Silver-Coated Tibia Prosthesis: Sarcoma Infection Study

The Journal of Arthroplasty 32 (2017) 2208e2213
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The Journal of Arthroplasty
journal homepage: www.arthroplastyjournal.org
Revision Arthroplasty
Silver-Coated Megaprosthesis of the Proximal Tibia in Patients With
Sarcoma
Jendrik Hardes, MD *, Marcel P. Henrichs, MD, Gregor Hauschild, MD,
Markus Nottrott, PhD, Wiebke Guder, MD, Arne Streitbuerger, MD
Department of Orthopaedics and Tumour Orthopaedics, Münster University Hospital, Münster, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 September 2016
Received in revised form
2 February 2017
Accepted 20 February 2017
Available online 1 March 2017
Background: Proximal tibia arthroplasty is associated with high rates of infection. This study is the
largest one that has compared the infection rates with titanium vs silver-coated megaprostheses in
patients treated for sarcomas.
Methods: The infection rate in 98 patients with sarcoma or giant-cell tumor in the proximal tibia who
underwent placement of a titanium (n ¼ 42) or silver-coated (n ¼ 56) megaprosthesis (MUTARS) was
assessed, along with the treatments administered for any infection.
Results: As the primary end point of the study, the rates of infection were 16.7% in the titanium group
and 8.9% in the silver group, resulting in 5-year prosthesis survival rates of 90% in the silver and 84% in
the titanium group. Whereas in the titanium group 37.5% of patients ultimately had to undergo amputation in the present study, these mutilating surgical procedures were only necessary in the silver group
in one patient (14.3%).
Conclusion: The use of silver-coated prosthesis reduced the infection rate in a relatively large and
homogeneous group of patients. In addition, less-aggressive treatment of infection was possible in the
group with silver-coated prosthesis.
© 2017 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords:
prosthesis-related infections
bone neoplasms
silver
implantation
proximal tibia
sarcoma
Periprosthetic infection continues to be a frequent and very
serious complication after the placement of tumor endoprosthesis
[1e4]. Particularly with proximal tibia arthroplasties, there is a
high risk of infection owing to the difficulty of muscle coverage.
Grimer et al [5] reported an infection rate of 36% before the
introduction of routine use of a gastrocnemius rotation flap, with
the rate subsequently being reduced to 12%, thanks to the better
muscle coverage. Treatment options for periprosthetic infection
range from general rinsing of the prosthesis and exchanging of the
polyethylene components to a need for secondary amputation
[2,6]. Periprosthetic infection is, thus, usually associated with a
prolonged burden of suffering for the patient and, in the worst
case, also with a permanent deterioration in quality of life.
No author associated with this paper has disclosed any potential or pertinent
conflicts which may be perceived to have impending conflict with this work. For
full disclosure statements refer to http://dx.doi.org/10.1016/j.arth.2017.02.054.
Jendrik Hardes and Marcel P. Henrichs contributed equally to this study.
* Reprint requests: Jendrik Hardes, MD, Department of Orthopaedics and Tumour
Orthopaedics, Münster University Hospital, Albert Schweitzer Campus 1, 48149
Münster, Germany.
Preventing periprosthetic infection is, therefore, of utmost
importance.
Among the metals known to have antimicrobial activity, silver
has attracted interest among many investigators because of its
excellent level of antimicrobial activity and low toxicity [7,8]. In a
previous study, we reported a reduction in the periprosthetic
infection rate when silver-coated tumor endoprosthesis was used
[9]. However, the study only included a small number of patients,
and the follow-up period was short. To the best of our knowledge,
there have been no studies investigating the use of silver-coated
tumor endoprosthesis to prevent infection.
The aim of the present study was therefore to compare the
actual infection rate among patients with titanium tumor prosthesis with the infection rate in a larger number of patients in
whom silver-coated prosthesis was implanted in the proximal tibia
as the primary implant. Possible differences in the ways in which
periprosthetic infections were treated were also documented.
Patients and Methods
A total of 98 patients were treated with a proximal tibia
arthroplasty (MUTARS; implantcast, Buxtehude, Germany).
http://dx.doi.org/10.1016/j.arth.2017.02.054
0883-5403/© 2017 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
J. Hardes et al. / The Journal of Arthroplasty 32 (2017) 2208e2213
Fifty-six patients (median age, 19 years; range, 11-78 years)
received a silver-coated prosthesis between 2005 and 2014, and
42 patients (median age, 16 years; range, 11-69 years) received a
titanium prosthesis between 1996 and 2004. Some of the patients
were included in a previous study but now have a longer follow-up
period [9]. The silver-coated prosthesis used has been described
in previous studies [7e9]. No silver coating was applied at the
articulating surfaces or prosthetic stems.
Patients who received a silver-coated prosthesis had a median
follow-up period of 38 months (mean, 17 months; range, 5-120
months) and 44 months for the surviving patients. At the final
follow-up, 46 patients had no evidence of disease, 4 patients
were alive with disease, and 5 patients had died of the disease
(median follow-up period, 16 months). One patient died due to
leukemia 79 months, postoperatively. Patients with titanium
prosthesis had a median follow-up period of 128 months (mean,
111 months; range, 3-212 months) and 146 months for the
surviving patients. At the final follow-up, 31 patients had no
evidence of disease, 2 patients were alive with disease, and
9 patients had died of the disease (median follow-up period,
51 months).
Only patients with bone or soft-tissue tumors with osseous
infiltration and stage III giant-cell tumors were included. Patients
who had previously undergone treatment with an intralesional
procedure (eg, curettage, osteosynthesis due to a pathologic fracture) were also included. In contrast, patients who had received
their current megaprosthesis after a failed megaprosthesis were
excluded. Patients with an extra-articular knee resection were
excluded. The clinical charts for the 56 patients treated with a
silver-coated megaprosthesis were assessed prospectively, with
particular attention being given to demographic data, diagnosis,
preoperative intralesional procedures, pathologic fracture, preoperative leukocyte count, adjuvant or neoadjuvant therapy, reconstruction length, operating time, muscle flaps, skin grafting, and
complications. Special emphasis was given to revision operations
due to mechanical failures (eg, change of the bushing, aseptic
loosening, periprosthetic fracture; Table 1).
Surgery was carried out in both groups in the same operating
rooms with laminar air flow; staff did not use body-exhaust suits.
Postoperatively, all patients received an intravenous thirdgeneration cephalosporin for 3-7 days, followed by oral therapy
with a second-generation cephalosporin until wound healing
was achieved. The proximal tibia arthroplasties were routinely
combined with a tube for soft-tissue refixation [10,11].
Table 1
Data of 98 Patients Who Received Proximal Tibia Arthroplasties.
Titanium (n ¼ 42)
Leukocyte count (median)
Previous intralesional
operations (%)
Diagnoses (%)
Chemotherapy (%)
Radiotherapy (%)
Median reconstruction
length, mm
Median operating time, min
Wound healing problems
Superficial (%)
Deep/hematoma (%)
Revision operations
(mechanical failure, %)
3.2
9.5
Osteosarcoma (78.5)
Ewing sarcoma (11.9)
Chondrosarcoma (4.7)
Silver (n ¼ 56)
4.6
16.1
90.5
7.1
145
Osteosarcoma (55.4)
Ewing sarcoma (19.6)
GCT (8.9)
MFH (7.1)
80.0
3.6
140
245
220
11.9
7.1
50.0
10.7
7.1
14.3
GCT, giant-cell tumor; MFH, malignant fibrous histiocytoma.
2209
An implant-associated infection was diagnosed in accordance
with the Musculoskeletal Infection Society criteria [12]. However,
using the Musculoskeletal Infection Society criteria, 2 patients
would have had no infection in the silver group (number 1 and 3 in
Table 2). Both patients had a clearly elevated C-reactive protein
level, wound secretion, and redness of the distal wound directly
over the prosthesisdbut without a clear fistula. Therefore, we
evaluated this clinical scenario in immunocompromised patients as
a periprosthetic infection. Table 2 summarizes the data for patients
with periprosthetic infection. In patients with periprosthetic
infection, curedwith no clinical signs of inflammation and negative
C-reactive protein level findingsdwas assessed by the treating
clinician at the date of the last available follow-up. Treatment for
periprosthetic infection was documented at the final follow-up.
Statistical Analysis
The primary end point of the study was periprosthetic infection
without any previous revision surgery. The secondary end point
was the outcome of treatment for any periprosthetic infection that
occurred. Event-free survival of the prosthesis relative to the
parameter of infection was assessed using the Kaplan-Meier survivorship analysis. Possible risk factors for periprosthetic infection
were screened using univariate analysis for the whole patient
group and for the titanium and silver subgroups. Comparison of the
infection rates between the silver and titanium groups was done
using the chi-square test.
Results
Statistically Significant Risk Factors for Periprosthetic Infection
Univariate analysis of the whole study group (n ¼ 98) identified
only superficial wound healing disturbances as a significant risk
factor for infection (P ¼ .04). Significant influences on the risk of
infection were noted only in the silver group, in relation to prior
intralesional surgery (P ¼ .04) and operating time (P ¼ .001). It
should be emphasized that revision surgery due to mechanical
failures, which occurred in 14.3% of cases in the silver group and
50% of those in the titanium group, did not have a significant
influence on the infection rate (Table 1).
Incidence of Periprosthetic Infection
In the titanium group, an infection rate of 16.7% (7 of 42) was
noted when the occurrence of infection was the primary end point.
In the silver group, the infection rate was only 8.9% (5 of 56). The
difference was not statistically significant (P ¼ .247; Table 3). The
5-year event-free survival rates for the prosthesis relative to
the parameter of infection were 90% (95% confidence interval [CI],
81.5-98.7) in the silver group and 84% (95% CI, 73.2-96.4) in the
titanium group. The 10-year survival rate in the titanium group was
81% (95% CI, 68.2-94.2), as only 1 patient developed an infection
after 5 years (Fig. 1; P ¼ .415).
Overall, 7 of the 56 patients in the silver group (12.5%) developed periprosthetic infections; 2 patients became infected after
revision surgery after mechanical failure of the prosthesis (Table 2).
In the titanium group, 1 patient developed a periprosthetic infection after revision surgery (which was required in 50% of patients)
due to a mechanical failure of the prosthesis, resulting in an overall
infection rate of 19.0% (8 of 42).
None of the patients who died of disease during a median of
16 months postoperatively had periprosthetic infections in
the silver group, whereas 2 patients (patients 12 and 13) with
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J. Hardes et al. / The Journal of Arthroplasty 32 (2017) 2208e2213
Table 2
Characteristics of the 15 Patients With Periprosthetic Infection.
Type of Revision
Patient Age (y) Silver
Interval to Infection Any Revision Surgery
Surgery
Due to Mechanical
Coating After Primary
Failure Before Infection
Operation (mo)
Interval Between
Revision Surgery
and Infection (mo)
Fistula Isolated Microorganism C-Reactive Protein
Level (mg/dL)
1
2
3
4
74
38
16
60
Yes
Yes
Yes
Yes
6
8
3.5
77
No
No
No
Yes
d
d
d
66
No
No
No
No
No
MRSA
No
P. aeruginosa
5
63
Yes
69
Yes
2
Yes
S. caprae
6
18
Yes
19
No
d
d
d
Change of the femur
stem due to
periprosthetic
fracture
Change of the femur
stem due to aseptic
loosening
d
d
No
7
8
9
10
67
16
15
10
Yes
No
No
No
9
1
47
1
No
No
No
No
d
d
d
d
d
d
d
d
No
Yes
No
No
11
12
13
14
15
14
16
21
60
14
No
No
No
No
No
71
18
5
18
99
No
No
No
No
Yes
d
d
d
d
Change of the bushing
d
d
d
d
3
No
No
No
No
No
S. caprae, Streptococcus
agalactiae
S. epidermidis
No
S. pyogenes
S. epidermidis, MRSA
(at second infection)
S. aureus
S. epidermidis
S. haemolyticus
S. epidermidis, E. faecalis
S. lugdunensis
5.1
20.2
12.4
15.6
0.5
28.7
8.5
25.7
36.5
4.8
36.8
1.5
0.5
14.7
17.0
MRSA, methicillin-resistant Staphylococcus aureus; P., Pseudomonas; S., Staphylococcus; E., enterococcus.
titanium prosthesis developed periprosthetic infections in the first
2 postoperative years and ultimately died of the disease.
Time to Periprosthetic Infection
In the titanium group, periprosthetic infection led to a surgical
intervention at a median of 18 months (range, 1-71 months) after
implantation of the prosthesis, without any previous revision
surgery. In the silver group, periprosthetic infection occurred at a
median of 8 months (range, 3.5-19 months) after primary
implantation of the prosthesis in 5 patients without any previous
revision surgery (Table 2). In 2 patients with periprosthetic infection after mechanical revision surgery, infection developed
2 months and 66 months postoperatively, respectively. In the
titanium group, 1 patient developed infection after revision surgery
3 months postoperatively. Overall, 9 of 12 (75%) periprosthetic
infections in the 2 groups occurred within the first 2 postoperative
years, if no later revision surgery due to mechanical failure was
necessary.
Although 3 of the 8 patients in the titanium group (37.5%)
ultimately had to undergo amputation due to an infected proximal
tibia arthroplasty, this type of mutilating surgical procedure was
only necessary in 1 patient in the silver group (14.3%; Table 3). It
must be borne in mind here, however, that 2 of the 3 amputations
in the titanium group were carried out in patients who had
previously undergone radiotherapy, resulting in poor soft-tissue
conditions. Two-stage revision surgery with a temporary
antibiotic-impregnated cement spacer was ultimately successful in
4 of 8 patients in the titanium group (50.0%), but this was necessary
in only 1 patient (14.3%) in the silver group (Table 3). In the silver
group, by contrast, antibiotic treatment alone (n ¼ 1, 14.3%,
follow-up 72 months) and minor revision surgery (n ¼ 2, 28.6%,
follow-up 2 and 82 months, respectively) with 1-stage exchange of
the prosthetic body without removal of the stems were ultimately
successful.
Discussion
Table 3
Infection Rates and Ultimately Successful Treatments for Infection.
Patients with infection as a
primary end point (n)
Infection rate in patients with
no revision surgery (%)
Patients with infection over the
whole study period (n)
Secondary infection rate (%)
Antibiotic treatment, n (%)
One-stage prosthesis exchange
without stem removal, n (%)
Two-stage prosthesis exchange
without stem removal, n (%)
Two-stage exchange of whole
prosthesis, n (%)
Explantation of prosthesis and
permanent spacer, n (%)
Amputation, n (%)
Treatment of Periprosthetic Infection
Silver
(n ¼ 56)
Titanium
(n ¼ 42)
Total
5
7
12
8.9
16.7
11.2
7
8
15
12.5
1 (14.3)
2 (28.6)
19.0
0
0
15.3
1 (7.1)
2 (13.3)
0
1 (12.5)
1 (6.7)
1 (14.3)
4 (50)
5 (33.3)
2 (28.6)
0
2 (13.3)
1 (14.3)
3 (37.5)
4 (26.7)
Periprosthetic infection of megaprosthesis continues to be a
common and serious complication in orthopedic oncology [2,3,13].
In a systematic review of the literature including a total of 4838
patients with a tumor endoprosthetic reconstruction of the lower
extremity, Racano et al [13] reported periprosthetic infection in
10% of cases. However, the authors do not provide any data on the
infection rate relative to the site of endoprosthetic arthroplasty.
However, it is well known that patients with proximal tibia
arthroplasties, in particular, are at high risk for periprosthetic
infection, with rates ranging from 14% to 36% [5,14,15].
The high infection rates reported with the use of tumor endoprosthesis in the area of the proximal tibia emphasize the importance of reducing the infection rate even further. Silver has been
used as an antimicrobial agent for centuries [16]. It has been used
successfully in the topical treatment of burns and chronic wounds
and as a coating for medical devices [17]. However, negative results
with silver-coated devices have also been reported [18e20].
J. Hardes et al. / The Journal of Arthroplasty 32 (2017) 2208e2213
2211
Fig. 1. Kaplan-Meier survival curve, showing infection-free survival of the primary implant in the silver and titanium groups.
The potential benefits of silver-coated orthopedic hardware are still
as yet unproved [17].
Silver coating of orthopedic megaprosthesis was first reported
by our group in an animal trial [7] and in humans [8]. We also
reported that there was a lack of toxicologic side effects with silvercoated megaprosthesis [8]. Glehr et al [21] confirmed these results
in patients treated with a silver-coated prosthesis but documented
local asymptomatic argyria in 23% patients.
Studies dealing with silver-coated megaprosthesis have mainly
used them in cases of previous periprosthetic infection or other
revision surgery and not as the primary implant [21,22]. Glehr et al
[21] reported an infection rate of 12.5% in 32 patients treated with a
silver-coated MUTARS tumor endoprosthesis. However, 28 patients
had a previous periprosthetic infection. In a recently published
matched control study, Wafa et al [22] compared infection rates
between an uncoated tumor prosthesis (Stanmore Implants) and a
silver-coated implant (Agluna, Stanmore Implants). In this study
as well, however, most of the patients were treated with a
silver-coated prosthesis for 1-stage or 2-stage revision after periprosthetic infection. The key message of the study was the significantly lower (P ¼ .05) reinfection rate after a 2-stage revision
with silver-coated implants (15%) in comparison with uncoated
implants (42.9%).
To the best of our knowledge, the first and still the only study
dealing with silver-coated megaprosthesis in the proximal femur
and proximal tibia to prevent periprosthetic infection was published in 2010 by our own group [9]. In that study, the infection
rate with 51 silver-coated prostheses was compared with the data
for 74 patients in whom uncoated titanium megaprostheses were
implanted. Periprosthetic infection was observed in 5.9% patients
who received silver-coated prostheses in comparison with 17.6%
patients treated with a titanium prosthesis (P ¼ .062). Specifically,
for patients with a proximal tibia arthroplasty, the overall infection ratedinfection of the primary implant or infection after
revision surgery of the primary implant due to mechanical
failuredwas reduced from 17.1% in the titanium group to 6.9% in
the silver group (P ¼ .289). However, both due to the short
follow-up period and also the small numbers of patients, the
results only provide initial evidence of the potential effectiveness
of silver coating.
Within a period of 6 years, our sarcoma center has succeeded
both in substantially increasing the number of patients receiving
silver-coated proximal tibia arthroplasties for a rare tumor location
and also in achieving a much longer follow-up. Although the overall
infection rate increased to 12.5% in the silver group in comparison
with our 2010 report [9], it is markedly below the value of 19% in
the titanium group. In comparison, Puchner et al [15] noted an
overall infection rate of 24.7% with uncoated proximal tibia
arthroplasties. With regard to the infection rate in the primary
implant alone (without including revision operations), silver
coating can lead almost to a halving of the figure, at 8.9% vs 16.7% in
the titanium group. By comparison, Puchner et al [15] noted an
infection rate in 12.3% of primary implants that were not silver
coated. Wafa et al [22] reported on 18 patients with silver-coated
proximal tibia arthroplasties. However, only 9 patients underwent primary implantation, whereas the remainder received
2212
J. Hardes et al. / The Journal of Arthroplasty 32 (2017) 2208e2213
silver-coated prostheses during 1-stage or 2-stage exchanges.
Infection occurred in 1 of 9 patients (11.1%).
Although it was not possible to demonstrate a statistically
significant reduction in the periprosthetic infection rate, the present study confirms our initial results from 2010 indicating that
silver-coated tumor prostheses are apparently able to reduce the
infection rate. But why has the decline in the infection rate not been
clearer? In our view, this may be explained by the fact that active,
free, silver ions bind to proteins and become inactivated [23]. This
means that the surgeon has to avoid hematoma and poor muscle
coverage of the prosthesis, resulting in superficial wound healing
problems, which can result in bacterial colonization. In these areas,
the silver coating is unable to develop an adjuvant effect. The silver
coating can inhibit bacterial colonization of the prosthetic body,
with subsequent periprosthetic infection, and can kill bacteria near
the prosthesis. In our view, the development of periprosthetic
infection cannot normally be attributed to bacterial resistance to
the silverdalthough this is in principle possible with Gramnegative bacteria [16]dbut instead results from inactivation of
the free silver ions owing to binding to proteins.
Revision surgery for a tumor endoprosthesis may also be associated with a not-inconsiderable risk of periprosthetic infection
[4,15], with bacterial contamination taking place during the revision procedure. Puchner et al [15] reported that 10 of 81 patients
(12.3%) developed periprosthetic infection with proximal tibia
arthroplasties after revision surgery performed for other reasons.
Overall, 10 of 20 infections (50%) occurred after revision surgery. In
the present study, previous revision surgery might have been
responsible for periprosthetic infection in only 3 patients (2 in the
silver group and 1 in the titanium group) among 15 patients with a
periprosthetic infection (20%). A significant risk factor is not
evident in the present study, but it cannot of course be excluded in
the future.
In the present study, 75% of periprosthetic infections in both
groups occurred within the first 2 postoperative years. However, it
is possible that further periprosthetic infections may become
clinically apparent in the silver group later, as the silver helps to
control infection but may dissociate from the prosthetic surface
over time. In the case of periprosthetic infection, silver ions will go
into solution, since the surrounding tissue has a negative pH value.
If the infection cannot be controlled, the silver ions can in principle
degrade completely away from the prosthetic surface, and
the infection will become clinically apparent. In clinical reality,
however, periprosthetic infection in the titanium group led to
surgical interventionsda median of 18 months after implantation
of the prosthesis without any previous revision surgery. In contrast,
periprosthetic infection in the silver group occurred earlier after
primary implantation of the prosthesis. We would, therefore,
assume that in spite of the shorter follow-up period in the silver
group, no further substantial change can be expected in the
groupdunless further revision operations become necessary due to
mechanical complications.
In addition to the reduction in the rate of periprosthetic infection as the primary end point of the study, attention also needs to
be given as a secondary end point to the implications of infections
that occur nevertheless. Despite the small group of patients, at least
a trend can be noted toward less-invasive treatment measures in
the silver group in the presence of periprosthetic infectiondsuch as
debridement, antibiotics, irrigation, and retention and 1-stage
revision. In the aforementioned study, Wafa et al [22] also
showed that in cases of periprosthetic infection of uncoated tumor
prosthesis, 1-stage exchanges of the prosthesis for a silver-coated
one were only followed by reinfection in 2 of 39 patients (5.1%).
By contrast, repeat infections occurred in 5 of 40 patients (12.5%)
with 1-stage exchanges of the prosthesis for an uncoated one. There
are some studies in the literature that report a high percentage of
secondary amputations due to periprosthetic infection, in 19%e46%
of cases, with the highest rate in proximal tibia arthroplasties
[2,6,14]. Whereas in the titanium group 37.5% of patients ultimately
had to undergo amputation in the present study, these mutilating
surgical procedures were only necessary in the silver group in one
patient (14.3%).
The most important limitation of the present study is the
retrospective nature of the titanium group, whereas the data for the
silver group were collected prospectively. The patient numbers are
still small, of course, but in our opinion, they are large enough for
such a rare procedure. The advantage of this study lies in the fact
that an implant system was used that has been used over many
years, always in the same surgical setting and only by a few
experienced surgeons.
Conclusions
Silver represents a reasonable addition to the armamentarium
for the treatment of periprosthetic infection. However, it would be
unrealistic to assume that periprosthetic infection can be
completely avoided, since active, free, silver ions can only exert
their effects in close proximity to the prosthetic surface. In cases of
periprosthetic infection, despite the use of silver-coated prosthesis,
minor revision surgery or even adequate antibiotic therapy alone
may be successful. In the future, studies with larger numbers of
patients and longer follow-up periods are warranted to confirm
these results.
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