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20 Microbiology andTreatment ofDiabetic Foot Infection
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cae, Klebsiella aerogenes, and Citrobacter freundii with
moderate to high-frequency and extended-spectrum betalactamases (ESBLs) which should be suspected in Klebsiella
spp. or Escherichia coli that test non-susceptible to ceftriaxone [57]. Carbapenem-resistant Enterobacterales (CRE) are
infrequent but must be considered in patients with an extensive history of prior infection and antibiotic exposure [58].
Additionally, while P. aeruginosa, Acinetobacter species,
and other antibiotic-resistant gram-negative bacilli are
uncommon in previously untreated infections, these organisms are not infrequent isolates from sporadically treated
infected chronic ulcers [8, 46, 47] and from ulcers in patients
with previous hospitalizations for the same wound [58–60].
Similarly, MRSA and vancomycin-resistant enterococci
(VRE) may be encountered commonly in patients with
chronically infected foot ulcers that have persisted in spite of
multiple prior courses of antimicrobial therapy or in patients
with extensive healthcare requirements, e.g., chronic dialysis, hospitalization for comorbid conditions, residence in
skilled nursing facilities, or particularly those with a prior
history of infection with either organism [58, 61, 62]. These
resistant bacteria are probably acquired nosocomially or
alternatively emerge from endogenous ora during repetitive
antibiotic treatment of nonhealing foot ulcers. Accordingly,
when selecting an antimicrobial regimen to treat a foot infection in a patient who has had contact with the healthcare system or prior courses of antibiotics, physicians should
anticipate the presence of antibiotic-resistant pathogens.
It is also important to note the potential geographic variation in the etiology of diabetic foot infection as well as antimicrobial resistance rates based on differences in climate as
well as antimicrobial exposure. A prospective multicenter
study in Turkey collected 522 specimens from infected diabetic foot wounds for culture from 447 individual patients.
Gram-negative organisms constituted 60.2% of all isolates,
the most common of which was E. coli (15%) followed by P.
aeruginosa (12.4%). Antimicrobial resistance for these isolates was higher in specimens taken from patients with
moderate- severe infection compared to mild-moderate infection. While S. aureus was the most common gram-positive
organism isolated (11.4%), MRSA was present in only 1.8%
of cultures [63]. In two studies of diabetic foot infection in
India, gram-negative bacilli accounted for >50% of isolates,
33–44% of which were extended-spectrum beta-lactamase
(ESBL) producers [64, 65]. A retrospective review of patients
with diabetic foot osteomyelitis in China demonstrated a
26–37% isolation rate of multidrug-resistant organisms with
MRSA and multidrug-resistant Enterobacterales being the
most common [66]. Given this notable geographic variation,
the expected microbiology of diabetic foot infection needs to
consider the local prevalence of pathogens, especially
antibiotic- resistant strains, but be further amplied by culture results.
The role in infection of relatively avirulent bacteria, many
of which are part of skin ora, is uncertain. Staphylococcus
epidermidis and other coagulase-negative staphylococci
have been recovered, usually in conjunction with other bacteria, from 4 to 32% of foot infections, and may reect ulcer
colonization [8, 51]. On the other hand, S. epidermidis on
occasion has been the sole organism recovered from deep
tissue curetted from an infected ulcer; this suggests that these
organisms may be pathogens in some patients. Enterococci,
viridans streptococci, and Corynebacterium species, organisms that are often considered colonizers and not pathogens
when isolated from skin and soft tissue infections, are among
the isolates recovered frequently from polymicrobial limbthreatening foot infections. When recovered from specimens
in conjunction with typical pathogens, these organisms are
often disregarded [33, 67]. Often, foot infections respond to
therapy with antimicrobials which are active invitro against
the pathogens but not against these presumed colonizers [54,
68]. These observations support the designation of these
organisms as non-pathogens; alternatively, this response
could indicate that with the eradication of major pathogens,
host defenses and surgical debridement can control these less
virulent organisms. On occasion enterococci, viridans streptococci, and Corynebacterium species are isolated from
uncontaminated specimens and may even be the sole bacterial isolate from an infection [69]. Thus, these organisms too
should not be routinely disregarded but rather interpreted in
the clinical context.
Microbiologic Assessment
Establishing a microbiologic diagnosis is key to informing
antibiotic therapy in diabetic foot infection, particularly in
those patients with limb-threatening infection, risk factors
for antibiotic resistance, or failure of prior antimicrobial
therapy.
Cultures of open foot ulcers cannot be used to establish
the presence of infection and clinically uninfected ulcers
should not be cultured. Foot ulcers whether infected or not
will often contain multiple commensal or colonizing bacteria, some of which have the potential to become invasive
pathogens. As a foot ulcer transitions from uninfected to
infected, organisms isolated from the ulcer cavity include
both colonizing ora and invasive pathogens. Assigning specic signicance to organisms isolated from ulcers may be
difcult and should be done in the context of severity of
infection as well as specimen collection technique.
In the setting of soft tissue infection, the aseptic collection
of a tissue specimen by curettage or biopsy from the ulcer is
the recommended approach [1]. Whenever feasible, before
beginning antibiotic therapy, the skin should be cleansed,
any overlying eschar debrided, and specimens for culture
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obtained by curettage or biopsy of the necrotic base of the
ulcer. Specimens should be handled and processed as both
routine wound cultures and primary anaerobic cultures [55,
70, 71]. If patients have been febrile, blood cultures should
also be obtained before initiating antimicrobial therapy. With
subsequent debridement during early days of therapy, specimens from necrotic purulent tissue or exposed bone should
be cultured again if the response to therapy has been inadequate. Concurrent antimicrobial therapy may preclude isolation of susceptible organisms during effective therapy;
however, resistant organisms missed or present on the initial
cultures can be recovered from these later debridement specimens and be interpreted in the context of the clinical
response [71, 72].
Multiple studies have demonstrated a signicant discordance between tissue specimens and deep wound swabs;
however, results vary based on the method of swab collection
and severity of infection. Sapico and colleagues demonstrated that the organisms cultured from specimens obtained
by aspiration or by curettage of the base of a cleansed ulcer
were most concordant with those isolated from necrotic
infected tissue excised from adjacent to the ulcer base [73].
However, cultures of aspirated material failed to yield pathogens recovered from curettage or excised tissue in 20% of
patients. Pellizzer et al. found that in severe diabetic foot
infection, culture of swab specimens taken from deep in the
ulcer yielded the same bacterial species as did cultures of
deep tissue biopsies, with the exception that Corynebacterium
species, likely colonizers or contaminants, were isolated
from swab cultures [71]. Slater etal. found that in wounds
that did not extend to bone, essentially the same organisms
were recovered from cultures of swab specimens and deep
tissue specimens [70]. In contrast, when wounds extended to
bone, cultures of swab specimens recovered only 65% of
organisms cultured from deep tissues. The CODIFI study
assessed the agreement of paired wound swab samples and
tissue samples obtained by curette or scalpel in a prospective
multicenter study of 400 patients with diabetic foot infection. A 58% difference in pathogen results between wound
swab and tissue culture was observed with additional pathogens identied in 37% of the tissue cultures. In addition,
organisms typically considered non-pathogenic were more
frequently isolated from wound swabs [50]. Manas et al.
observed only fair concordance of cultures of a deep wound
swab when compared to those from surgical bone sample in
patients with severe diabetic foot infection and evidence of
osteomyelitis. The best concordance of samples was
observed when Staphylococcus aureus was present [72].
When taken in sum, these results suggest that culture of
material obtained from an ulcer base by curettage or biopsy
after the ulcer has been cleansed and debrided is recommended. Culture of material swabbed from an ulcer base is a
less desirable alternative.
When osteomyelitis involves bones in the forefoot that
are totally resected, bone cultures are not required; that is,
antibiotic therapy for the residual wound can be designed
using the results of appropriate wound cultures. If en bloc
resection of the involved bone, i.e., foot-sparing amputation,
is not performed, more precise microbiologic data from bone
biopsy rather than tissue culture or wound swab alone is
desirable to allow selection of optimal antibiotic therapy for
the residual wound and potentially infected bone [24, 33,
67]. Biopsy of abnormal bone underlying infected ulcers is
generally safe and in severely neuropathic patients may not
require anesthesia. Bone in the mid-foot or hindfoot that can
be probed or that lies beneath an ulcer and appears infected
on imaging studies should be biopsied for culture and histopathology. Ideally, this should be done either surgically or
percutaneously with uoroscopic guidance through a route
other than the ulcer [24, 31, 33, 67]. Here, in the mid-foot or
hindfoot, where debridement is likely to be piecemeal, rather
than en bloc resection of all involved bone, precise microbiologic data from bone is required for selection of optimal antimicrobial therapy. Alternatively, bone biopsy may be
deferred when osteomyelitis is not strongly suspected based
on radiologic ndings of bone that remains unexposed after
debridement; here the infection can be treated as if it is limited to soft tissue. Careful clinical and radiologic follow-up
of this bone in 2–4weeks will often resolve the question of
residual osteomyelitis.
Treatment
Determine Need forHospitalization
The determination of whether a patient requires hospital
admission for diabetic foot infection should be based on the
following: the severity of infection (informs the need for surgical intervention and intravenous antibiotic therapy), individual patient factors including medical comorbidities, social
factors, and local factors informing access for interventions
in the ambulatory setting. All patients with severe diabetic
foot infection should be hospitalized to provide prompt surgical debridement, empiric intravenous antibiotic therapy,
uid resuscitation, and management of metabolic derangements as required [1, 2]. Patients with severe infection
require an urgent assessment, preferably by a multidisciplinary team including a surgeon with expertise in diabetic
foot infection, for what may be a limb-threatening infection
and a risk for sepsis. Patients with moderate infection should
be hospitalized if they require urgent surgical debridement
and empiric intravenous antibiotic therapy for deep tissue
involvement (including abscess, gangrene, or involvement of
muscle, tendon, joint, or bone). Additionally, patients with
moderate infection often require admission if they have
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known or suspected severe peripheral arterial disease necessitating urgent assessment for revascularization, or other
complex medical comorbidities requiring inpatient management. Osteomyelitis in and of itself does not require hospitalization unless concurrent soft tissue infection is present or
if surgical debridement or foot-sparing amputation in an
effort to heal foot ulceration is required. Typically, patients
with mild infection may be managed entirely in the ambulatory setting [1, 2].
Debridement andSurgery
With the exception of cellulitis or lymphangitis arising
from an unrecognized (or microscopic) portal of entry,
moderate or severely infected foot ulcers generally require
surgical debridement [74]. Urgent surgical intervention is
required when patients present with foot infection complicated by extensive necrosis or gangrene, crepitus, or gas in
tissues on imaging, necrotizing fasciitis (or pain out of proportion to ndings thus suspected necrotizing fasciitis),
critical ischemia, or sepsis. For apparent moderate nonlimb-threatening infections, debridement may be limited
but nevertheless useful in allowing full evaluation of the
portal of entry and preparing the site for culture or to
address foot deformity and maldistribution of weight bearing in order to allow healing and prevent recurrent ulceration. Occasionally, what appeared to be a
non-limb-threatening infection is discovered on debridement to be more severe with extension of infection to deep
tissue planes. Severe limb-threatening infection by virtue
of extension to deep tissue planes requires surgical debridement [75]. Early surgical intervention can reduce the duration of hospitalization and the need for major amputations
[74]. Failure to decompress involved compartments and
debride necrotic tissue and drain purulent collections
increases the risk of amputation [74, 75]. Percutaneously
placed drains or aspiration drainage is inadequate; rather
devitalized tissue must be resected and purulent collections
drained by incision. Uncertainty about the patient’s arterial
circulation status should not delay initial urgent surgical
debridement but should prompt an evaluation of arterial
supply and a vascular surgery consultation. Effective
debridement may require multiple procedures as the extent
of tissue destruction becomes progressively more apparent.
If the infection has destroyed the function of the foot or if it
threatens the patient’s life, a guillotine amputation to allow
prompt control of the infection with a subsequent denitive
closure is advised [76].
Optimal surgical treatment that minimizes tissue loss and
results in a suitable weight-bearing foot requires a thorough
understanding of resulting foot function, avoidance of subsequent deformities that will predispose to recurrent ulcer-
ation, and recognition of the potential need for
revascularization to ensure healing. The experience of the
surgeon in this area and the availability of vascular surgery
support are important in achieving optimal results [75].
Antibiotic Therapy
In view of the potential adverse consequences, including
colonization with resistant bacteria, antibiotic therapy is not
recommended for clinically uninfected neuropathic ulcers
[33, 77]. Similarly, continuation of antibiotics beyond a limited course that was sufcient to eradicate infection has not
been required to accomplish the healing of ulcers that remain
open [33, 40, 78].
The use of topical antimicrobials, such as silver sulfadiazine, polymyxin, gentamicin, and mupirocin, has not been
shown to have benet and is not routinely recommended in
the treatment of diabetic foot infection [1, 79].
Antimicrobial treatment should be started promptly
after obtaining appropriate cultures for all clinically
infected ulcers. Therapy of foot infections in patients with
diabetes has begun empirically. The best regimen is based
on the anticipated pathogens suggested by the clinician’s
assessment of the severity of infection with further renement based on the local antibiogram and patient-specic
factors such as prior culture results, antibiotic exposure,
and antibiotic side effect prole. Revision of antibiotic
treatment should be guided by the results of cultures, which
were obtained prior to therapy and on occasion during therapy, plus the clinical response of the infection to empiric
therapy. The potential toxicity of various antibiotics for
individual patients and the unique vulnerability of individual patients as well as persons with diabetes as a group
must be considered. The route of therapy should be based
on the severity of infection. Oral therapy is sufcient for
most mild infections as well as many moderate infections
when an antibiotic with good oral bioavailability may be
utilized. Antibiotic therapy is administered intravenously
when patients are systemically ill, have severe local infection, are unable to tolerate oral therapy, or are infected by
bacteria that are not susceptible to available oral antimicrobials. Some antimicrobials are fully bioavailable after oral
administration, e.g., uoroquinolones, linezolid, trimethoprim-sulfamethoxazole clindamycin, and metronidazole. When appropriate microbiologically and clinically,
these can often be used in lieu of initial parenteral therapy.
After control of infection and contingent upon the susceptibility of the implicated bacteria, continued antimicrobial
therapy where indicated can commonly be administered
orally. For patients who require prolonged courses of parenteral therapy, e.g., for osteomyelitis, generally treatment
can be provided in an outpatient setting [80].
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Table 20.3 Selected antibiotic regimens for initial empiric therapy of
mild non-limb-threatening foot infections in patients with diabetes
mellitus
Antimicrobial regimen
Amoxicillin-clavulanate (875/125mg) one q 8–12h
Cephalexin 500mg p.o. q 6h
Clindamycin 300mg p.o. q 8h
Dicloxacillin 500mg p.o. q 6h
Doxycycline 100mg po bid
Levooxacin 500–750mg p.o. q d
Linezolid 600mg p.o. bid
Moxioxacin 400mg p.o. q d
Trimethoprim-sulfamethoxazole DS, one or two tablets p.o. bid
a
Doses for patients with normal renal function
b
Use if clinical information suggests possible methicillin-resistant
S. aureus infection (MRSA) Trimethoprim-sulfamethoxazole may be
less effective against streptococcal infection and require addition of a
second antimicrobial. Clindamycin (resistance may emerge during
therapy if the isolate is resistant to macrolides) and doxycycline are
active against some MRSA
a
b
b
Empiric therapy for patients with mild or moderate infection, many of whom can be treated as outpatients, is directed
primarily at aerobic gram-positive cocci, i.e., staphylococci
and streptococci (Table 20.3) [33, 67, 81]. At a time when
MRSA were uncommonly encountered, studies demonstrated that in patients with non-limb-threatening infection,
oral therapy primarily with rst-generation cephalosporins,
dicloxacillin, or clindamycin directed at staphylococci and
streptococci resulted in satisfactory clinical outcomes [40,
41]. Currently, when selecting therapy for mild or moderate
infection, the need for MRSA coverage must also be considered. Treatment that encompasses MRSA is required if there
is a known history of MRSA colonization or if local
prevalence is high. Oral trimethoprim-sulfamethoxazole or
linezolid may be used for this purpose. Trimethoprimsulfamethoxazole may be less effective against streptococci
and thus should be combined with a second agent. Use of
doxycycline or clindamycin, both of which may be active
against some MRSA, should be based on local susceptibility
patterns. Several newer agents that are active against grampositive cocci including MRSA and are FDA approved for
acute bacterial skin and skin structure infection, but not diabetic foot infection, include dalbavancin and oritavancin
(intravenous long-acting lipoglycopeptides), delaoxacin
(quinolone), and omadacycline (tetracycline) [82–85]. If
MRSA is not suspected, oral agents directed at MSSA and
streptococci such as cephalexin, dicloxacillin, amoxicillinclavulanic acid, levooxacin, moxioxacin, and clindamycin
may be considered. The duration of treatment, which is
determined by the time course of the clinical response, is
usually 1–2weeks.
If patients with supercial ulcers present with more extensive cellulitis, which warrants hospitalization and parenteral
antimicrobial treatment, intravenous therapy should be initiated. Cefazolin should be effective in patients without MRSA
risk factors. Linezolid, which is fully bioavailable when
administered by mouth and thus can be given orally or intravenously, is generally active against MRSA and thus could
be used as anti-staphylococcal therapy for non-limbthreatening or limb-threatening foot infections [86]. Other
antimicrobials active against MRSA available for intravenous administration in the setting of more extensive cellulitis
or severe foot infections include vancomycin, daptomycin,
telavancin, and ceftaroline [86–91].
For patients with severe infection, the randomized controlled trials to date have not clearly delineated a preferred
single agent or combination of agents [92, 93]. In selecting
empiric therapy for severe limb-threatening foot infections,
reasonable principles emerge from clinical trials and other published studies [33, 39, 67, 81, 94]. The choice of agents used
empirically should be based upon the known polymicrobial
nature of these infections and modied, where appropriate, to
address anticipated highly resistant pathogens that might have
been selected in the process of prior hospitalizations and treatment (Table 20.4) [95]. In addition, drug selection should
attempt to minimize toxicity and be cost-effective. Given the
high prevalence of MRSA, empiric therapy for limb-threatening infection should include an agent effective against
MRSA.These agents will also provide therapy for infections
caused by streptococci, including group B organisms.
Additionally, when infection occurs in a chronic ulcer which
has failed to heal despite treatment with multiple antibiotics,
empiric therapy should be effective against an array of
Enterobacterales including potentially multidrug- resistant
organisms. Due to the complexity of interpreting resistance
patterns and local antibiogram data, concern for multidrugresistant gram-negative pathogens should prompt an infectious
disease consultation when feasible [57]. Anaerobes, including
B. fragilis, should be treated empirically in the more severe
infection where there is tissue necrosis and gangrene, or the
wound is fetid. In limb-threatening infection (but not in lifethreatening infection), initial empiric therapy does not have to
be effective invitro for all potential pathogens. Broad-spectrum
therapy, which is active against many, but not necessarily all,
gram-negative bacilli, as well as against anaerobes, S. aureus
and streptococci when combined with appropriate debridement
and good wound care, may be as effective as even broaderspectrum antimicrobial therapy. Adequate debridement not
only shortens required duration of therapy but is required for
effective therapy. However, pending culture results, patients
with life- threatening infections, e.g., those with sepsis, hypotension, or severe ketoacidosis, should be treated with maximal
broad-spectrum regimens. These might include a carbapenem
and an agent directed against MRSA, plus if highly resistant
gram-negative bacilli are anticipated, newer novel beta-lactam-beta-lactamase inhibitor combination agents or aminoglycosides can be utilized [57, 96]. In these patients, emergent
debridement is essential for satisfactory outcome.
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Table 20.4 Antibiotics for empiric therapy of moderate or severe limb-threatening foot infection
Antibiotic agent Comments
Amoxicillin- clavulanic acid/
ampicillin- sulbactam
Cefepime Active against many gram-negative bacilli including Amp-C producers and P. aeruginosa.
Ceftaroline Active against streptococci, staphylococci including MRSA, and many Enterobacteriaceae
Ceftazidime Active against many gram-negative bacilli and P. aeruginosa. Not active against ESBL producers.
Ceftriaxone Active against streptococci and staphylococci (not MRSA), and many gram-negative bacilli
Daptomycin Active against streptococci, staphylococci including MRSA
Ertapenem Active against streptococci, staphylococci (not MRSA), and many gram-negative bacilli including
Levooxacin/moxioxacin Active against streptococci and staphylococci (not MRSA) and many gram-negative bacilli
Linezolid Active against streptococci and staphylococci including MRSA
Meropenem/
imipenem- cilastatin
Metronidazole Only active against anaerobes
Piperacillin- tazobactam Active against streptococci and staphylococci (not MRSA) and many gram-negative bacilli including
Telavancin Active against streptococci and staphylococci including MRSA (not available in the United States)
Vancomycin Active against streptococci and staphylococci including MRSA
Not all agents are approved by the US Food and Drug Administration (FDA) for treatment of diabetic foot infections
ESB extended-spectrum beta-lactamase (use meropenem, imipenem- cilastatin, or ertapenem). Use doses suggested for complicated skin-soft tissue
infection unless concomitant infection requires higher dose
AmpC beta-lactamase (for severe infection, use cefepime or a carbapenem). Use dose suggested for complicated skin-soft tissue infection unless
concomitant infection requires higher dose. Enterobacter cloacae, Klebsiella aerogenes, and Citrobacter freundii have moderate to high frequency
for clinically signicant AmpC production
a
Often may need combined therapy, especially when considering MRSA and gram-negative bacillus polymicrobial infection. This list is not
exhaustive and alternate agents may be required for more difcult to treat multidrug-resistant organisms or in setting of allergy history or adverse
drug reaction
Active against streptococci and staphylococci (not MRSA) and many gram-negative bacilli
(not P. aeruginosa or ESBL producers, also active against anaerobes
Not active against ESBL producers
(not ESBL producers). Not active against P. aeruginosa
Reduced gram-positive activity compared to other cephalosporins
(not ESBL producers, P. aeruginosa, or anaerobes)
ESBL and Amp-C producers (not P. aeruginosa), active against anaerobes. Use when considering
ESBL and Amp-C-producing organisms
Active against streptococci and staphylococci (not MRSA) and many gram-negative bacilli including
P. aeruginosa, also active against anaerobes. Use when considering ESBL and Amp-C-producing organisms
P. aeruginosa, also active against anaerobes
a
Multiple antibiotics have been demonstrated to be effective therapy in prospective treatment trials of complicated
skin and soft tissue infections, many of which were foot
infections. Additionally, some of these antimicrobials have
been proven effective in prospective studies of diabetic foot
infections, many of which have been limb-threatening:
amoxicillin-clavulanate, ampicillin-sulbactam, piperacillintazobactam, cefoxitin, ciprooxacin, moxioxacin,
imipenem- cilastatin, ertapenem, linezolid, daptomycin, telavancin, and ceftaroline [8, 68, 86, 89, 91, 97–104]. In comparative prospective (sometimes blinded) trials of treatment
for limb-threatening foot infections comparing a new agent
to purported standard of care, the clinical and microbiologic
response rates for the studied agents have been similar. No
head-to-head multi-antimicrobial trial has been conducted;
thus, no single agent has been proven superior to all others
[33, 67, 81]. A review examining patients across controlled
trials suggested that carbapenem therapy was associated
with fewer failures compared with multiple other antimicrobials but also noted the association of MRSA infection with
failed therapy [105]. Lauf et al. demonstrated that tigecycline did not meet criteria for noninferiority when compared
to ertapenem plus vancomycin in the treatment of diabetic
foot infection, and thus this agent is not recommended for
use in diabetic foot infection including in patients with
osteomyelitis [106].
Empiric antimicrobial treatment should be reassessed
between day 3 and 5 of treatment in the light of culture
results and clinical response. When patients have responded
clinically and therapy is unnecessarily broad spectrum
(effective therapy for the bacteria isolated could be achieved
by less broad-spectrum antimicrobials with possible cost
savings, avoidance of toxicity, or a reduction in selective
pressure for emergence of antimicrobial resistance), treatment regimens should be simplied based on culture data
[33, 67]. If a bacterium resistant to the current therapy has
been recovered and yet the clinical response is satisfactory,
treatment need not be expanded. This is true particularly for
less virulent organisms and gram-negative bacteria; however,
it seems imprudent to ignore MRSA.Alternatively, if in the
face of an isolate resistant to treatment the response to therapy is unsatisfactory, the wound should be examined for
undrained deep space abscess or necrotic tissue that has not
been debrided and for the adequacy of arterial circulation.
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Because the resistant organism might be a pathogen (rather
than colonizing ora), antimicrobial therapy should be
expanded to treat this isolate, particularly in the absence of
other explanations for an inadequate response to antimicrobial therapy.
The duration of antimicrobial therapy for severe soft tissue foot infection is based upon the temporal response to
wound care and antimicrobial therapy. Two weeks of therapy
is often effective; however, some recalcitrant infections will
require longer courses of treatment [8, 33, 39, 95]. After
acute infection has been controlled, antimicrobial therapy
that was begun parenterally should be changed to oral therapy with comparable orally bioavailable antibiotics. Even if
the ulcer has not fully healed, antibiotics can in general be
discontinued when the infection has resolved [33, 67].
Persistent ulcers must be managed with wound care and
avoidance of weight bearing so that healing can be achieved,
and the ulcer eliminated as a portal for later infection. The
occurrence of bacteremia, especially if remote sites are
seeded, may require extended therapy. Of note, S. aureus
bacteremia entails a distinct risk for secondary endocarditis
as well as for seeding other sites such as bones, joints, and
the epidural space. These potential complications may
require targeted evaluation and assistance from an infectious
disease consultant [107]. If no additional complications are
present, typically the major determinant for appropriate
duration of therapy for diabetic foot infection is whether
osteomyelitis is present and if so, the extent of surgical
debridement performed.
Treatment ofOsteomyelitis
The therapy of osteomyelitis, which is one of the most
debated and controversial areas in the treatment of foot
infection, should coordinate antibiotic treatment with considerations of the surgical debridement of involved bone.
Selection of antibiotic therapy is ideally based on the precise
microbiology of bone infection. Cultures from curettage of
soft tissue deep in the infected ulcer overlying bone may sufce to design therapy when surgical resection of all infected
bone is planned, i.e., therapy will be directed at residual soft
tissue infection. When bone debridement will not be done or
is limited, as in mid-foot or calcaneal osteomyelitis, bone
culture to dene the microbiology is of paramount importance. Culture of soft tissue adjacent to bone does not adequately dene bone microbiology [29]. Additionally,
favorable outcome of therapy is more likely using antibiotics
based on bone culture [108].
Some reports have suggested that osteomyelitis of bones
in the foot can be cured or at least arrested for extended periods with minimal debridement plus prolonged courses of
antimicrobial therapy [7, 24, 33, 67, 99, 108–111]. Others
have suggested that cure rates for osteomyelitis (particularly
where bone destruction is evident or bone is visible or detectable by probing the infected ulcer) will be enhanced by
aggressive debridement and even foot-sparing excision of all
infected bone when feasible [39, 74, 94, 112]. Recent data
suggests that in carefully selected patients, medical therapy
alone may be sufcient to achieve cure [113, 114]. Careful
review of the literature on the treatment of osteomyelitis in
the feet of diabetic patients concluded that no particular
management strategy could be shown superior. This conclusion emerges because of heterogeneity in treated infections
and patients, diversity in the surgical approaches, biases in
the selection of treatment modality, variability in antibiotic
treatments, and different denitions of outcome [115, 116].
Thus, clinicians must carefully weigh patient factors with the
advantages and disadvantages of each approach, including
cost, treatment toxicity, time to ulcer healing and reduced
risk of recurrent ulceration, and impact on quality of life to
determine the optimal plan of care.
Medical Versus Surgical Management
Surgical resection of infected bone has historically been the
standard treatment of osteomyelitis; however, recent data
suggests that in carefully selected patients, medical therapy
alone may also be an effective strategy [49, 108, 113, 114].
Lázaro-Martinez etal. published a prospective randomized
controlled trial of 52 patients with diabetic foot osteomyelitis comparing antibiotic treatment for 90days with conservative surgery with antibiotic treatment for 10days. Of note,
patients with severe infection according to IDSA classication, peripheral arterial disease, Charcot arthropathy, glycated hemoglobin >10%, renal insufciency, or bone exposed
at the base of the ulcer were excluded from the study. Cure
rates in both groups were similar to no difference in the need
for later minor amputation. All patients were treated with
oral therapy including amoxicillin-clavulanic acid, ciprooxacin, and trimethoprim-sulfamethoxazole [114]. This
study and an additional prospective randomized controlled
trial including 40 patients managed nonsurgically published
by Tone [49] demonstrated healing rates at 1 year ranging
from 60 to 85%, suggesting that contiguous osteomyelitis
complicating an infected diabetic foot ulcer can be effectively treated with antibiotics alone. It is important to note
that both studies were small and that the enrolled patients
were highly selected (enrolling only 20–30% of patients
screened over an extended period). Thus, physicians should
be cautious in generalizing from these data. Alternatively,
Aragon-Sanchez etal. reported healing rates of 81% in 111
patients treated for osteomyelitis with antibiotics and conservative foot-sparing surgery [37]. Taken in sum, the available
data and current guidance best support medical therapy alone
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in well-selected cases of osteomyelitis involving the forefoot, for whom an oral agent with excellent bioavailability is
available, and no other mechanical reasons for considering
surgery are present [1].
While not an optimally selected approach to achieve cure,
nonsurgical management may also be preferred when aggressive resection would lead to unacceptable foot dysfunction,
if limb ischemia precludes surgery, and surgery carries
excessive risk or is declined by the patient. In these cases,
inference of optimal duration of therapy from the available
studies is challenging and more prolonged treatment may be
required.
More aggressive surgery is required if infection is lifethreatening or may be preferred if there is extensive bone
necrosis, foot remodeling is required to correct bony prominences with maldistribution of plantar pressure and improve
function and reduce the risk of recurrent ulceration, the
patient wishes to avoid very prolonged antibiotic therapy, or
the potential toxicity of required antibiotic therapy can be
minimized by aggressive surgery.
Route ofAntibiotic Administration
andDuration ofTreatment forOsteomyelitis
Adequate antibiotic therapy, contingent on pathogen susceptibility, can be achieved by intravenous administration or the
use of highly bioavailable oral agents. Often sequential intravenous to oral therapy is used. A randomized controlled trial
including 1054 patients with bone or joint infection treated
with intravenous or oral therapy for at least 6weeks showed
comparable rates of treatment failure (14.6% in intravenous
group and 13.2% in oral group), further supporting oral therapy for osteomyelitis in well-selected patients [117]. While
only 19.5% of patients had diabetes, 6% had peripheral vascular disease, and 20.5% of infections involved the foot, this
study provides additional pragmatic data supporting the use
of oral therapy in well-selected patients with osteomyelitis
[49, 114].
A multicenter randomized study by Tone etal. questioned
the need for very prolonged courses of therapy for all patients
treated with medical therapy alone. In this study, 40 patients
with diabetic forefoot osteomyelitis receiving either a full
oral course of therapy or a short course of intravenous therapy followed by a transition to an oral agent with good bioavailability were randomized to receive either 6 or 12weeks
of therapy. Patients with severe peripheral arterial disease
were excluded from the study. No signicant difference in
outcome was seen in patients receiving 6weeks compared to
12weeks of therapy [49]. Given the lack of clear benet of
more prolonged therapy, current guidance recommends
treating diabetic foot osteomyelitis for no longer than
6weeks of therapy [1].
The duration of antibiotic treatment for osteomyelitis in
patients undergoing surgical debridement is based upon the
amount of residual infected bone and soft tissue (Table20.5).
If all infected bone is resected en bloc, e.g., amputation of a
phalange or phalanges and the related distal metatarsals, the
residual infection has in essence been converted to a soft tissue process and can be treated accordingly, i.e., for 2–3weeks
[8, 33, 39, 94, 118].
In patients for whom the adequacy of the debridement
cannot be assured because osteomyelitis involves bones that
cannot be resected en bloc without disruption of the func-
Table 20.5 Duration of antibiotic therapy for osteomyelitis of pedal bone
Site/setting Duration
Surgical debridement performed
Amputation with no residual infection 2–5days after surgery
Intravenous or oral therapy
En bloc resection (all infected bone resected) with residual soft tissue infection present 2–3weeks
Intravenous or oral therapy
Residual infected bone (piecemeal debridement)
Debridement performed with any of the following:
• Proximal margin with histologic evidence of osteomyelitis
• Proximal margin with microbiologic evidence of osteomyelitis
• Clinical suspicion for non-debrided infected bone at the time of surgical
debridement
Residual devitalized bone
No surgical debridement performed
Medical therapy—well-selected candidate (e.g., uncomplicated forefoot osteomyelitis
with no alternate indication for surgery)
Medical therapy—nonoperative candidate (e.g., severe peripheral arterial disease,
devitalized bone, retained orthopedic hardware)
Adapted from reference [33]
3–6weeks after debridement
Initial intravenous therapy, then consider
oral therapy
≥3months
Initial intravenous therapy, then consider
oral therapy
6weeks after debridement
May start with po regimen if highly bioavailable
option available
≥3months
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tional integrity of the foot, (i.e., piecemeal debridement is
performed), specic antimicrobial therapy has been administered for 6weeks or based on proximal bone margin histopathology and/or culture [24, 33, 39, 67, 118]. The rationale for
this approach has been that failure of antibiotic therapy has
been noted when bone resection was incomplete and residual
osteomyelitis was present at the proximal margin [119–121].
However, more recent data has suggested that shorter durations of therapy may be sufcient for some patients after
minor amputation, despite the presence of a positive bone
margin culture. Gariani etal. published a prospective, randomized noninferiority pilot trial enrolling 93 patients with
diabetic foot osteomyelitis postsurgical debridement randomized to 3 vs. 6weeks of antibiotic therapy. No signicant
difference in short-term outcomes was observed between
groups and the overall clinical remission was 78%.
Additionally, there was no difference in outcome observed in
patients undergoing partial amputation with residual infection determined by preoperative imaging and/or intraoperative assessment [122]. This study suggests that patients
undergoing minor amputation may be effectively treated
with a shorter duration of therapy; however, additional data
is required to determine the optimal candidates for (<6weeks)
duration of therapy post debridement with evidence of
residual infection.
Conversely, very prolonged antibiotic therapy continues
to be used when medical cure is attempted in the setting of
residual necrotic infected bone. Therapy has been given for
3–6months and occasionally for a year and may be part of a
palliative approach: however, the risks and benets of excessively prolonged therapy must be continuously reviewed.
In every setting, the need for debridement, the choice of a
specic antimicrobial regimen, and the duration of therapy
must be individualized and reect not only local foot ndings but also possible concomitant metastatic infection and
potential for antibiotic-related adverse events. Apparently
even though appropriate treatment infection fails to respond
and ulcers do not heal, the foot should be reassessed for adequacy of arterial supply, persistence of necrotic soft tissue or
bone requiring debridement, presence of an unresponsive or
antibiotic-resistant pathogen, or ineffective antibiotic delivery. Patient noncompliance with treatment or non-weight
bearing must be considered as well. Therapy should be redesigned addressing defects found in the prior treatment
strategy.
Adjunctive Therapy
The effective treatment of foot infection requires far more
than the administration of antibiotics that are active invitro
against the implicated pathogens. Optimal therapy involves
the integration of appropriate dressings and wound care,
control of glucose metabolism, effective debridement, and
possibly reconstructive foot surgery. Wound care should
include non-adherent dressing products that maintain a moist
wound bed, control exudate, and avoid maceration of surrounding skin [16]. Non-weight bearing (off-loading) on
neuropathic ulcers whether infected or non-infected is essential for healing. When ischemia is a limiting factor, vascular
reconstruction may result in healing and foot salvage [123].
Hyperbaric oxygen therapy is not recommended due to limited data supporting its effect in treating soft tissue or bone
infection [1]. Negative pressure dressings (vacuum-assisted
closure or VAC dressings) in controlled trials have been
shown to be safe and, in treating surgical wounds, to accelerate granulation tissue formation, reduce the time to wound
closure, and yield a higher overall rate of wound healing
[124]. Although widely used, their role in infected diabetic
foot wounds is unclear, and VAC dressings are not currently
recommended for routine use [1, 2]. Data supporting healing
benet of various topical preparations is equivocal and is discussed elsewhere.
Outcome
Ideally, foot ulcers and their subsequent infection in patient
with diabetes should be prevented; unfortunately, this
remains a largely aspirational goal. The goals of effective
treatment of these infected foot ulcers are (1) to prevent both
mortality associated with the current episode and subsequent
ulcer-related mortality and (2) to effectively treat infection,
heal the ulcer, and preserve a weight-bearing foot. Patients
with diabetes who develop a foot ulcer, a population commonly with multiple comorbidities, experience over a 1–3year follow-up a 1.5–2.45 increased relative risk of all-cause
death compared to those with diabetes who do not develop a
foot ulcer [125, 126]. Although the risk of death may be signicantly driven by multisystem comorbidity associated
with diabetes, a component relates to infection associated
with foot ulcers.
The strategies for treatment of infected foot ulcers, which
often require the collaboration of multiple care providers,
including diabetologists, infectious disease specialists, podiatrists, and vascular surgeons, can often both preserve a
walkable foot and mitigate mortality risk. However, to
achieve the latter, the importance of ulcer healing, the prevention of recurrent ulceration, and particularly the hazards
of protracted nonhealing diabetic foot ulcers must be
addressed [51]. In a study of 819 patients hospitalized for a
diabetic foot ulcer, over the subsequent 2years of follow-up,
there were 172 episodes of life-threatening non-foot infection (bacteremia, endocarditis, osteomyelitis, septic arthritis,
deep tissue abscesses, and others) caused by organisms that
were present in the ulcer. These invasive infections were sig-
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nicantly associated with ulcers that remained open for
>145 days and wherein initial cultures were positive for
MRSA. Surgical debridement, including that directed at
osteomyelitis, and surgical ulcer closure were associated
with decreased invasive infection. These nonhealing ulcers
and subsequent invasive infections were each independently
associated with increased mortality (hazard ratio 1.91 (95%
CI 1.05–3.46) and 1.99 (95% CI 1.11–3.57)), with death
often occurring within a month of infection [48]. While this
was a single-institution retrospective study, other care systems have reported the association of culture-positive diabetic foot ulcer, particularly with S. aureus, associated with
increased risk for severe invasive infection [127], and there
are many case reports of life-threatening non-foot infections
arising from an infected foot ulcer portal of entry. Overall,
these studies suggest the importance of aggressive efforts to
achieve prompt foot ulcer healing on initial encounter and on
subsequent follow-up in the effort to reduce mortality.
Treatment studies from centers of excellence suggest that
with appropriate care, a satisfactory clinical response can be
anticipated in 90% of patients with mild non-limb- threatening
infection [40, 41] and at least 60–80% of those with moderate or severe limb-threatening infection [37, 49, 114].
Effective treatment of limb-threatening infections may
require foot-sparing amputations with salvage of a weightbearing foot and vascular reconstruction to facilitate healing
of more distal surgery. Real-life studies, however, indicate
that ulcer treatment and foot salvage remain a challenge.
Analysis of the large Medicare Limited Data Set indicate
that healing of foot ulcer in patients with diabetes by
12 weeks is achieved in only 29% of patients and that
recurrent ulceration occurs in 27% and 36% of these patients
at 6months and 1year, respectively. Similarly in a prospective follow-up of 299 diabetic patients with infected foot
ulcers in the United Kingdom at 12months, healing occurred
in 45% and recurrent ulceration in 10%. Of these patients,
17% required amputation of part of the foot and 19% required
vascular surgery [128]. Thus, although the clinical science of
treating diabetic foot infections has advanced signicantly,
challenges remain in dening optimal care and disseminating that knowledge. Many foot infections could be prevented,
effective therapy provided, and extremities salvaged if current knowledge was more widely applied.
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