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Infection inDiabetes: Epidemiology,
https://t.me/med1917
Immune Dysfunctions,
andTherapeutics
RuchiRoy, RajSingh, andSashaH.Shakhani
17
Abstract
Diabetes is a chronic metabolic disorder that affects
approximately 10% of the global population.
Unfortunately, diabetic individuals are also at a high risk
of developing diabetic foot ulcers (DFUs), with an estimated 19–34% of individuals affected at some point in
their lives. These DFUs are a leading cause of lower
extremity amputations (LEAs), responsible for 60–70%
of all cases, and have a 5-year mortality rate of approximately 49%. The mortality rate associated with DFUs is
even more alarming when compared to that of all cancers,
which is approximately 31%. The economic burden of
DFUs is also staggering, with a global estimated cost of
$78.2 billion USD. The incidence of DFUs is further
compounded by the fact that 50–60% of cases develop
infections, increasing the risk of amputation by 50% compared to patients with uninfected DFUs. This chapter
aims to provide a comprehensive overview of infections
in diabetes, with a particular focus on infections in DFUs.
We will explore the microbiome shift toward pathogenic
bacteria in DFU, and how this shift impacts healing outcomes. Additionally, we will examine various factors that
make diabetic patients prone to infections, including dysregulations and dysfunctions in the innate immune sys-
Ruchi Roy and Raj Singh contributed equally with all other
contributors.
R. Roy
UICentre for Drug Discovery, College of Pharmacy, University of
Illinois at Chicago, Chicago, IL, USA
R. Singh
Department of Medicine, Rush University Medical Center,
Chicago, IL, USA
S. H. Shakhani (*)
Department of Medicine, Rush University Medical Center,
Chicago, IL, USA
Cancer Center, Rush University Medical Center, Chicago, IL, USA
e-mail: Sasha_Shakhani@rush.edu
tem. Finally, we will review the conventional,
unconventional, and emerging therapeutic options available to address infections in DFUs. By providing an indepth understanding of the challenges associated with
infections in diabetes, this chapter aims to contribute to
the development of more effective treatment strategies
that can help reduce the burden of DFUs on individuals
and society as a whole.
Abbreviations
ADCC Antibody-dependent cell-mediated
cytotoxicity
AGEs Advanced glycation end products
AgNPs Silver nanoparticles
AGP α1-Acid glycoprotein
AMPs Antimicrobial peptides
BJIs Bone and joint infections
CAMs Cell adhesion molecules
CCL2 Chemokine (C-C motif) ligand 2
CCL3 Chemokine (C-C motif) ligand 3
CCR1 C-C motif chemokine receptor 1
CD14 Cluster of differentiation 14
CDI Clostridium difcile infection
CFU Colony-forming unit
CI Condence intervals
COVID-19 Coronavirus disease 2019
CXCR2 CXC chemokine receptor 2
DAMPs Damage-associated molecular patterns
DEFB4A Defensin Beta 4A
DFUs Diabetic foot ulcers
DM Diabetes mellitus
ECM Extracellular matrix
eDNA Extracellular DNA
ENT Ear, nose, and throat
EPO Erythropoietin
fMLF fMet-Leu-Phe
FOXM1 Forkhead box protein M1
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
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FPR Formyl peptide receptor
G-CSF Granulocyte colony-stimulating factor
GI Gastrointestinal
GM-CSF Granulocyte-macrophage colony- stimulating
factor
GPRD General Practice Research Database
HbA1c Hemoglobin A1c
HBD Human β-defensin
HBOT Hyperbaric oxygen therapy
HCV Hepatitis C virus
HICs High-income countries
HMGB1 High mobility group box 1
HNP Human neutrophil peptide
HSP Heat shock protein
ICAM-1 Intercellular adhesion molecule 1
ICU Intensive care unit
IDF International Diabetes Federation
IFN-γ Interferon gamma
IL-10 Interleukin-10
IL-1β Interleukin-1β
IRAK-1 Interleukin 1 receptor-associated kinase 1
IRRs Incidence rate ratios
LEAs Lower-extremity amputations
LPS Lipopolysaccharide
MARCO Macrophage receptor with collagenous
structure
MDT Maggot debridement therapy
MMPs Matrix metalloproteinases
MPO Myeloperoxidase
MyD88 Myeloid differentiation factor 88
NETs Neutrophil extracellular traps
NF-κB Nuclear factor kappa B
NIDDK National Institute of Diabetes and Kidney
Disease
NK Natural killer
NLRP3 Nucleotide-binding domain, leucine-rich-
containing family, pyrin domain-containing-3
NLRs Nucleotide oligomerization domain (NOD)-
like receptors
NO Nitric oxide
OR Odds ratio
PAMPs Pathogen-associated molecular pattern
molecules
PARP1 Poly [ADP-ribose] polymerase 1
Phox Phagocyte NADPH oxidase
PI Predictive interval
PMN Polymorphonuclear leukocytes
PRRs Pattern recognition receptors
RNASE7 Ribonuclease 7
RNS Reactive nitrogen species
ROS Reactive oxygen species
RR Relative risk
SSIs Surgical site infections
SSTI Skin and soft tissue infections
STAT1 Signal transducer and activator of transcription
STAT3 Signal transducer and activator of transcription
STZ Streptozotocin
T1D Type 1 diabetes
T2D Type 2 diabetes
TDM Trehalose 6,6′-dimycolate
TLRs Toll-like receptors
TNF-α Tumor necrosis factor-α
TRAF6 Tumor necrosis factor receptor-associated fac-
U/LMICs Upper-middle and lower-middle income
UTIs Urinary tract infections
VCAM-1 Vascular cell adhesion molecule 1
VEGFR2 Vascular endothelial growth factor receptor 2
WHO World Health Organization
Introduction
Diabetes is a group of metabolic disorders characterized by
chronic hyperglycemia resulting from insufcient insulin
production, impaired cellular response to extracellular insulin, and/or impaired glucose metabolism [1, 2]. Diabetes has
negative impacts on various organs that can lead to severe
and life-threatening complications, such as cardiovascular
diseases, neuropathy, retinopathy, nephropathy, and hearing
impairment [3, 4]. Diabetes also increases the risk of certain
cancers and is a known risk factor for mental health disorders, such as Alzheimer’s disease [5, 6]. Moreover, diabetes
signicantly increases the susceptibility to infections of any
origin, including bacterial, fungal, and viral infections, and
infections, in turn, cause considerable morbidity and mortality among diabetic patients [7–12].
(DFUs) and they can lead to severe complications, including
the risk of amputation and even death. Approximately
50–60% of DFUs become infected, and this risk increases
with the duration of the ulcer, severity of the neuropathy, and
the presence of peripheral vascular disease [7–12]. Infection
in DFUs also increases the risk of hospitalization and contributes to the signicant healthcare burden associated with
managing these wounds [7–12].
bone infection that requires aggressive treatment, including
surgical debridement and prolonged antibiotic therapy.
Osteomyelitis can progress to limb amputation in severe
cases, which is a devastating outcome for patients and has
signicant social and economic implications [13].
1
3
tor 6
countries
Infections have a signicant impact on diabetic foot ulcers
Infection in DFUs can lead to osteomyelitis, a severe
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The presence of bacteria in DFUs leads to the activation
of the host immune response, which results in the release of
cytokines, inammatory mediators, and enzymes that impair
tissue healing [14, 15]. Moreover, the presence of bacteria in
DFUs can lead to biolm formation, a complex microbial
community that forms a protective barrier against the host’s
immune system and antimicrobial therapies [16, 17].
Effective management of DFUinfections is critical in
preventing the progression of these wounds and reducing the
risk of amputation [18]. Proper wound care, including appropriate wound dressings, wound debridement, and antimicrobial therapy, is necessary for managing DFU-related
infections [18]. Additionally, addressing underlying risk factors, such as controlling blood glucose levels, managing comorbidities, and promoting healthy lifestyles, can reduce the
risk of infections in DFUs [18].
In this chapter, we provide an overview of the incidence
of diabetic foot ulcer infections. We next discuss different
types of infections in diabetic patients while focusing on
DFU infections and their impact on healing outcomes in
DFUs. We then review the dysregulations and dysfunctions
in innate immune system that render DFUs vulnerable to
infections. We conclude the chapter by discussing the conventional, unconventional, and emerging therapeutics to
address infection in DFUs.
Infection inDiabetes
Diabetes signicantly increasesthe risk to infection, regardless of the origin of infective microorganism (bacterial, fungal, or viral); and infection in turn causes considerable
morbidity and mortality in diabetic patients [7–12]. A recent
large study conducted in South Korea assessed diabetes as a
risk factor for infection, involving 66,426 diabetes patients
and 132,852 age-sex-region-matched non-diabetes controls
from the general population. The study found that people
with diabetes had signicantly higher incidence rates of
infection-related hospitalizations, intensive care unit (ICU)
admissions, and deaths than the general population [19].
Another large retrospective study of primary care patients
found that type 1 and type 2 diabetes accounted for nearly
6% of infection-associated hospitalizations and 12% of
infection-associated mortalities [20].
It is worth noting that no organ in a diabetic patient is
spared from infection. The most common sites of infection in
diabetic patients are the skin, soft tissues, urinary tract, and
respiratory tract, but the infections with highest mortality
rates in diabetic patients include bone and joint infections,
bloodstream infections and sepsis, central nervous system
infections, diabetic foot ulcers, and cellulitis [7, 20–23].
Interestingly, infection has also been identied as a risk
factor for development of insulin resistance and diabetes. For
example, Norovirus infection has been linked to the development of type 1 diabetes by increasing the Firmicutes/
Bacteroidetes ratio and promoting the α-diversity in the gut
microbiome [24]. Similarly, a meta-analysis involving 34
studies found a signicantly higher risk for type 2 diabetes
in hepatitis C virus (HCV) patients as compared to matched
controls, and patients with other forms of chronic liver disease [25]. Another study found an estimated 33% of noncirrhotic chronic HCV patients to also be diabetic as
compared to only 5.6% in the control group without HCV
and liver disease [26], although another study disputed these
ndings and found a negative association between HCV and
diabetes in patients with liver cirrhosis [27]. A possible
mechanism by which viral infections can increase the risk of
diabetes development is through virally-induced insulin
resistance due to down-regulation of insulin receptor by
virally induced IFN-γ productionin skeletal muscle [28].
Below, we review the common infections in diabetic
patients before discussing infections in diabetic foot ulcers.
A summary of these infections can be found in Table17.1.
Table 17.1 Important infections in diabetes
Infection type Prevalent causes of infection References
Ear, nose, and
throat (ENT)
infections
Respiratory tract
infections
Urinary tract
infections (UTI)
and
pyelonephritis
Surgical site
infections
Bone and joint
infections
Bloodstream
infections
Oral infections Candida albicans [71–75]
Gastrointestinal
infections
Pseudomonas aeruginosa, fungal
species (Absidia, Mucor,
Rhizomucor, and Rhizopus genera)
Staphylococcus aureus,
Streptococcus pneumoniae,
Mycobacterium tuberculosis,
Pseudomonas aeruginosa, fungi,
inuenza virus, COVID-19
Patients are more prone to have
resistant pathogens: extendedspectrum β-lactamase-positive
Enterobacteriaceae, e.g., Klebsiella
spp., Proteus spp., Enterobacter
spp., and Enterococci;
uoroquinolone-resistant
uropathogens, carbapenem-resistant
Enterobacteriaceae, and
vancomycin-resistant Enterococci,
Candida
Pyelonephritis causes further insulin
resistance
Pseudomonas aeruginosa,
Staphylococcus aureus
Staphylococcus spp., aerobic
Gram-negative rods, Neisseria
gonorrhoeae, Pseudomonas
aeruginosa, fungal, Klebsiella liver
abscesses, malignant otitis externa,
and emphysematous cholecystitis
Escherichia coli, Klebsiella
pneumoniae
Clostridium difcile, Clostridia
perfringens, Escherichia coli
[32–34,
36]
[10, 37,
38]
[46,
86–91]
[52–57,
59, 92]
[61–65,
93]
[68]
[77, 78,
82, 84]
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Ear, Nose, andThroat Infections
Ear, nose, and throat (ENT) infections are more common in
individuals with diabetes [29–31]. Malignant otitis externa
and Rhinocerebral mucormycosis are head-and-neck infections seen almost exclusively in immunocompromised
patients, particularly in diabetic individuals [32, 33].
Malignant or necrotizing otitis externa is a severe infection
of the external auditory canal and skull base, which occurs in
individuals with diabetes older than 35years, and it is almost
always due to Pseudomonas aeruginosa [32, 33]. Infection
starts in the external auditory canal and spreads to adjacent
soft tissue, cartilage, and bone. Patients typically present
with severe ear pain and otorrhea (ear discharge).
Rhinocerebral mucormycosis is another serious infection
caused by various fungal species (belonging to the Absidia,
Mucor, Rhizomucor, and Rhizopus genera), which also
occurs in poorly controlled diabetic patients [33, 34]. After
initial colonization in the nose or paranasal sinuses, the
organisms spread to adjacent tissues via the blood vessels,
causing necrotic lesions in the soft tissues and bone erosion.
Despite aggressive surgical treatment and antifungal therapy,
the mortality rates associated with Rhinocerebral mucormy-
cosis infections can be as high as 25–80% [35]. ENT infec-
tions also tend to be more severe in individuals with diabetes.
In a retrospective study involving patients with deep neck
infections, abscess formation was found to occur at a signicantly higher rate in diabetic patients (89.3%) than in nondiabetic individuals (71.3%) [36]. Diabetic patients also
required surgical drainage more frequently (86%) than nondiabetic patients (65.2%).
Respiratory Tract Infections
Respiratory tract infections are among the most severe infections associated with diabetes [10]. The most frequent respiratory infections associated with diabetes are caused by
Streptococcus pneumoniae and inuenza virus [37]. In some
cases, diabetes increases the incidence rates (e.g., pulmonary
infections caused by Mycobacterium tuberculosis,
Staphylococcus aureus, P. aeruginosa, and fungi); whereas
in other cases (e.g., COVID-19, S. pneumoniae, or inuenza), diabetes also increases the severity of disease, manifested by higher morbidity and mortality rates [10, 38]. For
example, diabetic patients with COVID-19 infection have a
twofold increase in the risk for severe disease and related
death when compared to non-diabetic patients with
COVID- 19 [39]. Epidemiological evidence demonstrate an
increase in the risk for hospitalization with pneumonia associated with diabetes [40]. In a population-based cohort study
involving 29,900 patients, the 30- and 90-day mortality rates
associated with pneumonia were found to be higher in dia-
betic patients than in non-diabetic patients, and admission
hyperglycemia was found to be a predictive risk factor for
pneumonia-associated death [41]. In another study, the risk
of pneumonia-associated death correlated with the level of
glycemic control with relative risk (RR) for those with
HbA1c <7% being 1.22, versus an RR of 1.6 when HbA1c
was ≥9% [42]. Interestingly, a recent meta-analysis study
involving pooled analysis of 5,787,027 humansubjects from
four observational studies reported a 59% higher risk of
developing incident diabetes in post-acute COVID-19 phase
as compared to healthy controls, suggesting a possible link
between infection and prolonged diabetes [43].
Urinary Tract Infections
Diabetic patients are also at a signicantly elevated risk for
urinary tract infections (UTIs), including asymptomatic and
symptomatic pyuria and cystitis (signs of UTI), bacteriuria,
and more serious upper urinary tract and kidney infections
[44, 45]. In an observational study of all patients with type 2
diabetes in the UK General Practice Research Database
(GPRD), the incidence rate of UTI was reported to be 56.9%
higher among diabetic patients (46.9 per 1000 person-years)
when compared to non-diabetic patients (29.9 per 1000
person- years) [46]. Diabetic patients also experience more
severe UTIs [22]. Life-threatening complications of UTIs,
such as emphysematous cystitis and pyelonephritis, renal
papillary necrosis, and renal abscesses, occur more frequently in diabetic patients than in the non-diabetic general
population [47, 48]. Pyelonephritis (kidney infection) makes
control of diabetes more difcult as it may lead to further
insulin resistance in diabetic patients [22, 49, 50]. It is recommended that renal infection be considered in the differential diagnosis of any patient with diabetes who presents with
ank or abdominal pain [51].
Surgical Site Infections
Surgical site infections (SSIs) include supercial incisional
infections, deep incision space infections, and organ space
infections [52–54]. SSIs are rampant in diabetic patients, and
diabetes is associated with elevated risks for morbidity and
mortality following SSI [55]. A recent systematic review and
meta-analysis involving 866,427 procedures and 32,067
SSIs identied diabetes as an independent risk factor for
SSIs in multiple surgical procedure types with odds ratio
(OR) = 1.53 (95% predictive interval [PI], 1.11–2.12; I2,
57.2%) [55]. The association was higher for cardiac surgery
2.03 (95% PI, 1.13–4.05). Consistent with this report, type 1
and type 2 diabetic animals are also highly vulnerable to
SSIs [56–59].
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Bone andJoint Infections
Bone and joint infections (BJIs) include osteomyelitis, prosthetic joint infections, septic arthritis, and spinal infections
[60]. The incidence rates of BJIs are signicantly higher in
diabetic patients than in the general population [61–65].
Osteomyelitis is a common DFU infection, occurring in
10–15% of moderate and in 50% of severe infections [66].
The ulcers complicated by osteomyelitis often require surgical treatments and long-term antibiotic therapy [66, 67]. In a
meta-analysis study involving 119,244 patients from 18
studies, diabetic patients were found to have 1.84 times
higher risk of prosthetic joint infections and 1.96 times
higher risk of developing deep tissue infection following
total knee arthroplasty [63].
Bloodstream Infections
Patients with diabetes also have a higher incidence of bloodstream infections (BSIs) compared to non-diabetic patients.
A clinical study reported that diabetics have a 4.4-fold higher
risk of BSI, and they are also more susceptible to sepsis of
unknown origin with a greater incidence of septic complications than non-diabetic patients [68]. Although urinary tract
infections were the primary source of BSIs in both diabetic
and non-diabetic patients, Escherichia coli was the most
common pathogen responsible for BSIs. However, diabetics
were found to have a signicantly higher frequency of
Klebsiella pneumoniae BSIs than non-diabetics (18% vs.
5%) [68]. In another observational cohort study involving
2551 patients at two teaching hospitals in Boston,
Massachusetts, diabetes was determined to be an independent risk factor for community-acquired bloodstream infections (OR, 1.42; 95%; CI, 1.10–1.82; p=0.006) relative to
non-diabetic patients [69]. HbA1c≥6.5% was also found to
be associated with the risk of community-acquired bloodstream infections in the critically ill patients. In a recent retrospective case-controlled analysis involving 151 subjects,
patients with type 2 diabetes had signicantly higher incidence of BSIs (odds ratio [OR]: 2.27, p< 0.001), but the
90-day mortality rates were similar. This study also found
urinary tract infections as the primary source and E. coli as
the primary bacterial pathogen in BSIs in both diabetic and
non-diabetic patients.
Oral Infections
the non-diabetic general population (59.6% vs. 39% respectively) [71, 72]. If left untreated, periodontitis can lead to
pain, bad breath, chewing difculties, and even tooth loss
[72, 73]. Diabetes also negatively impacts healing, which in
turn can interfere with the treatment of periodontal disease
[70]. Similarly, the prevalence of oral candidiasis in diabetic
patients has been reported to be as much as 64%, with
Candida albicans accounting for 75–86.5% of oral fungal
infections in this cohort [74]. In another study, 90% of
uncontrolled diabetic patients and 63.3% of controlled diabetic patients cultured positive for oral (saliva) Candida,
compared to only 20% of non-diabetic patients [75].
Reduction in antimicrobial factors due to decreased salivary
ow rate, poor glycemic control, and impaired innate
immune defenses are among the factors contributing to the
increased risk for oral infection in diabetic patients [70, 72,
76].
Gastrointestinal Infections
Diabetes is a major risk factor for various bacterial, viral, and
fungal gastrointestinal (GI) infections [77–82]. In a retrospectivestudy involving 7670 patients, diabetes was reported
to be an independent risk factor for Clostridium difcile
infection (CDI), while metformin appeared to be protective
against CDI, by likely altering the microbiota toward an
increased Bacteroidetes and decreased Firmicutes populations in the gut [77, 78]. In another report, diabetes was
found to be an independent risk factor for recurrent CDI and
CDI-associated diarrhea (adjusted OR ranged from 3.79 to
5.46, minimum lower 95% condence level: 2.01, all p-
values <0.0001) [77]. Diabetes is also a risk factor for
Emphysematous cholecystitis which is a rare and deadly
form of GI infection, caused primarily by Clostridia perfrin-
gens and E. coli [82]. It is characterized by the presence of
the infection-generated gas in the gallbladder wall and has a
mortality rate of 15–20% in diabetic patients [82]. Diabetes
has also been reported as a predisposing factor for hepatitis
C virus (HCV) infection [83, 84]. A meta-analysis results
showed that patients with T2DM were at a signicantly
higher risk of HCV infection than non-diabetic patients
(summary OR=3.50, 95% CI=2.54–4.82, I2=82.3%) [84].
These results were corroborated by another study which also
found T2DM patients to be more susceptible to HCV infections [85]. Similarly, T1DM patients have also been found to
be at elevated risk for HCV infections [80, 83].
Diabeticpatients have a higher risk of developing various
oral bacterial and fungal infections, such as periodontitis and
thrush [70]. Prevalence of severe periodontitis has been
reported to be over 20% higher in diabetic patients than in
Skin andSoft Tissue Infections
Skin and soft tissue infections (SSTI) include cellulitis,
osteomyelitis, and postoperative wound infections [20]. A
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Table 17.2 Skin and soft tissue infections in diabetes
Infection Prevalent pathogens References
Cellulitis Staphylococcus aureus [103]
Osteomyelitis Staphylococcus aureus, S.
Wound infections
Postoperative
wound
infections
Diabetic foot
ulcer
infections
epidermidis, Streptococci,
Enterobacteriaceae, Escherichia coli,
Klebsiella pneumoniae, Proteus,
Pseudomonas aeruginosa
Methicillin-resistant Staph aureus
(MRSA) and vancomycin-resistant
Enterococci (VRE), Escherichia coli,
Klebsiella pneumoniae, Pseudomonas
aeruginosa, Enterococcus faecalis,
Staphylococcus epidermidis, and
Enterobacter cloacae
S. aureus, Escherichia coli, P.
aeruginosa, Proteus spp., Klebsiella
spp., coagulase-negative
Staphylococci, Enterococcus spp., and
Streptococcus spp., Acinetobacter
spp., Coryneform spp., β-hemolytic
Streptococcus spp., coagulase negative
Staphylococcus spp., Proteus
mirabilis, and M. morganii
[61, 104,
105]
[106, 107]
[95, 100,
101, 108,
109]
summary of SSTI infections and the responsible microorganismscan be found in Table17.2. Hyperglycemia, sensory
neuropathy, and vascular disease all predispose patients with
diabetes to skin and soft tissue infections [94]. A large retrospective cohort study compared the infection rates in type 1
(T1) and type 2 (T2) diabetics (n = 5863 T1DM and
n=96,630 T2DM) with 203,518 age-sex-practice–matched
control subjects without diabetes [20]. They found diabetic
patients to have higher rates for all infections, with bone and
joint infections (BJIs) and skin cellulitis being amongst the
highest disparities. The incidence rate ratios (IRRs) for BJIs
in T1D and T2D patients were IRR 22.34 [95% CI, 12.12–
41.20] and IRR 4.93 [95% CI, 4.34–5.61], respectively; and
the IRRs for skin cellulitis were 2.84 [95% CI, 2.48–3.25]
and 2.03 [95% CI, 1.97–2.08], respectively.
Diabetic Foot Ulcer Infections
Statistics
A recent meta-analysis (involving 16,159 diabetic patients
and 22,198 microbial isolates) assessed the global microbiology of diabetic foot infections [95]. Of the 112 studies
included in this meta-analysis, 55 studies tested for both
aerobic and anaerobic microorganisms, while 57 studies
only tested for aerobic microorganisms. In this meta-analysis
report, 89.4% of diabetic ulcers were found to be infected of
which 58.9% were polymicrobial and 41.1% were monomicrobial infections. Importantly, of the 22,198 microbial isolates from DFUs that were examined, the overwhelming
majority (~98%) were found to be of bacterial origin, 258
(1.62%) isolates were of fungal origin, and one isolate was of
archaeal origin. Interestingly, when they stratied the analysis based on high-income countries (HICs) versus uppermiddle and lower-middle income countries (U/LMICs), a
different pattern in infection microbial structures emerged.
In HICs, the Gram-positive bacteria were predominant
accounting for 62.4% of all isolates, whereas in U/LMICs,
Gram-negative bacteria were predominant accounting for
59.6% of all bacteria. The differences in the proportions of
Gram-negative vs. Gram-positive infections between HICs
and U/LMICs were highly signicant (p<0.0001). Although
the underlying reasons for these differences remain poorly
understood, sanitation, diet, and antibiotic stewardship
should be considered as possible contributing factors.
Another prospective study, involving 261 diabetic patients
with DFUs in a reference tertiary hospital in India, found
82.4% to be infected of which 44.3% were monomicrobial
and 55.7% were polymicrobial [100]. In this report, Gramnegative pathogens were predominant accounting for 58.5%
of all wound isolates. Another notable nding in this report
was the high percentage (55%) of diabetic patients undergoing amputation of the affected areas due to DFU infections.
A different prospective study, involving 162 diabetic
patients with infected foot ulcers in a diabetes and endocrinology center in India, found 68.5% of DFU infections to be
biolm-associated [101]. They also determined male sex,
necrotic ulcer, previous antibiotic use, subcutaneous infection and polymicrobial infection, duration of diabetes
(>10 years), duration of ulcer (>1 month), size of ulcer
(>4cm2), and ulcer grade (Grade II), as signicant risk factors for biolm-producing infection (p<0.001in all cases).
Infection in diabetic foot ulcers (DFUs) is very common and
can lead to serious comorbidities and life-threatening complications. Nearly 50–89% of DFUs develop infection which
in turn, increases the chance of amputation by approximately
50% as compared with diabetic patients with uninfected
DFUs [95–99]. Majority of infections in diabetic ulcers are
polymicrobial and biolm-associated, although 33–44.3% of
infections are non-biolm and planktonic and 23–44.3% are
monomicrobial in nature [95, 100–102].
Microbiome Composition inDFU
The microbial burden and the microbiome compositions of
skin varies based on factors such as distribution of sweat
glands, skin pH, the availability of oxygen, anatomical features such as skin thickness and folds, hygiene practices such
as feet-washing, and physical activities [110–112]. Overall,
the number of bacteria on healthy foot has been reported to
range between 7.6×103CFU/cm2 and 1.2×105CFU/cm2 in
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men, with younger men having more bacteria on their feet
[110]. The overall bacteria load on women’s feet tends to be
approximately an order of magnitude higher than on men
[110]. Moreover, healthy foot is predominantly colonized by
commensal bacteria belonging to Firmicutes, Actinobacteria,
and Proteobacteria families, although pathogenic bacteria
have also been detected on healthy foot [110, 111]. Of note,
pathogenic bacteria (e.g., S. aureus or P. aeruginosa) are
rarely detected on healthy foot [110–112]. In contrast, diabetic foot skin harbors increased populations of pathogenic
bacteria (e.g., S. aureus) and increased bacterial diversity
[108, 109]. However, the microbiome in diabetic ulcers are
nearly all pathogenic bacteria.
In a recent meta-analysis study involving 112 publications and 16,159 diabetic patients, the isolated bacteria in
DFUs were all pathogenic variety [95]. The most prevalent
bacterial pathogens were S. aureus which accounted for
23.4% of all isolates, followed by Escherichia coli (11. 5%),
P. aeruginosa (11.1%), Proteus spp. (8.3%), Klebsiella spp.
(6.9%), coagulase-negative Staphylococci (5.8%),
Enterococcus spp. (5.4%), and Streptococcus spp. (5.2%).
Gram-negative pathogens were more predominant in DFUs
overall, but interestingly, when the data were stratied based
on country income (high-income countries (HICs) vs. uppermiddle and lower-middle income countries (U/LMICs)), a
different pattern emerged. In HICs, the Gram-positive bacteria were predominant accounting for 62.4% of all isolates,
whereas in U/LMICs, Gram-negative bacteria were predominant accounting for 59.6% of all bacteria. The differences in
the proportions of Gram-negative vs. Gram-positive infections between HICs and U/LMICs were highly signicant
(p<0.0001). Although the underlying reasons for these differences remain unknown; sanitation, diet, and antibiotic
stewardship should be considered as possible factors contributing to the observed differences in the microbiome compositions in HICs vs. U/LMICs.
In another prospective study involving infected footulcers
in 261 diabetic patients [100], Gram-negative pathogens
were predominant accounting for 58.5%, of which P. aerugi-
nosa was the most prevalent isolate found in 20.9% samples,
while S. aureus was the most prevalent Gram-positive bacte-
rium accounting for 26.9% all samples. Other bacterial
pathogens detected in DFUs in high frequencies included
Enterococcus faecalis (12.7%), E. coli (12%), K. pneumoniae (9.5%), and Proteus mirabilis (9%). In a different
prospective study involving 162 diabetic patients with
infected foot ulcers [101], E. coli was found to be the most
predominant Gram-negative pathogen (27.8%), followed by
P. aeruginosa which accounted for 15.6% of all isolates.
This study also found S. aureus to be the most predominant
Gram-positive pathogen (23.5%) in the ulcers. Other bacteria detected in these ulcers included K. oxytoca (7%), K.
pneumonia (5.8%), P. vulgaris and E. faecalis (3.5% each),
Acinetobacter spp. (3.1%), Coryneform spp. (2.7%),
β-hemolytic Streptococcus spp. (2.3%), coagulase-negative
Staphylococcus spp. (2.3%), P. mirabilis (1.5%), and M.
morganii (0.7%).
Consequences ofMicrobiome Shift Toward
Pathogenic Bacteria inDFU
What is clear from these studies is that pathogenic bacteria
make up almost the entire microbial structure in DFUs, indicating a shift toward pathogenic bacteria in diabetic ulcers.
This shift has been observed in longitudinal studies of human
diabetic patients and diabetic animal models [113–115]. The
consequences of microbiome shift toward pathogens are
severe and negatively impact healing outcomes. In fact,
strain-level variations in S. aureus sub-species and genetic
signatures of biolm formation have been identied as independent risk factors for poor outcomes in DFU in a prospective study of patients with neuropathic diabetic foot ulcers
[115]. Moreover, numerous studies have demonstrated that
S. aureus and P. aeruginosa-infected chronic wounds,
including DFUs, exhibit signicant healing impairments
compared to other DFUs [116–125]. Why is the presence of
pathogenic bacteria harmful to the healing of diabetic
wounds? The reason may bethat these bacteria produce various virulence factors that can weaken the immune response
and make diabetic wounds more susceptible to infection and
delayed healing. In the following section, we will give some
examples of important bacterial virulence factors that have
been found to have a negative impact on immune responses
in diabetic wounds.
Biolm
As discussed above, majority of infections in DFU are
biolm- associated. Biolm is perhaps one of the most important, if not the most important, virulence factors that is associated with impaired healing in DFU [16, 126]. Biolm is a
collection of single or multi-species microbial communities
that adhere to biotic (e.g., wound) or abiotic (e.g., implants)
surfaces, embedded within a complex structure composed of
exopolysaccharides, extracellular DNA (eDNA), proteins,
and lipids [127, 128]. Approximately 80% of lower-limb
amputations in diabetic patients occur following biolminfected foot ulceration, highlighting the devastating impact
of biolm on healing outcomes [16, 129]. There are multiple
reasons why biolms can be harmful to healing processes in
diabetic ulcers. Biolms can trigger sustained inammatory
responses which are harmful to healing processes; they can
protect pathogens from antibiotics, and from detection and
phagocytosis-mediated killing by immune leukocytes, thus,
prolonging infection; and they can function as physical barrier to cellular migration of cells that play pivotal role infec-
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