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Journal of Antimicrobial Chemotherapy (2004) 53, 329334

DOI: 10.1093/jac/dkh032
Advance Access publication 19 December 2003

Release of gentamicin and vancomycin from temporary human hip


spacers in two-stage revision of infected arthroplasty
E. Bertazzoni Minelli1*, A. Benini1, B. Magnan2 and P. Bartolozzi2
1Department
2Department

of Medicine and Public Health, Unit of Pharmacology, Policlinico G.B. Rossi, 37134 Verona;
of Biomedical and Surgical Sciences, Orthopaedic Clinic, University of Verona, Verona, Italy
Received 4 July 2003; returned 25 July 2003; revised 10 October 2003; accepted 14 October 2003

Methods: Twenty industrially produced spacers containing gentamicin (1.9%) were utilized. Vancomycin
(2.5%) mixed with PMMA cement was used to fill holes drilled in the cement of 14 of the 20 spacers immediately before implantation. The spacers were removed from 20 patients 36 months after implantation and
then immersed in phosphate buffer at 37C for 10 days. Antibiotic concentrations were determined by fluorescence polarization immunoassay.
Results: Gentamicin and vancomycin were still present in all the spacers removed from the patients. The
release of gentamicin alone and in combination with vancomycin was in the range 0.05%0.4% of the initial
amount present, whereas the release of vancomycin was in the range 0.8%3.3%. The release kinetics
showed a similar pattern for both drugs. After a high initial release of drug, a reduced, but constant, elution
was observed over the next few days.
Conclusions: The delivery of gentamicin and vancomycin from PMMA cement was high initially, with sustained release over several months. Incorporation of vancomycin into the surface of the spacers permitted
spacers to be prepared with multiple antibiotics present and without adversely affecting the release kinetics
of the agents. The gentamicinvancomycin combination shows potential for the treatment of infection
following total hip replacement in specific patients.
Keywords: antibiotic combination, antibiotic-loaded cement, drug delivery system, surgical wound infection, topical
administration

Introduction
Total hip replacement (THR) is a successful procedure for restoring
hip function, but bacterial infection constitutes a major complication
sometimes associated with this technique. Delivery of antibiotics to
the surgical area as prophylaxis is normally used to reduce the frequency of infections in THR,1 and the use of antibiotic-containing
cement for THR is now recognized as an effective component of such
prophylaxis. A recent study that evaluated 10 950 primary THRs
demonstrated that there is a lower incidence of THR revision when
systemic antibiotic therapy is used in combination with antibioticcontaining cement.2 For the treatment of THR infection, a two-stage
protocol is commonly used, characterized by the implantation of
temporary antibiotic-loaded polymethylmethacrylate (PMMA) hip
spacers, after removal of the infected prosthesis and adequate surgical
debridement.

However, the increase in antibiotic resistance rates in bacteria


isolated from infected hip joints, particularly staphylococci,3,4 is an
emerging problem and has prompted us to investigate the usefulness
of antibiotic combinations such as gentamicin plus vancomycin in
PMMA spacers.
PMMA bone cements containing different antibiotics, such as
penicillins, fluoroquinolones and aminoglycosides are now under
investigation as carrier systems for the local delivery of antibiotics.57
However, data from the literature are difficult to compare because of
the difference in the elution methods, experimental conditions,
cements and in vivo models used. Few experimental data have been
obtained to describe the in vivo release of antibiotics beyond the
initial period of prosthesis implantation, and to the best of our knowledge no data are available on the release of antibiotics in the months
following prosthesis implantation.

..................................................................................................................................................................................................................................................................

*Corresponding author. Tel: +39-45-8027603/7611; Fax: +39-45-581111; E-mail: elisa.bertazzoni@univr.it


...................................................................................................................................................................................................................................................................

329
JAC vol.53 no.2 The British Society for Antimicrobial Chemotherapy 2003; all rights reserved.

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Aim: Evaluation of the delivery of gentamicin and vancomycin from polymethylmethacrylate (PMMA) spacers
before and after implantation for the treatment of total hip replacement infections.

E. Bertazzoni Minelli et al.


Patients

In a preliminary in vitro study, we observed that vancomycin was


released poorly from PMMA test specimens; and that this release was
further decreased by the presence of gentamicin.8 Therefore, in this
study we placed vancomycin-containing PMMA cement into holes
drilled in the surface of industrially produced spacers impregnated
with gentamicin to evaluate: (i) whether spacers removed after prolonged implantation are still capable of releasing antibiotics from
PMMA cement; and (ii) the release rates of gentamicin and vancomycin alone and in combination from PMMA cements.

Patients and methods


Temporary hip prostheses (spacers)
The spacers loaded with gentamicin (n = 20) were commercially available
products (Spacer-G, Tecres SpA, Verona, Italy) resembling hip prostheses
in shape and prepared as follows: 1.9 g of gentamicin powder (Eu. Ph.
grade) was mixed with 100 g of PMMA polymer powder (Cemex,
Tecres, Verona) in a plastic container. The liquid monomer (35 mL) was
then added and an exothermic polymerization reaction occurred yielding
solidification over a period of 10 min. Before solidification, the cement
mixture was placed in a mould under aseptic conditions. After 1 h the
mould was disassembled and the spacer surface sterilized with ethylene
oxide. The weight of the spacers (including the central stainless steel
cylindrical bar) was 177.5 2.1 g with a surface area of 165180 cm2.

Spacers loaded with the antibiotic combination


Vancomycin-loaded cement was prepared by mixing 40 g of powdered
cement polymer (Cemex, Tecres) and 1 g of vancomycin (Vancocin, Eli
Lilly, Milan, Italy) in a plastic container, after which 35 mL of liquid
monomer was added. After careful mixing with a metal spatula, the
cement mixture was added to 1718 holes (1012 mm diameter, 23 mm
deep) drilled immediately before implantation on the surface of the spacers (Spacer-G) as shown in Figure 1. The amount of cement utilized in
each prosthesis was 67 g, corresponding to 150170 mg of vancomycin.
Of the 20 spacers, 14 were used for the combination with vancomycin.

Antibiotic determination
Elution of antibiotics.The spacers were immersed in Pyrex tubes with
500 mL of phosphate buffer [0.2 M, pH 8.0, phosphate buffer (PB)] at
37C for 10 days. The PB was removed and replaced with the same
volume of fresh PB after 1, 3 and 10 days of immersion. The removed
buffer was subdivided into small aliquots and frozen at 24C.
The PB samples from each prosthesis were analysed in the same
experiment. One non-implanted spacer with gentamicin and one with
gentamicinvancomycin served as controls.

Fluorescence polarization immunoassay


Concentrations of gentamicin and vancomycin in the PB samples were
determined by fluorescence polarization immunoassay (FPIA; TDx,
Abbott). Vancomycin and gentamicin can be measured separately by the
FPIA method even when used in combination. The kits, calibrators,
controls and buffers were purchased from an Italian supplier. The method
was calibrated and applied according to the manufacturers recommendations (TDx, Abbott).12 The lowest measurable level of drug concentration was 0.27 mg/L for gentamicin and 2.0 mg/L for vancomycin,12
and all tests were carried out in duplicate.
Since we could not measure the local concentration of antibiotics
released from the spacers in vivo, we were unable to determine the drug
concentrations at the site of infection. We therefore decided to relate the
total amount of antibiotics released during 10 days to the spacer surface
area. These values were expressed in g per cm2, a non-conventional
unit, that could, in our opinion, be considered as representative of the
conditions at the implantation site and also of the residual release capacity
of the removed spacers.

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Figure 1. Spacers with gentamicin and vancomycin after surgical preparation


using the surface drill hole technique. On the right, a removed spacer; on the
left, a control spacer.

Twenty patients (13 male, seven female, aged 69.3 7.1 years, mean
S.D.) who presented with clinical evidence of THR infection were
treated with a two-stage revision procedure. Removal of the prosthesis
and debridement of the infected periprosthetic tissues was followed by
implantation of an antibiotic-loaded pre-formed PMMA spacer in the
femoral canal during the same surgical procedure. Samples of periprosthetic tissues and/or pus obtained from the patients were analysed by
routine methods in the microbiological department of our hospital. The
organisms identified were Staphylococcus aureus (4), Staphylococcus
epidermidis (2), Streptococcus -haemolyticus (1), Escherichia coli (1)
and Pseudomonas aeruginosa (1).
Six patients were implanted with PMMA spacers impregnated with
gentamicin alone (1.9% final concentration) and 14 with the combined
gentamicinvancomycin spacers.
The spacers were removed after 1236 weeks in the infection site
when the inflammation and infection parameters, erythrocyte sedimentation rate and C-reactive protein9 had returned to normal values, or, in the
absence of this, if the case was considered a failure and therefore not suitable for a prosthetic reimplantation (two patients). The spacers were
removed, without instrumentation, by the excision of the soft tissues
interfering at the proximal femur, and carefully handled taking care to
avoid mechanical damage of the cement surface. The spacers removed
from patients were rinsed with sterile water and kept in sterile conditions
at 4C until analysis. Samples of periprosthetic tissues were also obtained
during surgery for bacteriological assessment.
Following implant of the spacers, all patients were treated with a
4 week course of intravenous teicoplanin (400 mg daily) followed by a
4 week oral treatment with ciprofloxacin (1.5 g daily).10,11
The patients taking part in the study gave their informed consent, and
the protocol was approved by the local hospital ethics committee.

Gentamicin and vancomycin delivery from human hip spacers


Table 1. Release of gentamicin from control spacers and spacers
removed from patients in PB at 37C after 10 days of elution
Gentamicin

Spacer no.

Duration of
implantation
(months)

1
2
3
4
5
19
Mean S.D.

4.0
4.5
3.0
6.5
6.0
5.0
4.8 1.3

Control

aThe

total release
(g)

total
% of initial release
amount
(g/cm2)a

1350
1030
1800
1500
850
1320
1308.3 337.0

0.07
7.5
0.05
5.7
0.09
10.0
0.08
8.3
0.05
4.7
0.07
7.3
0.07 0.02 7.3 1.9

15 550

0.82

86.1

surface area of the spacers was taken to be 180 cm2.

Spacers loaded with gentamicin


The release of gentamicin from the non-implanted spacer (control)
amounted to 0.82% of the initial concentration, showing good, early
release of the antibiotic. After 1224 weeks in the hip, the removed
spacers still released appreciable amounts (8501800 g) of gentamicin, representing 0.05%0.09% of the initial total amount, and in
the range 4.710.0 g/cm2 (Table 1).
The release of gentamicin from the removed spacers was initially
high in the first 24 h of immersion, followed by low, but constant,
release over the following days (Figure 2) with a pattern of release
similar to that obtained with the control spacer.

Spacers with the gentamicinvancomycin combination


Spacers with gentamicin and surface-filled holes containing vancomycin maintained their ability to release both antibiotics. The residual
release of gentamicin from the removed spacers modified by the surface drill hole technique was higher (3889.6 1806.5 g, mean S.D.)
than that seen for spacers with gentamicin alone (1308.3 337.0 g,
mean S.D.), as shown in Tables 2 and 1, respectively. This difference is possibly due to the increase in surface area, due to drilling the
holes, and factors such as the roughness of the new surface and the
different porosity of the cement.
Vancomycin from the surface-drilled holes was released in large
amounts (24 114 g, corresponding to 16.1% of the initial amount)
from the control spacer and was still present (release 0.8%3.3% of
the initial amount) in the spacers removed several months after
implantation (Table 2).
The initial high release of vancomycin from both control and
removed spacers during the first 24 h of immersion was followed by a
lower elution over the following days and was similar to that seen
with gentamicin (Figure 2).
The surface drill hole technique for vancomycin on spacers
loaded with gentamicin resulted in equivalent release of the two antibiotics, giving 1:1 concentration ratios (Figure 3). In the first 24 h the
elution of gentamicin and vancomycin was 1285.4 563.3 g (mean
S.D.) and 1158.2 456.7 g, respectively, whereas in the following

Clinical results
Seventeen patients achieved a substantial decrease in serological
infection markers. In three cases no such decrease occurred, and this
was considered a contraindication to prosthesis re-implantation; the
surgical procedure therefore consisted of removal of the spacer. The
microorganisms responsible for the infections in these three cases
were Mycobacterium tuberculosis in one case and a multiresistant
S. aureus strain in another, whereas in the third case the pathogen was
not detected.
Samples for bacteriological examination taken in the operating
room from all re-implanted patients yielded negative findings.
The patients were assessed after the prosthesis re-implantation
procedure over a mean follow-up period of 49 months (minimum 24,
maximum 77), which revealed no clinical, radiological or laboratory
signs of recurrence of infection.

Discussion
Our results demonstrate that gentamicin and vancomycin are present
in spacers removed after prolonged periods of implantation. There
would appear to be a prompt, appreciable release of antibiotics from
spacers during the implantation period.
Antibiotic-impregnated PMMA cements are regarded as a safe
method of delivering antibiotics to the infection site, with a high
initial release of drug followed by elution that progressively
decreases over a period of time ranging from a few weeks to several
months.5,13 In this study, the drug elution kinetics from the spacers
were similar before (control) and after prolonged implantation.
The release of both gentamicin and vancomycin was biphasic,
with good, early release from the cement in the first 24 h of elution
followed by a gradual release over the following days. These results
are similar to the findings of studies on the elution kinetics of
aminoglycosides and vancomycin from acrylic bone cements.5,7 The
high initial release of antibiotics from removed spacers is thought to
be a surface mechanism resulting from mechanical erosion of the
head of the device, whereas the prolonged release relates more to the
antibiotic-loaded cement and elution system (environment).14 We
opted for surface application of the vancomycin-containing cement
on the basis of previous studies we had conducted on cylinder test
specimens.8 Vancomycin mixed with PMMA cement (Cemex)
eluted less effectively than gentamicin. These results are consistent
with the data reported by other authors7,15 utilizing different brands of
acrylic cement (Palacos and Simplex), and highlight the difficulties
in preparing cements that have good vancomycin-elution kinetics.5,13
Our results with the combination differ from those obtained by
Klekamp and co-workers,16 in that we found a further decrease in the
amount of vancomycin released from the cement in the presence of
gentamicin.

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Results

9 days the amount corresponded to 2589.3 1331.4 g and 2318.8


787.7 g, respectively.
The total release of gentamicin (23.0 11.1 g/cm2) and vancomycin (20.9 6.4 g/cm2) after several weeks in situ would appear, in
our opinion, to be enough to inhibit the common susceptible microorganisms involved in orthopaedic infections.
Although there was a wide range in the release of antibiotic
between patients, the differences were only partly related to the duration of the implantation period, as we found similar antibiotic
elution in spacers implanted for 34 months and in those implanted
for 6.5 months.

E. Bertazzoni Minelli et al.

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Figure 2. Kinetics of the release of gentamicin and vancomycin during 10 days of elution from control (a) and removed spacers (b). Values are extrapolated as elution
(g/day, mean S.D.).

The poor elution of vancomycin may depend on many factors,


such as the physicochemical characteristics of vancomycin, molecular weight, interference with cement polymers, and the stability of
the drug in the presence of heat and biological fluids, as well as the
different consistency of the cement itself (degree of porosity, roughness, size of preparation and surface area, etc.). The results reported
in the literature, however, are difficult to compare because of the different elution methods,16,17 types of cement,18 size of specimens
used1921 and the antibiotic determination methods.22
Spacers can be supplied pre-formed, but can also be prepared in
the operating room by the surgeons themselves. In this case, one has
to consider the potential disadvantages of a lack of uniform mixing of

the drug in the cement and of irregular porosity and size, resulting in
unpredictable antibiotic availability.23
The superficial application of vancomycin using the surface drill
hole technique eliminates the problem of interference between
release of gentamicin and vancomycin from PMMA cement. Moreover, the concentrations of gentamicin (1.9%) and superficial vancomycin (2.5%) enabled us to obtain an optimal ratio (1:1) in this
elution system.
The release of antibiotics from the non-implanted spacers was
much higher than that from the removed spacers. It is reasonable to
assume that the measured antibiotic amount in the spacer before
implantation would reflect the amount of drug available for release at

332

Gentamicin and vancomycin delivery from human hip spacers


Table 2. Release of gentamicin and vancomycin from control spacers and spacers removed from patients after 10 days of elution at 37C
Gentamicin

Spacer no.

Duration of
implantation
(months)

Control

5
9
4
7
3
5
3
5.5
5
3
3
6.5
9
4

1095
2725
2560
3684
3498
3636
8004
4914
3762
1854
6192
4039
4602
ND
3889.6 1806.5
14220

% of initial
amount (1.9 g)

g/cm2

release
(total g)

0.06
0.14
0.13
0.19
0.18
0.19
0.47
0.26
0.20
0.10
0.33
0.21
0.24
ND
0.21 0.11

6.1
15.1
15.5
22.3
21.2
22.0
48.5
29.8
22.8
11.2
37.5
19.5
27.9
ND
23.0 11.1

1200
4490
4990
3924
3636
3882
3372
2148
3156
2682
2694
4865
4764
ND
3484.81092.9

0.75

86.2

24114

% of initial
amount (150 mg)
0.8
3.0
3.3
2.6
2.4
2.6
2.2
1.4
2.1
1.8
1.8
3.2
3.2
ND
2.30.8
16.1

g/cm2
7.3
24.9
30.2
23.8
22.0
23.5
20.4
13.0
19.1
16.3
16.3
25.5
28.9
ND
20.96.4
146.1

ND, not determined.

Figure 3. Release of gentamicin and vancomycin from removed spacers determined


with FPIA after 24 and 240 h of elution. Values (g) are expressed as mean S.D.

the moment of the implantation. This amount is very high and can be
bactericidal, as shown by other authors with this device.22
These results enable us to assess the effects of time and implantation conditions (such as the presence of fluids, cells, pus, blood circulation, absorption, microorganisms, etc.) upon the release of
antibiotics after a prolonged implantation period in human subjects.
Moreover, in addition to the cement and drug characteristics, other

factors, such as the dynamic fluid flow system, tissue absorption


capability, limb mobility, and so on, can influence drug delivery from
cement and contribute to the wide range of residual antibiotic
recorded in different patients.
Although it is always difficult to relate the results from in vitro
studies to the situation in vivo, in two cases it was possible to determine the antibiotic levels in periprosthetic tissue samples (repair
tissue) obtained during the explantation. Drug concentrations corresponded to 12.0 1.5 g/g and 10.31.5 g/g for gentamicin and
vancomycin, respectivelyvalues higher than those determined in
the elution studies. These antibiotic concentrations obtained at the
infection site exceed the MICs of most of the common pathogens
involved in orthopaedic prosthesis infections.2426
The results of other authors2022 reporting high concentrations of
antibiotics in drainage fluids in the first few days after implantation in
patients with primary THR and in experimental studies24 with bone
cement in vivo support our conclusions.
The treatment was well tolerated and no serious adverse reactions,
including allergic reactions, were observed. In general, a low frequency of local and systemic adverse reactions has been reported
with antibiotic-containing spacers,7 and the time of recovery and
clinical outcome are satisfactory.27
Given the high clinical response rate and favourable outcomes in
this case series, spacers loaded with multiple antibiotics can be considered a valuable adjunct to the standard antimicrobial therapy regimens for revision of infected hip prostheses, and secondary or
complementary to radical debridement. The dosage and duration of
adjunctive therapy, however, are aspects that remain to be addressed
in future studies.
Our results appear to support the potential clinical efficacy of the
vancomycingentamicin combination in treating orthopaedic THR
infections in two-stage revision.

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6
7
8
9
10
11
12
13
14
15
16
17
18
20
Mean S.D.

total release
(g)

Vancomycin

E. Bertazzoni Minelli et al.


However, the therapeutic rationale for using a combination of
antibiotics depends on the susceptibility of the infecting pathogens,
and the use of vancomycin should be reserved for infections likely
to be caused by more resistant Gram-positive bacteria, such as
S. epidermidis, methicillin-resistant staphylococci, coagulasenegative staphylococci or enterococci.28,29
In conclusion, these results provide data on the release of gentamicin
from antibiotic-containing acrylic cement after prolonged implantation in a human infection site, and methods for the modification of
commercially available spacers to provide the delivery of multiple
antibiotics. Such spacers gave good release kinetics for vancomycin
and gentamicin and would appear to warrant further investigation in
the management of patients with infected THR using the two-stage
revision procedure.

Acknowledgements
The authors wish to thank Dr Roberto Biscaglia for his invaluable
collaboration and Chiara Caveiari for her excellent technical assistance.

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