Chapter 178. Non-Necrotizing Infections of the Dermis and Subcutaneous Fat: Cellulitis and Erysipelas

Skin and soft tissue infections (SSTI) are characterized by clinical findings that include an acute, tender, spreading, edematous, suppurative inflammation of the skin, subcutaneous fat, or muscle, often associated with systemic symptoms of malaise, fever, chills, and local pain. Cellulitis is an infection of the dermis and subcutaneous fat, while erysipelas is a more superficial variant affecting the superficial dermal lymphatics and adjacent tissues. Along with the pyodermas (see Chapter 176), cellulitis and erysipelas, are the predominant forms of non-necrotizing SSTI, which account for 7%–10% of hospitalizations in North America.1 Over the past two decades, the incidence of SSTI has increased faster than the incidence of other acute infections, paralleling the rise of methicillin-resistant Staphylococcus aureus (MRSA) rates.2

Cellulitis and erysipelas are usually caused by S. aureus or β-hemolytic Streptococci [primarily group A Streptococcus (GAS)] (see Table 178-1). Factors that increase the likelihood of SSTI include exposure to pathogenic organisms, local breach of the skin barrier function (including atopic dermatitis, and less often, allergic contact dermatitis, psoriasis, trauma, intravenous drug use, surgical and cosmetic procedures, toe-web intertrigo, arthropod bites, and chronic ulcers), immunocompromise (including acquired immunodeficiency syndrome [AIDS], diabetes, end-stage renal disease/dialysis, neutropenia, cancer, and immunosuppressive medications), obesity, and circulatory compromise (see Chapter 175).

Several risk factors, relatively specific to erysipelas, include extremes of age (children and the elderly), diabetes mellitus, and nephrotic syndrome.3 In the adult patient with erysipelas, lymphedema (including congenital lymphedema), venous stasis, web intertrigo, and obesity are common risk factors. Lymphedema in particular may be an important feature in erysipelas even when subclinical and only evident by lymphosyntigraphy.4

For all variants of cellulitis, there is less predictability in immunocompromised hosts where organisms may include a range of traditional and rare pathogens, usual commensals, yeast, fungi, and parasites. Because traditional patterns of symptoms and physical findings may be lacking or nonspecific in immunocompromised patients, determining an etiologic diagnosis is especially important.5 In both immunocompetent and immunocompromised hosts, bullae, necrosis, or gas-forming bacterial infections signal urgency in establishing the location of infection and in defining the cause (see Chapter 179).

Pathogens isolated from cellulitis are split primarily between S. aureus and GAS; the best estimates place the rate of S. aureus cellulitis at approximately 50%, and GAS at approximately 35%.6 However, microbiologic studies are limited by the low yield of cultures from cellulitis (see Section “Diagnostic Studies”), and anecdotal experience suggests that S. aureus may now be a far more common cause of cellulitis than GAS. Haemophilus influenzae is an important cause of cellulitis in much of the world, but the widespread use of the Haemophilus influenza type b vaccine has greatly decreased the incidence in the United States.

The remainder of cellulitis cases are caused primarily by groups B and G Streptococcus,7,8 enteric-Gram-negative rods,9 coagulase-negative Staphylococcus,10 and Streptococcus pneumoniae.11 These unusual pathogens are particularly common and problematic in association with extremes of age, prolonged hospitalization, percutaneous intravascular lines, diabetes, obesity, immunocompromised states, and glucocorticoids.8 Liposuction and percutaneous drug use are reported risk factors that may also lead to cellulitis from less common organisms.

Erysipelas is a distinct type of superficial cutaneous cellulitis with marked dermal lymphatic vessel involvement. GAS has classically been considered the predominant cause of erysipelas, but erysipelas may also be caused by S. aureus and group C or G Streptococcus.

Virulence Mechanisms

Both S. aureus and GAS possess effective mechanisms of bypassing the immune system and establishing infection. GAS appears capable of inactivating cathelicidin LL-37, thereby mediating resistance to the innate immune system.12 Although it is classically regarded as an extracellular pathogen, GAS also appears able to evade immune detection and antibiotic therapy by entering macrophages and endothelial cells.13,14 Both GAS and S. aureus may produce exotoxins that result in systemic toxic reactions, including toxic shock syndrome (see Chapter 177). Panton–Valentine Leukocidin (PVL) is a β-pore forming toxin produced by many strains of S. aureus that damages leukocytes and predisposes to severe SSTI and other infections.15

Antimicrobial Resistance

Methicillin-Resistant Staphylococcus Aureus (MRSA), and Related Pathogens

Antibiotic resistance is of increasing concern, particularly in the case of MRSA, which, in many series across disparate geographic areas in the United States and Europe, now accounts for more than 50% of cellulitis from which a pathogen could be cultured.16–19 Healthy individuals are frequently affected, but certain populations appear to be at particular risk for MRSA skin infections, including those with immunosuppression, chronic illness (including end-stage renal disease), prisoners,17 athletes,20 and men who have sex with men.21 Other risks noted in the literature include youth, recent sexual contact, presence of abscess, low body mass index, spontaneity of infection, and group home living.16

Methicillin resistance arises from the mecA gene, a component of a mobile genetic element, the staphylococcal cassette chromosome (SCCmec). This gene results in the production of an altered penicillin-binding protein (PBP2a), with a lower affinity for β-lactam groups, resulting in a minimum inhibitory concentration (MIC) to oxacillin of at least 4 μg.22 This mechanism imparts resistance to all β-lactam antibiotics currently available, including penicillins, cephalosporins, monobactams, and carbapenems. Similar resistance mechanisms to β-lactams have been increasing in several important pathogenic strains of coagulase-negative Staphylococcus species, including S. sciuri and S. haemolyticus.23,24

Relative to infection with Methicillin-sensitive S. aureus (MSSA) and other pathogens, infection with MRSA is associated with a higher rate of adverse outcome and treatment failure,25 as well as higher economic costs of care.26 These unfavorable outcomes likely arise from the virulence factors closely associated with dominant MRSA strains in both community and nosocomial settings. Many MRSA strains, including the CA300 strain, which has emerged as the dominant community-acquired (CA) strain in the United States, have a very high rate of PVL expression,27,28 and they also appear to be more effective colonizers than MSSA strains.29

Both hospital-acquired (HA) and CA-MRSA strains have accumulated mutations that result in resistance to other classes of antibiotics, including macrolides, tetracyclines, fluoroquinolones, and sulfonamides, though the resistance patterns to these non-β-lactam antibiotics vary widely by region. With increased use of mupirocin and chlorhexidine as adjunctive therapies for MRSA, or as part of decolonization regimens, resistance to these topical agents is also on the rise, topping 10% in some settings.30,31 Resistance to mupirocin has been associated with increased resistance to other antibiotics,30 and with poor outcome measures, including increased mortality in at least one study of MRSA in an intensive care unit setting.32 In addition, resistance to the drugs often considered “salvage” medications, including vancomycin19 and linezolid,33 is of increasing prevalence and concern.

Vancomycin-Resistant Enterococcus (VRE)

Vancomycin-resistant Enterococcus is most often a colonizing organism in SSTI, but it may act as a pathogen in nosocomial SSTI in immunocompromised patients.34 Despite its relatively low virulence, VRE is of increasing concern because of its ability to transmit resistance to other bacterial species, and because of the increasing prevalence of immunocompromised patients worldwide from HIV disease/AIDS and immunosuppressive medications.35

Classical Cellulitis

Cellulitis presents with erythema, pain, firm and tender induration, and less commonly, fluctuance. The erythema may rapidly intensify and spread. The margins are generally indistinct. In some cases of cellulitis, the overlying epidermis undergoes bulla formation or necrosis, resulting in extensive areas of epidermal sloughing and superficial erosion (Figs. 178-1 and 178-2). Regional lymphadenopathy may be associated with cellulitis on an extremity. In older individuals, thrombophlebitis may complicate lower leg cellulitis. Systemic symptoms, such as fever, chills, and malaise are variable, and sometimes may antedate localizing complaints and signs of SSTI. In a study of 50 patients with cellulitis, only 26% had fever higher than 38°C (100.4°F). A potential portal of entry was identified in 66% of patients.36

The infection may also cause deeper necrosis, resulting in dermal and subcutaneous abscess formation, fasciitis, and myonecrosis. Pain in the absence of erythema, or out of proportion to the appearance of the local area, should raise suspicion for an early deep-seated infection. Crepitus is a rare sign that signifies a gas-forming pathogen (see Chapter 179).

Cellulitis usually presents at the site of an antecedent lesion, including acute and chronic ulcers, traumatic wounds (abrasions, lacerations, animal and human bites), surgical procedure sites, dermatoses, or percutaneous catheters. Less commonly, bacteremia from systemic infections such as osteomyelitis and diverticular abscesses may cause SSTI.

Erysipelas

Although erysipelas shares many clinical features with classical cellulitis (pain, tenderness, erythema, and edema), the plaque-like edema has a more sharply defined margin to normal tissue, and the erythema is classically bright red (Fig. 178-3). The surface findings are often described as peau d'orange (skin of an orange) in appearance. In the presence of antecedent edema or other anatomic abnormalities, the margin between normal and diseased soft tissue may be more obscure, much as in primary cellulitis.

Seventy-five to 90% of cases involve the lower extremities, while the face is affected in 2.5%–10% of cases.37 Facial erysipelas begins unilaterally but may spread by contiguity over the nasal prominence to involve the face symmetrically (Fig. 178-4). There may not be an obvious portal of entry, and skipped areas may confuse the nature of the process. The oropharynx is a common portal of entry, and throat culture may show GAS. Inflammatory edema can extend to the eyelids, but orbital complications are rare.

Fever may precede local signs, and occasionally before distal extremity findings, patients complain of groin pain caused by swelling of femoral lymph nodes. Lymphangitis and abscess are not common, but the process may spread rapidly from the initial lesion. Infrequently, bullae or epidermal sloughing may occur in the involved area.38

Cellulitis Complicating Surgical Wounds

Surgical wound infections are the most common adverse events in hospitalized patients undergoing surgery and are classified as incisional (superficial) or deep.39 Incisional wound infections involve the skin, subcutaneous tissue, and/or muscle (see Fig. 178-2B). Up to 80% of wound infections are incisional. A wound is considered to be infected if there is drainage of purulent material and evidence of inflammation. Incisional infections present with erythema, pain, tenderness, local swelling and often, with low-grade fever. Cultures of the purulent drainage most often grow S. aureus. However, the microbiologic profile of cellulitis complicating surgery may reflect the structures incised during the procedure, such as an Enterobacteriaceae cellulitis after a genitourinary operation.40

Deep infections involve structures adjacent to the surgical wound that were entered or exposed during the procedure, such as subfascial layers, viscera, and/or spaces within the peritoneum, thorax, or joints. Deep-wound infections may be more subtle and delayed, and often present as fever of uncertain cause. Progressive bacterial synergistic gangrene and other variants of gangrenous cellulitis can arise in surgical wounds or around sutures (see Chapter 179).

The complications of superficial and deep-wound infections include poor healing, bacteremia, local and systemic effects of prolonged hospitalization, poor nutrition, residual compromised tissue integrity, and the consequences of prolonged antibiotic therapy. Additionally, wounds infected with toxin-producing S. aureus or GAS may result in systemic complications such as toxic shock syndrome or scarlet fever (see Chapter 177).

Cellulitis Complicating Pressure Ulcers

Pressure ulcers, particularly those located in the sacrum of elderly, frail, malnourished individuals, become contaminated by a variety of facultative and anaerobic microorganisms from the skin and the bowel, including S. aureus, Enterococci, Pseudomonas aeruginosa, and Bacteroides fragilis. In addition to pain and cellulitis, the ulcer may eventually be complicated by bacteremia, often polymicrobial, or the underlying bone can become infected. Given a high burden of colonizing organisms, the identity of the active pathogen(s) may be difficult to determine. Pressure ulcers complicated by cellulitis or sepsis should be urgently debrided.41

Cellulitis Complicating Human and Animal Bites

Domestic dog and cat bites are common and can give rise to cellulitis caused by Pasteurella multocida, Capnocytophaga canimorsus (especially in asplenic individuals), and a host of other aerobes and anaerobes from the animal's mouth or the skin of the infected individual. Dog bites are often accompanied by a crush injury that devitalizes tissues. The bite of cats can inject organisms (via sharp incisors) deep into tissues, including joint spaces, tendon sheaths, or bone (see Chapters 180 and 209).

With rates of cellulitis approaching 15%, human bites have a higher incidence of infection than do animal bites because of the mix of oral bacteria (aerobes and anaerobes), as well as the crush injury imparted by the bite.42,43 Organisms include various Streptococci, S. aureus, Eikenella, Corynebacterium, and the anaerobic Peptostreptococci and Peptococci. Cellulitis from bites should be monitored carefully for progression to a necrotizing infection.

Acute cellulitis, with or without abscess formation, has a tendency to spread through the lymphatics and bloodstream and may be a serious disease, if not treated early. In patients with chronic edema, the process may spread extremely rapidly and recovery may be slow, despite drainage and sterilization of the lesions by antibiotics.

Uncomplicated erysipelas remains confined primarily to the lymphatics and subcutaneous tissues. Even in the days before antibiotic therapy, it was often a self-limited process, subsiding over 7–10 days. Occasionally, untreated erysipelas or cellulitis may be complicated by bulla formation, abscess, necrotizing fasciitis, and bacteremia with sepsis or metastatic infection in various organs. Prompt diagnosis and treatment prevents both suppurative and nonsuppurative complications. However, in young infants and elderly debilitated patients, and in individuals receiving glucocorticoids, the disease may progress with devastating rapidity to a fatal outcome.

Both classical cellulitis and erysipelas tend to recur in the same area, probably as a result of chronic lymphatic obstruction and persistent edema. Recurrent infection may specifically be seen along the lines of venectomy following saphenous vein harvest (with tinea pedis as a portal of entry). Irradiation and nodal dissection with mastectomy predisposes to recurrent cellulitis and erysipelas over the nodal basin, or involving any part of limb distal to the procedure.

Recurrent erysipelas may produce persistent swelling of the lips (macrocheilia), cheeks (particularly the lax tissues beneath the eyes), abdomen, and lower extremities, sometimes resulting in elephantiasis nostra verrucosa (see Chapter 174). The resultant edema predisposes to further bouts of recurrent erysipelas or cellulitis, creating a cycle that can be difficult to break.37

Early pathogen identification, therapy, and prolonged elevation of the affected area can help to preserve better tissue resistance to reinfection. Historically, some patients with frequently recurrent GAS erysipelas have benefited from prophylactic antibiotics, usually monthly benzathine penicillin injections, but recurrences may persist in cases of noncompliance, unusual pathogens, or inappropriate antibiotic selection or dosage.44

Dermatologists are frequently called upon to differentiate between cellulitis and many other conditions with similar clinical presentations, including both infectious and noninfectious mimickers of cellulitis45,46 (see Box 178-1).

Stains and Cultures

The typical appearance of an SSTI, coupled with epidemiologic and clinical data, may guide antimicrobial therapy but is not completely reliable, particularly in patients who are immunocompromised. Cultures and stains from swabs, aspirates, tissue biopsies, and blood may provide valuable microbiologic data in select situations. This data can be particularly helpful with the rise of resistant bacteria and resultant uncertainty over appropriate empiric therapy.

Culture of Surface Swabs, Needle Aspirates, and Punch Biopsies

Epidermal swabs are rarely helpful in cases of simple cellulitis or erysipelas, since any organism found is likely to be a colonizer or contaminant rather than a true pathogen.47

Needle aspirates may be of greater utility, yielding a likely pathogen at published rates of between 2% and 40% of cases.48,49 The procedure is performed by injecting nonbacteriostatic saline into the advanced border of the infected site, followed by aspiration of tissue fluid, which is then subjected to staining and culture. Sampling the most inflamed area of the lesion, rather than the advancing edge, may increase the yield of cultures.50 Open lesions such as postsurgical, traumatic, and pressure ulcers, may contain multiple organisms, some of which may be significant whereas others are contaminants.51

While the yield of needle aspirates varies widely in the literature, punch biopsies for culture can predictably identify a pathogen from a plaque of simple cellulitis in 20%–30% of the cases.48 The Gram stain may help initially to identify the morphology of most significant staining bacteria, but cultures with sensitivities are ultimately more useful when the stains reveal bacteria with potential resistance to the commonly used antibiotics.

Blood Cultures

Most studies that include only immunocompetant patients with uncomplicated, non-necrotizing cellulitis or erysipelas demonstrate positive blood cultures in only 2%–5% of patients, suggesting that blood cultures should not necessarily be part of the routine evaluation for all simple SSTI, especially because the rate of false-positive contaminants approaches the rate of true pathogens identified.37,48,52,53 However, the risk of bacteremia is notably higher in patients with comorbid HIV disease/AIDS and other forms of immunocompromise (approximately 25%), and in patients with an abscess, lymphedema, fever, or clinical evidence of a necrotizing or otherwise severe infection. Other factors that may signal a higher utility for blood cultures include proximal location of the infection, duration of symptoms for less than 2 days, multiple comorbid factors, and lack of pretreatment with antibiotics.54

Histopathology

In addition to direct stains and cultures, pathologic investigation with special staining can be very useful. Histologically, erysipelas is characterized by intense edema, marked lymphatic and vascular dilatation of the superficial dermis, and a profuse infiltration of tissue spaces and lymphatic channels with Streptococci and neutrophils. The Streptococci are not found in the blood vessels, but their presence in the lymphatics produces an inflammatory reaction about these vessels. Histiocytes and granulation tissue may be seen in chronic lesions. Edema may cause dermal pallor and epidermal spongiosis.

Direct immunofluorescent techniques have been reported to identify streptococcal pathogens in 19 of 27 cases of erysipelas and in 10 of 15 cases of cellulitis, yielding a sensitivity of 70% for in situ detection of Streptococci.55 Lesional skin punch biopsy is often helpful in ruling out a cellulitis-simulating noninfectious inflammatory lesion or a coexisting diagnosis such as erythema nodosum, vasculitis, or eosinophilic cellulitis.

Imaging

Imaging modalities in the setting of SSTI are most commonly employed to rule out abscess, necrotizing fasciitis, pyomyositis, and gas forming anaerobic bacterial infections (see Chapter 179). The most common feature of cellulitis noted on MRI or ultrasound is subcutaneous tissue thickening.56

Antibiotics

Antibiotics for Infections in Which Staphylococcus Aureus Is Suspected (Including MRSA)

Empiric therapy for patients with suspected or potential staphylococcal infections has changed in recent years with the increased prevalence of MRSA infections. Traditionally, simple cellulitis not requiring hospital admission has most commonly been treated with a penicillinase-resistant penicillin (e.g., dicloxacillin), or an oral cephalosporin (e.g., cephalexin) (see Box 178-2). In areas where MRSA rates are highest, clindamycin, trimethoprim-sulfamethoxazole, fluoroquinolones, and tetracyclines such as doxycycline and minocycline have recently played a more significant role in empiric therapy. However, each of these agents has deficiencies worth considering when choosing an empiric agent. The great majority of CA-MRSA and most HA-MRSA, remains susceptible to trimethoprim-sulfamethoxazole, but this drug is largely ineffective against GAS. Streptococci, MRSA, and MSSA, all have significant resistance to clindamycin, fluoroquinolones, and tetracyclines in some areas.57,58

Moreover, data supporting a switch to non-β-lactam empiric therapies of outpatient SSTI is lacking at this time. A cost-effectiveness analysis modeling the use of cephalexin, clindamycin, and trimethoprim-sulfamethoxazole for simple SSTI found cephalexin to be the most cost-effective choice in most clinical situations, including situations reflective of even the highest rates of MRSA documented in the literature currently.59 A retrospective study of cellulitis in Philadelphia-area pediatric practices found that failure of empiric therapy was more likely with trimethoprim-sulfamethoxazole than with either cephalexin or clindamycin. Other factors associated with therapeutic failure across all three antibiotics included markers of infection severity, such as fever, abscess, or presentation to an emergency department; while not always statistically significant, cephalexin had the lowest failure rate in every clinical situation examined.60 A multicenter retrospective study from Idaho found no statistically significant difference between the clinical effectiveness of β-lactam antibiotics compared with MRSA empiric coverage for outpatient cellulitis cases, but the non-β-lactams were associated with higher rates of adverse effects.61

The retrospective nature of these studies does not generally account for the reasons empiric MRSA coverage was selected in some cases and not others, and so these studies do not rule out the possibility that non-β-lactam drugs are more effective empiric coverage in some situations. However, at this time, despite the shift in prescribing practices to favor therapy that may cover MRSA, the data appears to favor continued use of penicillinase-resistant β-lactam antibiotics in most cases of simple SSTI not requiring hospitalization.

More severe cases of cellulitis requiring hospitalization are usually treated with parenteral antibiotics; the same controversy over whether to use a β-lactam or empiric MRSA coverage is important for hospitalized patients, but the risks of choosing an inappropriate initial therapy are potentially greater in cases of more severe infections, perhaps shifting the balance in favor of empiric MRSA-coverage, especially vancomycin, in many situations. The most common agents chosen are intravenous semisynthetic penicillinase-resistant penicillins (e.g., nafcillin 2 g intravenously every 4 hours) and cephalosporins (e.g., cefazolin 1g intravenously every 8 hours), or vancomycin (1g intravenously twice daily) when MRSA is suspected, or when the patient has a history of an immediate type reaction (immunoglobulin E mediated) to penicillin or cephalosporin. A recent abstract presented compelling retrospective data supporting use of vancomycin over β–lactam antibiotics as empiric therapy for cellulitis in hospitalized patients.62 Carbapenems have very broad coverage and are useful agents for severe infections when MRSA is not suspected, or when combined with anti-MRSA therapy.63

Linezolid (600 mg orally twice daily) is an oxazolidinone that has emerged as an effective oral alternative for infections caused by MRSA, MSSA, GAS, and VRE,64 but linezolid resistance, while still rare, is increasing.33 In outpatients, its use is limited largely by cost, though it may prove cost effective in many inpatient situations because it has been shown to decrease hospitalization times when compared to vancomycin.65

Other agents, approved by the US Food and Drug Administration (FDA) for the treatment of SSTI, include quinupristin-dalfopristin, daptomycin, and tigecycline. Use of quinupristin-dalfopristin (a streptogramin combination antibiotic) is limited by the large volumes of intravenous infusions required to achieve adequate cutaneous penetration. Daptomycin (4 mg/kg/day) is a bactericidal lipopeptide that achieves very good concentrations in the skin, and has been shown to be equivalent to vancomycin and other antibiotics in the treatment of SSTI.66 In addition, given its novel mechanism of action, which is poorly understood but includes disruption of bacterial membrane electric potential, less chance for bacterial resistance is postulated.67 Tigecycline, a new generation glycylcycline derived from minocycline, overcomes existing tetracycline resistance mechanisms and is broadly effective against Gram-negative and Gram-positive bacteria (including MRSA), as well as anaerobes and some atypical pathogens.68

Newer agents include oritavancin, dalbavancin, and telavancin, new lipoglycopeptides with long half-lives that belong to the same class as vancomycin.69–71 More recently, two novel cephalosporins with activity against MRSA have been developed—(1) ceftaroline and (2) ceftobiprole.72,73 Finally, a new diaminopyrimidine dihydrofolate reductase inhibitor related to trimethoprim, iclaprim, is under review by the FDA.74

Antibiotics for Predominantly Streptococcal Infections

It is rare in current practice that S. aureus can be ruled out with sufficient confidence to empirically treat with antistreptococcal drugs alone, without drugs that cover Staphylococcus well, but mild cases of early erysipelas known to be caused by GAS can be treated on an outpatient basis with either oral or intramuscular penicillin (See Box 178-2). Dicloxacillin or cephalexin (both 500 mg four times a day) is more commonly used because it is so difficult to rule out S. aureus clinically (see Box 178-2). Macrolides and clindamycin can be used in penicillin-allergic individuals, but increasing resistance of Streptococcus pyogenes to erythromycin has been reported.75,76 Severe streptococcal SSTI, or SSTI complicated by comorbidities including diabetes, should be treated with high dose intravenous aqueous penicillin G (1–2 million units every 4–6 hours), but it is now rare to administer penicillin alone for cutaneous infections, without tissue culture proving monomicrobial streptococcal infection.

Adjunctive Therapies

Care of the local lesions of erysipelas and cellulitis includes bed rest and elevation of the involved area to reduce local edema. Cool, sterile saline dressings decrease the local pain and are particularly indicated in the presence of bullous lesions. The application of moist heat may aid in the localization of an abscess in association with cellulitis. Surgery is not generally needed for erysipelas or cellulitis unless an abscess or necrotizing infection is suspected. When present, an abscess should be drained and cultured (see Chapter 176).

Education of health care providers, adherence to infection-control measures, and judicious use of antimicrobials are paramount to SSTI prevention. Decolonization strategies have thus far failed to demonstrate consistent efficacy, and development of further resistance from these protocols is a feared complication.77 Several vaccines have been developed against S. aureus, which in theory circumvent staphylococcal resistance mechanisms, but so far, none has proven effective beyond phase III trials.78 Antistaphylococcal IgG was also found to be ineffective in late testing.79 Vaccines against the M-protein of GAS are being investigated.80