4 iso-lates in their wounds?

A) 3B) 2C) 5D) 1

8) Which office based modalitieswere used to routinely follow patients’ course of infection?

A) CT ScansB) MRI ScansC) X-raysD) Tc 99 Scan

9) Which devices/dressing materials were used to heal the internal structures of theulcer?

A) Composite pads (Ex-U-Dry™)B) OrthoticsC) CollagenD) Gauze pads

10) In this report how many patients had MRSA?

A) 1B) 2C) 3D) 4

11) Culture biopsy revealed howmany patients had resistance togentamycin?

A) 2B) 4C) 6D) 8

1) Collagen has been used as avehicle to topically deliver whichof the following drugs?

A) pilocarpineB) macrolide antibioticsC) lidocaineD) All of the above

2) Which material delivers a high-er concentration of antibiotics ina steady state level to the infect-ed wound?

A) Methyl-Methacrylate BeadsB) CollagenC) IVD) Oral

3) Which of the following labstudies may be utilized to deter-mine the body’s inflammatory re-sponse to the infection?

A) CBC with DifferentialB) Glucose for diabeticsC) C-Reactive ProtienD) ANA

4) Which antibiotic was not usedtopically in this article?

A) Sulfamethoxizole/Trimethoprim (Bactrim™)B) Clindamycin (Cleocin™)C) Vancomycin (Vancocin™)D) Gentamycin (Garamycin™)

5) Which antibiotic was not usedorally in this article?

A) Doxycycline (Vibramycin™)B) Ofloxacin (Floxin™)C) Gentamycin (Garamycin™)D) Cephalexin (Keflex™)

6) What blood tests were repeatedto monitor patient cellulitis care?

A) Comprehensive Meta-

12) Type I collagen is NOT foundwhere?

A) Skin and BoneB) Hyaline Cartilage, and Base-ment MembraneC) Nerve and blood vessel tis-suesD) Dermal layers, Tendon

13) In delivering antibiotics totissues which of the following iscorrect?

A) Topical delivery has beenreported to be higher at theinfected site than IV deliverywhen combined with collagenB) Antibiotics are not tissueconcentration-dependant fortheir killing effectC) Adequate blood flow is notneeded to oxygenate the tis-sues as the antibiotic deliverysystem with collagen containsoxygenD) They are all correct

14) In this article oral agents werecontinued, discontinued, orchanged based upon what criteria?:

A) Tissue biopsy culture resultsand sensitivity.B) Clinical localization of infec-tion, with general resolutionof cellulitis; clinically thedrainage no longer appearedpurulent.C) Due to potential of adversedrug reaction reported forclindamycin in long term use,change was made when cul-ture allowed, to limit the riskof pseudomembranous colitis.D) All of the above

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15) Which of the following antibiotics was reportedto require blood level peaks and troughs drawn?

A) Clindamycin (Cleocin™)B) Vancomycin (Vancocin™)C) Gentamycin (Garamycin™)D) None of the above

16) In this article which of the following antibioticswas used empirically until C & S results were received?

A) Clindamycin (Cleocin™)B) Vancomycin (Vancocin™)C) Gentamycin (Garamycin™)D) None of the above

17) According to the initial instructions given whichof the following is not part of the instructions?

A) Continue regular or special dietB) Start vitamins; multivitamins (Centrum) threetimes daily (x 30 days) then 1 bid, vitamin C, 1gram twice daily (until healed)C) Monitor blood sugars twice dailyD) Change dressing after bathing or showering

18) According to the article mixings what concen-tration of Clindamycin was achieved?

A) 30mg/ccB) 60mg/ccC) 90mg/ccD) 120mg/cc

19) According to the article mixings what concen-tration of Vancomycin was achieved?

A) 22 mg/ccB) 44mg/ccC) 66mg/ccD) 88mg/cc

20) According to the article mixings what concen-tration of Gentamycin was achieved?

A) 10mg/ccB) 20mg/ccC) 30mg/ccD) 40mg/cc

E X A M I N A T I O N

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116 PODIATRY MANAGEMENT

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E N R O L L M E N T F O R M & A N S W E R S H E E T (cont’d)

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LESSON EVALUATION

Please indicate the date you completed this exam

_____________________________

How much time did it take you to complete the lesson?

______ hours ______minutes

How well did this lesson achieve its educational objectives?

_______Very well _________Well

________Somewhat __________Not at all

What overall grade would you assign this lesson?

A B C D

Degree____________________________

Additional comments and suggestions for future exams:

__________________________________________________

__________________________________________________

__________________________________________________

__________________________________________________

__________________________________________________

__________________________________________________

EXAM #12/2001Collagen

(Kollenberg)

1. A B C D

2. A B C D

3. A B C D

4. A B C D

5. A B C D

6. A B C D

7. A B C D

8. A B C D

9. A B C D

10. A B C D

11. A B C D

12. A B C D

13. A B C D

14. A B C D

15. A B C D

16. A B C D

17. A B C D

18. A B C D

19. A B C D

20. A B C D

Circle:


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