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tion control and in healing (e.g., neutrophils, macrophages,
broblasts, and keratinocytes) [130–132]. For example, biolm has been shown to play an important role in mediating
wound damage in diabetic animals infected with P. aerugi-
nosa and S. aureus (two of the most important pathogens in
DFUs as discussed above) [133–135]. Therefore, it is very
important to manage biolm formation in diabetic ulcers to
promote successful wound healing.
Bacterial Toxins
In diabetic wounds, cytotoxins produced by pathogens can
dampen antimicrobial defenses in wound by multiple mechanisms. (1) Bacterial cytotoxins can cause death in the cells
that protect wound from infection and/or function in wound
healing, such as neutrophils, macrophages, broblasts, and
keratinocytes. For example, P. aeruginosa and S. aureus pos-
sess many cytotoxins that induce cell death in these target
host cells by a variety of mechanisms [58, 136–143]. Not
surprisingly, these cytotoxins have been shown to contribute
to inhibition of wound healing in diabetic animals infected
with these pathogens [92, 122, 144]. (2) Bacterial cytotoxins
can directly dampen immune system and render diabetic
wounds vulnerable to infection. For example, both P. aerugi-
nosa and S. aureus express many cytotoxins that can dampen
innate immunity against infection via multiple mechanisms
[140, 145–147]. For example, P. aeruginosa Exotoxin T
dampens the production of IL-1β and IL-18in wounds by
inhibiting the NLRC4 canonical inammasome [145]. (3)
Bacterial cytotoxins can dampen inammatory responses
toward infection by inhibiting proliferation. For example, P.
aeruginosa produces a toxin which inhibits cell division in
epithelial target cells by causing cell cycle arrest in G1 interface or by blocking cytokinesis (separation of daughter cells
after mitosis) at multiple steps [148, 149]. (4) Bacterial toxins can dampen inammatory responses in wound by reducing angiogenesis, thus reducing the trafcking of
inammatory cells from circulation into the wound tissue.
For example, S. aureus β-Toxin exerts anti-angiogenic effects
by inhibiting reendothelialization and neovessel formation
[150]. Similarly, P. aeruginosa Pseudolysin and Protease IV
have been shown to impede cutaneous wound healing by
inhibiting neovascularization and epithelialization, although
in this study their impacts on inammatory leukocytes was
not directly evaluated [151]. Reduced angiogenesis is a recognized contributing factor to impaired healing in diabetic
ulcers [152, 153]. (5) Bacterial cytotoxins can also trigger
inammation which further exacerbate tissue damage and
impair healing. P. aeruginosa and S. aureus recognition by
innate immune system has been shown to contribute to
increased inammatory responses in chronic diabetic
wounds [58, 140, 147, 154–156].
Immune Dysfunctions That Underlie
Susceptibility toInfection inDiabetes
The innate immune system plays a crucial role combating
infection in wounds [157]. This system encompasses both
cellular and humoral components, with phagocytic leukocytes, particularly neutrophils and macrophages, serving as
the primary cellular components responsible for defending
against infection in wounds [158, 159]. Meanwhile, the
humoral components of innate immunity include proinammatory cytokines, antimicrobial peptides (AMPs), and complements [158, 159]. However, dysregulation in the dynamics
of the cellular and humoral branches of innate immunity, as
well as impairments in the antimicrobial functions of phagocytic leukocytes due to hyperglycemia, are the most critical
factors that render diabetic wounds vulnerable to infection.
Subsequent sections will provide further details on dysfunctions in innate immunity that underlie defective antimicrobial defenses in diabetes. These immune dysfunctions are
also outlined in Table17.3.
Delayed Leukocytes Responses inDiabetic
Wound
In normal tissue, inammatory responses are triggered
within minutes in wound in response to various cues such as
damaged tissue products, known as damaged associated
molecular pattern molecules(DAMPs), microbial products,
known as pathogen associated molecular pattern molecules
(PAMPs), and degranulating platelets [160, 161]. The peak
of the inammatory responses occurs 2–3 days after the
injury and gradually subsides as the wound transitions into
the proliferation phase, also known as the new tissue regeneration phase [160, 161]. The primary functions of inammatory responses are to protect the wound from invading
pathogens and to initiate subsequent healing processes.
Neutrophils are the rst inammatory leukocytes to inltrate the wound from the circulation [162]. Their primary
functions are to destroy invading pathogens using various
antimicrobial functions [153–155] and to recruit and activate
other leukocytes (such as monocytes/macrophages) and nonimmune cells (such as broblasts) to the wound site, where
they contribute to fortify defenses against infection and participate in subsequent healing processes [163–167].
However, in diabetes, the dynamics of the inammatory
responses, including those of neutrophils and macrophages,
are dysregulated. Diabetic ulcers are locked in a persistent
non-resolving inammation characterized by increased neutrophils and macrophages in the chronic phase [106, 161,
162]. In contrast, during the acute phase of healing early
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Table 17.3 Immune dysregulations and dysfunctions underlying infections in diabetes
Impairments/dysfunctions Source/cells Descriptions/references
Impaired chemotaxis • Neutrophils
(PMNs)
• Macrophages
(Møs)
Impaired phagocytosis • PMNs
• Møs
• Impaired bactericidal
functions
• NK cell dysfunctions • NK cells
• Dysregulated AMPs • DFU
• PMNs
• Møs
• Gastric corpus
• Urine
• Uroepithelial
cells
• Keratinocytes
• Epithelial cells
• Epidermal cells
• PMNs
• Peripheral blood
cells
(1) Reduced FPR signaling (shown in diabetic PMNs, but likely to be true for diabetic Møs
as well)
(2) Dysregulated CAMs
(3) Reduced FOXM1/STAT3 signaling
(4) Inadequate proinammatory ligands due to elevated IL-10
(5) Ischemia? (to be determined)
• References: [59, 168, 178–181, 183, 186, 201, 202]
(1) Reduced opsonization
(2) Oxidative stress
(3) Reduced expression of genes involved in phagocytosis (e.g., CD14 and MARCO)
• References: [222–225]
(1) Reduced nitric oxide (NO)
(2) Reduced NADPH
(3) Reduced phagocyte NADPH oxidase (Phox)
(4) Reduced granule enzymes
(5) Reduced granule release
• Increased sorbitol in PMN was responsible at least in one case
• References: [215, 228–230, 234, 235, 278, 279]
(1) Defective intracellular killing due to reduced IFN-γ production
(2) Reduced TNF-α production
• References: [248–250]
(1) CAMP (LL-37); low or undetectable in DFUs; low in diabetic mouse skin; low in
various cell types from diabetic patients or cells exposed to high glucose
(2) HBD-1; reduced in gastric corpus and in keratinocytes under diabetic conditions
(3) HBD-4; reduced in peripheral blood cells of type 2 diabetic patients
(4) Psoriasin, DEFB4A, and RNASE7; reduced in urinary bladder and uroepithelial cells
under diabetic conditions
(5) HBD-2; contradictory results. High in grade 3 DFUs in one report [259] and low in
grades 2–5 DFUs in another report [263]
(6) HBD-2; reduced in keratinocytes due to high glucose-induced reduction in STAT-1
• References: [259–263, 266]
307
after injury, diabetic wounds suffer from inadequate neutrophil and macrophage responses, making diabetic wounds
susceptible to infection [63, 64, 163, 164]. Impaired chemotaxis in phagocytic leukocytes, dysregulated pro- and antiinammatory cytokines production, and ischemia (reduced
angiogenesis) are factors that contribute to reduced inammatory leukocytes trafcking into diabetic wounds early
after injury [58, 59, 168, 169]. These factors are discussed
below.
Impaired Chemotaxis
Neutrophil trafcking in response to injury and/or infection
occurs in multiple waves, mediated by approximately 30
chemokine receptors on neutrophils, and involves multiple
signaling pathways [170–176]. However, the initial neutrophil chemotaxis in response to injury or infection involves
the activation of G protein-coupled formyl peptide receptor
(FPR) by N-formyl peptides, such as fMet-Leu-Phe (fMLF,
a.k.a., fMLP), which is released either by injured tissues or
by invading bacteria [170, 177]. Studies have shown that
neutrophils from both type 1 and type 2 diabetic patients, as
well as human and murine neutrophils and macrophages
exposed to high glucose, display impaired chemotaxis and
cellular mobility toward proinammatory ligands [178–181].
The skin at the margin of diabetic foot ulcers in humans
exhibits a noteworthy decrease in the presence of inammatory leukocytes compared to inamed tissues in non-diabetic
individuals [182, 183]. This observation suggests that the
impaired migration of leukocytes from circulation into
wound tissue could be the underlying cause.
Chemotaxis impairment in diabetic neutrophils was initially overlooked because it appeared to contradict clinical
observations that attributed excessive and prolonged neutrophil and macrophage inux as a signicant barrier to healing
in chronic diabetic ulcers [116, 184]. However, recent
research has demonstrated that impaired chemotaxis of diabetic neutrophils is a fundamental factor contributing to the
inability of diabetic wounds to control infection [59].
Specically, impaired signaling through the FPR chemokine
receptors (due to hyperglycemia-induced dampened expression of FPR) has been found to be responsible for chemotaxis impairment in human and murine diabetic neutrophils
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[59]. Interestingly, the authors also reported that some auxiliary chemokine receptors (e.g., CCR1) remain functional
under diabetic conditions but these receptors are not activated in diabetic wounds early after injury due to insufcient
inammatory ligands which will be discussed in the next
section. Importantly, treating diabetic wounds with CCL3
(a.k.a. MIP-1α), a ligand for CCR1, reduced infection by
over 99% and substantially improved healing in diabetic animals [59].
Another factor that may adversely affect chemotaxis in
diabetic neutrophils is the concentrations of cellular adhesion molecules (CAMs). CAMs are glycoproteins expressed
on the surface of various cell types such as leukocytes and
endothelial cells [185]. Although CAMs are critical for neutrophil interaction with endothelium and their transmigration
into the wound site from circulation [186], their excessive
expression can impede neutrophil mobility [187]. The baseline levels of circulating E-Selectin, Intercellular Adhesion
Molecule 1 (ICAM-1), Vascular Cell Adhesion Molecule 1
(VCAM-1), and soluble Intercellular Adhesion Molecule-1
(sICAM-1) were found higher in patients with type 2 diabetes compared to healthy controls [188].
Another defective mechanism that contributes to reduction in the inammatory leukocytes’ migration in diabetic
wounds during the acute phase of healing is the dysregulation in FOXM1 and STAT3 expression and function.
Transcription factors FOXM1 and STAT3, which function to
activate and promote survival of immune cells, are dampened in DFUs and their inhibition in the Streptozotocin
(STZ)-induced T1D and db/db T2D mice leads to decreased
neutrophil and macrophage recruitment in diabetic wounds
during the acute phase of healing early after injury [183].
and NF-κB) and proinammatory cytokines (e.g., CCL2,
CCL3, G-CSF, GM-CSF, IL-1β, and TNF-α) in diabetic
wounds, during the acute phase of healing early after injury,
making these wounds vulnerable to infection and impair
healing processes [59, 168, 169, 196–198]. The reduction in
the expression of and signaling through the TLRs in diabetic
wounds during the early acute phasefollowing injury has
been attributed to increased levels and signaling of the
immunosuppressive cytokine IL-10 [168].
Ischemia
Angiogenesis, which involves the formation of new blood
vessels and capillaries, plays a vital role in the wound healing process. It facilitates the creation of provisional granulation tissue, supplies essential nutrients and oxygen, and
serves as a pathway for inammatory cells to migrate from
the circulation into the wound site [162, 199, 200].
Endothelial dysfunction along with derangements in numerous biochemical pathways has been implicated as causes of
microcirculation impairment and reduced angiogenesis
(ischemia) in diabetic foot and diabetic foot ulcers [201,
202]. While the extent of ischemia and its impact on reduced
inammatory responses in diabetic wound during the acute
phase of healing early after injury has not been directly
investigated; if present, decreased angiogenesis could also be
a contributing factor to this impairment.
Impairments inAntimicrobial Functions
inPhagocytic Leukocytes
Dysregulations inPro- andAnti-inammatory
Cytokines
Toll-like receptors (TLRs), nucleotide oligomerization
domain (NOD)-like receptors (NLRs), and inammasomes
play critical roles in the expression of proinammatory cytokines and the recruitment of inammatory leukocytes to
wound sites [189–191]. However, in people with diabetes,
the expression and activation dynamics of these proinammatory complexes become dysregulated, leading to imbalanced production of proinammatory cytokines. Studies
have shown that diabetic ulcers in the chronic phase contain
elevated levels of TLR1, TLR2, TLR4, TLR6, MyD88,
NF-κB, NLRP3, Caspase-1, IL-1β, TNF-α, HSP60, HSP70,
and HMGB1, which mirror the neutrophil and macrophage
contents in chronic ulcers as discussed above [190, 192–
195]. In contrast, recent studies in diabetic animals have
reported signicant reductions in the expression of TLR signaling cascades (e.g., TLR1, TLR2, TLR4, MyD88, TRAF6,
Phagocytic leukocytes, including neutrophils (also known as
PMNs) and macrophages (Møs), are essential components of
the innate immune system and play a critical role in defending against pathogens [162, 203–205]. They employ a plethora of antimicrobial functions, including phagocytosis and
microbial killing by oxidative burst, nitric oxide, AMPs,
complements, and neutrophil and macrophage extracellular
traps (NETs and METs respectively) [206–214]. Apart from
chemotaxis impairment and dysregulation in the dynamics
of inammatory leukocyte migration in diabetic wounds,
diabetic leukocytes also display many dysfunctions in their
antimicrobial functions which further contribute to making
diabetic wounds susceptible to infection [179, 215–217].
The following section discusses these antimicrobial functional impairments in diabetic leukocytes.
Impaired Phagocytosis
Phagocytosis is a crucial process by which leukocytes, especially neutrophils and macrophages, ingest and eliminate
foreign particles like pathogens, as well as dead or dying
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cells and cellular debris [209, 218]. During phagocytosis,
leukocytes recognize and interact with pathogens directly
through non-opsonic receptors (e.g., C-type lectins, lectinlike recognition molecules like CD33, and scavenger receptors) or indirectly through surface Fc receptors (FcR) and
complement receptors (CR) that recognize opsonized pathogens. They then extend pseudopodia around the target pathogens, forming a phagosome that fuses with lysosomes to
create a phagolysosome, where pathogens are destroyed and
their products are recycled or excreted [219]. However, the
ability to engulf and destroy pathogens has been shown to be
diminished in neutrophils and macrophages extracted from
diabetic patients and diabetic animals, leading to reduced
bacterial clearance [178, 220, 221]. Factors contributing to
impaired phagocytosis in diabetic neutrophils and macrophages include reduced opsonization, increased oxidative
stress, and altered expression of genes involved in phagocytosis or phagocytosis regulation, such as CD14 and macrophage receptor with collagenous structure (MARCO)
[222–225].
Impaired Bactericidal Functions
Neutrophils and macrophages contain phagocyte NADPH
oxidase (Phox) and inducible nitric oxide synthase (iNOS)
that produce superoxides and reactive oxygen species (ROS),
such as superoxide anion (O
•−
), hydrogen peroxide (H2O2),
2
and peroxynitrite (ONOO−), which have potent antimicrobial properties against phagocytosed pathogens [226, 227].
However, diabetic neutrophils’ ability to kill engulfed pathogens is compromised due to reduced production of nitric
oxide (NO), ROS, and granule enzyme activity caused, at
least in one case, by sorbitol production in neutrophils [215,
228, 229]. Similarly, NADPH levels and Phox activity were
found to be lower in alveolar macrophages from diabetic
patients than in the controls [230].
Aside from generating reactive oxygen species (ROS),
neutrophils also utilize microbicidal substances produced during degranulation to eliminate pathogens [231]. Degranulation
plays a crucial role in pathogen elimination, but it also impacts
the immune response during both infectious and non-infectious diseases [231]. Neutrophils possess various types of
granules that possess antimicrobial properties, including primary or azurophilic granules, secondary or specic granules,
and tertiary or gelatinase granules [232, 233]. Azurophilic
granules contain elastase, myeloperoxidase, cathepsin G, and
defensins all with antimicrobial properties. Specic granules
contain lactoferrin, cathelicidin, lysozyme, and proteins that
disrupt the membranes of pathogens, causing their demise.
Gelatinase granules contain lactoferrin which prevents bacterial growth by sequestering iron [232, 233]. However, several
studies have reported reduced granule content and/or release
in diabetic neutrophils, potentially impairing their ability to
eliminate pathogens [234, 235].
Impaired NETosis
Neutrophil extracellular traps (NETs) are complex networks
of brous structures composed of DNA, histones, and granular proteins, which neutrophils release at infection sites during the wound healing process [236, 237]. NETs are widely
acknowledged as a protective mechanism against pathogens,
but they have also been implicated in other physiological and
pathological processes, such as wound healing, inammation, and autoimmune diseases [236–239]. However, in diabetes, high blood sugar levels predispose neutrophils to
undergo NETosis, and excessive NETosis has been shown to
hinder the wound healing processes in both diabetic mice
and humans [240–243]. Yet, despite excessive NETs, these
wounds continue to be highly susceptible to infection, as previously discussed. The extent to which NETosis contributes
to antimicrobial defenses in diabetic wounds remains uncertain and warrants further study.
Dysfunctions inNK Cells
Natural killer (NK) cells are another essential cellular components of the innate immune systemwhichplay an important role, primarily against viral infections or intracellular
bacterial pathogens. NK cells employ several mechanisms to
ght infections [244–247]. These include (1) direct cytotoxicity where they destroy infected cells by releasing cytotoxic
granules containing perforin and granzymes; (2) antibodydependent cell-mediated cytotoxicity (ADCC) in which they
recognize and bind to the Fc region of antibodies attached to
infected cells, which in turn triggers NK cell activation and
the subsequent killing of infected cells; and (3) cytokine production that amplies inammatory responses (e.g., TNF-α)
and boost antimicrobial defenses in both infected and uninfected neighboring cells through the release of IFN-γ.
However, diabetes adversely impacts the function of NK
cells, leading to impairments in their antimicrobial functions. NK cell cytotoxicity and their capacity to produce
IFN-γ and TNF-α have been found to be reduced in diabetic
patients [248–250]. While these studies did not directly
assess NK cells’ antimicrobial function in wound, they demonstrated the involvement of NK cells in ghting infections,
which can be extrapolated to the context of wound infections. Further research is needed to better characterize the
specic role of NK cells in wound healing and infections.
Dysregulation inAntimicrobial Peptides
Production
Antimicrobial peptides (AMPs) are essential part of the
innate immune system and play a critical role in preventing
infections in all organs including wounds [251, 252]. They
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are small, mostlycationic peptides that can directly or indirectly kill bacteria, fungi, and viruses, function as immunomodulators to mobilize and activate immune responses
against pathogens, and/or interfere with pathogens’ virulence factors by either neutralizing them (e.g., binding LPS),
or by blocking their production, such as inhibition of biolm
production by blocking bacteria communications through
quorum sensing [252–254]. Some of the most important
AMPs involved in wound healing include defensins,
cathelicidins, and histatins. Defensins are small, cysteinerich peptides that are divided into three subfamilies:
α-defensins, β-defensins, and θ-defensins [255]. Cathelicidins
are a family of AMPs that contain a conserved cathelin
domain. The lone member of cathelicidinin human isLL-37,
which has been shown toplay a signicant role in wound
healing through its immunomodulatory and antimicrobial
functions [256]. Histatins are histidine-rich peptides that
exhibit antimicrobial activity against bacteria and fungi
[257]. Although primarily expressed in the oral cavity and
found in saliva, histatin-5, (a key member of this family), has
been shown to be expressed in wounds and participate in
healing processes [258].
Dysregulation in the expression of AMPs has been
observed in diabetic ulcers or under diabetic conditions,
contributing to increased susceptibility to infections and
impaired wound healing. For example, the expression of
CAMP (LL-37) is notably low or even undetectable in diabetic woundscompared to wounds innon-diabetic healthy
individuals [259]. CAMP expression has also been found to
be reduced in the peripheral blood cells from type 2 diabetic patients; in cultured epidermal cells from human diabetic foot ulcers (DFUs); in the skin of type 1 diabetic
mice; and in keratinocytes exposed to high glucose levels
[259, 260]. In addition, reduction in the expression of
HBD-1 (human β-Defensin-1) has been reported in the gastric corpus of the diabetic patients, as compared to the control group [261]. HBD-4 (human β-Defensin-4) expression
is also reduced in the peripheral blood cells of type 2 diabetic patients [260]. Moreover, Psoriasin levels were found
to be decreased in the urine of diabetic patients compared
to non-diabetic controls, and the decrease in Psoriasin was
associated with increased E. coli presence in the urinary
bladder of diabetic patients [262]. However, there are conicting reports regarding the levels of HBD-2 (human
β-Defensin-2) in DFUs. One study shows a reduction in
grade 2–4 DFUs, as dened by Wagner’s classication
[263], while another study reports overexpression in grade
3 DFUs [259]. Despite these conicting results, it is evident
that diabetes overall has a detrimental impact on the production of AMPs, which in turn increases the susceptibility
of diabetic patients to infections.
Hyperglycemia
The primary culprit underlying impaired antimicrobial functions in diabetes appears to be hyperglycemia and exposure to
high glucose. Hyperglycemia dampens superoxides and ROS
production and degranulation in leukocytes, leading to
reduced phagocytosis and bacterial killing [216, 264, 265].
Exposure to high glucose levels has also been shown to downregulate the expression of AMPs (e.g., S100A7, DEFB4A,
and RNASE7) in uroepithelial cells [262]. Similarly, high
glucose has been shown to dampen the expression of
HBD-2 in human keratinocytes due to reduction in signal
transducer and activator of transcription 1 (STAT-1) signaling
[266]. Another mechanism by which exposure to high glu-
cose can dampen antimicrobial functions in leukocytes is by
inducing a metabolic redox imbalance, which impairs neutrophil antimicrobial functions by damaging cellular components [228, 267]. One of the main mechanisms by which
hyperglycemia dampens antimicrobial functions in leukocytes is through the production of advanced glycation end
products (AGEs). AGEs are formed by the non-enzymatic
glycation of proteins, lipids, and nucleic acids in the presence
of elevated glucose levels [268], and have been shown to
adversely impact antimicrobial functions in leukocytes by
disrupting cell signaling and altering gene expression [269–
271]. Not surprisingly, the most effective way to combat
infection in diabetic patients and diabetic animals is by controlling their blood glucose levels [56, 272–275]. Interestingly,
short-term exposure (1–3h) to high glucose results in a shift
toward an anti-inammatory phenotype in human and murine
neutrophils and monocytes, while long-term exposure (24–
72h) results in a proinammatory shift in human and murine
monocytes [59, 168, 276, 277]. What causes this biphasic
response behavior in monocytes toward short- and long-term
exposure to high glucose remains unknown.
Therapeutics
In this chapter, we will discuss the conventional, unconventional, and emerging treatment modalities whose goal is specically to address infection in diabetic ulcers.
Conventional (Standard) Therapies
The management of diabetic foot ulcers (DFUs) begins with
a comprehensive clinical evaluation that involves a detailed
patient history and a thorough physical examination [280,
281]. Healthcare providers must carefully assess any signs of
diabetic neuropathy, peripheral arterial disease, and infection
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[281]. If possible, prompt standard treatments should follow
this evaluation. Standard therapies, including debridement,
ofoading, and wound dressing, form the cornerstone of DFU
treatment [278, 282–284]. Debridement is aimed at removing
infected and necrotic tissue and resetting a chronic wound
into an acute fresh wound [282–284]. Ofoading is used to
minimize and redirect the weight that is exerted on the foot,
thereby promoting wound healing [278]. Wound dressing
plays a vital role in protecting against harmful environmental
exposures and infections, moisturizing the wound area, and
promoting new tissue formation, granulation, angiogenesis,
faster epidermal cell migration, and debridement [278, 280].
For more information on these treatment modalities, please
refer to other sections of this book. Other important conventional therapies include glycemic control and the use of antibiotics that are discussed below and outlined in Table17.4.
Glycemic Control
As discussed above in this chapter, hyperglycemia dampens
innate immune responses, increases susceptibility to infections, delays wound healing, and exacerbates the severity of
ulcers [216, 264, 265, 278, 285]. Numerous studies highlight
the signicant benets of glycemic control in reducing the
incidence of infections and related complications, including
Table 17.4 Conventional (standard) therapies to manage infection in
DFU
Conventional therapies
Practice Description Function/indication/type
Glycemic
control
Antibiotic therapies
Infection types Recommended antibiotics
• Pseudomonas aeruginosa
• Aerobic, Gram-positive
cocci
• Methicillin-resistant
Staphylococcus aureus
(MRSA)
• Gram-negative bacilli
facultative anaerobes;
Gram-negative cocci
facultative anaerobes
• Gram-negative bacilli
obligate anaerobes; Gramnegative cocci obligate
anaerobes
• Marinating
blood glucose
levels in normal
range
• Reduces the risk of infection
• Decrease in the risk for lower
extremity amputation
• Improves wound healing and
hinders the detrimental effects of
infections
• References: [274, 278, 285,
286]
• Piperacillin/tazobactam,
ceftazidime, imipenem/cilastatin,
and uroquinolone
• Penicillin, rst generation,
cephalosporin
• Clindamycin, doxycycline,
trimethoprim/sulfamethoxazole,
linezolid, daptomycin, linezolid,
dalbavancin
• Second or third generation
cephalosporin, β-lactamase
inhibitor, carbapenem,
uroquinolone
• Piperacillin/tazobactam
clindamycin±uroquinolone,
β-lactamase inhibitor, carbapenem,
second or third generation
cephalosporin
• References: [304–306]
lower extremity amputations [278, 285–287]. Corroborating
these reports, short-term and long-term glycemic control has
been shown to be highly effective in lowering infections in
both type 1 and type 2 diabetic animals [56, 288, 289].
Therefore, maintaining appropriate blood glucose levels is
considered crucial and perhaps the most effective approach
to managing and preventing the adverse outcomes of infections in diabetic patients [216, 264, 265, 278, 285].
Antibiotics
At present, there are no approved biological therapies available to address infection in diabetic wounds, leaving antibiotics as the primary form of management for infection in
diabetic ulcers. Diabetic patients receive a signicantly
higher number of antibiotic prescriptions than their age and
sex-matched counterparts [290, 291]. Before addressing a
local wound, it is crucial to determine the severity of the
infection. Proper wound care is essential in preventing the
spread of harmful infection throughout the body [278, 292].
For supercial infections, removing any dead tissue and
cleaning the wound is necessary [66, 293]. Patients with
mild wound infections are typically prescribed oral antibiotics, while those with moderate to severe infections, such as
necrotizing fasciitis or sepsis, require intravenous antibiotic
therapy and immediate hospitalization to prevent the risk of
amputation [278, 292]. It is critical to administer empiric
antibiotics directed at aerobic Gram-positive cocci and aerobic Streptococci while considering recent patient antibiotic
use and local susceptibilities [294]. The antibiotic treatment
may need to be adjusted based on both the clinical response
and culture ndings [295]. While antibiotic administration
may be necessary in certain situations, it is essential to practice antibiotic stewardship due to the many potential negative
side effects. These side effects include the emergence and
spread of antibiotic resistance, as well as nephrotoxicity, ototoxicity, hepatotoxicity, acute renal failure, mitochondrial
damage, an increased risk of infection with C. difcile, and
dysbiosis in the gut microbiome. Dysbiosis has been associated with obesity, diabetes, and immunological and neurological diseases such as Parkinson’s disease [296–302].
Additionally, antibiotic use has been shown to interfere with
wound healing processes [303]. Therefore, caution should be
exercised when using antibiotics, and alternative
approachesshould be explored whenever possible. A list of
frequently used antibiotics for the treatment of common
infections in DFUs is presented in Table17.4.
Unconventional Therapies
The treatment of infections in diabetic wounds has also
involved the use of various unconventional therapies. These
therapies, which include silver nanoparticles, honey, hyper-
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baric oxygen therapy (HBOT), and maggot debridement
therapy, are discussed below and summarized in Table17.5.
Silver
Silver has been extensively studied as an antimicrobial agent,
showing effectiveness against bacteria, fungi, and certain
viruses [307]. The antimicrobial properties of silver are
attributed to its positively charged ions (Ag+), which can act
against microorganisms through multiple mechanisms [307].
Table 17.5 Unconventional therapies
Therapy Application Outcomes/indications
Silver • Silver is incorporated
into different types of
wound dressings, such as
hydrocolloids, alginates,
foams, and hydrogels
• Silver nanoparticles
(AgNPs) have a large
surface area and can
release silver ions more
effectively than bulk silver.
(incorporated in wound
dressings)
• Silver nitrate used in
debridement
• Silver sulfadiazine is a
topical antimicrobial cream
Honey • Has antibiotic,
antibacterial, antioxidant,
and anti-inammatory
features
Hyperbaric
oxygen
therapy
(HBOT)
Maggot
debridement
therapy
(MDT)
• HBOT tends to speed
up the healing of wounds
and alleviate infections in
which tissues are starved
for oxygen by providing
pure oxygen in a
pressurized environment
• Incorporates live, sterile
maggots to combat DFUs
• Has broad
antimicrobial properties
• Disrupts biolm
• Has antiinammatory effects
• Activate cellular
mechanisms toward the
healing of chronic
wounds
• References: [308,
309, 323–326]
• Can help diminish
wounds and burns
• Draws uid from
surrounding vessels and
provides a moist
environment
• Shown to accelerate
the healing of wounds
• Alternative or
adjunctive therapy
option for healing
wounds
• References: [278,
280]
• Adjunctive therapy
with debridement,
ofoading, and
comprehensive wound
care to boost DFUs
healing
• Patients with severe,
irreversible ischemia
should not use HBOT
• References: [314,
316]
• Debride necrotic
tissue and slough
within a wound, along
with the simultaneous
increase in granulation
tissue and
epithelization
• References: [317,
318]
In treating diabetic wounds, silver nanoparticles (AgNPs)
have been employed to produce anti-inammatory and antibacterial effects [308]. They have been shown to activate cellular mechanisms that promote the healing of chronic
wounds, prevent infection, and aid in the differentiation of
broblasts into myobroblasts to increase the healing rate
[309]. AgNPs are typically administered topically at the
wound site in combination with wound dressings [308, 310].
Numerous studies have demonstrated the efcacy of AgNPs
as a treatment for diabetic wounds, leading to the commercialization of certain compounds [308]. However, the potential toxicities of these nanoparticles remain a concern and
optimal dosing of AgNPs must be considered before this
unconventional therapy can be widely used as a wound care
product [308].
Honey
Honey is a popular natural therapy for patients with DFU,
and in conventional medicine, it is administered through
gamma-irradiated wound care instruments as medical grade
honey [278, 280]. This ancient treatment has been utilized
for various skin conditions and is valued for its antibacterial,
antioxidant, and anti-inammatory properties, which can aid
in the healing of wounds and burns [278, 280]. Additionally,
its ability to draw uids from surrounding vessels and provide a moist environment makes it useful in treating DFUs
[280]. Corroborating these anecdotal evidence, several animal experiments have shown that honey can accelerate
wound healing, highlighting its potential as an alternative
treatment for DFUs [278, 280]. The main concerns regarding
the use of honey in treatment plans is the potential risk of
botulism associated with contaminated honey and lack of
high-quality clinical evidence showing its efcacy in diabetic patients[311].
Hyperbaric Oxygen Therapy
Hyperbaric oxygen therapy (HBOT) is a treatment that
involves breathing pure oxygen in a pressurized chamber and
is used for various conditions, such asdecompression sickness which is a potential risk of scuba diving, and serious
infections [312–314]. There is moderate-quality evidence to
support the use of HBOT as an adjunctive therapy to debridement, ofoading, and comprehensive wound care for boosting the healing of DFUs [314]. Adjunctive HBOT has been
shown to have a positive effect on wound healing in diabetic
foot with infection [315]. Moreover, in comparison to standalone standard therapy, HBOT has been shown to have a signicant benecial effect in enhancing the healing rate and
reducing the risk of major amputations [314, 316]. This
effect has been consistent across randomized controlled trials and controlled cohorts when analyzed both pooled and
separately [314]. The antimicrobial effects of HBOT are
believed to be due to the formation of reactive oxygen spe-
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cies (ROS) and the enhancement of the immune system’s
antimicrobial effects, which can have an additive or synergistic effect with certain antimicrobial agents [57, 313, 314].
However, HBOT is not recommended for patients with
severe, irreversible ischemia because the therapy is unlikely
to reach ischemic areas and stimulate angiogenesis [314,
316].
Maggot Debridement Therapy
The use of maggot debridement therapy (MDT) has also
emerged as a therapeutic option to combat diabetic foot
ulcers [317]. MDT is a biological therapy that involves
incorporating live, sterile maggots into non-healing skin and
soft tissue wounds to debride necrotic tissue and slough
within a wound [317]. This method promotes granulation tissue and epithelization while the maggots clean out the wound
[317]. Recently, a newly established strain from human
corpses associated with high feeding activity has shown signicant promise in MDT [318]. MDT can also be used in
outpatient settings and tends to be a safe and effective tool
that can be utilized by non-physicians [318, 319]. Tian etal.
conducted an experiment using MDT on patients with DFUs
and found all the wounds to show a marked decrease in
necrotic tissue and slough, along with a reduction in pain and
no further complications [317]. Compared with other usual
treatment options, MDT for DFUs tends to be low-cost
[320]. It is also a valuable treatment choice for numerous
ambulatory, home-bound, and extended-care patients with
nonhealing wounds [318, 319]. When used in conjunction
with surgical debridement, MDT has shown promising management of DFUs [321]. However, only a few maggot species yield desirable outcomes for medical applications, thus,
identifying the most effective strain for MDT remains a challenge [318]. Another common side-effect to MDT is discomfort at the site of application. Patients may experience a
sensation resembling a “nipping” or “picking,” which may
necessitate oral pain relief or early discontinuation of treatment in some cases [322].
Emerging Therapies
Despite the aforementioned efforts, there is currently no
approved biological therapy that can effectively address
infection concerns in DFUs. While Becaplermin, a recombinant human platelet-derived growth factor-BB (rhPDGF BB), is the onlyapproved biologic for treating neuropathic
DFUs, it falls short in terms of infection management, has
limited efcacy in promoting healing, and poses potential
safety risks such as malignancies [327–330]. In light of the
increasing problem of antimicrobial resistance and the limited discovery of new antibiotics, researchers have redirected
their attention toward alternative strategies and have identi-
ed several encouraging approaches to tackle infections in
DFUs. The following section examines these emerging and
innovative therapies which are also summarized in
Table17.6.
Antimicrobial Peptides
As previously discussed, antimicrobial peptides (AMPs) are
naturally occurring peptide-based antimicrobials that can
eliminate pathogens through various mechanisms, including
membrane disruption [331]. AMPs have been extensively
researched as a promising new therapy for managing chronic
wound infections, with some undergoing clinical trials [332,
333]. For instance, LL-37 (also known as cathelicidin) is
among the most potent broad-spectrum AMPs found in
humans and has been utilized as a potential treatment for
polymicrobial-infected wounds [334]. Additionally, LL-37
has demonstrated effectiveness in reducing drug-resistant
bacteria in diabetic foot ulcers [280] and has been shown to
be effective instimulating the healing of challenging chronic
wounds in a clinical trial [335]. However, there are signicant limitations to the therapeutic use of AMPs, including
inherent cellular and tissue toxicity, potential activity limitations against pathogens, and the emergence of resistance to
AMPs [333, 336, 337].
Bacteriophage Therapy
Bacteriophages are viruses thatspecically target and eliminate bacteria [338]. In recent years, the use of bacteriophage
therapy (also known as phage therapy) has gained popularity
as an alternative or adjuvant approach for treating infections
[339, 340]. Bacteriophages can be applied topically to manage localized infections in wounds, burns, and trophic ulcers,
including diabetic foot ulcers [339, 340]. One instance of
successful application of this therapy was observed in a diabetic patient with Staphylococcal osteomyelitis, resulting in
a durable outcome [341]. The same approach was also found
to be highly effective in controlling MRSA infection in persistent diabetic toe ulcers [342, 343]. Bacteriophage therapy
has been shown to be an effective therapeutic strategy for
DFUs, which can be administered directly through topical
application [340, 342, 343]. This therapy is particularly
effective in the early stages of acute wound infection, with
positive clinical results reported in most cases [340, 344].
However, the efcacy of bacteriophage therapy largely
depends on the species of the pathogen, with the best results
observed against Staphylococcus spp. and Streptococcus
spp. infections [340, 344, 345]. Despite its usefulness in
treating infected chronic ulcers through long-term application, bacteriophage therapy has limitations such as the
requirement for identifying phages with an effective host
range against the infecting bacteriain wound, emergence of
phage-resistant bacteria, the possibility of triggering host
immune responses that could hinder the healing process, and
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Table 17.6 Emerging therapies
Therapy Function Outcome in DFU
Antimicrobial peptides (AMPs) • Small peptides (usually cationic)
• Expressed by various inammatory and
non-inammatory cells in wound, such as
PMNs, Møs, and keratinocytes
• Have potent antimicrobial properties, killing
pathogens by various direct and indirect
mechanisms
• Direct killing mechanisms; membrane
disruption, and inhibiting transcription and
translation processes
• Indirect mechanisms; modulate immune
responses; neutralize bacterial virulence factors
(e.g., bind to LPS); inhibit biolm
Bacteriophage therapy • Uses viruses that can infect and kill specic
bacteria
• Finding the right viruses may be challenging
• Bacteria can become resistant to the viruses
• Viruses can trigger undesired immune
responses
• References: [342, 343, 360]
Immunomodulators
GM-CSF
CCL3 (MIP-1α)
Anti-IL-10
• GM-CSF: promotes myobroblast
differentiation, facilitates wound contracture,
proliferates epidermal cells
• CCL3 recruits and activates inammatory
leukocytes by engaging the CCR1 and CCR5
auxiliary chemokine receptors
• References: [176, 356–358]
• IL-10 is a potent immunosuppressive
cytokine that inhibits the production of
proinammatory cytokines by blocking
signaling through TLRs
• References: [361–364]
• Benecial against the spread of bacteriaresistant organisms in DFU patients
• Effective against a wide range of organisms
of bacterial, fungal, viral, and malignant decent
• May be utilized as a monotherapy or in
combination with antibiotics in DFUs
• References: [252–254, 280]
• Utilized for treating localized infections in
wounds, burns, and trophic ulcers, including
diabetic foot ulcers [340]
• More effective in the early stage of acute
wound infection
• References: [340, 344]
• GM-CSF reduces infection and stimulates
healing when used in combination with
antibiotic and insulin therapy
• Reference: [355]
• CCL3 reduces infection in diabetic wound
by ~99% and in normal wound by ~90%
• Stimulates healing in both infected and
uninfected diabetic and normal wounds
• References: [59, 365]
• In acute diabetic wounds, topical treatment
with anti-IL-10 and anti-IL-10R antibodies: (1)
increase the expression and signaling through
TLRs; (2) increase the expression of
proinammatory cytokines; (3) increase Møs
and leukocytes; (4) stimulate healing
• Effect of anti-IL-10 therapies on infection in
diabetic wound has not been examined
• Reference: [168]
R. Roy et al.
issues associated with invivo pharmacokinetics and pharmacodynamics [346, 347]. Moreover, successful bacteriophage
therapy is largely dependent on the efciency of phage preparations [65].
Immunomodulators
As previously discussed, impairments in innate immune
responses and functions are critical factors that render
diabetic wounds vulnerable to infection and impaired healing. To overcome these immune dysfunctions, several immunomodulators have shown promising results in enhancing
infection control and/or stimulating healing in diabetes. The
following section discusses these emerging approaches in
more detail.
GM-CSF
Granulocyte/macrophage colony stimulating factor
(GM-CSF) belongs to a class of growth factors known as
colony stimulating factors which support survival, clonal
expansion, and differentiation of hematopoietic progenitor
cells [348–351]. GM-CSF induces partially committed progenitor cells to divide and differentiate in the granulocytemacrophage pathways which include neutrophils, monocytes/
macrophages, and myeloid-derived dendritic cells [352,
353]. GM-CSF has been approved by the Food and Drug
Administration (FDA) in the United States for systemic use
to accelerate neutrophil recovery and reduce infections in
cancer patients following chemotherapy and in patients
undergoing allogeneic or autologous stem cell transplantation (reviewed in [354]). It has also shown therapeutic potential to stimulate healing in DFUs, following topical or
systemic administration [355]. GM-CSF has the potential to
promote myobroblast differentiation, facilitate wound contracture, proliferate epidermal cells, increase superoxide production, differentiate hematopoietic progenitor cells, and
recruit inammatory cells to the site of injury for overall
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healing [355]. When used in conjunction with antibiotic and
insulin therapy, GM-CSF has been shown to accelerate
pathogen clearance, reduce hospitalization time, and shorten
duration of antibiotic use in diabetic patients [355].
CCL3
The proinammatory cytokine CCL3, also known as MIP-1α,
plays an important role in recruiting and activating phagocytic leukocytes by interacting with their auxiliary chemokine receptors, specically CCR1 and CCR5 [176, 356–358].
As was discussed earlier, neutrophils and macrophages from
type 1 and type 2 diabetic patients, as well as neutrophils
from diabetic mice, exhibit impaired chemotaxis due to
defective signaling through their primary FPR chemokine
receptors, which in turn make diabetic wounds vulnerable to
infection [59, 178–181]. Intriguingly, the CCR1 auxiliary
chemokine receptor remains functional under diabetic conditions and engaging this receptor by topical treatment with
CCL3 has been demonstrated to reduce infection by over
99% and improve healing substantially by jumpstarting neutrophil and leukocyte responses in wound during the acute
phase of healing after injury in diabetic mice [59]. These fascinating ndings suggest that the antimicrobial functional
impairments of diabetic neutrophils may be correctableif the
dynamics of neutrophil responses can be restored during the
acute healing phase shortly after injury. It is noteworthy that
the application of topical CCL3 has also demonstrated a signicant reduction in wound infection rates by approximately
90%, as well as a moderate stimulation of wound healing in
both infected and uninfected healthy mice, highlighting the
potential of CCL3 as a therapeutic agent in wound care
[359]. The ability of CCL3 to achieve these impressive outcomes in diabetic patients after surgical debridement is yet to
be established.
Anti-IL-10
The primary cause of inactivity in auxiliary receptors, such
as CCR1, during the early acute phase of healing in diabetic
wounds is the insufcient expression of their proinammatory ligands like CCL3, due to the overexpression of immunosuppressive cytokine IL-10 [59, 168]. Studies have shown
that administering blocking antibodies against IL-10 or the
IL-10 receptor (IL-10R) enhances the production of proinammatory cytokines by activating TLR signaling, consequently restoring macrophage and leukocyte responses in
diabetic wounds during the acute healing phase and promoting healing [168]. It is worth noting that similar to topical
CCL3 treatment, anti-IL-10 therapies did not result in persistent inammation in diabetic wounds. Rather, inammatory
responses increased during the acute healing phase but eventually subsided in CCL3 and anti-IL-10-treated diabetic
wounds as the healing processes progressed [59, 168]. These
fascinating ndings indicate that diabetic wounds can avoid
a sustained inammatory environment as long as the dynamics of inammatory responses are properly regulated in
them. While the effect of anti-IL-10 therapies on infection
control mechanisms in diabetic wounds has yet to be investigated, the fact that inammatory responses (which are crucial for ghting infection) increased in diabetic wounds
treated with anti-IL-10 implies that anti-IL-10 immunomodulatory therapies could also be effective against infections in
diabetic wounds.
Concluding Remarks
Infection is a widely recognized complication that can signicantly impact the health and well-being of individuals
with diabetes. No organ in a diabetic patient is immune to
infection. In this chapter, we presented a summary of prevalent infections in diabetes (Table17.1), specically concentrating on wound and foot ulcer infections (Table 17.2).
Additionally, we discussed the immune dysregulation and
dysfunction that make individuals with diabetes more prone
to infections (Table17.3).
The research studies reviewed in this chapter highlight the
reasons behind the increased vulnerability of diabetic
wounds to infection. The underlying cause is the disturbance
of proinammatory responses, particularly in neutrophils
and macrophages, during both acute and chronic phases of
wound healing, as well as their compromised bactericidal
capabilities. These issues arise from various factors such as
insulin resistance, obesity, dyslipidemia, the buildup of
advanced glycation end products (AGEs), and most importantly, persistent hyperglycemia, which can inuence all
these factors.
In the initial phase of wound healing following an injury,
when neutrophils and macrophages should be at their highest
levels to prevent infection and initiate healing processes,
they are reduced in diabetic wounds. This reduction is due to
defective leukocyte chemotaxis (caused by diminished signaling through chemokine receptors like FPR), increased
immunosuppressive IL-10 levels, and potentially reduced
angiogenesis (Fig. 17.1). The delay in inammatory
responses in diabetic wounds effectively invites pathogenic
bacteria, such as S. aureus and P. aeruginosa, to colonize
these wounds and take advantage of the glucose-rich environment, promoting their growth. Figure17.1 illustrates the
immune dysregulations and dysfunctions in diabetic wounds
during the acute healing phase. Early following an injury,
diabetic wound’s environment is characterized by a lower
number of phagocytic leukocytes (PMNs and Møs) due to
dysregulated cell adhesion molecules, reduced expression of
FPR and CXCR2 chemokines, and elevated IL-10 levels.
This combination of low PMNs and Møs and high IL-10 levels leads to decreased expression and signaling through
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