The Art to Manage diabetic Foot Infection Focus : on Ertapenem (INVANZ®)

The Art to Manage diabetic Foot Infection
Focus : on Ertapenem (INVANZ®)

Diabetes is a serious chronic disease. In 2003 the global prevalence of diabetes was estimated at 194 million. This figure is predicted to reach 333 million by 2025 as a consequence of longer life expectancy, sedentary lifestyle and changing dietary patterns. This rise is to bring a proportional increase in the people with diabetes complications, including problems of the foot.
Diabetes mellitus is a disorder that primarily affects the microvascular circulation. In the extremities, microvascular disease due to "sugar-coated capillaries" limits the blood supply to the superficial and deep structures. Pressure due to ill-fitting shoes or trauma further compromises the local blood supply at the microvascular level, predisposing the patient to infection. The infection may involve the skin, soft tissues, bone, or all of these tissues. Diabetes also accelerates macrovascular disease, which is evident clinically as accelerating atherosclerosis and/or peripheral vascular disease.

Infection is a common and serious complication of diabetic foot wounds. Infection leads to formation of microthrombi, causing further ischemia, necrosis, and progressive gangrene. Massive infection is the most common factor leading to amputation. Response to infection is often altered in the patient with diabetes. Infection-fighting capability is often diminished because of impaired leukocyte function. Aerobic gram-positive staphylococci and streptococci usually are the cause of infection; however, gram-negative organisms are frequently present as well. Anaerobic infection is common. The serious infections in their series were polymicrobial. Antibiotic therapy with a broad spectrum antibiotic should begin immediately after cultures have been obtained; the antibiotic can then be adjusted based upon the sensitivities of the causative organisms. Many diabetic foot infections contain gram-negative organisms; therefore, the initial antibiotic chosen should be effective against gram-negative as well as gram-positive organisms.
Ertapenem could be consider antibiotic in diabetic foot infection based on the results of the SIDESTEP study, the largest prospective, randomized and double-blind clinical trial ever conducted in diabetic patients with moderate to severe complicated foot infection. Ertapenem, a garbapenem related to class of antibiotics known as beta lactams is 1 gram dose, once-daily, parenteral group 1 carbapenem. Ertapenem (INVANZ®) is indicated for the treatment of moderate to severe complicated skin and skin structure infections including diabetic foot infections without osteomyelitis


Introduction
Diabetes is a serious chronic disease. In 2003 the global prevalence of diabetes was estimated at 194 million. This figure is predicted to reach 333 million by 2025 as a consequence of longer life expectancy, sedentary lifestyle and changing dietary patterns. This rise is to bring a proportional increase in the people with diabetes complications, including problems of the foot.
People with diabetes are at risk of nerve damage (neuropathy) and problems with the blood supply to their feet (ischemia). Both neuropathy and ischemia can lead to foot ulcers and slow-healing wounds which, if they get infected, may result in amputation. Diabetic foot ulcers as a result of neuropathy or ischemia are common. In developed countries, up to five per cent of people with diabetes have foot ulcers, and one in every six people with diabetes will have an ulcer during their lifetime. Foot problems are the most common cause of admission to hospital for people with diabetes. Without action, global amputations rates will continue to rise. Extensive epidemiological surveys have indicated that between 40% and 70% of all lower extremity amputations are related to diabetes. This means that every 30 seconds a lower limb is lost to diabetes. The vast majority (85%) of all diabetes-related amputations are preceded by foot ulcers(Gachi,2005; Geurini, 2005) .
In most cases, however, diabetic foot ulcers and amputations can be prevented. It is imperative, healthcare professionals, policymakers and diabetes representative organizations undertake concerted action to ensure that diabetic foot care is structured as effectively as local resources will allow. The
improvements in foot care for people with diabetes bring about a reduction in diabetic-foot-related morbidity and mortality.
In this article will explain diabetic foot infection in some topics that includes: pathophysiology diabetic foot, management diabetic foot, management infection in diabetic foot and ertapenem treatment in diabetic infection.


Pathophysiology
Diabetes mellitus is a disorder that primarily affects the microvascular circulation. In the extremities, microvascular disease due to "sugar-coated capillaries" limits the blood supply to the superficial and deep structures. Pressure due to ill-fitting shoes or trauma further compromises the local blood supply at the microvascular level, predisposing the patient to infection. The infection may involve the skin, soft tissues, bone, or all of these tissues. Diabetes also accelerates macrovascular disease, which is evident clinically as accelerating atherosclerosis and/or peripheral vascular disease. Most diabetic foot infections occur in the setting of good dorsalis pedis pulses; this finding indicates that the primary problem in diabetic foot infections is microvascular compromise. Impaired microvascular circulation hinders white cell migration into the area of infection and limits the ability of antibiotics to reach the site of infection in an effective concentration. Diabetic neuropathy may be encountered in conjunction with vasculopathy. This may allow for incidental trauma that goes unrecognized (eg, blistering, penetrating foreign body) (Ganchi,2005, Giurini, 2005).
Figure.1. The various pathways and contributing factors leading to diabetic foot ulceration.


Peripheral Arterial Disease
The atherosclerotic plaques that occur in patients with diabetes are no different than those occurring in the nondiabetic. Patients with diabetes should have a vascular examination at least once a year, while those who have evidence of PAD should be examined at least every 4 months. The most important steps in evaluating PAD are a medical history and a thorough vascular examination. In general, a history of intermittent claudication is one of the first symptoms of vascular insufficiency. Because of loss of sensation, however, diabetic patients may have ischemia without symptoms(Frykberg,2000). Coldness of the foot and absence of pulses are hallmark clinical signs of PAD, as are shiny, atrophic skin and loss of hair. When the medical history and physical examination reveal signs or symptoms of ischemia, the vascular laboratory can be of help. Patients with diabetes may have normal ankle pressures but significantly decreased toe pressures. It is extremely important, therefore, to measure toe pressures in patients with diabetes. Arterial waveforms as well as segmental pressures help to indicate areas of arterial narrowing. Further noninvasive testing is warranted. Noninvasive arterial studies (NIAS) should be performed to determine lower extremity
perfusion. Such studies may include Doppler segmental arterial pressures, and waveform analysis, ankle-brachial indices (ABI), toe pressures, and transcutaneous oxygen tension (TcPO2) (Frykberg, 2000). Ankle-brachial indices may be misleading since ankle pressures can be falsely elevated due to medial arterial calcinosis and noncompressibility of affected arteries . A growing body of evidence suggests that toe blood pressures may have a role in predicting those diabetic patients at risk for foot ulceration as well as
in the prediction of successful wound healing. Transcutaneous oxygen tension measurements have received similar support in the literature. Although not consistently predictive of wound healing outcomes, these physiologic measures of tissue oxygenation are highly predictive of wound healing failure at levels below 25 mm Hg.(Frykberg,2000)


Peripheral Neuropathy
Peripheral neuropathy with loss of sensation is the major cause of diabetic foot ulcers and amputation. Although the exact etiology of PN is unknown, it is probably the result of a combination of metabolic events, including the accumulation of glucose, sorbitol, and fructose in the nerve; a decrease in myo-inositol, which is important for nerve conduction; and ischemia due to narrowing of the vessels in the vasa nervorum. Patients with diabetes should undergo examination of the peripheral nerves at least once a year. Loss of the Achilles tendon reflex and vibratory sensation are the earliest symptoms of PN. Although these symptoms usually occur together, they can occur independently(Ganchi,2005, Giurini, 2005).
The most important neurologic finding in PN is the loss of protective sensation. The use of a pinprick to assess sensation is outdated. Sensation assessments are now carried out using the Semmes-Weinstein 5.07 monofilament. This simple device is pressed against the skin until it buckles; the amount of pressure is equal to 10 grams of linear strength. Inability to perceive pressure at this level indicates severe PN and puts the patient at high risk for the development of foot ulcers. This is a simple test that the patient can do at home and it is currently believed to be the most practical method of risk assessment for PN (Levin, 2002; Ganchi,2005, Giurini, 2005).
Foot deformities are notoriously common in the diabetic patient with PN. Patients with diabetes are prone to having cocked-up toes, hammer toes, and/or claw toes. These deformities are frequently associated with thinning or shifting of the fat pad under the metatarsal heads. The areas at the top of the toes, the tips of the toes, and under the metatarsal heads are therefore vulnerable to ulceration, infection, and, subsequently, osteomyelitis, gangrene, and amputation. The ideal treatment is prophylactic surgery to straighten the toes while circulation is good. When surgery is not possible, the patient should wear a shoe with a large toe-box to accommodate the cocked-up toes and/or an in-depth shoe with a cushioned insole to reduce the pressure over the metatarsal heads and the tips of the toes. This will decrease the probability of ulceration in those areas(Ganchi,2005, Giurini, 2005).


Charcot's foot is the classic diabetic foot deformity. Patients with this deformity frequently present with bounding pulses in a swollen, red, warm foot. The patient often gives a history of having sustained a sprain or minor injury to the ankle or foot a few days to a week before the development of swelling and erythema of the foot. These signs represent the acute onset of the Charcot foot. Despite these changes in the foot, there is only minimal discomfort. At this acute stage, the presence of cellulitis must be ruled out. Radiographs taken at this time usually reveal no abnormalities. The classic history of minor trauma, the absence of any portal of entry for infection, and the absence of other clinical signs or laboratory findings of infection are highly suggestive that the patient has an acute Charcot's foot(Levin, 2002; Ganchi,2005, Giurini, 2005).
Failure to recognize the acute stage of Charcot's foot is not uncommon. These patients frequently are treated for months with a variety of antibiotics until finally the foot collapses. At that time, the correct diagnosis is made, usually as a result of x-rays. The end result is a foot that is vulnerable to ulceration. Failure to diagnose the Charcot's foot in a timely fashion frequently leads to a malpractice suit for substandard care. Adapted from Levin and O'Neal's The Diabetic Foot.(Levin,2002]
Classification of Ulcers
Appropriate classification of the foot wound is predicated upon its thorough assessment, should facilitate its treatment, and be generally predictive of expected outcomes. Several systems of ulcer classification are currently in use an attempt to meaningfully describe these lesions and to communicate severity. Perhaps the easiest system is to simply classify the lesions as neuropathic, ischemic, or neuroischemic with descriptors of wound size, depth, and infection. Regardless of which system is ultimately used, the clinician must be able to easily categorize the wound and, once classified. Although no single system has been universally adopted, the classification system most often used was described and popularized by Wagner. Since system fails to consider the important roles of infection, ischemia and other comorbid factors, subsequent authors have modified the classification systems by including descriptors for these considerations. Another hybrid method for classifying diabetic foot lesions has been popularized by the University of Texas and has been retrospectively validated within that center. This scheme employs
four grades of depth with four associated stages based on ischemia, infection, or both (Frykberg,2000; Amstrong, 2005).


Table 5 University of Texas Wound Classification System
Management
The steps in the management of diabetic foot ulcers and notes the impediments to wound healing in the diabetic patient, all of which must be considered in planning a management strategy. The first step in management of the ulcer is to establish its size and depth; what appears to be a superficial ulceration may be only the tip of the iceberg. Penetration may extend deep into the tissues.
Step treatment of Foot Ulcers (Levin,2002):
1. Evaluation:
a. Clinical appearance
b. Establish for depth
c. X-ray for: Osteomyelitis, Foreign objects, Subcutaneous air
d. Biopsy if indicated
2. Metabolic control
3. Debridement, sharp radical
4. Bacterial cultures (aerobic, anaerobic)
5. Antibiotics: Oral, Parenteral
6. Do not soak the feet
7. Do not use whirlpool
8. Non-weight-bearing :Bed rest,Crutches,Walkers, Contact casting, Special shoes
9. Improve circulation (vascular surgery)
10. Consultation
Impediments to Wound Healing :
1. Vascular :Atherosclerosis, Increased viscosity
2. Neurologic: insensate foot
3. Infection: Inadequate debridement, Poor blood supply, Microthrombi, Hyperglycemia, Decreased neutropil function, Polymicrobial infection, Changing bacterial flora,and Osteomyelitis
4. Immunosuppression
5. Mechanical : Edema, Weight bearing
6. Poor nutrition: Low serum albumin
7. Poor patient compliance
8. Delayed treatment and referral
9. Managed care
Radiographs are necessary to rule out osteomyelitis, gas formation, the presence of foreign objects, and asymptomatic fractures. Previously unrecognized traumatic fractures were found in 22% of patients with neuropathic foot ulceration. Radiographs should, therefore, be taken of any foot with ulceration or infection. Neuropathic ulcers should be aggressively debrided by sharp dissection, with removal of all necrotic material and eschar. Not infrequently, there is infection beneath the eschar; the infection must be identified so that it can be treated. Removal of eschar in a patient with severe PAD should be done cautiously, since healing can be significantly impaired.
Debridement of a diabetic foot ulcer should be carried down to healthy, bleeding tissue. After debridement, the ulcer will probably be larger than it was at presentation. Whirlpool is not an effective method of debridement. Enzymatic debridement will be superficial. Debridement using maggots is an old form of treatment used for centuries by military surgeons. It was introduced to the civilian population in the 1930s, and recent reports have again suggested the effectiveness of maggots in cleansing wounds. When
the foot is insensitive, minor sharp debridement can be carried out at the bedside. In many cases, however, the patient must be taken to the operating room for adequate debridement under anesthesia (Levin, 2002).
Infection
Infection is a common and serious complication of diabetic foot wounds. Infection leads to formation of microthrombi, causing further ischemia, necrosis, and progressive gangrene. Massive infection is the most common factor leading to amputation. Response to infection is often altered in the patient with diabetes. Infection-fighting capability is often diminished because of impaired leukocyte function. Impaired leukocyte function is significantly influenced by the degree of hyperglycemia; therefore, tight blood glucose control is extremely important when infection is present. In addition, patients with diabetes and severe foot infection often do not respond to the infection with elevation of body temperature and/or white blood cell (WBC) count. Elevated sedimentation rates, the mean WBC count was 9,700/102/mm3, the absence of temperature elevation, chills, or leukocytosis in two thirds of the patients with limb-threatening infection, including abscesses and extensive soft tissue infection. The clinician should not depend on elevated WBC counts and/or temperature elevation alone as indications of the severity of a diabetic foot infection.


Aerobic gram-positive staphylococci and streptococci usually are the cause of infection; however, gram-negative organisms are frequently present as well. Anaerobic infection is common. The serious infections in their series were polymicrobial ; 72% of organisms cultured were gram-positive and 49% were gram-negative (Citron, 2007). Culturing technique is extremely important in cases of diabetic foot infection. Simply swabbing the ulcer is not satisfactory and frequently produces inaccurate results. Specimens for culture should be obtained from tissue deep in the wound after debridement. Cultures should be obtained anaerobically as well as aerobically. Antibiotic therapy with a broad spectrum antibiotic should begin immediately after cultures have been obtained; the antibiotic can then be adjusted based upon the sensitivities of the causative organisms. Many diabetic foot infections contain gram-negative organisms; therefore, the initial antibiotic chosen should be effective against gram-negative as well as gram-positive organisms. Selection of an oral or a parenteral antibiotic for treatment of a diabetic foot infection must be based upon medical judgment (Ganchi,2005; Sentohnic,2005).


If an oral antibiotic is selected, it is not advisable to simply instruct the patient to take the medication and return in a week. In the diabetic patient, infection can progress significantly in just 24 to 48 hours.The diabetic patient taking oral antibiotic therapy should therefore be seen within a few days after initiation of therapy. In addition, the patient must be instructed to notify the physician at once if any increase in redness or drainage or any evidence of lymphangitis is noted. While many of these patients have insensate feet, the development of pain is indicative of deep infection and requires immediate attention. The development of a foul odor also indicates worsening infection and may indicate the presence of anaerobes. It is important that diabetic patients with infection monitor their blood glucose levels closely, since rising blood glucose levels strongly suggest worsening infection, even when other signs and symptoms are absent(Ganchi, 2005; Citron, 2007).
The criteria for hospitalization and treatment with parenteral antibiotics include sepsis, leukocytosis, PAD, and uncontrolled diabetes. Another indication for immediate hospitalization is when what appears to be a minor infection on the plantar surface of the foot is accompanied by erythema and edema of the dorsum of the foot. When such signs are present even though the patient is not septic, there is a high probability that the infection has penetrated deep into the tissues and has spread to the dorsum of the foot. Such infections require incision, drainage of probable abscess, debridement, administration of parenteral antibiotics, and tight blood sugar control (Giurini, 2005).
When infection fails to respond to aggressive treatment, the wound should be debrided and recultured, since the flora may have changed. Chronic, recurrent, or treatment-resistant infection suggests the presence of osteomyelitis. Osteomyelitis is a frequent complication of diabetic foot ulcers and infection, but it may be difficult to detect on a clinical basis. In fact, Newman found that only one third of biopsy-proven cases of osteomyelitis had been clinically suspected (Levin, 2002). If bone is visible or if the ulcer can be probed to the bone, the probability of osteomyelitis is high. Scanning techniques for osteomyelitis are not always successful. The triple-phase scan with technetium lacks specificity, but scanning with indium 111 is highly specific. Magnetic resonance imaging (MRI) is a helpful technique(Fyeberkg, 2000). Although soaking of the feet has been a traditional approach to treatment, it is of no benefit; in fact, it can lead to maceration and worsening infection. Because the foot is insensitive, soaking may take place in
water that is too hot, resulting in severe burns. Chemical soaks can result in chemical burns. Soaking the feet or using the whirlpool delays appropriate and aggressive therapy (Levin, 2002; Giurini, 2005).
Edema is frequently present and can contribute to vascular insufficiency by compressing the capillaries. Elevation of the feet to the thickness of one pillow can be beneficial, but higher elevation may impede circulation. Careful compression may be helpful.
The worst impediment to wound healing or clearing of infection in the diabetic patient is vascular insufficiency. When an ulcer does not heal despite good metabolic control, adequate debridement, parenteral antibiotic therapy, and avoidance of weight bearing, vascular insufficiency should be suspected as the reason. In a study conducted by Mills et al, all appropriately treated neuropathic ulcers and forefoot infections healed in patients with palpable pedal pulses. When foot pulses were absent and arteriography confirmed significant stenosis, foot lesions and infections healed with revascularization (Ganchi, 2005; Levin, 2002). Ankle/brachial indices of less than 0.50 and transcutaneous oxygen pressures of less than 30 mm Hg are highly predictive of infections that will not resolve and ulcers that will not heal. Vascular surgery should be considered in these cases.
Antibiotics
Appropriate monotherapy for cellulitis includes cefazolin or clindamycin. Although gram-negative organisms are the unusual causes of cellulitis, even in diabetes, if they are suspected, a fluoroquinolone (eg, levofloxacin) may be used in conjunction with clindamycin (Gadepelli, 2006; Lily,2008; Cunha, 2008). Aerobic gram-positive staphylococci and streptococci usually are the cause of infection; however, gram-negative organisms are frequently present as well. Anaerobic infection is common. The serious infections in their series were polymicrobial
In patients with diabetes, deep skin and severe soft tissue infections are usually due to mixed aerobic and anaerobic organisms (Freyberk, 2000,Cunha, 2008). These infections may be treated with monotherapy involving meropenem or piperacillin and tazobactam. Alternatively, clindamycin plus levofloxacin or metronidazole may be used.
Acute osteomyelitis, which usually is due to S aureus, may be treated with cefazolin, clindamycin, and an antistaphylococcal penicillin (eg, nafcillin). In chronic osteomyelitis, coverage must be directed against S aureus, group A and group B streptococci, aerobic gram-negative bacilli (excluding P aeruginosa), and B fragilis. Monotherapy for chronic osteomyelitis may include ampicillin and sulbactam, piperacillin and tazobactam, or meropenem. In chronic osteomyelitis, antimicrobial therapy without adequate debridement does not eliminate the infection.
Ertapenem in diabetic foot infection
To help curb antibiotic resistance, however, authorities have urged doctors to avoid long-term use of overly broad-spectrum therapy and to consider narrowing the regimen when culture and sensitivity results are available. Ertapenem could be consider antibiotic in diabetic foot infection based on the results of the SIDESTEP study, the largest prospective, randomized and double-blind clinical trial ever conducted in diabetic patients with moderate to severe complicated foot infection. Ertapenem, a garbapenem related to class of antibiotics known as beta lactams is 1 gram dose, once-daily, parenteral group 1 carbapenem. Ertapenem (INVANZ®) is indicated for the treatment of moderate to severe complicated skin and skin structure infections including diabetic foot infections without osteomyelitis due to Staphylococcus aureus (methicillin susceptible isolates only), Streptococcus agalactiae, Streptococcus pyogenes, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Bacteroides fragilis, Peptostreptococcus species, Porphyromonas asaccharolytica, or Prevotella bivia. In SIDESTEP study show clinical and microbiological outcomes for patients treated with ertapenem were equivalent to those for patients treated with piperacillin/tazobactam, suggesting that this once-daily antibiotic should be considered for parenteral therapy of diabetic foot infections, when deemed appropriate ( FDA,2005;Lipsky, 2005).


Reference
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