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Early Initiation of Appropriate Empiric Broad-Spectrum Antimicrobial Therapy with AntiMRSA Coverage and Consideration of Risk Factors for Specific Pathogens

Antimicrobial therapy is an essential element in the management of severe SSTIs. As in all serious lifethreatening infections, it is important to initiate early and appropriate empiric antimicrobial therapy.

It is well established that prompt appropriate treatment of hospitalized infections reduces mortality.2

Similar findings were reported in studies of patients with ventilator-associated pneumonia 50 and

sepsis.51 A study of ICU patients found that the higher mortality rate associated with inappropriate

initial therapy is still observed when antibiotics are switched from an inappropriate to an appropriate

treatment.52

Furthermore, appropriate and timely antibiotic therapy improves treatment outcomes for SSTIs

caused by MRSA.53 In a study of 492 patients with community-onset MRSA SSTIs, 95% of episodes

treated with an active antibiotic within 48 hours were treated successfully, compared with an 87% rate

of successful treatment in patients who did not receive an active antibiotic. In logistic regression

analysis, failure to initiate active antimicrobial therapy within 48 hours of presentation was the only

independent predictor of treatment failure. Similarly, in a study of patients admitted to the hospital

with MRSA sterile-site infection, multivariate analysis found inappropriate antimicrobial treatment to be

an independent risk factor for hospital mortality.54

An empiric treatment algorithm for SSTI directed against community-associated MRSA (CA-MRSA) in

the emergency department that promotes both the use of antibiotics likely active against CA-MRSA and

early incision and drainage of abscesses was examined. Clinical failure occurred in only 3% of cases

treated according to the algorithm, compared with 62% of those not treated according to the algorithm.

Furthermore, among cases that underwent immediate incision and drainage, initial treatment with

antibiotics active in vitro against the MRSA isolate was associated with a decreased clinical failure rate

when compared to those treated with inactive antibiotics (0% vs. 67%).55

Empiric antibiotic therapy should be initiated in all patients with SSTIs. IV broad-spectrum

antimicrobial therapy should be initiated when an infection is severe or progresses rapidly, when there

are signs of systemic illness, when the patient has comorbidities or is immunosuppressed, for very old

or young patients, when an abscess cannot be completely drained, and when the infection does not

respond to incision and drainage.56

Timely initiation of antimicrobial therapy is also important in the treatment of severe SSTIs,

particularly if associated with septic shock. In a study of 2,731 adult patients with septic shock, a strong

relationship between the delay in effective antimicrobial initiation and in-hospital mortality was noted.4

Administration of an antimicrobial effective for isolated or suspected pathogens within the first hour of

documented hypotension was associated with a survival rate of 79.9%. Each hour of delay in

antimicrobial administration over the ensuing 6 hours was associated with an average decrease in

survival of 7.6%. By the second hour after onset of persistent/recurrent hypotension, in-hospital

mortality rate was significantly increased relative to receiving therapy within the first hour. In

multivariate analysis (including Acute Physiology and Chronic Health Evaluation II score and

therapeutic variables), time to initiation of effective antimicrobial therapy was the single strongest

predictor of outcome. Interestingly, only 50% of septic shock patients received effective antimicrobial

therapy within 6 hours of documented hypotension.

Necrotizing Soft Tissue Infections

NSTIs are aggressive soft tissue infections that cause widespread necrosis, and can include necrotizing

cellulitis, fasciitis, and myositis/myonecrosis.57,58 Establishing the diagnosis of NSTI can be the main

challenge in treating patients with NSTI, and knowledge of all available tools is key for early and

accurate diagnosis.59 There have been a number of recent advances in the definition, pathogenesis,

diagnostic criteria, and treatment of NSTIs.60,61

Patients with NSTIs require prompt aggressive surgical debridement, appropriate IV antibiotics, and

intensive support. Despite aggressive treatment, their mortality and morbidity rates remain high, with

some series reporting mortality rates of 25% to 35%.62 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. Early operative debridement is the major determinant of

outcome in NSTIs.

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A recent single-institution series of 166 patients documented that the overall mortality rate was 17%

and limb loss occurred in 26% of patients with extremity involvement.63 Independent predictors of

mortality included white blood cell count greater than 30,000 × 103/μL, creatinine level greater than 2

mg/dL, and heart disease at hospital admission. Independent predictors of limb loss included heart

disease and shock (systolic blood pressure <90 mm Hg) at hospital admission. Clostridial infection was

an independent predictor for both limb loss and mortality and was highly associated with IV drug use

and a high rate of leukocytosis on hospital admission.

A 30-day postoperative mortality risk calculator for NSTI was developed using the NSQIP which

identified seven independent variables that correlated with mortality: age older than 60 years,

functional status, requiring dialysis, American Society of Anesthesiologists (ASA) class 4 or higher,

emergent surgery, septic shock, and low platelet count. The receiver operating characteristic area was

0.85, which indicated a strong predictive model that can aid physicians in the decision-making

process.64

13 Early operative debridement is the 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 LRINEC score (Table 8-11).65 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 2 tertiary care hospitals. The cutoff value for the LRINEC

score was 6 points with a positive predictive value of 92% and negative predictive value of 96%. The

LRINEC score is a robust score capable of detecting 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.

Table 8-11 The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) Score

Since the initial development of the LRINEC score, a number of other cohort studies have validated its

utility in the diagnosis of NSTIs. A multicenter study in 229 patients with NSTIs from 2002 to 2005

reported an overall mortality rate of 16% and amputation rate of 26%. This study also documented that

a LRINEC score ≥6 was associated with a higher rate of both mortality and amputation.66

Diagnostic Imaging in Necrotizing Soft Tissue Infections

NSTIs necessitate prompt aggressive surgical debridement for satisfactory treatment in addition to

antimicrobial therapy. 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.67 MR imaging has been documented to effectively differentiate between

necrotizing and nonnecrotizing infections of the lower extremity and other areas of the body, but should

not delay prompt surgical intervention in NSTIs management.68–70

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Microbiology of Necrotizing Soft Tissue Infections

Necrotizing fasciitis and myonecrosis are typically caused by infection with group A streptococcus

(GAS), 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.71,72 A retrospective review of patients

presenting with necrotizing fasciitis indicated that MRSA was the most common pathogen, accounting

for one-third of the organisms isolated.73

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 GAS, C. 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.

Increasingly, MRSA has been identified as the causative microbe in NSTIs, but a separate category for

this NSTI does not currently exist.74–78 Given this finding, anti-MRSA empiric antimicrobial therapy

should be initiated in all patients with NSTIs and pathogen-directed antimicrobial therapy considered

once tissue culture results are available.

Uncommon microbiologic causes of NSTIs and primary sepsis include Vibrio and Aeromonas species,

virulent gram-negative bacteria, and members of the Vibrionaceae family that thrive in aquatic

environments.79 These NSTIs are likely to occur in patients with hepatic disease, diabetes, and

immunocompromised conditions.80 These organisms are found in warm sea waters and are often present

in raw oysters, shellfish, and other seafood. The diagnosis of vibrio NSTIs should be suspected when a

patient has the appropriate clinical findings and a history of contact with seawater or raw seafood.81

Early fasciotomy and culture-directed antimicrobial therapy should be aggressively performed in those

patients with hypotensive shock, leukopenia, severe hypoalbuminemia, and underlying chronic illness,

especially a combination of hepatic dysfunction and diabetes mellitus. The rates of amputation and

mortality are very high in these patients, and early definitive management is of paramount

importance.82–84 A study of 125 patients identified that a LRINEC score of 2 or greater and the presence

of hemorrhagic bullous/blistering lesions in patients with Vibrio vulnificus SSTI are associated with an

12-fold increased risk for the presence of NSTI and necrotizing fasciitis.85

Pyomyositis

Myositis is a rare infection that may lead to serious and potentially life-threatening local and systemic

complications.86 The infection can progress rapidly, and early recognition and proper medical and

surgical management is therefore the cornerstone of therapy. With the increasing prevalence of

community-associated MRSA as a pathogen in severe SSTIs, pyomyositis is more common than in past

years.87,88 Myositis often occurs in muscle sites that have been compromised by injury, ischemia,

malignancy, or surgery. The predominant pathogens are S. aureus, GAS, gram-negative aerobic and

facultative bacilli, and the indigenous aerobic and anaerobic cutaneous and mucous membranes local

microflora.

CT scan imaging is a rapid and sensitive diagnostic test and commonly demonstrates diffuse

enlargement of the involved muscle and may demonstrate the presence of fluid or gas collections within

the muscle suggesting the presence of abscesses. MRI is more sensitive in showing early inflammatory

changes prior to development of abscesses in myositis.89 Emergency surgical exploration is warranted in

order to define the nature of the infective process which is accomplished by direct examination of the

involved muscles. Surgical intervention is required to perform appropriate abscess drainage and

debridement and also to evaluate for necrotizing myositis. Fasciotomies and extremity amputation are

sometimes necessary.

SURGICAL SITE INFECTIONS

Epidemiology

SSI is the leading nosocomial infection among surgical patients and the second most common

nosocomial infection overall. In the United States, greater than 40 million inpatient and outpatient

surgical procedures are performed each year and 2% to 5% are complicated by SSIs. SSIs result in

increased length of stay (7 days) and additional cost ($400 to $2,600 per infection; total $130 to $845

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