B. KOCJAN^I^ et al.: THE IMPORTANCE OF SONICATION AND PRE-OPERATIVE ANTIMICROBIAL THERAPY
913–918
THE IMPORTANCE OF SONICATION AND PRE-OPERATIVE
ANTIMICROBIAL THERAPY
POMEN SONIKACIJE PRI PREDOPERATIVNI ANTIBIOTI^NI
TERAPIJI
Bo{tjan Kocjan~i~*, Andrej Lapo{a, Drago Dolinar
Department of Orthopaedic Surgery, University Medical Centre Ljubljana, Zalo{ka cesta 9, 1000 Ljubljana, Slovenia
Prejem rokopisa – received: 2019-06-17; sprejem za objavo – accepted for publication: 2019-09-24
doi:10.17222/mit.2019.130
The purpose of the study was to evaluate the use of sonication in the detection of prosthetic joint infections with the emphasis
on patients who received pre-operative antimicrobial therapy. Consecutive patients that required revision surgery of the hip or
knee arthroplasty were enrolled in the study. An algorithm for the diagnosis of prosthetic joint failure based on the culture of
intraoperative tissue samples and the sonication of explanted orthopaedic material was used. The results of both methods were
compared and evaluated. Between November 2010 and December 2013, 103 patients were enrolled, which underwent 136
revision procedures. In 31 cases (22.8 %) the patient received pre-operative antimicrobial therapy. Prosthetic joint infection and
aseptic failure was diagnosed in 69 (50.7 %) and 45 (33.1 %) cases. In 22 cases (16.2 %) microbiology was inconclusive.
Sonication was a significantly better diagnostic method for the detection of prosthetic joint infection when pre-operative
antimicrobial therapy was received (p < 0.05). In recent years sonication has become vital for the diagnosis of prosthetic joint
infection. According to our results, it is especially crucial in patients that received pre-operative antimicrobial therapy.
Keywords: sonication, prosthesis-related infection, antimicrobial therapy, revision
Namen {tudije je bil oceniti uporabo sonikacije za odkrivanje oku`b endoprotez, s poudarkom na bolnikih, ki so prejeli pred-
operativno antibioti~no terapijo. V {tudijo so bili vklju~eni zaporedni bolniki v obdobju od 1.1.2010 do 31.12.2013, pri katerih
smo opravili revizijsko operacijo endoproteze kolka ali kolena. Uporabili smo algoritem za diagnozo oku`be endoproteze sklepa
na podlagi mikrobiolo{kih kultur intraoperativnih vzorcev tkiv in ultrazvo~ne obdelave odstranjenega ortopedskega materiala
(sonikacija komponent ali celotnih endoprotez). Rezultate obeh metod smo primerjali in ovrednotili. V zgoraj omenjenem ~asu
smo opravili 136 revizijskih postopkov pri 103 bolnikih, ki so bili vklju~eni v {tudijo. V 31 primerih (22,8 %) so bolniki prejeli
predoperativno antibioti~no zdravljenje. Vzrok za revizijsko operacijo je bila oku`ba endoproteze sklepa in asepti~na odpoved,
ki smo ju diagnosticirali pri 69 (50,7 %) oziroma 45 (33,1 %) primerih. V 22 primerih (16,2 %) je bila mikrobiolo{ka analiza
nezanesljiva. Sonikacija je bila bistveno bolj{a diagnosti~na metoda za odkrivanje endoproteti~ne oku`be sklepov potem, ko je
bila izvedena predoperativna antibioti~na terapija (p < 0,05). V zadnjih letih je postala sonikacija odstranjenih komponent
endoprotez klju~na za diagnozo oku`be endoproteti~ih sklepov. Na{i rezultati ka`ejo, da je to {e posebej pomembno pri
bolnikih, ki so prejemali predoperativno antibioti~no zdravljenje.
Klju~ne besede: sonikacija, oku`be endoproteti~nih sklepov, antiboti~na terapija, revizija
1 INTRODUCTION
Accurate differentiation between aseptic failure and
infection is a key component in the successful treatment
of orthopaedic implant-associated complications. A clear
differentiation between the two conditions remains one
of the goals of modern orthopaedic surgery. With the
ageing population there is a steady increase in the
number patients requiring total joint arthroplasty.
1
Consequently, there is an increase in the number of
revision procedures, with8%o fprostheses requiring
revision surgery within 10 years. Approximately 75 % of
revision procedures are due to aseptic loosening and 8 %
of the cases due to primary or secondary prosthetic joint
infections.
2
The treatment of aseptic loosening differs
significantly from the treatment of prosthetic joint
infection (PJI), where the therapeutic approach is
individualized according to the infection stage, pathogen
and patient characteristics.
3
The role of biofilm in orthopaedic implant infections
has been well established and represents a diagnostic
challenge.
4
Microorganisms in biofilm grow clustered in
a highly hydrated extracellular matrix attached to a
surface. After an initial phase micro-organisms enter a
stationary phase, making them more resistant to antimi-
crobial therapy and host defences.
5
In recent years the introduction of the sonication of
removed orthopaedic implants has improved the diag-
nosis of PJI. Since the first report of the use of sonication
in the diagnosis of orthopaedic implant infections by
Tunney, the method has gained wide approval and is
implemented in the diagnostic protocols of the majority
of orthopaedic centres.
6
The method applies ultrasound
waves to disrupt biofilm from the surface of materials
without affecting the viability of the micro-organisms.
7
The obtained material can then be further processed
using standard or advanced microbiologic techniques.
Sonicate-fluid culture has a higher sensitivity
compared to periprosthetic tissue culture (78.5 % versus
60.8 %), with similar specificities (98.0 % versus
Materiali in tehnologije / Materials and technology 53 (2019) 6, 913–918 913
UDK 616-089:616-085:615.036:615.33 ISSN 1580-2949
Original scientific article/Izvirni znanstveni ~lanek MTAEC9, 53(6)913(2019)
*Corresponding author's e-mail:
bkocjancic@gmail.com (Bo{tjan Kocjan~i~)

95.1 %). The value of sonication is even greater in cases
of pre-operative antimicrobial therapy, where the sen-
sitivity remains high (75 % versus 45 %).
8
Sonication
can be further enhanced using polymerase chain reaction
(PCR) analysis of the sonicate fluid, which has, com-
pared to the sonicate-fluid culture, additionally improved
the sensitivity (78 % versus 62 %).
9
In a recent report
multiplex PCR of sonicate-fluid has demonstrated a high
sensitivity (96 %) and specificity (100 %) for the diag-
nosis of PJI.
10
Since the introduction of sonication, aseptic loosen-
ing has in many cases been proven to be clinically silent
PJI.
11
It is believed that 4–13 % of patients with a pre-
operative diagnosis of aseptic loosening have culture-
negative PJI.
12,13
In patients treated for aseptic loosening
with marked osteolysis and negative periprosthetic tissue
cultures, the sonicate-fluid cultures were positive in
57 % of patients.
14
There is still no clear consensus on the diagnostic
criteria for PJI.
15,16
According to the latest recommen-
dations, the diagnosis is based on clinical status, iso-
lation of pathogen, laboratory parameters, cell count of
synovial fluid and histologic analysis of periprosthetic
tissue. Although the use of sonication is rapidly growing,
it has not yet been widely implemented in the guidelines
of prosthetic joint infection detection and is only
recommended in doubtful cases.
17
The purpose of our study was to evaluate the use of
sonicate-fluid cultures and periprosthetic tissue culture
for the detection of prosthetic joint infections. The study
was directed towards the assessment of the impact of
pre-operative antimicrobial therapy on the accuracy of
the methods. Furthermore, we wanted to evaluate ideal
cut-off values of pre-operative C-reactive protein (CRP)
concentration and erythrocyte sedimentation rate (ESR)
in cases of aseptic loosening and PJI using ROC anal-
ysis.
2 METHODS
2.1 Study population
In a level II diagnostic study consecutive patients
admitted to the Department of Orthopaedic Surgery of
the University Medical Centre, Ljubljana, Slovenia for
revision surgery of hip or knee arthroplasty, were invited
to participate. Patients were excluded from the study if
there was inadequate number of tissue samples sent to
the microbiological laboratory for culture or if there
were signs of comorbidities, which alter the systemic
inflammatory response. The study was approved by the
Republic of Slovenia National Medical Ethics
Committee (No. 93/02/13).
2.2 Pre-operative and peri-operative procedures
Pre-operatively, the patients were examined for the
presence of local signs of infection, plasma concen-
tration of C-reactive protein (CRP) and erythrocyte
sedimentation rate (ESR). Pre-operative antimicrobial
therapy was defined if any antimicrobial therapy was
given for  24 hours within 14 days prior to revision
surgery. After careful pre-operative planning according
to the accepted algorithm for the treatment of aseptic
loosening or PJI revision surgery followed. During the
surgical procedure, 2–5 samples of periprosthetic tissue
were sampled in standardized sterile containers. After-
wards, the prosthesis (partial or complete) was removed
and placed in sterilized transport containers (Lock&
Lock, Hana Cobi Plastic Co, Ltd., Seoul, Korea) to
which 100–500 ml of Ringer’s solution was added.
2.3 Microbiologic evaluation
The removed orthopaedic material was first vortexed
(30 s) and then subjected to sonication (frequency
40 kHz, duration 1 min). 50 mL of sonicate-fluid was
then centrifuged (3200 min
-1
, duration 1 min) and
sediment cultured on aerobic and anaerobic agar plates
(sheep-blood agar, chocolate agar, Schaedler agar) and
three liquid media (thyoglycollate broth, BacTalert FA
and BacTalert FN, both bioMerieux, France). Cultures
were incubated for 14 d and bacterial growth was
assessed quantitatively in colony-forming units per mL
of sonicate-fluid (CFU/ml). Periprosthetic tissue was
homogenized prior to culture on aerobic and anaerobic
agar plates and in thyoglycollate broth for 14 d. Bacterial
growth was assessed semi-quantitatively (0-absent
growth – 3+ extensive growth).
2.4 Diagnostic criteria
The diagnosis of PJI was determined if the following
criteria were met: (1) the presence of a sinus tract
communicating with the prosthesis, (2) isolation of a
single pathogen from two separate samples, (3) isolation
of a pathogen from one sample, under the condition that
inflammatory parameters were elevated (CRP
>10 mmol/L, ESR >30 mm/h), (4) isolation of a patho-
gen from sonicate fluid at a concentration 50 CFU/mL,
(5) isolation of a pathogen from sonicate fluid at a
concentration <50 CFU/mL, under the condition that
inflammatory parameters were elevated (CRP
>10 mmol/L, ESR >30 mm/h). In cases of pre-operative
antimicrobial therapy, isolation of a pathogen of any
number or concentration was considered an infection.
2.5 Statistical analysis
Basic demographic and clinical data were analysed
using descriptive methods. The sensitivities and specifi-
cities of different culture methods were compared using
McNemar’s test. The impact of antimicrobial therapy on
the microbiologic methods was assessed using logistic
regression. The results were presented as odds ratios
with corresponding 95 % confidence intervals (CI). The
limit of statistical significance was at = 0.05. The data
B. KOCJAN^I^ et al.: THE IMPORTANCE OF SONICATION AND PRE-OPERATIVE ANTIMICROBIAL THERAPY
914 Materiali in tehnologije / Materials and technology 53 (2019) 6, 913–918

was analysed with the statistical program SPSS 20
(SPSS Inc., Chicago, Illinois, USA) and the R pro-
gramming language.
3 RESULTS
Between November 2010 and December 2013, 103
patients were enrolled in the study. Cumulatively they
underwent 136 revision procedures: 105 hip revisions
and 31 knee revisions. Forty-one (39.8 %) patients were
males and 62 (60.2 %) were females. The average patient
age at the time of revision surgery was 65.9 y (±12.9 y).
The surgical type distribution is shown in Table 1.
Table 1: Surgical procedure type distribution (n=136)
Type of surgical procedure No. (proportion)
mobile parts exchange 26 (19.1 %)
one-stage revision 59 (44.7 %)
two-stage revision
(spacer/re-implantation)
38 (27.9 %)
explantation (Girdlestone) 10 (7.4 %)
osteosynthetic material removal 3 (2.2 %)
In 31 (22.8 %) revision surgery procedures the
patient received pre-operative antimicrobial therapy. The
average duration of pre-operative antimicrobial therapy
was 18.8 d (±21.5 d) and the average antimicrobial free
interval before surgery was 2.7 d (±4.6 d).
Based on pre-operative clinical criteria and post-
operative microbiologic results, PJI was diagnosed in 69
(50.7 %) cases. In 22 (16.2 %) cases, micro-organisms
were isolated in a single specimen or at a concentration
<50 CFU/mL of sonicate fluid, which was interpreted as
inconclusive and in 45 (33.1 %) cases, the culture
remained negative and the prosthetic joint failure was
determined as aseptic. Among PJI cases, 33 (47.8 %)
were classified as early-onset (i.e., <3 months after
primary arthroplasty), 17 (24.6 %) were delayed (i.e.,
3–24 months after primary arthroplasty) and in 19
(27.5 %) were late-onset (i.e., >24 months after primary
arthroplasty).
Sonicate-fluid cultures and periprosthetic tissue
cultures were microbiologically positive (i.e., detection
of at least one bacterial species in any culture media) in
79 (58.1 %) and 69 (50.7 %) cases, respectively. Con-
sidering the diagnostic criteria for PJI, sonicate-fluid
culture was diagnostic in 57 (82.6 %) cases, of which 12
(21.1 %) cases were periprosthetic tissue culture
negative. Periprosthetic tissue culture was diagnostic in
52 (75.4 %) cases, of which 7 (13.5 %) cases were
sonicate-fluid culture negative. In 45 (65.2 %) cases the
infection was diagnosed by both methods and in 4
(5.8 %) cases the diagnosis of PJI was made based on
both methods, whereas if considering a single method
independently, the result was inconclusive. In 1 (1.4 %)
case, both methods failed to isolate a micro-organism
even though clinical criteria were sufficient to diagnose
PJI and the patient had sinus tract, elevated CRP con-
centration and ESR. However, the patient received
pre-operative antimicrobial therapy.
Among 31 procedures where patients received
pre-operative antimicrobial therapy sonicate-fluid culture
and periprosthetic tissue cultures were diagnostic in 26
(83.9 %) and 22 (71.0 %) of cases, respectively. Both
methods failed to isolate the pathogen in 1 (3.2 %) case.
According to the diagnostic criteria, the isolation of any
amount of micro-organism is considered diagnostic for
PJI in the case of pre-operative antimicrobial therapy.
Sonicate-fluid culture was monomicrobial (i.e.,
single microorganism isolated) in 38 (66.7 %) cases and
polymicrobial (i.e., >1 microorganism isolated) in 19
(33.3 %) cases. On the other hand, periprosthetic tissue
culture was monomicrobial in 24 (46.2 %) cases and
polymicrobial in 28 (53.9 %) cases. The distribution of
microorganisms isolated by both methods is shown in
Table 2.
Table 2: Distribution of micro-organism detected by both sonicate
fluid and periprosthetic tissue cultures (monomicrobial samples)
Sonicate fluid No. (proportion)
Coagulase-negative staphylococci 16 (28.1 %)
Staphylococcus aureus 10 (17.5 %)
Burkholderia cepacia 3 (5.3 %)
Cutibacterium acnes 3 (5.3 %)
Streptococcus spp. 3 (5.3 %)
Escherichia coli 1 (1.8 %)
Enterococcus faecium 1 (1.8 %)
Klebsiella pneumoniae 1 (1.8 %)
Periprosthetic tissue culture No. (proportion)
Coagulase-negative staphylococci 8 (15.4 %)
Staphylococcus aureus 6 (11.5 %)
Cutibacterium acnes 5 (9.6 %)
Streptococcus spp. 2 (3.8 %)
Enterococcus faecium 1 (1.9 %)
Klebsiella pneumoniae 1 (1.9 %)
Lactobacillus rhamnosus 1 (1.9 %)
In a logistic regression model, sonicate-fluid culture
of explanted orthopaedic material has proven to be
superior to periprosthetic tissue culture for the detection
of PJI in the case of pre-operative antimicrobial therapy
(OR = 0.01, 95 % CI: <0.01-0.26, p = 0.005). In case of
no pre-operative antimicrobial therapy, there was no
significant difference in the PJI detection rate by both
methods (OR = 0.76, 95 % CI: 0.02-25.22, p = 0.938).
Overall, there was no significant difference in the
detection of PJI using sonicate-fluid culture (41.9 %) and
periprosthetic tissue culture (38.2 %) using McNemar’s
test (p = 0.264).
The analysis of pre-operative laboratory parameters
using a ROC curve has shown that the ideal cut-off value
of CRP for the detection of infection is 11 mmol/L
(77.2 % sensitivity, and 83.5 % specificity) for the
analysis using sonicate-fluid culture and 12 mmol/L for
the analysis of periprosthetic tissue culture (80.4 %
B. KOCJAN^I^ et al.: THE IMPORTANCE OF SONICATION AND PRE-OPERATIVE ANTIMICROBIAL THERAPY
Materiali in tehnologije / Materials and technology 53 (2019) 6, 913–918 915

sensitivity and 84.7 % specificity). The ideal cut-off
value of pre-operative SR is 25 mm/h for the analysis
using sonicate-fluid culture (73.7 % sensitivity and
68.4 % specificity) and 32 mm/h (72.6 % sensitivity and
78.8 % specificity) for the analysis using periprosthetic
tissue culture.
The pre-operative value of CRP is a better predictor
of PJI using periprosthetic tissue culture analysis than
using sonicate-fluid culture analysis, AUC = 0.78 (95 %
CI: 0.69–0.87) versus AUC = 0.74 (95 % CI: 0.65–0.82),
respectively. Furthermore, ESR is also a better predictor
of PJI using periprosthetic tissue culture analysis than
using sonicate-fluid culture analysis, AUC = 0.87 (95 %
CI: 0.81–0.94) versus AUC = 0.84 (95 % CI: 0.77–0.91),
respectively.
4 DISCUSSION
The purpose of the study was to evaluate the use of
sonication as an additional diagnostic tool for the
detection of PJI, with the emphasis on patients receiving
pre-operative antimicrobial therapy. We have predicted
that the sonicate-fluid culture of explanted orthopaedic
material obtained during revision surgery of prosthetic
joint failure will be superior compared to periprosthetic
tissue culture in the isolation of causative micro-orga-
nisms and the detection of PJI.
The obtained results have shown that in cases where
the patients received pre-operative antimicrobial therapy,
sonication was superior compared to periprosthetic tissue
culture. Pre-operative antimicrobial therapy is a risk
factor for culture-negative prosthetic joint infection.
18,19
In our study, one case of PJI remained culture-negative
and the antimicrobial therapy was introduced on an
empirical basis. Similar results were obtained in previous
studies, emphasizing the importance of sonication in the
cases of pre-operative antimicrobial therapy.
8
Pre-opera-
tive antimicrobial therapy can jeopardize the pathogen
isolation; therefore, antimicrobial therapy is selected
empirically, which is suboptimal.
On the other hand, sonication of explanted ortho-
paedic material in the absence of pre-operative antimi-
crobial therapy did not show a significant improvement
of the detection of PJI. These results are not concordant
with previously published studies, where the sonication
of explanted material has shown a superior diagnostic
value.
8,20–22
The discrepancy of results could reflect diffe-
rent diagnostic criteria for PJI used among studies. At
our institution the isolation of low-virulent micro-
organisms, especially Coagulase-negative staphylococci
(CNS) and Cutibacterium acnes, are considered highly
suspicious for PJI and additional criteria should be
evaluated. Isolation of a pathogen in a single sample or
isolation in a concentration of <50 CFU/mL with the
presence of elevated inflammatory parameters should be
considered as PJI, if other causes of elevated CRP value
and ESR are excluded. Because of the moderate
accuracy of intraoperative periprosthetic frozen section
histologic evaluation, it is not performed routinely at our
facility.
23
In our study, a large proportion of both sonicate-fluid
and periprosthetic tissue cultures were polymicrobial,
33.3 % and 53.9 %, respectively. Compared to other
authors that have reported much lower proportions of
polymicrobial cultures of 10–11 %,
8,24
these proportions
were surprising. However, the latest research on biofilm
formation and structure has led to new insights into
polymicrobial growth with a diverse bacterial compo-
sition.
25
In a recent study, polymicrobial biofilm for-
mation was detected in 9/14 PJI cases using the 16S
rRNA gene PCR, compared to 1/10 polymicrobial
samples using conventional diagnostic methods.
26
Accordingly, monomicrobial samples isolated from PJI
are most probably a consequence of an inadequate
sampling and cultivation, as only certain bacteria have
optimal conditions for growth. In our study, the incu-
bation period was 14 days for both aerobic and anaerobic
cultures, allowing even most fastidious bacteria enough
time to grow. The other possible explanation of the high
ratio of polymicrobial infection is also the contamination
of samples, which can occur during the entire process of
sampling, transport and cultivation.
The analysis of cut-off values for pre-operative CRP
concentration and ESR using ROC analysis has revealed
that the ideal cut-off values are lower in the case of
infection detection using sonication than periprosthetic
tissue cultures. The proposed and widely accepted
cut-off value for the detection of PJI is CRP concen-
tration of 10 mmol/L and ESR of 30 mm/h, which was
also acknowledged by the Workgroup of the Musculo-
skeletal Infection Society and was used also in the
present study.
27
In a recent study, the diagnostic cut-off
value of pre-operative CRP concentration and ESR were
set to 20.5 mg/L and 31 mm/h, respectively.
28
These
values are significantly higher than our results and most
probably reflect the lack of sonication, but also different
diagnostic criteria for the evaluation of PJI. In another
study, lower cut-off values were considered to be optimal
for the detection of PJI: 14.5 mg/L and 10.3 mg/L for
CRP and 19 mm/h and 13 mm/h for ESR, for knee and
hip infection, respectively.
29
The main benefit of our study is a recognition that
sonicate-fluid cultures perform significantly better than
periprosthetic tissue cultures in a clinical setting where
pre-operative antimicrobial therapy was used and there-
fore enabling guided antimicrobial therapy. Accurate
detection of the causative micro-organism reduces the
risk of revision surgery because of the missed PJI. The
study has also shown that an adequate number of peri-
prosthetic tissue samples is sufficient for the detection of
PJI in patients without pre-operative antimicrobial
therapy.
The main limitation of the study is a lack of poly-
merase chain reaction (PCR) analysis of the sonicate
B. KOCJAN^I^ et al.: THE IMPORTANCE OF SONICATION AND PRE-OPERATIVE ANTIMICROBIAL THERAPY
916 Materiali in tehnologije / Materials and technology 53 (2019) 6, 913–918

samples. Furthermore, pre-operative diagnostic aspir-
ation of synovial fluid was not regularly performed at
our institution; therefore, the method was not included in
the study.
5 CONCLUSIONS
Sonicate-fluid cultures of explanted orthopaedic
material represent an important tool for the accurate
detection of a pathogen in cases of pre-operative
antimicrobial therapy. It is crucial for the detection of the
pathogen and the introduction of guided antimicrobial
therapy. Nonetheless, despite accurate pre-operative
assessment, meticulous tissue and material sampling and
microbiologic analysis, culture-negative PJI remains a
serious problem. In patients who did not receive
pre-operative antimicrobials, a thorough pre-operative
assessment and an adequate number of periprosthetic
tissue samples could be sufficient for the detection of
PJI.
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