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Treatment of osteomyelitis with antibiotic-soaked porous glass ceramic VOL. 80-B, N
O
. 3, MAY 1998
527
K. Kawanabe, MD, Assistant Professor
Y. Okada, MD, Orthopaedic Surgeon
Y. Matsusue, MD, Lecturer
H. Iida, MD, Associate Professor
T. Nakamura, Chairman and Professor of Orthopaedics
Department of Orthopaedic Surgery, Faculty of Medicine, Kyoto Uni-
versity, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-01, Japan.
Correspondence should be sent to Professor T. Nakamura.
©1998 British Editorial Society of Bone and Joint Surgery
0301-620X/98/38576 $2.00
Treatment of osteomyelitis with
antibiotic-soaked porous glass ceramic
K. Kawanabe, Y. Okada, Y. Matsusue, H. Iida, T. Nakamura
From the University of Kyoto, Japan
W
e have developed a new drug delivery system
using porous apatite-wollastonite glass ceramic
(A-W GC) to treat osteomyelitis. A-W GC (porosity,
70% and 20% to 30%), or porous hydroxyapatite
(HA) blocks (porosity 35% to 48%) used as controls,
were soaked in mixtures of two antibiotics, isepamicin
sulphate (ISP) and cefmetazole (CMZ) under high
vacuum.
We evaluated the release concentrations of the
antibiotics from the blocks. The bactericidal
concentration of ISP from A-W GC was maintained
for more than 42 days, but that from HA decreased to
below the detection limit after 28 days. The
concentrations of CMZ from both materials were
lower than those of ISP. An in vivo study using rabbit
femora showed that an osseous concentration of ISP
was maintained at eight weeks after implantation.
Osteoconduction of the A-W GC block was good.
Four patients with infected hip arthroplasties and
one with osteomyelitis of the tibia have been treated
with the new delivery system with excellent results.
J Bone Joint Surg [Br] 1998;80-B:527-30.
Received 24 November 1997; Accepted after revision 8 January 1998
The surgical treatment of chronic osteomyelitis often pro-
duces large bone defects which should be lled to reduce
recurrence. Various antibiotic carrier systems have been
developed, particularly antibiotic-impregnated polymethyl-
methacrylate (PMMA) beads which are widely used.
1,2
When such beads are used for chronic osteomyelitis, a
subsequent removal operation is required. Recently, drug
delivery systems (DDSs) using resorbable materials such as
collagen,
3
brinogen
4
and polylactic acid
5
have been devel-
oped. These do not require removal, but do not replace
bone grafting.
We have developed a new DDS using an antibiotic-
soaked porous A-W glass ceramic (GC) block which has
previously been shown to form a chemical bond with living
bone and to have a mechanical strength almost equal to that
of cancellous bone.
6
Materials and Methods
In vitro study. Two types of porous A-W GC (Nippon
Electric Glass Co, Ltd, Otsu, Japan) were made into 8 mm
3
blocks. They had a porosity of 70% (A-W GC 70) and 20%
to 30% (A-W GC 20-30) and pore sizes of 200
m and 10
to 50
m, respectively. The chemical composition of A-W
GC in terms of weight percentage is MgO 4.6, CaO 44.9,
SiO
2
34.2 and CaF
2
0.5. It contains oxyuorapatite and
-wollastonite. Apatite accounts for approximately 35% of
the weight, wollastonite for 40% and glass for 25%. The
method of synthesis has previously been reported by Koku-
bo et al.
7
Porous hydroxyapatite (HA) blocks of the same
size (porosity, 35% to 48%; pore size, 50 to 300 m;
Sumitomo Pharmaceutical Co, Ltd, Tokyo Japan) were
used as controls. The compressive strength of A-W GC 70
is 20 MPa, that of A-W GC 20-30 is 236 MPa and that of
HA is 45 to 70 MPa.
We used two antibiotics, isepamicin sulphate (ISP; Asahi
Chemical Industry Co, Ltd, Osaka, Japan) and cefmetazole
(CMZ; Sankyo Co, Ltd, Tokyo, Japan). The minimum
inhibitory concentration against Staphylococcus aureus was
0.39
g/g for ISP and 1.56
g/g for CMZ.
8,9
The three types of porous ceramic block were placed in
a bone cement mixer (Mixevac II High Vacuum System;
Stryker, Michigan) into which solutions of 100 mg/ml of
ISP or CMZ were poured until all the blocks were covered.
A vacuum of 500 mmHg was sustained for 10 minutes. To
evaluate the elution ability of the porous blocks, each block
was placed in a test tube (15 ml), covered with 3 ml of
phosphate-buffered saline (PBS) (pH 7.4) and stored in a
thermostatic chamber at 37°C. The PBS was replaced every
two days and the preserved PBS was then frozen at 20°C until assayed. The concentrations of antibiotic in each
eluate were assayed by high-performance liquid
chromatography.
In vivo study. The porous A-W GC 70 cylinders (4 mm/
diameter, 4 mm/height) were soaked under vacuum with
the ISP or CMZ solution (100 mg/ml). A hole about 4 mm
in diameter was drilled into the bone-marrow cavity of the
intercondylar region of the right femur of four groups of
three mature male rabbits weighing 3 to 3.5 kg. Seven
small cylinders of antibiotic-soaked porous A-W GC were
inserted, and the opening was closed with bone wax. The
groups were killed at 1, 2, 4 and 8 weeks after implantation,
and the right femur and blood were collected. Slices of
bone were obtained from the proximal, middle and distal
thirds of each femur. After removal of soft tissue and bone
marrow, the cancellous and cortical bone was pulverised,
homogenised with PBS, and centrifuged. The supernatant
uid was collected for evaluation.
Results
To obtain the absorption rate the change in weight of a
ceramic block from before soaking to after soaking was
divided by its weight before soaking. The antibiotic absorp-
tion ratio of A-W GC 70 was 76.1%, that of A-W GC 20-30
21.8% and that of HA 25.3%. The absorption ratio was thus
roughly proportional to the porosity for the A-W GC
material but not for the HA block.
In the in vitro study, the highest level of ISP was released
from A-W GC 70, and the bactericidal concentration was
maintained for 42 days. The concentration released from
HA decreased to below the detection limit after 28 days.
A-W GC 20-30 showed an intermediate release concentra-
tion (Fig. 1). The concentration of CMZ was lower than
that of ISP and decreased to below the level of detection
after 14 days for all three types of ceramic.
To calculate the release ratio, the total amount of anti-
biotic released in PBS was divided by the antibiotic soaked
up in the ceramic blocks before elution in PBS. All ceramic
blocks showed a release ratio of 90% to 100% for ISP, but
of only 40% to 50% for CMZ.
The osseous concentration of ISP in rabbit femora
decreased gradually at rst, but then increased eight weeks
after implantation. The distal part of the femur showed the
highest levels (Fig. 2) while the serum concentrations did
not reach toxic levels. By contrast, the concentration of
CMZ remained below the detection limit for eight weeks.
Formation of new bone in the centre of the cylinder was
528
K. KAWANABE,
Y. OKADA,
Y. MATSUSUE,
H. IIDA,
T. NAKAMURA
THE JOURNAL OF BONE AND JOINT SURGERY
Fig. 1a
Fig. 1b
In vitro release of ISP (a) and CMZ (b) from A-W GC 70, A-W GC 20-30 and HA.
Fig. 2
The osseous concentration of ISP in the rabbit femur. observed in the rabbit femora two months after implanta-
tion. SEM showed bone formation along the circumference
of the pores without any intervening fibrous layer (Fig. 3).
Pilot clinical study. We used these antibiotic-soaked
ceramic blocks to treat ve patients, four with infected
arthroplasty and one with osteomyelitis of the proximal
tibia. In one case, a 34-year-old-man with recurrence of
osteomyelitis had curettage of the infected focus and
implantation of antibiotic-soaked A-W GC 70 blocks into
the defect. Two years later, the border between the bone
and ceramic blocks had become almost indistinguishable
(Fig. 4). In another, a 64-year-old woman with an infected
total hip replacement had revision. A large actabular defect
was lled with antibiotic-soaked A-W GC 70 and the new
socket was xed with PMMA bone cement and a Kerboul
cross shell; there was an excellent result at 1.5 years. The
other three patients all had excellent results
Discussion
The use of antibiotic-impregnated PMMA beads for the
treatment of chronic osteomyelitis has been reported,
10-13
but the disadvantages include low biocompatibility, a very
low release ratio and possible thermal damage to the
antibiotics. Hoff, Fitzgerald and Kelly
14
reported that the
total amount of antibiotic released from PMMA bone
cement was very low, with only 5% elution of penicillin or
gentamicin from the cement.
We have shown that antibiotic-soaked porous A-W GC
blocks had good osteoconductive properties in clinical
studies of the correction of large bone defects in the iliac
crest and for the replacement of vertebrae.
15,16
Ijiri et al
6
have reported ectopic bone formation in porous A-W GC
combined with bone morphogenic protein in rats.
Our study has shown that 90% to 100% of total ISP and
529
TREATMENT OF OSTEOMYELITIS WITH ANTIBIOTI