86 The Open Orthopaedics Journal, 2011, 5, 86-91
1874-3250/11 2011 Bentham Open
Diagnosis and Management of Infected Total Knee Arthroplasty§
Niraj V. Kalore1 Terence J. Gioe1 and Jasvinder A. Singh*,1,2,3
1Minneapolis VA Medical Center and University of Minnesota, Minneapolis, USA
2Mayo Clinic College of Medicine, Rochester, MN, USA
3Birmingham VA Medical Center and University of Alabama, Birmingham, AL, USA
Abstract: Infection following total knee arthroplasty can be difficult to diagnose and treat. Diagnosis is multifactorial and
relies on the clinical picture, radiographs, bone scans, serologic tests, synovial fluid examination, intra-operative culture
and histology. Newer techniques including ultrasonication and molecular diagnostic studies are playing an expanded role.
Two-stage exchange arthroplasty with antibiotic cement and 4-6 weeks of intravenous antibiotic treatment remains the
most successful intervention for infection eradication. There is no consensus on the optimum type of interval antibiotic
cement spacer. There is a limited role for irrigation and debridement, direct one-stage exchange, chronic antibiotic
suppression and salvage procedures like arthrodesis and amputation. We examine the literature on each of the diagnostic
modalities and treatment options in brief and explain their current significance.
Keywords: Infection, Diagnosis, management, total Knee arthroplasty, knee replacement, periprosthetic infection.
end-stage knee arthritis that is associated with significant
improvements in pain, function and quality of life. Outcomes
following TKA are excellent in the majority of the patients.
Perhaps the most challenging complication following TKA
is periprosthetic infection (PPI). PPI occurs in 1-2 % of
primary TKAs and 3-5 % of revision TKAs . It is also
possible that certain aseptic TKA failures may actually not
be truly aseptic but secondary to undiagnosed periprosthetic
infections. An improvement in our ability to diagnose TKA
infections with more sensitive diagnostic algorithms and
tests could reveal more PPI than currently estimated . In
this paper, we review the current literature regarding
diagnosis and management of PPI in TKA.
Total knee arthroplasty (TKA) is a common surgery for
CLASSIFICATION AND PATHO-
PPI in TKA. A commonly accepted definition was proposed
by Ghanem et al. as meeting one of the following three
abscess or sinus tract communicating with the joint
There is currently no clear consensus on the definition of
a positive pre-op culture of aspirate on solid medium ;
>2 positive intra-op culture of same organism, or one
positive culture on solid medium plus gross
*Address correspondence to this author at the University of Alabama,
Faculty Office Tower 805B, 510 20th Street S, Birmingham, AL 35294,
USA; Tel: 205-934-8158; Fax: 205-966-9685;
§The views expressed in this article are those of the authors and do not
necessarily reflect the position or policy of the Department of Veterans
Affairs or the United States government.
intracapsular purulence or abnormal histological
findings (>5 PMNs/HPF) .
classified TKA infections into four types: (1) acute post-
operative (?4 weeks post-op); (2) late chronic (indolent
infection >4 weeks post-operative); (3) acute hematogenous
(acute onset at the site of a previously well-functioning
prosthetic joint); and (4) positive intra-operative culture
(clinically unapparent infection with two or more positive
Based on the timing of the TKA infection, Cui et al. 
formation of biofilms on the implant surfaces. Biofilm is an
aggregate of microorganisms in which cells are adherent to
each other and/or to a surface. Bacteria secrete extracellular
polymeric substance (EPS) which forms the basic
architecture of biofilms . These adherent bacterial cells
are frequently embedded in small clusters within the EPS
matrix, often forming favorable environments which can be
very heterogeneous in the same biofilm. EPS isolates
bacteria from the surrounding environment and help bacteria
survive in the biofilm. EPS also protects bacteria from host
defenses resulting in an ineffective inflammatory response,
which in turn causes more damage to the host and aids the
growth of bacteria by providing additional nutrients from
damaged cells [6, 7]. Antibiotics are ineffective in the non-
physiologic environment of the biofilm due to poor
penetration. The biofilm itself is responsible for many of the
challenges underlying diagnosis & management of PPI in
TKA [8, 9].
TKA infections, like other PPI, are mediated by the
CLINICAL FEATURES OF INFECTED TKA
symptoms of joint infection or more insidiously, especially
beyond the early post-operative period. The clinical signs
and symptoms of infected TKA include persistent pain,
swelling, erythema, local warmth or drainage after TKA.
Infected TKA can present acutely with obvious signs and
Diagnosis and Management of Infected Knee Arthroplasty The Open Orthopaedics Journal, 2011, Volume 5 87
Examination findings include tenderness and limitation of
range of motion and/or painful range of motion of the joint
that is new or disproportionate to the expected recovery from
the surgery. However, PPI in TKA can present with few, if
any, of these symptoms and signs.
DIAGNOSIS OF INFECTED TKA
diagnosis challenging. Because there is no single test that
can diagnose PPI in TKA, the diagnosis is typically based on
a combination of clinical, serologic, imaging and laboratory
The presentation of PPI in TKA can be varied and the
TKA infections and affords little diagnostic help.
Erythrocyte sedimentation rate (ESR) is a nonspecific
indicator of inflammation that peaks 5-7 days after TKA
surgery and usually returns to baseline in 3 months to 1 year.
Continued elevation of ESR after TKA is suggestive of
infection. With an abnormal level defined as >30 mm/hr 3
months to 1 year after TKA, ESR has a sensitivity of 82%
and specificity of 87% in diagnosing TKA infections .
Based on receiver operating curves, a cutoff level of 22.5
mm/hr 3 months to 1 year after TKA would have sensitivity
of 93% and specificity of 83%. However, ESR is elevated in
both inflammatory conditions and infections in locations
other than infected TKA (10), and thus specificity is low.
The peripheral leukocyte count is frequently normal in
produced by hepatocytes in response to infection,
inflammation or acute injury. CRP levels peak 2-3 days after
surgery and return to baseline in 14-21 days. With an
abnormal level defined as >10 pg/mL 14-21 days after TKA,
CRP has sensitivity of 93% and specificity 83% . Based
on receiver operating curves, a cutoff level of 13.5 pg/ml 14-
21 days after TKA, would have sensitivity of 91% and
specificity of 86% .
C - reactive protein (CRP) is an acute phase reactant
TKA is serum interleukin-6 (IL-6) level. IL-6 is cytokine
that stimulates the liver cells to produce acute phase
reactants like CRP. Serum IL-6 levels can be measured by a
simple ELISA test. IL-6 levels peak 6-12 hrs after surgery
and return to baseline in 48-72 hrs. With a cut-off defined as
<10 pg/mL, IL-6 level has a sensitivity of 100% and a
specificity of 95% in diagnosing TKA infections .
However, more studies are needed to examine its clinical
utility. Other conditions causing elevated serum IL-6 are
chronic inflammatory diseases like rheumatoid arthritis,
previous antibiotic treatment prior to surgery, multiple
sclerosis, Pagets disease of bone and acquired immune
deficiency syndrome. IL-6 may prove to be useful in early
post-operative diagnosis of infection and pre-operative
diagnosis prior to revision total knee arthroplasty .
A new investigational test used in the diagnosis of PPI in
surgeons in diagnosing PPI in TKA. Radiographs showing
periosteal new bone formation, scattered foci of osteolysis
and subchondral bone resorption are highly suggestive of
infection, but are typically late findings. Periprosthetic
radiolucency may be unrelated to a septic process and serial
Several imaging modalities are available to assist
radiographs help rule out other conditions like wear,
osteolysis or fracture.
PPI in TKA, because their results are not impacted by the
presence of metallic implants. Triple-phase technetium-99
bone scan (TPBS) is a simple, widely available test which is
quite sensitive in detecting bone remodeling changes around
TKA components; however, it cannot distinguish between
aseptic loosening and TKA infection . TPBS does have a
high negative predictive value, however, making it a useful
initial screening test [13, 14].
Nuclear medicine tests may be helpful in the diagnosis of
TPBS, but has low specificity. Combining an indium111
WBC scan with a technetium 99m bone scan improves the
accuracy for detecting deep infection up to 95% .
WBC imaging with indium-111 is more sensitive than
(FDG-PET) scans have been recently evaluated for diagnosis
of PPI in TKA. Inflammatory cells express more glucose
transporters, resulting in intracellular accumulation of
deoxyglucose which cannot be metabolized by the cell and
can be identified by PET imaging. One study found 91%
sensitivity and 72% specificity for diagnosis of TKA
infections . The advantages of a PET scan are that only
one injection is required and the results are available within
4 hrs. However, it is not widely available, is expensive and
can produce false positives secondary to uptake of FDG in
aseptic inflammation around implants .
Fluro-deoxyglucose positron emission tomography
accuracy of the TPBS, WBC imaging, and FDG-PET scan
was 81%, 84% and 83% respectively .
In their meta-analysis, Reinartz et al. reported that the
JOINT FLUID AND TISSUE ANALYSIS
case of suspected PPI in TKA. The knee aspirate should be
sent for cell count and differential, culture and crystal
analysis. Use of antibiotics prior to aspiration can lead to
false-negative results. In the setting of a 2-stage exchange
arthroplasty, studies have shown that delaying knee
aspiration at least 4 weeks from the discontinuation of
antibiotic therapy can significantly lower the false-negative
rate [18, 19]. The synovial fluid (SF) leukocyte count and
differential are two helpful parameters to examine. With an
abnormal value defined as >1100 WBC/ml, the SF leukocyte
count has a 91% sensitivity and 88% specificity in
diagnosing PPI in TKA . With an abnormal value defined
as >64%, SF neutrophil percentage is 95% sensitive and 94%
specific in diagnosing TKA infection . If both SF
leukocyte count and neutrophil percentage, are below their
cutoff values, then infection
(NPV= 98.2%). If both tests are above their cutoff values,
then the likelihood of infection is 98.6 % (PPV= 98.6%) .
When SF neutrophil percentage and the C-reactive protein
level are less than the cutoff values of 64% and 10 mg/L,
respectively, the presence of periprosthetic infection is very
Knee aspiration is a simple test recommended in every
is highly unlikely
tissue obtained from the joint capsule or periprosthetic
membrane has been used to help intra-operative decision
making. The exact histologic critera used for diagnosis of
infection are not yet uniform . However, one commonly
Intra-operative frozen section looking for neutrophils in
88 The Open Orthopaedics Journal, 2011, Volume 5 Kalore et al.
quoted study  found that with abnormal frozen section
defined as >5 neutrophils /5 separate high power fields
(500x), excluding surface fibrin and inflammatory exudates,
the sensitivity is 25% and specificity is 95%. Frozen section
is less sensitive at the time of reoperation than in the setting
of primary arthroplasty .
helpful. Morgan et al.  found that intra-operative Gram
staining has poor sensitivity (27%) and a poor negative
predictive value, and its results did not alter the treatment of
any patient undergoing revision TKA because of a suspected
Gram staining of intra-operative specimens is not very
considered the gold standard for PPI diagnosis. However,
nearly 10 % of infections may be culture-negative.
Conventional culture results may be delayed for 2-5 days
and contamination of samples causes false positive results
Intra-operative cultures have traditionally been
withheld until cultures are obtained, multiple cultures
including anaerobic cultures be obtained from different sites
during surgery, fluid be injected directly into culture tubes
instead of using swabs , strict aseptic protocol be
maintained, and only > 2 positive cultures of same organism
be regarded as a positive result .
It is recommended that pre-operative antibiotics be
MOLECULAR DIAGNOSTIC TESTS
armamentarium for diagnosis of PPI. Polymerase chain
reaction (PCR) amplifies strains of bacterial DNA to allow
detection of infectious bacteria. PCR can detect non-viable
bacteria that do not grow on culture as well as bacteria lysed
by ultrasonication, with results within 12-13 hrs. Results of
the PCR are unaffected by the administration of antibiotics.
However, PCR is exquisitely sensitive; co-amplification of
contaminating DNA causes false positives mandating strict
aseptic measures. The specific nature of infection can only
be identified by comparing DNA sequences with global
sequence databases and PCR results are not dependable in
polymicrobial infections [23, 24].
Molecular diagnostic techniques are new tools in the
fluorescent- labeled oligonucleotide probes that hybridize to
their intracellular targets permitting single-cell identification
and quantification by either epifluorescence microscopy or
flow cytometry. Complex cell envelopes of some bacteria
may inhibit penetration of the probes. Autofluoresecence of
some organisms make interpretation difficult .
FISH (Fluorescent In Situ Hybridization) utilizes
2-3 hrs . The technique is relatively inexpensive
(excluding the microscope itself) and does not require strict
aseptic protocol. Immunofluorescence microscopy can
distinguish between biofilm organisms (large aggregates)
and contaminants (single dispersed cells/ small aggregates)
by direct visualization.
Immunofluorescence microscopy can give results within
surface epitope (SSPA). SSPA-ELISA test can detect
antibodies to this epitope. This is a very sensitive and
specific test in the detection of staphylococcal biofilms (p <
Biofilm cells of S. aureus and S. epidermidis produce a
dislodge by scraping. Ultrasonication uses ultrasound energy
to mechanically disrupt biofilm on retrieved implants in
revision surgery. This increases the number of bacteria
isolated on culture or other techniques enabling the detection
of bacteria that would have been missed by conventional
tissue culture [5, 26]. Sonicate cultures have 78.5%
sensitivity and 98.8% specificity as compared to 60.8% and
99.2% for tissue culture. Improvement in sensitivity is
particularly notable in patients who have been on antibiotics
within 2 weeks of surgery [5, 26].
Biofilms are known to be tenacious and difficult to
bacteria and make them non-viable on cultures. PCR can be
used to detect these lysed bacteria thereby further improving
microbiological diagnosis from retrieved implants [5, 26].
Ultrasonication for a longer time (30 min) can lyse the
MANAGEMENT OF INFECTED TOTAL KNEE
requires more surgical and inpatient time than non-infected
revision TKA, and is more prone to failure. The goal of
treatment is eradication of the infection and maintenance of a
pain-free, functional joint .
Treatment of infected TKA is complex, expensive,
with component retention (with or without polyethylene
exchange), one-stage or two-stage exchange, antibiotic
suppression, resection arthroplasty and rarely arthrodesis or
Treatment options include irrigation and debridement
(with or without polyethylene exchange), is suitable for
selective cases where infection occurs within the first 4-6
weeks of primary TKA or in the setting of acute
hematogenous Gram positive infection with stable implants
[28, 29]. Polyethylene liner exchange is preferred as it
allows better debridement of the posterior synovium and
eliminates biofilm on the polyethylene . Success of open
debridement with polyethylene exchange is limited (23 to
28% success rate) by persistence of organisms on retained
implants, cement and dead bone . Factors associated
with success include early debridement, absence of sinus
formation, multiple debridements rather than a single
debridement, gram positive infection, and use of 4-6 weeks
of sensitive systemic antibiotics [32-34].
Irrigation and debridement with component retention
Insall, has been the most successful treatment alterantive for
infected total knee arthroplaty (91% success rate for
eradicating infection) . The first stage involves removal
of all total knee components and cement, thorough
debridement and irrigation followed by implantation of an
antibiotic cement depot in the joint. The antibiotic cement
depot releases antibiotics locally at high concentrations
helping to eradicate the infection. This is supplemented by
intravenous antibiotics per sensitivity for six to eight week
period. If there are no clinical signs of infection and the
sedimentation rate and CRP levels are declining, a decision
for second stage reimplantation is made. A more extensile
approach like quadriceps snip, VY-quadricepsplasty or tibial
tubercle osteotomy may be necessary because of scarring
between stages . The second stage involves removal of
the cement depot, thorough debridement and irrigation and
Two-stage exchange arthroplasty, first described by
Diagnosis and Management of Infected Knee Arthroplasty The Open Orthopaedics Journal, 2011, Volume 5 89
implantation of appropriate new total knee components with
improved the chances of success in treatment of infected
arthroplasties . Antibiotics suitable for this purpose
should be heat- stable, broad-spectrum, bactericidal at low
concentrations, at low risk
hypersensitivity, and available in powder form with low
serum binding, which facilitates release from the spacer at
high concentrations for prolonged periods. Antibiotics in
common usage for this
vancomycin, tobramycin and cefuroxime.
Use of antibiotic-impregnated cement has greatly
of allergy /delayed
purpose are gentamycin,
dose, the combination of antibiotics used, and the type of
cement . The recommended doses of antibiotics are 2-5
times higher for therapeutic use than for prophylactic use
. Most antibiotics have a high initial release followed by
a reduced, constant, elution over the next several days.
Antibiotic elution from PMMA depends on the antibiotic
the amount of antibiotic initially released and prolong the
duration of the bactericidal level of the antibiotic. However,
higher doses of vancomycin may not increase the in vivo
elution characteristics [39,
synergistically increase the release of vancomycin in the
cement mix by “passive opportunism”- a phenomenon that
one antibiotic dissolves, resulting in increased porosity, it
allows increased elution of the other antibiotic .
Tobramycin elutes better from Palacos cement (Heraceus
Medical, Hanau, Germany; marketed by Zimmer Inc.,
Warsaw, IN) than from Simplex cement (Stryker,
Kalamazoo, MI). Premixed antibiotic cements have low dose
of antibiotics . Hand mixing without a vacuum results in
increased porosity, which increases antibiotic elution.
A higher dose of gentamicin or tobramycin will increase
40]. Tobramycin may
antibiotic spacer to be used. Static spacers, first described by
Cohen,  were historically preformed in the shape of a
hockey puck that was inserted loosely in the joint space after
the cement was polymerized. This technique was associated
with spacer subluxation and secondary bone loss and erosion
of quadriceps mechanism. This led to the development of the
molded arthrodesis block. In this technique cement is placed
in the knee joint in a doughy state so that it conforms to the
shape of the bone ends and stabilizes the knee joint by
interdigitation. Static spacers have infection eradication rates
approximating 88% [43-47]. Static spacers restrict knee
movement between stages, distract & preserve the joint
space, provide stability to the limb and give rest to the
infected joint. Problems with static spacers include
contracture of the extensor mechanism, collateral ligament
shortening, arthrofibrosis, tibial and femoral bone loss
(incidence-60%) and potential difficulty with secondary
exposure for reimplantation [45,48].
There is an on-going controversy over the optimal type of
stages and cause less periarticular scarring resulting in easier
surgical exposure at reimplantation. They result in
marginally better post-operative ROM and function as
compared to static spacers, though statistical significance is
not reached . Infection eradication rates with articulating
spacers approximate 92% [44, 45, 49-57].
Articulating spacers maintain joint motion between
components or recycled components) or cement on cement.
Cement on cement articulating spacers can be pre-formed or
manufactured in the operating room with cement molds or
can be hand-made. Articulating spacers reduce bone loss as
compared to static spacers [45, 48]. Problems with
articulating spacers include risk of cement fracture, spacer
dislocation, and potential problems with wound healing .
Articulating spacers can be metal on polyethylene (new
area for antibiotic elution, though these are expensive, take
more OR time and are prone to cement fracture and
formation of cement debris . Preformed cement spacers
(Interspace Knee, Exactech, Gainesville, F) deliver a lower
dose of single antibiotic . The prosthesis of antibiotic
loaded acrylic cement (PROSTALAC) (Depuy, Warswaw,
IN) includes a bicompartmental metal femoral component
articulating with a polyethylene tibial component. This has a
91% infection eradication rate but has not yet been approved
by the US Food and Drug administration [53, 55]. Metal on
polyethylene spacers [44, 53-57] use a new or recycled
femoral component and polyethylene insert for articulation.
This provides an inexpensive articulation that can be custom
fitted to each patient. However, there is a lower surface area
for antibiotic elution as compared to cement on cement
Cement on cement spacers [45, 49-52] have more surface
knee components, thorough debridement, copious irrigation
and reimplantation of new appropriate total knee
components with antibiotic impregnated cement followed by
6-12 weeks of systemic antibiotic therapy. This is primarily
indicated in high morbidity patients unsuitable for multiple
operations who are infected with susceptible organisms.
Advantages of one-stage exchange include abbreviated
recovery and decreased cost and morbidity due to avoidance
of a second operation. There are few studies published with
this technique with an average success rate of 81% . One
of the studies with a higher (89%) success rate  found
that factors associated with success are absence of sinus
formation, Gram positive infection, use of antibiotic cement
in reimplantation and 12 weeks of antibiotic therapy.
Another online publication of 1,000 septic knee revisions at
the Endo-Klinik in Hamburg over the past 25 years using the
one-stage revision procedure, the success rate with the one-
stage revision procedure was reported to be 75%
One-stage exchange involves explantation of all total
special circumstances because the prognosis for infection
eradication is poor with only 6% success rate . It may be
considered if the implant is stable, the microorganism has
low virulence and is susceptible to oral antibiotics, and the
patient has a high anesthesia risk [61, 62]. Long term
antibiotic suppression has a risk of antibiotic related adverse
effects and emergence of resistant bacteria .
Antibiotic suppression alone is considered only under
patients after failure of other treatments in patients with
polyarticular rheumatoid arthritis. This eradicates infection at
the cost of stability and function of the knee .
Resection arthroplasty is suitable for low demand
extensor mechanism and in cases with highly resistant
Arthrodesis is indicated for infected TKA with deficient
90 The Open Orthopaedics Journal, 2011, Volume 5 Kalore et al.
organisms or salvage after failed treatments. Mabry 
found that arthrodesis by intramedullary nailing has a union
rate of 96% as compared to 67% with external fixation.
However, the risk of recurrent infection associated with IM
nailing is 8.3% as compared to 4.9 % with external fixation.
Infection eradication rates with arthrodesis approach 94%,
though the complication rate is also very high (40%) .
systemic sepsis or persistent local infection combined with
massive bone loss and intractable pain . The prognosis
for amputation is poor as more than half of the patients
become wheelchair-bound . Fortunately, less than 5 % of
patients with TKA infections need amputation .
Arthrodesis should be considered early in the treatment of
persistent infection as multiple revision surgeries may
ultimately require amputation .
Above knee amputation is considered for life-threatening
diagnose and treat. Diagnosis is based on a combination of
clinical findings, serologic tests, and imaging and laboratory
findings. Knee aspiration for cell count and neutrophil
differential can be very helpful. Ultrasonication of retrieved
implants in combination with molecular diagnostic
techniques is improving our ability to diagnose infections.
Two stage exchange utilizing antibiotic cement has better
success at infection eradication than direct exchange. Use of
an articulating spacer preserves motion between stages and
reduces scarring and bone loss, with potential improvements
in ROM, function, and second-stage exposure. Two stage
exchange with an articulating spacer is the most accepted
Periprosthetic TKA infections remain difficult to
RR024151-01 (Mayo Clinic Center for Clinical and
Translational Research) and the resources and the use of
facilities at the Birmingham VA Medical Center and
Minneapolis VA Medical Center, USA.
JS was supported by the NIH CTSA Award 1 KL2
POTENTIAL FINANCIAL CONFLICT:
No funding was obtained for completing this review.
NK- no financial support received
TG- research funding from Depuy, Inc. and Zimmer, Inc.
grants from Takeda, Savient, Wyeth and Amgen; consultant
fees from Savient and URL pharmaceuticals
JS- speaker honoraria from Abbott; research and travel
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Received: October 9, 2009
Revised: April 4, 2010 Accepted: July 7, 2010
© Kalore et al.; Licensee Bentham Open.
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