Aims: this study compared the patient and microbiological profile of prosthetic
joint infection (PJI) for patients treated with two-stage revision for knee
arthroplasty with that of lower-limb endoprostheses for oncological
resection.
Patient and methods:
a total of 118 patients were treated with two-stage revision surgery for infected knee
arthroplasty and lower-limb endoprostheses between 1999 and 2019. A total of 74
patients had two-stage revision for PJI of knee arthroplasty, and 44 had
two-stage revision of oncology knee endoprostheses. There were 68 men and
50 women. The mean ages of the arthroplasty and oncology cohorts were 70.2 years (range of 50–89) and 36.1 years (range of 12–78) respectively (p<0.01). Patient host and extremity criteria were categorized according to the
Musculoskeletal Infection Society (MSIS) host and extremity staging system. The patient microbiological culture, the
incidence of polymicrobial infection, and multidrug resistance (MDR) were
analysed and recorded.
Results:
polymicrobial infection was reported in 16 % (12 patients) of knee
arthroplasty PJI cases and in 14.5 % (8 patients) of endoprostheses PJI cases
(p=0.783). There was a significantly higher incidence of MDR in
endoprostheses PJI, isolated in 36.4 % of cultures, compared with knee
arthroplasty PJI (17.2 %, p=0.01). Gram-positive organisms were isolated
in more than 80 % of cultures from both cohorts. Coagulase-negative
Staphylococcus (CoNS) was the most common Gram-positive organism, and Escherichia coli was the most common
Gram-negative organism in both groups. According to the MSIS staging system,
the host and extremity grades of the oncology PJI cohort were significantly
worse than those for the arthroplasty PJI cohort (p<0.05).
Conclusion:
empirical antibiotic prophylaxis against PJI in orthopaedic oncology is
based upon PJI in arthroplasty, despite oncology patients presenting with
worse host and extremity staging. CoNS was the most common
infective organism in both groups; however, pathogens showing MDR were significantly
more prevalent in oncological PJI of the knee. Therefore, empirical broad-spectrum treatment is recommended in oncological patients following revision
surgery.
Introduction
The majority of patients presenting with bone and soft-tissue sarcomas are
managed with limb-salvage surgery (Cirstoiu et al., 2019; Wafa and Grimer, 2006). Limb-salvage surgery
with endoprosthetic reconstruction (EPR) provides a good level of function
with an acceptable implant survivorship of over 80 % at 10 years
(Gosheger et al., 2006). However, the complication profile compared with that of
primary arthroplasty is significantly higher. The prosthetic joint
infection (PJI) rate of proximal and distal femoral EPR for sarcoma is
approximately 10 % compared with approximately 1 % in primary hip and knee
arthroplasty (Racano et al., 2013; Kapadia et al., 2016). Pulido et al. (2008) described
multiple independent predictors for PJI including patient morbidity,
allogenic transfusion, and longer hospitalization. Orthopaedic oncology
patients are at a higher risk of PJI due to their immunosuppression
secondary to neo-adjuvant chemoradiotherapy and having an underlying
malignancy, longer and more extensive operative procedures, higher
transfusion rates due to levels of soft-tissue dissection, and increased
length of stay than primary arthroplasty patients.
Although successful eradication of PJI in primary hip and knee arthroplasty
may be quoted to be as high as 90 %, whether using a single-stage or two-stage protocol, these results are not reproduced within the context of EPRs
due to multifactorial local and systemic disparities (Kapadia et al., 2016).
Perioperative antibiotic prophylaxis for EPRs is typically based upon local
guidance for non-oncological arthroplasty to cover common infective
organisms (Christensen et al., 2021). In oncological PJI, the most common infective
organism is reportedly coagulase-negative Staphylococcus, mirroring that of primary
arthroplasty PJI (Jeys et al., 2005).
The aim of this study was to compare the microbiological organisms responsible
for PJI in patients who underwent two-stage revision of infected primary
total knee arthroplasty (TKA) with those of patients who underwent two-stage revision of infected
oncological EPRs of the knee at a single institution. Current antibiotic
prophylaxis for oncological patients is based upon evidence from primary
arthroplasty, despite significant differences in both patient and procedure.
This will subsequently guide decision-making regarding antibiotic
prophylaxis at primary implantation for oncological procedures and empirical
antibiotics for infected revision procedures (where the infecting
organism(s) are unknown).
Patients and methods
After local approval, a retrospective analysis of the departmental PJI
database was conducted to identify a consecutive cohort of patients who
underwent two-stage revision surgery for infected primary TKA and patients
with infected EPRs of the lower-limb following tumour resection at a
tertiary arthroplasty and oncology centre in the United Kingdom between
1999 and 2019.
Inclusion in the study was defined as confirmed PJI defined using the
Musculoskeletal Infection Society International Consensus Meeting (MSIS ICM; Parvizi et al., 2018). As a comparator group to oncological patients managed with
staged revision for PJI, a consecutive cohort of staged revision for PJI of
a primary TKA were identified. Two-stage revision is the current standard of
practice for the surgical management of infected TKA within our institution.
Patients were excluded from both cohorts if any previous procedures to
manage their infection prior to their first-stage procedure (e.g. washout or
debridement and implant retention procedure) had taken place. A minimum of 2 years of follow-up was required for inclusion. Antibiotic prophylaxis for
all primary procedures in both groups was flucloxacillin and gentamicin
within 30 min of knife to skin with three post operative doses of
flucloxacillin. If the patient was allergic to penicillin, teicoplanin was used as an
alternative to flucloxacillin. During the first-stage revision, vancomycin
and meropenem were used empirically with second-stage antibiotic prophylaxis; this was decided upon during the preoperative bone infection multidisciplinary team (MDT) discussion.
Polymicrobial infection was defined as the presence of two or more infecting
organisms. Multidrug resistance (MDR) was defined as the presence of a single
organism resistant to three or more antimicrobial classes (Parvizi et al., 2018).
All patients were classified according to the MSIS host and extremity
staging system which categorizes host status, including comorbidity, and
soft-tissue status in lower-limb PJI patients (Fehring et al., 2017). A systematic
sampling method was undertaken in the theatre to minimize the risks of
contamination. A minimum of five samples were sent for microbiological
analysis at each first- and second-stage procedure, and antibiotics were
withheld prior to surgery unless the patient was systemically septic and
compromised. All cases were Gram stained and cultured by direct and
enrichment methods for 15 d along with antibiotic susceptibility
testing. Only organisms that were cultured from at least two samples were
included in this dataset.
Statistical analysis
Statistical analysis was performed with IBM SPSS Statistics 24.0 (IBM, Armonk,
New York, USA). Median and mean values with ranges were calculated for
continuous variables. A chi-square test was used to test statistical
significance for categorical variables. An independent t test was conducted
for normally distributed continuous variables. A Mann–Whitney U test was
conducted for non-normally distributed variables. A p value of < 0.05 was set to be statistically significant.
Results
A total of 118 continuous patients were identified as having undergone two-stage revision
surgery to eradicate PJI between 1999 and 2019 in both groups: 74 patients
had PJI following primary TKA, and 44 patients had PJI following oncological
resection and reconstruction with a distal femoral EPR. All microbiological
data are available in Table S1 in the Supplement. There was no significant difference in
sex between the two groups (p=0.729). The mean ages for the TKA cohort
and lower-limb EPR cohort were 70.2 years (range of 50–89) and 36.1 years (range of 12–78)
respectively (p<0.01). The patients and limb status for both groups
were categorized according to the MSIS staging system for host and
extremity, as shown in Table 1. Patients with infected lower-limb EPRs were
noted to be significantly worse hosts, with the majority of patients
categorized in grade C (66 %), whereas most patients with PJI following TKA
were grade A (39 %) or B (45 %) (p<0.001, chi-square test).
Regarding extremity status, the TKA group had a better limb status
(63 % in grade 1 and 21 % in grade 2) compared with the group with infected
EPR (95 % of patients in grade 2) (chi-square test, p<0.001). The mean time to first-stage revision for the TKA group was 67.5 months (range of 2–267). Six patients had a first-stage revision within 6 months of the primary procedure. The mean time to first-stage revision for
the infected EPR group was 96.1 months (range of 2–397) with two patients having
their first-stage revision within 6 months.
The distributions of isolated organisms based on Gram staining for both
groups (primary TKA PJI vs. EPR PJI) are shown in Figs. 1 and 2
respectively. More than 80 % of isolated organisms were Gram-positive in
both groups. The most common Gram-positive organism for both groups was
coagulase-negative Staphylococcus (CoNS), which was isolated in 51 % of the Gram-positive
organisms from primary TKA PJI and in 50 % of the Gram-positive
organisms from the endoprosthetic PJI. The
most common Gram-negative organism was Escherichia coli in both groups, which was isolated in 30 %
(3 of 10) of the Gram-negative organisms from the primary TKA PJI and in 40 %
(2 of 5) of the Gram-negative organisms from the EPR PJI group.
Patient and limb status for both groups.
Primary TKA PJILower-Limb EPR PJIp valueN7444Men (% of group)43 (58.1)25 (56.8)0.73Women (% of group)31 (41.9)19 (43.2)Age (% of group)70.2 (50–89)36.1 (12–78)2.92MSIS host, N (%)A34 (39.1)5 (9.1)≤<0.01B39 (44.8)3 (5.5)1.41C1 (1.1)36 (65.5)2.24MSIS limb/extremity, N (%)155 (63.2)01.69218 (20.7)42 (95.4)3.1831 (1.1)2 (4.5)0.55MSIS host and extremity, N (%)A125 (33.8)0≤0.01A29 (12.2)5 (11.4)1.00B129 (39.2)09.02B29 (12.2)2 (4.5)0.21B301 (2.3)0.37C11 (1.4)01.00C2035 (79.5)8.77C301 (2.3)0.38Polymicrobial, N (%)12 (16.2)8 (14.5)0.78Multidrug resistance (MDR), N (%)15 (17.2)20 (36.4)0.01
PJI culture results from infected primary TKA.
PJI culture results from infected lower-limb EPR.
Multiple comparisons with Bonferroni correction were conducted for all
organisms by species. There were no significant differences amongst the
infecting organisms between the TKA and EPR patients (p>0.05).
The incidence of PJI with CoNS as the causative organism was reported to
have an increasing trend from 2000 up to 2015 followed by a decline towards
the end of the study period. Similarly, the incidence of PJI due to
Staphylococcus aureus also peaked in 2015.
There was no difference in the incidence of polymicrobial infection in both
groups, with an incidence of 16 % in the infected TKA group and an incidence of 15 % in the
infected EPR group (p=0.783, chi-square test). However, the incidence of multidrug resistant organisms (MDROs) in EPR PJI was 36 %, which was significantly
higher than the primary TKA group with an incidence of 17 % (p=0.01,
chi-square test). The highest incidence of MDR was observed in
coagulase-negative Staphylococcus (80 % of all MDROs) followed by Enterococcus spp. (6 %) and
other organisms, including Klebsiella spp., Kocuria spp., Serratia spp., and vancomycin-resistant Enterococci (VRE). Comparing the
infected primary arthroplasty and the infected endoprosthesis group, there
was no statistically significant difference regarding the organisms grown,
with both groups reporting CoNS as the most common MDRO grown
(p=0.548). A total of 10 patients (22.7 %) in the oncological group had previously
had radiotherapy, and 34 patients (77.3 %) had undergone chemotherapy. Six oncology
patients had local flap coverage at the time of their index surgery. A total of 31
patients (70.5 %) had silver-coated implants for their second-stage
revision surgery. Within the oncological group, there were no statistically
significant differences in MDR rates depending upon whether the patient had undergone
radiotherapy (p=0.15) or chemotherapy (p=0.62) or whether they had flap coverage (p=0.48) or silver-coated implants (p=0.44).
In the oncological patient group with infected EPR, 6 patients (13.6 %)
demonstrated resistance to gentamicin, and 16 patients (36.4 %) showed
resistance to flucloxacillin. In the primary arthroplasty group with
infected EPRs, 11 patients (12.6 %) showed resistance to gentamicin, and 15
patients (17.2 %) showed resistance to flucloxacillin. Comparing the two
cohorts, patients with an infected EPR demonstrated a higher proportion of
resistance to flucloxacillin than infected primary arthroplasty patients, but there
was no statistical significance achieved. (36.4 % vs. 17.2 %; p=0.098,
chi-square test). Regarding MDR cases, in the infected EPR group, 77.8 %
(14) of cases showed resistance to flucloxacillin, whereas 27.8 % (5) of cases showed resistance
to gentamicin. In the primary arthroplasty cohort with MDROs,
13.5 % (10) of cases showed resistance to flucloxacillin, and 10.8 % (8) of cases showed
resistance to gentamicin.
Discussion
Our study demonstrated a significantly higher incidence of MDROs in
oncological PJI compared with TKA PJI (36 % vs. 17 %; p=0.01). In
80 % of MDR cases (28 of 35), the organism was CoNS. VRE and methicillin-resistant Staphylococcus aureus (MRSA) were
isolated as causative agents of PJI in infected EPRs, whereas none were reported
in the primary arthroplasty group.
PJI remains one of the most devastating complications following primary
joint arthroplasty and endoprosthetic reconstruction surgery. The
pathogenesis of PJI is either by intraoperative inoculation, haematogenous
spread after implantation, or direct contact with nearby infected tissues
(Li et al., 2018). Prevention of acute PJI is multifactorial, including patient
optimization and intra-operative factors such as skin preparation, draping,
and prophylactic antibiotics. It has been known for over 50 years that
prophylactic antibiotics are one of the most potent measures for preventing
PJI (Fogelberg et al., 1970). Appreciation of a local and up-to-date antibiogram
guides mibrobiologists in deciding upon the preferred antibiotic prophylaxis
(Bosco et al., 2015).
Although PJI can begin with an MDRO, such as Acinetobacter spp., it is more common that
antibiotic drug resistance is acquired through mechanisms such as prevention
of access to drug target (e.g. reduced membrane permeability), alteration of
drug target (mutational or non-mutational), or drug disruption (e.g.
hydrolytic degradation) (Zmistowski and Alijanipour, 2014). Previously, Dhanoa et al. (2015) reported MDR in 52.6 % of the isolated strains in
orthopaedic oncology patients. The higher incidence of MDR in the
orthopaedic oncological group in our study may be attributed to the poor
host and extremity criteria, with the majority of patients categorized as
host grade C and limb status grade 2 or 3 according to the MSIS staging
system (Fehring et al., 2017). This may be explained by their exposure to
compromising factors, such as previous chemotherapy or radiotherapy,
that increased their risks of recurrent antimicrobial therapy for hospital- or
community-acquired infections. Initial undertreatment of PJI with
antibiotics can also increase the risk of drug resistance (Li et al., 2020).
Specifically related to coagulase-negative Staphylococcus species, selection
pressures on commensal bacteria from antibiotics in healthcare settings
and possible cross-contamination of resistant organisms between
patients and healthcare staff can result in preoperative skin colonization or post-operative wound colonization by multidrug resistant
species (Pantosti et al., 2007).
The incidence of polymicrobial infection in our study was 16.2 % in
primary TKA PJI cases and 14.5 % in EPR PJI cases. Risk factors for polymicrobial PJI
include host factors such as obesity, diabetes, and peripheral vascular
disease (McPherson et al., 2002). The previous literature has reported a polymicrobial
incidence of 4 %–27 % of all PJI (Gallo et al., 2006;
Tsukayama et al., 1996) compared with a multi-institutional study by Morii
et al. (2013) assessing the outcomes of deep infection in oncology EPRs of the knee
with a polymicrobial incidence rate of 3.5 %. Within the
oncology group, the mean age was lower; thus, associated age-related comorbid factors were largely absent. Despite this, the polymicrobial rate in the oncology group was
equivalent to that of the arthroplasty group. This suggests that the oncological
patients are independently at risk of polymicrobial infection.
CoNS was the most common Gram-positive organism responsible for PJI in both
groups, accounting for 41 % of total organisms isolated in PJI of primary
TKA surgery and 42 % in PJI of the oncology EPR in our study. This is
consistent with previous oncology and arthroplasty literature (Nickinson et al.,
2010; Jeys and Grimer, 2009). The most common Gram-negative organisms were Escherichia coli in 3.4 %
and 3.6 % of the knee arthroplasty PJI and oncological PJI respectively,
which is also consistent with previous reports describing the epidemiology of PJI
(Tsai et al., 2019; Legout et al., 2006).
There are several limitations to the present study, including its
retrospective data collection which may lead to reporting biases. Revision
of primary TKA cases for PJI was chosen as a comparator group to the
oncological PJI group because perioperative antibiotic protocols for PJI are typically
based upon this group and the typical microbiology from these cases.
However, there were differences between groups with respect to age and MSIS grading; therefore, although these are close comparator groups, biases may stem
from the differences in age-related comorbid/host status and soft-tissue
status. Due to the application of the ICM (Parvizi et al., 2018) classification of PJI to
our dataset from 1999 to 2019, not all novel diagnostic methods were available
during the study period (e.g. synovial markers such as α-defensin and
D-dimer). Therefore, during this time, patients may have been misdiagnosed as
aseptic failure rather than PJI and subsequently not included in the
study. The numbers of patients in each group are small and unequal, although
these represent relatively large groups compared with the previous literature
concerning oncological PJI.
Conclusions
Despite empirical antibiotic prophylaxis and empirical management of PJI for
oncological EPR being based upon the management of arthroplasty PJI, there
are notable differences regarding their host and soft-tissue status.
Oncology patients suffered worse host and extremity criteria. Coagulase-negative Staphylococcus species were
the most common infective organism in both study groups; however, oncology
EPR PJI has a significantly higher incidence of MDR infection. Therefore,
the authors would recommend broad-spectrum empirical antibiotics
pre-emptively when oncological patients undergo revision. The common
finding of MDR would support the preferential strategy of a two-stage revision
procedure over a single-stage revision procedure which is the practice
within our institution. Finally, the rarity of fungal organisms, even in
complex oncological cases, would not support the use of empirical antifungal treatments
unless confirmed with preoperative sampling.
Data availability
All raw data can be provided by the corresponding authors upon request.
The supplement related to this article is available online at: https://doi.org/10.5194/jbji-7-177-2022-supplement.
Author contributions
RM, JS, and LJ conceptualized the paper. RM and AA were responsible for the data
collection. AA completed the data analysis. RM was responsible for the first draft. All authors completed the editing process.
Competing interests
The contact author has declared that none of the authors has any competing interests.
Ethical statement
Approval of this study was confirmed by the local ethical and research committee.
Disclaimer
Publisher's note: Copernicus Publications remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Review statement
This paper was edited by Rihard Trebse and reviewed by four anonymous referees.
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