REVIEW ARTICLE Drugs 2000 Jun; 59 (6): 1223-1232

0012-6667/00/0006-1223/$25.00/0

© Adis International Limited. All rights reserved.

Carrier Systems for the Local Delivery

of Antibiotics in Bone Infections
Kyriaki Kanellakopoulou1 and Evangelos J. Giamarellos-Bourboulis2
1 4th Department of Internal Medicine, Athens Medical School, Athens, Greece
2 1st Department of Propedeutic Medicine, Athens Medical School, Athens, Greece

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1223
1. Criteria for the Production of a Local Delivery System for Antibacterial Agents . . . . . . . . . . . 1224
2. Nonbiodegradable Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1224
2.1 Polymethylmethacrylate (PMMA) Cement Beads . . . . . . . . . . . . . . . . . . . . . . . . . 1224
3. Biodegradable Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1227
3.1 Collagen-Gentamicin Sponge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1227
3.2 Lactic Acid Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1227
3.3 Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1229
4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1230

Abstract Carriers used for the local delivery of antibacterial agents may be classified
as nonbiodegradable or biodegradable. A major representative of the former cat-
egory are the polymethylmethacrylate (PMMA) beads often impregnated with
gentamicin which have been commercially available for the last 2 decades. Ex-
amples of the latter category include the collagen-gentamicin sponge, apatite-
wollastonite glass ceramic blocks, hydroxyapatite blocks, polylactide/polyglycolide
implants and the polylactate polymers. All of the above systems release antibiot-
ics at concentrations exceeding those of the minimum inhibitory concentrations
(MICs) for the most common pathogens of chronic osteomyelitis without releas-
ing any antibiotic in the systemic circulation and without producing adverse effects.
The major disadvantage of the PMMA beads is the need for their surgical removal
at the completion of antibiotic release, which usually takes place 4 weeks after
their implantation. The biodegradable carriers do not require surgical removal, and
of those listed, the collagen-gentamicin sponge has been applied successfully
over the last decade for bone infections. Among the other biodegradable systems
which are still in experimental stages, polylactate polymers carrying quinolones
seem very promising, since they are characterised by prolonged duration of re-
lease at concentrations 100 to 1000 times the MICs of the causative bacteria impli-
cated in bone infections; preliminary results have shown these carriers to be very
effective in the management of experimental osteomyelitis caused by methicillin–
resistant Staphylococcus aureus. Further development of such biodegradable sys-
tems will provide a novel approach in the future for the eradication of chronic
osteomyelitis.
1224 Kanellakopoulou & Giamar

Chronic osteomyelitis is difficult to treat because Table I. Carriers used for local delivery of antibacterial agents

it is often associated with necrosis of bone and poor Type of system Antibacterial References
released
vascular perfusion accompanied by infection of the
surrounding tissues.[1] As a consequence, access to Nonbiodegradable
PMMA bone cement Gentamicin, 3, 6
the site of infection by antibacterial agents admin- Tobramycin
istered either orally or intravenously is limited, and PMMA beads Gentamicin 3, 6
clinicians tend to be pessimistic about patient out-
Biodegradable
comes.[2] Surgical debridement and prolonged ad- Collagen-gentamicin sponge Gentamicin 3, 7, 8
ministration of antibacterial agents constitute the Apatite-Wollastonite glass Cefmetazole, 9
current regimen of therapy. New methods such as ceramic blocks Isepamicin
local delivery of antibiotics have evolved in an at- Hydroxyapatite blocks Cefmetazole, 9, 10
Isepamicin,
tempt to improve the prognosis of these patients; Arbekacin
the characteristics of the existing systems of local Polylactide/polyglycolide Gentamicin 11
drug delivery are analysed in this review. implants
Fibrin clots Ciprofloxacin 12
Dilactate polymers Ciprofloxacin, 13, 14
1. Criteria for the Production of a Local Pefloxacin,
Fleroxacin
Delivery System for Antibacterial Agents
Biomedical polyurethanes Flucloxacillin, 15
Gentamicin,
Antibacterial agents selected for use in a system Ciprofloxacin,
designed for local delivery should have the follow- Fosfomycin
Fibres Tetracycline 16-18
ing characteristics:[3]
PMMA = polymethylmethacrylate.
• be active against the most common bacterial patho-
gens involved in chronic osteomyelitis
• be locally released at concentrations exceeding the need for their surgical removal when all the
several times (usually 10 times) the minimum in- antibiotic has been released.[3]
hibitory concentration (MIC) for the involved Release of the antibacterial agent in such systems
pathogen is governed by the rate of dissolution of the drug in
• not provoke any adverse effects its matrix allowing its penetration through the
• not enter the systemic circulation pores of the carrier. For highly soluble agents, e.g.
• be stable at body temperature and water soluble β-lactams agents, the amount of released drug de-
to ensure diffusion from the carrier. pends on the surface area of the carrier and on the
The most commonly described bacterial isolates initial concentration of the drug in the prepared sys-
in patients with chronic osteomyelitis are staphy- tem. For relatively insoluble agents, e.g. quinolones,
lococci and Gram-negative bacteria, particularly the rate of drug release depends on the porosity of
Enterobacteriaceae such as Enterobacter spp., and the matrix and on the dissolution of the drug in the
Pseudomonas aeruginosa.[4,5] Based both on the matrix.[19]
above criteria and on bacteriological findings in
chronic osteomyelitis, the most widely applied agents 2. Nonbiodegradable Systems
in local delivery systems are the aminoglycosides
2.1 Polymethylmethacrylate (PMMA)
and to a lesser extent various β-lactam agents and
Cement Beads
quinolones. Depending on the material used for bio-
synthesis of the carrier, these systems are divided The idea of applying polymethylmethacrylate
into nonbiodegradable and biodegradable; the most (PMMA) beads as a means of local antibacterial
common of these are listed in table I. The major chemotherapy was introduced in the literature in
disadvantage of the nonbiodegradable systems is 1970 by Buchholz et al.,[6] with the incorporation

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Local Delivery of Antibiotics in Bone Infections
of an antibiotic in bone cement. PMMA beads im-
pregnated with gentamicin were then developed
and have been commercially available in Europe
since 1977. They exist in 2 forms: that of antibiotic-
impregnated bone cement applied in arthroplasties;
and antibiotic-impregnated PMMA bead chains for
musculoskeletal infections.[20] The success of
these carriers is attributed to 2 factors: PMMA does
not usually trigger any immune response from the
host, and the form of a bead confers a wide surface
area, allowing rapid release of the antibiotic.[20]
Gentamicin, tobramycin and vancomycin have
been applied in antibiotic-impregnanted bone ce-
ment. In the US only tobramycin-impregnated
bone cement is currently commercially available.
Various brands of PMMA cement are available,
and the in vitro elution of antibiotics from these
varies between brands.[21] PMMA beads are found
in both commercial and noncommercial prepara-
tions. Commercially available beads have a consis-
tent diameter of 7mm and are available in strands
of 10 or 30.[22] Noncommercial preparations, pre-
pared by surgeons themselves, have the disadvan-
tages of a lack of thorough mixing of the antibiotic
into the beads and a lack of uniform size of bead,
resulting in lower antibiotic availability.[22] Selec-
tion of the type of antibiotic that might be applied
in commercially prepared beads is based on its sta-
bility at the high temperatures (up to 100°C) at
which polymerisation occurs. The aminoglycosides
are heat stable and are thus widely used in these
preparations.
Table II. Characteristics of the in vitro elution of different antibiotics from polymethylmethacrylate (PMMA) beads
Study Antibacterial released
Nelson et al.[22] Tobramycin
Gentamicin
Adams et al.[23] Cefazolin
Ciprofloxacin
Clindamycin
Kuercle et al.[24] Amikacin
Vancomycin
Mader et al.[25] Clindamycin
Tobramycin
Vancomycin
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1225
Cumulative data on the in vitro elution of antibi-
otics in PMMAbone cement are given in table II,[22-25]
where it is clearly shown that both aminoglycosides
and quinolones are released at very high concentra-
tions, but the peak of release occurs on the first day.
As the viscosity of the acrylic cement decreases,
the amount of released antibiotic increases.[26] Se-
rum, inflammatory fluid and antibiotic collect around
the beads as a seroma. It has been shown that the
in vivo elution of cefazolin, ciprofloxacin and clin-
damycin follow characteristics analogous with those
seen in vitro, so that the antibiotic reaches its high-
est concentration in the seroma over the first day,
with a total duration of release of 28 days.[23] The
same first day peak was also documented for tobra-
mycin and vancomycin;[27] the release lasted for a
total period of only 1 week. The concentration of
gentamicin around the implant remains high up to
2 to 3cm from the beads, whereas its concentration
in the serum and organs remains very low, almost
undetectable, thus avoiding toxicity.[2]
To achieve adequate killing of bacteria, beads
should not be used in combination with an irriga-
tion system, and moisture should be excluded by
application of artificial skin. With these precautions
the amount of gentamicin released by the beads
does not exceed 25% of the total amount implan-
ted.[3] In chronic osteomyelitis, healing of the
wound is expected within 5 days but PMMA beads
may remain implanted for up to 4 weeks, after
which surgical removal is necessary followed by
osseous reconstitutive surgery. The need for re-
Duration of release (days) Peak release (mg/L) Day on which
peak observed
30 234-299 1
30 125-355 1
28 250 1
28 74.5 1
28 407 1
5 200 1
5 250 1
220 >250 1
220 >250 1
12 >200 1
Drugs 2000 Jun; 59 (6)
1226
moval is the major disadvantage of the beads, al-
though in some patients small chains of beads might
be removed in the ward via a small skin incision.[2]
Antibiotic-impregnated bone cement can be ap-
plied either in infected arthroplasties or as surgical
prophylaxis during hip arthroplasty. Cumulative
results of clinical studies involving its application
for both purposes are given in table III.[28-34] It should
be mentioned that the treatment of an infected pros-
thesis by revision arthroplasty normally occurs in
3 stages: removal of the foreign body and surgical
debridement of soft tissues, parenteral administra-
tion of antibiotics for 6 weeks, and reimplantation
of the joint. In these patients, the application of
PMMA cement beads[28-31] is equivalent to an at-
tempt to abbreviate the 3-stage procedure to 1 stage.
A recent study reviewing 10 905 patients undergo-
ing total hip replacement revealed that survival of
the arthroplasty was greatly prolonged over the
first 2 years of follow-up in patients receiving pro-
phylaxis with both systemic antibiotics and genta-
micin bone cement, compared with those receiving
only systemic or local prophylaxis.[35]
A recent development for the treatment of infec-
tions at the site of total hip arthroplasty accompa-
nied by extensive loss of the proximal part of the
femur is the application of a prosthesis of antibiotic-
loaded acrylic cement consisting of an acetabular
cup filled with antibiotic-loaded bone cement and
an endoskeleton also coated with antibiotic-loaded
bone cement.[36,37] The use of this prosthesis allows
a 2-stage operative procedure: the first stage involves
removal of all foreign material, thorough debride-
Table III. Cumulative data from clinical trials with antibiotic-impregnated polymethylmethacrylate (PMMA) beads
Study Purpose of application
Garvin et al.[28] Periprosthetic hip infection
Hanssen et al.[29] Periprosthetic hip infection
Whiteside[30] Infected knee prosthesis
Raut et al.[31] Infected knee prosthesis
Cho et al.[32] Chronic osteomyelitis
Josefsson et al.[33] Prophylaxis in total hip arthroplasty
Izquierdo & Prophylaxis in total hip arthroplasty
Northmore-Ball[34]
a No observed infection or recurrence.
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Kanellakopoulou & Giamar
ment and placement of the prosthesis; the second
involves removal of the acetabular cup by fragmen-
tation of the cement bolus. The antibiotic usually im-
pregnated is tobramycin or vancomycin. The former
is eluted at intra-articular concentrations of between
4.35 and 123.88 mg/L, unlike the latter, which
sometimes remains undetected.[38] This 2-stage re-
vision resulted in a success rate of 94% in 61 patients
after an average follow-up of 43 months.[39]
Anecdotal case reports referring to the success-
ful cure of osteomyelitis of the pelvis and of the hip
caused by methicillin-resistant Staphylococcus au-
reus (MRSA) by the application of PMMA beads
impregnated with vancomycin[40] reinforce the con-
cept of their use for chronic infections of bone and
joints. It should also be mentioned that PMMA is
a nonbiodegradable material that has been applied
in various forms to achieve healing of infections
followed by reconstitutive surgical operations. In
one such report, a PMMA spacer impregnated with
tobramycin and vancomycin was used for salvage
of the proximal phalanx of the index finger infected
by S. aureus followed by a vascularised bone flap
from the first metatarsal bone.[41]
Many of the bacterial pathogens involved in
chronic osteomyelitis, particularly S. epidermidis,
produce a biofilm that limits the activity of antibi-
otics.[42] This biofilm, known as the extracellular
slime or glycocalyx, is produced by strains of S.
aureus and S. epidermidis;[43] it also provides these
strains with the capacity to adhere to foreign bod-
ies, such as the PMMA beads.[43] Consequently, de-
spite adequate killing of these micro-organisms by
No. of patients Patients with favourable Average follow-up
outcome (%)a
40 95 1y + 5mo
183 84.2 7y + 9mo
33 96.9 2y
86 89.6 4y + 4mo
31 87 3y
1688 99.2 1-2y
184 95.1 10-11y
Drugs 2000 Jun; 59 (6)
Local Delivery of Antibiotics in Bone Infections 1227

in vitro elution of antibiotic in close proximity to
the beads, the same micro-organisms survive on
their surface.[44] This stable adherence might pro-
vide a mechanism of recurrence of the infection and
of development of resistance, since small colony
variants of S. aureus resistant to gentamicin have
been isolated from the wounds of patients with bone
infections treated with gentamicin-impregnated
PMMA beads.[45]
3. Biodegradable Systems
3.1 Collagen-Gentamicin Sponge
The collagen-gentamicin sponge appears to be
equally as popular as PMMA beads for the treat-
ment of chronic bone infections.[7] It has been com-
mercially available for 10 years and is produced
from sterilised bovine tendon in which gentamicin
is suspended. Sterilisation is achieved either by
ethylene oxide or by gamma irradiation. Sponges
sterilised by ethylene oxide achieve greater local con-
centrations of gentamicin than those sterilised by
gamma irradiation, but the latter facilitates degra-
dation of the sponge.[8] Gentamicin is generally re-
leased at higher concentrations than those eluted
from PMMA beads, equal to 108.7 µg per gram of
tissue at the bone marrow and 13.2µg per gram of
tissue at the bone cortex.[2] The elution of gentami-
cin takes place by its diffusion from the sponge upon
Copolymers of polylactide and polyglycolic acid
have been produced with ratios between the 2 com-
posites varying between 90 : 10 and 50 : 50. Their
biodegradation is achieved by their decomposition
at the pH of body fluids. In vitro studies showed that
the 90 : 10 ratio provides better stability, delayed
decomposition and superior eluted concentrations
of clindamycin, tobramycin and vancomycin than
copolymers produced at other ratios.[26] In experi-
mental osteomyelitis in dogs, 50 : 50 copolymers
releasing gentamicin produced similar results to
those of PMMA beads but superior results to those
achieved by intravenous administration of genta-
micin.[11] Composites releasing minocycline or
amikacin also limited experimental soft tissue in-
fection of the dorsum of guinea-pigs caused by Es-
cherichia coli and S. aureus.[47]
Our study group was one of the first, to our knowl-
edge, in the literature to evaluate biodegradable car-
riers derived from the polymerisation of lactic acid
at various molecular weights[13,14] and to apply these
polymers for the delivery of quinolones. Quinolones
have long been considered the drugs of choice for
chronic osteomyelitis because of their favourable
penetration in poorly vascularised sites of infec-
1400 2kD
26kD
Pefloxacin (mg/L)

1200
100kD
implantation and principally during the degradation 1000
of collagen by the collagenases of macrophages. 800
600
Degradation is usually complete within 8 weeks[7] 400
but recent in vitro results indicate antibiotic release 200
from collagen sponges may be complete within 0

only 4 days.[46]
600
Ciprofloxacin (mg/L)

500
3.2 Lactic Acid Polymers 400
300
Polymerised lactic acid is a novel carrier that ap-
200
pears to be a promising candidate for use in clinical
100
practice as a carrier of antibacterial agents. Its main 0
advantages are that it is biodegradable and the anti- 1 2 3 4 5 6 7 8 9 10 11
bacterial agents eluted by it have favourable pharma- Time (wks)
cokinetics. It has 2 forms: polylactide/polyglycolide Fig. 1. Release of ciprofloxacin and pefloxacin versus time by
composite beads[11] and polymerised dilactide of var- polylactide polymers in relation to their molecular weight (mod-
ious molecular weights.[13] ified from Kanellakopoulou et al.[14]).

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1228 Kanellakopoulou & Giamar

tion, their advantageous bactericidal effect on all
the probable pathogens of chronic osteomyelitis,
their availability in both oral and parenteral prepar-
ations, and the lack of serious adverse reactions seen
with the best studied ciprofloxacin and pefloxacin.[48]
Three polymers have been developed so far, with
molecular weights of 2, 26 and 100kD. The first is
derived by direct polymerisation of l-lactate and the
other two after polymerisation of crystalline d,l-
dilactide using Sn(Oct)2 as a catalyst. Ciprofloxacin,
pefloxacin and fleroxacin have been added to the
polylactate carrier at a concentration of 10%, and the
in vitro release over time of ciprofloxacin and
pefloxacin is represented in figure 1.
The characteristics of the in vitro elution of anti-
biotics from the lactic acid polymers compared with
the other biodegradable systems of local delivery are
shown in table IV. Although it is difficult to compare
the in vitro efficiency of these systems with that of
PMMA beads, the data presented in tables II and
IV support the contention that lactic acid polymers
produce sustained release of the antibacterial agent
over a longer period and at higher concentrations
than all other systems. The only study comparing
the efficiency of PMMA beads and lactic acid poly-
mers in the in vitro release of fleroxacin revealed a
total duration of quinolone elution by both carriers
of 60 days, with a peak concentration of 15.5 mg/L
for PMMA beads on the 1st day of release and a
peak concentration of 750 mg/L for the lactic acid
polymer on the 10th day.[49] However, it should be
borne in mind that the total period of release is longer
than that of other systems, especially when consid-
ering the 100kD molecular weight compounds,
which have a total period of release approaching 350
days. Quinolones are released at concentrations ex-
ceeding 100 to 1000 times their MIC for the com-
mon pathogens of chronic osteomyelitis, and the
peak of release is observed over the 20th, 50th and
1st days for the low, medium and high molecular
weight polymers, respectively (table IV).
To confirm the relevance of the above in vitro re-
sults as an adequate criterion for the initiation of
studies of lactic acid polymers as therapy, the drug

Table IV. Comparison of the in vitro characteristics of antibiotic local delivery systems
Study System Characteristics Antibacterial Duration of release Peak release Day on which
released (days) (mg/L) peak observed
Wachol-Drewek et Collagen sponge Gentamicin 4 613.7 1
al.[46] Vancomycin 2 2521 1
Garvin et al.[11] Polylactide/polyglyco- Clindamycin 38-50a >300 10-14a
lide copolymer Tobramycin 36-75a >300 25-35a
Vancomycin 38-51a >300 1-10a
Tsourvakas et al.[12] Fibrin clot Ciprofloxacin 60 49.9 1
Kanellakopoulou et Polylactate 2kDb Ciprofloxacin 51 1500 16
al.[14] Pefloxacin 56 822 13-20
26kDb Ciprofloxacin 97 661 46-51
Pefloxacin 102 1448 41-47
100kDb Ciprofloxacin 350 1760 1-2
Pefloxacin 295 2164 1-2
Dounis et al.[13] Polylactate 2kDb Fleroxacin 56 1500 17
Schierholz et al.[15] Polyurethanes Ciprofloxacin 5 100 1
Kawanabe et al.[9] Apatite-wollastonite 20-30% porosity Isepamicin 42 5000 2
ceramic Cefmetazole 8 1000 2
70% porosity Isepamicin 42 10000 2
Cefmetazole 8 50000 2
a Depending on the ratio of polylactate and to polyglycolate.
b Molecular weight of the polymer.

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Local Delivery of Antibiotics in Bone Infections 1229

Table V. Comparative in vivo elution of various antibacterial agents from biodegradable systems for local drug delivery
Study System Antibacterial Animal model Duration of Peak release Day on Serum
released release (days) (µg/g of bone which peak concentration
cortex) observed at peak (mg/L)
Stemberger et Collagen Gentamicin Rabbit 56 13.2 7 NA
al.[7] sponge
Itokazu et al.[10] Hydroxyapatit Arbekacin Rat NA NA NA 1.4
Tsourvakas et Fibrin clot Ciprofloxacin Rabbit 15 32.5 2 0.8
al.[12]
Kanellakopoulou 2kD lactate Pefloxacin Rabbit 33 125.3 15 0.0
et al.[50] polymer
NA = no measurement performed.

elution achieved in tissues by this novel system
was verified in animal studies of experimental osteo-
myelitis.[12,50,51] Pharmacokinetic results for these
polymers compared with those provided by other
biodegradable systems are shown in table V. The
polylactate polymers achieve prolonged in vivo quin-
olone release at higher levels than the other sys-
tems. It is perhaps most important to note that all
other systems, except the apatite-wollastonite ce-
ramic blocks,[47] produce their peak of drug release
in the first days after implantation. The polylactate
polymers, however, produce their peak drug release
after 15 days,[50] which might be crucial in the ther-
apy of chronic osteomyelitis.
On the basis of the adequacy of elution of quin-
olones from the polylactate carrier, this carrier im-
pregnated with pefloxacin was used for therapy of
an experimental bone infection caused by local ap-
plication of a 1 × 108 colony-forming units (cfu)/ml
tions released by these carriers are much higher
than the MIC90s for MRSA.[52] Novel compounds
such as sitafloxacin and trovafloxacin, which are
very potent in vitro against MRSA,[52] would suit
application in such local drug release systems.
3.3 Miscellaneous
Other systems include apatite-wollastonite glass
ceramic blocks,[9] hydroxyapatite blocks[9,10] and
biomedical polyurethanes[15] whose characteristics
in both in vitro and in vivo elution of antibacterial
agents are shown in tables IV and V. The apatite-
wollastonite glass ceramic blocks exist in 2 forms:
one with a porosity of 20 to 30% and the other of
70%. They have been applied in a pilot clinical study
to treat 5 patients with an infected arthroplasty. Ex-
9
Log10 [no. of viable cell counts (cfu/ml)]

inoculum of MRSA in rabbits. Animals were di- 8

vided into several groups killed at 3-day intervals, 7
when the remaining viable cell counts were deter-
6
mined.[50] Unpublished results on the change of
5
bacterial load over time by the 2kD polylactate car-
4
rier of pefloxacin are given in figure 2. A >3 log10
3
reduction of the implanted inoculum was observed Control
2 2kD polymer
from day 9, leading to very low cell counts by day
1
33, after which no relapse was observed, thus con- 0 3 6 9 12 15 18 21 24 27 30 33 47
firming the adequacy of such a system for the erad- Time (days)
ication of experimental bone infection. It should be
Fig. 2. Effect of an implanted 2kD polylactate carrier of pefloxacin
borne in mind that MRSA is usually resistant to
on viable cell counts of experimental osteomyelitis caused by
fluoroquinolones, but this limitation is overcome methicillin-resistant Staphylococcus aureus (Kanellakopoulou et
by using polylactate polymers, since the concentra- al., unpublished results). cfu = colony-forming units.

 Adis International Limited. All rights reserved. Drugs 2000 Jun; 59 (6)
1230
cellent results were observed 2 years after treat-
ment and the implanted material triggered osteo-
genesis so as to produce a complete radiological
replacement of the osseous defect.[9] Analogous re-
sults concerning healing were obtained with hydr-
oxyapatite blocks carrying arbekacin achieving
bacteriological eradication of osteomyelitis caused
by S. aureus.[10] Only in vitro data exist for biomed-
ical polyurethanes as carriers of flucloxacillin, fos-
fomycin, ciprofloxacin and gentamicin,[15] releas-
ing these agents for a short period at concentrations
analogous to the amount of the incorporated anti-
biotic.
A method presenting favourable results is the
application of antibiotic-impregnated autogenic
cancellous bone grafting, which has already been
introduced in clinical practice. The concept is the
management of chronic osteomyelitis with one op-
eration instead of several. Chan et al.[53] reported
results from 36 patients with infected fractures re-
sulting from traffic accidents. After surgical debride-
ment an iliac cancellous bone graft was taken and
mixed by the surgeon with piperacillin and/or van-
comycin, depending on the susceptibility of the iso-
lated infective micro-organism. The graft was then
implanted at the site of infection inside the osseous
defect, which occurred principally in the proximal,
middle or distal segment of the left or right tibia.
Four to 5 months were necessary for bone union,
and the only complications presented were skin
rashes.
Finally, in recent years, fibres locally releasing
tetracycline hydrochloride have been successfully
introduced for the therapy of persistent or recurrent
periodontitis,[16-18] but their description is beyond
the scope of this review.
4. Conclusions
The use of gentamicin-impregnated PMMA beads
and the collagen-gentamicin sponge was initiated
in clinical practice more than a decade ago,[3] and
they present results that characterise them as a nec-
essary adjuvant to the systemic administration of
antibacterial agents both in the treatment of chronic
bone infections and in orthopaedic surgical pro-
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Kanellakopoulou & Giamar
phylaxis. The collagen-gentamicin sponge has an
advantage over PMMA beads in that it does not need
surgical removal on completion of the release of
gentamicin. Novel biodegradable carriers such as
polylactate polymers combined with the newer
quinolones are under development. These achieve
longer release at very high concentrations in vitro,
sometimes surpassing 1000 mg/L, and preliminary
results are favourable regarding the elimination of
experimental osteomyelitis caused by MRSA. It
should also be emphasised that whereas most of the
antibacterial agent contained in a biodegradable sys-
tem is eluted, only 25% is actually released from
PMMA beads. Furthermore, the majority of clini-
cal isolates of S. aureus implicated in chronic os-
teomyelitis are resistant to gentamicin released by
PMMA beads, but not to the newer quinolones.[52]
Consequently, polylactate polymers offer the op-
portunity for local therapy with very potent anti-
bacterial agents such as the newer quinolones, and
therefore they deserve careful evaluation for fur-
ther development.
References
1. Mader JT, Landon GC, Calhoun J. Antimicrobial treatment of
osteomyelitis. Clin Orthop 1993 Oct; 295: 87-95
2. Walenkamp GHIM. Chronic osteomyelitis. How I do it. Acta
Orthop Scand 1997; 68 (5): 497-506
3. Rushton N. Applications of local antibiotic therapy. Eur J Surg
1997; Suppl. 578: 27-30
4. Rissing JP. Antimicrobial therapy for chronic osteomyelitis in
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Kanellakopoulou, MD, PhD, 4th Department of Internal Med-
icine, Sismanoglion General Hospital, 1 Sismanogliou Str.,
151 26 Maroussi Attikis, Greece.
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