Treatment of Severe Skin and Soft Tissue Infections

A Review

Jason P. Burnham; Marin H. Kollef


Curr Opin Infect Dis. 2018;31(2):113-119. 

In This Article

Types of Severe Soft Tissue Infections

For all SSTIs, immune status, exposure history (animals, water, trauma), and travel history (particularly to regions with high rates of multidrug-resistant organisms) are important to inform empiric antimicrobial decisions.[4,6] Patients with severe forms of purulent SSTIs, cellulitis, or surgical site infection should receive broad-spectrum antibiotic therapy [including a Methicillin-resistant Staphylococcus aureus (MRSA) agent when high risk] and source control, when applicable.

Toxic Shock Syndrome

TSS is a fulminant infection typically due to Staphylococcus aureus or Streptococcus pyogenes, though similar syndromes can occur with groups B, C, and G streptococci, and Clostridium species. The annual incidence of staphylococcal TSS (SaTSS) is ~0.5/100 000 and ~0.4/100 000 for streptococcal TSS (SeTSS), though local rates may vary.[7] Mortality rates are less than 5% for menstrual SaTSS, 5–22% for nonmenstrual SaTSS, and 30–70% for SeTSS.[7] Clostridial toxic shock is rare and its incidence is uncertain.[8,9]

When TSS is suspected, empiric therapy must cover for drug-resistant infections. Expert opinion based on retrospective studies and in-vitro data highlight vancomycin and clindamycin or linezolid alone as possible treatment regimens.[10–13] Nafcillin or oxacillin are good choices for methicillin-sensitive SaTSS, but must be used in combination with clindamycin as nafcillin alone can increase toxin production.[12] Clindamycin or linezolid are essential in treatment as they reduce superantigen production in both SaTSS and SeTSS.[11–13] When susceptibilities are available, antibiotics should be de-escalated while still including an agent that suppresses toxin production until clinical stability is achieved. For clostridial TSS, clindamycin and penicillin should be used, though there is limited data on this syndrome to guide treatment.

Intravenous immunoglobulin (IVIG) nonspecifically binds and inactivates superantigens, limiting cytokine storm in TSS, though the clinical benefits are controversial. Recruitment for randomized controlled trials (RCTs) of IVIG has been difficult due to the rarity of TSS.[14] One study found significantly improved mortality in patients that received IVIG or clindamycin for SeTSS.[15] IVIG is less studied in SaTSS, though in one study five confirmed cases received IVIG and none expired.[16]

In a cohort of patients with mixed bacterial causes of necrotizing SSTI, IVIG showed no benefit in mortality or functional outcomes,[17] though only roughly one-thirds had S. pyogenes or S. aureus. Adding further to the debate, in a recent propensity score-matched analysis of patients with necrotizing fasciitis and shock, IVIG use was rare, but not associated with improved outcomes, regardless of pathogen type.[18] Given the ongoing mixed evidence, IVIG can be considered in patients with TSS, but benefit is unclear and specific dosing regimens are not well studied (Figure 1).

Figure 1.

Proposed management algorithm for necrotizing soft tissue infections.

Necrotizing Soft Tissue Infections: Gas Gangrene/Myonecrosis and Necrotizing Fasciitis

Necrotizing SSTIs are difficult to treat and require aggressive surgical debridement, broad-spectrum antimicrobials, and intensive care. Table 2 and Figure 1 demonstrate factors associated with increased likelihood of necrotizing infection and a proposed management tree.[19] Source control of infection is paramount and serial surgical debridements are generally required. The frequency and number of required debridements varies, but generally debridement should occur every 24–48 h until there is no evidence of necrosis. Daily wound dressing changes should be done to look for ongoing infection (e.g., bullae, devitalized tissue, spreading erythema) that would require repeat debridement. Increased requirements for intensive care support or laboratory parameters suggestive of worsening infection (e.g., progressive renal failure, increasing leukocytosis, increasing lactate) should prompt discussion of repeat debridement. Surgical control of infection is particularly important because diffusion of antimicrobials into affected tissues is limited due to significant tissue edema, necrosis, inflammation, and penetrating vessel thromboses.[20]

Gas Gangrene/Myonecrosis

Gas gangrene or myonecrosis is caused by Clostridium species and should be managed surgically with adjunctive broad-spectrum antibiotics while awaiting culture results (Table 1). Though rare, Clostridium sordellii infections are notable as they can be associated with a toxic-shock like syndrome, particularly in patients with recent parturition or abortion.[8,9,21] TSS from clostridial infection is pathophysiologically dissimilar to SeTSS or SaTSS, making IVIG of dubitable benefit.[8,9,21]

Necrotizing Fasciitis

Necrotizing fasciitis (Figure 2) is a rare SSTI that involves the deep fascia.[19] Rates of necrotizing fasciitis vary widely based on region (0.18–15.5 per 100 000) and are increasing over time.[22,23] Despite patients with necrotizing fasciitis having a higher severity of illness than patients with cellulitis, a recent study found that patients with cellulitis and necrotizing fasciitis had similar in-hospital and 90-day mortality, presumably due to higher comorbidity burden in patients with cellulitis.[24] However, the study had a small number of patients and may not have been powered to detect a difference in mortality between the groups.

Figure 2.

Necrotizing fasciitis of the lower extremity. Retiform purpura with bullae formation (a) or rapidly spreading erythema with bullae formation (b) should prompt urgent surgical consultation. Adapted from [19].

Type I necrotizing fasciitis is polymicrobial, including aerobic and anaerobic organisms. Type II necrotizing fasciitis is classically caused by S. pyogenes, though S. aureus also falls into this category. There are a variety of less frequently encountered agents causing necrotizing fasciitis, which makes it important for practitioners to realize the importance of surgical debridement with attendant bacterial cultures in combination with broad-spectrum antimicrobials as the first lines of therapy.[25,26]

Though the classic teaching for necrotizing fasciitis is pain out proportion to physical examination findings, it is important to remember that superficial nerves can undergo necrosis, resulting in anesthesia of affected areas. A high degree of suspicion for necrotizing SSTI is required due to variability in physical examination findings and low sensitivity of imaging modalities. Imaging findings cannot rule out necrotizing fasciitis and may delay surgical intervention, which is associated with poor outcomes.[27] However, in clinically stable patients, MRI may be helpful in distinguishing necrotizing from nonnecrotizing infection.[28]

Necrotizing fasciitis predominates on the lower extremity and predisposing conditions such as diabetes and peripheral vascular disease reflect this localization. Due to the relative rarity and heterogeneity of microbiologic causes, no clinical trials are available to guide duration of therapy. Based on expert opinion, recent guidelines suggest antimicrobial therapy directed against cultured organisms for at least 48–72 h after patients are clinically stable and require no further operative interventions.[4]

Surgical Considerations

For all patients with severe SSTIs, general resuscitative measures should be followed in accordance with institutional protocols. Source control is paramount, which may include surgical debridement, removal of invasive devices, or vaginal examination in the case of menstrual TSS. Prolonged time from presentation to first surgical intervention is associated with increased mortality.[27,29] In a mixed cohort of severe sepsis/septic shock patients that included patients with SSTIs, source control was associated with reduced mortality despite patients requiring source control having greater severity of illness.[30]

In conjunction with serial debridements, vacuum-assisted closure of wounds may contribute to healing.[31] For cases of necrotizing infection involving the perineum or other sites with potential for stool contamination, temporary colostomy may be required to assist in wound healing. Rates of amputation in lower extremity necrotizing fasciitis vary from 15 to 72% based on comorbidities, with diabetes being a strong risk factor for amputation.[32] Although potentially life-saving, it is important to recognize that amputations, among other factors, may be associated with significant functional limitations after discharge.[33]

Hyperbaric Oxygen Therapy

The use of hyperbaric oxygen therapy (HBOT) for necrotizing SSTI remains controversial due to mixed evidence of benefit, a lack of RCTs, and variable access to hyperbaric oxygen chambers.[34–38] In the absence of RCTs or well done propensity score analyses, we cannot recommend for or against the use of adjunctive HBOT for the management of necrotizing SSTI. For centers with HBOT readily available, its use can be considered, but should not be a substitute for or result in delays in surgical or antimicrobial therapy (Figure 1).

Antimicrobial Considerations

As a general rule, all severe SSTI should be treated empirically with broad-spectrum antibiotics directed against typical pathogens, specifically MRSA, resistant Gram-negatives, and anaerobes (Table 1 and Table 3). Notably, patients with complicated SSTI have more rapid achievement of clinical stability if empiric antimicrobials are appropriate for isolated pathogens.[39] All practitioners should consider local antibiograms when choosing empiric antimicrobials, as antibiograms can vary significantly. In regions such as Northern Europe with low rates of MRSA,[40] it may be prudent to exclude MRSA coverage from empiric therapy in patients at low risk of MRSA infections. Preliminary work with MRSA risk prediction tools in SSTIs show promise, but more data are needed before implementing these tools and foregoing empiric MRSA coverage.[41]

De-escalation of antibiotic therapy should be based on clinical improvement, cultured pathogens, and results of rapid diagnostic tests where available. Rapid diagnostic testing for SSTIs is a relatively new area, but there is some promising data to show that their use results in increased appropriateness of therapy as well as increased rates of de-escalation.[42]

Considerations for Selected Antimicrobials

Dalbavancin and oritavancin are long-acting semisynthetic lipoglycopeptides that are approved for a wide range of Gram-positive organisms. However, further studies are needed before their use can be recommended for severe SSTI. Daptomycin use may be contraindicated in patients with necrotizing fasciitis and elevated creatine kinase levels. As MRSA is one of the most common causes of SSTIs and severe illness is associated with higher rates of bacteremia, caution is advised when using linezolid, as its use in MRSA bacteremia may be associated with worse outcomes in patients with acute physiology and chronic health evaluation II scores at least 14.[43] Tedizolid has been shown to be noninferior to linezolid across a range of SSTI severity,[44] but there is no reason to believe it would be more efficacious in MRSA bacteremia than linezolid, so concerns about its empiric use remain. Telavancin is associated with higher rates of toxicity than other available agents for SSTI, and we therefore do not recommend its use when other agents can be employed. Though approved for SSTIs, tigecycline has been linked with worse outcomes in patients with severe illness. Tigecycline may also be a risk factor for treatment failure in patients with drug-resistant infections. As such, we recommend avoiding tigecycline therapy when other options are available.

Future Therapies

There are some exciting new drugs in the pipeline for SSTI treatment, including delafloxacin and omadacycline, but discussion of their use will be covered by other articles in this issue. Nontraditional therapies for SSTIs, such as an antistaphylococcal alpha toxin antibody, have recently shown some promise in animal models, but are not available for human use.[45]