1. Early diagnosis and differentiation of necrotizing vs. non-necrotizing SSTI
2. Early initiation of appropriate empiric broad-spectrum antimicrobial therapy with anti-MRSA coverage and consideration of risk factors for specific pathogens
3. “Source control” of SSTI (i.e., early aggressive surgical intervention for drainage of abscesses and debridement of necrotizing soft tissue infections)
4. Pathogen identification and appropriate de-escalation of antimicrobial therapy
25.2 Classification of SSTIs
The US Food and Drug Administration (FDA) previously classified SSTIs into two broad categories for the purpose of clinical trials evaluating new antimicrobials for the treatment of SSTIs: uncomplicated and complicated (Table 25.2). Uncomplicated SSTIs include superficial infections such as cellulitis, simple abscesses, impetigo, and furuncles. These infections can be treated by antibiotics and/or surgical incision for drainage of abscess alone. In contrast, complicated SSTIs include deep soft tissue infections that require significant surgical intervention, such as infected ulcers, infected burns, and major abscesses, and these patients also have significant underlying comorbidities, that is, disease states which complicate (and usually delay) response to treatment. Complicated SSTIs are a significant clinical problem, in part related to the increasing resistance of infecting bacteria to our current antibiotic therapies.
Table 25.2
Comparison of old and new classification of SSTIs by FDA
Uncomplicated | Complicated |
Superficial infections, such as: Simple abscesses Impetiginous lesions Furuncles Cellulitis Can be treated by antibiotics or surgical incision alone | Deep soft tissue, such as: Infected ulcers Infected burns Major abscesses Significant underlying disease state which complicates response to treatment Requires significant surgical intervention and antimicrobials |
New FDA definition (October 2013): | |
Acute bacterial skin and skin structure infections (ABSSSI) defined as bacterial infection of the skin with a lesion size area of at least 75 cm2 (lesion size measured by the area of redness, edema, or induration), including the following: | |
Cellulitis/erysipelas: A diffuse skin infection characterized by spreading areas of redness, edema, and/or induration | |
Wound infection: An infection characterized by purulent drainage from a wound with surrounding redness, edema, and/or induration | |
Major cutaneous abscess: An infection characterized by a collection of pus within the dermis or deeper that is accompanied by redness, edema, and/or induration |
Uncomplicated SSTIs are associated with low risk for life- or limb-threatening infection. These patients can be treated with empiric antibiotic therapy according to likely pathogen and local resistance patterns.
Complicated SSTIs are associated with high risk for life- or limb-threatening infection. In these patients, it is of paramount importance to initiate appropriate and adequate broad-spectrum initial empiric antimicrobial therapy with coverage for MRSA and to consider the need for surgical intervention for abscess drainage or debridement.
Patients with complicated SSTIs require hospitalization for treatment. Specific circumstances that warrant hospitalization include the presence of tissue necrosis, sepsis, severe pain, altered mental status, immunocompromised state, and organ failure (respiratory, renal, and hepatic). SSTIs can lead to serious potentially life-threatening local and systemic complications. The infections can progress rapidly and early recognition and proper medical and surgical management is the cornerstone of therapy. A recent prospective observational US study of complicated SSTI patients (n = 1033) determined that the mean length of hospital stay was 7.1 days, 41.2 % underwent surgical procedures related to the study infection, the most common class of initial intravenous antibiotic prescribed was vancomycin, and the hospital mortality rate was 0.4 % [7]. In contrast, a similar study in Europe reported mean hospital length of stay of 18.5 days with a mortality rate of 3.4 % [8].
In October 2013, FDA changed the SSTI terminology and issued final guidance for the treatment of acute bacterial skin and skin structure infections (ABSSSI) [9]. This guidance defined ABSSSI as cellulitis, erysipelas, wound infection, and major cutaneous abscess. An ABSSSI is defined as a bacterial infection of the skin with a lesion size area of at least 75 cm2 (lesion size measured by the area of redness, edema, or induration). The minimum area of involvement of 75 cm2 is chosen to select patients with acute bacterial skin infections for which a reliable control drug treatment effect can be estimated for the conduct of new antimicrobial treatment trials. While the FDA generally requires two Phase III trials to support approval of drugs to treat acute bacterial skin and skin structure infections (ABSSSI), this guidance stated that a single Phase III study that is supported by additional independent evidence may suffice.
Patients with the following infection types can be enrolled in ABSSSI clinical trials:
Cellulitis/erysipelas: A diffuse skin infection characterized by spreading areas of redness, edema, and/or induration
Wound infection: An infection characterized by purulent drainage from a wound with surrounding redness, edema, and/or induration
Major cutaneous abscess: An infection characterized by a collection of pus within the dermis or deeper that is accompanied by redness, edema, and/or induration
Unfortunately, this new guidance does not address less serious skin infections, such as impetigo and minor cutaneous abscess, or more serious infections needing more complex treatment regimens, such as infections resulting from animal or human bites, necrotizing soft tissue infections, diabetic foot infection, decubitus ulcer infection, myonecrosis, osteomyelitis, and ecthyma gangrenosum.
25.3 Specific Types of SSTIs
25.3.1 Traumatic Wound Infections
A recent report from the Lower Extremity Assessment Project (LEAP), a multi-institutional prospective observational study of 545 patients with limb-threatening lower extremity trauma with 2-year follow-up at eight Level-1 trauma centers, documented that wound infection (34 %) was the most common complication in the primary amputation group, and that nonunion (31.5 %) and wound infection (23.2 %) were the most common complications in the limb salvage group. Furthermore, the late amputation group had the highest complication rate (68 %), mostly due to wound infection [10]. When traumatic wound infections occur, it is recommended to initiate early empiric broad-spectrum antibiotic therapy to cover methicillin-resistant S. aureus (MRSA) and all other potential pathogens, obtain wound cultures, and then tailor definitive antimicrobial therapy once the culture results return. In addition, the wound may require surgical debridement to provide adequate source control.
25.3.2 Surgical Site Infections (SSIs)
SSIs are one of the most common SSTIs that occur in orthopedic and trauma care. SSIs are defined as “superficial incisional” or “deep incisional” SSI based on the depth of the infection as defined by the Centers for Disease Control (CDC) and the National Healthcare Safety Network (NHSN) (Table 25.3).
Table 25.3
CDC/NHSN classification of surgical site infections (SSIs)
Type of SSI | Definition |
---|---|
Superficial incisional | Infection occurs within 30 days after the operative procedure and involves only skin and subcutaneous tissue of the incision and patient has at least one of the following: |
(a) Purulent drainage from the superficial incision | |
(b) Organisms isolated from an aseptically obtained culture of fluid or tissue from the superficial incision | |
(c) At least one of the following signs or symptoms of infection: pain or tenderness, localized swelling, redness, or heat, and superficial incision is deliberately opened by surgeon and is culture positive or not cultured. A culture-negative finding does not meet this criterion | |
(d) Diagnosis of superficial incisional SSI by the surgeon or attending physician | |
Deep incisional | Infection occurs within 30 days after the operative procedure if no implanta is left in place or within 1 year if implant is in place and the infection appears to be related to the operative procedure and involves deep soft tissues (e.g., fascial and muscle layers) of the incision and patient has at least one of the following: |
(a) Purulent drainage from the deep incision but not from the organ/space component of the surgical site | |
(b) A deep incision spontaneously dehisces or is deliberately opened by a surgeon and is culture positive or not cultured when the patient has at least one of the following signs or symptoms: fever (.388 C), or localized pain or tenderness. A culture-negative finding does not meet this criterion | |
(c) An abscess or other evidence of infection involving the deep incision is found on direct examination, during reoperation, or by histopathologic or radiologic examination | |
(d) Diagnosis of a deep incisional SSI by a surgeon or attending physician |
It has recently been determined that scores commonly used to predict SSI in other types of surgery [National Nosocomial Infection Surveillance System (NNIS) and Study on the Efficacy of Nosocomial Infection Control (SENIC) scores] are not predictive of SSI after orthopedic fracture surgery [11]. A new score [RIOTS Composite Score includes fractures classification AO type C3 or Sanders type 4, 2 points; BMI < 30 kg/m2, 1 point; ASA class ≥ 3, 1 point] was proposed for SSI prediction in orthopedic fracture surgery that incorporates fracture classification, American Society of Anesthesiologists classification, and body mass index with area under the ROC curve of 0.75, significantly higher than NNIS and SENIC scores.
25.3.2.1 SSI Prevention
A number of SSI prevention strategies have significantly decreased the rate of SSIs following orthopedic surgery and fracture repair in the past decade [12]. The Surgical Care Improvement Project (SCIP) has implemented three measures for antibiotic prophylaxis for SSI prevention: (1) antibiotic received within 1 h prior to surgical incision, (2) appropriate antibiotic selection based on surgical procedure performed, and (3) antibiotic discontinued within 24 h after surgery completed (Table 25.4). Additional evidence-based strategies for SSI prevention include the following: (1) appropriate hair removal (clipping, no shaving); (2) maintenance of normothermia intraoperatively and perioperatively; (3) glycemic control; (4) appropriate skin preparation; (5) supplemental oxygen administration.
Table 25.4
Antibiotics for SSI prevention in orthopedic surgery
Choice of antimicrobial agent |
Cefazolin |
If ß-lactam allergy, use clindamycin or vancomycin |
Consider preoperative screening for MRSA colonization |
If infected or colonized with MRSA, use vancomycin |
Timing of administration |
Start up to 60 min before incision: Cefazolin, Clindamycin |
Start up to 120 min before incision: Vancomycin |
Infusion completed 10 min before tourniquet inflation |
Dosing |
Cefazolin, 1–2 g (2 g for patient weighing >80 kg) |
Vancomycin (15 mg/kg) and Clindamycin (600–900 mg) dosing based on patient mass |
Pediatric dosing based on patient mass |
Duration of antimicrobial use |
Single preoperative dose |
Redose antimicrobial intraoperatively for prolonged procedure or significant blood loss |
Mupirocin should be given intranasally to all patients with documented colonization with S. aureus |
25.3.2.2 Microbiology of SSIs
Staphylococcus aureus (S. aureus) is the most common causative pathogen for all SSIs in the United States data reported by the NHSN (Table 25.5), and an increasing percentage of these S. aureus isolates are methicillin-resistant (MRSA). Comparison of the causative pathogens for SSI in US hospitals documents that S. aureus increased from 22.5 % (1986–2003) to 30 % (2006–2007), with MRSA now the leading causative pathogen, comprising 49.2 % of all isolates [13, 14]. The advent of community-associated MRSA (CA-MRSA) has impacted SSI significantly. Recent studies document that CA-MRSA is replacing traditional health care-associated or nosocomial MRSA strains in SSI among inpatients [15]. CA-MRSA has emerged as a leading cause of health care-associated infections among patients with prosthetic joint SSIs [16].
Table 25.5
Causative pathogens for surgical site infections (SSI) in US hospitals 2006–2007, National Healthcare Safety Network
Organism | SSIs from all types of surgeries No. (%) of SSIs Total n = 7025 | SSIs from orthopedic surgeries No. (%) of SSIs Total n = 963 |
---|---|---|
Staphylococcus aureus Methicillin-sensitive (MSSA) Methicillin-resistant (MRSA) | 2108 (30.0 %) 1102 (50.8 %) 1006 (49.2 %) | 548 (48.6 %) |
Coagulase-negative staphylococci | 965 (13.7 %) | 173 (15.3 %) |
Enterococcus spp. | 788 (11.2 %) | 104 (10.8 %) |
Escherichia coli | 671 (9.6 %) | 34 (3.0 %) |
Pseudomonas aeruginosa | 390 (5.6 %) | 38 (3.4 %) |
Enterobacter spp. | 293 (4.2 %) | 37 (3.3 %) |
Klebsiella spp. | 213 (3.0 %) | 19 (2.0 %) |
In a study of 8302 patients readmitted to US hospitals from 2003 to 2007 with culture-confirmed SSI, the proportion of infections caused by MRSA increased significantly, from 16.1 to 20.6 %, and these infections were associated with higher mortality rates, longer stays, and higher hospital costs [17]. In view of this important finding, some surgeons have advocated strongly that patients be screened for nasal carriage of MRSA prior to elective surgery, with consideration of decolonization prior to surgery, and modification of antimicrobial agents for SSI prevention on the basis of the results.
Interestingly, when evaluating the microbiology of SSIs related to orthopedic surgical cases, S. aureus comprised an even greater percentage of isolates (48.6 %) when compared to isolates reported for SSIs from all surgical cases (30 %) (Table 25.5). Although knowledge of national microbiology of SSIs related to specific surgical procedures is important, it is of even greater importance to know the microbiology of SSIs within your own institution, and this should help to guide empiric antimicrobial management for treatment of SSIs in your local setting. Reports of resistant gram-negative isolates, particularly multi-drug-resistant Enterobacter isolates producing extended spectrum beta-lactamases (ESBLs), as the etiology of SSIs in orthopedic and trauma surgery is worrisome [18, 19]. This highlights the importance of pathogen identification, that is, obtaining material for gram stain and culture, in the management of all SSIs.
25.3.3 Closed Long Bone Fractures
A Cochrane Database systematic review of patients undergoing surgery for proximal femoral and other closed long bone fractures (data from 8447 participants in 23 studies) documented that single dose antibiotic prophylaxis significantly reduced deep incisional SSI (risk ratio 0.40, 95 % CI 0.24–0.67), superficial incisional SSI, urinary infections, and respiratory tract infections. Multiple dose antibiotic prophylaxis had an effect of similar size on deep incisional SSI. Therefore, appropriate antibiotic prophylaxis should be used in all patients undergoing surgical management of hip or other closed long bone fractures [20].
The recent publication of the “Clinical practice guidelines for antimicrobial prophylaxis in surgery” by the American Society of Health-System Pharmacists (ASHP), Infectious Diseases Society of America (IDSA), Surgical Infection Society (SIS), and Society for Healthcare Epidemiology of America (SHEA) provides evidence-based national recommendations [21].
The recommended regimen in hip fracture repair or other orthopedic procedures involving internal fixation is cefazolin. Clindamycin and vancomycin should be reserved as alternative agents. If there are surveillance data showing that gram-negative organisms are a cause of SSIs for the procedure, practitioners may consider combining clindamycin or vancomycin with another agent (cefazolin if the patient is not β-lactam-allergic; aztreonam, gentamicin, or single-dose fluoroquinolone if the patient is β-lactam-allergic). Mupirocin should be given intranasally to all patients with documented colonization with S. aureus. (Strength of evidence for prophylaxis = A.)
25.3.4 Open Fractures
Antibiotics reduce the incidence of early infections in open fractures of the limbs, confirmed by a Cochrane Database systematic review of 913 participants in 7 studies. The use of antibiotics had a protective effect against early infection compared with no antibiotics or placebo (relative risk 0.41 [95 % confidence interval (CI) 0.27–0.63]; absolute risk reduction 0.08 (95 % CI 0.04–0.12); number needed to treat (NNT) 13 (95 % CI 8–25). There were insufficient data in the included studies to evaluate other outcomes [22]. The Surgical Infection Society evidence-based guidelines for prophylactic antibiotic use in open fractures recommend the use of a short course of first-generation cephalosporins, begun as soon as possible after injury, in addition to modern orthopedic fracture wound management (Table 25.6) [23]. Open fracture grade (Gustilo) and the degree of associated soft-tissue injury are independent determinants of infection risk. A recent single-institution review of patients with Gustilo IIIB tibial fractures (n = 52) determined that nosocomial bacterial pathogens (Enterococci, Pseudomonas, Enterobacter, and MRSA) were responsible for deep tissue infections, and advocated for tailoring antimicrobial prophylaxis against nosocomial organisms at the time of definitive wound closure [24].
Table 25.6
Risk of SSTI in adult trauma patients with open extremity fractures and antimicrobial prophylaxis recommendations
Grade of open fracture | Characteristics of Gustilo grade open fracture | Infection rate | Amputation rate |
---|---|---|---|
Grade I | Clean wound smaller than 1 cm in diameter, simple fracture pattern, no skin crushing | 0–2 % | 0 % |
Grade II | A laceration larger than 1 cm but without significant soft tissue crushing, including no flaps, degloving, or contusion. Fracture pattern may be more complex | 2–7 % | 0 % |
Grade III | An open segmental fracture or a single fracture with extensive soft tissue injury. Also included are injuries older than 8 h. Type III injuries are subdivided into three types: | ||
Grade III A | Adequate soft tissue coverage of the fracture despite high energy trauma or extensive laceration or skin flaps | 5–10 % | 2.5 % |
Grade III B | Inadequate soft tissue coverage with periosteal stripping. Soft tissue reconstruction is necessary | 10–50 % | 5.6 % |
Grade III C | Any open fracture that is associated with an arterial injury that requires repair | 25–50 % | 25 % |
Grade of open fracture | Recommended antibiotic | Alternate if PCN allergy |
---|---|---|
Grade I or II | Kefzol 1–2 g load then 1 g IV q8h for 48 h | Clindamycin 900 mg IV q8h for 48 h |
Grade III | Ceftriaxone 1 g IV q24h for 48 h | Clindamycin 900 mg IV q8h and Aztreonam 1 g IV q8h for 48 h |
25.3.5 Necrotizing Soft Tissue Infections (NSTIs)
NSTIs are aggressive soft tissue infections that cause widespread necrosis, and can include necrotizing cellulitis, fasciitis, and myositis/myonecrosis [25, 26]. Establishing the diagnosis of NSTI can be the main challenge in treating patients with NSTI, and knowledge of all available tools is the key for early and accurate diagnosis (Table 25.7) [27]. There have been a number of recent advances in the definition, pathogenesis, diagnostic criteria, and treatment of necrotizing soft tissue infections [28, 29].
Table 25.7
Clinical clues to the diagnosis of necrotizing soft tissue infections
Skin findings: | Erythema |
Tense edema | |
Gray or discolored wound drainage | |
Vesicles or bullae | |
Skin necrosis | |
Ulcers | |
Crepitus | |
Systemic features: | Severe pain out of proportion to physical findings |
Pain that extends past margin of apparent skin infection | |
Fever | |
Tachycardia, tachypnea | |
Diaphoresis | |
Delirium |
Patients with NSTIs require prompt aggressive surgical debridement, appropriate intravenous antibiotics, and intensive support. Despite aggressive treatment, their mortality and morbidity rates remain high, with some series reporting mortality rates of 25–35 % [30]. A high index of suspicion should be used in conjunction with laboratory and imaging studies to establish the diagnosis as rapidly as possible. Successful treatment requires early, aggressive surgical debridement of all necrotic tissue, appropriate broad-spectrum systemic antibiotic therapy, and supportive care (fluid resuscitation, organ and critical care support) to maintain oxygenation and tissue perfusion. Delayed definitive debridement remains the single most important risk factor for death.
A recent single-institution series of 166 patients documented that the overall mortality rate was 16.9 % and limb loss occurred in 26 % of patients with extremity involvement [31]. Independent predictors of mortality included white blood cell count greater than 30,000 × 103/μL, creatinine level greater than 2 mg/dL (176.8 μmol/L), and heart disease at hospital admission. Independent predictors of limb loss included heart disease and shock (systolic blood pressure <90 mmHg) at hospital admission. Clostridial infection was an independent predictor for both limb loss (odds ratio, 3.9 [95 % confidence interval, 1.1–12.8]) and mortality (odds ratio, 4.1 [95 % confidence interval, 1.3–12.3]) and was highly associated with intravenous drug use and a high rate of leukocytosis on hospital admission.
A 30-day postoperative mortality risk calculator for NSTI was recently developed using the National Surgery Quality Improvement Project (NSQIP) which identified seven independent variables that correlated with mortality: age older than 60 years (odds ratio [OR] = 2.5; 95 % CI 1.7–3.6), functional status (partially dependent: OR = 1.6; 95 % CI 1.0–2.7; totally dependent: OR = 2.3; 95 % CI 1.4–3.8), requiring dialysis (OR = 1.9; 95 % CI 1.2–3.1), American Society of Anesthesiologists class 4 or higher (OR = 3.6; 95 % CI 2.3–5.6), emergent surgery (OR = 1.6; 95 % CI 1.0–2.3), septic shock (OR = 2.4; 95 % CI 1.6–3.6), and low platelet count (<50 K/μL: OR = 3.5; 95 % CI 1.6–7.4; <150 K/μL but >50 K/μL: OR = 1.9; 95 % CI 1.2–2.9). The receiver operating characteristic area was 0.85 (95 % CI 0.82–0.87), which indicated a strong predictive model that can aid physicians in the decision-making process [32].
25.3.5.1 Aids to Diagnosis of NSTIs
Early operative debridement is a major determinant of outcome in NSTIs. However, early recognition of NSTIs is difficult clinically. A novel diagnostic scoring system for distinguishing NSTIs from other severe soft tissue infections based on laboratory tests routinely performed for the evaluation of severe SSTIs is called the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score (Table 25.8) [33].
Table 25.8
Laboratory risk indicator for necrotizing fasciitis (LRINEC) score
Variable, units | Score |
---|---|
C-reactive protein, mg/L | |
<150 | 0 |
≥150 | 4 |
Total white cell count, per mm3 | |
<15 | 0 |
15–25 | 1 |
>25 | 2 |
Hemoglobin, g/dL | |
>13.5 | 0 |
11–13.5 | 1 |
<11 | 2 |
Sodium, mmol/L | |
≥135 | 0 |
<135 | 2 |
Creatinine, μmol/L | |
≤141 | 0 |
>141 | 2 |
Glucose, mmol/L | |
≤10 | 0 |
>10 | 1 |
The LRINEC score was initially developed in a retrospective observational study including 145 patients with necrotizing fasciitis and 309 patients with severe cellulitis or abscesses admitted to the two tertiary care hospitals. The cutoff value for the LRINEC score was 6 points with a positive predictive value of 92.0 % and negative predictive value of 96.0 %. The LRINEC score is a robust score capable of detecting even clinically early cases of necrotizing fasciitis. The variables used are routinely measured to assess severe soft tissue infections. Patients with a LRINEC score of ≥6 should be carefully evaluated for the presence of necrotizing fasciitis.
Since the initial development of the LRINEC score, a number of other cohort studies have validated its utility in the diagnosis of NSTIs [34]. A multicenter study in 229 patients with NSTIs from 2002 to 2005 reported an overall mortality rate of 15.8 % and amputation rate of 26.3 %. This study also documented that a LRINEC score ≥6 was associated with a higher rate of both mortality and amputation [34].
25.3.5.2 Diagnostic Imaging in NSTIs
A high clinical index of suspicion is required if the diagnosis is to be made sufficiently early for successful treatment. NSTIs necessitate prompt aggressive surgical debridement for satisfactory treatment in addition to antimicrobial therapy. It is critical to remember that because of the rapidly progressive and potentially fatal outcome of this condition, if imaging cannot be performed expeditiously, delaying treatment is not justified. Plain film findings may reveal extensive soft tissue gas. CT examination can reveal asymmetric thickening of deep fascia in association with gas, and associated abscesses may also be present. MR imaging can also assist in the diagnosis of NSTIs [35]. MR imaging has been documented to effectively differentiate between necrotizing and non-necrotizing infection of the lower extremity and other areas of the body, but should not delay prompt surgical intervention in NSTIs management [36–38].
25.3.5.3 Microbiology of NSTIs
Necrotizing fasciitis and myonecrosis are typically caused by infection with Group A streptococcus, Clostridium perfringens, or, most commonly, aerobic and anaerobic organisms as part of a polymicrobial infection that may include S. aureus. In case series, CA-MRSA has recently been described as a predominantly monomicrobial cause of necrotizing fasciitis [39, 40]. A retrospective review of patients presenting with necrotizing fasciitis between 2000 and 2006 indicated that MRSA was the most common pathogen, accounting for one-third of the organisms isolated [41].
NSTIs have been classified into two types, either polymicrobial (Type I) or monomicrobial (Type II). Polymicrobial infections are more common, due to both aerobic and anaerobic organisms, and commonly occur in the trunk and perineum. NSTIs that are monomicrobial in origin commonly occur in the limbs and are typically caused by infection with Group A streptococcus, Clostridium perfringens, or S. aureus. NSTIs are categorized into these two specific types based on the microbiologic etiology of the infection, and this classification does impact on the specific antimicrobial agents required for treatment of these NSTIs.
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