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Diabetes & Risk of Infections

USV as your reliable healthcare partner, believes in supporting

your endeavour to make India a ‘Diabetes Care Capital’. We, at

USV, believe in partnering with healthcare leaders with

knowledge based platform to make better diabetes

management decisions.

It is believed that every 10 seconds a person dies from

diabetes-related complications. Infections are of particular

concern for diabetics. People with diabetes are more susceptible

to developing infections, as high blood sugar levels can weaken

the patient's immune system defences. In addition, some

diabetes-related health issues, such as nerve damage and

reduced blood flow to the extremities increase the body's

vulnerability to infection.

Glycomet GP presents –

, is a compilation series of major diabetes-related

complications, bringing to you various Indian facts, newer

diagnostic techniques and management tips to make better

clinical decisions and ways to prevent some of them. In this issue,

we aim to critically review the current knowledge on the

mechanisms associated with the greater susceptibility of

diabetes for developing infectious diseases and to describe the

main infectious diseases associated with this metabolic disorder.

Hope this new age approach will benefit you in your day-to-day

clinical practice.

Sincere regards,

‘Incyclopedia on diabetes

complications’

refacep

Disclaimer: This incyclopedia provides information and content on the major complications seen in diabetes patients. This incyclopedia

has been made in good faith with the literature available on this subject. Every effort is made to ensure the accuracy of information but

USV Limited will not be held responsible for any inadvertent error(s). Professional are requested to use and apply their own professional

judgement, experience and training and should not rely solely on the information contained in this publication before prescribing any diet,

exercise and medication. USV Limited assumes no responsibility or liability for personal or the injury, loss or damage that may result from

suggestions or information in this book.

CONTENTS

Sr. No. Title Page

1. Epidemiology of diabetes in India 1

2. Diabetes and infections: An overview 2

3. Urinary tract infections 7

4. Respiratory tract infections 9

5. Skin and soft tissue infections 12

6. Periodontal infections 21

7. Unusual infections 22

8. In patient’s own words 25

9. Common infections in diabetes and their 27

initial presumptive therapy

10. Infections related to therapeutic interventions 28

11. Infections in special populations with diabetes 29

12. Case study 30

13. Points to ponder 33

14. Suggested readings 35

1

EPIDEMIOLOGY OF DIABETES IN INDIA

Diabetes, an ‘iceberg disease’ can be described as the ‘sleeping snake’, which

bites when it wakes up. Diabetics are normally not aware of the possible

catastrophic end results of harbouring this sleeping snake.

Diabetes is growing at epidemic proportions worldwide with 38.7 crore people

suffering from diabetes. This number will rise to 59.2 crores by 2035. Of the

current diabetic population, 77% of them live in low- and middle-income

countries. India itself is home to a staggering 6.68 crore diabetics, i.e., almost

88% of the diabetics in South-East Asia region ( . According to the

projections made by Wild et al., the total population in India will reach

79 crores by 2030 overtaking China (Fig. 1 [A & B]).

Table 1)

diabetic

A

People livingwith diabetes

in 2035

AFR (109.1%)MENA (96.2%)

SEA (70.6%)

SACA (59.8%)

WP (46%)

NAC (37.3%) EUR (22.4%)INC

REA

SE

2013 2035

WORLD

592 M

WORLD

382 M

55%

AFR: Africa; MENA: Middle East and North Africa; SEA: South East Asia; SACA: South and Central America;WP: Western Pacific; NAC: North America and Caribbean; EUR: Europe

Fig. 1 (A & B): Epidemiology of diabetes

USA

China

India

0 20 40 60 80 100

30.3

42.3

79.4

B

Projected rise in diabetes by 2030 (in crores)

2

DIABETES AND INFECTIONS: AN OVERVIEW

It is well recognised that diabetes is associated with an increased propensity

for infections. While some infections are more frequent in diabetics; some

occur almost exclusively in diabetes subjects, and some other infections run a

different and more aggressive course in diabetics. Despite the advances in

diabetes management and availability of newer insulin, along with newer and

more potent antimicrobial agents, infections still account for huge morbidity

and mortality in diabetics. This is particularly true of the feet where vascular

disease and neuropathy lead to a background conducive for soft tissue

infections and osteomyelitis. Infections may also precipitate diabetic

ketoacidosis (DKA) in both type 1 and type 2 diabetes.

The prevalence of diabetes is predicted to increase globally by 2030with the maximum rise in number of cases in India

South-East Asia 74,957.00

Bangladesh 5,982.18

Bhutan 23.39

Maldives 17.05

Mauritius 209.71

Nepal 700.74

Sri Lanka 1,177.05

India 66,846.88

Table 1: Epidemiology of diabetes in South-East Asia (in thousands)

3

Data on mortality studies from India show that infections are a very common

contributing cause for mortality among diabetes patients. Zargar et al. reported

that 40.9% patients had infection as a contributing cause for mortality, and

among these, in 10.7%, it was the only cause for mortality. Another study

reported that infections accounted for 46.5% of the deaths, being the largest

contributing factor for mortality.

Owing to multiple defects in immunity in diabetes patients,

they are highly

susceptible to infections. Although the causal relationship between

hyperglycaemia and infections is not proven, there is compelling evidence that

shows that improved glycaemic control decreases the morbidity and mortality

associated with several infections in patients with diabetes. Poorly controlled

diabetes in the presence of DKA and microvascular complications like

neuropathy and macrovascular disease aggravates the problem leading to a

chronic course.

The effects of hyperglycaemia on the immune system

WHY DIABETICS ARE MORE PRONE TO INFECTIONS?

including

impairment of polymorphonuclear leucocyte functioning,

Normoglycaemic immune response

PMN mobilisationChemotaxis Phagocytosis Bacterial

destruction

IgG fixation ofcomplement

Complement binds tobacterial surfaces

Oxidative burst withsuperoxide radical production

NormalWBC count

A

4

PATHOGENESIS OF INFECTIONS IN DIABETES AND HYPERGLYCAEMIA

(Figs. 2 [A & B], 3)

Innate immunity

The early phase of the innate immune response is inflammatory. It includes

vasoactive components of the complement system, mast cell secretions and

the kinin-bradykinin system. They induce local vasodilation and elevate

vascular permeability and blood flow. In diabetes, dysregulation of the nitric

oxide production and blunted nitric oxide response to bradykinin leads to

vasoconstriction instead. This potentially attenuates the ability of phagocytes

to reach their target.

Chemotaxis and phagocytosis

Diabetes patients have impaired polymorphonuclear functions, including

chemotaxis, adherence, phagocytosis and intracellular killing.

Adaptive immunity: Cell-mediated and humoural immunity

Patients with poorly controlled diabetes have impaired T-lymphocyte function

that may or may not be related to the degree of hyperglycaemia. Glycation of

IgG has been shown to occur in proportion to the level of glycosylated

haemoglobin (HbA1c), but it is not clear if it translates into clinical relevance.

Fig. 2 (A & B): Hyperglycaemia – Effects on immune system

Hyperglycaemic immune responsePMNs adhere toendothelium Decreased

chemotaxisDecreased

phagocytosisDecreasedbacterial

destruction DecreasedIgG fixationof complement

Glycosylation

Decreased complementbinds to bacterial surfaces

Decreased oxidative burstwith superoxide radical production

DecreasedWBC count

B

PMN: Polymorphonuclear leucocytes; WBC: White blood cell; IgG: Immunoglobulin G

5

PREDISPOSING FACTORS FOR INFECTIONS IN DIABETES MELLITUS

Primary factors

• Granulocyte adherence, chemotaxis and phagocytic dysfunction

• Myeloperoxidase deficiency

• Complement pathway defects

• Cytokine-mediated (e.g., interleukin-1, tumour necrosis factor)

Secondary factors

• Ketoacidosis

• Use of intravascular access lines

• Antibiotic misuse/resistance

• Frequent hospitalisation

• Peripheral vascular disease

• Neuropathy

• Gastroparesis, reflux and aspiration

• In-dwelling urinary catheters

Infections

GIT: Gastrointestinal tract

Neutrophil function

Disorders ofhumoural immunity

Anti-oxidantsystem depression

Angiopathy NeuropathyLarge number of

medical interventions

Hyperglycaemia:Increased virulence

of infectiousmicroorganisms andapoptosis of PMN

GIT dysmotility

T-lymphocyteresponse

Glycosuria

Lower secretion ofinflammatory cytokines

DM

Fig. 3: Pathophysiology of infections associated with DM

6

• Chronic renal failure and dialysis

• Total parenteral nutrition

Infections possibly related to diabetes (common infections)

• Urinary tract infections

• Staphylococcus aureus infections

• Soft tissue infections including necrotising fasciitis and Fournier’s gangrene

• Synergistic necrotising colitis

• Non-clostridial anaerobic cellulitis

• Tuberculosis (TB)

• Fungal infections

Infections strongly associated with diabetes (occurring principally in patients

with diabetes and unusual infections typical in diabetic population)

• Mucormycosis

• Malignant external otitis

• Emphysematous pyelonephritis

• Emphysematous cholecystitis

• Infections in the diabetic foot

• Necrotising fasciitis

Infections related to therapeutic interventions in diabetes

• Penile implants, cardiac pacemaker, defibrillators

• Organ transplantation

• Continuous ambulatory peritoneal dialysis

• Haemodialysis

CATEGORISATION OF INFECTIONS IN PATIENTS DIABETES

The greater frequency of infections in diabetes patients is due tohyperglycaemic environment that leads to immune dysfunction

(e.g., damage to the neutrophil function, depression of theantioxidant system and humoural immunity)

7

URINARY TRACT INFECTIONS

PREVALENCE

The most frequently observed category of urinary tract involvement in diabetes

patients is asymptomatic bacteriuria (ASB), which is defined as presence of 5at least 10 colony-forming units per millilitre of a bacterial species in a culture

of clean-voided midstream urine sample from an individual without symptoms

of a urinary tract infection. It is three times more common in diabetic women

compared to diabetic men.

Upper urinary tract is involved in more than half of the patients with ASB. The

prevalence of ASB is similar in diabetic and non-diabetic men. The overall

prevalence of ASB is around 26% in diabetic women. In women with type 1

diabetes it is 21%, and in type 2 diabetes it is 29%.

RISK FACTORS

The risk factors for ASB infections in type 1 diabetes patients include longer

duration of diabetes, macroalbuminuria and presence of peripheral neuropathy,

whereas older age, lower body mass index, macroalbuminuria, and urinary tract

involvement in the previous year elevate the risk in patients with type 2 diabetes

mellitus.

8

ASB may significantly increase the risk of symptomatic urinary tract

involvement and hospitalisation caused by urosepsis. It does not, however,

increase the risk of a faster decline in renal function or hypertension.

Escherichia coli is the most common organism causing ASB.

Diabetes mellitus seems to cause a rise in the risk of complications associated

with urinary tract, including rare complications like emphysematous

pyelonephritis, xanthogranulomatous pyelonephritis, emphysematous cystitis,

renal abscess, renal carbuncle and papillary necrosis. Fungal infections in the

urinary tract are commonly caused by Candida spp. and rarely present as

‘fungus ball’. Unusual organisms and Gram-negative pathogens other than

may also cause infection in patients with diabetes mellitus.

Available evidence does not support antimicrobial treatment of ASB among

patients with diabetes mellitus and routine screening for bacteriuria is not

indicated. Antibiotic use neither delays nor decreases the frequency of

symptomatic urinary tract involvement or number of hospitalisations.

Treatment of urinary tract involvement in diabetes patients is similar to non-

diabetics except for the duration. Since diabetics frequently demonstrate

involvement of the upper urinary tract, antibiotic therapy should be given for

7 to 14 days. Antibiotic choices should be based on the local microbiology and

in vitro susceptibility data. A urinalysis and urine culture should be checked

whenever possible. Antibacterials, such as trimethoprim-sulphamethoxazole

and ciprofloxacin, are commonly used as the initial presumptive therapy to

target Enterobacteriaceae. Though well tolerated in most patients,

trimethoprim-sulphamethoxazole use may be associated with severe and

protracted hypoglycaemia, which might be incorrectly attributed to anti-

hyperglycaemic agents used in patients with diabetes mellitus. Attempts

should be made to confirm cure after treatment because patients with diabetes

may have microbiological peculiarities compared to non-diabetic patients.

COMPLICATIONS

TREATMENT

Escherichia coli

Elevated glucose concentration in the urine of diabetes patients mayfavour the growth of pathogenic microorganisms leading to ASB,

characterised by the presence of significant amount of bacteria in urine

9

RESPIRATORY TRACT INFECTIONS

Respiratory tract infections are responsible for a significant number of medical

appointments by diabetes patients.

Following are some of the common respiratory ailments associated with

diabetes mellitus:

• Pneumonia

• Tuberculosis

• H1N1

• Influenza

The most frequent respiratory infections associated with diabetes mellitus are

caused by Streptococcus pneumoniae and influenza virus. People with

diabetes mellitus need hospitalisation during influenza epidemics

than non-diabetes patients. Diabetes is also a common co-existing

condition and a risk factor for complications in patients with H1N1 (pandemic

influenza virus) infection. The American Diabetes Association (ADA) and the

Centers for Disease Control and Prevention Advisory Committee on

Immunization Practices (CDC-ACIP) recommend anti-pneumococcal and

influenza vaccination for people with diabetes mellitus, respectively. The

World Health Organization (WHO) recommends vaccination against the H1N1

virus, which is a single-dose vaccine, to minimise virus-related morbidity and

mortality.

PNEUMONIA AND INFLUENZA

six times

more likely

10

Prevalence

India accounts for one-fifth of the incidence of TB cases and ranks one among

the 22 high burden countries, which are contributing to 80% of global TB

burden. Nearly 40% of Indian population has been infected with TB bacilli and

nearly 15% of TB burden in India in the year 2000 was attributed to diabetes.

According to a study conducted by MV Hospital for Diabetes along with World

Diabetes Foundation for screening TB patients for diabetes in India, 25.3% of

TB patients had diabetes and another 24.5% had pre-diabetes. Out of 25.3%,

9% were newly detected and 16% were already diagnosed with diabetes.

These vaccines reduce the number of respiratory infections, the number and

length of hospitalisation stay, the deaths caused by respiratory tract

infections, and the medical expenses related to influenza and pneumonia.

Despite these benefits, the vaccination coverage in people with diabetes

mellitus remains inadequate.

TUBERCULOSIS

11

Moreover, the study revealed that men with TB were more likely to have

diabetes than women. Nearly half of the subjects, who had TB and diabetes,

had infectious form of pulmonary TB.

Pathophysiology

The diabetes patients have evidence of impaired cell-mediated immunity,

micronutrient deficiency, pulmonary microangiopathy and renal insufficiency,

all of which predispose to pulmonary tuberculosis (PTB). Innate and type 1

cytokine responses are higher in TB patients with associated diabetes than in

non-diabetes control subjects.

Presentation

The presentation of TB in diabetes subjects may not be always different as

they may also manifest themselves with the common symptoms, as in any

other individual without diabetes mellitus. The diabetes subjects with TB are

more likely to have higher bacillary load.

TB in diabetes is 2 to 5 times more common, and is usually diagnosed late, is

asymptomatic and is normally due to re-activation of an old focus than a fresh

infection. These patients have a higher sputum positivity and more extensive

lung involvement. particularly noted. Previously, it was thought

that lower lobe involvement is common in diabetics; however, recent

observations do not confirm this. The prevalence of multi-drug resistant

tuberculosis (MDR-TB) is more common amongst diabetics.

Both these diseases may stimulate the symptoms of the other. Symptoms that

are common to both include lethargy, fatigue, weight loss, fever and loss of

appetite. It is not unheard of for people with diabetes to present to the doctor

with complaints of worsening of blood glucose control only to find out later

that they have TB.

Treatment

Treatment regimen remains the same as in non-diabetes patients. An increase

in doses of oral hypoglycaemic agents is needed because of interaction with

rifampin, and an addition of pyridoxine is recommended because of worsening

of peripheral neuropathy with isoniazid.

Diabetologists opine that the management of diabetes in patients with co-

existing TB infection is individualised and recommend the use of insulin in the

intensive phase of TB treatment, and gradually prescribe oral hypoglycaemic

agents depending upon the blood glucose control of the individuals in the

Cavitation is

12

SKIN AND SOFT TISSUE INFECTIONS

Infections involving the skin, nails and subcutaneous tissues are common in

diabetics in a setting of poor glycaemic control. Candidal infection and

bacterial infections such as furunculosis (Fig. 4) are common and may lead to

the diagnosis of diabetes. Cutaneous forms of mucormycosis (Fig. 5) and other

fungal infection may occur and are diagnosed following skin biopsy.

Diabetics often have asymptomatic nasal, mucosal and skin colonisation with

Staphylococcus aureus. Colonisation with Candida albicans is also common

and may involve the genitalia, mouth, skin and nails. Balanitis and

vulvovaginitis are commonly the presenting features of diabetes.

The vascular effects of diabetes tend to alter lung function, leading toincreased susceptibility to respiratory infections

continuation phase of TB treatment. Diabetes subjects with complications

such as neuropathy and nephropathy should be closely monitored when they

are on anti-TB treatment.

Fig. 4: Furunculosis

Fig. 5: Cutaneous mucormycosis

13

DIABETIC FOOT INFECTION

Foot infections are the most common soft tissue infections associated with

diabetes. Peripheral neuropathy and peripheral arterial disease are both

important in the aetiology of foot infection. Foot infections may clinically

present with predominantly neuropathic or neuroischaemic features. The

complications include osteomyelitis, amputation, Charcot joint or even death.

Prevalence

One-third of all diabetes patients have significant peripheral neuropathy and/or

peripheral vascular disease. Diabetic foot problems are the commonest reason

for hospitalisation of diabetes patients (about 30% of admissions) and absorb

about 20% of the total healthcare costs of the disease more than other

diabetes complications. In India, prevalence of foot ulcers in diabetes patients

in clinic is 3%, which is much lower than that reported in the Western world. A

possible reason for the low prevalence in Indians is younger age and shorter

duration of diabetes.

Pathogenesis

Foot problems are common in people with diabetes because of their increased

risk of peripheral neuropathy, peripheral vascular disease, abnormal pressure

on the foot and impaired resistance to infection. These factors frequently

combine and result in ulceration and infection, progression to gangrene and

14

Fig. 6: diabetic foot ulcer and diabetic foot infection Pathophysiology of

DM

Polyneuropathy

Autonomic Sensitive Motor

Medial calcification(Monckeberg sclerosis)

HyperfluxArterio-venousshunts opening

Extrinsic trauma(e.g., shoes)

Neutrophil dysfunction

Ulceration

Infection

Muscular atrophy

Insensible anddeformed foot

Footdeformation

Biomechanical alteration

Intrinsic trauma(hyperpressure)

Hot and turgid foot

Epidermalcutaneous ischaemia Pain insensibility

DistalHypoperfusion

Cold and pale foot

Atherosclerosis

Peripheral vasculardisease

Posterior tibial

Pedal

Myelin

ABS

ENCE

OF

PULS

ES

Gangrene

Infection

NEUROPATHIC Time

NEUROISCHAEMIC

subsequent lower limb amputation. In diabetes patients, multiple factors

may exist that increase the risk of ulceration. These include paronychia,

cellulitis, myositis, abscesses, necrotising fasciitis, septic arthritis,

tendonitis and osteomyelitis. Once the protective layer of skin is breached,

underlying tissues are exposed to bacterial colonisation (Fig. 6).

15

Factors increasing the risk of diabetic foot ulceration

• Peripheral neuropathy: Somatic or autonomic

• Peripheral vascular disease

• Past foot ulcer history (annual risk of re-ulceration is found to be up to 50%)

• Plantar callus and elevated foot pressure

• Foot deformity, nail abnormalities

• Psychosocial factors (anxiety, depression, non-compliance)

• Other microvascular complications, especially chronic renal failure

• Diabetic nephropathy, patients with end-stage renal disease on dialysis,

subjects with renal or pancreas-renal transplants

• Interdigital infection in feet

• Temperature difference between feet

Fig. 7: Qualitative and quantitative aspects of wound microbiology

RESISTANCE

NEUROPATHIC

Monomicrobial

Species number

Enterobacteriaceae

Pseudomonas spp.

Non-fermenting Gram-negative bacilli

Anaerobes

Polymicrobial

Strict anaerobes

Beta-haemolytic streptococci Staphylococcus aureus

Coagulase-negative staphylococci Enterococcus spp. Gram-positive aerobic bacilli

NEUROISCHEMIC

Time

Gram-negative aerobic bacilli

!

NEUROPATHIC

The qualitative and quantitative aspects of wound microbiology is illustrated

below in Fig. 7.

NEUROISCHAEMIC

16

• Oedema

• Ethnic background

• Living alone

• Poor social background

• History of smoking

Classification of diabetic foot ulceration

Traditional Meggitt-Wagner ulcer classification system

Grade 0: No ulcer, but high risk foot (bony prominences, callus, deformities,

etc)

Grade 1: Superficial, full thickness ulcer

Grade 2: Deep ulcer, may involve tendons, but without bone involvement

Grade 3: Deep ulcer with osteomyelitis

Grade 4: Local gangrene (toes or forefoot)

Grade 5: Gangrene of whole foot

Assessment of diabetic foot

Foot ulcer evaluation should include assessment of neurological status,

vascular status and evaluation of the wound itself. Neurological status can be

checked by using the Semmes-Weinstein monofilaments to determine

whether the patient has ‘protective sensation’, which means determining

whether the patient is sensate to the 10-g monofilament (Fig. 8).

Fig. 8: 10-g Semmes-Weinstein monofilament test

17

Another useful instrument is the 128 Hz tuning fork, which can be used to

determine whether a patient's vibratory sensation is intact by checking at the

ankle and first metatarsal-phalangeal joints (Fig. 9). The notion is that

metabolic neuropathies have a gradient in intensity and are most severe

distally. Thus, a patient who cannot sense vibration at the big toe but can

detect vibration at the ankle when the tuning fork is immediately transferred

from toe to ankle demonstrates a gradient in sensation suggestive of a

metabolic neuropathy.

Vascular assessment is important for eventual ulcer healing and is essential in

the evaluation of diabetic ulcers. Vascular assessment includes checking pedal

pulses, the dorsalis pedis on the dorsum of the foot, and the posterior tibial

pulse behind the medial malleolus, as well as capillary filling time to the digits.

The capillary filling time is assessed by pressing on a toe enough to cause the

skin to blanch and then counting the seconds for skin colour to return. A

capillary filling time > 5 seconds is considered prolonged. If pedal pulses are

non-palpable, the patient should be sent to a non-invasive vascular laboratory

for further assessment, which may include checking lower extremity arterial

pressures by Doppler and recording pulse volume waveforms.

Ulcer evaluation should include documentation of the wound's location, size,

shape, depth, base and border. A sterile stainless steel probe is useful in

assessing the presence of sinus tracts and determining whether a wound

probes to a tendon, joint or bone. X-rays should be ordered on all deep or

infected wounds, but magnetic resonance imaging often is more useful

because it is more sensitive in detecting osteomyelitis and deep abscesses.

Fig. 9: 128 Hz Rydel-Seiffer tuning fork

18

Signs of infection, such as the presence of cellulitis, odour or purulent drainage

should be documented, and aerobic and anaerobic cultures should be obtained

of any purulent exudates.

Treatment of ulcers and infections

In a high-risk patient, callus, nail and skin pathology should be treated

regularly, preferably by a trained foot care specialist. If possible, foot

deformities should be treated non-surgically (e.g., with an orthosis). For foot

ulcers, it is important to identify the causes, types, sites and depth, and signs

of infections of the ulcer before starting treatment procedures.

Treatment of foot ulcers must combine the following strategies:

• Relief of pressure and protection of the ulcer (by off-loading)

• Restoration of skin perfusion (management of ischaemia)

• Treatment of infection (effective debridement and appropriate antibiotics)

• Proper glycaemic control

• Local wound care (regular wound inspection and consideration of advanced

techniques like negative pressure wound therapy in post-operative wounds)

Debridement

Debridement is done by removing all necrotic tissue, peri-wound callus and

foreign bodies down to viable tissue. In order to reduce

proper debridement is crucial. After debridement, the wound should

be irrigated with saline or cleanser, and a dressing should be applied. Dressings

should prevent tissue dessication, absorb excess fluid, and protect the wound

from contamination.

Timely incision and drainage procedures can help to save the infected limb,

whereas failure to perform these procedures can lead to the loss of limb.

Treating a deep abscess with antibiotics alone leads to delayed appropriate

therapy and further morbidity and mortality.

Off-loading

The most effective method of off-loading to heal a foot ulceration is to

recommend the use of a

the risk of infection and

reduce peri-wound pressure, which can impede normal wound contraction and

healing,

wheelchair or crutches to completely stop weight-

bearing on the affected foot.

19

Total contact casts (TCCs) are difficult and time consuming to apply but

significantly reduce pressure on wounds and have been shown to heal

between 73 and 100% of all wounds treated with them. Inappropriate

application of TCCs may result in new ulcers, and TCCs are contraindicated in

deep or draining wounds or for use with non-compliant, blind, morbidly obese,

or severely vascularly compromised patients.

Post-operative shoes or wedge shoes are also used and must be large enough

to accommodate bulky dressings. Proper off-loading remains the biggest

challenge for clinicians dealing with diabetic foot ulcers.

Infection control

Limb-threatening diabetic foot infections are usually polymicrobial. Commonly

encountered pathogens include methicillin-resistant Staphylococcus aureus,

beta-haemolytic streptococci, Enterobacteriaceae, Pseudomonas aeruginosa,

and enterococci. Anaerobes, such as Bacteroides, Peptococcus and

Peptostreptococcus are rarely the sole pathogens but are seen in mixed

infections with aerobes.

Antibiotics selected to treat severe or limb-threatening infections should

include coverage of Gram-positive and Gram-negative organisms and provide

both aerobic and anaerobic coverage. Patients with such wounds should be

hospitalised and treated with intravenous antibiotics. Mild-to-moderate

infections with localised cellulitis can be treated on an outpatient basis with

oral antibiotics such as amoxicillin with clavulanate potassium, moxifloxacin,

or clindamycin. The antibiotics should be started after initial cultures are taken

and changed as necessary.

Adjunctive treatments

• Hyperbaric oxygen

• Negative pressure wound therapy

• Bioengineered skin substitutes

• Larval therapy

• Growth factors

20

NECROTISING FASCIITIS

Fig. 10: Necrotising fasciitis

Skin

Fat

Fascia andmuscular tissue

Changing skincolour representsspread that is notvisible on the surface

Medial (inside) view

It is a deep seated infection of subcutaneous tissue wherein progressive

destruction of fascia fat and muscles ensues. It is relatively uncommon and

occurs in diabetics and other immune-compromised subjects. It is a life-

threatening condition. Necrotising fasciitis spreads initially along facial planes,

however as infection and inflammation progress, necrosis of muscle,

subcutaneous tissues and skin occurs. The usual sites are limbs, abdominal

wall and perineum (Fig. 10). Necrotising fasciitis carries a high mortality and is

rapidly fatal. Prompt diagnosis and aggressive treatment are necessary. A high

index of suspicion is required for diagnosis. It starts like cellulitis with the local

pain disproportionate to the inflammation accompanied with high fever and

systemic toxicity. The cellulitis spreads rapidly and a crepitus may also be

present. Violaceous discolouration of the skin is followed by blistering and

bullae formation. Timely diagnosis and treatment with empirical broad

spectrum antibiotic therapy with anaerobic cover and extensive surgical

debridement of affected tissue are crucial components of management.

21

Fournier’s gangrene

It is a specific form of necrotising fasciitis involving the perineum, scrotum and

penis. This is associated with a high mortality. The most common aetiological

agents are Escherichia coli, Klebsiella spp., Proteus spp. and

Peptostreptococcus. The aetiology can also be polymicrobial, involving

Clostridium, aerobic or anaerobic streptococci and Bacteroides.

Skin and soft tissue infections in diabetes patients are characterised byinduration, erythema, warmth and pain or tenderness, and range frommild self-limiting furunculosis to life-threatening necrotising fasciitis

PERIODONTAL INFECTIONS

The association between diabetes and periodontal disease is well known.

There is an increased prevalence, severity, and progression of periodontal

disease in both type 1 and type 2 diabetes. Periodontal destruction can start

very early in life in diabetes and become more prominent with age.

The contributing factors involve higher salivary glucose, low salivary pH,

microangiopathy and abnormal collagen metabolism. The pathogenetic link

involves diabetes-induced changes in immune cell function causing up-

regulation of inflammatory cytokines, which predisposes to chronic

inflammation, progressive tissue breakdown and diminished repair capacity.

22

Periodontal tissue is constantly wounded by substances emanating from

bacterial biofilms. Hyperlipidaemia associated with diabetes also been

implicated in immune cell alterations contributing to periodontitis. Chronic

periodontitis itself can exacerbate diabetes-induced hyperlipidaemia.

Porphyromonas gingivalis can lead to periodontitis in diabetes patients, and

poorly responds to periodontal therapy.

The diagnosis of periodontal infections is made on clinical and radiological

grounds. Gingivitis often results in minor bleeding. Prevention of periodontal

disease is an important aspect of management of patients with diabetes,

which consists of maintenance of oral hygiene, cessation of tobacco use and

regular professional care. Patients with periodontal infections need

professional cleaning and local treatment with antiseptics, minor surgical

procedures, etc. They may also require systemic antibiotic therapy if they have

fever or lymphadenopathy.

has

Evidence suggests that control of periodontal infection hasan impact on improvement of glycaemic control as seen by alleviation in

demand for insulin and decreased HbA1c level

UNUSUAL INFECTIONS

MUCORMYCOSIS (ZYGOMYCOSIS)

Mucormycosis is a rare opportunistic and invasive infection caused by fungi of

the class Zygomycetes. The genus most commonly associated with human

infections is Rhizopus, followed by Mucor and Cunninghamella. This infection

occurs in approximately 50% of the cases in individuals with diabetes mellitus

due to the greater availability of glucose to the pathogen that causes

mucormycosis, the decrease in serum inhibitory activity against the Rhizopus

in lower pH, and the increased expression of some host receptors that mediate

the invasion and damage to human epithelial cells by Rhizopus.

Mucormycosis can be acute or chronic. The classical triad is characterised by

paranasal sinusitis, ophthalmoplegia with blindness, and unilateral proptosis

with cellulitis. Facial or eye pain and necrotic wound of the palate of the nasal

23

mucosa may occur. Black necrotic eschar in the nasal cornets is a

characteristic sign.

Invasive external otitis is an infection of the external auditory canal that can

extend to the skull base and adjacent regions. It often affects elderly diabetic

individuals and the aetiologic agent is usually Pseudomonas aeruginosa.

Excruciating pain, otorrhoea and hearing loss are the characteristic features of

the infection. Skull base osteomyelitis and cranial nerve involvement may

occur. Facial paralysis occurs in 50% of the cases. The best diagnostic method

is the magnetic resonance imaging. There is no role for topical anti-

pseudomonal antibiotic therapy in malignant otitis externa. Systemic anti-

pseudomonal antibiotics remain the mainstay of treatment.

Although ciprofloxacin still remains the first line of treatment in outpatient

settings, these patients should be monitored closely. Generally, a 6- to 8-week

treatment is recommended. Patients with more severe infection and resistant

Pseudomonas aeruginosa generally require hospitalisation for biopsy,

debridement, and treatment with prolonged course (12 weeks) of parenteral

antibiotics including an anti-pseudomonal beta-lactam agent (e.g., ceftazidime,

piperacillin, imipenem) with or without an aminoglycoside.

Liposomal amphotericin, for more than 12 weeks, is indicated if Aspergillus is

the causative organism. Hyperbaric oxygen can be used in refractory cases as

an adjuvant therapy, but efficacy is unproved.

Emphysematous cystitis affects people with diabetes mellitus more frequently

than non-diabetics. It is characterised by the presence of gas in the bladder cavity

and infiltration of the bladder wall due to infection by bacteria that produce

carbon-dioxide. The most frequent pathogen is Escherichia coli, followed by

Enterobacter, Proteus, Klebsiella and Candida. Women are more affected than

men. Computerised tomography is the standard diagnostic method.

Emphysematous pyelonephritis is a more serious complication. Diabetes

accounts for 70 to 90% of all cases and this infection carries a high mortality, if

left untreated. About 21% cases can be complicated by papillary necrosis.

Most common organisms include Escherichia coli, Klebsiella pneumoniae,

Proteus mirabilis, Pseudomonas aeruginosa, Citrobacter and rarely yeast.

Escherichia coli and Kleibsiella pneumoniae together account for more than

90% of infections. Thrombocytopaenia, mental status changes, and

proteinuria are independent risk factors for poor outcome.

MALIGNANT (INVASIVE) OTITIS EXTERNA

EMPHYSEMATOUS CYSTITIS AND PYELONEPHRITIS

24

Symptoms, which include fever, chills, abdominal and flank pain, nausea,

vomiting, dysuria, and pyuria, usually mimic those of classic pyelonephritis,

and clinical suspicion for this urgent condition should be raised in every

diabetes patient. In the absence of response of fever in 3 to 4 days after

treatment for urinary tract infection in a diabetes patient, the uncommon

possibility of emphysematous pyelonephritis must be considered. Rarely,

emphysematous pyelonephritis and emphysematous cystitis might coexist in a

diabetes patient. It carries a higher mortality of close to 50%. Emphysematous

cystitis is suggested by the presence of pneumaturia.

Acute emphysematous cholecystitis predominantly affects elderly diabetic

men. It usually presents with right upper quadrant pain, vomiting, jaundice, and

in severe cases with gangrene of gall bladder, peritonitis and septic shock.

Overall mortality can be as high as 15 to 25%, and morbidity 50%. Plain

abdominal radiographs or ultrasound can lead to the diagnosis. The main

causative organisms include Clostridium perfringens, Escherichia coli and

Bacteroides fragilis. Emergency cholecystectomy and presumptive antibiotic

therapy with ampicillin-sulbactam is recommended. Alternatively, ampicillin

plus gentamicin plus clindamycin, or ceftriaxone plus clindamycin (or

metronidazole) can be used.

Diabetes mellitus predisposes to a range of different and unusual infections,

including psoas and spinal epidural abscesses. The primary causative organism

is Staphylococcus aureus. It is usually caused by haematogenous spread of

organism from an occult source of infection and in many cases is associated

with vertebral osteomyelitis or bowel infections. Percutaneous drainage of the

abscess and presumptive antibiotic treatment covering Staphylococcus aureus

in primary psoas abscess (haematogenous) and broad-spectrum antibiotics

covering aerobic and anaerobic bowel flora in secondary psoas abscess

(acquired from adjacent source) is recommended.

EMPHYSEMATOUS CHOLECYSTITIS

PSOAS ABSCESS

Atypical infections with rare organisms at unusual sites is common indiabetes patients, which if not treated properly can lead to

increased mortality and morbidity

• Malayalam: Pani Malayalam: Thanuppu

Tamil: Kayccal / Kaaichal Tamil: Kulir

Kannada: Jwara Kannada: Chali

Telugu: Jvaram Telugu: Chali

Marathi: Taap Marathi: Thandi vazne

Oriya: Jwara Oriya: Thariba/ Sita lagiba

Bengali: Jbara Bengali: Sita laga

Hindi: Bukhaar Hindi: Thand lagna

Gujarati: Taap Gujarati: Thandi lage che

•

• •

• •

• •

• •

• •

• •

• •

• •

• Malayalam: Virayal Malayalam: Kuthunanna nenju vedana

• Tamil: Kulir nadukkam Tamil: Allai vali

Kannada: Mainaduka Kannada: Edhe chuchu vantha novu

Telugu: Vanuku Telugu: Guunde noppi

Marathi: Thartharne Marathi: Shwas ghetana chaati dukhane

Oriya: Kampa Oriya: Chhati byatha

Bengali: Kapuni Bengali: Swas nile buke byatha

Hindi: Kathorata Hindi: Phepharon ki jhilli mai dard

Gujarati: Dukhri waghe che Gujarati: Chatimam dukhavo

•

•

• •

• •

• •

• •

• •

• •

• •

• Malayalam: Kabhamulla chuma wella, manga kabham Malayalam: Karutha kabham

Tamil: Saliyudan koodiya irumal Tamil: Iratham kalada sali

Kannada: Kemmu kaffa yondhige Kannada: Kempu bannadha kaffa

Telugu: Khapam tho kudina daggu Telugu: Coffe rango khapam / Tuppu rango kalli

Marathi: Bedkhe asalela Khhokala Marathi: Thunki vate rakt jane

Oriya: Kashare kaffa padhiba Oriya: Rakta saha kafa

Bengali: Kasite holod kaf Bengali: Kaliche kof

Hindi: Bulgum mein kuff ka hona Hindi: Lal kathai sa bulgum

Gujarati: Udharasa Gujarati: Udharasa

•

• •

• •

• •

• •

• •

• •

• •

• •

25

Fever Chills

Rigors Pleuritic chest pain

Productive mucopurulent cough Rusty sputum

IN PATIENT’S OWN WORDS

The list of commonly used terms related to various infections in different Indian

regional languages are mentioned below.

26

• Malayalam: Swasathivegam Malayalam: Oxygen kurayuka

Tamil: Athiga moochu yaangudal Tamil: Pirana vaivu kuraithal

Kannada: Jaasthi Vusirata Kannada: Aamla janaka korathe

Telugu: Yekkuva ga svasa pilchuta Telugu: Aksijan thakkuva/ Rakthamlo aksijan korata

Marathi: Shwas fulne Marathi: Oksijan purvatha na hone

Oriya: Jorre niswas neba Oriya: Amlajan kami jiba

Bengali: Ghana ghana sbasa neya Bengali: Sbasa nite kasta hawa

Hindi: Swaas lene ki gati badh jaana Hindi: Rakta mai oksijan ki kami

Gujarati: Jhadapi svasa Gujarati: Svasa leba ma takleef

•

• •

• •

• •

• •

• •

• •

• •

• •

• Malayalam: Hrudaya midippu koovuthal Malayalam: Sareera ksheenam

Tamil: Athga idaya thudippu Tamil: Kalaippu

Kannada: Jaasthi edhe voditha Kannada: Aalasya

Telugu: Gunde yekkuva kottukovadam Telugu: Sariram noppulu

Marathi: Dhaddhadne /hrdayache thoke vadhane Marathi: Galalyasarkhe vatane

Oriya: Chhati dhad dhad heba Oriya: Deha byatha

Bengali: Buk dharphar

Hindi: Hridye ka tej dhadakna Gujarati: Chhakar avi gayo

•

• •

• •

• •

• •

• •

• • Hindi: Bechani

• •

• Malayalam: Thalarcha Malayalam: Thala vedhana

Tamil: Udal asathi Tamil: Talai vali

Kannada: Sustu Kannada: Talenovu

Telugu: Neerasam Telugu: Talanoppi

Marathi: Asaktapana Marathi: Doke dukhane

Oriya: Durbalata Oriya: Munda bindha

Bengali: Durbalta Bengali: Matha byatha

Hindi: Durbalta Hindi: Sar mein dard

Gujarati: Chhakar, ashakti Gujarati: Mathano dukhavo

•

• •

• •

• •

• •

• •

• •

• •

• •

Tachypnoea Hypoxia

Tachycardia Malaise

Weakness Headache

27

COMMON INFECTIONS IN DIABETES AND THEIR INITIALPRESUMPTIVE THERAPY

The list of commonly encountered infections along with their treatment is

summarised below in Table 2.

Table 2: Common infections in diabetes

Type of infection

Asymptomatic bacteriuria

Urinary tract infection

Community-acquired pneumonia

TB

Periodontal infections

Fournier's gangrene

Diabetic foot infections

Mild-to-moderate infections

Severe infections

Common organisms

E. coli

E. coli

Pneumococci

M. tuberculosis

Porphyromonas gingivalis

Mixed aerobes and anaerobes

Polymicrobial in most cases

S. aureus, beta-haemolytic

streptococci and

Enterobacteriaceae

Mixed aerobes and anaerobes

(e.g., Pseudomonas aeruginosa,

Enterobacteriaceae, anaerobes)

Therapy

None

aFQ or TMP-SMX

Newer FQ, or beta-lactam plus a

macrolide or doxycycline

Anti-TB regimen

Professional cleaning, antiseptics,

antibiotics

Surgical debridement plus broad-bspectrum antibiotics (beta-lactam+ BLI

or carbapenems plus clindamycin or

metronidazole)

Debridement plus antibiotics (e.g.,

dicloxacillin, clindamycin, TMP-SMX,

amoxicillin-clavulanate, levofloxacin,

cephalosporins (cephalexin, cefoxitin,

celbiaxone, and so forth) with or without

metronidazole, ertapenem, linezolid,

daptomycin, anti-pseudomonal beta-

lactam + BLI, clindamycin plus FQ,

carbapenems, vancomycin p lus

ceftazidime

• Malayalam: Shareera vedhana Malayalam: Channa vedhana

Tamil: Thasai vali Tamil: Iduppu vali

Kannada: Mai novu Kannada: Pakke novu

Telugu: Kandarala noppi Telugu: Nadumu yenuka noppi

Marathi: Manspeshi dukhane Marathi: Kambar dukhi / Potat dukhane

Oriya: Deha bindha/ Mansapesi re jantrana Oriya: Karkalatale katiba

Bengali: Mangso pesi byatha Bengali: Komore byatha

Hindi: Mansapesiyom mein dard Hindi: Kamar mein tez dard

Gujarati: Snayu dukhavo

•

• •

• •

• •

• •

• •

• •

• •

•

Myalgia Flank pain

INFECTIONS RELATED TO THERAPEUTIC INTERVENTIONS

Infections related to injection sites and insulin pump infusion sites are

uncommon, and deserve attention if and when these occur. Proper hygiene in

handling devices should minimise such infections. Since penile implants have

become less popular owing to better medical treatment for erectile

dysfunction, infections are no longer a problem. There is no increase in

pacemaker insertion site infections in diabetes patients. This was once

foreseen as a potential problem.

Thrombosis of arteriovenous fistula and subsequent infections in diabetes

patients undergoing haemodialysis can be very difficult to eradicate. Localised

graft infections typically present as tenderness, warmth, and erythema over

the graft. Staphylococcus aureus is estimated to cause about 80% of graft

infections. The infection rate of continuous ambulatory peritoneal dialysis

catheters does not seem to be higher in diabetes patients than in non-diabetes

patients.

28

Table 2: Common infections in diabetes (table contd...)

Type of infection

Mucormycosis (rhinocerebral)

Malignant otitis externa

Psoas abscess:

Primary-Secondary

Emphysematous cholecystitis

Emphysematous pyelonephritis

Common organisms

Rhizopus spp., Mucor spp.,

Absidia spp.

P. aeruginosa, Aspergills spp.

S. auerus

Mixed aerobic, anaerobic

C. perfringens, E. coli, B. fragilis

E. coli, K. pneumoniae

Therapy

Surgical debridement plus glycaemic

control plus lipid-liposomal amphotericin

B or posaconazole

FQ, ceftazidime, piperacillin, imipenem,

meropenem, amphotericin B

Drainage plus antibiotics against

S. aureus; broad-spectrum antibiotics

Emergency cholocystectomy plus

antibiotics (e.g., beta-lactam + BLI,

ampicillin plus gentamicin or ceftriaxone

plus clindamycin or metronidazole

Percutanous drainage plus antibiotics

FQ: Fluoroquinolone, TMP-SMX: Trimethoprim-sulphamethoxazolea Newer (e.g., levofloxacin, moxifloxacin, gemifloxacin)b Beta-lactam + BLI, piperacillin-tazobactam or ticarcillin-clavulanate (anti-pseudomonal); ampicillin-sulbactam or amoxicillin-clavulanate (non-anti-pseudomonal)

fluoroquinolones

29

Careful blood sugar control is important during any infection topromote healing and prevent further complications related to the infection

INFECTIONS IN SPECIAL POPULATIONS WITH DIABETES

Infections in the elderly can be serious if not promptly treated. Because

infections present in subtle and atypical fashion, a high index of suspicion is

advised. Dosage adjustments are often needed for many antimicrobial

therapies because of altered renal and fluid electrolyte status.

Infections in burn victims with diabetes also deserve special attention because

of high risk of sepsis and community-acquired burn wound cellulitis.

Staphylococci, Streptococci, Proteus, Pseudomonas and Candida are the most

common organisms in diabetic burn infections.

30

CASE STUDY

PRESENTING HISTORY

PAST MEDICAL HISTORY

PHYSICAL EXAMINATION

• A 59-year-old woman with a 12-year history of type 2 diabetes treated with

a thiazolidinedione and multiple daily injections of insulin presented to the

outpatient department with a 10-week history of painful skin lesions on her

abdomen that had been increasing in size

• The lesions developed at the site of insulin injections

• She was injecting in the abdomen, using a new needle each time

• She had received a 14-day course of levofloxacin 750 mg 7 weeks before

the clinic visit and had been instructed to change the insulin bottles and to

use her arms for injection

• The skin lesions did not seem to improve, but she did not develop new

lesions

• H/o severe asthma requiring chronic oral steroids and hypertension

• Her glycaemic control was poor (HbA1c:13.2%)

• BP: 136/84 mmHg; HR: 84/min; RR: 16/min; Temperature: Afebrile

• On her abdomen, she had multiple tender, red, indurated, haemorrhagic

crusted papules and nodules, 0.5 to 2 cm in size in the periumbilical region

bilaterally (Fig. 11)

• There was no peripheral oedema, and there were no lesions elsewhere on

her body

Fig. 11: Pink nodules and pink, crusted, scaly papules coalescinginto plaques on the right mid-abdomen

31

LABORATORY TESTS

• Leucocyte count with differential, platelets, electrolytes, creatinine and

liver enzymes were within normal range

• A skin biopsy was performed from one of the nodules and was sent for

histopathology and culture

• The biopsy demonstrated numerous acid fast bacilli in the inflamed dermis

(Fig. 12)

• Unfortunately, due to lab error, a culture was not performed

Fig. 12: Multiple acid fast bacilli in the dermis (original magnification 100X)

After careful questioning, it was found that the insulin bottle was the culprit.

After she changed it, she did not develop new lesions. She admitted that there

was water dripping in the refrigerator where she had kept the insulin bottle, as

a possible explanation of how the bottle was contaminated with the

environmental pathogen.

Mycobacterial skin infection secondary to uncontrolled diabetes and

contamination (insulin).

She was treated with clarithromycin for 3 months with resolution of the lesions

and only mild residual hyperpigmentation in the area.

Occasionally, mycobacteria are isolated from nodular skin lesions of

immunosuppressed patients. Many cases are linked to injections and diabetic

DIAGNOSIS

MANAGEMENT

DISCUSSION

32

patients are especially at high risk. Non-tuberculous mycobacteria grow

slowly. Even the rapid growers may take 3 to 7 days to form visible colonies on

media, whereas slow-growing mycobacteria take weeks or do not grow at all.

The slow growth complicates antibiotic susceptibility testing. Antibiotics may

be degraded during prolonged incubation.These mycobacteria are notoriously

resistant to most anti-tuberculosis drugs. Debridement is best combined with

2 or 3 antibiotic drugs. Most commonly used antibiotics are clarithromycin,

clofazimine, amikacin, rifabutin and sulphonamide.

It is important to consider the rare but potential skin infection with atypical

mycobacteria (Fig.13) in diabetes patients who do not respond to antibiotic

therapy for common skin pathogens.

RED ALERT

Fig. 13: Atypical mycobacterium

33

POINTS TO PONDER

1. The most common soft tissue infection associated with diabetes

is__________.

a. Diabetic foot infection

b. Necrotising fasciitis

c. Fournier’s gangrene

2. These infections principally occur in patients with diabetes:

a. Malignant otitis externa, mucormycosis and emphysematous

pyelonephritis

b. Malignant otitis externa, mucormycosis and renal failure

c. Diabetic foot ulcer and streptococcal infections

3. ASB is more prevalent in diabetic women as compared to diabetic men.

a. True

b. False

4. ___________is the most common organism causing ASB.

a. Proteus vulgaris

b. Klebsiella pneumoniae

c. Escherichia coli

d. None of the above

5. The common respiratory ailment/s associated with diabetes mellitus

is/are_______.

a. Pneumonia

b. TB

c. H1N1

d. Influenza

e. All of the above

f. None of the above

34

6. Grade 3 of diabetic foot ulceration classification includes__________.

a. Superficial, full-thickness ulcer

b. Local gangrene (toes or forefoot)

c. Deep ulcer with osteomyelitis

d. Gangrene of whole foot

e. None of the above

7. Emphysematous cholecystitis is more frequent in elderly males with

diabetes mellitus.

a. True

b. False

8. The evaluation of foot ulcer should include assessment/s of ___________.

a. Neurological status

b. Vascular status

c. Wound itself

d. All of the above

9. ______________ can lead to periodontitis in diabetes patients.

a. Peptostreptococcus

b. Clostridium

c. Bacteroides

d. Porphyromonas gingivalis

10. The overall morbidity due to emphysematous cholecystitis is

about_______percent.

a. 15

b. 30

c. 50

d. 80

Answers: 1-a; 2-a; 3-a; 4-c; 5-e; 6-c; 7-a; 8-d; 9-d; 10-c

35

SUGGESTED READINGS

th1. IDF diabetes atlas. 6 edition . Available at: http://www.idf.org/diabetesatlas/update-2014

2. Mahajan HD, Padvi MV. Health profile of diabetic patients in an urban slum of Mumbai, India.

Innovative Journal of Medical and Health Science. 2013;3(3):102–109.

3. Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: Estimates for the year 2000

and projections for 2030. Diabetes Care. 2004;27(5):1047–53.

4. Sahay BK. Infections in diabetes mellitus. Available at: http://www.apiindia.org/medicine_

update_2013/chap48.pdf

5. Shilling AM, Raphael J. Diabetes, hyperglycemia, and infections. Best Practice & Research

Clinical Anaesthesiology. 2008;22(3):519–535.

6. Casqueiro J1, Casqueiro J2 and Alves C. Infections in patients with diabetes mellitus: A

review of pathogenesis. Indian J Endocrinol Metab. 2012;16(Suppl1): S27–S36.

7. Mendes JJ, Neves J. Diabetic foot infections: Current diagnosis and treatment. The Journal

of Diabetic Foot Complications. 2012;4(2):26–45.

8. Gupta S. Management of diabetic foot. Available at: http://apiindia.org/pdf/medicine_

update_2012/diabetology_10.pdf

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NOTES

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NOTES

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NOTES

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