Open Access Diabetic Foot Infection, Biofilm & New Management Strategy

Diabetes Research: Open Access

Original Article DOI: https://doi.org/10.36502/2019/droa.6152 Diabetic Foot Infection, Biofilm & New Management Strategy Ruke MG1, Savai J2

1Consultant Diabetic foot surgeon, Associate professor in surgery GGMC, JJ Hospital, Mumbai, India 2Department of Medical Affairs, JBCPL, Mumbai, India

Corresponding Author: Dr. Milind Gajanan Ruke Address: Advanced Diabetic Foot Clinic, Business Point, 203d-K Sandhu Marg, Near Malhaar Hotel, Chembur, Mumbai 400071, India; Ph: 9820029711; Email: [email protected]; [email protected] Received date: 15 October 2019; Accepted date: 05 November 2019; Published date: 11 November 2019

Citation: Ruke MG, Savai J. Diabetic Foot Infection, Biofilm & New Management Strategy. Diab Res Open Access. 2019 Nov 11;1(1):7-22.

Copyright © 2019 Ruke MG, Savai J. This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The world is facing a major epidemic of diabetes mellitus (DM) & available reports suggest that all these patients are at risk of developing diabetic foot ulcer (DFU). Approximately 50 - 60% of all DFUs can be classified as neuropathic. Signs or symptoms of vascular compromise are observed in 40 to 50% of all patients with the vast majority having neuro-ischemic ulcers, and only a minority of patients has purely ischemic ulcers. Diabetic foot infections are usually polymicrobial in nature, involving both aerobes and anaerobes, which can decay any part of the body especially the distal part of the lower leg. However, one of the hidden barriers to wound healing is the presence of biofilm in chronic DFUs. Biofilms are difficult to identify & diagnose, recalcitrant to topical antibiotics & can reoccur even after sharp debridement. More than 90% of chronic wounds are complicated with biofilms. Hence, early identification and management of diabetic foot infections becomes imperative in order to prevent complications & amputation. Debridement is considered to be the gold standard treatment approach for managing DFU manifested with necrotic tissue. However, biofilm can reform even after sharp debridement and can delay healing & recovery. Also, antibiotics & few antiseptics have limited role in managing DFUs complicated with biofilm. Until recently, Cadexomer iodine, a new generation iodine formulation with microbead technology has taken a different profile in wound care. It can effectively manage biofilm along with exudate & possesses superior desloughing action. Additionally, appropriate ways of offloading, dressings & use of newer treatment strategies like negative pressure wound therapy (NPWT), hyperbaric oxygen therapy (HBOT) and / or use of growth factors can ensure faster healing & early wound closure. Although, commendable efforts in recent years have been taken in the diagnosis and treatment of DFU, it still remains a major public health concern.

Keywords Diabetic foot ulcer (DFU); Neuropathy; Biofilm; Cadexomer Iodine; Negative Pressure Wound Therapy (NPWT); Hyperbaric Oxygen Therapy (HBOT)

Introduction remaining undiagnosed [1]. Available reports suggest The world is facing a major epidemic of DM. that all these patients are at risk of developing DFU. A According to International Diabetes Federation, there DFU is any full-thickness wound below the ankle in a are an estimated 425 million diabetic patients diabetic patient, irrespective of duration [2]. DFUs worldwide with 1 in 10 living with diabetes & 1 in 2 are characterized by an injury to all the layers of skin,

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Citation: Ruke MG, Savai J. Diabetic Foot Infection, Biofilm & New Management Strategy. Diab Res Open Access. 2019 Nov 11;1(1): 7-22. Original Article resulting into necrosis or gangrene as a result of every 20 seconds. According to the Vascular Society of neuropathy or peripheral arterial disease [3,4]. DFUs India, about 1 lower leg amputations occur every year are often infected which can decay any part of the due to diabetes-related problems. Australia has body especially the distal part of the lower leg [5-7]. declared a national medical emergency as 16 legs are This review focuses on epidemiology & amputated every day. Diabetes UK reports 23 legs are pathophysiology of DFU, its complication associated being amputated daily in the NHS system [12]. The with infection & biofilm along with clinical prevalence of diabetic ulcer patients in the United assessment, management & newer treatment States is 15-20% & the risk of amputation is 15-46% strategies. more compared with non-DM patients [9].

Epidemiology of diabetic foot ulcers: Reported literature suggests that approximately Incidences of DFU continue to increase worldwide 58% of DFU patient becomes clinically infected. [8]. The prevalence of DFU is not accurately known Patients with DM frequently require minor or major and the difference in prevalence rates in each country amputations of the lower limbs and in more than 50% is estimated at 4-27% of DFU sufferers worldwide of cases; infection is the predominant causative factor. [9]. The lifetime risk of foot ulcers until recently was Major amputation is associated with significant generally believed to be 15–25%; however, recent data morbidity and mortality (ranging from 13 to 40% at 1 suggest that the figure may be as high as 34% [10]. year to 39 to 80% at 5 years) in addition to immense Studies have shown that 15% of patients with DM will social, psychological, and financial consequences [2]. experience complications of DFU in the future [9]. Pathophysiology of Diabetic Foot Ulcers [2,9] One out of four diabetic patients have a lifetime In DM, patients are characterized by high blood risk of developing foot ulcer disease, which often lead glucose levels which results in endothelial to amputations, the incidence of which is quite high dysfunction, mitochondrial dysfunction, cellular nerve (one out of five patients) in India [11]. Each year there damage, microvasculature damage & also impaired are nearly one million lower extremity amputations myelin regeneration. DFUs result from interaction done for diabetic patients worldwide, that’s one in between two major risk factors: neuropathy and

Fig-1: Pathophysiology of Diabetic Foot Ulcer

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Citation: Ruke MG, Savai J. Diabetic Foot Infection, Biofilm & New Management Strategy. Diab Res Open Access. 2019 Nov 11;1(1): 7-22. Original Article peripheral vascular disease. Neuropathy leads to insensitive and possibly deformed as the varying degrees of alterations in sensory, motor & disease progresses. autonomic functions (Fig-1). Approximately, 50 to 60% of all DFUs can be classified as neuropathic. In Diabetic foot infection: 40 to 50% of all patients, signs or symptoms of In patient with DFU, deep tissues are exposed to vascular compromise are observed with the vast bacterial colonization, once the protective layer of skin majority having neuro-ischemic ulcers, and only a is broken [13]. Wound healing outcome majorly minority of patients has just ischemic ulcers. depends on qualitative and quantitative aspects of wound microbiology which are critical determinants. • Autonomic neuropathy: firstly, non-myelinated ß-hemolytic streptococci and Staphylococcus aureus autonomic nerve fibers are affected resulting firstly colonize and acutely infect breaks in the skin. in autosympathectomy with consequent medial Further, chronic wounds become polymicrobial, arterial calcification, microvascular including aerobic Gram-negative rods and anaerobes. thermoregulatory dysfunction, and Gram-negative bacilli, mainly Enterobacteriaceae & arteriovenous shunting. Autonomic Pseudomonas aeruginosa, are found in many patients neuropathy can cause dry skin, cracking, and with chronic or previously treated infections [14]. fissuring which can create a portal for entry of Anaerobes often participate in mixed infection bacteria. especially in cases of deep tissue infection with • Sensory neuropathy: begins with poorly aerobes [15]. Such mixed infections can lead to tolerated tactile allodynia and thermal microbial synergy, further increasing the severity of hyperalgesia, progressively affecting the infection [13]. Diabetic foot infections (DFI) are thicker myelinated fibers further leading to polymicrobial in nature, involving both aerobes and objective loss of sensation and proprioceptive anaerobes. A recent prospective study including 289 dysfunction. isolates obtained from 178 tissue samples of patients • Motor neuropathy: results from the axonal (n=261) with DFIs revealed that 44.3% of DFIs were degeneration of the large motor myelinated monomicrobial and 55.7% DFIs were polymicrobial fibers causing atrophy of anterior crural [16]. Etiological agents reported in DFIs are enlisted in muscle or wasting of intrinsic muscle. Further, Fig-2 [15]. Though it is generally believed that acute it results in foot deformity and consequent infection that has not been previously treated with altered foot biomechanics with foot pressure antibiotics is monomicrobial while the chronic ones redistribution. The foot becomes clinically treated with antibiotics previously are polymicrobial,

Fig-2: Etiological agents causing diabetic foot infections [15].

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Citation: Ruke MG, Savai J. Diabetic Foot Infection, Biofilm & New Management Strategy. Diab Res Open Access. 2019 Nov 11;1(1): 7-22. Original Article

Involving aerobes as well as anaerobes [17], it has method can discriminate between biofilm- growing been demonstrated that anaerobes were the bacteria or planktonic organisms responsible for predominant pathogens seen in both, new and delayed healing. However, several surrogate markers recurrent ulcers [18]. The co-existence of aerobes and can aid diagnosis: (a) Failure of response to anaerobes in a DFI helps protect the anaerobe from appropriate antimicrobials (both antibiotics & the harmful effects of oxygen, and hence, their antiseptics), since bacterial cells within biofilm matrix survival [18]. are inherently tolerant to both, unlike planktonic bacteria; (b) high exudate levels & recurrent Biofilm: the hidden barrier to healing: inflammation/infection; (c) presence of gelatinous A biofilm is a bacterial cluster which resides within material on the wound that reforms quickly after its a matrix offering protection from antimicrobials & removal [24]. Infection due to presence of biofilm is host defenses (Fig-3). A single planktonic bacteria very different from planktonic (acute) infection; thus, (free-floating) forms the biofilm following attachment health care practitioners should understand that within a protective matrix (extracellular polymeric treatment protocols for acute infections are not substance [EPS]), which creates coherent clusters of effective for treating non-healing chronic wounds cells [19]. A non-healing wound is an indicator of the complicated with biofilm. Thus, treatment with an presence of biofilm [20]. Biofilms cause a delay in appropriate antimicrobial therapy becomes imperative healing by initiating an immune response leading to which must be able to disrupt and penetrate the EPS chronic inflammatory cycle and tissue damage due to matrix, kill the bacterial cells and provide sustained high levels of proteases and reactive oxygen species action that prevents the biofilm reformation [21,22]. Biofilms are prone to reformation and also [19,25,26]. difficult to treat because: (a) EPS matrix protects bacterial cells against topical antimicrobials; (b) Assessment & Clinical Diagnosis of Diabetic Bacteria within biofilms are also metabolically Foot Ulcer dormant, resulting into antibiotic tolerance; (c) EPS Recognizing important risk factors and assessing components also neutralizes several antimicrobials DFI requires a consistent and thorough diagnostic that penetrate the matrix [23,24]. approach. Such an evaluation involves careful assessment of foot, wound history; physical Biofilm detection and diagnosis: examination; and several complementary diagnostic Currently, no routine identification or detection procedures [27,28].

Fig-3: Schematic representation of polymicrobial biofilm formation

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Citation: Ruke MG, Savai J. Diabetic Foot Infection, Biofilm & New Management Strategy. Diab Res Open Access. 2019 Nov 11;1(1): 7-22. Original Article

History: pressed on the foot with sufficient pressure Symptoms of peripheral neuropathy include until the monofilament is bent, this would hyperesthesia, paresthesia, hypoesthesia, disesthesia, indicate that the patient has neuropathy. radicular pain and anhidrosis. People with Another diagnostic tool is a 128 Hz tuning fork, atherosclerotic disease in the lower extremity which can be used to examine the vibration experience claudication, ischemic pain at rest & leg sensation at the ankle and the first pain [29]. metatarsophalangeal joint. Generally, patients with DFU cannot feel the vibration of the Physical examination: garputala when kept for more than 10 seconds. According to Stillman, physical examination in DFU [30,31,33]. patients is divided into three parts, namely: 1. Examination of extremities and ulcers: Laboratory examination: [9] DFUs occur in certain areas such as heels, area • Blood tests: leukocytosis indicates an abscess of metatarsal head on the sole, fingertips; or other foot infections. since, it often gets traumatized easily which is • Metabolic profile: blood glucose, glycosylated characterized by hypertrophic callus, brittle or hemoglobin (HbA1c) measurement and serum broken nail, hammer toes and fissure. creatinine helps to determine the adequacy of 2. Assessment of possible vascular insufficiency: glucose regulation and renal function. Physical examination shows decrease in • Noninvasive vascular laboratory examination: peripheral pulse, cyanosis of toes, ischemic pulse volume recording (PVR) or necrosis and ischemic necorsis and palor plethymosgraphy. become pale. Noninvasive vascular examinations include transcutaneous oxygen Radiological examination: [9] measurements, ankle brachial index (ABI) & • A plain examination of the diabetic foot may systolic pressure of the toes. ABI is easily show demineralization and the Charcot joint performed using Doppler ultrasonography and the presence of osteomyelitis (Fig-5). (Fig-4) [30-32]. • Computed tomographic (CT) scan and 3. Assessment of possible peripheral neuropathy: magnetic resonance Imaging (MRI): although Neurologic status can be examined using an experienced examiner can diagnose an Semmes-Weinsten monofilament to check abscess with a physical examination, a CT scan whether the patient has protective sensation. If or MRI may be used to help diagnose an the patient cannot feel the monofilament when abscess if the physical examination is unclear.

Fig-4: Vascular examination2

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Citation: Ruke MG, Savai J. Diabetic Foot Infection, Biofilm & New Management Strategy. Diab Res Open Access. 2019 Nov 11;1(1): 7-22. Original Article

Alternatives to conventional angiography: [9] or 64 channels) can improve the resolution of Magnetic resonance angiography (MRA): MRA is angiographic images and at relatively high an alternative that can be used in high-risk patients or speeds. However, MDCT does use iodine-based patients who are allergic to contrast material. The contrast agents and, as with the use of all such contrast used was Gadolinum chelates, potentially contrast agents, there is a risk of contrast causing side effects in patients with renal induced nephropathy (CIN). insufficiency: acute renal injury and • Carbon dioxide angiography is an alternative pseudohypokalemia. to patients with renal insufficiency, but it is not widely applicable and still requires iodine Nephrogenic systemic fibrosis and exposure to contrast material as an additional carbon radiation are the main limitations of CT and MR dioxide gas to obtain a good image. angiography in patients with impaired renal function. Management of Diabetic Foot Ulcers

• Multi-detector computed tomographic The main goal in the management of diabetic angiography (MDCT) avoids arterial stabbing. ulcers is the closure of the wound. Treatment of DFUs By using IV contrast injection, MDCT scans (16 in DM patient depends on the presence or absence of

Fig-5: Evaluation for the presence of osteomyelitis [2] ischemia & severity of the ulcer. DFU therapy wound healing. Evidence suggests that debridement includes: debridement, reducing pressure/load on the plays an important role in the granulation tissue injured area (offloading), managing infection with formation that would aid wound healing. adequate antibiotics / antiseptics with appropriate dressing which might keep the wound clean and There are five different ways debridement is carried moist that would ensure faster healing [34,35]. out: surgical, mechanical, autolytic, enzymatic and biological. Surgical debridement is a sharp Debridement: debridement with the help of scissors & scalpel to Debridement should be performed on all chronic remove all dead tissue and bone. Mechanical wounds to remove dead and unhealthy necrotic tissue debridement can be carried out physically with the which are difficult to recover from injury [36,37]. It help of wet-to-dry dressing, pressure irrigation, also helps in eliminating the base of abnormal injury, lavage and hydrotherapy. Autolytic debridement callus (epidermal hyperkeratosis), necrotic dermal occurs naturally in healthy, moist and perfused ulcers. tissue, and bacterial elements which can impede Enzymatic debridement involves use of proteolytic

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Citation: Ruke MG, Savai J. Diabetic Foot Infection, Biofilm & New Management Strategy. Diab Res Open Access. 2019 Nov 11;1(1): 7-22. Original Article enzymes such as collagenase, DNAse, trypsin, Diabetic ulcers are often infected and polymicrobial papain/urea from papaya, streptokinase etc. in nature. Because of the high incidence rate of Biological debridement can be carried out using infection in diabetic ulcers, a systematic approach is proteolytic enzyme secreted by the larvae of Lucilia required for complete assessment & management sericata fly which can dilute the necrotic tissue [36]. which involves appropriate use of antimicrobials like antibiotics or antiseptic either topically or systemically Limitations: Surgical debridement include adverse [40]. events from the debridement itself, for example, bleeding and possible general complications from the 1. Antibiotics: anesthesia. On the other hand, relative Mild and moderate infections can be treated contraindication of enzymatic debridement is its use using oral antibiotics, such as cephalexin, in heavily infected wounds. Furthermore, collagenase amoxicillin-clavulanic acid, moxifloxacin or should not be used in conjunction with silver-based clindamycin [29,31,40]. Patients with severe products or with Dakin solution. Additionally, infections should be hospitalized & treated with biological debridement have several limitations and antibiotics that includes imipenem-cilastatin, B- are contraindicated in abdominal wound contiguous lactam B-lactamase (ampicillin-sulbactam and with the intraperitoneal cavity, pyoderma piperacillin-tazobactam) and broad-spectrum gangrenosum in patients with immunosuppression cephalosporin [29]. therapy, and wounds in proximity to areas afflicted by septic arthritis. The lists of empirical antibiotics are summarized in Table-1, which refers to the Infectious Disease Offloading: Society of America (IDSA) and International Ulceration usually occurs in the high pressure Working Group on the Diabetic Foot (IWGDF) bearing area of the foot. Offloading through several guidelines [41]. Despite widespread use of broad methods or tools helps to shift the weight fulcrum spectrum antibiotics, emergence of antimicrobial away from the side of the ulcer. The main objective of resistance has restricted their use against several offloading is to facilitate wound healing by reducing clinical isolates causing wound infection. pressure on the ulcer & thereby preventing any trauma to the tissue [34,37]. Thus, offloading is An emerging paradigm for biofilm-based wound becoming an important component of the DFU care takes the form of a simple step-down management. Although bed rest is an ideal way to approach, following initial aggressive reduce pressure, it is not a feasible option in every debridement, then step-up to advanced therapies patient population. Alternatively, total contact casting if needed to enhance healing (summarized in (TCC) which is made up of specially formed casts is Fig-6). the most effective way of offloading, to spread the patient's burden out of the ulcer area. Thus, it is 2. Antiseptic: useful for controlling edema that can interfere with Antiseptics are agents that hinder the growth or wound healing & also allows the patient to walk destroy micro-organisms on living tissue [42]. during treatment. Evidence suggests that TCC can Antiseptics have broad spectrum activity when facilitate healing in 73-100% of cases with successful compared to antibiotics due to their multiple reduction of pressure on the wound. Additionally, mechanisms of action targeting various aspects several other ways by which offloading can also be of cell biology in microbes which also reduces achieved with variable results includes use of the likelihood of emerging resistance [42,43]. wheelchairs, walkers to shoes that are specially Literature supports the use of numerous designed etc. [38,39]. antiseptics which has proven efficacy in the prevention and treatment of infection in wound Management of diabetic foot infection: care which includes iodine carriers (iodophores)

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Citation: Ruke MG, Savai J. Diabetic Foot Infection, Biofilm & New Management Strategy. Diab Res Open Access. 2019 Nov 11;1(1): 7-22. Original Article

Fig-6: Pathway for biofilm treatment as part of good wound bed preparation practice.

Table-1: Antibiotic recommendations for the empirical treatment of diabetic foot infections. Severity of Additional Factors Usual Pathogen(s) Potential Empirical Regimens Infection 1st generation cephalosporin, No complicating features MSSA, Streptococcus spp. ampicillin/sulbactam, amoxicillin/clavulanate, clindamycin

β-lactam allergy or Clindamycin, levofloxacin, moxifloxacin, Mild (usually MSSA, Streptococcus spp. intolerance doxycycline treated with oral agents) MSSA, Streptococcus spp., Levofloxacin, moxifloxacin, 2nd or 3rd Recent antibiotic exposure Gram-negative rods generation cephalosporin

Clindamycin, doxycycline, High risk for MRSA MRSA trimethoprim/sulfamethoxazole

MSSA, Streptococcus spp., 2nd or 3rd generation cephalosporin ± No complicating features ± Gram-negative rods aminoglycoside

3rd generation cephalosporin ± MSSA, Streptococcus spp., Recent antibiotic exposure aminoglycoside, ertapenem, piperacillin ± Gram-negative rods / tazobactam, cefepime

Macerated ulcer and Gram-negative rods, Piperacillin/tazobactam, cefepime, warm climate including Pseudomonas imipenem, meropenem Moderate (oral or initial parenteral) Piperacillin/tazobactam, ertapenem, MSSA ± Streptococcus or Severe Ischemic 2nd or 3rd generation cephalosporin or spp. ± Gram-negative (parenteral) limb/necrosis/gas forming cefepime + clindamycin or rods±anaerobes metronidazole Vancomycin or teicoplanin + 3rd MRSA ± Streptococcus MRSK risk factors generation cephalosporin, cefepime, spp. ± Gram-negative rods piperacillin / tazobactam, ertapenem

Risk factors for resistant ESBL, multi-drug resistant Piperacillin/tazobactam + Gram-negative rods Gram-negative aminoglycoside, imipenem, meropenem

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Citation: Ruke MG, Savai J. Diabetic Foot Infection, Biofilm & New Management Strategy. Diab Res Open Access. 2019 Nov 11;1(1): 7-22. Original Article

with polyvinylpyrrolidone (PVP or povidone) iodine in wound care has taken a different iodine, silver, chlorhexidine, benzalkonium profile [42]. chloride, triclosan, octenidine, and polyhexamethylene biguanide (PHMB) [43]. Dressing: Dressing is a material used topically on the wound However, in vitro studies have demonstrated to protect the wound and help wound healing. that antiseptics can inhibit collagen synthesis & Dressing will experience direct contact with the microcirculation, toxic to fibroblasts, wound and is distinguished by plaster as a dressing keratinocytes, leukocytes and impair epithelial barrier. There are several types of dressings: Hydrogel cell migration [42,44]. Clinicians today have dressing, film, composite film is well used for cuts innumerable options of antiseptics; yet, the with a small amount of exudate, whereas for wound debate was born in the shadow of the several in with high exudate levels hydrocolloid, alginate, foam vitro evidences on cytotoxicity. and other absorptive dressings are used widely. Injuries with large necrotic tissue should be done Use of iodine in wound care dates back to 1919 debridement before dressing [47,48]. (Fig-7) when Alexander Fleming studied the effect of antiseptics in septic wounds. The study found Newer Management Strategy that wounds treated with 2% iodine compared Formerly, it was believed that simply saline to carbolic acid showed lower incidence of gas dressings & conventional therapeutic interventions gangrene in hospitalized patients during World might be sufficient to heal the wound. However, very War I [45]. However, use of antiseptics declined recently newer concepts have been introduced, that when Fleming discovered penicillin in 1929 and have completely revolutionized the wound during the late 1980s the routine use of management strategy. antiseptics was questioned [46]. With the emergence of multi-resistant strains of Cadexomer Iodine: organisms and a better understanding of the Cadexomer iodine is a new generation iodine dynamics of wound healing, the use of topical formulation manufactured using smart microbead

Fig-7: Management of diabetic foot infections (DFIs) [2].

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Citation: Ruke MG, Savai J. Diabetic Foot Infection, Biofilm & New Management Strategy. Diab Res Open Access. 2019 Nov 11;1(1): 7-22. Original Article technology for managing infected chronic exudative colonization, preparing the wound due to its unique wounds. It consists of three dimensional lattices of pharmacological 4 in 1 actions which are presented in micro spherical, polysaccharide beads of cadexomer the fig-8 [52]. Clinical evidences for managing iodine with 0.9% elemental iodine loaded into it. The infection & biofilm complicated diabetic foot ulcers are sterile antimicrobial dressing of cadexomer iodine is a summarized in the Table-2. water-soluble preparation which provides controlled release of iodine at the wound site [49,50]. Growth factors: Cadexomer iodine is different from povidone iodine Currently, new generation of modern wound since it is made up of micro beads of modified dressing is gaining importance; these more advanced biodegradable starch which has a considerable affinity dressings can release therapeutic agents and healing for wound exudate. As the starch becomes wet, it enhancers such as growth factors (GFs), stem cells, allows slow and sustained release of iodine into the peptides and other bioactive substances. Importance wound bed and maintains a concentration gradient of extracellular matrix for wound healing has between the ulcer surface and the cadexomer beads. influenced researchers to generate more advanced Iodide is normally inactivated in a few minutes by wound dressings including collagen and other ECM protein. However, this form allows slow release of proteins, also called biological dressings, such as this ion, thus conferring a prolonged antiseptic action. collagen, hyaluronic acid, chitosan, elastin and fibrin In addition, the cadexomer starch forms a gel on [57,58]. Such dressings could reduce inflammation contact with exudate, and this gel supports autolytic and wound proteases & increase GFs in the wound debridement and desloughing of the wound bed. environment. For patients with recalcitrant foot Conversely, in povidone iodine, iodine is loosely ulcers, advanced biological therapies including combined with PVP which allows only for gradual recombinant growth factors (r-GF), platelet-rich release of free iodine, suggesting that iodine is rapidly plasma, bioengineered cell-based therapies may consumed by protein component and its antiseptic benefit the patients with optimum healing and effect is attenuated promptly [51]. improving their quality of life. Among r-GFs, the only FDA-approved GF for DFUs is platelet derived growth In highly exuding, infected and chronic wounds, factor (PDGF) which is most widely investigated & cadexomer effectively decreases the critical infection shows promising results [59]. Moreover, a novel

Fig-8: Unique pharmacological actions of cadexomer iodine [52]

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Citation: Ruke MG, Savai J. Diabetic Foot Infection, Biofilm & New Management Strategy. Diab Res Open Access. 2019 Nov 11;1(1): 7-22. Original Article

Table-2: Clinical evidences for managing infection & biofilm complicated diabetic foot ulcers

Treatment Author Study Type Study Patients Study Results Study Conclusion Duration

i) Cadexomer iodine significantly reduces Fifteen diabetic DFU bioburden by foot ulcer 46% following 3 patients weeks treatment & Cadexomer iodine displaying 89% following 6 Prospective, decreases wound Schwartz JA et clinical signs of weeks. Longitudinal 6 weeks bioburden and heals al [53] infection or Cohort difficult to treat diabetic critical bacterial ii) Overall patients foot ulcers. colonization showed 53.6% were enrolled in reduction in ulcer the study surface area and 50% decrease in ulcer depth from baseline.

Forty-one i) Percentage patients patients with showing complete diabetes were healing was higher randomized to with CI (29%) Cadexomer iodine treatment with compared to standard ointment is a cost- cadexomer treatment (11%). effective and useful Open, iodine (CI) addition in the treatment Apelqvist J randomized (n=22) and 12 weeks of exudating cavity ulcers [54] comparative standard ii) Fewer weekly in diabetic patients trial dressings (n=19; dressing changes were compared with standard gentamicin required for CI (4.7) treatment, including solution, compared to standard topical antibiotics. streptokinase, treatment (9.9). dry saline gauze). i) The median value of DFU biofilm architecture reduced between pre- and post- treatment with cadexomer iodine; pretreatment median was 4 (large 17 patients with microcolonies 100 cells Cadexomer iodine chronic diabetic and a continuous effectively reduces foot ulcer (DFU) 1 week (total film/matrix) and the Malone M et al Clinical, in microbial load in chronic due to suspected three post- treatment [55] vivo non- healing diabetic foot biofilm applicatio ns) median was 3 ulcers complicated by involvement (largemicrocolonies100 biofilm. were enrolled. cells).

(ii) 64.7% patients showed significant reduction in mean microbial load post- treatment with Cadexomer iodine.

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Citation: Ruke MG, Savai J. Diabetic Foot Infection, Biofilm & New Management Strategy. Diab Res Open Access. 2019 Nov 11;1(1): 7-22. Original Article

i) Percentage reduction in wound A total of 81 area from baseline to patients with 12 weeks was found to chronic exuding be 94.3% with wounds (like cadexomer iodine and diabetic foot 67.8% with standard Cadexomer iodine, when Open-label, ulcer, pressure dressing (p=0.0001). tested in Indian patients randomized, ulcer & venous with chronic exuding Raju R et al prospective, ulcer) were 12 weeks wounds was found to be [56] multi-centre, enrolled and ii) Mean reduction in effective significantly as comparative randomized to exudate following compared to standard receive treatment with saline dressings. cadexomer Cadexomer iodine vs. iodine (n=41) & baseline was found to standard saline be 80.8% by end of dressing (n=40) 4th week & 84.6% at the end of 10th week treatment.

therapy involving the use of intralesional injection of In recent years, hyperbaric oxygen therapy (HBOT) recombinant human epidermal growth factor can has shown increased attention as an adjuvant prevent amputations in selected complicated DFUs, treatment for managing DFUs [57]. Chronic wounds non-responsive to standard care [60]. Further clinical are usually hypoxic, which means for adequate wound trials are required to evaluate the clinical efficacy and healing, it requires an increase in oxygen supply. safety of such therapies, although these products are HBOT is a technique by virtue of which oxygen is the benchmarks of biological therapies [57]. delivered at pressures greater than normal atmospheric (sea level) pressure or more pressure Negative pressure wound therapy (NPWT): than one atmosphere absolute (ata). In HBOT, the NPWT or wound closure with a vacuum using a patient is exposed & allowed to breathe in 100% sponge on the wound, covered with an airtight oxygen in a high pressure chamber. The barometric dressing can be used for wounds with large lymphatic pressure can be increased up to three time’s normal leaks and fistulas. Several studies have suggested that atmospheric pressure (3ata). When patients breathe this novel system presents potential advantages, oxygen at two to three times atmospheric pressure, which includes removal of infectious organism and the amount of dissolved oxygen in the blood non-viable material [9]. The main mechanism of significantly increases; subsequently more oxygen is NPWT is also to eliminate edema that removes the delivered to the affected area thereby alleviating the fluid of the lymph or the lymph in interstitial, thus wound hypoxia. HBOT has a bactericidal effect improving oxygen diffusion into the cell [57]. It also through the oxygen free radicals which are generated eliminates collagenase and matrix metalloproteinase along with increased leukocyte activity [62]. Clinical (MMP) enzymes that are increased in chronic wounds evidence strongly emphasize the role of HBOT in which hinder wound healing and is one of the most reducing the risk of amputation in patients with DFU effective current strategies in reducing the risk of compared to those managed without HBOT (13.63% amputation and improving healing rates in patients versus 30.07%) [63]. with DFUs [9]. A more recent meta-analysis of 11 RCTs further supported the use of NPWT in the Low-level laser therapy in wound healing: management of patients with DFUs [61]. Low level laser therapy (LLLT) or low-intensity laser therapy (LILT) is also known as cold laser Hyperbaric oxygen therapy (HBOT): therapy, photobiomodulation, or monochromatic infrared light therapy which shows positive effect on

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Citation: Ruke MG, Savai J. Diabetic Foot Infection, Biofilm & New Management Strategy. Diab Res Open Access. 2019 Nov 11;1(1): 7-22. Original Article the three overlapping phases of wound healing which growth factors. Although, commendable efforts in can reduce inflammation, cause earlier initiation of recent years have been taken in the diagnosis and the proliferative phase, and augments the rate of treatment of DFU, it still remains a major public contraction as angiogenesis increases [62]. There are health concern. Therefore, primary prevention should also a significant number of research articles be the main strategy for reducing the burden of the describing the effects of LLLT on mast cells, diabetic foot. Despite significant medical and surgical macrophages and fibroblasts, all of which are critical improvements, more research is currently required to for optimum wound healing. Several reports & define optimal treatment approaches in clinical literature suggests that most chronic wounds like practice. diabetic neuropathic foot ulcers, pressure ulcers, venous insufficiency and arterial insufficiency respond References well to this treatment intervention (Fig-9) [62,64]. [1] Toniolo A, Cassani G, Puggioni A, Rossi A, Colombo A, Onodera T, Ferrannini E. The diabetes pandemic and associated infections: suggestions for clinical microbiology. Rev Med Microbiol. 2019 Jan;30(1):1-17. [PMID: 30662163] [2] Mendes JJ, Neves J. Diabetic Foot Infections: Current Diagnosis and Treatment. The Journal of Diabetic Foot Complications. 2012;4(2):26-45. [3] Alavi A, Sibbald RG, Mayer D, Goodman L, Botros M, Armstrong DG, Woo K, Boeni T, Ayello EA, Kirsner RS. Diabetic foot ulcers: Part I. Pathophysiology and prevention. J Am Acad Dermatol. 2014 Jan;70(1):1.e1- Fig-9: 18. [PMID: 24355275] Multi-cluster diode probe for use in low-level laser [4] Wang A, Xu Z, Mu Y, Ji L. Clinical characteristics therapy for wound healing. and medical costs in patients with diabetic amputation

and nondiabetic patients with nonacute amputation in Conclusion central urban hospitals in China. Int J Low Extrem The incidences of DFUs are increasing and require Wounds. 2014 Mar;13(1):17-21. [PMID: 24659623] a high cost of care; since, it often takes long time to [5] Gibbons GW, Marcaccio EJ, Habershaw GM. heal due to polymicorbial infection & biofilm Management of diabetic foot. In: Callow AD, Ernst CB, complication. DFU, if not managed well can lead to eds. Vascular surgery: theory and practice. amputation in several cases and thus exacerbating Connecticut: Appleton and Lange. 1995:167-79. patients quality of life. Wound healing requires [6] Rutherford RB. Recommended standards for infection control, inflammatory repair, regeneration of reports on vascular disease and its management. connective tissue matrix, & finally wound constriction Vascular surgery: theory and practice. Stamford, and re-epithelization. Infection control & Appleton& Lange. 1995:1145-59. inflammatory repair can be achieved successfully with [7] American Diabetes Association. Consensus the use of appropriate topical &/or systemic Development Conference on Diabetic Foot Wound antimicrobials. However, while managing wounds Care: 7-8 April 1999, Boston, Massachusetts. American complicated with biofilm, a newer generation iodine Diabetes Association. Diabetes Care. 1999 formulation, cadexomer iodine could be the first-line Aug;22(8):1354-60. [PMID: 10480782] treatment option in addition to debridement. [8] Terashi H, Kitano I, Tsuji Y. Total management of Subsequently, regeneration of connective tissue diabetic foot ulcerations--Kobe classification as a new matrix, & finally wound constriction and re- classification of diabetic foot wounds. Keio J Med. epithelization can be aided with newer treatment 2011;60(1):17-21. [PMID: 21460599] strategies like HBOT, NPWT & use of epidermal [9] Rosyid FN. Etiology, pathophysiology, diagnosis

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Keywords: Diabetic foot ulcer (DFU); Neuropathy; Biofilm; Cadexomer Iodine; Negative Pressure Wound Therapy (NPWT); Hyperbaric Oxygen Therapy (HBOT) Manuscript no: DROA-1-7-22 Volume: 1 Issue: 1 22 Diab Res Open Access