Antimicrobial Therapy for Complicated Skin and Skin Structure Infections in Diabetes

Wanda C. Reygaert Department of Biomedical Sciences

Oakland University William Beaumont School of Medicine, USA

1 Introduction

Diabetic patients may have a higher risk for certain types of bacterial infections. While there are a large number of possible sites of infection on the body, these infections most frequently are found in skin and skin-structures (and may extend deeper into the soft tissues), and in diabetics commonly occur in the lower extremities. Up to 25% of adult diabetics can expect to develop a foot infection in their lifetime, and the risk increases with age and/or the length of time that they have had diabetes. These infections usually result in major increases in healthcare costs and morbidity and mortality rates. Any type of injury that damages the skin, or undergoing surgery, greatly increases the risk of infection. Conditions that may predispose a diabetic patient to foot infections include poor blood glucose control, peripheral neuropathy, and peripheral vascular disease. Foot infections may eventually lead to amputation. These foot infections commonly become classified as complicated skin and skin-structure infections. Skin and skin-structure infections are generally classified into four levels, with level 1 considered to be uncomplicated, up to level 4 considered as the most severe complicated infections. In addition, diabetic foot wounds have de-fined classification systems. The most common bacteria isolated from foot infections in diabetics are gram-positive cocci. More severe foot infections tend to be polymicrobial, and in addition to gram-positive cocci, isolates may be members of the gram-negative Enterobacteriaceae, or even anaerobes. These foot infections in diabetics can become serious in a short amount of time if appropriate treatment is not given promptly. As with most infections, there is a major concern about antimicrobial-resistant bacte-ria being present in diabetic infections, which add to the length of infections and cause an increase in treatment costs. Healthcare professionals are looking at the newer antimicrobial drug options to help eliminate these problems.

It has recently been estimated that by 2030 as many as 500 million people worldwide will have diabetes (Whiting et al., 2011). In spite of government initiatives, such as Healthy People 2010, to im-prove health and lower the incidence of disease, the prevalence of diabetes in the U.S alone has risen from 18.2 million (6.3% of the population) in 2002 to 25.8 million (8.3% of the population) in 2010 (CDC, 2012; NDIC, 2012). In England, in 2009, the prevalence of diabetes was 5.4% (NICE, 2011).

2 Increased Cost, Morbidity, and Mortality

The cost of diabetes in the U.S. alone has risen dramatically in the last 20 years, from $92 billion ($45 billion in direct healthcare related costs, $46 billion in indirect costs for disability, work loss, and prema-ture mortality) in 1992, to $132 billion ($92 billion in direct costs, $40 billion in indirect costs) in 2002, to $174 billion ($116 billion direct and $58 billion indirect costs) in 2007 (ADA, 2008; CDC, 2012; Javitt & Chiang, 1995; NDIC, 2012). An estimated 284,00 deaths in the U.S. were attributed to diabetes in 2007 (ADA, 2008). Hyperglycemia correlates directly to increased costs. A 3-year study shows that medical costs increased by approximately 30% as the A1c value increased from 6% to 10% (Gilmer et al., 2005).

Of skin and skin-structure infections, the most common type in diabetics is foot infections (ul-cers). In complicated foot ulcers, the presence of neuropathy and ischemia result in decreased ability to heal, and increased tissue death. If the ulcer does not heal quickly (becomes chronic), the tissue death may continue until amputation is necessary. In 2008, in the U.S., the estimated cost of caring for a diabet-

ic foot ulcer for a 2-year period was approximately $45,000 (Snyder & Hanft, 2009). A study conducted in 2003 and 2004 in ten European countries found that the average direct cost per foot ulcer episode was as high as $23,000 (Prompers et al., 2008).

A study reported in 2004 compared the costs of lower extremity amputation in six countries: Bel-gium, Netherlands, Sweden, Switzerland, U.K., and U.S. The average extra cost of an amputation was between $30,000 and $33,500 (Ragnarson Tannvall & Apelqvist, 2004).

By 2009, in the U.S., the 5-year mortality rate of diabetic patients with a complicated foot ulcer was higher than that for breast, colon, or prostate cancer. The 10-year mortality rate, by 2009, for diabetic patients with a foot ulcer was 49% compared with 10.5% for nondiabetics (Snyder & Hanft, 2009).

3 Risk of Infection

There are a variety of reasons why diabetic patients may have a higher infection rate. The excess glucose that is present in the blood stream of a diabetic patient may result in impaired microvascular circulation and/or peripheral motor neuropathy. These conditions make it difficult for the skin and skin-structures to heal in the event of damage. Therefore, infected tissues do not heal as easily in diabetic patients. Neurop-athy is common in the lower extremities of diabetics. Untreated or improperly treated or monitored infec-tions in the lower extremities lead to an increased incidence of amputations in diabetics. In 2006, approx-imately 65,700 people with diabetes in the U.S. underwent a nontraumatic lower-limb amputation (NDIC, 2012). In a study conducted in France, it was found that 52% of patients undergoing lower limb amputation were diabetic (Fosse et al., 2009). Table 1 shows the increased risk factors for some of the more common infections that may affect diabetics (Boyko & Lipsky, 1995; Calvet & Yoshikawa, 2001; Shah & Hux, 2003; Muller, et al., 2005; Koh, et al., 2012).

Type of Infection Increased risk in diabetics Respiratory Infections community-acquired pneumonia

1.3-1.5

Gastrointestinal Infections cholecystitis

1.6

Urinary Tract Infections (especially in women) cystitis pyelonephritis

1.3-3 1.4 2-5

Skin and Soft Tissue Infections foot infections necrotizing fasciitis Fournier's gangrene

1.4-1.9 9.3 3

1.5

Table 1: Increased risk for certain infections in diabetics.

3.1 Hyperglycemia

One issue with too much glucose in the blood or tissues is the fact that many microorganisms prefer glu-cose for use in metabolism, so more glucose helps them establish colonization at a more rapid rate. In addition, the presence of high glucose levels is harmful itself. The types of negative effects of hypergly-

cemia may involve several aspects of the immune system which decrease the body's ability to fight off invading microorganisms. These effects include inhibiting leukocyte function, chemotaxis, and phagocy-tosis (Chin-Hong 2006; Ellger et al., 2006; McManus et al., 2001; Turina et al., 2006; van Känel et al., 2001). Other negative immune effects include malfunctioning of the complement cascade and cytokines (Koh et al., 2012; Shilling & Raphael, 2008). Hyperglycemia has also been found to have a proinflamma-tory effect, because of an increase in levels of IL-6, IL-8, and TNF-α (Koh et al., 2012; Shilling & Raph-ael 2008; Weekers et al., 2003).

3.2 Peripheral Vascular Disease

The initial damage to the vascular system is most likely a result of the increased levels of proinflammato-ry molecules along with increased production of nitric oxide by the endothelium cells. Oxidation of the excess glucose increases the formation of reactive oxygen species which damage the endothelium (Cam-eron et al., 2001; Christopherson, 2003; King, 2001). During hyperglycemic episodes there is non-enzymatic production of advanced glycation end-products (AGEs) which then accumulate on proteins in the microvascular cell walls resulting thickening of the basement membrane (Christopherson, 2003; King, 2001; Shimizu et al., 2011). This thickening eventually alters the membrane charge and permeabil-ity of capillaries is increased, resulting in edema. Tissue edema is a result of hyperglycemia causing con-version of glucose to sorbitol in the endothelial cells (sorbitol is not able to diffuse across the cell mem-brane, so water moves into the cell). The thickening of the basement membrane also results in a reduced response to tissue injury because of the decreased ability of white blood cell movement and function (Christopherson, 2003; King, 2001). Collagen can also undergo non-enzymatic glycosylation by AGEs which can result in stiffening of connective tissue around joints, and decreased joint mobility (Chris-topherson, 2003; Merza & Tesfaye, 2003).

3.3 Peripheral Neuropathy

Up to 50% of Type II diabetics experience significant neuropathy. Neuropathy can affect the eye (caus-ing blindness), the kidney (end-stage renal disease), and the skin. The neuropathy may present as painful, but perhaps the most dangerous type presents with a loss of sensation. This loss of sensation increases the risk of unnoticed injuries and friction damage to the skin, which in turn open up a pathway for bacteria to invade and cause infection. Patients who are not feeling any pain, etc. are less likely to think that there is anything wrong, and so less likely to do regular skin assessments, or have reason to seek medical atten-tion. Another result of neuropathy may be a reduction in sweat production. This results in skin that is vulnerable to cracking because it is too dry (Merza & Tesfaye, 2003). Peripheral neuropathy (PNP) can be a caused by a decrease in microvascular blood flow and the resulting endoneural hypoxia (Cameron et al., 2001).

4 Classification of Infections

To better understand the problem of skin and skin-structure infections in diabetes, it is useful to know how these types of infections are classified. Skin and skin-structure infections are generally classified into four levels, with level 1 considered to be uncomplicated, and levels 2, 3, and 4 considered to be complicated infections (Eisenstein, 2008; Reygaert, 2012). Because diabetics have a greater risk of de-

veloping an infection and a reduced ability for wound healing, they quite often suffer with complicated skin and skin-structure infections. These complicated infections are most frequent in the lower extremi-ties. Complicated skin and skin-structure infections (cSSSIs) are generally described as infections that have moved from the skin deeper into structures such as the muscles or fascia, and/or those infections that require surgical intervention (Fung et al., 2003; Reygaert, 2010). These cSSSIs are also more likely to be polymicrobial, or contain antimicrobial resistant microorganisms (May et al., 2009; Reygaert, 2010).

4.1 Diabetic Foot Infections (DFIs)

Diabetic foot wounds have defined classification systems. Two commonly used classification systems are the Wagner system and the University of Texas system. These systems are based on the size and depth of the wound (ulcer), plus the presence of neuropathy, vascular disease, and infection. These systems may help to predict clinical outcome (Oyibo et al., 2001). The Infectious Diseases Society of America (IDSA) and the International Working Group on the Diabetic Foot (IWGDF) have also published guidelines for classification of these infections. The wounds are first assessed for signs of inflammation and purulent secretions. Those considered to have signs of infection are then classified on the basis of size and depth of the infection plus signs of systemic involvement, into mild, moderate, or severe infections (Lavery et al., 2007). Complicated DFIs quite often present as cellulitis. If the infection is not treated promptly, or with the appropriate antimicrobial therapy, it may escalate into a much more severe infection such as ne-crotizing fasciitis (including Fournier’s gangrene), and eventually osteomyelitis. Once an infection reaches the bone, amputation is a likely outcome.

4.2 Necrotizing Fasciitis

Necrotizing fasciitis is uncommon, but is a rapidly progressing and life threatening condition, especially for patients who are diabetic. It is common for necrotizing fasciitis to be initiated from an already present skin wound, such as a diabetic foot ulcer (Austgarden & DiDiodato, 2009). Necrotizing fasciitis, then, usually presents with typical signs of inflammation, such as swelling, pain, and erythema at the site (Hasham et al., 2005; Wong et al., 2003). Necrotizing infections can be classified into three groups based on level of tissue involved: necrotizing cellulitis (skin and subcutaneous tissue) - superficial, necrotizing fasciitis (deep fascia and nearby tissues), and myelonecrosis (muscle necrosis) - deep. These infections can also spread to the surrounding muscle (myonecrosis) or penetrate further into the bone to cause oste-omyelitis (Aragon-Sanchez & Lázarro-Martinez, 2011). A study of patients with necrotizing fasciitis in Singapore, between 1997-2002, showed that almost 71% of the patients also had diabetes. The most common site of the infection was in the lower limbs (nearly 70%). When amputation was necessary to control the infection, nearly 90% of the amputations were in patients with diabetes (Wong et al., 2003). Infections in necrotizing fasciitis are most often polymicrobial, and usually a mixture of aerobic and an-aerobic microorganisms (Hasham et al., 2005; Hsaio et al., 2008). Mortality from necrotizing fasciitis varies greatly, and averages around 25% (Hsaio et al., 2008).

4.3 Fournier’s Gangrene

Fournier's gangrene is a very rare form of necrotizing fasciitis that is also rapidly progressive. It is usual-ly found in the genital, perianal, and perineal areas, but may spread to the abdomen, legs, or thorax. The

most common symptoms are erythema, pain, and swelling in the infected area. Studies have shown that it more commonly affects males, with up to 90% of the patients being male. As many as 66% of sufferers also have diabetes. The mortality rate is high, varying greatly (20-43%), but doesn't appear to be higher for diabetics than nondiabetics (Chen et al., 2010; Jeong et al., 2005; Jimenz-Pacheco et al., 2012; Kabay et al., 2008; Lujan et al., 2010; Morua et al., 2009).

4.4 Gas Gangrene

Gas gangrene is usually caused by anaerobic clostridial bacteria species (Clostridial myonecrosis).It is characterized by the bacteria producing pockets of gas in the tissues. It can spread rapidly and can be le-thal if not treated promptly. It is most commonly initiated by some sort of trauma, such as surgery, and can occur in diabetics who have intramuscular injections of insulin or other drugs (Aggelidakis et al., 2011; Brook, 2008; Kershaw & Bulstrode, 1988).

4.5 Pyomyositis

Pyomyositis is a rare primary infection of the muscle which initiates from trauma. The most common muscles infected are the quadriceps and gluteal. Sufferers often are injection drug users, and so insulin-dependent diabetics may be at risk. The infection usually begins as an abscess, but may progress to ne-crotizing fasciitis or sepsis. The most common bacterial cause is Staphylococcus aureus, with the danger that it may be a MRSA strain (Bickels et al., 2002; Ebright & Pieper, 2002; Sharma et al., 2010; Yu et al., 2004).

4.6 Osteomyelitis

Osteomyelitis in diabetic patients is usually a complication of a severe foot infection. The unchecked infection spreads from the surrounding tissue into the bone. The incidence of osteomyelitis in diabetic patients with severe foot infections has been found to be as high as 66% (Hartemann-Heurtier & Senne-ville, 2008). In diabetics, osteomyelitis most commonly is found in bones near the site of the seeding foot infection: the toes, metatarsal heads, and the heel bone (Berendt et al., 2008). Diabetic patients with oste-omyelitis have also been found to have more than 2 times the risk for amputation if they also had hyper-glycemia (Aragon-Sanchez & Lázarro-Martinez, 2011). These bone infections in diabetics are usually caused by the same microorganisms that commonly cause foot infections in diabetics. The infections are most often polymicrobial, with Staphylococcus aureus being the most common isolate (Berendt et al., 2008; Hartemann-Heurtier & Senneville, 2008).

5 Microorganisms Isolated from Complicated Diabetic Wounds

The most common cause of mild to moderate skin and skin-structure infections in diabetics are gram-positive cocci. More severe infections tend to be polymicrobial, and besides gram-positive cocci, isolates often are members of the gram-negative Enterobacteriaceae, or even anaerobes. The organism(s) isolated may vary depending on the age of the patient, the length of time that the patient has had diabetes, the type/site of infection, and even the geographic location of the patient.

5.1 Fungal Isolates

Although fungal organisms are not usually the cause of severe/complicated infections in diabetic patients, these patients are at a higher risk of developing fungal infections, especially in the nails (onychomyco-sis). The same conditions (hyperglycemia, neuropathy, resulting skin damage) that are risk factors for developing bacterial infections can also lead to fungal infections (Matricciani et al., 2011). Studies have shown an incidence of onychomycosis in diabetics between 18-26%, with the risk for onychomycosis in diabetics being nearly 3 times that for nondiabetics (Al-Mutairi et al., 2010; Matricciani et al., 2011; Robbins, 2003; Saunte et al., 2006). Diabetic patients who develop onychomycosis are also at greater risk of developing infected foot ulcers, gangrene, and osteomyelitis (Mayser et al., 2009). The most common fungal isolates from onychomycosis are dermatophytes; yeasts, especially Candida albicans, may also be the causative agents (Al-Mutairi et al., 2010; Mayser et al., 2009; Robbins, 2003; Saunte et al., 2006). Because the majority of complicated DFIs are polymicrobial, fungal organisms that originate from an earlier onychomycosis may still be present.

5.2 Necrotizing Fasciitis

Necrotizing fasciitis can be classified into types (up to four types) based on causative organisms. Type I is seen in 80% of cases, and is caused by a mixture of aerobic and anaerobic bacteria that act synergisti-cally. Type II is the next most common type (somewhat less than 20%), and is usually caused by a single organism (most often group A β-hemolytic streptococci), or sometimes, with group A streptococci and Staphylococcus aureus (Morgan, 2010; Wong et al., 2003). In diabetics these infections may be either type I or II and still be polymicrobial because diabetics are at higher risk for polymicrobial infections, and there may be bacteria present that would not be able to cause the initial infection but which opportun-istically take-up residence in the damaged tissue. Those infections in which group A streptococcus is found are the most aggressive, and have the worst prognosis (Morgan, 2010). Common isolates from polymicrobial infections may be group A streptococci, staphylococci, and may also commonly include Enterococcus, enteric gram negative bacilli (Escherichia coli, Proteus mirabilis, Klebsiella spp.), Pseu-domonas species, and anaerobes such as Bacteroides, Clostridium, and Peptostreptococcus species (Bosco Chandra Kumar et al., 2011; Elliott et al.,2000; Hsiao et al., 2008; Morgan, 2010; Wong et al., 2003).

5.3 Diabetic Foot Infections (DFIs)

Organisms isolated from DFIs may vary depending on the classification of the wound (see section 4.2). Here, we will address primarily those infections considered to be severe or complicated, which are usual-ly deep wounds, or are a result of another serious infection (such as necrotizing fasciitis). In diabetic wounds, an important issue is that of the potentially inhibited host immune response (see section 2). Some organisms might not normally be considered pathogenic because the host's immune system can keep their numbers under control; such as normal skin flora that enter wounds because of a break in the skin. Without the control exerted by the host's immune system, these bacteria may be able to colonize in much higher numbers and actually be a hindrance to wound healing. Other factors affecting the potential organisms isolated from these wounds are whether the infection is acute or chronic, and whether the pa-tient has previously been under antimicrobial therapy, which is more likely in patients with chronic wounds (Roberts & Simon, 2012).

A major part of providing proper care for complicated infections has to do with determining which organisms present are likely pathogens, and which are simply opportunistic colonizers. Acute in-fections are more likely to contain only one or fewer different types of organisms than chronic infections, which are most often polymicrobial (Powlson & Coll, 2010; Rao & Lipsky, 2007). In complicated DFIs there is also more likely to be a polymicrobial population (Armstrong, 2011). Not only is there a possible mix of pathogens and nonpathogens, there may be aerobic and anaerobic organisms present, as well as a mix of gram negative and gram positive organisms. While not all of these are potentially pathogens, some bacteria that are not dangerous when isolated alone, will work synergistically with other bacteria, and may form biofilms when they are growing together in the same wound (Brook, 2008; Citron et al., 2007; Williams et al., 2004).

There are specific organisms that are known to produce tissue damaging toxins, and so are always considered to be pathogens when isolated from complicated wounds. Two examples of these pathogens are group A β-hemolytic streptococci (GAS) and certain clostridial species. GAS organisms are often responsible for causing type II necrotizing fasciitis, and if that infection spreads to surrounding tissue, those organisms will often be isolated from severe foot infections as well (Hasham et al., 2005). The same is true of the clostridial species that can cause gas gangrene (Aggelidakis et al., 2011; Brook, 2008). Another organism that may be isolated from these diabetic foot wounds because of specific treat-ment conditions is Pseudomonas species. This organism is most likely to be found only in those wounds that are soaked in water as part of wound management (Rao & Lipsky, 2007).

The mix of different organisms that are found in polymicrobial infections varies as to patient de-mographics, but also can depend on the underlying cause of the infection (e.g. necrotizing fasciitis), and prior antimicrobial therapy. Chronic wounds that have previously been treated with antimicrobial therapy are much more likely to contain a polymicrobial population that has numerous multi-drug resistant organ-isms (MDROs) present (Rao & Lipsky 2007). In most polymicrobial infections (those that do not have conditions that foster specific organisms), the general mix of organisms is expected to be approximately two thirds gram positive to one third gram negative organisms, and two thirds aerobic to one third anaer-obic organisms (Gerding, 1995). There are, of course, many conditions that will change those mixtures of organisms, and we will consider several specific studies of diabetic foot wound isolates.

The collected results of studies on DFIs from several independent sources show variations on the expected mix of bacteria isolated (See Table 2). These studies were looking at moderate to severe infec-tions, and cover the years between 1999-2009. The results follow the general expected ratio of organisms fairly closely. There were 66.1% gram positive to 33.9% gram negative organisms, and 71.1% aerobic organisms to 28.9% anaerobic organisms. The largest variation in data is on whether the wound speci-mens were polymicrobial or not. While the average is around 52.5% polymicrobial, the range among the various studies was 40%-73% polymicrobial (Citron et al., 2007; Crouzet et al., 2011).

There can be some interesting geographical differences in isolates. A study performed in India, looking at data from 1991-2008, found that the largest percentage of isolates were gram negative bacilli, instead of gram positive cocci (57.1% to 31.3%, respectively). This study also showed very few anaero-bic isolates (<1%) (Ramakant et al., 2011). Another study performed in Taiwan, looking at data from necrotizing fasciitis infections between 2002-2005 (the majority of the patients were diabetic), found a high percentage of Vibrio species isolated. A Vibrio species was isolated from over 20% of the wound cultures, with Staphylococcus aureus (~18%) being the next most common isolate (Hsiao et al., 2008).

All of the other studies mentioned above do not include any Vibrio species isolates. These variations can have an impact on therapy, especially on initial antimicrobial therapy choices.

Organisms Percent Isolated

Gram positive aerobic cocci 51.7 Staphylococcus species 31.3 S. aureus 22.1 MSSA 18.7 MRSA 3.4 Streptococcus species 12.3 Enterococci 8.7 Gram negative aerobic bacilli 17.3 Enterobacteriaceae 11.3 Escherichia coli 2.0 Proteus mirabilis 2.0 Pseudomonas aeruginosa 3.3 Anaerobes 25.8

MSSA - methicillin-sensitive Staphylococcus aureus; MRSA - methicillin-resistant Staphylococcus aureus

Table 2: Organisms Isolated From Diabetic Foot Infections.

6 Antimicrobial Resistance Issues

The steady increase in antimicrobial-resistant bacteria has added to the severity of diabetic infections, and has made the management and treatment of these infections far more complex and costly (and with potentially greater mortality). Methicillin-resistant Staphylococcus aureus (MRSA) is of major concern, as are vancomycin-resistant enterococci (VRE), the extended-spectrum-β-lactamase(ESBL)-producing Enterobacteriaceae, and Pseudomonas aeruginosa which has innate antimicrobial resistance capabilities. The occurrence of multidrug-resistant organisms (MDROs) in DFIs can vary greatly and the incidence is increasing (Ambrosch et al., 2011; Kandemir et al., 2007; Matthews et al., 2007; Ramakant et al., 2011; Richard et al., 2008).

The Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) came out with some guidelines for the prevention of antimicrobial resistance in hos-pitals. The recommended guidelines that have shown promise for control of resistance include: restricting or eliminating the use of antimicrobials agents that have high and/or increasing resistance rates; the rota-tional use of antimicrobial agents; and the use of combinations of antimicrobial agents in therapy (Shlaes, et al., 1997). Various studies have shown that implementation of these guidelines can have a positive effect toward decreasing antimicrobial resistance (Shlaes, et al., 1997; Shlaes, 1999; Bennett, et al., 2007; Caron & Mousa, 2010).

6.1 Risk Factors for Antimicrobial Resistance in Diabetic Infections

Severe wound infections in diabetics are commonly caused by, or accompanied with, decreases in the efficiency of the microvascular circulation. This can lead to poor tissue penetration of the antimicrobial drugs being used to treat the infection (Kandemir et al., 2007). In addition, hyperglycemia, neuropathy, and changes in the microvascular circulation can lengthen the time for wound healing (see section 2). Studies have shown that the main risk factors for infections with resistant organisms in diabetics are: pri-or hospitalization (usually for treatment of the same wound), a history of inappropriate antimicrobial treatment, the wound has a chronic course, or the wound progresses to osteomyelitis (also related to depth of wound) (Hartemann-Heurtier et al., 2004; Kandemir, Richard et al., 2008). Studies have also shown that proper initial treatment and use of the appropriate antimicrobial therapy can eliminate longer healing time of wounds with MDROs (Hartemann-Heurtier et al., 2004; Richard et al., 2008).

6.2 Methicillin-Resistant Staphylococcus aureus (MRSA) in Diabetic Foot Infections

Because Staphylococcus aureus is one of the most commonly isolated organisms from DFIs, that in-creases the risk for MRSA infections as well. The number of S. aureus infection isolates that are methi-cillin-resistant has been increasing steadily for many years (Reygaert, 2009a). This increase then, can also be found in isolates from DFIs (Dang et al., 2003; Nelson, 2009). The strain of MRSA involved in the infection can have a direct impact on the outcome of treatment. While most strains of S. aureus share the same types of virulence factors, there is a difference in certain strains of MRSA. Hospital-acquired (HA-MRSA) strains are more likely to be multidrug-resistant, but contain the usual types of virulence factors. Community-acquired (CA-MRSA) strains are less likely to be multidrug-resistant, but most pro-duce an extra virulence factor, the Panton-Valentine leukocidin (PVL). This virulence factor is associated with necrotizing infections (Reygaert, 2009b).

6.3 Vancomycin-Resistant Organisms

Although members of the enterococci are not isolated frequently from DFIs, when present, there is a risk they will be vancomycin-resistant. These strains of vancomycin-resistant enterococci (VRE) are also be-coming more prevalent. Strains of S. aureus with decreased sensitivity to vancomycin are also beginning to be seen. The decreased sensitivity may be present in either of two distinct types, vancomycin-intermediate S. aureus (VISA), or vancomycin-resistant S. aureus (VRSA). The first case of VRSA de-scribed was from a diabetic foot wound. This patient had recurring foot ulcers and had prior treatment with many different antimicrobial agents (Chang et al., 2003; Matthews et al., 2007; Reygaert, 2009b).

6.4 Extended-Spectrum-β-lactamase (ESBL) Organisms

Certain members of the Enterobacteriaceae family of gram negative bacilli have been found to produce extended-spectrum-β-lactamases. This makes them virtually resistant to all of the β-lactam drugs. These organisms, usually strains of Escherichia coli or Klebsiella pneumoniae, may also be resistant to any number of other drug classes (especially frequently to the fluoroquinolones), which makes them very difficult to treat. While not isolated frequently from DFIs, in areas where gram negative bacteria are seen more frequently, extreme caution should be used in selecting antimicrobial therapy (Matthews et al., 2007; Nelson, 2009; Richard et al., 2008).

6.5 Resistance in Pseudomonas Strains

Many strains of Pseudomonas aeruginosa have natural antimicrobial resistance virulence factors. Alt-hough these strains are not isolated very commonly from DFIs, the risk is high for wounds that have been soaked as part of the therapy (Muscarella, 2004; Rao & Lipsky, 2007). The strains may be naturally re-sistant to β-lactam, aminoglycoside, and fluoroquinolone drugs, among others (Alvarez-Ortega et al., 2011; Breidenstein et al., 2008; Overhage et al., 2008; Schurek et al., 2008). In addition to the natural antimicrobial-resistance factors, these strains may also acquire other types of resistance factors, such as resistance to carbapenems (Pagani et al., 2005; Vinodkumar et al., 2011).

7 Current Antimicrobial Therapies

Traditional antimicrobial therapy is now proving to be ineffective, and new guidelines, and some of the more recently discovered drugs, are showing promise for use in these infections. The recommended an-timicrobial therapy is based on (among other things): the severity of the infection, whether the infection is monomicrobial or polymicrobial, the type of bacteria isolated (gram-positive, gram-negative, anaero-bic), and whether or not any of the isolated bacteria are resistant to any of the potential therapeutic agents.

7.1 Initial Antimicrobial Therapy

For severe/complicated DFIs it is recommended that initial antimicrobial therapy be broad-spectrum. Considerations include the fact that gram positive cocci are commonly isolated, then, is the patient from an area where gram negatives are frequently seen, does the patient have a history of antimicrobial thera-py, and does the patient have a history of MRSA infection. Additional considerations may include whether the wound has been soaked (possible Pseudomonas), and whether anaerobic organisms are commonly isolated from wounds in the area. Keep in mind that these severe infections are very likely to be polymicrobial. It may be impractical to try to provide initial therapy that would cover all possible or-ganisms. It is better to consider the patient's history and the regional data for organism’s isolation and susceptibility, and target the potentially most dangerous ones. This initial therapy should probably be parental, and then when the causative organisms have been identified, and/or when the results of suscep-tibility testing is available, the antimicrobial therapy can be adjusted accordingly. Oral therapy may not be practical initially if the patient has severe neuropathy and microvascular damage, because of consider-ations for proper tissue penetration of the drug. For patients who have not previously been treated with antimicrobials for a foot ulcer, the initial therapy is suggested to be from the more commonly prescribed broad-spectrum drugs (β-lactam/ inhibitor combination, third or fourth generation cephalosporins, etc.) More directed therapy will be necessary if antimicrobial-resistant organisms are suspected as being pre-sent (Armstrong, 2011; Lipsky et al., 2012; Rao & Lipsky, 2007; Roberts & Simon, 2012).

7.2 Specific Antimicrobial Recommendations

A large number of studies have been conducted over the last ten plus years using specific antimicrobials or combinations of these to treat DFIs. The results of these studies vary as to efficacy of treatment. The variations in treatment outcomes can usually be attributed to the variations in organisms that may be iso-

lated and the antimicrobial treatment history of the patients. The knowledge of increasing antimicrobial-resistance in organisms isolated from DFIs, means that timely susceptibility testing is crucial for making treatment recommendations. A study looking at data from two sets of patients (years 1991-1999, and 2000-2008) showed huge increases in antimicrobial-resistance from the earlier group to the later group for all eleven of the antimicrobials tested (Ramakant et al., 2011). This suggests that what was effective ten years ago is probably not going to be effective now.

General treatment suggestions for severe/complicated diabetic foot infections now include: ampi-cillin/sulbactam; clindamycin plus ceftazidime, ciprofloxacin or levofloxacin; imipenem/cilastin, pipera-cillin/tazobactam; and in very severe or life threatening infections, vancomycin plus aztreonam or ceftazidime, and if anaerobes are likely to be present, metronidazole (Lipsky, Berendt et al., 2004; Rao & Lipsky, 2007).

7.3 Newer Antimicrobial Agents

While standard antimicrobial recommendations may be proper for patients without a history of antimi-crobial treatment for foot infections, a large number of patients will have chronic or recurrent infections that have failed to respond adequately to more standard therapy. There are, fortunately, several newer antimicrobial agents that show promise for use in these infections. These include ceftaroline, ceftobi-prole, dalbavancin, daptomycin, ertapenem, iclaprim, linezolid, moxifloxacin, quinupristin/ dalfopristin, and tigecycline. Table 3 summarizes the coverage of these antimicrobial agents for DFIs.

7.3.1 Ceftaroline

Ceftaroline was approved by the FDA in 2010 for treatment of complicated skin and skin structure infec-tions, and is classified as a fifth-generation cephalosporin. It has shown activity against S. aureus, includ-ing MRSA, VISA, and VRSA strains, but not against VRE strains. It is also active against some gram negative bacilli, but not ESBL producers, or Pseudomonas spp. (Kosinski & Lipsky, 2010; Nannini et al., 2010).

7.3.2 Ceftobiprole

Although not yet approved for use in the U.S., this drug has been approved for treatment of complicated skin and skin structure infections in Russia, Ukraine, and Hong Kong (among others). It is considered to be a fifth-generation cephalosporin, and has shown good activity against many gram positive cocci, in-cluding S. aureus (including MRSA and VISA strains), but is not very effective against the enterococci. The activity against gram negative bacilli is variable, with good activity against non-ESBL producing E. coli and K. pneumoniae, but questionable against P. aeruginosa. It has also shown to be active against gram positive anaerobes (Goldstein et al., 2006a; Reygaert, 2011).

7.3.3 Dalbavancin

Dalbavancin is a newer lipoglycopeptide drug with an unusually long half-life that allows for once-a-week dosing. Not yet approved by the FDA, it is in phase 3 clinical trials. It has shown good activity against most gram positive organisms, including MRSA, but not VRE strains. It also has no activity against gram negative organisms. The suggested use of dalbavancin for severe DFIs would be in combi-

nation with an antimicrobial agent(s) effective against gram negative and anaerobic organisms (Goldstein et al., 2006; Kosinski & Joseph, 2007; Streit et al., 2004).

7.3.4 Daptomycin

Daptomycin is a lipoglycopeptide drug that was FDA approved for treatment of complicated skin and skin structure infections. It has been shown to be very effective against all gram positive cocci, including MRSA and VRE strains. Because it does not have activity against gram negative or anaerobic organisms, in severe DFIs that are polymicrobial, it would need to be used in combination with other antimicrobial agents (Lipsky & Stoutenburgh, 2005; Pfaller et al., 2007).

7.3.5 Ertapenem

Ertapenem is a newer member of the carbapenem drug class, and is approved by the FDA for treatment of complicated DFIs. It has broad spectrum activity against gram positive cocci (not against enterococci or MRSA), gram negative bacilli (not P. aeruginosa), and anaerobes. It could be useful for patients who have not previously received antimicrobial therapy for a diabetic foot infection (Kosinski & Joseph, 2007; Lipsky et al., 2005).

7.3.6 Iclaprim

Iclaprim is a dihydrofolate reductase inhibitor, is still awaiting FDA approval, and is in clinical trials. It has a broad-spectrum of activity against gram positive cocci, including MRSA, VISA, VRSA, and VRE; and against a variety of gram negative bacilli, including some ESBL producing strains, but not against P. aeruginosa. It has varied activity against anaerobes, and will probably not be recommended for use against those organisms (Armstrong, 2011; Krievins et al., 2009; Morgan et al., 2009).

7.3.7 Linezolid

Linezolid is the first of the oxazolidinone drugs to be approved for treatment of complicated skin and soft tissue infections. It is somewhat more flexible than most of the newer drugs in that it is available for oral or parenteral administration. It has been shown to have good activity against gram positive cocci, includ-ing MRSA and VRE, but has little activity against gram negative and anaerobic organisms. For polymi-crobial infections, linezolid should be used in combination with other drugs (Kosinski 2010, Lipsky 2004, Stevens).

7.3.8 Moxifloxacin

Moxifloxacin is a fourth-generation fluoroquinolone with FDA approval for treatment of complicated skin and skin structure infections. Like linezolid, it is available for oral and parenteral administration. It has a broad-spectrum of activity against most aerobic and anaerobic gram positive (not Methicillin-resistant strains) and gram negative (not ESBL producers or P. aeruginosa) organisms. In complicated DFIs that are polymicrobial and/or where resistant organisms may be present, it would be best to use it in combination with other drugs (Edmiston et al., 2004; Kosinski & Lipsky, 2010; Lipsky et al., 2007).

7.3.9 Quinupristin/Dalfopristin

Quinupristin/dalfopristin is a combination streptogramin B/streptogramin A antimicrobial that is ap-proved for treatment of complicated skin and skin structure infections caused by S. aureus and Strepto-coccus pyogenes. It has a very narrow spectrum of activity (gram positive aerobic and anaerobic cocci), but has good activity against MRSA, VISA, VRSA, vancomycin-resistant Enterococcus faecium (not Enterococcus faecalis), and penicillin-resistant Streptococcus pneumoniae. To date, no studies have been conducted on its use for DFIs (Baudoux et al., 2010; Jones et al., 1998; Lentino et al., 2008).

Antimicrobial agent

General coverage Coverage of resistant strains

DFI pathogens not cov-ered

Ceftaroline Gram positive cocci Gram negative bacilli

MRSA, VISA, VRSA VRE, ESBL producers, P. aeruginosa, anaerobes

Ceftobiprole Gram positive cocci - aerobes and anaerobes Gram negative bacilli

MRSA, VISA enterococci, ESBL pro-ducers, P. aeruginosa

Dalbavancin Gram positive aerobes MRSA VRE, gram negative or-ganisms, anaerobes

Daptomycin Gram positive cocci MRSA, VRE Gram negative organisms, anaerobes

Ertapenem Gram positive cocci Gram negative bacilli Anaerobes

None MRSA, enterococci, P. aeruginosa

Iclaprim Gram positive cocci Gram negative bacilli

MRSA, VISA, VRSA, VRE, some ESBL producers

Anaerobes, P. aeruginosa

Linezolid Gram positive cocci MRSA, VRE Gram negative organisms, anaerobes

Moxifloxacin Gram positive and gram negative aerobes and anaerobes

None MRSA, VRE, ESBL pro-ducers, P. aeruginosa

Quinupristin/ dalfopristin

Gram positive cocci - aerobes and anaerobes

MRSA, VISA, VRSA, vancomycin-resistant E. faecium

Gram negative organisms, E. faecalis,

Tigecycline Gram positive and gram negative aerobes and anaerobes

MRSA, VRE, ESBL producers

P. aeruginosa, Proteus mirabilis

ESBL - extended-spectrum β-lactamase, MRSA - methicillin-resistant S. aureus, VISA - vancomycin-intermediate S. aureus, VRSA - vancomycin-resistant S, aureus,

VRE - vancomycin-resistant enterococci

Table 3: Coverage of Newer Antimicrobial Agents for Isolates From Diabetic Foot Infections

7.3.10 Tigecycline

Tigecycline is a glycylcyline derived from the tetracycline drug class, and is approved for treatment of complicated intra-abdominal infections and complicated skin and skin structure infections. It has a broad-spectrum of activity against aerobic and anaerobic gram positive (including MRSA and VRE) and gram negative (including ESBL producers, but not P. aeruginosa or Proteus mirabilis) organisms. This broad-spectrum of activity makes it a viable choice for complicated polymicrobial DFIs (Fritsch et al., 2005; Reygaert, 2010; Sotto et al., 2007).

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