Introduction: The most common complication following transcutaneous
osseointegration for amputees is infection. Although an obvious source of
contamination is the permanent stoma, operative site contamination at the
time of implantation may be an additional source. This study investigates
the impact of unexpected positive intraoperative cultures (UPIC) on
postoperative infection.
Methods: Charts were reviewed for 8 patients with UPIC and 22 patients
with negative intraoperative cultures (NIC) who had at least 1 year of
post-osseointegration follow-up. All patients had 24 h of routine
postoperative antibiotic prophylaxis, with UPIC receiving additional
antibiotics guided by culture results. The main outcome measure was
postoperative infection intervention, which was graded as (0) none, (1)
antibiotics unrelated to the initial surgery, (2) operative debridement with implant retention, or (3) implant removal.
Results: The UPIC vs. NIC rate of infection management was as follows: Grade 0, 6/8 = 75 % vs. 14/22 = 64 %, p= 0.682; Grade 1, 2/8 = 25 % vs. 8/22 = 36.4 % (Fisher's p= 0.682); Grade 2, 1/8 = 12.5 % vs. 0/22 = 0 %
(Fisher's p= 0.267); Grade 3, 0/8 = 0 % vs. 1/22 = 4.5 % (Fisher's p= 1.000). No differences were statistically significant.
Conclusions: UPIC at index osseointegration, managed with directed
postoperative antibiotics, does not appear to increase the risk of
additional infection management. The therapeutic benefit of providing
additional directed antibiotics versus no additional antibiotics following
UPIC is unknown and did not appear to increase the risk of other adverse
outcomes in our cohort.
Introduction
When performing elective reconstructive orthopedic surgery involving
implantation of large permanent metal implants, it is generally considered
optimal to have a patient and local wound environment without infection in
order to optimize wound healing and infection risks. There is substantial
literature investigating the significance of unexpected positive
intraoperative cultures (UPIC) identified during surgery for primary total
hip, knee, and shoulder replacement (Zmistowski et al., 2021; Wong et al., 2018; Jonsson et al., 2014; Ferro et al., 2020), revision total joint
implantation (Padegimas et al., 2017; Hipfl et al., 2021; Pérez-Prieto et al., 2021), and open fractures (Agrawal et al., 2013).
Transcutaneous osseointegration, a relatively recent reconstructive
rehabilitative option for amputees (Hoellwarth et al., 2020), is receiving
increasing attention and is different from other prosthetic reconstruction
scenarios for several reasons. The primary distinction is that a
transcutaneous permanently open skin stoma remains, through which the
skeletally anchored metal implant is attached to the external prosthetic
limb. This skin interruption is a site of potential frequent and direct
bacterial ingress which can colonize or infect the soft tissues, bone, and
implant. Unsurprisingly, the most common adverse event following
osseointegration is infection (Reif et al., 2021), which may require oral
antibiotics, operative debridement with implant retention, or implant
removal with additional debridement (Al Muderis et al., 2017). Prior
investigations of post-osseointegration infection have reported
postoperative occurrence rates and management (Al Muderis et al., 2017; Reif
et al., 2021; Hoffmeister et al., 2017; Atallah et al., 2020). However, it
is currently unknown to what extent UPIC impacts the risk of subsequent
infection.
To investigate that question, this study compared the infection-related
adverse events of two cohorts of osseointegrated amputees: those with UPIC
versus those with negative intraoperative cultures (NIC). The primary
outcome was whether patients eventually had any intervention for a
postoperative infectious concern (antibiotics or surgery).
Methods
Following institutional ethics approval, all 55 patients in our
prospectively maintained osseointegration registry were retrospectively
evaluated. Included patients met the following criteria: index
osseointegration performed at least one year prior to this study (October 2017 to October 2020) (n=37), with intraoperative cultures taken. Seven
patients did not have intraoperative cultures taken: two because they had
primary amputation with simultaneous osseointegration (not already an
amputee), so they were not considered a potential risk for latent infection, and
five others inadvertently did not have cultures taken. These seven were
excluded from the study, yielding 30/37 (81 %) of potentially eligible
patients who were evaluated. All patients had at least 1 year of
follow-up.
Charts were reviewed for the following perioperative information:
demographic data, the results and sensitivity of intraoperative cultures,
the immediate postoperative antibiotic regimen for patients with UPIC, any
relevant prior surgery, and any postoperative infection-related management.
The operative routine was to take five culture swabs prior to implant
insertion, and if at least one of these swabs resulted positive, to provide
antibiotics as guided by the infectious disease consultants. The main
outcome of postoperative infection management was graded as zero to three,
defined in Table 1.
Grading system for infection-related management of osseointegrated
patients.
Frequency comparison was performed using Fisher's exact test. Means were
compared using Student's t test. Significance was defined as p≤0.05.
General osseointegration consideration and technique
In general, amputees are offered osseointegration if they express
dissatisfaction with their socket prosthesis in regards to fit, pain,
mobility, or overall quality of life. Patients with an intact limb are
offered amputation with osseointegration if they have complex deformity or
pain for which an amputation is expected to provide functional improvement.
We perform osseointegration with custom-ordered press-fit titanium implants
featuring porous coating at the bone interface and a smooth surface at the
skin interface (Osseointegrated Prosthetic Limb, Permedica Medical
Manufacturing, Lecco, Italy; and Signature Orthopaedics, New South Wales,
Australia). General contraindications to osseointegration include active
disease which puts healing at risk, such as active infection. Patients who
appear to have active infection are provided a disinfection surgery which
debrides nonviable soft tissue and bone and places a local antibiotic depot,
which is followed by a recovery period of approximately 6 or more weeks.
If the patients have physical examination and laboratory markers consistent
with infection eradication, osseointegration may be provided. We do not
place osseointegration implants if there is any concern or perceived risk
for a contaminated wound bed. We routinely take five culture swabs from the
intramedullary canal upon initial preparation, prior to reaming, which are
incubated for aerobic (5 days) and anaerobic (14 days) bacteria.
The first three patients had two-stage osseointegration approximately 2
months apart, but the remainder had single-stage surgery. All incisions are
primarily closed leaving the stoma surrounding the transcutaneous dual cone
prosthesis adapter. Patients are admitted postoperatively for approximately
3–5 days for pain control, early rehabilitation, and stoma
self-care education. Routine perioperative antibiotics (weight-based
cefazolin unless contraindicated) are continued for 24 h
postoperatively. For patients whose intraoperative cultures result positive,
an antibiotics course is constructed in consultation with infectious disease
physicians. Patients are routinely evaluated by the surgeon with
radiographic and physical examination at 3 weeks, 3 months, 6
months, and annually after osseointegration. At each office visit, we remind
patients that if they experience symptoms concerning for infection, they
should directly inform our office, rather than a local doctor or emergency
department, in order to minimize antibiotic over-prescription or
under-diagnosis.
Results
The patient demographic summary is presented in Table 2. The following
comparisons were statistically different. UPIC had a greater proportion of
right-sided surgery and traumatic etiology for amputation than NIC. Cohorts
were not statistically different regarding age at osseointegration, age at
initial amputation, gender distribution, height, weight, tobacco use, stages
of osseointegration, implant used, implant diameter or length, erythrocyte
sedimentation rate (ESR), C-reactive protein (CRP), or prior staged
disinfection surgery. No patients had remnant orthopedic hardware at the
time of osseointegration, other than the one who had an antibiotic spacer
placed in preparation for osseointegration.
Patient demographics, organized by operative culture status. Boldface type indicates statistical significance.
UPIC – cohort with unexpected positive intraoperative cultures.
NIC – cohort with negative intraoperative cultures.
ESR – erythrocyte sedimentation rate; our institution considers 15 or
greater abnormal.
CRP – C-reactive protein; our institution considers 1 or greater abnormal.
* The techniques for frequency and means comparison are described in the
Methods section.
Table 3 profiles the UPIC patients along with their subsequent antibiotic
regimens. All patients had antibiotic therapy organized by the infectious
disease consultants. The duration of all treatment regimens was 6–8
weeks. No patients experienced major adverse effects such as Clostridium difficile colitis.
Summary of patients with UPIC.
Patient no.Age sex boneEtiology ofamputationCultured bacteria*Treatment regimen147 M humerusElectrocutionPropionibacterium acnes (1/5)Clindamycin (300 mg, oral twice daily, 6 weeks)226 M femurTraumaStaphylococcus capitis subspecies ureolyticus (1/6)Sulfamethoxazole–trimethoprim (800–160 mg, oral twice daily, 12 weeks)360 M femurInfectionStaphylococcus epidermidis (2/5)Sulfamethoxazole–trimethoprim(800–160 mg, oral twice daily, 6 weeks)456 F tibiaTraumaStaphylococcus epidermidis (3/3)Vancomycin (red man syndrome) switched to daptomycin (rhabdomyolysis) switched to doxycycline (100 mg, oral twice daily, 6 weeks)560 M tibiaTraumaEnterococcus casseliflavus (3/3); Stenotrophomonas (Xanthomonas) maltophilia (3/3)Daptomycin (500 mg, intravenous daily, 12 weeks) along with levofloxacin (750 mg, oral daily, first 6 weeks) followed by amoxicillin (875 mg, oral daily, second 6 weeks) and sulfamethoxazole–trimethoprim (800–160 mg, oral daily, second 6 weeks)666 M femurTraumaFinegoldia magna (5/5)Ertapenem (1000 mg, intravenous daily, 8 weeks)760 M tibiaDeformityStaphylococcus epidermidis (5/5)Daptomycin (500 mg, intravenous daily, 6 weeks858 M femurInfectionProteus mirabilis (5/7); Klebsiella pneumoniae (4/7); Morganella morganii (2/7)Ciprofloxacin (750 mg, oral twice daily, 6 weeks)
* Following each bacteria, the parentheses identify the number of cultures
which were positive for this bacteria/the number of cultures that were
taken.
Table 4 presents the postoperative infection-related events. All oral
antibiotics were prescribed in response to the clinical appearance of the
stoma or skin. The rate of oral antibiotic prescription for UPIC patients
was 2/8 = 25 %; for NIC patients it was 8/22 = 36.4 % (Fisher's
p=0.682). The UPIC vs. NIC rate of debridement was 1/8 = 12.5 % vs.
0/22 = 0 % (Fisher's p=0.267), and for implant removal it was 0/8 = 0 % vs. 1/22 = 4.5 % (Fisher's p=1.000), neither a significant difference.
The number in each cell identifies the number of patients who had at most
that grade of infectious management. The parenthetical number (x) indicates
the total number of patients who were provided that level of intervention
(such as oral antibiotics) but eventually escalated to a greater degree of
intervention (such as debridement or implant removal). Specifically, 3
transtibial patients had UPIC, 2 patients were provided additional oral
antibiotics of which 1 progressed to having irrigation and debridement;
8 transfemoral patients had UPIC, 2 patients were provided additional
oral antibiotics of which 1 progressed to having irrigation and
debridement; 22 transfemoral patients had NIC, 7 were provided
additional oral antibiotics of which 1 progressed to having the implant
removed.
Osseointegration implant and clinical patient photograph. The
Osseointegrated Prosthetic Limb (OPL) which was the implant used for nearly
every patient in this study. It is a forged titanium alloy, stem-shaped
implant whose surfaces have a plasma-sprayed coating, up to 0.5 mm thick, to
promote bone ingrowth and rapid integration. The external portions of the
collars are treated with titanium niobium oxynitride ceramic to promote
smooth soft-tissue gliding, limiting the probability of symptomatic
soft-tissue adhesion and tethering. Proximal fluted fins provide initial
rotational stability, akin to a Wagner-style hip arthroplasty stem. (a)
Exploded view with the components arranged at approximately the
proximal–distal levels in which they would be once assembled and implanted
in a patient who had undergone a femoral amputation: (1) proximal cap screw;
(2) OPL body; (3) safety screw; (4) dual cone abutment adapter; (5) permanent
locking propeller screw; (6) proximal connector; and (7) prosthetic connector. (b) Photograph of a 28-year-old male with bilateral transfemoral
amputations, requiring a wheelchair for locomotion. (c) Preoperative left
and right femur radiographs, assembled to portray patient's preoperative
osteology. (d) Three months following osseointegration, the patient was fit
with bilateral prosthetic legs. Note the transcutaneous nature of the
skeletally linked prostheses. (e) Long standing radiographs of the patient
with the osseointegrated implants connected to the prosthetic legs. Note
that unlike many transfemoral amputees using a socket prosthesis whose hip
joints are abducted against the socket liner, this patient's femurs are
anatomically oriented with the hip, knee, and ankle in excellent mechanical
alignment. (f) Photograph of patient standing without a walking aid 1 year
after osseointegration.
Two patients had additional surgery to manage infectious issues. One
transtibial UPIC patient (Patient 5) had a draining sinus tract near the
skin closure, without pain, without radiographic osteolysis. Nine months
after index osseointegration, he had irrigation and debridement of the sinus
tract, soft tissue, and a minimal amount of unhealthy appearing bone,
retaining the implant. His cultures at index osseointegration grew
Enterococcus casseliflavus; Stenotrophomonas (Xanthomonas) maltophilia and he had the antibiotic regimen as reported in Table 3. His debridement
cultures grew Pseudomonas aeruginosa (3/5), Staphylococcus epidermidis (5/5), and Serratia marcescens (1/5), and his antibiotic treatment was Daptomycin
(500 mg, intravenous daily, 6 weeks) along with levofloxacin (750 mg, oral
daily, 6 weeks). He remains fully active without additional issues in the
6 months since (Fig. 2). The transtibial NIC patient had persistent pain,
reported subjective micro-motion, and had radiographic evidence of
peri-implant lucency. His first additional surgery was unsuccessful
attempted removal of the osseointegration implant; it was fixed so sturdily
it was considered a greater risk to remove it than to retain it. After 2
more months of symptoms, a second surgery successfully removed the implant
without antibiotic depot placement. His index cultures were negative, and
the removal cultures grew Streptococcus agalactiae (8/8), and his antibiotic management was
amoxicillin–clavulanate (875–125 mg, oral daily, 30 d). Nine months after
explantation he had revision osseointegration and has been active without
issue for more than 1 year.
UPIC patient who had additional surgery to manage infection. (a)
Clinical photograph identifying the patient was unable to wear his
prosthesis before surgery and was relegated to crutch ambulation because (b)
the socket prosthesis caused painful skin ulcers. (c) He developed a sinus
tract which was debrided 9 months after the index surgery. (d) Within
5 months, the patient was able to return to a higher level of activity
than before osseointegration, seen here demonstrating the ability to plant
on his osseointegrated leg in order to turn a dance partner.
Four patients had disinfection surgery prior to their subsequent
osseointegration. Three had absorbable calcium sulfate antibiotics placed
locally, and the fourth had a polymethyl methacrylate cement antibiotic
spacer placed which was removed at osseointegration. All four patients had
NIC at subsequent osseointegration. One patient was later provided a single
10-day course of doxycycline for minor stoma drainage. The other three
patients had no postoperative infectious events.
Discussion
The most important finding of this study is that UPIC at the time of primary
osseointegration does not appear to predispose to an increased risk of
additional infection-related management at 1-year-plus follow-up. The UPIC vs.
NIC rates of oral antibiotic prescription (2/8 = 25 % vs. 8/22 = 36.4 %,
p=0.682) and additional surgery to manage infection (1/8 = 12.5 % vs.
1/22 = 4.5 %, p=0.469) were not statistically different.
The selection of antibiotics for UPIC in osseointegration has not been
directly analyzed before. The delivery of antibiotics to the affected area
depends on the vascularity of the local bone and surrounding tissues and is
unpredictable in osseointegration cases. This is because amputated bone has
been previously traumatized, perhaps more than once, and may be less
biologically active since amputees load their amputated residual limb less
than their unaffected limb (Bemben et al., 2017). In general, intravenous
antibiotics seem to offer no advantage to oral antibiotics for orthopedic
infections (Li et al., 2019). Within orthopedics, however, specific
indications for the higher concentrations of drug achievable using a
parenteral route may exist but remain poorly described. Therefore, in the
context of managing UPIC after osseointegration, the effect and optimal
choice of antibiotic remains relatively unguided.
An additional consideration is that the unique transcutaneous placement of
osseointegration devices poses concerns about infection which go beyond the
usual concerns of UPIC. Unlike other surgical reconstructions where the skin
is eventually closed, new microbes can presumably enter the body via the
stoma and cause infection throughout the lifespan of the transcutaneous
osseointegrated device. This study did not evaluate those risks but instead
sought to evaluate the risks of UPIC at the time of implantation surgery.
Although no prior osseointegration studies consider the utility of cultures
taken during implantation, principles based on the following studies provide
context to this investigation and guided our practice. One of the earliest
large studies, from 1973 (Fitzgerald et al., 1973), identified 111 positive
cultures among 437 (25 %) operation-naive total hip replacements (THRs) and
84 positive cultures among 221 (38 %) previously operated hips.
Importantly, they evaluated a subset of 100 patients whose cultures grew
“more significant” bacteria. Of 23 patients treated with antibiotics
targeted toward the cultured bacteria, none developed wound infections,
whereas 5 of 77 patients (6.5 %) who were not provided an antibiotic
regimen developed wound infection (p=0.587). Carlsson et al. (1977) identified
that routine postoperative empiric prophylactic antibiotic administration
decreased total hip infection from 15 % to 2 %.
More recently, Picado et al. (2008) reported postoperative infection of 1 in 241 (0.4 %)
THRs with zero or one UPIC which received routine postoperative antibiotics,
versus 12/22 (55 %) of THRs with two or more cultures despite them
receiving targeted extended postoperative antibiotics (p<0.001). A 2006 study identified 4 of 142 (2 %)
primary THRs had UPIC; three patients received directed antibiotics and none
developed infection (Mehra et al., 2006). A 2014 study found that of 41 UPIC
among 90 total hip and knee replacements, there was no difference in implant
revision rates (septic or aseptic) through 15 years (Jonsson et al., 2014).
In total shoulder replacement, two groups identified very different rates of
UPIC but no discernible impact on eventual infection (Zmistowski et al., 2021; Wong et al., 2018; Maccioni et al., 2015). There appears to be low
consensus regarding the optimal management of UPIC in revision total joint
replacement (Purudappa et al., 2020). Although some literature suggests a
single positive culture at revision joint replacement may not require
treatment (Neufeld et al., 2021), we prefer to treat even a single positive
culture at osseointegration.
Since existing amputees have had prior surgery, there is risk for bacterial
contamination seeded at the prior operation. Additionally, osseointegration
leaves the intraosseous implant permanently exposed to the outside world, a
relatively high risk for colonization to eventually become infection (Kazmers
et al., 2016). Admittedly, it is often difficult to differentiate whether
mild erythema and non-odorous drainage is due to mere colonization or actual
infection. We believe that infection potentially compromising the
implant–bone interface may be prevented if the bone can grow onto the
implant surface before bacteria do (Hall et al., 1975; Gristina et al., 1988), although with a permanent skin disruption to accommodate the
osseointegrated device, it is uncertain whether the antibiotics truly change
outcomes (Fragomen et al., 2017). Given the potential high risk of
under-treating an bacterial infection that could compromise the implant,
versus the relatively low risk of clinically meaningful adverse events
associated with a 6-week course of antibiotics featuring close laboratory
monitoring (Kokado et al., 2019), we currently choose to provide directed
antibiotic augmentation of routine perioperative prophylactic antibiotics
for osseointegration patients who have UPIC.
The most notable limitation of this study is the sample size, in particular
having only eight UPIC patients. Further, due to sample size, risk factors
for UPIC cannot be reliably proposed. Relative strengths of this study are
that all included patients had at least 1 year of follow-up with none lost
to follow-up, and all culture results and antibiotic plans were fully
evaluable. Additionally, interventions are unlikely to have been
undocumented since patients were instructed to notify us directly about any
infectious concerns and to procure related antibiotic prescriptions only
from our team.
Conclusions
UPIC at the time of primary osseointegration with subsequent antibiotic
therapy does not appear to predispose to an increased risk of additional
infection-related management versus NIC through 1-year-plus follow-up.
Although the therapeutic benefit of providing a course of antibiotics versus
no additional antibiotics following UPIC is unknown, it did not appear to
increase the risk of other adverse outcomes in our cohort.
Ethical statement
Our institution's ethics committee approved this research. The photographed
patient consented to publication of de-identified photographs.
Data availability
The underlying research data are not accessible because of university and
research institution policies.
Author contributions
JSH, TJR, and SRR were involved in the study conceptualization. JSH and TJR were involved in formal analysis and data curation. JSH wrote the original draft. MWH and AOM provided resources. JSH, TJR, MWH, AOM, SRR, and ACK performed review and editing.
Competing interests
The contact author has declared that neither they nor their co-authors have any competing interests.
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 Marjan Wouthuyzen-Bakker and reviewed by two anonymous referees.
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