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2 Antibiotic Stewardship inOrthopedic Surgery
11
related toxicity and secondary infections like
Clostridioides difcile colitis. Additionally, the
prudent use of antibiotics for a shorter period
lessens the selection pressure on microbes, reducing the possibility of resistance emerging [5].
This strategy supports responsible antibiotic use
in the context of bone and joint infections while
aligning with the larger antimicrobial stewardship agenda, protecting antibiotic effectiveness
for coming generations.
Combination Therapy: Treatment for complex
bone and joint infections, often characterized by
biolm development or the presence of multidrugresistant organisms, presents special difculties.
Combination antibiotic treatment, which involves
giving two or more antibiotics simultaneously
with various modes of action, may be the answer
[9]. Combination treatment may improve microbiological eradication and stop the establishment
of resistance by treating the infection from many
perspectives [12]. Combination treatment has
several advantages, but these must be carefully
evaluated against any negative effects it can have,
such as higher toxicity or the possibility of medication interactions [23]. A thorough knowledge
of the relevant organisms, their resistance proles, and their synergistic interactions should be
the basis for selecting antibiotics. Meticulous
clinical surveillance is necessary to evaluate the
effectiveness and side effects of combination
regimens [13]. As a result, although combination
treatment has promise in treating complex infections, it must be used carefully and based on evi-
dence if patient safety and therapeutic
effectiveness are to be guaranteed.
Optimal Dosing and Route of Administration:
Therapeutic antibiotic levels must be reached at
the injection site for bone and joint infections to
be successfully treated. Pharmacokinetic and
bioavailability factors have a signicant inuence on dosing regimens [14]. Clinicians may
adjust doses to reach effective concentrations at
the infection site while reducing systemic toxicity by being aware of the drug’s distribution,
metabolism, and elimination characteristics.
Additionally, new administration techniques
have increased the range of available treatments
[15]. The focused release of antibiotics at the
infection site is made possible by local antibiotic
delivery systems, such as antibiotic-impregnated
bone cement or implant coatings, which encourage greater drug concentrations and minimize
systemic exposure [5]. This targeted strategy
reduces the possibility of systemic adverse effects
while simultaneously improving antibacterial
effectiveness [16]. The best delivery method,
whether oral, intravenous, or local, depends on a
thorough comprehension of the illness’ features
and the selected antibiotics’ pharmacokinetics. In
order to maximize therapeutic efcacy while limiting possible damage, it is important to achieve
appropriate dose and administration procedures
[17]. It ensures that antibiotics are delivered
exactly where they are required.
An example of a “Comparative Antibiotic
Protocols” table
Orthopedic
surgery type
Joint
replacement
Fracture
xation
Spinal fusion Vancomycin and
Revision
surgery
Recommended
antibiotics Dosage and administration
Cefazolin 2g IV within 1h prior to
Ceftriaxone 1g IV pre-op, repeat if surgery
cefazolin
Vancomycin and
ciprooxacin
incision
>3h
15–20mg/kg IV within 1h
prior to incision, plus cefazolin
2g IV
Vancomycin 15–20mg/kg IV
within 1h prior to incision,
plus ciprooxacin 400mg IV
Duration of
prophylaxis Additional considerations
Single dose, up
to 24h post-op
Single dose, up
to 24h post-op
Single dose, up
to 24h post-op
Multiple doses
as per procedure
duration
Consider patient
allergies, MRSA
colonization
Tailor for open
fractures, patient’s
immune status
Address MRSA risk,
patient allergies
Tailor for implantrelated infections,
microbial culture results
12
K. M. Emara et al.
2.5 Surgical Management
The complete care of bone and joint infections
includes surgery, a reliable ally that enhances the
effectiveness of antibiotic therapy. Recent
improvements in surgical methods have brought
forth a new age of accuracy and inventiveness,
enhancing the toolkit against these difcult illnesses [18]. The use of minimally invasive techniques and biolm-targeted strategies is
highlighted in this section, which also examines
the changing landscape of surgical interventions.
It also emphasizes the critical value of surgical
debridement, the removal of infected hardware,
and careful soft tissue management [19]. The surgical treatment of bone and joint infections has
been transformed by the development of less
invasive procedures. These procedures provide
patients with quicker recoveries and lower postoperative morbidity since they have fewer incisions and less tissue damage. In order to precisely
debride and remove infected tissue while limiting
collateral damage, arthroscopy, for instance,
offers a clear view into joint areas [20].
Additionally, the development of biolm- targeted
therapies intends to address the ongoing problem
presented by bacteria entrenched in biolms.
These tenacious populations may be eliminated,
recurring infections prevented, and more effective treatment made possible by methods utilizing antimicrobial coatings on implants or targeted
drug delivery systems [21]. The precise surgical
debridement procedure is essential to successfully managing bone and joint infections.
In order to stop the spread of the infection and
provide an environment favorable for healing,
this operation entails the excision of diseased tissue, necrotic bone, and surfaces coated with biolm. It is often essential to remove contaminated
hardware simultaneously as the germs, such as
prosthetic joints or xation devices [22]. To prevent recurrence and ensure that the future stages
of therapy go as smoothly as possible, these
niduses of infection must be carefully removed.
Surgical procedures that include tissue preservation, reconstruction, or ap covering are essential
to restore the integrity of the injured region.
Surgeons strengthen the basis for later interven-
tions and assist in eliminating infection by establishing a healthy environment for wound healing
[23]. The idea of single-stage treatments has
attracted interest in certain circumstances because
it can simplify therapy. In one surgical procedure,
this method involves the removal of contaminated implants, complete debridement, and
prompt implant exchange [24].
Additionally, single-stage treatments seek to
manage infection while limiting the patient’s
exposure to many operations using well-thoughtout guidelines and patient selection criteria [25].
In addition to maximizing patient comfort, this
strategy may save healthcare expenditures and
cut the length of antibiotic medication.
2.6 Antibiotics’ Importance
inOrthopedic Surgery
Each orthopedic surgical approach is intended to
address a specic musculoskeletal issue. No matter how complicated fracture xations or subtle
joint replacements are, lowering infection risks is
a problem that affects all of them. Within this
spectrum of surgical therapies, antibiotics stand
out as crucial allies in the ght against infectionrelated issues [26]. Orthopedic surgeons can
effectively stop the potential damage from postsurgical infections by harnessing their strength. It
is not easy to overstate how crucial it is to use
antibiotics sensibly in this situation. It signicantly inuences how quickly wounds heal, how
long patients must stay in the hospital, and how
well they will eventually recover from surgery
[27]. The deliberate use of antibiotics by the
orthopedic profession enhances its dedication to
enhancing patient outcomes and ensuring that the
promise of successful surgical treatments is
upheld without exception.
2.7 Preventing Antibiotic
Resistance
Stewardship of antibiotics is an essential part of
the worldwide response to the growing danger of
antimicrobial resistance. Orthopedic doctors sig-
2 Antibiotic Stewardship inOrthopedic Surgery
13
nicantly impact preventing the spread of microorganisms resistant to antibiotics in orthopedic
surgery, where bone and joint infections are
common [28]. This crucial function encompasses a range of tactics intended to maintain the
effectiveness of antibiotics for both the present
and future generations, in addition to clinical
judgments.
Infection Prevention Measures The key to
infection control is still prevention. By applying
strict infection prevention methods, orthopedic
surgeons may signicantly reduce the prevalence of infections in the bones and joints [29].
It calls for using sterile methods while performing surgery, appropriate wound care techniques,
and fostering aseptic conditions in healthcare
settings. The need for antibiotics may be
decreased by avoiding infections altogether,
lowering the selection pressure that feeds antibiotic resistance.
Adhering to Evidence-Based Guidelines
Orthopedic surgeons have access to a multitude
of clinical advice and guidelines. Adopting evidence-based recommendations guarantees that
the newest research and industry standards
inuence antibiotic treatment [30]. This method
decreases the empirical use of antibiotics while
maximizing treatment choice, dosage, and duration. Orthopedic surgeons may achieve positive
patient outcomes while minimizing the probability of antibiotic resistance development by
making treatment choices based on the best
available data.
Promoting Awareness among Healthcare
Providers
Fostering an awareness and education
culture among medical professionals is essential
in bone and joint infections. By participating in
educational activities that stress the signicance
of sensible antibiotic use and the effects of antibiotic resistance, orthopedic surgeons may assume
a leadership position in the medical community
[31]. Surgeons may encourage a community
commitment to antibiotic stewardship by facilitating multidisciplinary teamwork and disseminating information about emergent resistance
trends. To ensure the healthcare team is informed
and in sync with the most recent developments,
they should also promote ongoing education on
new diagnostic techniques, therapeutic modalities, and infection control techniques.
2.8 VI.Future Directions
With the persistent advancement of research and
the introduction of cutting-edge technology,
treating bone and joint infections is about to
undergo signicant changes. The use of pharmacogenomics in treatment plans is one possible
route [31]. Clinicians can maximize treatment
effectiveness while limiting adverse responses by
customizing antibiotic selections depending on a
patient’s genetic prole [32]. This precise strategy has the potential to completely change the
way we treat infections by guaranteeing that
patients get the best care with the fewest risks.
The subject of immunotherapy, which is quickly
developing, provides a fascinating complement
or alternative to conventional antibiotic treatment. A potential approach to preventing bone
and joint infections is using the body’s immune
responses to pinpoint and eliminate invading
organisms [18]. Monoclonal antibodies, vaccinations, and immune-modulating drugs all have the
potential to strengthen the host’s defenses,
thereby improving outcomes and reducing the
need for antibiotics.
Moreover, nanomedicine, which can control
materials at the nanoscale, opens up new possibilities for treating infections and delivering
drugs [3]. Antibiotic concentrations may be
increased while systemic exposure is decreased
by using nanoparticles to deliver the drugs
directly to the sites of infection. By limiting the
use of antibiotics widely, this focused strategy
improves treatment effectiveness and slows the
development of resistance [11]. While these
developments provide promising futures, the
core idea of antibiotic stewardship must remain
unwavering. Responsible antibiotic usage guarantees that the limited supply of powerful antibiotics is preserved for the next generations in the
face of developing therapies. Maintaining a bal-
14
K. M. Emara et al.
ance between implementing new tactics and preserving the effectiveness of current antibiotics
becomes more important when breakthrough
medicines are developed.
In conclusion, a multidisciplinary approach to
diagnosis and treatment is required for bone and
joint infections, a serious concern in orthopedic
surgery. Orthopedic surgeons may improve
patient care while ensuring the continued effectiveness of antibiotics by practicing antibiotic
stewardship, which is supported by current
research and recommendations. Orthopedic surgeons may make a signicant and scientically
sound contribution to the ght against musculoskeletal infections by adopting customized therapy, surgical innovation, and techniques to
overcome resistance [12]. Additionally, the
explosive expansion of antibiotic usage in orthopedic surgery is evidence of recent medical
advances. Thanks to the adoption of cutting-edge
techniques, like preoperative prophylaxis, intraoperative redosing, and precisely devised postoperative care, orthopedic surgeons are now at the
forefront of infection management [20]. These
cutting-edge techniques show a strong commitment to evidence-based approaches, ensuring
patient welfare is always prioritized in orthopedic
therapy. These recommendations improve patient
outcomes, which is a testament to the dedication
and expertise of medical professionals.
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Optimizing Antibiotic Treatment
ofBone andJoint Infections:
Pharmacokinetics
andPharmacodynamics
MarcoTrevenzoli, VincenzoScaglione,
andAnnamariaCattelan
3
3.1 Introduction
As a general rule, in bone and joint infections
(BJIs) clinical success is obtained through the
combination of antimicrobial and surgical
approaches [1, 2] (Fig.3.1).
Whenever possible, starting antibiotic therapy
should be delayed until bone or synovial cultures
are obtained, although blood cultures, if signicant, can be reliable for aetiological in situ diagnosis. Patients treated with antibiotics recently,
who do not require surgical intervention immediately, should discontinue antibiotics for at least
2weeks before debridement to optimize microbiologic diagnosis [2].
The length of the clinical course before clinical approach is important since chronic BJIs are
associated with avascular necrosis, determining
bone sequestra (dead bone), and surgical debridement is necessary to restore optimal bone vascu-
M. Trevenzoli · V. Scaglione
Infectious and Tropical Diseases Unit, Department of
Medicine-DIMED, Padua University Hospital,
Padova, Italy
A. Cattelan (*)
Infectious and Tropical Diseases Unit, Department of
Medicine-DIMED, Padua University Hospital,
Padova, Italy
Department of Molecular Medicine-DMM,
University of Padua School of Medicine,
Padova, Italy
e-mail: annamaria.cattelan@unipd.it
larization. Conversely, acute BJIs may be treated
with antibiotic therapy alone because pathophysiological alterations should have only a small
effect on drug exposure.
The choice of the adequate antibiotic therapy
should take into account by presence of orthopedic hardware since bacteria may produce biolm, determining a greater risk of clinical failure.
Therefore, the therapeutic strategy must include
the removal of prosthetic materials, which is an
“overture” to an effective antibiotic therapy,
determining source control, starting the real cure
effectiveness.
As empiric antibiotic treatment, we recommend molecules highly penetrating bone and
joint tissues with adequate coverage spectrum
against Gram-positive bacteria (i.e.,
Staphylococcus spp.).
In a setting with high rates of methicillinresistant Staphylococcus aureus (MRSA) or
patients with risk factors for MRSA infections,
adequate coverage should be included empirically, while extensive Gram-negative coverage
should be tailored to patient characteristics.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2025
P. Ruggieri et al. (eds.), Bone and Joint Infections, https://doi.org/10.1007/978-3-031-96383-4_3
17
18
Pathophysiological scenarioTherapeutic scenario
Fig. 3.1 Key elements
characterizing
osteoarticular infections
Antibiotic therapy
PK/ PD
MIC
Biofllm activity
Surgery
Surgical debridment
M. Trevenzoli et al.
Necrosis: bone sequestra
Vascolarization
Characteristics of
bacterial strains
3.2 Pharmacokinetics
Most pharmacokinetics (PK) studies are based on
drug concentrations measured in plasma or
serum, but this may not be the best measure of
drug exposure at the action site, such as in bone.
Bone is a complex tissue composed of both
organic and inorganic materials. Representing
around 30–35% of bone mass, the organic matrix is
made up of extracellular uid, collagen brils, glycoproteins, and proteoglycans. Bone blood vessels
pass through Havers’ and Volkmann’s canals, which
are channels that run through the matrix of the bone.
Bone cells (osteocytes in the mature form) are
enclosed in the matrix and represents only 1–2% of
bone mass, are enclosed in the matrix in their most
mature form, osteocytes. The inorganic matrix,
which makes up 65–70% of bone mass, is made up
of hydroxyapatite (calcium- phosphate) crystals
deposited within the organic matrix [3].
Bacteria and antibiotics are unlikely to be
evenly distributed in bone tissue due to its heterogeneous composition. The precise localization of
pathogens within bone remains a topic requiring
further exploration. Considering bacterial size,
for instance, the approximate diameter of
Staphylococcus aureus (~1μm), it is anticipated
that these bacteria may disseminate through the
Haversian canals and Volkmann canals, each
with a diameter of around (~70μm), yet not penetrate calcium-phosphate crystals. S. aureus
demonstrates the ability to invade and persist
within osteoblasts, potentially contributing to
instances of relapse. Additionally, this pathogen
is able to adhere to bone matrix components like
collagen [4].
It is difcult to isolate and measure the concentrations of different components of bone.
Therefore, most published studies rely on homogenized samples of bone, reporting total concentrations of the drug in these samples. It is worth
noting that only the unbound drug is known to be
active microbiologically, and this should be borne
in mind when interpreting bone penetration ndings. Total drug concentrations in the bone
homogenate, however, if determined reliably and
analyzed using Monte Carlo simulations and
population pharmacokinetic (PK) modeling,
might provide a better prediction of therapeutic
success compared to serum concentrations, as
serum concentrations are less representative of
what is happening in the bone matrix [5].
Median bone: serum concentration ratio
3 Optimizing Antibiotic Treatment ofBone andJoint Infections: Pharmacokinetics andPharmacodynamics
Fig. 3.2 Different
antibiotic groups’ bone
penetration. The lines
indicate the medians of
the groups, and each
symbol indicates the
median concentration
ratio of one study.
(Reproduced with
permission of Springer
from [5])
3
2
1
0.5
0.3
0.2
0.01
0.05
19
3.3 Fluoroquinolones
Fluoroquinolones are commonly used to treat
bone infections due to their exceptional ability to
penetrate bone tissue [5]. Compared to other antibiotic groups, uoroquinolones exhibit some of
the greatest median bone:serum concentration
ratios, typically ranging from 0.3 to 1.2 (Fig.3.2).
This remarkable penetration might be attributed
to the interaction between quinolones and calcium present in bone. However, it is important to
note that only unbound or “free” antibiotic molecules are regarded as microbiologically active.
Therefore, the actual concentrations of quinolones that are available for antimicrobial action
are probably less than the overall concentrations
in bone.
Interestingly, the bone:serum concentration
ratios of the majority of quinolones tend to rise
with time since the last dose, as recently observed
for ciprooxacin. This suggests a slow redistribution of quinolones from bone back into the blood
circulation [6].
Macrolides
Quinolones
Clindamycin
Linezolid
Rifampicin
Glycopeptides
Penicillins
Cephalosporins
-Lactamase-inhibitors
Fosfomycin
Fusidic acid
Tetracycliness
Additionally, quinolones generally exhibit
good cellular penetration, which could be benecial in treating osteomyelitis caused by S. aureus,
as S. aureus has been shown to invade and persist
within invitro osteoblasts [4].
3.4 Macrolides andClindamycin
Macrolides seem to be a heterogeneous group
with respect to their pharmacokinetics in bone,
with probably low bone penetration being
reported for erythromycin and very high bone
penetration being reported for azithromycin.
Indeed, concentrations in cortical bone of
erythromycin were detected only in two of
eight patients [7] while better data are reported
for azithromycin in two recent studies in
which patients were treated with 500 mg of
azithromycin once a day for 3 days before
periodontal surgery [8, 9]. In both studies, the
average concentration of azithromycin in bone
increased slightly from 12 h to 2.5 days,
20
M. Trevenzoli et al.
reached a peak of over 6, and then slowly
decreased to about 2.5 at 6.5 days [8, 9].
However, it is not known how quickly azithromycin penetrates bone because the first samples were taken at 12h.
Clindamycin is frequently said to have good
bone penetration. However, the median
bone:serum concentration ratio of 0.35 obtained
from four clindamycin investigations is lower
than that of uoroquinolones (0.50) and linezolid (0.48) [5]. The majority of clindamycin
research was carried out in the 70 s, before
azithromycin, linezolid, and uoroquinolones
became available. So, at the time, clindamycin
had better bone penetration than other antibiotics. All clindamycin investigations utilized bioassays, which may be affected by clindamycin’s
active metabolites. The ndings of several
investigations indicate that clindamycin has a
bone penetration extent of 0.21–0.45, which is
comparable to or somewhat greater than that of
cephalosporins [5].
3.5 Tigecycline andTetracyclines
Scant research is available regarding tetracyclines, and ndings differ despite the high
calcium- binding afnity of tetracyclines.
Regarding tigecycline, initial bone sample analysis from 25 uninfected surgical patients
revealed relatively low concentrations [10].
When the same samples were reanalyzed using
a new liquid chromatography–tandem mass
spectrometry (LC-MS/MS) assay, with a stabilizing agent, bone concentrations were found to
be on average 9.5 times greater than with the
previous approach [11]. This highlights how
important it is to validate all facets of analytical
approaches. Extensive penetration of tigecycline into bone has been reported in a more
recent study in 33 uninfected surgical patients.
Using a validated LC-MS/MS assay, the authors
reported a bone:serum concentration ratio of
4.77 based on the ratio of appropriate use criteria (AUCs) in the matrices [12].
3.6 Cephalosporins
Many studies have been done on how well cephalosporins penetrate bone. For cefuroxime, the
average ratio of bone concentration to serum concentration was 0.32 (range 0.09–0.55, 10min to
6.5h after a dose) in ve investigations in which
serum and uninfected bone concentrations were
reported, with most samples above the limit of
detection [5]. A recent study looked at the bone
penetration of cefuroxime in uninfected surgery
patients undergoing knee replacement [13]. In 9
patients who received the drug by short-term
infusion and 9 patients who received it by continuous infusion, the respective bone:plasma concentration ratios on the basis of unbound AUCs
after population PK modeling were 1.03 for cancellous bone and 0.35 for cortical bone; the corresponding ratios for continuous infusion were
1.15 and 0.65.
Ceftriaxone and cefamandole were tested in
the same study on patients having hip replacement surgery. At 10–30min after the dose, the
average ratio of bone concentration to serum concentration was 0.156 (0.123–0.190) for ceftriaxone. At 8 h after the dose, the ratio of bone
concentration to serum concentration for ceftriaxone was 0.142 (0.073–0.210), which is very
similar to the ratio at 10–30min. This suggests
that ceftriaxone reaches equilibrium between
serum and bone quickly [14]. However, a more
recent study suggested that equilibrium is reached
more slowly [15]. In 11 patients who were having
surgery to remove dead bone from a broken leg
that had become infected, the average ratio of
bone concentration to plasma AUC for ceftriaxone was 0.093in the outer bone (cortical bone)
and 0.241 in the inner bone (cancellous bone)
[16]. For cefazolin, the median ratio of bone concentration to serum concentration in eight
patients with infected bones was 0.25 (range
0.06–0.41) over the course of a continuous infu-
sion, with concentrations assessed using bioassay
[17]. A more recent investigation performed
using 24-h plasma sampling and bone microdialysis, and quantied cefazolin by high-
3 Optimizing Antibiotic Treatment ofBone andJoint Infections: Pharmacokinetics andPharmacodynamics
21
performance liquid chromatography (HPLC),
showed mean AUC-based bone:plasma concentration ratios of 0.74±0.36 and 0.99±0.59 for
the left and right sternum of coronary artery
bypass graft (CABG) patients [18].
3.7 Ceftobiprole
Ceftobiprole has been shown to penetrate bone
tissue, with a cortical and cancellous bone-toserum penetration ratio of 0.22 and 0.06, respectively, in patients undergoing elective total hip
replacement [19]. However, there is no data on
trough concentrations in bone, so it is not possible to assess whether PK/PD targets are achieved
at the infection site [20].
3.8 Penicillins, Carbapenems,
andβ-Lactamase Inhibitors
Two studies by different groups in 1994 and 2001
looked at how well piperacillin/tazobactam penetrates uninfected hip bone in 12 patients each.
The studies used the same methods to prepare
and analyze the samples and found similar
results. The ratio of bone concentration to plasma
concentration was 0.2–0.3 for both piperacillin
and tazobactam in both the outer bone (cortical
bone) and the inner bone (cancellous bone)
1–1.5h after the dose [21, 22]. More recently, a
study looked at how well piperacillin/tazobactam
penetrates uninfected jaw (7 patients) and hip (2
patients) bone [23]. The samples were prepared
in a similar way to the previous studies, and the
concentrations were assessed using a different
method called LC-MS/MS. On average, 3 h
(range 1–7h) after the start of the infusion, the
ratio of bone concentration to plasma concentration was 0.13 for tazobactam and 0.15 for piperacillin. These ndings were somewhat lower and
more varied than the results from the previous
studies, which may be because different types of
bone were studied and the samples were taken at
different times. Studies using a different method,
the bioassay, have reported a broad range of mean
amoxicillin bone:serum concentration ratios. A
study of 20 patients undergoing hip replacement
surgery found that the ratio of bone AUC to
serum AUC was 0.18 (0.11–0.29) for cancellous
bone and 0.20 (10–90th percentile for interpatient variability 0.16–0.25) for cortical bone
[24]. The ratio of bone AUC to serum AUC for
clavulanic acid in the same study was 0.10
(0.051–0.21) for cancellous bone and 0.15
(0.11–0.21) for cortical bone. Recently, a report
reported bone-serum ucloxacillin concentration
ratios, using HPLC analysis, of 0.07–0.08 and
0.05–0.06 for hip and knee bone, respectively, in
the rst hour and a half following administration
of the drug [25]. Carbapenems have been the subject of only a few investigations, and the results
are difcult to interpret because of problems with
the methods used [5]. However, a recent study on
ertapenem that involved taking samples over
2–28h and analyzing them using liquid chromatography–mass spectrometry (LC-MS) and population PK modeling reported a bone:plasma
concentration ratio of 0.025in 10 patients [26].
3.9 Linezolid
Linezolid is more stable than many β-lactams,
and all linezolid bone penetration studies have
used HPLC to assess the drug concentrations. In
12 hip replacement patients, the average
bone:serum concentration ratio at 30–50 mins
following infusion initiation was 0.51 (95% condence interval: 0.43–0.75) [27]. Similar penetration (0.40 ±0.24) was found at 1.5 h in 12
elderly patients during knee replacement [28].
However, in 11 patients with infections associated with implants, the mean bone:plasma concentration ratio was lower (approximately 0.23)
at the same dose as the two joint replacement
studies and 0.5–1.5h after the dose [29].
Two investigations have used microdialysis to
measure linezolid concentrations in bone [18,
30]. In three patients with severe diabetic foot
infections, the unbound AUC (fAUC) ratio in
cancellous bone to plasma over 12 h was
1.09±0.11 [30]. The 24-h sternal bone ratio in
nine uninfected subjects undergoing coronary
artery bypass grafting was 1.02 ±0.47 for the