Christie Nelson, Jaime R. Hornecker, and Randy Wesnitzer
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Discuss characteristics of the skin that render it resistant to infection.
2. Describe the epidemiology, etiology, pathogenesis, clinical manifestations, diagnostic criteria, and complications associated with skin and soft tissue infections (SSTIs).
3. Identify the desired therapeutic outcomes for patients with SSTIs.
4. Recommend appropriate empirical and definitive antimicrobial regimens when given a diagnosis, patient history, physical examination, and laboratory findings.
5. Monitor chosen antimicrobial therapy for safety and efficacy.
KEY CONCEPTS
Impetigo commonly afflicts young children, is usually caused by Group A streptococci or Staphylococcus aureus, and is characterized by numerous blisters that rupture and form crusts. Dicloxacillin, cephalexin, and topical mupirocin are considered the antibiotics of choice for treatment of impetigo.
Folliculitis, furuncles, and carbuncles refer to the inflammation of one or more hair follicles, often attributed to infection with S. aureus. Treatment depends on severity and may involve local heat, incision and drainage, and/or oral or topical antibiotic therapy.
Erysipelas is a superficial infection of the upper dermis and superficial lymphatics distinguished from cellulitis by its well-defined borders and slightly raised lesions. It is usually caused by β-hemolytic streptococci and treated with penicillin.
Cellulitis, a bacterial infection of the dermis and subcutaneous tissue, is most commonly caused by S. aureus and β-hemolytic streptococci. Though β-lactams active against penicillinase-producing strains of S. aureus have historically been the drugs of choice, the increasing prevalence of infection with community-acquired methicillin-resistant S. aureus (CA-MRSA) is concerning. In areas with high rates of CA-MRSA, or in patients with risk factors for CA-MRSA infection, treatment with antibiotics active against this organism should be initiated.
Persons who are immunocompromised, have diabetes or vascular insufficiency, or use injection drugs are at risk for polymicrobial cellulitis, often requiring broad-spectrum antibiotic coverage.
Necrotizing fasciitis (NF) is an uncommon, rapidly progressive, life-threatening infection that causes necrosis of the subcutaneous tissue and fascia. Immediate surgical débridement is key to reducing its associated mortality.
The pathogenesis of diabetic foot infection stems from three key factors: neuropathy, angiopathy, and immunopathy. Aerobic gram-positive cocci, such as S. aureus and β-hemolytic streptococci, are the predominant pathogens in acutely infected diabetic foot ulcers. However, chronically infected wounds are subject to polymicrobial infection and require treatment with broad-spectrum antibiotics.
Prevention is key in the management of pressure sores. Mild superficial pressure sore infections may be treated with topical antimicrobial agents. Systemic antibiotics are indicated for serious pressure ulcer infections, including those associated with spreading cellulitis, osteomyelitis, or bacteremia.
Bite wound infections generally are polymicrobial. Amoxicillin-clavulanate is the drug of choice for treating infected bite wounds and is also used as infection prophylaxis for human bites, deep punctures, and bites to the hand, or those requiring surgical repair.
Every patient receiving antimicrobial therapy for skin and soft tissue infections (SSTIs) must be monitored for efficacy and safety. Efficacy typically is manifested by reductions in temperature, white blood cell count, erythema, edema, and pain that begin within 48 to 72 hours after treatment initiation. To ensure safety, adjust antibiotic dosages for renal and hepatic dysfunction as appropriate, and monitor for and minimize adverse drug reactions, allergic reactions, and drug interactions.
Skin and soft tissue infections (SSTIs) are frequently encountered in both acute and ambulatory care settings. They can range in severity from mild, superficial, and self-limiting, to life-threatening deep tissue infections that require intensive care, surgical intervention, and IV broad-spectrum antibiotics. Staphylococcus aureus and β-hemolytic streptococci are the most common causative bacteria.1,2 Complicated infections in persons with immune suppression, diabetes, vascular insufficiency, burns, decubitus ulcers, or traumatic wounds are often polymicrobial.2
The role of MRSA, particularly Community-acquired methicillin-resistant S. aureus (CA-MRSA), is of increasing importance. In many U.S. cities, MRSA has become the most frequently isolated pathogen from patients presenting to emergency departments with SSTI.3 MRSA infections were historically associated with exposures to health care settings (including hospitals, long-term care facilities, and dialysis centers), but have recently become problematic in previously healthy persons. Though risk factors for acquisition of CA-MRSA are not well established, outbreaks of CA-MRSA infection have occurred in prison inmates, homosexual males, athletes, military recruits, Native Americans, children, and injection drug users.4 In these patients, or in areas with high rates of CA-MRSA, empiric therapy including antibiotics active against this pathogen must be considered.2 This chapter will cover the epidemiology, pathogenesis, clinical manifestations, and pharmacologic management of the more common and severe bacterial SSTIs.
Intact skin generally is resistant to infection. In addition to providing a mechanical barrier, its relative dryness, slightly acidic pH, colonizing bacteria, frequent desquamation, and sweat (which contains IgG and IgA) prevent invasion by various microorganisms.5 Conditions that predispose a patient to SSTIs include: (a) high bacterial load (greater than 105 microorganisms); (b) excessive skin moisture; (c) decreased skin perfusion; (d) availability of bacterial nutrients; and (e) damage to the corneal layer of the skin.6
IMPETIGO
EPIDEMIOLOGY AND ETIOLOGY
Impetigo, which stems from the Latin word for “attack,” is a common skin infection worldwide.7 
It predominately afflicts children between 2 and 5 years of age but may occur in any age group.1 β-hemolytic streptococci and S. aureus are the most common causative pathogens1,7 Impetigo is a superficial infection and is spread easily, especially in settings of poor hygiene and crowding, and particularly during the summer months. The offending microorganisms colonize the skin surface and invade through abrasions, insect bites, or other small traumas. The scabby, crusty eruption of impetigo ensues. These lesions may occur anywhere on the body, but are most common on the face and extremities.1
CLINICAL PRESENTATION AND DIAGNOSIS
Impetigo lesions are numerous, well-localized, and erythematous. They develop either as small, thin-walled blisters (impetigo contagiosum), or as larger blisters (bullous impetigo) which may be associated with mild systemic symptoms.1,7–9 S. aureus is most often implicated in bullous impetigo. The blisters rupture easily, leaving behind a friable crust reminiscent of cornflakes. The lesions of impetigo are rarely painful, but are pruritic. Scratching the lesions can spread the infection to other areas of the body.7 In order to avoid further spread and complications, antibiotic therapy is usually indicated. If left untreated, mild, localized cases of impetigo typically resolve within two to three weeks.7,10 Sequelae of impetigo are uncommon, and when complications do occur, they seem to be more frequent in adults. Rarely, glomerulonephritis secondary to Group A streptococcus (GAS) may occur in nonbullous impetigo. Development of impetigo into more serious infections such as cellulitis or sepsis is another rare, but serious consequence.9
TREATMENT
Desired Outcomes
The primary goals of therapy for impetigo include preventing the spread of infection within the patient and to others, resolution of infection, and preventing recurrence. Secondarily, relief of symptoms associated with impetigo, such as itching, and improving cosmetic appearance are also important. Prevention of the rare, but serious complications of impetigo is an alternative goal.10
Nonpharmacologic Treatment
Because impetigo is rarely painful, there is often a delay in seeking medical attention. However, the lesions will resolve with time and increased hygiene. Soaking and cleansing the lesions with mild soap and water and the use of skin emollients to dry skin areas may reduce spread.7
Pharmacologic Treatment
Antibiotic therapy is recommended to achieve the desired outcomes of preventing the spread of infection and complications. Because GAS historically has been the primary causative organism, penicillin has been the mainstay of therapy. However, the incidence of S. aureus impetigo is increasing, so oral penicillinase-stable penicillins or first-generation cephalosporins are now preferred. Clindamycin or a macrolide are alternative choices when penicillin allergy is a concern; however, the clinician should be aware that some strains of GAS and S. aureus may be resistant to macrolides. Topical mupirocin may be used alone when there are few lesions.1
Table 73–1 Folliculitis, Furuncles, and Carbuncles
FOLLICULITIS, FURUNCLES, AND CARBUNCLES
See Table 73–1.
CELLULITIS AND ERYSIPELAS
EPIDEMIOLOGY AND ETIOLOGY
Cellulitis and erysipelas are bacterial infections involving the skin. 
Cellulitis is an infection of the dermis and subcutaneous tissue, whereas erysipelas is a more superficial infection of the upper dermis and superficial lymphatics. Although both can occur on any part of the body, about 90% of infections involve the leg.12,13 These infections develop after a break in skin integrity, resulting from trauma, surgery, ulceration, burns, tinea infection, or other skin disorder. However, they may occur after an inapparent break in the skin, and the skin may appear previously intact. In rare cases, cellulitis develops from blood-borne or contiguous spread of pathogens.1,14
Etiologic microorganisms vary according to the area involved, host factors, and exposures. Erysipelas is generally caused by β-hemolytic streptococci, mainly GAS, and rarely by S. aureus. 
The predominant pathogens associated with cellulitis are S. aureus, including methicillin-resistant strains, and β-hemolytic streptococci. Persons who are immunocompromised, have diabetes or vascular insufficiency, or use injection drugs are at risk for polymicrobial cellulitis.1,2
CLINICAL PRESENTATION AND DIAGNOSIS
The manifestations of and diagnostic criteria for erysipelas and cellulitis are presented in Table 73–2. Once diagnosed, cellulitis may be characterized as complicated or uncomplicated. Complicated infections are those that involve abnormal skin or wounds, occur in immunocompromised hosts, require substantial surgical intervention, or are polymicrobial in origin.15
Table 73–2 Presentation of Erysipelas and Cellulitis
Symptoms
• The infected area is described as painful or tender. In the case of erysipelas, the patient may complain of “burning pain” at the lesion site
Signs
• Both erysipelas and cellulitis are manifested by rapidly spreading areas of redness, edema, and heat. Lymphangitis and regional lymphadenopathy may be observed
• Important clinical differences between erysipelas and cellulitis exist:
• In erysipelas, low-grade fever and flu-like illness are common prior to development of the lesion. The lesion is fiery red, raised above the level of surrounding skin, and has well-defined borders
• In cellulitis, the lesion is not raised and has poorly defined margins
Laboratory Tests
• Leukocytosis may be present
• Cultures and sensitivities:
• Blood cultures are only positive about 4% of the time but should be obtained for complicated or severe cases. Cultures aspirated from the lesion have an organism isolation rate of less than 20%, but also may be considered
• Abscess drainage and débrided tissue, if obtainable, should be cultured and will yield the causative organism(s) up to 90% of the time
Imaging Studies
• Imaging studies may identify abscess formation, gas in the soft tissues, or osteomyelitis
From Refs. 1, 13, 14.
With early diagnosis and appropriate therapy, the prognoses for cellulitis and erysipelas are excellent. Severe or repeated episodes can cause lymphedema. Rare complications include the spread of infection to deeper skin and soft tissue layers, bacteremia and sepsis.1 If the circumference of an extremity is cellulitic, compartment syndrome becomes a concern, and a surgical consult may be required. Recurrent cellulitis can be problematic. About 30% of patients hospitalized with cellulitis will develop a recurrent episode within 3 years. Vascular and lymphatic insufficiencies increase the risk of recurrences.14,16
TREATMENT
Desired Outcomes
The goals of therapy for cellulitis and erysipelas are rapid and successful eradication of the infection and prevention of related complications.
Nonpharmacologic Treatment
Nonpharmacologic treatment includes elevating and immobilizing the involved limb to decrease swelling. Sterile saline dressings should be placed on any open lesions to cleanse them of purulent materials. Surgical débridement is indicated occasionally for severe infection. Drainage of abscesses are imperative to achieving clinical cure.14
Patient Encounter 1, Part 1: Cellulitis
A 56-year-old male presents to the emergency department with complaints of right lower leg pain and redness. Examining his leg, you notice that he has erythema and edema extending from his ankle to proximal tibia. The area feels warm. The patient states that the redness started approximately 2 days ago. He has felt feverish over the previous 48 hours but did not check his temperature. He has had no other symptoms. He states that he bumped his shin on the bed frame last week and sustained a bruise but no apparent breaks in the skin. His vital signs at the clinic reveal a temperature of 38.3°C (100.9°F), pulse 110 bpm, blood pressure 110/72 mm Hg, and respiratory rate 25 breaths per minute. The physician diagnoses this patient with cellulitis.
What clinical manifestations are suggestive of cellulitis?
What additional information do you need before developing a therapeutic plan for this patient?
Pharmacologic Treatment
Most patients with erysipelas or cellulitis are not hospitalized. Hospitalization and treatment with IV antibiotics should be considered if there are systemic signs and symptoms of infection (such as fever, chills, or hypotension), the patient has significant comorbid conditions (such as immunocompromise, diabetes, cirrhosis, cardiac failure, or renal insufficiency), or the cellulitis is spreading rapidly, involves a large area of the body, or is chronic.14
Penicillin is the treatment of choice for erysipelas. In uncomplicated cases, a 5-day course is as effective as a 10-day course.1 Other agents that are acceptable for treatment include clindamycin, cephalexin, and dicloxacillin.
Though β-lactams, such as dicloxacillin, active against penicillinase-producing strains of S. aureus (commonly known as methicillin-sensitive S. aureus, or MSSA) have historically been the drugs of choice for acute bacterial cellulitis in otherwise healthy individuals, the increasing prevalence of infection with CA-MRSA is concerning, particularly in patients presenting with abscess.1,17,18 In areas with high rates of CA-MRSA (e.g., greater than 15% of community S. aureus isolates show methicillin resistance), or in patients with risk factors for CA-MRSA infection, treatment with antibiotics active against this organism should be initiated.2,17 Vancomycin continues to be the drug of choice for severe cellulitis due to MRSA because of its efficacy, safety, and low cost. Daptomycin or linezolid are also acceptable. Tigecycline is an alternative, however, due to its broad spectrum of activity, it is best reserved for patients with intolerances to the aforementioned drugs or in those with polymicrobial infections. For less severe, uncomplicated infections, many CA-MRSA strains can be treated with clindamycin, doxycycline, or trimethoprim-sulfamethoxazole.1,2,17–20 However, it should be mentioned that though these agents are widely used for uncomplicated SSTI, this is an off-label use supported predominantly by data from observational and small interventional trials.21 Also, trimethoprim-sulfamethoxazole and doxycycline have less than optimal activity against GAS and should be empirically combined with an agent with such activity (e.g., cephalexin) if GAS is also a suspected causative organism.17,18
In addition to being at risk for staphylococcal and streptococcal cellulitis, patients with immune suppression, diabetes, vascular insufficiency, or wounds are also at risk for disease caused by gram-negative bacilli such as Escherichia coli and Pseudomonas aeruginosa, with or without anaerobes.2 Empirical broad-spectrum antimicrobial coverage, including coverage for resistant organisms such as health care–associated MRSA (HA-MRSA) and P. aeruginosa, is appropriate for severe cellulitis and/or severe systemic illness. The clinician should be diligent in attempting to isolate a causative pathogen in these individuals.1
Injection drug use also predisposes individuals to polymicrobial cellulitis. The antecubital region of the arm is usually the site of infection. S. aureus, the most common isolate, is frequently associated with abscess formation. Because some injection drug users lick their needles to “clean” them, antibiotics that cover oropharyngeal anaerobes should be included. Occasionally, Candida spp. are isolated, and the patient may require antifungal therapy.22
Table 73–3 Empirical Antimicrobial Therapy for Cellulitis
Patient Encounter 1, Part 2: Cellulitis: Medical History, Physical Examination, and Diagnostic Tests
PMH: Hypertension. He is not aware of any other illnesses.
FH: Father died of stroke at age 72. Mother, age 79, is alive with diabetes and a history of breast cancer. One brother, age 59, is alive and healthy.
SH: Works as a college professor; married; three grown children. Denies tobacco use; drinks approximately four glasses of wine on weekends; denies illicit drug use.
Meds: Atenolol 100 mg by mouth daily, multiple vitamin 1 tablet by mouth daily.
Allergies: No known drug allergies.
ROS: (+) pain and swelling in the right lower extremity; (-) headache, chest pain, shortness of breath, cough, nausea, vomiting, diarrhea, and weight loss.
PE:
Gen: Patient is in no acute distress. Wt 95 kg (209 lb); ht 5 ft, 11 in. (180 cm).
Chest: Lungs bilaterally clear to auscultation.
CV: Regular rate, rhythm. No murmurs/rubs/gallops.
Ext: Right lower extremity with erythema and edema from the ankle to just below the knee. Warm to the touch. LLE within normal limits.
Labs: WBC 17.3 × 103/mm3 (17.3 × 109/L), serum creatinine 0.8 mg/dL (70.7 μmol/L) The patient is diagnosed with cellulitis and admitted to the medical floor.
What are the most likely causative organisms in this case of cellulitis?
What are the goals of therapy for this patient?
What nonpharmacologic interventions would you recommend for him?
What antimicrobial therapy would you recommend? Include drug, dosage, route, interval, and duration of therapy.
How would you monitor your selected regimen for safety and efficacy?
If CA-MRSA represents 35% of all S. aureus isolates at your hospital, would you change your pharmacologic recommendation? If so, how?
Table 73–3 lists some recommended antibiotic regimens for the treatment of cellulitis. Because antimicrobial susceptibilities vary considerably between geographic locations, clinicians should select empirical treatment based on the antibiograms at their respective institutions. To decrease the spread of resistance, antibiotic therapy should be narrowed based on culture and sensitivity results whenever possible. The duration of therapy for uncomplicated cellulitis typically ranges from 7 to 10 days. For complicated cellulitis, therapy with IV antibiotics is generally initiated and a switch to oral therapy can be made once the patient is afebrile and skin findings begin to resolve. Typically, this is done after 3 to 5 days. The complete duration of therapy can range from 10 to 14 days and longer in cases where abscess, tissue necrosis, underlying skin wounds, or delayed response to therapy are involved.1,14
NECROTIZING FASCIITIS
EPIDEMIOLOGY AND ETIOLOGY
Necrotizing fasciitis (NF) is an uncommon, rapidly progressive, life-threatening infection that causes necrosis of the subcutaneous tissue and fascia. When due to GAS infection, its associated mortality rate approaches 25%.23 NF can affect any age group. Although the risk of NF is higher in injection drug users and in patients with diabetes, immune suppression, or obesity, healthy hosts can become infected as well.24
NF typically erupts after an initial trauma, which can range from a small abrasion to a deep penetrating wound. The infection begins in the fascia, where bacteria replicate and release toxins that facilitate their spread.25
In approximately 70% of cases, NF is polymicrobial and typically involves anaerobes (i.e., Bacteroides or Pepto-streptococcus),facultative anaerobes (i.e., β-hemolytic streptococci), and Enterobacteriaceae (e.g., Escherichia coli, Enterobacter, Klebsiella). P. aeruginosa is occasionally implicated as well.24 Polymicrobial NF develops in the following clinical settings: after surgery or deep penetrating wounds involving the bowel; from decubitous ulcer, perianal, or vulvovaginal infection; or from the injection site in an IV drug user.1,8
The remaining 30% are monomicrobial, caused by invasive GAS, or less frequently, Clostridium perfringens. CA-MRSA is more recently being implicated in these infections as well.24 Monomicrobial NF is generally more severe than polymicrobial NF. GAS NF often occurs after minor trauma, such as an insect bite or abrasion, whereas infection with C. perfringens typically develops from surgical or traumatic wounds.1,26 Once introduced, these organisms produce toxins that induce systemic toxicity, multiorgan failure, and shock.26,27 Clostridial myonecrosis is more commonly known as gas gangrene.1,26
CLINICAL PRESENTATION AND DIAGNOSIS
Patient outcomes rely on the clinician’s ability to recognize NF early in the course of disease. This is often difficult because early disease tends to be indistinguishable from cellulitis. The clinical presentation of NF is presented in Table 73–4.
NF is perhaps the most devastating SSTI. Left untreated, it can invade the muscles and circulation, resulting in myonecrosis and septic shock, respectively. Half of the cases caused by GAS are accompanied by GAS toxic shock-like syndrome. The syndrome is endotoxin-mediated, manifested by hypotension and multiorgan dysfunction, and highly lethal.8,24 Amputation is required in up to 50% of patients with extremity infections.28 Once the patient recovers from acute NF, he or she often requires skin and/or muscle grafting and consequent physical rehabilitation depending on the amount and types of tissues removed during surgical intervention and the duration of hospital stay.29
Table 73–4 Presentation of NF
Symptoms
• Early: Severe pain that is disproportionate to clinical signs and extends beyond the margins of the infected area
• Late: Area may become numb secondary to muscle and nerve involvement
Signs
• Early: Skin is erythematous, edematous, and warm; the clinical presentation is similar to that of cellulitis
• Intermediate (within 24-48 hours): Blisters and bullae indicate severe skin and tissue ischemia
• Late: The skin becomes violaceous and progressively gangrenous; hemorrhagic bullae may be present. Systemic signs may include fever, tachycardia, hypotension, and shock
Laboratory Tests
• White blood count, serum creatinine, and C-reactive protein may be elevated
• Deep tissue specimens obtained during surgical irrigation and débridement should be sent for Gram stain, culture, and sensitivity
Imaging Studies
• MRI and CT scans may reveal fluid and gas along fascial planes
• Typically, imaging studies are avoided when making a diagnosis because they may delay surgical intervention and increase mortality
NF, Necrotizing fasciitis.
From Refs. 1, 24, 25.
TREATMENT
Desired Outcomes
The goals of therapy for NF include eradication of infection and reduction of related morbidity and mortality.
Nonpharmacologic Treatment
After resuscitation and hemodynamic stabilization, prompt surgical intervention is key in the treatment of NF. Delayed operative débridement increases mortality.1,25 Some clinicians recommend hyperbaric oxygen (HBO) as an adjunct treatment for NF, although its use is controversial. Clinical data supporting the use of HBO in NF are inconsistent, with some trials showing reduced mortality rates and others showing no benefit.30
Pharmacologic Treatment
As an adjunct to surgery, broad-spectrum IV antibiotic therapy should be initiated immediately in patients with NF. Piperacillin/tazobactam or a carbapenem is appropriate for empiric therapy. These agents should be used in combination with vancomycin, daptomycin, or linezolid until MRSA infection is ruled out. The protein synthesis inhibitors clindamycin or linezolid are often utilized to decrease bacterial toxin production, thereby limiting tissue damage. This is particularly beneficial in streptococcal or clostridial infection.24
If GAS or C. perfringens is identified as the sole causative organism from deep tissue culture, antimicrobial therapy can be narrowed to high-dose IV penicillin G plus clindamycin. Antibiotic therapy should be continued until further operative débridements are unnecessary, the patient displays substantial clinical improvement, and fevers have abated for at least 48 to 72 hours.1
IV immune globulin (IVIG) may also be a usefuladjunctive treatment in patients with GAS NF who present with shock. In one small randomized study, IVIG was associated with a reduction in mortality in such patients, however the finding was not statistically significant.31
DIABETIC FOOT INFECTIONS
EPIDEMIOLOGY AND ETIOLOGY
Foot ulcers and related infections are among the most common, severe, and costly complications of diabetes mellitus. Fifteen percent of all patients with diabetes develop at least one foot ulcer, resulting in direct health care expenditures of approximately $9 billion annually in the United States.32,33
Infected diabetic foot ulcers typically contain a multitude of microorganisms. 
Aerobic gram-positive cocci, such as S. aureus and β-hemolytic streptococci, are the predominant pathogens in acutely infected diabetic foot ulcers. However, chronically infected wounds are subject to polymicrobial infection. The clinician should suspect the involvement of gram-negative (Enterobacteriaceae and P. aeruginosa) and possibly low-virulence pathogens (including enterococci and S. epidermidis) in chronic or necrotic wounds. Foul-smelling, necrotic or gangrenous wounds are also commonly infected with anaerobic bacteria. Patients recently hospitalized or treated with broad-spectrum antibiotics are at risk for infection with antibiotic-resistant organisms, including MRSA and vancomycin-resistant enterococci (VRE).34
PATHOPHYSIOLOGY
The pathogenesis of diabetic foot infection stems from three key factors: neuropathy, angiopathy, and immunopathy.35,36 Neuropathy, the most prominent risk factor for diabetic foot ulcers, develops when continuously high blood glucose levels damage motor, autonomic, and sensory nerves. Damage to motor neurons that supply the small intrinsic muscles of the foot causes deformation, resulting in altered muscular balance, abnormal areas of pressure on tissues and bone, and repetitive injuries. Damage to autonomic neurons results in the shunting of blood through direct arteriole-venous communications, thereby decreasing capillary flow. The secretion of sweat and oil is also diminished, producing dry, cracked skin that is more prone to infection. Finally, damage to sensory neurons produces a loss of protective sensation so that the patient becomes unaware of injury or ulceration.35,36
Angiopathy of large (macroangiopathy) and small (microangiopathy) vessels is also the result of high blood glucose concentrations. Angiopathy results in ischemia and skin breakdown.35,36
Finally, persons with diabetes have altered immune function that predisposes them to infection. Although their humoral immune responses remain intact, leukocyte function and cell-mediated immunity are compromised in poorly-controlled disease. Achieving and maintaining tightly controlled blood glucose levels can wholly or partially reverse diabetic immunopathy35,36
CLINICAL PRESENTATION AND DIAGNOSIS
Not all diabetic foot ulcers are infected. However, infection is often difficult to detect when perfusion and the inflammatory response are limited in the patient with diabetes. The common signs and symptoms (i.e., pain, erythema, and edema) of infection may be absent.37 Still, the diagnosis of diabetic foot infection depends mostly on clinical evaluation.
Purulent drainage from the ulcer is indicative of infection. When pus and inflammatory symptoms are not present, the clinician must be astute to more subtle findings. These include delayed healing, increase in lesion size, prolonged exudate production, malodor, and tissue friability. Abnormal granulation tissue also may be present, as evidenced by color change (from bright red to dark red, brown, or gray) and increased bleeding. The ability to probe the ulcer to the underlying bone is highly indicative of osteomyelitis.37
Diabetic foot infections are classified into four categories based on clinical presentation using the PEDIS scale (perfusion, extent/size, depth/tissue loss, infection, sensation). Grade 1 signifies no infection; grade 2, involvement of skin and subcutaneous tissue only; grade 3, extensive cellulitis or deeper infection; and grade 4, systemic inflammatory response syndrome.34 Grade 2 infections are classified as nonlimb-threatening infections, whereas grades 3 and 4 infections are limb-threatening.34,36 Table 73–5 provides detailed information regarding these grades.
Imaging studies, such as x-ray and MRI, can identify osteomyelitis. Blood cultures should be obtained from all patients with signs and symptoms of systemic illness. Deep tissue cultures may help to direct therapy. Bone also may be sent for culture in cases of osteomyelitis. Superficial cultures of ulcers are unreliable and should be avoided.34
Spreading soft tissue infection and osteomyelitis are often the first complications that develop from diabetic foot infection. Some patients develop bacteremia and sepsis.
Table 73–5 Clinical Classification of a Diabetic Foot Infection
Patient Encounter 2, Part 1: Diabetic Foot Infection
A 47-year-old man with a long-standing history of type 1 diabetes presents to the primary care clinic with complaints of a nonhealing sore on his left foot. He has also noticed more pain and swelling than usual in his left lower extremity. While examining his foot, you see a mildly purulent lesion with induration 4 cm (1.6 in.) in diameter, and the presence of lymphangitic streaking. His foot is erythematous, warm, and tender to touch, and slightly malodorous, despite good foot hygiene. The patient indicates that the sore has been present for about 3 months, and he first noticed it after a day at the beach, where he spent most of the day barefoot. The patient’s vital signs are within normal limits with the exception of a blood pressure of 135/88 mm Hg. He is afebrile.
What signs and symptoms present in this patient are indicative of a diabetic foot infection?
Based on presentation, classify this patient’s diabetic foot infection using the PEDIS grading scale.
What additional information do you need before developing a therapeutic plan for this patient?
The most feared complication of infected diabetic foot ulcers is lower extremity amputation. More than 60% of all nontraumatic lower extremity amputations performed each year in Western nations are linked to diabetic foot infection; nearly 71,000 were performed in the United States in 2004.38
TREATMENT
Desired Outcomes
The goals of therapy for diabetic foot infection are eradication of the infection and avoidance of soft tissue loss and amputation.
Prevention
Comprehensive foot care programs can reduce the rate of diabetic foot ulcers and associated amputations by 45% to 85%.35 Periodic foot examinations with monofilament testing and patient education regarding proper foot care, optimal glycemic control, and smoking cessation are key preventative strategies. Custom orthotic footwear and prophylactic reconstructive foot surgeries also may be effective in reducing the incidence of foot ulcers.32
Nonpharmacologic Treatment
The nonpharmacologic treatment of diabetic foot ulcers may include off-loading, chemical or surgical débridement of necrotic tissue, wound dressings, HBO, vascular or orthopedic surgery, and the use of human skin equivalents.36
Pharmacologic Treatment
The severity of a patient’s infection, based on the PEDIS scale, guides the selection of empirical antimicrobial therapy. While most patients with grade 2 diabetic foot infections can be treated as outpatients with oral antimicrobial agents, all grade 4 and many grade 3 infections require hospitalization, stabilization of the patient, and broad-spectrum IV antibiotic therapy.34
Table 73–6 Empirical Pharmacologic Treatment of Diabetic Foot Infection
Patient Encounter 2, Part 2: Diabetic Foot Infection: Medical History, Physical Examination, and Diagnostic Tests
PMH: Type 1 diabetes mellitus × 37 years, hypertension, dyslipidemia, peripheral neuropathy, and GERD
FH: Father died of an MI at age 77; mother died at age 56 of esophageal cancer. Two siblings alive with no significant PMH.
SH: Divorced, with two teenage children who live with their mother. Works in the computer tech industry. Smoked 1 PPD for 20 years, quit at age 39. Denies alcohol use.
Meds: Lantus 55 units at bedtime, Humalog Sliding Scale with meals, lisinopril 20 mg daily, hydrochlorothiazide 25 mg daily, Lipitor 40 mg at bedtime, gabapentin 600 mg three times daily, Prilosec OTC 20 mg daily, and aspirin 81 mg daily
Allergies: Sulfa (rash)
ROS: (+) left foot findings per HPI; (−) headache, chest pain, shortness of breath, cough, nausea, vomiting, diarrhea, and weight loss
PE:
Gen: Patient is in no acute distress. Wt 84 kg (185 lb); ht 5 ft 11 in. (180 cm)
Chest: CTAB
CV: RRR. No murmurs/rubs/gallops Ext: 4-cm purulent, erythematous lesion present on the plantar aspect of the left foot proximal to the great toe. 1+ edema in the left foot; diminished sensation bilaterally
Labs: At previous visit 4 months ago: BUN 14 mg/dL (5.0 mmol/L), SCr 1.0 mg/dL (88.4 μmol/L), Glu 154 mg/dL (8.5 mmol/L), A1C 7.7%
The patient is diagnosed with a diabetic foot infection.
Explain the role of neuropathy, angiopathy, and immunopathy in the development of this patient’s diabetic foot infection.
What are the best preventative strategies for diabetic foot infections, and complications such as LEA?
Antimicrobial therapy for this patient’s infection should provide coverage for which microorganisms?
What antimicrobial therapy would you recommend? Include drug, dosage, route, interval, and duration of therapy.
How would you monitor your selected regimen for safety and efficacy?
How would your antimicrobial therapy change if this patient was experiencing fever, chills, blood glucose values in the 400s, and obvious deep tissue involvement?
Multiple antibiotic options exist for the treatment of diabetic wound infections. Table 73–6 provides both general treatment strategies and specific, though not all-inclusive, antibiotic recommendations. The duration of therapy correlates with infection severity. Antibiotics should be continued until the infection has resolved, but not necessarily until the ulcer has healed. Grade 2 infections generally require 7 to 14 days of therapy, whereas grade 3 to 4 necessitate treatment durations of 14 to 28 days. If osteomyelitis is present, treatment duration depends on whether infected and necrotic bone is surgically debrided. In the case of amputation, where all infected bone and tissue is removed, 2 to 5 days of therapy is sufficient. Residual infection, status-post surgical debridement, requires 2 to 6 weeks of antibiotic therapy. Without surgery, antibiotic therapy should continue for at least 12 weeks.34
INFECTED PRESSURE SORES
EPIDEMIOLOGY AND ETIOLOGY
Pressures sores, also known as decubitus ulcers or bedsores, affect approximately 7% to 24% of long-term care and 10% to 18% of hospitalized patients. Patients of advanced age and those with spinal cord or orthopedic injuries are highest risk.41
A pressure sore is a chronic wound that results from continuous pressure on the tissue overlying a bony prominence. This pressure impedes blood flow to the dermis and subcutaneous fat, resulting in tissue damage and necrosis.42,43
Pressure sore infections develop from breaks in skin integrity and contamination from dirty areas of close proximity. Pressure sore infections generally are polymicrobial.44
CLINICAL PRESENTATION AND DIAGNOSIS
Approximately two-thirds of all pressure sores occur on the sacrum and heels. The remaining third occur predominately on the elbows, ankles, trochanters, ischia, knees, scapulas, shoulders, or occiput.45Pressure sores are classified according to the extent of tissue destruction.46 The most commonly used system for staging of pressure sores is presented in Table 73–7.
Bacterial colonization of pressure sores is common. Because infection impairs wound healing and may require systemic antimicrobial therapy, the clinician must be able to distinguish it from colonization. Table 73–8 describes the clinical presentation of infected pressure sores.
Most complications are infectious. The most common is osteomyelitis, which is present in approximately 38% of infected pressure sores.42 Less frequently, NF, clostridial myonecrosis, and sepsis can occur.
Table 73–7 Staging of Pressure Ulcers
Suspected Deep Tissue Injury
• Intact skin with localized area of purple or maroon discoloration or presence of a blood-filled blister
• The area may be preceded by tissue that is painful, firm, mushy, boggy, warmer or cooler as compared to adjacent tissue
Stage I
• Intact skin with localized area of nonblanchable redness, usually over a bony prominence
• May be difficult to detect in darkly pigmented skin; its color may differ from the surrounding area
Stage II
• Partial-thickness loss of dermis presenting as a shallow open ulcer with a red pink wound bed or an intact or ruptured serum-filled blister
• This stage should not be used to describe skin tears, tape burns, perineal dermatitis, maceration, or excoriation
Stage III
• Full thickness tissue loss. Subcutaneous fat may be visible but bone, tendon, or muscle are not exposed. Slough may be present but does not obscure the depth of tissue loss. May include undermining and tunneling
Stage IV
• Full thickness tissue loss with exposed bone, tendon or muscle. Slough or eschar may be present on some parts of the wound bed. Often include undermining and tunneling
Unstageable
• Full thickness tissue loss in which the base of the ulcer is covered by slough (yellow, tan, gray, green, or brown) and/or eschar (tan, brown, or black) in the wound bed
• Until enough slough and/or eschar is removed to expose the base of the wound, the true depth, and therefore stage, cannot be determined. Stable (dry, adherent, intact without erythema or fluctuance) eschar on the heels serves as “the body’s natural (biological) cover” and should not be removed
From Ref. 46.
TREATMENT
Desired Outcomes
The goals of therapy for infected pressure sores include resolution of infection, promotion of wound healing, and establishment of effective infection control.43
Prevention
Prevention is the most humane and cost-effective component in the management of pressure sores. Key prevention strategies include monitoring of high-risk patients, reducing skin exposure to pressure and moisture, and promoting good nutritional status.
Table 73–8 Presentation of Infected Pressure Sores
Symptoms
• Because many high-risk patients lack sensation, pain may not be a primary symptom
Signs
• Infection generally is diagnosed when erythema and edema of the surrounding skin, purulent drainage, malodor, or delayed wound healing are present
• Patients with bacteremia often develop fever, chills, confusion, and/or hypotension
Laboratory Tests
• Deep tissue cultures may help to direct therapy. Bone also may be sent for culture in cases of osteomyelitis. Superficial cultures are unreliable and should be avoided
Imaging Studies
• Imaging studies, such as CT, MRI, or bone scan, can be used to detect osteomyelitis and to determine the depth and extent of tissue destruction
From Refs. 43, 45.
Careful monitoring and preventative care of high-risk patients can begin once these patients are identified. Intrinsic, or host-related risk factors for the development of pressure sores include age greater than 75 years, limited mobility, loss of sensation, unconsciousness or altered sense of awareness, and malnutrition. Extrinsic, or environmental risk factors include pressure, friction, shear stress, and moisture.42,47
Turning and repositioning the patient at least every 2 hours can reduce skin pressure and prevent pressure sores. However, because this level of care is difficult to achieve in most hospital and nursing home environments, multitudes of pressure-reducing mattresses have been manufactured. Although these can help to decrease pressure on susceptible areas, they do not negate the need for position changes.42,47
Maintaining a clean, dry environment can prevent skin maceration and subsequent tissue damage. This can be accomplished with frequent changes of bed sheets and clothing, thorough drying of skin after bathing, and prompt disposal of incontinent stool or urine.
Malnutrition is a significant but reversible risk factor. High-protein diets have been shown in multiple studies to improve wound healing in patients with pressure sores.42
Nonpharmacologic Treatment
Pressure relief, adequate nutrition (high-protein diet), and surgical débridement or abscess drainage are the mainstays of nonpharmacologic treatment.43
Pharmacologic Treatment
Systemic antibiotics are indicated for serious pressure ulcer infections, including those associated with spreading cellulitis, osteomyelitis, or bacteremia.43 Pressure ulcer infections are generally polymicrobial. Thus, antimicrobial agents with a broad spectrum of activity should be initiated and narrowed according to the results of cultures obtained surgically. The duration of treatment is generally 10 to 14 days, unless osteomyelitis is present.43
Mild superficial infections, such as those that present clinically with delayed wound healing or minimal cellulitis, may be treated with topical antimicrobial agents such as silver sulfadiazine 1% cream or combination antibiotic ointments.42 Systemic options for more extensive cellulitis are available in Table 73–3.
INFECTED BITE WOUNDS
EPIDEMIOLOGY AND ETIOLOGY
Fifty percent of Americans will be bitten by an animal at least once during their lifetimes. Although most of these injuries are minor, approximately 20% will require medical treatment.1
Dogs cause approximately 80% of all bites. These bites most commonly involve the extremities, and young children are particularly at risk.48,49 Approximately 15% to 25% of dog bites become infected.49
Cat bites are the second most common animal bite, most often occurring in women and elderly individuals. Most involve the hand. Because cats have long, thin teeth that cause puncture wounds, their bites are more likely to become infected than a dog bite. Approximately 50% of cat bites become infected.48,49
Human bites are third most common and the most serious.49 Before the availability of antibiotics, up to 20% resulted in amputation. Currently, human bite-associated amputation rates remain at 5%, secondary to vascular compromise and infectious complications.49
There are two types of human bite injuries. Occlusal injuries are inflicted by actual biting, whereas clenched-fist injuries are sustained when a person’s closed fist hits another’s teeth. Of the two, clenched-fist injuries typically are more prone to infectious complications.48,49
Bite wound infections generally are polymicrobial. On average, five different bacterial species can be isolated from an infected animal bite wound.1 Both the normal flora of the biter’s mouth and that of the bite recipient’s skin can be implicated. The bacteriology of the cat and dog mouth is quite similar. Pasteurella multocida, a gram-negative aerobe, is one of the predominant pathogens, isolated in up to 50% of dog and 75% of cat bites. Viridans streptococci are the most frequently cultured bacteria from human bite wounds.1,48 Table 73–9 provides a comprehensive list of cat, dog, and human bite-wound pathogens.
CLINICAL PRESENTATION AND DIAGNOSIS
The clinical presentation of infected bite wounds is presented in Table 73–9.
Complications of infected bite wounds include lymphangitis, abscess, septic arthritis, tenosynovitis, and osteomyelitis. Bites to the hand are particularly complication-prone.48,49
Table 73–9 Etiology and Presentation of Infected Bite Wounds
Bacterial Pathogens
• Dog and cat: Pasteurella multocida, staphylococci, streptococci Moraxella spp., Eikenella corrodens, Capnocytophaga canimorsus, Actinomyces, Fusobacterium, Prevotella, and Porphyromonas spp.
• Human: Viridans streptococci, Staphylococcus aureus, E. corrodens, Haemophilus influenzae, and β-lactamase-producing anaerobic bacteria
Signs and Symptoms
• The onset of infectious symptomatology is typically 12-24 hours after the bite
• Pain at the wound site is common
• Erythema, edema, and purulent or malodorous drainage at the wound site are manifestations of infected wounds. The patient may be febrile
• Limited range of motion may be present, especially if the hand is bitten
Laboratory Tests
• Leukocytosis may be present
• The clinician should obtain anaerobic and aerobic wound cultures only if the wound appears clinically infected
Imaging Studies
• X-rays should be obtained if the bite is on the hand, could have damaged bone or joints, or if an embedded object or tooth fragment is suspected
From Refs. 48, 49.
TREATMENT
Desired Outcomes
The goals of therapy for an infected bite wound are rapid and successful eradication of infection and prevention of related complications.
Nonpharmacologic Treatment
Thorough irrigation with normal saline is the first step in the care of an infected bite wound. The wound should be elevated and immobilized. Surgical closure may be advocated, especially for facial wounds. Wounds that are infected, at higher risk for infection, or older than 24 hours should be left open because premature closure can lead to disastrous infectious complications. 
Wounds at higher risk for infection include human bites, deep punctures, and bites to the hand.48
Pharmacologic Treatment
Most bite wounds require antibiotic therapy only when clinical infection is present. However, prophylactic therapy is recommended for wounds at higher risk for infection and bites requiring surgical repair.48
The most effective agent for the treatment (and prophylaxis) of human and animal bite-wound infections is amoxicillin-clavulanate. Alternatives for patients with significant penicillin allergies include either a fluoroquinolone (such as ciprofloxacin) or trimethoprim-sulfamethoxazole in combination with clindamycin. The durations of prophylaxis and treatment generally are 3 to 5 and 10 to 14 days, respectively.1
Patient Care and Monitoring
Choosing antibiotic therapy for SSTIs:
1. To select the most effective empirical antibiotic agent(s) for SSTIs, review the following:
• The diagnosis
• Clinical manifestations and severity of illness (to assess the need for IV versus oral therapy).
• Past medical history, chronic disease states (to determine suspected pathogens).
• Patient’s ability to adhere to the regimen (if outpatient treatment indicated).
In pediatric patients especially, consider duration of therapy, frequency of dosing, method and ease of administration, and palatability and tolerability of oral formulations.
2. To ensure the safety of your selected antibiotic agent(s), review the following:
• Current medications (over-the-counter, prescription, and alternative) for potential drug interactions.
• History of medication allergies and adverse effects.
• Current laboratory analyses to determine renal and hepatic function.
• Chronic disease states or acute conditions that could be worsened by certain antimicrobial agents (e.g., QT prolongation or acute renal failure).
• Other disease modifiers that may preclude use (e.g., pregnancy, age).
Monitoring antibiotic therapy for SSTIs:
1. Ensure that antimicrobial therapy is effective by monitoring for:
• Resolution of local and systemic signs and symptoms of infection.
• Resolution of laboratory evidence of infection.
2. Narrow antibiotic coverage when possible with the use of culture and sensitivity data.
3. Assess patient adherence.
4. Ensure that antimicrobial therapy is safe by monitoring for and treating (as appropriate):
• Common and severe adverse effects.
• Drug interactions.
Patient education regarding antibiotic therapy for SSTIs:
1. It is imperative to take the antibiotic as prescribed and to finish the therapy.
2. If no symptomatic improvement is noted within 3 days, contact your health care provider.
3. Many antibiotics cause diarrhea. If it is severe, contact your health care provider.
4. Consider health initiatives to improve wound healing, such as smoking cessation and glycemic control.
If the wound is associated with significant cellulitis and edema, systemic signs of infection, or possible joint or bone involvement, hospitalization and IV antibiotics (typically ampicillin-sulbactam 3 g IV every 6 hours) should be initiated. Bone and joint infections will require longer durations of therapy of up to 6 weeks.49
RABIES AND TETANUS
Patients with animal bite wounds may require rabies prophylaxis.48,49 If the bite is from a bat, a wild animal, a domestic animal that has or is suspected to have rabies, or an unavailable animal, the patient should receive rabies immune globulin and vaccine immediately.50
Crush injuries and those greater than 1 cm (0.4”) in depth are at risk for tetanus. A tetanus and diphtheria toxoid booster (Td) should be administered to any patient who has not received one in 5 or more years. A Td and tetanus immune globulin are indicated in those patients who have not previously received at least three Td boosters or whose immunization history is unknown.48,49
OUTCOME EVALUATION
Patients receiving antibiotic therapy for SSTIs require monitoring for efficacy and safety. Efficacy typically is manifested by reductions in temperature, white blood cell count, erythema, edema, and pain.Initially, signs and symptoms of infection may worsen owing to toxin release from certain organisms (i.e., GAS); however, they should begin to resolve within 48 to 72 hours of treatment initiation. If no response, or worsening infection is noted after the first 3 days of antibiotics, reevaluate the patient.1 Lack of response may be due to a noninfectious or nonbacterial diagnosis, a pathogen not covered by or resistant to current antibiotic therapy, poor patient adherence, drug or disease interactions causing decreased antibiotic absorption or increased clearance, immunodeficiency, or the need for surgical intervention. To ensure the safety of the regimen, dose antibiotics according to renal and hepatic function as appropriate, and monitor for or minimize adverse drug reactions, allergic reactions, and drug interactions.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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