Bacterial skin and soft tissue infections in adults: A review of their epidemiology, pathogenesis, diagnosis, treatment and site of care
Abstract
Skin and soft tissue infections (SSTIs) involve microbial invasion of the skin and underlying soft tissues. They have variable presentations, etiologies and severities. The challenge of SSTIs is to efficiently differentiate those cases that require immediate attention and intervention, whether medical or surgical, from those that are less severe. Approximately 7% to 10% of hospitalized patients are affected by SSTIs, and they are very common in the emergency care setting. The skin has an extremely diverse ecology of organisms that may produce infection. The clinical manifestations of SSTIs are the culmination of a two-step process involving invasion and the interaction of bacteria with host defences. The cardinal signs of SSTIs involve the features of inflammatory response, with other manifestations such as fever, rapid progression of lesions and bullae. The diagnosis of SSTIs is difficult because they may commonly masquerade as other clinical syndromes. To improve the management of SSTIs, the development of a severity stratification approach to determine site of care and appropriate empirical treatment is advantageous. The selection of antimicrobial therapy is predicated on knowledge of the potential pathogens, the instrument of entry, disease severity and clinical complications. For uncomplicated mild to moderate infections, the oral route suffices, whereas for complicated severe infections, intravenous administration of antibiotics is warranted. Recognition of the potential for resistant pathogens causing SSTIs can assist in guiding appropriate selection of antibiotic therapy.
Résumé
Les infections de la peau et des tissus mous (IPTM) sont causées par une invasion microbienne de la peau et des tissus mous sous-jacents. Leur présentation, leur étiologie et leur gravité sont variables. Le défi des IPTM consiste à distinguer avec efficacité les cas qui doivent être soignés immédiatement et justifient des interventions médicales ou chirurgicales, de ceux qui sont moins graves. De 7 % à 10 % des patients hospitalisés souffrent d’une IPTM, et on les voit très souvent en soins d’urgence. La peau est dotée d’une écologie très diversifiée d’organismes qui peuvent provoquer une infection. Les manifestations cliniques des IPTM sont la culmination d’un processus en deux étapes mettant en cause l’invasion et l’interaction des bactéries avec les atteintes de l’hôte. Les signes cardinaux d’IPTM sont les caractéristiques de la réponse inflammatoire accompagnées d’autres manifestations comme la fièvre, la rapide progression des lésions et les cloques. Il est difficile de poser un diagnostic d’IPTM parce que ces infections imitent souvent d’autres syndromes cliniques. Pour améliorer la prise en charge des IPTM, il est avantageux de mettre au point une démarche de stratification de la gravité pour déterminer le foyer des soins et le traitement empirique pertinent. La sélection d’une thérapie antimicrobienne est préconisée dès que l’on connaît les pathogènes potentiels, le mode d’entrée, la gravité de la maladie et les complications cliniques. Dans le cas des complications légères à modérées sans complications, la voie orale suffit, tandis que dans le cas des infections graves accompagnées de complications, l’administration des antibiotiques par voie intraveineuse s’impose. Le fait d’admettre le risque que des pathogènes résistants soient responsables des IPTM peut orienter le choix pertinent de la thérapie antibiotique.
Skin and soft tissue infections (SSTIs) are clinical entities of variable presentation, etiology and severity that involve microbial invasion of the layers of the skin and underlying soft tissues. SSTIs range from mild infections, such as pyoderma, to serious life-threatening infections, such as necrotizing fasciitis. The minimum diagnostic criteria are erythema, edema, warmth, and pain or tenderness. The affected area may also become dysfunctional (eg, hands and legs) depending on the severity of the infection. A patient’s comorbidities (eg, diabetes mellitus and AIDS) can easily transform a normally mild infection into a rapidly advancing threat to life (1). SSTIs present clinically diverse challenges requiring management strategies that efficiently and effectively identify those cases requiring immediate attention and intervention, whether medical or surgical, from those less severe cases.
The difficulty stems from the paucity of robust research to support any particular approach (2,3). Current guidelines for stratifying SSTI patients to specific treatments are based primarily on retrospective data and clinical experience. Eron et al (2) have presented a preliminary algorithm for managing SSTIs based on a crude numerical scale. The goal of the algorithm is to evaluate patients expeditiously and refer them to a specific site of care treatment. Although this algorithm provides an approach to patient stratification, it is overly simplified and takes into account very few patient characteristics in the different classifications. Another schema designed for dermatologists by Elston (4) makes no attempt to differentiate complicated from uncomplicated SSTIs.
The primary purpose of the present paper is to review current practice and then formulate a more comprehensive clinical approach to managing patients with SSTIs. Given the higher prevalence of bacterial infections, the present review does not include a discussion of viral, fungal or parasitic SSTIs. This approach involves an assessment of patient characteristics in assigning infection severity through an algorithm that parallels the community-acquired pneumonia algorithm of severity proposed by Fine et al (5), and Halm and Teirstein (6).
EPIDEMIOLOGY
Given the variable presentation of SSTIs, an assessment of their incidence and prevalence has been difficult. The estimated incidence rate of SSTIs is 24.6 per 1000 person-years (7). Because a majority of SSTIs tend to resolve within seven to 10 days, an estimate of prevalence is highly variable. Among hospitalized patients, the estimated prevalence of SSTIs is 7% to 10% (8,9). Among all hospitalized patients with infections only, SSTIs take on a more prominent role. In the emergency care setting, SSTIs represent the third most common diagnosis after chest pain and asthma (2). There is an increased prevalence among men (60% to 70% of all cases) and patients between 45 and 64 years of age. Approximately 70% to 75% of all cases are managed in the outpatient setting (2,7), with many cases of SSTIs involving the lower leg region (7,9–11). Overall, the rate of complicated cellulitis is low (erysipelas 0.09 per 1000 person-years; lymphadenitis 0.16% of all cellulitis cases; lymphangitis 0.16 per 1000 person-years and necrotizing fasciitis 0.04 per 1000 person-years) (7).
RISK FACTORS
The presence of specific risk factors may potentiate SSTIs, and may dictate their etiology, the course of disease and the response to specific treatments. The presence of risk factors for developing an SSTI has not been shown to correlate with disease severity (9). Thus, the use of risk factors for diagnostic purposes requires further investigation.
Risk factors may be organized into two categories. First, there are patient-related factors, which may predispose to disease or have prognostic implications. Risk factors in this category include critical illness, elderly age, immunocompromised state, liver and kidney disease, and vascular (especially lymphatic or venous) insufficiency (1–3,9,12). Because the lower leg has been shown to be the most frequent location for SSTIs, studies have described specific patient-related risk factors for such infections. A recent study by Björnsdóttir et al (11) was able to quantify the likelihood of an SSTI of the lower limbs based on the presence of Staphylococcus aureus and/or beta-hemolytic streptococcus in toe webs, leg erosions or ulcers, and/or prior saphenectomy. These factors independently correlated with the development of SSTI of the lower leg. In the same population, if toe web bacteria were absent, the presence of tinea pedis had moderate predictive power for an SSTI. Moreover, multiple patient-related risk factors may correlate to a poorer prognosis, more rapid progression of disease, slower healing and, also, more resistant pathogens. Certain risk factors (chronic renal or liver failure, asplenia, immunocompromised state, vascular insufficiency or neuropathy) should be considered in the determination of disease severity.
The second category is etiological risk factors. The mechanism of injury (trauma or others) or specific exposures increases the likelihood of SSTIs caused by specific microbes. There is overlap between risk factors in this grouping and those listed in the above group. A comprehensive list of these etiological risk factors and their associated bacterial causes are presented by Eron et al (2) in Table 1.
TABLE 1
List of etiological risk factors for skin and soft tissue infections and their associated bacterial causes
| Risk factor | Associated etiological pathogen |
|---|---|
| Diabetes mellitus | Staphylococcus aureus, group B streptococci, anaerobes, Gram-negative bacilli |
| Cirrhosis | Campylobacter fetus, Klebsiella pneumoniae, Escherichia coli, Capnocytophaga canimorsus, other Gram-negative bacilli, Vibrio vulnificus |
| Neutropenia | Pseudomonas aeruginosa |
| Human bite wounds | Oral flora (Eikenella corrodens) |
| Cat bite wounds | Pasteurella multocida |
| Dog bite wounds | C canimorsus, P multocida |
| Rat bite wounds | Streptobacillus moniliformis |
| Animal contact | Campylobacter species |
| Reptile contact | Salmonella species |
| Hot tub exposure/loofah sponge | P aeruginosa |
| Freshwater exposure | Aeromonas hydrophila |
| Seawater (fish tank) exposure | V vulnificus, Mycobacterium marinum |
| IV drug abuse | MRSA, P aeruginosa |
| Subcutaneous drug abuse | Anaerobes, especially E corrodens |
IV Intravenous; MRSA Methicillin-resistant S aureus. Adapted from reference 2
MICROBIOLOGY
The principal barrier against microbial invasion is the skin. It constantly interacts with the external environment and is colonized with a diverse population of microbes. The vast majority of colonizing flora consists of bacteria. To help organize the distribution of flora, one can divide the body into two halves at the waistline. The typical organisms that colonize the skin above the waist are usually Gram-positive species such as Staphylococcus epidermidis, Corynebacterium species, S aureus and Streptococcus pyogenes (13). The latter two species are particularly significant because they contribute to a majority of SSTIs.
On the other hand, the typical organisms that colonize the skin below the waist are both Gram-positive and Gram-negative species. It is speculated that this difference is secondary to the proximity to the anorectal region. Enteric species, such as Enterobacteriaceae and Enterococcus species, gravitate to and colonize this area of the skin, the so-called ‘fecal veneer’.
The usual pattern of distribution consists of larger populations in the axilla, groin and intertriginous areas, where there is a higher moisture level. The microflora tend to occupy the stratum corneum and the upper parts of the hair follicles. Specific microbes tend to colonize specific anatomical structures depending on tropic stimuli, site-specific biochemical interactions and tissue-specific biofilm formation. The composition of the flora can vary drastically depending on climate, genetics, age, sex, stress, hygiene, nutrition and hospitalization (13).
The exact mechanisms of interaction between the normal microflora and the human skin are not well understood. A mutual relationship exists between the flora and the human host. In humans, the complex interactions with skin flora promote protection against colonization by other pathogenic species through site competition and production of antimicrobial substances (13). The latter process produces cross-reactive antibodies, which are active against other invasive microbes.
The microbiology of SSTIs may also vary with the means of entry (Table 1) (2). Thus, the etiology of SSTIs may be normal host flora transferred from the instrument of entry or transferred from the environment. In addition, etiologies differ between community-acquired and hospital-acquired SSTIs. Hospital-acquired SSTIs in North America showed an increase in more resistant organisms (14). Specifically, S aureus (45.9%) (approximately 40% of all cases were methicillin resistant), Pseudomonas aeruginosa (10.8%) and Enterococcus species (8.2%) ranked significantly higher than beta-hemolytic streptococci (2.3%), which constitute the majority of community-acquired SSTIs. New evidence suggest an increase in methicillin-resistant S aureus (MRSA) in community-acquired SSTIs (15–17). This isolate is characterized by the insertion of the staphylococcal chromosomal cassette mecA type IV and is associated with the Panton-Valentine leukocidin virulence factor (Table 2) (18).
TABLE 2
Examples of bacteria-specific virulence factors
| Classification | Bacteria | Virulence factor | Details |
|---|---|---|---|
| Adherence factors | S pyogenes | Fimbrillae | Allow adherence to host epithelial cells |
| M protein | Prevent phagocytosis | ||
| Protein F | Allow access into epithelial cells to avoid detection | ||
| S aureus | Clumping factor | Allow adherence to host epithelial cell | |
| Protein A | Prevent antibody opsonization and phagocytosis | ||
| Exotoxins | S aureus | Serine protease | Digest desmosome proteins and cause bullous disease (44) |
| Lipases | Digest skin fatty acids to invade through skin barrier | ||
| Panton-Valentine leukocidin | Membrane pore formation, especially in neutrophils and skin tissues leading to cell lysis (45); predilection for mitochondria may lead to elaboration of oxidative species leading to skin necrosis | ||
| Clostridium species | Collagenases | Connective tissue digestion, which can cause rapidly progressive disease | |
| Hyaluronidases | Matrix protein digestion, which can cause rapidly progressive disease | ||
| Alpha-toxin | Cell membrane and nerve sheath degradation; induce metabolic dysfunction through prostaglandin elaboration | ||
| E coli | Nonspecific exotoxin | Intracellular signalling disruption leading to cell death |
E coli Escherichia coli; S aureus Staphylococcus aureus; S pyogenes Streptococcus pyogenes. Adapted from reference 19
PATHOGENESIS
Human skin serves as the first line of defence against microbial infection as a physical barrier; by secreting low pH, sebaceous fluid and fatty acids to inhibit growth of pathogens; and by possessing its own normal flora, thus deterring colonization by other pathogenic organisms (19). Unfortunately, having penetrated the integumentary barrier, infecting organisms may cause tissue damage and may incite an inflammatory response.
Bacteria, initially in low numbers, colonize different layers of the skin architecture (ie, epidermis, dermis, subcutaneous and adipose tissues, and muscle fascia). As bacteria increase in number where the integumentary barrier is disrupted, invasion by these colonizing bacteria ensues and an SSTI develops. Involvement of pores in the epidermis may lead to folliculitis, furuncles or carbuncles. Infection of the superficial layers of skin is labelled erysipelas, whereas deeper involvement of the dermis and/or subcutaneous tissues is labelled cellulitis. Finally, involvement of yet deeper skin structures may lead to fasciitis and even myositis. For individuals with thick adipose tissues (eg, overweight or obese individuals), involvement of fat tissue causes panniculitis (20).
The clinical presentation of most SSTIs is the culmination of a two-step process. First, invasion occurs, and then a process follows that culminates in clinical effects resulting from the interaction of the bacteria and the host defences.
There are several means by which bacteria penetrate the skin barrier. The most common route is through a break in the barrier. Lacerations, bite wounds, scratches, instrumentation (eg, needles), pre-existing skin conditions, wounds (eg, chicken pox or ulcer), burns and surgery are the common mechanisms of compromising the skin barrier. These mechanisms permit the entry of normal skin flora and indigenous flora from the instrument of penetration. Other routes of penetration include contiguous spread from an adjacent infection (eg, osteomyelitis), entry of water into skin pores (eg, hot-tub folliculitis) and, rarely, hematogenous seeding (ie, emboli) (1–3).
Bacterial infection
The development of an SSTI depends on three steps – bacterial adherence to host cells, invasion of tissue with evasion of host defences and elaboration of toxins (19). Virulence genes, in most pathogenic bacteria, encode special proteins that confer these properties. Specific examples of the following virulence factors are found in Table 2.
Among the bacterial arsenal of virulence proteins, the toxins are most potent and responsible for clinical disease (19). There are two main classes of toxins – endotoxins and exotoxins. Endotoxins are lipopolysaccharide chains found abundantly in Gram-negative bacterial cell walls. In modest quantities, lipopolysaccharides may be beneficial by activating the immune system. They cause the release of chemoattractants and enhance T lymphocyte activation by inducing the expression of costimulatory molecules. Massive elaboration of liposaccharides may, however, lead to detrimental overstimulation of host immune and inflammatory systems. For example, the potent endotoxin expressed by Vibrio vulnificus usually causes rapidly progressive SSTIs, leading to necrotizing fasciitis (21), and culminating in septic shock, disseminated intravascular coagulation and adult respiratory distress syndrome.
Exotoxins, on the other hand, are actively secreted proteins that cause tissue damage or dysfunction through various mechanisms (19). They may cause tissue damage through enzymatic reactions, cellular dysregulation or pore formation, with subsequent cell lysis. A special group of exotoxins is the superantigens. These are most notably produced by virulent S aureus and S pyogenes strains (19). These antigens bind conserved portions of T cell receptors and are, therefore, able to activate a large number of T lymphocytes. The massive release of cytokines causes a grossly exaggerated inflammatory response. SSTIs caused by these strains develop rapidly and are associated with severe tissue necrosis. This phenomenon precipitates toxic shock syndrome.
Inflammation
The other portion of the infection process involves the host response to tissue invasion and damage. As a protective response, the goals of inflammation are to rid the body of the inciting organisms and begin tissue repair. Microbial invasion or tissue damage in skin or soft tissues induces changes in vascular tone to increase blood flow to the injured site. Additional changes in microvasculature promote and assist the extravasation of plasma proteins and leukocytes. These cells and proteins migrate, accumulate and are activated at the site of injury. With activation, cells phagocytize, and destroy foreign matter, dead tissue or microbes. Certain pyrogenic cytokines or exotoxins cause the febrile response. The orchestration of cells and cytokines is highly sophisticated and beyond the scope of the present review. Ultimately, the site of injury is quarantined, cleared and repaired gradually (19).
Unfortunately, there may be circumstances when this process continues unfettered. With diabetic foot ulcer infections, S aureus infections with Panton-Valentine leukocidin production and toxic shock syndrome, the persistence of tissue damage or pathogens may perpetuate the inflammatory response. As a result, inflammation may be the source of ongoing tissue damage (19). The tissue eventually becomes devitalized and hypoxia ensues, which predisposes to anaerobic infections, such as with Clostridium species. Urgent medical attention, including surgical debridement of necrotic tissues and aggressive antibiotic therapy, is essential to arrest inflammation and promote healing.
Clinical manifestations of inflammation
The cardinal manifestations of inflammation are warmth, erythema, edema, pain and dysfunction (22). Prolonged inflammation can lead to chronic edema, especially in the lower extremities, and can result in a postcellulitic syndrome. Ancillary systemic signs, such as fever, hypotension and tachycardia, result from cytokine-induced changes in thermoregulation and vascular resistance. The release of cytokines may be mediated by the normal immune cell function or by bacterial toxin stimulation. Out-of-proportion pain results from severe damage of the deep layers of skin produced by bacterial toxins, while bullous lesions are produced by toxin-mediated epidermal cleavage. Skin anesthesia, which may be present during the course of necrotizing fasciitis, occurs secondary to toxin-mediated nerve tissue damage. Also, violaceous lesions result from toxin-mediated lysis of erythrocytes and hemorrhage (3,8).
Clinical presentation
SSTIs produce a diversity of clinical manifestations. Typical presenting features, as mentioned above, are nonspecific, and include erythema, edema, pain and warmth. In contrast, more severe infections may present with more systemic signs and symptoms, including temperature higher than 40°C or lower than 35°C, hypotension, heart rate faster than 100 beats/min, altered mental status, with a rapidly progressive course and extreme pain (necrotizing fasciitis and myonecrosis) (3,8). On examination of severe infections, one may be able to palpate crepitus and fluctuance secondary to gas or fluid collections. With subsequent necrosis of the dermis, bullae form, which are initially filled with clear fluid and then with hemorrhagic, violaceous fluid (3,8). As mentioned above, skin anesthesia may be a late finding in severe skin SSTIs. Finally, ulcers develop in areas of high mechanical pressure (23), progressing to ischemia and necrosis (24,25).
DIFFERENTIAL DIAGNOSIS
Because of its delicate and intricate anatomy and physiology, the skin is very prone to irritation, abrasions or trauma, as well as the development of lesions generated from within its own structures (eg, folliculitis). Erythematous skin lesions do not always represent infections. A broad range of differential diagnoses exist, which may present similar to impetigo, erysipelas or even cellulitis. Falagas and Vergidis (26) have discussed various common and rare diseases that may mimic SSTIs (Table 3).
TABLE 3
Differential diagnoses of skin and soft tissue lesions
| Disease entity | Description |
|---|---|
| Superficial thrombophlebitis | Inflammation of superficial vein associated with thrombus |
| Usually caused by intravenous needle or catheter; may become secondarily infected | |
| Red, indurated area; tender, palpable vein | |
| Deep venous thrombosis | Blood clot formation in deep veins leading to venous obstruction and inflammation |
| Usually occurs in the setting of hypercoagulability, endothelial dysfunction and stasis | |
| Erythema, edema and warmth; palpable clot (rare); mild fever and leukocytosis | |
| Contact dermatitis | Irritant or allergic skin reaction to environmental agents |
| Sharply demarcated area of erythema and pruritis; may become secondarily infected | |
| Pyoderma gangrenosum | Ulcerative skin condition associated with systemic disease with unknown etiology |
| Commonly occurs with IBD, leukemia, monoclonal gammopathies and rheumatoides | |
| Papule or pustule progress to ulceration with violaceous or vesiculopustular borders | |
| Drug reactions | Erupt secondary to hypersensitivity reaction to consumption of specific medication |
| Usually associated with sulfur-based antibiotics and anti-inflammatory agents | |
| Pruritic or burning, well-demarcated plaque that recurs at the same site and spreads slowly | |
| Eosinophilic cellulitis (Wells’ syndrome) | Idiopathic acute dermatitis with dermal eosinophilic infiltration and eosinophilia |
| Associated with myeloproliferative, immunological and infectious disorders | |
| Recurrent; 2–8 weeks’ duration; multiple, pruritic, erythematous plaques | |
| Acute febrile neutrophilic dermatosis (Sweet’s syndrome) | Idiopathic neutrophilic skin plaque eruption |
| Associated with hematological malignancy (acute myelogenous leukemia) | |
| Red, tender plaques on face, neck and arms; fever; ocular, oral and joint pathology | |
| Gouty arthritis | Joint inflammation causing cutaneous erythema |
| Caused by joint space urate crystal precipitate-induced inflammatory response | |
| Erythema, warmth and tenderness; mild fever, chills and leukocytosis; urate crystals | |
| Erythromelalgia | Idiopathic paroxysmal foot or hand cutaneous disorder |
| Associated with myeloproliferative disorders; triggered by heat, fever and exercise | |
| Foot and hand burning, erythema and elevated skin temperature | |
| Relapsing polychondritis | Idiopathic inflammatory disease affecting cartilaginous structures |
| Commonly affects the ears, with ear lobe sparing | |
| Inflammatory lesions, nonerosive polyarthritis, ocular disease and aortic insufficiency | |
| Carcinoma erysipeloides (inflammatory carcinoma) | Metastatic disease invading into skin lymphatic vessels |
| Associated most with breast carcinoma | |
| Erythematous plaque on or under breast without fever or leukocytosis | |
| Familial Mediterranean fever | Autosomal recessive disease with self-limited fever, synovitis and serositis |
| Self-limited, recurrent, erysipelas-like skin lesions commonly below the knee | |
| Responds well to colchicines | |
| Familial Hibernian fever | Idiopathic, genetic disease with fever and similar symptoms as above |
| Erysipelas-like lesion on limb, which migrates distally from origin | |
| Does not respond to colchicines | |
| Foreign body reactions | Rare hypersensitivity reactions to metallic implants |
| Associated with hypersensitivity to nickel, chromium and cobalt | |
| Reaction causes overlying cutaneous, cellulitis-like erythema | |
| Polyarteritis nodosa | Multisystemic, necrotizing vasculitis |
| Subcutaneous, inflammatory nodules along affected artery that coalesce into plaques | |
| Often bilateral and involve lower extremities | |
| Erythema nodosum | Septal panniculitis, usually secondary to systemic disease |
| Associated with IBD, sarcoidosis and Behçet’s syndrome | |
| Coalescent raised, painful lesions, usually in arms and legs bilaterally; 4–6 weeks’ duration |
IBD Inflammatory bowel disease. Adapted from reference 26
The general lack of data has precluded the development of a standardized approach to categorizing the different skin diseases. For this reason, an approach to the differential diagnosis of SSTIs may be based on the specific anatomical site affected. First, for skin lesions that affect the upper extremities, venous thrombophlebitis, contact dermatitis, envenomations, Sweet’s syndrome, gouty arthritis, pseudogout, erythromelalgia and familial Hibernian fever should be considered. Second, for lesions that affect the head, acne, drug reactions, relapsing polychondritis, herpes zoster and psoriasis should be considered. Third, for chest and abdominal skin lesions, drug reactions, foreign body reactions, the familial fever syndromes, eosinophilic cellulitis, herpes zoster infection and carcinoma erysipeloides should be considered. Finally, for lower extremity skin lesions, deep venous thrombosis, gouty arthritis, pseudogout, relapsing polychondritis and erythromelalgia should be considered.
DIAGNOSIS
The diagnosis of most SSTIs is based on clinical impression. Laboratory investigations help to confirm the diagnosis and elucidate characteristics of specific etiologies. A diagnostic approach to a suspected SSTI is provided in Figure 1.
Diagnostic evaluation of skin and soft tissue infections (SSTIs). *As clinically indicated; †Ulcerated lesions should be cleaned and debrided before having wound base swabbed; ‡Most useful if vesicle/bullae or fluid abscess present; §Seek out bone trauma and air fluid levels; ¶Indications –neurological deficits, vision nonassessable, proptosis/deteriorating acuity or colour/bilateral edema/ophthalmoplegia, no improvement after 24 h and swinging pyrexia not resolving within 36 h (for head only); **Only if central nervous system involvement suspected and intracranial pressure excluded. CT Computed tomography; MRI Magnetic resonance imaging
The first step is clinical suspicion of an SSTI. The minimum criterion is a skin lesion with the typical inflammatory tetrad – tenderness, erythema, edema and warmth. Depending on the extent and location of infection, dysfunction of the affected area (eg, hand or foot) may also be present. The symptom that highly increases the suspicion of an SSTI is fever. Other signs and symptoms, including crepitus, bullae, anesthesia and hemorrhage, augment the suspicion and confirm the diagnosis.
Investigations may include blood cultures, tissue swab with culture, needle aspiration, x-ray, ultrasound and computed tomography (CT) scan or magnetic resonance imaging (MRI) screen, depending on the clinical manifestations. In the presence of systemic symptoms, such as fever and hypotension, blood cultures help to assess for bacteremia. Blood cultures produce a low yield, with less than 5% of cases being positive (27).
Swabs of tissue with culture, such as blood cultures, are also low-yield tests (27). Before swabbing, an ulcerated wound ought to be debrided and cleansed with normal saline irrigation. The difficulty with this test is determining which positive swab cultures represent pathogenic agents and which represent merely skin colonization. In wounds with skin breakdown characterized by the cardinal manifestations of SSTIs, tissue swabs are most useful, given the high pretest probability of infection. In addition, positive swabs of superficial ulcers – without penetration to the bone – in diabetic patients are also useful in determining the microbiological etiology of the underlying infection (28). However, such swabs may not be indicative of the etiology of underlying osteomyelitis (29).
Needle aspiration is a controversial investigation, and different approaches exist. Some studies advise a leading edge aspirate, while others attempt a central aspirate. The evidence, however, demonstrates no added benefit to either method. In one study, positive cultures were attained in approximately 10% of patients, regardless of method (30). Furthermore, it has also been demonstrated that patients with underlying diseases or fever are more likely to have positive needle aspirate cultures (31). Needle aspirations may be most useful in patients presenting with skin infections associated with fluid-filled vesicles.
An x-ray or ultrasound may be used to explore subdermal involvement. The x-ray may reveal bony involvement such as with osteomyelitis, although its sensitivity and specificity is limited (32). In addition, x-rays may reveal air in the tissues or air fluid levels, which are indicative of gas-producing organisms such as Clostridium species. Ultrasound, on the other hand, may be used to investigate fluctuance and crepitus. This modality is useful for detecting abscess formation or fascial inflammation (9,33). For more detailed exploration of deeper soft-tissues, a CT scan or an MRI screen may be useful. These latter two modalities are most helpful in diagnosing patients with rapidly progressive skin infections, because these lesions do not present superficially until later in their course (3,8,9). For these rapidly progressive lesions, such as necrotizing fasciitis, early surgical exploration may be prudent, because usual diagnostic testing may prove equivocal (2,3). In patients with cranial lesions suspected of being SSTIs, head CT scans and/or MRI screens are indicated in patients with the following findings: neurological deficits, nonassessable vision, proptosis, deteriorating visual acuity, bilateral ocular edema or ophthalmoplegia, head lesions with no improvement after 24 h or swinging pyrexia not resolving within 36 h (34). In patients suspected of central nervous system involvement, a lumbar puncture may be necessary after the exclusion of increased intracranial pressure.
Because involvement of the head or hand is associated with a higher perceived risk for loss of function, it is vital to assess patients with such infections vigilantly. Increased diagnostic testing is needed to determine the depth and extent of infection. This information is vital for the timely administration of treatment to prevent short- and long-term morbidity.
SEVERITY STRATIFICATION
Due to the diverse presentation of SSTIs, it has proven difficult to adopt a severity stratification approach. To improve the management of SSTIs, it is vital to develop an appropriate severity stratification approach to assist in determining the site of care and appropriate empirical treatment.
Eron et al (2) formulated a grading system of SSTIs based on a four-grade clinical description of the lesion and the patient. Once the severity grade of the infection is determined, an algorithm exists to assist in specifying the site of care. Unfortunately, because the descriptions of patient clinical presentations are quite ambiguous, the system is not very practical in its application.
To improve on the schema of Eron et al, a severity stratification system is proposed that mirrors the system designed by Fine et al (5) and Hahn and Teirstein (6) for grading community-acquired pneumonias (Figure 2). This system grades severity according to the presence or absence of specific historical and clinical findings. Its practical applicability requires further testing and validation.
Evaluation algorithm for severity of skin and soft tissue infection (SSTI). dx Dysfunction; HR Heart rate
To be considered an SSTI, the presenting skin or soft tissue lesion must meet the minimum criteria outlined above, but depending on the infection, not all of these signs are required. In addition, patient comorbidities may impact on the progression and the course of SSTIs. There are specific comorbid conditions that increase the risk of acquiring severe SSTIs (see above). The presence of these conditions must be assessed and factored in when judging severity for potential admission to the hospital.
The systemic manifestations of fever (lower than 35°C or higher than 40°C), hypotension, tachycardia (heart rate faster than 100 beats/min) or altered mental status represent systemic toxicity, and portend deeper penetration and invasion of the infection. If allowed to progress, patients with these clinical signs may go on to develop severe sepsis and/or shock, which carry high morbidity and mortality rates.
The next step in determining the severity of the infection is to assess the site of the lesion. The most common site for an SSTI is in the lower extremities. In contrast, involvement of the whole hand or head has the potential for more significant damage. Even if such infections seem clinically less severe, they should prompt more vigilant investigation and treatment. Head and hand SSTIs, therefore, carry a greater clinical severity.
The size of the lesion is a very important determinant of disease severity. Certain SSTIs, such as necrotizing fasciitis, have a tendency to involve large areas of skin and soft tissue, even though in their early stages, this may not be apparent (3,8,9). Large and rapidly progressive SSTIs require more urgent management, observation and intervention. To help distinguish large from smaller lesions, the use of the ‘rule of nines’ as previously applied to burn victims is recommended (35). For adults, each arm and the head constitute approximately 9% of body surface area, whereas each leg, the upper torso and the abdomen (when including both anterior and posterior aspects) each constitute approximately 18% of body surface area, respectively. Any SSTI that involves more than 9% of body surface area should be viewed as severe (Figure 3). The exception to this rule are head and hand infections. The whole head and the whole hand constitute approximately 9% and 2% of body surface area, respectively. The potential morbidity of these infections, as previously mentioned, requires a lower threshold for increasing severity. Therefore, for these regions, lesions covering the whole hand or one-half of the head should be considered to be as more severe infections.
Finally, one must consider specific signs and symptoms in determining disease severity. The presence of bullae, hemorrhage, out-of-proportion pain, crepitus, anesthesia and rapidly progressive character herald the presence of greater disease severity.
Following the determination of severity based on the proposed algorithm, one can establish the appropriate site of care. If the infection is mild, outpatient management is appropriate, which includes an antibiotic regimen (oral or intravenous) with or without specific wound care. If, however, the infection is severe, it is prudent to consider hospital admission or at least admission to an observational unit. If left untreated, mild infections may progress to severe infections.
ANTIMICROBIAL TREATMENT
Traditionally, pharmacotherapeutic recommendations have been based on bacterial etiology. Unfortunately, most often, the specific bacterial etiology of an SSTI is unknown and clinicians are forced to prescribe empirically. As a result, treatment recommendations based solely on organisms are difficult to apply clinically.
An approach based on clinical presentation offers a practical framework by which to organize SSTI treatment to help guide empirical therapy. However, deviations from this framework do occur under special circumstances. These special considerations may include the following – diabetic lower limb infections, nosocomial infections, infections secondary to specific environmental exposures, necrotizing infections and colonization with resistant organisms (eg, MRSA). Recommendations for treating routine SSTIs are presented first, followed by recommendations for managing SSTIs in special circumstances.
As presented earlier, the most common etiologies of SSTIs are the normal host flora. Above the waist, one should always consider staphylococcal and streptococcal species as the instigating organisms of SSTIs. Therefore, for all mild to moderate infections (according to the previous severity algorithm), empirical therapy should always be directed against these species (Table 4) (1–3,36).
TABLE 4
Antimicrobial table for different skin and soft tissue infections
| Clinical entity or risk factor | Common etiology | Empirical antibiotic(s) |
|---|---|---|
| Mild infections (above waist) | Staphylococcus aureus Streptococcus pyogenes | Cloxacillin, cephalexin or clindamycin (if penicillin allergy) |
| Infections of hand and head | S aureus S pyogenes* Haemophilus influenzae (head infection in children) | Cefazolin, ceftriaxone or cefuroxime (H influenzae) followed by cephalexin (step-down therapy) |
| Severe infections (above waist) without special considerations (see text below) | S aureus | Cefazolin, then cloxacillin or cephalexin (step-down therapy) |
| Mild infections (below waist) | S aureus | Cloxacillin or cephalexin |
| S pyogenes* | Add clindamycin or metronidazole (anaerobes) | |
| Coliform species possible | Add second-generation cephalosporin or fluoroquinolone (if Gram-negative) | |
| Severe infections (below waist) | Escherichia coli Enterococcus species Other coliform species S aureus S pyogenes* | Second-, third- or fourth-generation cephalosporin, fluoroquinolones or piperacillin-tazobactam (in addition to above Gram-positive coverage) |
Lesions affecting the head and hand deserve special mention. The typical etiologies are still staphylococcal and streptococcal species; however, for children, one ought to consider Haemophilus species infection that may involve the face. Current guidelines (36,37) recommend the use of intravenous cefazolin or ceftriaxone with or without clindamycin as the initial therapy, with cephalexin as the step-down agent of choice. For suspected Haemophilus infections, cefuroxime is the recommended empirical agent of choice.
For deeper and larger lesions above the waist associated with systemic signs and symptoms, but without other complicating factors or significant circumstances (refer to algorithm), the typical etiologies are similar. Empirical treatment of such lesions should still target staphylococcal and streptococcal species (especially S aureus and S pyogenes). Some would consider the addition of clindamycin to standard therapy for enhanced coverage of group A streptococcal species (3). Inhospital treatment may be necessary depending on patient status. It should be noted that out-patient intravenous therapy is advisable in cases in which there are issues with oral tolerance or compliance. With clinical improvement and stabilization, oral step-down therapy is recommended.
For SSTIs below the waist, special consideration must be given to the change in flora. As described earlier, in addition to the typical Gram-positive species, one needs to also consider enteric species – the so-called ‘fecal veneer’. Risk factors for increased Gram-negative or anaerobic colonization include bedridden patients, severe and chronic infections requiring multiple courses of antibiotic treatment, and extensive necrosis. The treatment recommendations are shown in Table 5 (1–3,36,37). Chronic diabetic ulcer infections, especially with extensive necrosis, warrant anaerobic coverage. With respect to beta-lactams or fluoroquinolones, there is evidence to suggest that these two agents have similar efficacy in empirical therapy (38). In fact, given the increased adverse event profile for fluoroquinolones, beta-lactams should be the preferred empirical agents in immunocompetent patients.
TABLE 5
Special considerations in treating skin and soft tissue infections
| Prolonged hospitalization or antibiotic exposure | MSSA
MRSA Pseudomonas aeruginosa Enterococcus species AR Enterobacteriaceae species | Second- or third-generation cephalosporin (mild to moderate), beta-lactam plus a fluoroquinolone or aminoglycoside; add vancomycin if MRSA suspected |
| New diabetic foot ulceration (antibiotic naive) | MSSA
Streptococcus pyogenes | Cloxacillin or cephalexin |
| Chronic foot ulceration (antibiotic sensitive) | MSSA
MRSA CNS S pyogenes AR Enterobactericiae species | Piperacillin-tazobactam, ceftriaxone, ciprofloxacin or meropenem with vancomycin (combination therapy recommended) |
| Chronic nonhealing foot ulceration (antibiotic sensitive) | P aeruginosa MSSA MRSA CNS S pyogenes AR Enterobactericiae species | Combination therapy (as above) with antipseudomonal activity: piperacillin-tazobactam, ceftazidime or ciprofloxacin |
| Necrotic or gangrenous foot infection | Bacteroides species
Other anaerobes P aeruginosa MSSA MRSA CNS S pyogenes AR Enterobactericiae species | Add clindamycin or metronidazole to baseline therapy |
| Rapidly progressive infections or necrotizing fasciitis | Group A streptococcus species
Staphylococcus aureus Anaerobic bacteria Clostridium species | Clindamycin with penicillin G or cefazolin (change depending on inciting event) |
| Bites | Animal bites
Streptococcus/Staphylococcus species Pasteurella species Capnocytophaga canimorsus Bacteroides species Porphyromonas species Fusobacterium species Prevotella heparinolytica Propionibacterium species Peptostreptococcus species Human bites Viridans streptococci Staphylococcus species Haemophilus species Eikenella corrodens | Amoxicillin-clavulanate (mild lesions), ceftriaxone plus metronidazole (moderate to severe lesions), clindamycin plus TMP-SMX (penicillin allergy) |
| Exposure to salt water or freshwater | Aeromonas hydrophila (freshwater) | Ciprofloxacin (freshwater) |
| Vibrio vulnificus (salt water) | Doxycycline (salt water) | |
| Injection drug use | S aureus | Cephalexin or cloxacillin with metronidazole |
| S pyogenes Gram-negative and anaerobic species (usually polymicrobial) | Ceftriaxone with metronidazole (marked necrosis) | |
| HIV | Gram-positive, Gram-negative and anaerobic polymicrobial infections | Piperacillin-tazobactam |
| Community-associated MRSA | Community-associated MRSA | Soaks, incision plus drainage, topical mupirocin (minor infections); clindamycin, TMP-SMX or doxycycline (mild infections); vancomycin, clindamycin or TMP-SMX (severe infections) |
AR Antibiotic resistant; CNS Coagulase-negative Staphylococcal species; MRSA Methicillin-resistant Staphylococcus aureus; MSSA Methicillin-sensitive S aureus; TMP-SMX Trimethoprim-sulphamethoxazole
Special considerations
With increased antibiotic exposure or prolonged hospitalization, patients are at an increased risk for infections with resistant organisms (Table 5). The pathogens in these infections are S aureus (including MRSA), P aeruginosa, Enterococcus species, Escherichia coli and other antibiotic-resistant Enterobacteriaceae species (37). Guidelines recommend second- or third-generation cephalosporins as first-line agents for mild to moderate infections. In P aeruginosa infections, combination therapy may be considered. A recent study (39) of P aeruginosa bacteremia demonstrated a significant mortality benefit with combination therapy directed against the pathogen. However, no studies have examined the impact of combination therapy on SSTIs. With more severe or rapidly deteriorating infections, therapy should be expanded to broad-spectrum agents. In the case of MRSA, vancomycin should be added to first-line therapy.
Diabetic lower extremity SSTIs are highly prevalent worldwide. Appropriate management of these infections requires targeted pharmacotherapy (2,3,27,36). First, for superficial infections suggestive of cellulitis, or new ulcer and antibiotic naivity, therapy should still target staphylococcal and streptococcal species. Second, for a chronic ulcer infection in a patient with a history of multiple antibiotic courses, one also needs to consider Enterobacteriaceae species (especially resistant strains), coagulase-negative staphylococcus and MRSA as etiological pathogens. Piperacillin-tazobactam, ceftriaxone, fluoroquinolones and the carbapenems, such as ertapenem, imipenem or meropenem, may be considered as first-line empirical agents for these lesions. For MRSA, vancomycin is the mainstay of therapy. Third, for the chronic nonhealing ulcer infections in patients with prolonged antibiotic exposure, one needs to consider the possibility of P aeruginosa infection. For these SSTIs, combination therapy should contain an antipseudomonal beta-lactam agent such as piperacillin, piperacillin-tazobactam, ceftazidime or a carbapenem, plus a fluoroquinolone such as ciprofloxacin. Finally, for SSTIs showing evidence of necrosis, the etiology is usually polymicrobial, and consists of both aerobic and anaerobic organisms. Initial therapy in these patients should be intravenous; however, with clinical improvement, therapy may be streamlined to oral antibiotics. The management of such infections requires careful monitoring and frequent therapeutic titration.
Rapidly progressive and necrotic SSTIs require urgent intervention. Because of their tendency to present with non-specific signs and symptoms, a delay in diagnosis may lead to severe complications. The management of these SSTIs requires early surgical consultation and supportive care measures, including fluid management, vasopressor agents and antibiotics. Many lesions require extensive debridement before any healing may begin (3,8). With regard to adjuvant medical therapy, antibiotic agents should target Gram-positive organisms: group A streptococcus, S aureus, group B streptococcus and Clostridium species. Current guidelines recommend intravenous clindamycin in combination with either penicillin G or cefazolin. Depending on the inciting event (eg, bite or environmental exposures), empirical therapy may need to be altered to cover for specific bacterial etiology (3). Ancillary intravenous immunoglubulin may also prove to be useful in severely septic patients (40).
Bite wounds are at risk for developing SSTIs. In these cases, it is important to determine the cause of the bite wound. Organisms involved in these SSTIs depend on the source agent as mentioned above. For human bites, because of the resistance pattern of Eikenella species, intravenous cefoxitin or a beta-lactam/beta-lactamase inhibitor are recommended for first-line empirical therapy (3). For mild lesions secondary to animal bites, treatment with oral amoxicillin-clavulanate suffices. For moderate to severe lesions, intravenous ceftriaxone in combination with metronidazole is recommended. For patients who have a penicillin allergy, a combination of trimethoprim-sulfamethoxazole and clindamycin is recommended (2,3,36).
Specific types of SSTIs may result secondary to exposure to salt water or freshwater. Current guidelines (2,3) recommend doxycycline or ciprofloxacin for salt water- and freshwater-exposed SSTIs, respectively.
Injection drug users may develop SSTIs at injection sites. Although staphylococcal species predominate in these infections, patients may present with polymicrobial infections. The approach to empirical therapy, therefore, must also consider Gram-negative and oral anaerobic organisms. Despite the possibility of Gram-negative infections, current guidelines recommend the combination of cephalexin or cloxacillin with metronidazole for empirical treatment. MRSA may also be isolated in these patients due to previous multiple antibiotic exposures (41). For such infections, agents directed against MRSA are necessary (vancomycin, trimethoprim-sulfamethoxazole with rifampin, tetracycline with rifampin, fusidic acid with rifampin, linezolid, daptomycin and tigecycline). In cases with necrosis in which Gram-negative species are suspected, a third-generation cephalosporin, such as ceftriaxone, may be substituted in the above regimen (2,3,30,37).
With increasing worldwide prevalence, patients with HIV may develop severe polymicrobial SSTIs. Although Gram-positive organisms predominantly cause the lesions in these patients, being immunocompromised increases HIV patients’ susceptibility to infections with Gram-negative organisms and anaerobic organisms. Current guidelines recommend the use of intravenous therapy with piperacillin-tazobactam (3).
Recently, there has been an acute rise in the incidence of infections involving community-associated MRSA (15,17,41). Currently recognized risk factors include the following: young age, contact sport athlete, injection drug use, military personnel, correctional facility inmate, MRSA carrier, recurrent or recent antibiotic use, and overcrowding (41). SSTIs with this organism may range from mild to severe. An expert committee has developed guidelines for the management of community-associated MRSA infections (41). Treatment guidelines were based on severity and organism susceptibility testing. For minor skin infections caused by community-associated MRSA, nonantibiotic treatment consisting of soaks, incision and drainage, and possibly topical mupirocin, suffice. Once MRSA is confirmed in mild, non-life-threatening SSTIs, clindamycin, trimethoprim-sulfamethoxazole or doxycycline may be used as first-line agents. For MRSA-positive life-threatening lesions, therapy with intravenous vancomycin, clindamycin or trimethoprim-sulfamethoxazole is recommended.
Duration of therapy
There are no guidelines to dictate specific durations of therapy. Clinicians should be guided by clinical response to drug therapy. Follow-up is of the utmost importance. On average, treatment for most lesions requires 10 to 14 days of antibiotic therapy. It should be noted that following initiation of antibiotic treatment, if there this no response in five days, this should prompt a change in the antibiotic regimen or other investigations to verify the diagnosis (41).
Intravenous versus oral therapy, step-down options and additional care
The decision to use intravenous or oral agents has been an ongoing controversy. At present, there is no evidence supporting any difference in efficacy between the two routes of therapy. Current consensus among clinicians, however, recommends oral therapy for mild infections and intravenous therapy for severe infections. The latter allows the achievement of high drug levels with rapid delivery. Intravenous therapy is also indicated in patients who experience oral intolerance. Moderate infections may be treated via the oral route, or perhaps with one to two intravenous doses and then graduating to oral therapy.
For patients with severe infections who are able to tolerate oral therapy and in whom clinical improvement has been documented, the goal should be to streamline therapy to the oral route as soon as possible. There is evidence to suggest that this approach positively impacts length of stay as well (42).
In choosing an appropriate step-down oral antibiotic, there are three options (42). First, one may choose the same active antibiotic in oral form with high bioavailability. Antibiotics in this group include amoxicillin, cephalexin, clindamycin, trimethoprim-sulfamethoxazole, metronidazole, doxycycline and linezolid. Second, one may choose the same active antibiotic in oral form with moderate bioavailability. Antibiotics in this group include penicillin V, ampicillin, cloxacillin, ciprofloxacin and tetracycline. Finally, one may choose an oral antibiotic from the same or a different class with a similar spectrum of activity and good bioavailability (43).
It is noteworthy to include basic wound care techniques as part of the management of SSTIs. Wound dressings that range from debriding agents to growth-enhancing measures, such as vacuum-assisted closure and occasionally compression, are part of the overall management of SSTIs. These practices may enhance the healing process.
SUMMARY
SSTIs are a highly prevalent but complex and diverse group of infections. As a result of the diversity of their presentation, clinical management is challenging. Furthermore, their management is complicated by the paucity of evidence from well-documented studies, and decisions regarding site of care and appropriate antimicrobial therapy may be inconsistent and inefficient.
One method of addressing site of care decisions is to determine disease severity based on the combination of several clinical findings. Disease severity should consider location, size, systemic symptoms, comorbidities and significant characteristics of the infection. Based on these criteria, SSTIs may be classified as either mild or moderate to severe. Following this stratification, one can determine the site of care: mild lesions can be treated in the outpatient setting with oral therapy, whereas moderate to severe lesions may require hospitalization or outpatient intravenous therapy.
Appropriate antibiotic therapy is the key to infection treatment. Empirical therapy should depend on several factors: potential pathogens, disease severity, clinical complications and the instrument of entry (eg, animal bite). For all uncomplicated lesions, empirical therapy should target the typical Gram-positive skin flora, such as S pyogenes and S aureus. For lesions below the waist, therapy should also be directed against enteric species. Characteristics that complicate SSTIs include prolonged hospitalization and antibiotic therapy, diabetes, rapidly progressive and necrotic lesions, bite wounds, exposure to salt water or freshwater, injection drug use, HIV and risk factors for community-associated MRSA. Empirical therapy for SSTIs in the above settings must include coverage of the commonly encountered pathogens. Finally, the duration of therapy and use of oral therapy are best determined by careful follow-up and astute clinical judgement. It is also unknown whether current therapy guidelines for outpatient and hospitalized patient care are optimal with respect to treatment efficacy and health care costs.