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176
Fig. 13.1 The epidemiology of diabetic foot infections [3]
B. A. Lipsky and S. A. V. van Asten
Pathophysiology
Most cases of DFO represent contiguous spread
of infection from adjacent soft tissues to bone
[1]. These infections typically begin with a break
in the skin envelope, most often related to a diabetic foot ulcer. The main predisposing factors
for these ulcers are the long-term presence of
peripheral neuropathy, usually accompanied by
peripheral arterial disease. Similarly, limited
joint mobility or structural deformities (either
spontaneous, traumatic, or postoperative) may
lead to abnormal weight bearing, thus ulceration.
Microorganisms, almost always bacteria, from
either contiguous skin ora or an exogenous
inoculation, will colonize any open wound. As
diabetes of long duration is often accompanied
by various humoral and cellular immunological
perturbations [10], colonizing organisms can
reach critical levels, usually dened as ≥105 colony forming units/gram of tissue. At this point
signs and symptoms of inammation, classically
redness, warmth, swelling, pain or tenderness, or
purulent secretions, may appear. The presence of
two or more of these ndings classies the
wound as infected. Unchecked, this supercial
infection can spread horizontally and vertically,
following the path of least resistance along the
tendons to involve progressively deeper soft tissues. At some point the infection can involve the
cortex of underlying bone (osteitis), and then
make its way into the bone medulla or marrow
(osteomyelitis). Only in rare instances is DFO
specically a consequence of vascular insufciency, hematogenous spread, or direct inoculation of microorganisms.
Microbiology
Any microorganism that infects the skin can
spread to involve bone. The etiologic agents
causing DFI depend on many factors, including
the geographic location of the patient (e.g., climate and socio-economic issues), the chronicity
of the wound (which can evolve over time),
where the infection was acquired (e.g., home versus a health-care institution), specic exposures
(e.g., waterborne pathogens like Pseudomonas),
and any recent antimicrobial treatment (often
leading to antibiotic-resistant pathogens). Most
DFIs in North American and European countries
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177
are caused by aerobic gram-positive cocci, especially Staphylococcus aureus, and to a lesser
extent streptococci, enterococci, and coagulasenegative staphylococci [11]. Cultures of specimens from chronic wounds often grow multiple
isolates on wound cultures, particularly if they
were from a swab rather than tissue. Wound cultures from a patient presenting in a warm climate,
with a chronic infection, or who has been recently
treated with antimicrobials are more likely to
grow aerobic gram-negative organisms, including Enterobacteriaceae and P. aeruginosa.
Obligately anaerobic bacteria are likely present
in many infections, but relatively infrequently
isolated because: (1) anaerobic cultures are not
specically ordered or available; (2) appropriate
specimens for growing anaerobes (tissue) are not
collected; (3) microbiology laboratories often do
not process specimens optimally for anaerobes;
and (4) reports of the presence of anaerobes are
often provided separately and later, and thus do
not inuence treatment. When anaerobic organisms are reported, they are most often isolated
from necrotic or ischemic wounds; they are also
more often detected by molecular (genotypic)
than standard (phenotypic) microbiologic techniques [12].
As with other DFI, bacteria causing DFO may
be resistant to commonly used antibiotics, especially if the patient has recently been treated with
antibiotics (topical or systemic). The most common drug-resistant pathogen in DFO is
methicillin- resistant S. aureus (MRSA) [13]. The
incidence of MRSA in DFI, after rising in the late
twentieth and early twenty-rst century, has
decreased more recently. A preliminary study
from Rome (likely conducted in the early 2000s)
reported that of 765 episodes of DFI among 482
patients, 59.4% of S. aureus isolates were MRSA
[13]. More recently, a case series of 302 patients
with osteomyelitis of the foot and ankle (84% of
whom had diabetes) from northern California
found that MRSA was isolated in 28.3% of
selected patients in 2005, but only 10.6% of
selected patients in 2010 (p=0.03) [11].
Several studies have shown that in cases of
DFO, cultures of specimens from bone are more
accurate than those from soft tissues, even deep
tissue specimens near the bone [14, 15]. In general, specimens of bone, compared to those of
soft tissue, grow fewer isolates, and most often
the predominant pathogen is S. aureus. Optimally,
a specimen of bone should be obtained by aseptic
sampling, either at the time of open surgery or by
percutaneous puncture though closed and uninfected skin. Bone specimens taken through an
open wound are likely to grow organisms that are
contaminants [16]. As with all bacterial cultures,
recent or current antibiotic therapy may result in
false-negative results. In this case, conducting a
histopathologic examination of the specimen
may help detect evidence of infection, and even
show the Gram-stain morphology of the infecting
organism(s). Only a few studies have examined
the results of employing molecular microbiological techniques on bone specimens from DFO.In
one study of 20 patients in Sydney, DNA sequencing found that 70% of the bone samples had polymicrobial ora, with the most commonly isolated
species being Corynebacterium, followed by
Finegoldia, Staphylococcus, Streptococcus,
Porphyromonas, and Anaerococcus [17]. Another
study found that molecular, compared to standard
culture, techniques for DFO bone specimens
more often revealed anaerobic and fastidious
organisms [12]. These results are similar to those
from molecular microbiologic studies of soft tissue infections. It remains unclear, however, how
to use these data clinically—specically, which
of the several isolated organisms are pathogens
that must be specically targeted with antibiotic
therapy.
While sampling a bone specimen provides the
most accurate microbiological information for
both diagnosing osteomyelitis and selecting
pathogen-specic antibiotic therapy, it is not
required in every case [18]. Certainly, obtaining a
bone specimen is easy if the plan is to operate on
the foot. If not, percutaneous bone biopsy is safe,
but it requires a skilled clinician, adds expense
(for both obtaining and processing the specimen),
and takes extra time both to obtain the specimen
and for processing (especially for histopathology) [14]. While not always needed, sampling
bone is particularly useful when the diagnosis of
osteomyelitis remains uncertain based on other
178
B. A. Lipsky and S. A. V. van Asten
diagnostic studies, or in cases where predicting
the pathogen (or its antibiotic susceptibility) is
difcult.
Treatment
Osteomyelitis is a difcult infection to treat [19].
Reasons for this include: the infection is usually
chronic (characterized by necrotic bone) by the
time it is diagnosed; bone has a limited blood
ow (and therefore relatively few leukocytes);
and the most common pathogens are virulent
(e.g., S. aureus) and usually biolm producers [9,
20]. Biolm infections are characterized by bac-
teria with a low multiplication rates and reduced
susceptibility to antibiotics [21].
Before the 1940s, surgical resection was the
only proven successful method of eradicating
bone infection. Amputations (most often abovethe- knee) were the main treatment for DFO
because of concern, in the absence of antibiotic
therapy, for infection spreading proximally if all
infected bone and soft tissue were not removed.
In the early 1940s oral sulfonamide therapy was
tried, but with what degree of success is unclear.
It was the arrival of penicillin antibiotics in the
mid-1940s that led to dramatically improved success rates in treating DFO [19]. While surgical
resection was still frequently employed, along
with antibiotics, they were more often bonesparing and any required amputations could usually be performed at a more distal level.
Starting in the mid-1980s reports of outcomes
for DFO patients who either refused or could not
tolerate surgery demonstrated that antibiotic therapy without bone resection could cure some
cases. There are now many published cases series
[22, 23], and at least one randomized controlled
trial [24], demonstrating that antibiotic therapy
without surgery for properly selected patients
with DFO can offer similar results to those with
surgery. A review of 10 studies of DFO managed
with nonsurgical antibiotic treatment found
remission rates of 64–83% (Fig.13.2) [25]. Even
with combined antibiotic and surgical therapy,
however, failure rates of treatment for DFO can
be high. One study that followed 184 cases of
foot osteomyelitis (89% of which were in patients
known to have diabetes) for a mean of 9 months
after they underwent surgical resection found that
an unplanned resection of bone or major amputation occurred in 34% of the patients at 1 year, and
in 41% by 2years [26]. Signicant risk factors
for failure by multivariate analysis included
infection with P. aeruginosa or E. coli and inad-
equately addressed peripheral arterial disease.
Perhaps the most recent and comprehensive guidance for treating DFO is found in the recently
updated guidelines on infection from the
International Working Group on the Diabetic
Foot (IWGDF) [3]. The IWGDF recommendations specic to managing DFO are summarized
in Table13.1.
Surgical Treatment
Surgical resection of infected and necrotic bone
was the rst, and perhaps remains the principal,
approach to treating chronic osteomyelitis. It
allows rapid and effective reduction of the bacterial load at the infected site, removes necrotic tissues, and may allow reconstruction that will
avoid future foot ulcerations [27]. Surgery may
be required in several situations, as when: bone
protrudes through the ulcer; imaging reveals
extensive bone destruction or progressive bone
damage in a patient undergoing antibiotic treatment; the soft tissue envelope is destroyed; or
there is gangrene or spreading soft tissue infection [28]. The presence of either limb ischemia or
soft tissue infection (especially both) in a case of
DFO is associated with a worse prognosis. One
study reported that when neither of these complicated DFO, conservative surgery achieved 100%
success, while in the cases with ischemia and
spreading soft tissue infection 78% required
some type of amputation and the mortality rate
was 13% [29]. The planned surgical approach to
DFO should balance removing as much infected
bone as possible against preserving foot function
[28]. In the hands of experienced surgeons, “conservative” (foot sparing) surgery, based on preop-
Jordano-Montenez 2014, Spai
83% 81% 80%
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179
Study Design
RCT
Prospective
Retrospective
% Remission
Game 2008, UK
Lessens 2011, France
Fig. 13.2 Reported rates of remission of diabetic foot osteomyelitis treated with antibiotic therapy but without surgical
resection. (Modied from [25], with permission). RCT randomized controlled trial
Table 13.1 Recommendations from the International Working Group on the Diabetic Foot (IWGDF) 2019 guidelines
specic to treatment of diabetic foot osteomyelitis (DFO) [3]
Number of the
recommendation Brief description of recommendation
Recommendation 21(A) In uncomplicated forefoot DFO with no other indication for
surgery, consider antibiotic therapy without surgical resection of
bone
(B) With probable DFO and concomitant soft tissue infection,
urgently evaluate the need for surgery and intensive postoperative
medical and surgical follow-up
Recommendation 22Select antibiotic agents for DFO from among those that have
demonstrated efcacy for osteomyelitis in clinical studies
Recommendation
23
Recommendation 24For DFO initially requiring intravenous therapy, consider switching
(A) Treat DFO with antibiotic therapy for ≤6 weeks. If infection is
not improving within 2–4 weeks: reconsider the need for bone
culture; undertake surgical resection; or select an alternative
antibiotic regimen
(B) Treat DFO with antibiotic therapy for just a few days if there is
no soft tissue infection and all the infected bone has been surgically
removed
to an oral regimen with high bioavailability after ~5 to 7 days, if the
likely or proven pathogens are susceptible to an available oral agent
and there is no clinical condition precluding oral therapy
Embil 2008, Canada
Vakabhji 2009, UK
75%
Lazraro Martinez 2014, Spain
75% 73%
70% 67%
n
Acharya 2013, UK
Pittet 1999, Switzerland
64% 64%
Zeun 2016, Uk
Senneville 2008, France
Strength of
recommendation; level
of evidence
Strong; moderate
Strong; moderate
Strong; moderate
Strong; moderate
Weak; low
Weak; moderate
erative imaging and intraoperative evaluation
Systemic Antibiotic Therapy
with attention to conserving bones and the soft
tissue envelope, has produced good long-term
outcomes. One prospective study reported a rate
of recurrence of infection after conservative surgery for DFO of only 4.6% [30].
Patients who undergo surgical resection for DFO
should almost always also receive systemic antibiotic therapy. Exceptions may include cases in
which it is clear that all infected bone and soft
180
B. A. Lipsky and S. A. V. van Asten
tissue have been removed. Treating patients with
DFO exclusively with antibiotics may offer the
potential to avoid: hospitalization; the expense
and risk involved with surgical procedures; and
biomechanical problems (e.g., transfer or recurrent ulcers) that may be induced by surgical
resection of all or part of the foot [20]. Appropriate
cases for nonsurgical treatment are generally
those: (1) with infection limited to the forefoot;
(2) that do not require extensive soft tissue resection; and (3) in which the causative pathogen is
susceptible to highly bioavailable oral antibiotic
agents.
After the introduction of penicillin, several
other newly developed antibiotic agents were
found to be useful for treating bone infections.
Starting in the 1970s, studies conducted mainly
in the laboratories of Carl Norden (Pittsburgh)
and John T.Mader (Galveston) with experimental animal models provided information on characteristics of antibiotics that were associated with
better outcomes [22]. In addition to covering the
most frequently isolated pathogens, agents that
penetrated bone (i.e., had a high bone/serum concentration) appeared to be most clinically useful
(Table13.2). These included penicillins, aminoglycosides, clindamycin, vancomycin, cephalosporins, co-trimoxazole, uroquinolones,
linezolid, and especially rifampi(ci)n. Some
believe that bactericidal antibiotics provide better
outcomes than bacteriostatic agents for treating
osteomyelitis, but there is little published evidence to support this assertion.
Route ofAdministration
To ensure achieving adequate bone levels of antibiotics, clinicians assumed that high serum concentrations were needed [31]. Achieving these high
serum levels to treat osteomyelitis was thought to
require parenteral (generally intravenous) therapy.
For almost 40years, however, evidence from case
reports and case series suggested that therapy with
orally administered antibiotics that had high bioavailability could successfully treat DFO
(Table13.2). The recently published OVIVA study,
a randomized controlled multicenter trial in the UK
of 1054 evaluable patients treated for complex
bone and joint infections (including DFO), demonstrated that predominantly oral antibiotic therapy
was noninferior to intravenous antibiotic therapy
when used during the rst 6weeks, and was associated with few catheter-related complications and
lower nancial costs [32]. A retrospective cohort
analysis from Switzerland assessing the role of oral
amoxicillin/clavulanate in treating DFI reported on
the results of 794 cases, including 339 with DFO
[33]. They found that the rate of clinical remission
with this oral agent was 74%, similar to that with
other antibiotic regimens and specically similar
for cases with DFO.
Specic Agents
Recent studies have addressed the value of antibiotics that have been available for decades, but for
Table 13.2 Bioavailability, bone to serum concentration, and activity against biolm of oral antibiotics for diabetic
foot osteomyelitis [27, 31]
Antibiotic agent Oral bioavailability (%) Bone/serum concentration (%) activity Biolm activity
Fluoroquinolones 65–85 65 Yes
Co-trimoxazole 50 70–90 Yes
Tetracyclines >90 >70 Yes
Clindamycin >90 40–67 Yes
Linezolid >90 >70 Yes
Rifampi(ci)n >90 40–>90 Yes
Fusidic acid 80–90 44 Yes
Amoxicillin/clavulanate <80 – No
Flucloxacillin 5–20 40–75 No
Cefuroxime-axetil <80 – No
Clarithromycin <80 – ?
Metronidazole >90 100 ?
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181
which there have been few studies in DFO
(Table13.3) [34]. A narrative review of the literature from Switzerland found that, in contrast to
prevailing opinions and the few descriptive stud-
ies available, treatment of osteomyelitis with oral
ucloxacillin (a narrow spectrum, safe, low-cost
agent) does not appear to be associated with more
clinical failures than other oral antibiotic agents
Table 13.3 Systemic (intravenous and/or oral) antibiotic agents to consider for treating diabetic foot osteomyelitis
based on bioavailability and bone concentration [34]
Infection
severity Pathogens Possible antibiotics Comments
Mild Staphylococcus aureus (MSSA) Levooxacin QD dosing; substandard for S. aureus
(MSSA) Amoxicillin-
clavulanate Cephalexin
Streptococcus spp. Dicloxacillin/
Relatively broad spectrum and anti-anaerobic
Requires QID dosing; inexpensive
Narrow spectrum; QID dosing; inexpensive
ucloxacillin
Clindamycin Covers (most macrolide sensitive) MRSA
and anaerobes
Methicillin-resistant Doxycycline MRSA, some gram negatives; QD dosing
Moderate/
severe
S. aureus (MRSA) Trimethoprim/
sulfamethoxazole
MSSA; Streptococcus spp.;
Ertapenem
a
Enterobacteriaceae; obligate
MRSA, some gram negatives; undened
against Streptococcus species
QD dosing. Broad-spectrum anti- anaerobic;
poor against Pseudomonas aeruginosa
anaerobes
Ampicillin-sulbactam Relatively broad spectrum but not for P.
aeruginosa or other resistant gram negatives
Imipenem-cilastatin
(other carbapenems)
Broad spectrum; not active for MRSA;
consider for proven/suspected ESBL
producing pathogens
Levooxacin or
ciprooxacin with
clindamycin
Both oral and parenteral dosage forms
suitable. Limited studies of clindamycin for
severe S. aureus infections; possible
anti-toxin effect
Moxioxacin QD dosing. Broad spectrum, including
anaerobes
Ceftriaxone QD dosing (IV or IM); 3rd gen.
cephalosporin
MRSA Linezolid
a
Oral and IV; adverse effects, drug
interactions
Tigecycline Broad spectrum including MRSA; frequent
gastrointestinal upset; less effective than
others
Vancomycin Narrow spectrum; rising MICs in MRSA
isolates
Daptomycin QD dosing; monitor CPK levels
Pseudomonas aeruginosa Piperacillin-
tazobactam
MRSA, Enterobacteriaceae, P.
Vancomycin plus: Very broad spectrum for empiric therapy in
aeruginosa, anaerobes
– Piperacillin-
tazobactam, or
a
TID or QID dosing
severe infections; narrow spectrum when
culture and sensitivity results become
available
– Ceftazidime vs.
cefepime, or
– A carbapenem
MRSA methicillin-resistant Staphylococcus aureus, MSSA methicillin-sensitive Staphylococcus aureus
a
US FDA-approved for diabetic foot infection indication
182
B. A. Lipsky and S. A. V. van Asten
[35]. The authors concluded that the few published studies demonstrate that after any required
debridement, treatment with ucloxacillin by a
short intravenous course followed by oral
administration is a safe and effective option for
treating osteomyelitis, perhaps including DFO.
Rifampi(ci)n is an antibiotic agent that has
high bioavailability when taken orally, good penetration into bone, and activity against biolm
organisms, including S. aureus. It has been used
(always in conjunction with another agent active
against S. aureus to avoid development of resistance) for decades (especially in Europe) to treat
osteoarticular infections, but many clinicians
avoid using it because of concerns about resistance and frequent interactions with many other
drugs [22]. Recent interest in the potential value
for adding rifampi(ci)n to combination therapy
for DFO led to an observational cohort study
using the database of the US Veterans Health
Administration [36]. They found that among
6174 patients treated for DFO with antibiotics
(and no amputation), only 130 (2.1%) received
rifampin. But, these patients had a signicantly
lower rate of mortality and amputation within 2
years of diagnosis than those treated without
rifampin (odds ratio by logistic regression 0.65,
p=0.04). Spurred by these ndings, this group is
currently conducting a randomized controlled
trial of 6 weeks of rifampin therapy (versus placebo) added to conventional treatment (without
rifampin) to see the effect on reducing pedal
amputations (VA INTREPID) [37].
Some newly marketed antibiotic agents have
been approved for treating acute bacterial skin
and soft tissue infections (ABSSI), but none have
been specically investigated for DFIs [38].
These include delaoxacin (available in IV and
oral formulations), which differs from older uoroquinolones in having an expanded spectrum of
activity that includes MRSA, P. aeruginosa, and
common obligate anaerobes. Another new agent
is omadacycline (available in oral formulation), a
tetracycline derivative that is approved for ABSSI
that has a very broad spectrum, which even
includes vancomycin-resistant enterococci,
extended spectrum beta-lactamase producing
gram-negative bacilli, and Acinetobacter bau-
mannii. These agents, if shown to be effective for
DFIs (and specically DFO), might be useful for
treating those that are more serious, polymicrobial, and particularly caused by drug-resistant
infections.
Duration ofTherapy
Antibiotic therapy is generally given for a considerably longer duration for osteomyelitis than
for soft tissue infections—typically 4–6 weeks.
Many clinicians, however, treat even longer if all
necrotic and infected bone has not been resected
[2]. This longer duration of therapy is based more
on the theoretical problems associated with treating infected bone, as discussed above, than on
data from trials comparing different durations of
therapy [22]. Certainly, prolonged treatment of
DFO is associated with adverse effects. For
example, a study from Dallas of 143 patients with
bone biopsy proven osteomyelitis found that 47
(33%) developed acute kidney injury [39]. If
there were evidence that prolonged therapy is
associated with better clinical outcomes, this
benet might well outweigh the potential risks of
higher rates of drug-related adverse events,
increased chances of antibiotic resistance developing, or greater nancial costs of therapy. The
limited available published evidence has not,
however, demonstrated any benet for prolonged
therapy.
One open-label, multicenter, controlled randomized study from France compared nonsurgical treatment of DFO with 6 weeks versus
12weeks of antibiotic therapy [40]. Among the
40 evaluable patients, the remission rate was
65%, with no signicant differences between the
treatment groups, but with signicantly fewer
gastrointestinal adverse events in the shorter (6
week) treatment group [40]. Similarly, a retrospective cohort analysis study from Switzerland
employing a cluster-controlled Cox regression
model assessed factors related to remission of
DFIs, including DFO [41]. They found that DFO
episodes treated with <3weeks of antibiotic therapy had similar outcomes to those receiving
>3 weeks. They also noted that outcomes were
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183
not signicantly different between episodes
treated with more than 1 week of intravenous
therapy (including the intravenous route
throughout the entire course) than for shorter
durations of intravenous therapy.
Based on these observations, a recent randomized, non-inferiority pilot trial in Switzerland
compared clinical remission and adverse event
rates in patients with DFO who underwent surgical debridement, and were then randomized to
either 3 weeks or 6 weeks of antibiotic therapy
[42]. Among 93 enrolled patients, remission of
infection was noted in 84% of patients in the
3-week arm compared to 73% in the 6-week arm,
and the rates of adverse events were similar. The
same group of investigators is currently conducting a larger trial (with a planned enrollment of
400 diabetic patients with soft tissue or bone
infection of the foot) designed to see if they can
conrm the results of this pilot study [43]. A
group from the UK is also currently undertaking
a randomized controlled open-label noninferiority trial on duration of systemic antibiotic
therapy for orthopedic infections treated operatively with local antibiotic therapy [44]. They
plan to enroll 500 patients (including those with
DFO) who will be treated with either a short
course (≤7days) or long course (≥4 weeks) of
systemic antibiotic therapy. The primary endpoint will be denite treatment failure within
12months of surgery, while secondary outcomes
will include treatment side effects, quality of life
scores, and cost analysis. For now, it seems
unnecessary to treat DFO for more than 6 weeks,
and even shorter durations may soon be proven to
be sufcient.
Several authorities have reviewed various
issues concerning the treatment of DFO in the
past few years. A narrative review from France
noted that most of the antibiotics that exhibit both
satisfactory bone diffusion and oral bioavailability, especially rifampi(ci)n, fusidic acid, and uoroquinolones, have a substantial propensity to
select for resistant mutants; thus, they should be
prescribed in combination with agents active
against the causative pathogen [31]. A systematic
review of interventions for management of DFI
identied 11 studies conducted in patients with
DFO [45]. The authors deemed that the quality of
most of the studies was good, and found no signicant differences in the outcomes between the
various treatment arms, except for poorer outcomes with tigecycline compared to ertapenem.
An evidence-based narrative review of treatment
of DFO that particularly focused on the role of
surgical as well as antimicrobial therapy included
65 articles [27]. The authors concluded that the
main advantage to treating DFO “medically” is
that it avoids the biomechanical changes that may
occur after surgical procedures, and that it may
be more cost effective. They noted that the medical approach is limited by the need for prolonged
administration of antibiotics, which is associated
with drug-related side effects (including
Clostridioides difcile disease and the emergence
of antibiotic-resistant organisms), risk of relapsing infections (from failing to adequately sterilize bone tissue), and the persistence of any
existing bone deformity at the site of the inciting
foot ulcer. They point out that antibiotics that
achieve the preferred bone to serum concentration ratios of >0.3 (i.e., uoroquinolones, sulfonamides, tetracyclines, macrolides, rifampi(ci)n,
fusidic acid, and oxazolidinones) are also those
with the highest oral bioavailability, making them
potentially good candidates for prolonged treatment of outpatients with DFO.
Intra-osseus or Topical Antimicrobials
For decades clinicians have treated DFO with a
variety of antimicrobial agents (particularly gentamicin, tobramycin, or vancomycin) delivered
directly into infected bone in one of several different ways, including in the form of beads (usually polymethylmethacrylate, and more recently
calcium sulfate/hydroxyapatite), spacers, or
cement [46]. These agents have been used not
only to deliver antibiotics to treat bone infection,
but to ll dead space, and in some cases to try to
prevent infection [47]. Ideal delivery agents
should: be biocompatible; have minimal toxicity;
allow for osteointegration; and yield prolonged
drug release. Although local antibiotic treatments
are widely used, there is little high-quality evi-
184
B. A. Lipsky and S. A. V. van Asten
dence on the appropriate indications, techniques,
dosages, types of antibiotics, elution properties,
or pharmacokinetics [48, 49].
Outcome ofTreatment
Determining the outcome of treatment of osteomyelitis requires having an agreed upon denition of clinical resolution of infection. Clinically,
healing of any overlying soft tissue infection or
wounds suggests likely clearing of the underlying bone infection. Bone imaging can be helpful
in demonstrating probable resolution of infection
but, just as evidence of the presence of infection
lags the clinical course, resolution of bony
changes can lag as well. A fall in previously elevated serum inammatory markers, especially
the erythrocyte sedimentation rate and to a lesser
degree C-reactive protein and procalcitonin, may
also suggest resolution of infection [14, 15]. In
one study of 24 cases of bone biopsy proven DFO
prospectively followed during 1 year, 17% had
re-infection based on bone biopsy, while 10–20%
had failed wound healing, re-ulceration, rehospitalization, or amputation [50]. Most recurrences of DFO that occur after treatment are
diagnosed within a few months, but some present
later. Thus, many consider stable and apparently
resolved DFO after treatment to be in “remission,” and should not be considered cured until
the patient has been followed for at least a year.
Key New Trends inTreating DFO
The basic principles of treating DFO were established almost 50 years ago, but in the past few
years studies have provided some useful new evidence on optimizing treatment. On the surgical
side, it appears that employing more “conservative” (bone sparing) operative procedures is clinically effective and may also reduce postoperative
biomechanical problems for patients requiring
surgery. On the antibiotic side there are new data
supporting some changes in therapy. First, evidence from available studies on the supposed
bone penetration of antibiotics is not sufciently
reliable to condently use this information in
selecting an antibiotic regimen. Clinicians should
select agents that have demonstrated their effectiveness in clinical trials. Second, antibiotic
agents that are active against biolm organisms
may be more effective in treating bone infection.
Third, treating osteomyelitis for more than 6
weeks is usually unnecessary, and even shorter
durations (perhaps 3 weeks) may be sufcient.
Fourth, antibiotic therapy administered predominantly by the oral route appears to be as effective
(with lower rates of adverse effects and cost)
compared with intravenous therapy. Finally, in
appropriately selected cases, antibiotic therapy
without surgical resection can resolve DFO.As
noted, there are several ongoing trials that should
soon further inform our approach to managing
this common and difcult infection.
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