1. health and fitness
2. disease

COLLATAMP
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SWEDISH ORPHAN BIOVITRUM AS
Trollåsveien 6, 1414 Trollåsen
Telefon 66 82 34 00, Fax 66 82 34 01
www.sobi.com
1) Mange opplever økt siving/sekresjon fra såret når man bruker Collatamp.
Hvorfor skjer dette?
Collatamp er et kollageninnplantat jevnt innsatt med gentamicin. Kollagenet absorberes av
kroppen i løpet av noen uker og denne absorbsjonen fører til en økning i sårsekresjonen i tidlig
postoperativ fase. Dette skyldes antagelig osmotisk lekkasje av intracellulær væske som en følge
av nedbrytningen.
2) Mange er også urolige for at denne økte væskesekresjonen kan tyde på en infeksjon
Svarer er at det er lite sannsynlig. Vedlagte artikkel av von Hasselbach (artikkelen med engelsk
oversettelse finner du på slutten av nyhetsbrevet) viser gentamicinnivå høye nok til å bekjempe
selv gentamicinresistente staphylococcus aureus fem dager etter operasjon.
I tillegg har alle aminoglycosider en post-antibiotisk effekt. Man har lite eller ikke noe detekterbart
antibiotika i blod men det er fremdeles en hemming av bekterieveksten. Dette skyldes en sterk,
irreversibel binding av virkestoff til ribosomene som gjør at det forefinnes intracellulært selv etter at
plasmanivåene har falt. Om man allikevel skulle være usikker på om det er en infeksjon som er
årsaken til væskesekresjonen anbefaler man at man tar en mikrobiologisk test eller sjekker
gentamicinnivået i væsken.
SWEDISH ORPHAN BIOVITRUM AS
Trollåsveien 6, 1414 Trollåsen
Telefon 66 82 34 00, Fax 66 82 34 01
www.sobi.com
3) Finnes det måter å legge Collatamp inn i såret på som kan bidra til og redusere denne
sekresjonen?
Mengden av lekkasje eller sårsekresjonen avhenger av såkalt «local-flow»- det vil si
gjennomstrømningen av intracellulær væske gjennom sårområdet. Dette avhenger igjen av vevet
(bedre blodgjennomstrømning= høyere lokal flow) og den er veldig individuell fra pasient til
pasient. Vi vet ikke om noen måte man kan applisere Collatamp på som evt. kan bidra til å
redusere denne sekresjonen.
4) Nedbrytingen av kollagenet i Collatamp tar ulik tid avhengig av hva slags vev det ligger i.
Kan ufullstendig nedbrutt kollagen (dvs. uten gjenværende gentamicin) forårsake en
infeksjonsrisiko?
Se svar under punkt 1. Absorbsjonen av kollagen fra Collatamp avhenger av blodtilførselen til det
vevet den ligger i. Generelt tar det fra 1 til 9 uker for at Collatamp er fullstendig nedbrutt. Det er lite
sannsynlig at disse bitene vil bidra til økt infeksjonsfare underveis, spesielt på grunn av den
tidligere nevnte post-antibiotiske effekten. Det er i denne sammenhengen viktig å nevne at dette
forutsetter at Collatamp har blitt brukt riktig; dvs at det legges tørt, direkte i såret.
Vi kommer til å lansere en nettside for Collatamp
i løpet av de første månedene av 2012
www.collatamp.no
Mer informasjon følger!
SWEDISH ORPHAN BIOVITRUM AS
Trollåsveien 6, 1414 Trollåsen
Telefon 66 82 34 00, Fax 66 82 34 01
www.sobi.com
Kliniske fordeler med Collatamp

Dokumentert effektivt kollagen/gentamicin innplantat som kan brukes både i
infeksjonsbehandling og forebygging.1-5

Eneste gentamicin/collagenplate som inneholder en kjent mengde gentamicin.
Gentamicinsulfat er jevnt fordelt i hele platen (2 mg/cm2 ) og frisettingen er kjent og
dokumentert 6,7

Effekten av gentamicin er konsentrasjonsavhengig- Collatamp gir så høye lokale
konsentrasjoner at det er effektivt selv mot de fleste gentamicinresistente bakterier 7,5

Collatamp brytes ned lokalt- krever ingen ekstra operasjon for å tas ut 5

Det ses ingen tegn til resistens ved langtids bruk 5,7,8
Referanser
Klikk på referansen for direkte link til artikkelen på PubMed. Ta gjerne kontakt med oss om du ønsker artikkelen
tilsendt
1.
2.
3.
4.
5.
6.
7.
8.
Rutten et al, Eur J Surg Suppl 1997
Rohde et al, Spine 1998
Friberg et al, Ann Thorac Surg 2005
Holdsworth et al, Ann R Coll Surg Engl 1999
Stemberger et al, Eur J Surg Suppl 1997
Collatamp pakningsvedlegg ( se siste side)
Ruszczak et al Adv Drug Deliv Rev 2003
Friberg et al, Interact Cardiovasc Thorac Surg 2009
Størrelser og varenummer
10 x 10 x 0,5 cm
Varenummer: 955104
5 x 20 x 0,5 cm
Varenummer: 902371
5 x 5 x 0,5 cm
Varenummer: 955096
Bestilling av Collatamp
Collatamp er ikke definert som legemiddel og kan bestilles enten via eget sykehusapotek eller direkte fra NMD.
Ved bestilling fra NMD brukes sykehusets/avdelingens “væskekundenummer”
Telefonnummer til NMD: 22 16 96 00
SWEDISH ORPHAN BIOVITRUM AS
Trollåsveien 6, 1414 Trollåsen
Telefon 66 82 34 00, Fax 66 82 34 01
www.sobi.com
Pakningsvedlegg Collatamp
Sammensetning
Renatuert bovint collagen, Gentamicin sulfat.
2
Collatamp G inneholder (pr.cm ):
Collagen 2,8mg
Gentamicin sulfat 2,0mg (tillsvarande 1,3mg gentamicin)
Indikasjoner
Collatamp G brukes for lokal haemostase i kapillærene, parenkymatøse områder og for sivende blødninger i områder
med høy risiko for infeksjon. Collatamp G kan også brukes som bærer av fibrinklebemiddel i henhold til anvisning gitt
for slik bruk. Dette produktet inneholder gentamicinsulfat i en dose med lokal effekt. Systemisk effektive terapeutiske
blod- eller plasmanivåer oppnås vanligvis ikke.
Kontraindikasjoner
Collatamp G skal ikke brukes ved kjent proteinallergi eller hvis overfølsomhet overfor gentamicin har blitt påvist. Man
har ingen erfaring ved bruk hos gravide eller ammende. Produktet bør derfor kun brukes under strenge vilkår til
gravide og ammende. Dette gjelder også for bruk hos pasienter med redusert nyrefunksjon.
Bivirkninger
Hittil er ingen bivirkninger rapportert. Dersom anbefalt maksdose overskrides kan gentamicinspesifikke bivirkninger
ikke utelukkes, særlig hvis pasienten har redusert nyrefunksjon.
Interaksjoner med andre substanser
Ingen interaksjoner er rapportert hittil. Dersom samtidig systemisk behandling av gentamicin, andre aminoglykosidantibiotika eller andre oto- eller nefrotiske legemidler er nødvendige, bør den kumulative effekten tas i betraktning.
Dosering og administrasjonsmåte
Hvis ikke annet er foreskrevet administreres Collatamp G slik: Produktet kan skjæres til slit at det passer til
behandlingsområdet. Inntil 3 Collatamp G implantat /10 x 10 cm) kan anvendes, avhengig av området som krever
haemostase. Pasientens kroppsvekt og total mengde gentamicin må også tas i betraktning. Total mengde gentamicin
skal generelt ikke overskride 9 mg per kg kroppsvekt og antall og størrelse på implantatet bestemmes ut fra dette.
Tørt Collatamp G implantat plasseres i behandlingsområdet. Dette må være så tørt som mulig. Implantatet presses
lett i ca. 3 minutter for at det skal klebe lettere.
Hansker og instrumenter fuktes for å hindre at Collatamp G klistrer seg til disse.
Oppbevaring og holdbarhet
Når pakningen er åpnet, kan ikke enkeltpakninger med Collatamp G spares til senere bruk eller steriliseres på nytt.
o
o
Collatamp G må oppbevares mellom 4 C og 25 C. Collatamp G må ikke anvendes etter angitt utløpsdato.
Den sterile pakningen må ikke brukes dersom den er åpnet eller ødelagt.
Produktet oppbevares utilgjengelig for barn.
Pakningsstørrelser
Collatamp G
5cm x 5cm x 0,5cm (1 stk)
Collatamp G
10cm x 10cm x 0, 5cm (1 stk)
Collatamp G
20cm x 5cm x 0,5cm (1 stk)
Egenskaper
Haemostase utløses når blod kommer i kontakt med utløste vevsfaktorer og utsatte endogene collagenfibre eller
renaturerte collagenfibre i Collatamp G. Adhesionen og aggregeringen av trombocyttene induseres på de renaturerte
collagenfibrillene av Collatamp G og plasmakoagulasjonsprosessen fremskyndes. Da Collatamp G absorberer en viss
mengde blod, vill den svampliknende strukturen stabilisere sårklumpen. Collagen fremmer også granulasjon og
epitelisering. Collatamp G absorberes raskt og fullstendig. Gentamicin er tilsatt for å forhindre at infeksjoner oppstår
på implantasjonsstedet
SWEDISH ORPHAN BIOVITRUM AS
Trollåsveien 6, 1414 Trollåsen
Telefon 66 82 34 00, Fax 66 82 34 01
www.sobi.com
Klikk på overskriften for å
hoppe til den engelske
oversettelsen
Clinical and pharmacokinetic aspects of collagen – gentamicin as
local adjuvant treatment in bony infections
C. von Hasselbach
Surgery and Trauma Surgery Department (Head of Department: Dr. A. Spickermann), Philippusstift
Catholic Hospital, Essen-Borbeck
Abstract: see original text
It has been accepted since the publication of the fundamental investigations carried
out by G. Hierholzer [15, 16] on post-traumatic osteomyelitis that local antibiotics are
of doubtful value. The substances and approaches to therapy in use at the time have
not been proven to have any beneficial therapeutic effect in clinical or
histomorphological terms; the only result has been the development of resistant
germs. The administration of local antibiotics in the form of fillings, powders,
injections, lavages or ointments has rightly come to be regarded as close to
malpractice, especially if insufficient attention has been paid to much more important
factors such as radical debridement, mechanical stability and correct surgical
technique.
Irrespective of all recent discoveries as to aspects such as the varying features
of different forms of osteomyelitis [3, 4] and immunological changes to non-specific
defence against infection [13, 26], there is only one reason for the persistent relative
lack of success of our therapeutic efforts: the topography of the infection site. It is
only in bone tissue that the body's own defence against infection can be impeded. The
architecture and biochemical composition of bone tissue mean that even tiny
quantities of pathogenic germs, that would cause no problems in soft tissue, are able
to cut off minute areas of the host tissue from the circulation. This, as it were,
removes the logistic base of the body's defence against infection. The field favours the
aggressor, which is also able to survive radical debridement in perifocal germ nests. If
pathogens can escape both local surgery and the body's defence system, it is not only
legitimate but also essential that we apply our minds to how we can make their
hiding-places uninhabitable for them.
The debate surrounding the treatment of chronic osteomyelitis was given fresh
impetus by the introduction of substance carriers by Klemm [19, 20] for use in local
antimicrobial therapy and the improvement of local perfusion conditions as a result of
modern flap techniques. A study carried out by Meissner in 1986 [28], who contacted
69 trauma surgery and orthopaedic hospitals in the German section of AO
International to inquire about the use of systemic and local antibiotics in cases of posttraumatic osteomyelitis, is very informative in this context. Of the 50 hospitals which
responded, only two (one orthopaedic hospital and one trauma surgery hospital) did
not perform antibiotic prophylaxis. 43 hospitals, or 86% of the German AO hospitals,
confirmed that they systematically used local antibiotics, almost exclusively in the
form of gentamicin PMMA chains. The relevant literature contains a number of
clinical case reports with PMMA chains, but hardly any substantial analytical studies
providing reliable confirmation of the in-vivo pharmacokinetic and bacteriological
aspects of the use of this carrier system. The variation in patient populations and
differences between peri- and intra-operative tactics make it difficult to evaluate
clinical case reports involving the use of the substance carrier methyl methacrylate
[18, 21, 23, 30, 34, 35, 38]. The small number of systematic investigations carried out
with reproducible measurement methods to determine local active substance levels in
sick people [6, 7, 24, 25] confirm doubts as to the efficacy of the system. It appears
unable to achieve the intended goal (following radical debridement, creation of
adequate stability and improving blood supply, creating an aggressive antimicrobial
environment in which any remaining germ nests can be controlled) with a sufficient
degree of certainty. Active substances are diffused over too short a distance, and their
initial levels are too low [36, 37] to eliminate bacterial strains, which are usually
already resistant in the case of chronic infection. Local application of
chemotherapeutic substances [27] such as Taurolin brings with it the problem of cell
toxicity [29], making it almost impossible to assess the narrow gap between
therapeutic use and necrosis [31].
After the first promising reports from Ascherl et al. [1, 2] on the use of
collagen as an absorbable active substance carrier, the aim of our investigation was
therefore to find out whether improved placement of the carrier matrix and more
favourable release kinetics of the active substance would increase the likelihood of
success in treating chronic osteomyelitis.
Equipment and methods
Collagen gentamicin has been used on 72 patients at the Philippusstift hospital since
September 1986. The high proportion of hip revision operations (table 1) is explained
by the fact that hip endoprosthesis is a speciality of our surgical department. No
colonisation by pathogenic germs was observed in nine of the 23 hip revision
operations. Collagen gentamicin together with bank spongiosa was used as infection
prophylaxis when building up the considerable amounts of lost bony substance in
these patients, most of whom had undergone several previous operations. When
dealing with an infected prosthesis that had worked loose, the site was normally
disinfected in two stages, with collagen gentamicin being used both in the first session
after removal of the prosthesis and debridement and in the second session, when final
hip reconstruction was performed after an infection-free interval of three months on
average. In all other cases debridement, stabilisation and reconstruction were
performed in a single session. Five cases of soft tissue infection treated with collagen
gentamicin must of course be excluded, and are listed here only for the sake of
completeness.
Table 1. Collagen gentamicin implants performed between September 1986 and
September 1988 (n = 72)
Collagen gentamicin
Hip
Calf
Thigh
Knee
Foot
Upper arm
Soft tissue
Hand
Forearm
Clavicle
Symphysis
Indications
23
11
6
6
6
5
5
4
3
2
1
Aetiology
Table 2 attempts to establish a connection between the aetiology of osteomyelitis and
its histological pattern. The criteria developed by Böhm [4] are used as the basis for
this. The higher overall number of histologies shown (n=75) is due to the fact that in
several cases multiple tissue samples were taken and the osteomyelitis was found to
display different histological patterns next to each other depending on the sampling
site (described as histological mixed forms). Nevertheless, the dominance of the
chronically aggressive form of osteomyelitis in the post-traumatic genesis group is
clear, which shows how pathophysiologically critical bone necrosis is to the
persistence of infection.
Bacteriology
Table 3 shows the spectrum of germs found on wound smears taken before and during
surgery. 42 single infections and 16 mixed infections were found on the 58 wound
smears. Staphylococcus aureus is clearly dominant, and in our patient cohort we also
found Staphylococcus epidermidis to be of increasing importance. Studies with large
groups have found the proportion of gentamicin-resistant strains of Staphylococcus
aureus to be around 10% [10]. The proportion of such strains in our cohort was
unusually high (28.2%, n=11), indicative of the fact that most of the patients had been
infected for a considerable period and had undergone corresponding previous
treatment. This is particularly true of the patients who had previously been treated
with PMMA chains, where all the antibiograms showed complete resistance to all the
antibiotics which had been fully tested, with the exception of gyrase inhibitors in one
case.
Pharmacokinetics
In order to measure the release kinetics of gentamicin from the carrier matrix we
tested gentamicin levels in the exudate and urine of 26 patients for five days. In all
cases drainage was applied in the form of overflow drainage without suction, with the
drain placed at the deepest part of the wound cavity and care being taken to ensure
that the drain end did not come into direct contact with the collagen sponge, leaving a
gap of at least 1 cm. The purpose was to measure the actual level of active substance
throughout the entire wound environment. Exudate and urine quantities were recorded
for each 24-hour period in order to work out the absolute volumes of gentamicin lost
via exudate and secreted via the kidneys. The exudate and urine samples taken were
prepared in our laboratory, then frozen and sent in this state to Munich where the
active substance concentrations were measured at the Infection Hygiene Department
of Munich Technical University's Institute for Medical Microbiology (Head of
Department: Prof. Dr. I. Braveny) using the fluorescence polarisation immunoassay
(TDx assay) method. In five cases we were also able to analyse the active substance
concentrations of PMMA chains which were still in place from the previous
operation. Where possible, we also took samples of the immediately adjacent incision
tissue and determined its gentamicin content (table 4). A. Stemberger of Munich
Technical University's Institute for Experimental Surgery (Head of Department: Prof.
Dr. G. Blümel) was kind enough to perform the elution of the PMMA beads and the
incision tissue. The first step involved agitating the beads in a sodium chloride
solution at room temperature for 12 hours and then measuring the amount of
gentamicin eluted by means of the TDx assay. In the second elution step the beads
were again agitated in a sodium chloride solution for 12 hours, this time at a
temperature of 100°, then finely crushed and elutriated again for 12 hours at room
temperature. The incision tissue samples also underwent the same elution process, as
did two control samples of unused PMMA beads manufactured by Merck.
All the patients undergoing treatment were given parenteral cephalosporins for
three to six days in order to offer systemic protection against perifocal bacterial
dissemination.
Table 2. Relationship between aetiology and morphology of osteomyelitis. 75 tissue
samples from 58 patients: histologically clear dominance of the chronically aggressive
form and post-traumatic genesis
Aetiology
Histology
Acute
Post-traumatic
Transmitted
Haematogenic
5
0
0
Chronically
aggressive
47
2
0
Chronically
persistent
10
6
0
Chronically
scarring
5
0
0
Total
67
8
0
Table 3. Germ spectrum of wound smears taken before and during surgery (n=58;
single infections n=42, mixed infections n=16). High proportion of Staphylococcus
aureus strains resistant to gentamicin (28.2%)!
Pathogen
n
Staphylococcus aureus
Staphylococcus epidermidis
Staphylococcus warneri
Staphylococcus hominis
Escherichia coli
Proteus mirabilis
Pseudomonas aeruginosa
Bacteroides melaninogeneus
Enterobacter cloacae
Enterococci
Sreptococcus mitis
Peptococcus asaccharolyticus
Veillonella parvula
39
11
4
3
6
3
3
3
2
2
1
1
1
Gentamicinresistant
11
4
0
3
1
0
1
0
0
2
1
1
0
Immunology
Inserting heterologous collagen into an already infected wound cavity would appear
in theory to present some problems. Although the product (a Sulmycin sponge) is a
type I highly purified bovine collagen, immunological reactions are not impossible.
We therefore took serum samples from 25 patients and had them tested. The samples
were taken before surgery, three weeks after surgery and 12 weeks after surgery. The
immunological tests were performed by B. Ardclamm-Grill of the Max Planck
Institute for Biochemistry, Munich (Director: Prof. Dr. K. Kühn), who received the
serum samples frozen after preparation. A high-resolution immunofluorescence
technique was used to identify any antibodies to the bovine collagen that might have
formed in the meantime.
Table 4. Gentamicin content of PMMA beads at various elution stages: marked
deviations in the distribution and absolute gentamicin content in unused PMMA beads
(rows 1 and 2). The gentamicin content in the interior of the beads was still around
40% after a retention period of 11.2 months on average had elapsed. Active substance
concentrations on the surface of the beads and in the incision tissue were subinhibitory!
Sample site
Control I
Control II
TEP socket
TEP femur
Arthrodesis knee
Tibia
Symphysis
Average
Retention
period
(months)
Agitated
for 12
hours at
RT (%)
Agitated
for 12
hours at
100° (%)
0
0
13
12
11
12
8
11,2
13,7
27,3
4,6
4,8
3,3
2,7
0,4
3,1
86,2
39,1
27,4
25,9
38,0
30,7
25,7
29,5
Crushed,
agitated
for 12
hours at
RT (%)
12,7
25,3
8,8
9,7
4,6
4,1
6,4
6,7
Total (%)
Surrounding
tissue
(mg/l)
103
91,7
40,1
40,4
45,9
37,5
32,5
39,3
0
0
0
0
0,4
1,8
0,6
0,9
Histology
In five other cases (patients undergoing revision surgery) we were also able to take
tissue samples containing collagen, or the collagen itself, and perform histological
tests on it. These tissue samples were taken on days 9, 15, 19 and 22 after surgery and
7, 9 and 12 weeks after surgery. Taking account of the sampling dates, the topography
of the insertion sites and the local blood supply conditions, this gave us valuable
information about the histomorphological fate of the collagen that had been inserted
and its rate of absorption. An unused collagen sponge was also embedded and
underwent histological tests. A PAS/EVG stain technique was used to display the
histological connective tissue. We should like to thank H. Breining of the Pathology
Institute I of the Bundesknappschaft miners' welfare association in Essen (Director:
Prof. Dr. H. Breining) for performing the histology tests.
Results
Clinical findings
We observed a total of four reinfections (5.5%) among the 72 patients who took part
in the study over a two-year period (September 1986 to September 1988). The
average monitoring period was 13.7 months. It would be appropriate to exclude the
five cases of soft tissue infection and the nine cases of prosthesis loosening under
questionable asepsis, most of which were treated with infection prophylaxis. This
leaves 58 cases of chronic osteomyelitis, so that the number of reinfections (n=4)
equates to a rate of 6.9%. One of these four failures was a case of putrid phlegmon of
the index finger following a bite injury, which healed in response to debridement and
insertion of collagen gentamicin although the central joint remained ankylosed. The
three true cases of reinfection consisted of one case of chronically persistent
osteomyelitis in the thigh following a war injury (gunshot fracture in 1945), one case
of chronically aggressive osteomyelitis following osteosynthesis of an unstable
pertrochanteric femoral fracture and once case of chronically aggressive calf
osteomyelitis with a seven-year history. In all three cases, reinfection occurred
rapidly, i.e. within the first three months after surgery. All were caused by insufficient
debridement. A second operation and replacement of the collagen gentamicin led to
the elimination of infection in all three cases (the three patients are still free from
infection at this date). All the other 54 patients have remained free from infection, for
over a year in 29 cases. We should like to draw your attention to the cases of septic
prosthesis loosening with in some cases extremely severe pelvic and femoral
substance defects. These all responded well, with no complications, to the use of
rotator cuff reconstruction prosthesis and a bank spongiosa-Sulmycin combination to
resolve the biological defects, as did three other cases of osteomyelitis caused by war
injuries, some of which dated back for over 30 years and involved up to 15 previous
operations. Another noteworthy feature of the study are the seven cases of chronically
aggressive osteomyelitis which had been unsuccessfully treated with PMMA chains
for many years (figures 1 to 5).
Pharmacokinetics
The graphs in figures 6 and 7 show the two extremes measured (the lowest and
highest initial gentamicin levels) in all 26 patients in whom active substance
concentrations in exudate were measured. Although both patients received the same
amount of gentamicin (two 120-mg collagen sponges), the amounts of active
substance released in the wound secretion varied from 381.5 mg/l (figure 7) to 5,117.5
mg/l (figure 6) in the first 24 hours after surgery (variation to the tenth power). It is
therefore impossible to establish a direct connection between the absolute amount of
gentamicin applied and the exudate level. This was also confirmed with all the other
cases investigated, where up to seven collagen sponges, equivalent to 840 mg of
gentamicin, were inserted. Most patients received two or three sponges, equivalent to
240 to 360 mg of gentamicin base. However, it was possible to show a direct
correlation between the levels of exudate measured and local flow over a given period
of time in all patients. Low flow was always associated with a high concentration of
active substance and especially with protracted release of the gentamicin (figure 6,
shin head osteomyelitis, level still at 1,661 mg/l three days after surgery), while in
cases of high flow the absolute initial level of active substance was indeed high
(figure 8, infected TEP replacement) at 636.0 mg/l, but the gentamicin level fell
sharply to 22.4 mg/l after 48 hours. The figures for all the cases of calf osteomyelitis
observed (n=9) are summarised in figure 9. The flow is low in most of these cases.
The active substance level fell from an initial figure of 1,542 mg/l after 12 hours to
384.3 mg/l on the third day after surgery; this level is still high enough to control
resistant strains of Staphylococcus aureus. The level on day five was 47.5 mg/l, still
ten times higher than the MIC threshold of 4 mg/l.
In the case of high local flow, i.e. when the body's own defence system is able
to be effective thanks to good blood supply and the need for local bactericidal
substances is less pronounced, we only find a very high local gentamicin level in the
decisive first 48 hours. In the reverse situation, the level of active substance remains
very high for several days if a poor blood supply prevents cellular and humoral
defence mechanisms working properly so that pathogenic germs would stand a better
chance of survival. This property of active substance release was confirmed in quite a
striking manner by measurements performed on our hip patients. Where the collagen
sponge was left to float free in the joint cavity, i.e. under conditions that were almost
more severe than normal in-vitro conditions, with the collagen floating in a sea of
aggressive fluid, the initial gentamicin level was always high but fell sharply after 48
hours. On the other hand, when the collagen was combined with spongiosa, applied to
remedy the defect and fixed and sealed with a vicryl mesh, the initial level of active
substance was much lower but the rate of release was slower, as the collagen was
largely protected from direct attack by bodily fluids. This means that a bactericidal
environment always exists, and is maintained for a longer period, in areas where the
risk of infection is greatest.
The hip revisions were summarised on the basis of the topographical position
of the collagen in order to clarify this release kinetics (figures 10, 11). In addition to
the typical pharmacokinetics as a function of local flow, the haemostyptic effect of
collagen is another factor leading to much lower exudate volumes when the collagen
is left to float free in the joint.
The reason why gentamicin release depends on local flow lies in the material
relationship between the carrier matrix and the active substance. Electron-optical
examinations of the collagen sponge by the inventors of the system [1] showed a pore
size of 200–500 µ in the collagen fibre network. Our measurements under an optical
microscope showed an average pore size of 100–200 µ (figure 12), about the size of a
pulmonary alveole. Gentamicin molecules are about 30–40 angströms in size. The
black dot marked in figure 12, which shows a collagen mesh, represents about
500,000 gentamicin molecules. It is obvious from these size statistics that gentamicin
molecules can easily be washed out of the collagen sponge mesh structure, especially
since the aminoglycoside is neither chemically nor mechanically bound to the carrier
matrix. There is some debate as to whether an electrostatic bond between
aminoglycosides and collagen exists, but this has not yet been proved. Table 4 lists all
the figures we observed during elution of PMMA beads. The figures for the controls
(unused PMMA beads) show that not only do the absolute gentamicin content figures
per bead vary (between 91.7 and 102.6% of the manufacturer's stated gentamicin
content of 4.5 mg per bead), but also that the distribution of the gentamicin within
each bead can be very different: in the second elution step (agitation at 100°C for 12
hours) we obtained 86.2% of the gentamicin contained in control 1 but only 39.1% in
the case of control 2. We were able to elute on average 40% of the gentamicin
contained in the original beads of the PMMA chains which had been used in patients
and had remained in place for on average 11.2 months. 36.2% was obtained in the
second and third elution steps (washing-out for 12 hours at 100°C and after crushing).
This means that the active substance was diffused only from the outer layers of the
beads. That is not surprising given the material density of PMMA and would not be
particularly relevant to the relationship between the carrier system and the active
substance were it not for the fact that it has a significant impact on the active
substance's release kinetics. The initial active substance level of no more than 100
mg/l [7, 24, 25], which is already inadequate to control resistant germs, gradually falls
to a very low elution gradient. The average gentamicin level we measured in the
incision tissue adjacent to the beads was 0.9 mg/l, i.e. below the 1 mg/l threshold at
which an MIC can be achieved with highly sensitive Staphylococcus aureus strains. In
other words, Staphylococcus strains were able to proliferate unhindered on the surface
of the beads. This practically provokes the development of resistant germs. The germs
found in the corresponding wound smears were, as is to be expected under such
conditions, almost all resistant (the only exception being to gyrase inhibitors in one
case). In the light of these analyses, it is more than questionable whether the bead
chains really do exert the "space-occupying effect" which is often claimed for them.
The theory is that they "occupy" a germ-free "space" which can be used for
subsequent defect restoration or insertion of an implant. But does it not rather often
simply provide additional room for the infection to spread in the infected cavity?
Immunology
The serum analyses investigating the possible formation of antibodies were not
available at the time of writing, and therefore the final results cannot be reported until
a later date. However, our clinical and histological observations, together with
Stemberger's experimental findings, indicate that the immune system is highly
unlikely to produce a significant reaction to highly purified bovine collagen.
Histology
All the tissue samples were obtained from hip patients, either during a second session
or in connection with post-operative dislocations requiring revision. As expected, no
collagen material was found in the joint capsule three months after the sponge had
been inserted. What was surprising was the absence of collagen material just nine
days after insertion. A histological examination of the hip joint cavity to which
collagen gentamicin had previously been applied found only fibrin, cell detritus and
young connective tissue. As had been the case with the pharmacokinetic examination,
this histological investigation was also able to establish a direct correlation between
blood supply, i.e. the arrival of phagocytes, and the rate at which the collagen was
absorbed. In cases where collagen was not directly exposed to attack by phagocytes,
for example when it was combined with spongiosa (figure 12), collagen fibres were
still to be found in the lacunae of the spongy bone two weeks and even nine weeks
later.
Discussion
The debate surrounding the topical use of antimicrobial substances certainly does not
affect the cornerstones of surgical treatment of bony infections, which are stability,
radical debridement and improvement of blood supply. When we think about such
therapeutic concepts, we are thinking of the "residual risk of infection" which remains
in the case of osteomyelitis after a correct surgical procedure has been performed.
This residual risk is however of enormous individual and economic importance,
because it can sometimes lead to the irreversible psychosocial decline of an
individual, which is all too often accompanied by the destruction of intact families,
and it can increase treatment costs to ten or twenty times what they would otherwise
have been [22]. The literature contains no large-scale retrospective studies in which
the reinfection rate of cases of osteomyelitis that have undergone treatment are
recorded and analysed; sadly, this is also the case for authors who reject the local use
of antibiotics, which means that no truly comparable figures are available. The long or
interminable treatment periods of over ten years [4], even when correct therapeutic
principles are strictly respected, have a marked effect on the inherent
pathophysiological dynamics of the condition, since disseminated perifocal nests of
accumulated germs can escape purely surgical techniques. This is particularly true of
haematogenic osteomyelitis, where Böhm [4] found that almost 60% of patients had
been undergoing treatment for more than ten years, both with and without PMMA
chains. But if carrier systems now give us the opportunity to create an additional local
bactericidal environment and so minimise the likelihood of 'residual risk of infection',
then reverting to the purely surgical approach is tantamount to medical nihilism. The
fact that 43 out of 50 German AO hospitals use local antibiotics also shows that
practice has changed and that the subject needs to be approached more rationally.
PMMA chains were used in the past in almost all cases, and the question of how
critical an approach to this system and to terms such as 'space-occupying effect' has
been taken [8, 14]. In any case, the data that is available does not provide grounds for
euphoria. Clinical case reports [4, 21, 23, 30, 33, 38] confirm a reinfection rate of 15–
45% in the first two years. The small number of active substance level findings in
exudate actually taken from patients [7, 24, 25] showed initial gentamicin
concentrations of 68.6 mg/l (n=10) and 100 mg/l (n=6). This carrier system is beset
by many drawbacks, such as inability to place it in a precise location, difficulty of
handling, need for it to be removed, etc.; but the major issue must be its unfavourable,
and in fact harmful, release kinetics. The German standard DIN 58940 [12] on
"Sensitivity testing of bacterial pathogens", which is used as the basis for such
investigations, gives the MIC threshold of gentamicin as 4 mg/l. Above 4 mg/l, germs
are recorded in the antibiogram as resistant. Grimm [10] investigated the gentamicin
resistance of a total of 36,748 identified germs, using a comprehensive set of samples
from 1987. 9.2% of the 5,129 Staphylococcus aureus findings were gentamicinresistant, and the equivalent figure for Staphylococcus epidermidis was 23.6% of
3,848 findings. These are figures from an unselected cohort. Our wound smears
showed a rate of resistance among Staphylococcus aureus of 28.2%. This means that
we must expect a higher than average rate of resistance among these particularly
relevant Staphylococci strains in cases of chronic osteomyelitis. Resistance is a form
of bacterial action based on enzymatic deactivation of aminoglycosides. This
enzymatic deactivation is a function of dose level and exposure time, i.e., at low
aminoglycoside concentrations and high bacterial counts, the enzymes released by the
bacteria are able to destroy enough aminoglycosides to make them ineffective. In
contrast, when aminoglycoside levels are very high, the rate at which bacteria are
killed exceeds the speed at which the active substance is deactivated. This means
resistance can be overcome by increasing the titre. In his unselected cohort, Grimm
[10] found a peak MIC level of up to 512 mg/l among gentamicin-resistant
Staphylococcus aureus strains, while MIC levels of over 64 mg/l were needed to
control 21.1% of the resistant samples. Leaving aside other imponderables, such as
the diffusion distance or the pH of the wound environment, an active substance carrier
must at least be expected to promote the release of gentamicin in sufficient quantities,
that is to say achieving an initial local active substance level of at least 300 mg/l.
PMMA chains are unable to arrive anywhere near this figure. In the case of resistant
germs such as those we must expect to find in cases of chronic osteomyelitis, only
sub-inhibitory concentrations are achieved, which simply has the effect of breeding
resistant germs. It is therefore not surprising that we see high reinfection rates when
chains are used, and complete, high germ resistance among our patients who have
previously undergone PMMA chain treatment. Winkelmann et al. [38] investigated 20
patients who had been treated with PMMA chains as long ago as 1976, and found
three cases of germs becoming resistant to gentamicin after the end of treatment. Of
course, considerable caution is necessary in interpreting our successes to date with the
use of collagen gentamicin, given the small number of cases, the heterogeneity of the
cohort and the as yet short observation period of no more than two years. However,
there is a clear trend in comparison to the treatment outcomes with earlier carrier
systems over the same period, indicating a qualitative leap forward. Without doubt,
the key to success lies in the significantly improved pharmacokinetics, which allow an
initial active substance level that is capable of controlling all germs irrespective of
their degree of resistance, although this does depend on local flow (i.e. it
complements the quality of the body's own defence systems against infection). In
particular, sub-inhibitory active substance concentrations do not remain in place
where they would increase the risk of the formation of resistant germs. Further
arguments in favour of this new therapy concept include the immunologically safe
absorbability of the carrier matrix, the fact that the material can be placed to fit neatly
into all surface patterns of bony defect cavities, and the ability of the active substance
carrier to combine with spongiosa and so take part in the biological reconstruction of
defect cavities.
Bibliography: see original text.
Figures 1a–h. 79-year-old male patient with infectious hip endoprosthesis loosening after three
previous prosthesis replacements. a, b Two-stage reconstruction with collagen gentamicin used to
disinfect the bone cavity and socket base in the first session, c–e and final procedure after the patient
had remained infection-free for three months, involving the use of rotator cuff reconstruction prosthesis
and restoration of the defect by means of a bank spongiosa/gentamicin combination. f, g Prosthesis
fully healed without complications after eight months (h).
Figures 2a–c. Fistula-forming Girdlestone hip in a 61-year-old female patient with PMMA chains, in
place for 13 months. a Two-stage reconstruction with complication-free healing. Check-up 18 months
after surgery (b, c).
Figures 3a–d. 67-year-old female patient with transmitted symphysisosteomyelitis and recurrent
vulvitis. a PMMA chains in place for eight months, b, c Healing with no reinfection after
administration of collagen gentamicin. d Check-up after two years.
Figures 4a–g. 59-year-old male patient with chronically persistent osteomyelitis after receiving a stab
wound in the upper arm in 1944. a-c Previous operations. Fistula smear: Staphylococcus hominis with
complete resistance. Debridement, cavity curettage and insertion of collagen gentamicin and
autologous spongiosa to fill the space. d-f Infection-free for 22 months (g).
Figures 5a–e. 63-year-old female patient with chronically aggressive osteomyelitis after three
replacements of a slipping prosthesis, arthrodesis and three operations to insert PMMA bead chains,
with an interval of one year between each operation. a–d Fistula smear: Staphylococcus aureus with
complete resistance. Gentamicin level of the PMMA incision tissue 0.47 mg/l! Debridement was
following by insertion of a bank spongiosa/Sulmycin mixture. Complication-free status after eight
months (e).
Exudate
(ml)
Gentamicin
(mg/l)
Exudate level
Total amount of
gentamicin (mg)
Gentamicin loss through
drainage (mg)
Urine level
Exudate volume
hours
days
Figure 6. Gentamicin levels in exudate in a case of chronically aggressive shin head osteomyelitis, 55year-old male patient: extremely high active substance level and minimal local flow.
Exudate
(ml)
Gentamicin
(mg/l)
Total amount of
gentamicin (mg)
Exudate volume
Gentamicin loss through
drainage (mg)
Exudate level
Urine level
hours
days
Figure 7. Gentamicin levels in exudate in a case of infected TEP replacement. Collagen gentamicin
bound in the defect restoration with bank spongiosa and vicryl mesh sealing. Lowest active substance
concentration measured with very high local flow.
Exudate
(ml)
Gentamicin
(mg/l)
Exudate level
Total amount of
gentamicin (mg)
Gentamicin loss through
drainage (mg)
Exudate volume
Urine level
hours
days
Figure 8. Gentamicin levels in exudate in a case of infected TEP replacement and collagen gentamicin
left to float free in the joint cavity: high initial active substance level and sharp decline after 48 hours as
the gentamicin is eluted directly from the carrier matrix.
Exudate
(ml)
Gentamicin
(mg/l)
Exudate level
Exudate volume
Urine level
hours
days
Figure 9. Average exudate level in nine cases of calf osteomyelitis on which measurements were
performed: bactericidal wound environment for resistant germs in the first three days after surgery.
Exudate
(ml)
Gentamicin
(mg/l)
Exudate level
Total amount of
gentamicin (mg)
Gentamicin loss through
drainage (mg)
Exudate volume
hours
days
Figure 10. Collagen gentamicin allowed to float free in the hip joint. Average values for seven
patients: high initial active substance level with rapid loss of active substance after 48 hours, relatively
high drainage loss and comparatively small exudate volume (haemostyptic effect?). Gentamicin eluted
rapidly by the direct effect of bodily fluids on the carrier matrix.
Exudate
(ml)
Gentamicin
(mg/l)
Total amount of
gentamicin (mg)
Exudate level
Gentamicin loss through
drainage (mg)
Exudate volume
hours
days
Figure 11. Collagen gentamicin in bank spongiosa used to remedy defects. Average values for eight
patients. Initial active substance level lower, but prolonged release of active substance with lower
exudate loss and higher exudate volume.
Figure 12. Collagen network under an optical microscope: pure collagen fibres with no nucleus
components. Pore size: 100 to 200 µ (equivalent to the size of a pulmonary alveole). The black dot in
the collagen mesh represents around 500,000 gentamicin molecules.