Bongard Frederic , Darryl Sue. Diagnosis and Treatment Critical Care

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INFECTIONS IN THE CRITICALLY ILL

367

Treatment

In all patients, initial antimicrobial therapy should target the

organism seen on the Gram-stained smear of the urinary

sediment. In the absence of an identified organism on Gram

stain, empirical therapy should consist of a third-generation

cephalosporin, an extended-spectrum penicillin (eg,

piperacillin), a fluoroquinolone, and/or an aminoglycoside

depending on the severity of the infection, the patient’s renal

function and risk for renal insufficiency, and other factors. If

Enterococcus is suspected, ampicillin or piperacillin with or

without an aminoglycoside is appropriate. For emphysema-

tous pyelonephritis, immediate nephrectomy usually is

required.

Hooton TM: The current management strategies for community-

acquired urinary tract infection. Infect Dis Clin North Am

2003;17:303–32. [PMID: 12848472]

Rubenstein JN, Schaeffer AJ: Managing complicated urinary tract

infections: The urologic view. Infect Dis Clin North Am

2003;17:333–52. [PMID: 12848473]



Infective Endocarditis

ESSENTIALS OF DIAGNOSIS



Clinical presentation varies depending on infecting

organism.



Patients with S. aureus infective endocarditis typically

present with a short prodrome and a sepsis syndrome.

Clues to the diagnosis of subacute infective endocardi-

tis include a new regurgitant murmur, Roth spots, Osler

nodes, Janeway lesions, splinter hemorrhages, hema-

turia, and splenomegaly.



Blood cultures are needed for diagnosis.

General Considerations

The incidence of infective endocarditis in the general popu-

lation is estimated to be 1.7–6.2 cases per 100,000 person-

years. Risk factors include underlying valvular abnormalities.

Congenital or rheumatic heart disease, mitral valve prolapse

(particularly when regurgitation or thickened, redundant

valve leaflets are present), calcific valvular heart disease, and

prosthetic valves are implicated in a large percentage of cases.

Another increasingly important risk factor is injection drug

use. Among injection drug users, the presentation of infec-

tive endocarditis is usually acute, reflecting the virulent

nature of S. aureus, the pathogen most commonly associated

with infective endocarditis in this population.

Pathophysiology

The first step in infective endocarditis is the establishment of

bacteremia, which may occur during a dental or other medical

procedure, as a complication of injection drug use, or from

minor trauma. However, in most cases, no initiating event is

identified. The organism attaches to the abnormal endothe-

lial surface of the cardiac valve, and the vegetation propa-

gates with further bacterial proliferation. The complications

that then arise are the result of either (1) direct local invasion

(eg, periannular abscess formation), (2) systemic emboliza-

tion (eg, splenic, renal, or cerebral embolic), or (3) immuno-

logic phenomena (eg, glomerulonephritis or vasculitis).

Microbiologic Etiology

The microbiologic etiology of infective endocarditis has

undergone a shift in the past 3–4 decades. In the 1960s and

1970s, viridans streptococci and enterococci accounted for

up to 80% of cases and staphylococci for approximately 15%.

In more recent series, the viridans streptococci and entero-

cocci still account for 50% of cases, but staphylococci are

now implicated in approximately 50% of cases of acute infec-

tive endocarditis.

The most common bacterial cause of native-valve infective

endocarditis remains the viridans streptococci group. As noted

earlier, S. aureus infective endocarditis usually occurs in injec-

tion drug users and diabetics, who tend to have skin and nasal

colonization with the organism. Other less common pathogens

include S. pneumoniae; groups A, B, C, and G streptococci; and

Listeria monocytogenes, P. aeruginosa, Serratia marcescens, and

rarely, Neisseria gonorrhoeae. In cases of culture-negative endo-

carditis, the HACEK group of microorganisms (Haemophilus

parainfluenzae, H. aphrophilus, Actinobacillus actinomycetem-

comitans, Cardiobacterium hominis, Eikenella corrodens, and

Kingella kingae); nutritionally variant streptococci (now

Abiotrophia species); Brucella, Legionella, and Bartonella

species; C. burnetii; and fungi all should be considered. The

most common reason for culture-negative infective endocardi-

tis is prior antibiotic therapy.

Clinical Features

A. Symptoms and Signs—The clinical presentation of

infective endocarditis varies dramatically depending on the

infecting organism. Patients with S. aureus infective endo-

carditis typically present with a short prodrome and a sepsis

syndrome. Only rarely are the immunologic phenomena

associated with subacute infective endocarditis present.

Among injection drug users, infection usually involves the

tricuspid valve. Thus pulmonary manifestations predomi-

nate, which may manifest as multiple parenchymal infil-

trates, cavities, pleural effusion, or empyema. A murmur may

not be readily appreciated. The less virulent organisms, such

as the viridans streptococci, typically present with the classic

subacute infective endocarditis syndrome. Nonspecific

symptoms such as fatigue, malaise, or back pain usually have

been present for weeks. Clues to the diagnosis of subacute

infective endocarditis include a new regurgitant murmur,

Roth spots, Osler nodes, Janeway lesions, splinter hemor-

rhages, hematuria, and splenomegaly.

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CHAPTER 15

368

Complications of infective endocarditis, such as conges-

tive heart failure or CNS emboli, may necessitate admission

to an ICU.

B. Laboratory and Radiographic Findings—The first clue

to the diagnosis of infective endocarditis is often a blood cul-

ture yielding growth of an appropriate organism. In the

patient with suspected infective endocarditis who presents

with subacute symptoms, three separate sets of blood cul-

tures should be obtained prior to initiating empirical antimi-

crobial therapy. A complete blood count may reveal only

leukocytosis in a patient with acute S. aureus infective endo-

carditis; however, evidence of anemia of chronic disease may

be present in a patient with subacute infective endocarditis.

Urinalysis may reveal hematuria, proteinuria, or pyuria. A

chemistry panel may demonstrate renal insufficiency (the

result of renal infarction), septic emboli, or immune-

complex glomerulonephritis. Patients may have other non-

specific indicators of acute inflammation, such as an elevated

erythrocyte sedimentation rate or C-reactive protein, hyper-

gammaglobulinemia, or a positive test for rheumatoid factor.

Chest x-ray may reveal multiple pulmonary infiltrates, cavi-

tary lesions, pleural effusion in right-sided disease, or pul-

monary edema in left-sided disease. A 12-lead ECG should be

obtained on all patients to look for intracardiac conduction

delay, manifested as a new first-, second-, or third-degree

heart block, suggesting the presence of an aortic ring abscess.

Any patient with neurologic symptoms should undergo brain

CT scan to look for embolic events or intracranial hemor-

rhage from rupture of an infected (“mycotic”) aneurysm.

Diagnosis of infective endocarditis is aided by use of the

modified Duke criteria (Table 15–4). Echocardiography

should be obtained on all patients in whom the diagnosis is

entertained because it provides both diagnostic and prog-

nostic information. The sensitivity of the transthoracic

echocardiogram for demonstrating valvular vegetations is

only about 60–70%, and for this reason, the procedure can-

not exclude infective endocarditis entirely. On the other

hand, transesophageal echocardiography has a reported sen-

sitivity approaching 95% and is particularly useful in detect-

ing periannular aortic abscess formation.

C. Complications—Because the most seriously ill patients

with infective endocarditis are admitted to the ICU, this pop-

ulation is likely to have a high rate of complications. Thus it

is important for the physician to remain vigilant for these

potential life-threatening events.

Congestive heart failure is the most common complica-

tion of acute infective endocarditis. It may occur acutely as a

result of perforation of a valve leaflet or rupture of a chorda

tendinea, from valvular outlet obstruction owing to large

vegetations, from creation of fistulous tracts leading to high-

output failure, or from prosthetic valve dehiscence.

Congestive heart failure also may present insidiously as a

result of progressive valvular insufficiency or ventricular dys-

function. Congestive heart failure that is refractory to med-

ical management necessitates valve replacement.

Systemic embolization occurs in up to a third of patients

with infective endocarditis. Risk factors for embolic events

include vegetation size greater than 1 cm on the trans-

esophageal echocardiogram, vegetation location on the ante-

rior leaflet of the mitral valve, increasing vegetation size

during appropriate antimicrobial therapy, and infection with

S. aureus, Candida species, one of the HACEK group, or the

Abiotrophia species. There is general agreement that the

occurrence of two or more serious embolic events while on

appropriate antimicrobial therapy is an indication for valve

replacement.

Periannular extension of infection occurs in 10–40% of

cases of native valve infective endocarditis and 55–100% of

cases involving a prosthetic valve. Periannular abscess forma-

tion is more common when the aortic valve is involved. The

infection spreads from the aortic ring and can rupture

through the membranous septum to involve the atrioven-

tricular node; thus the finding of a new intracardiac conduc-

tion delay is often a first clue to this life-threatening

complication. Creation of an intracardiac shunt also can

occur. Periannular extension of infection is best diagnosed by

transesophageal echocardiography, which has a sensitivity of

87% and a specificity of 95%. In most cases, periannular

abscess formation requires valve replacement.

In a patient with infective endocarditis who has persistent

bacteremia, fever, or sepsis in the setting of appropriate

antimicrobial therapy, the possibility of a splenic or renal

abscess should be considered. Splenic infarction occurs in

about 40% of cases of left-sided endocarditis; of these, 5%

progress to abscess formation. Abdominal CT scan or MRI

may be useful for diagnosis. Renal abscesses may require

drainage in conjunction with appropriate antimicrobial

therapy, depending on their size. Splenectomy is the defini-

tive treatment for splenic abscess.

One of the most feared complications of infective endo-

carditis is the development of an infected (“mycotic”)

aneurysm. The most common site of involvement is the

intracranial arteries, followed by the visceral bed and the

upper and lower extremities. The incidence of intracranial

mycotic aneurysms in patients with infective endocarditis is

about 1.2–5%. The overall mortality of this complication is

6–30% without rupture and 80% with rupture. The diag-

nostic method of choice is four-vessel cerebral angiography.

Decisions regarding therapy, including potential surgery,

should be individualized.

Treatment

The spectrum of initial antimicrobial therapy in a critically ill

patient with suspected infective endocarditis should be broad,

directed at the pathogens implicated most commonly in

this disease. Initial therapy should include vancomycin to

cover MRSA, a penicillin with activity against streptococci

and enterococci, and an aminoglycoside for synergy against

these organisms. If infection with S. aureus is highly likely,

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INFECTIONS IN THE CRITICALLY ILL

369

some infectious disease specialists use a semisynthetic peni-

cillin such as nafcillin or oxacillin in conjunction with van-

comycin to optimize coverage of both methicillin-sensitive

and methicillin-resistant strains. When faced with a patient

who has a history of a serious allergic reaction to penicillin,

the physician should use vancomycin in lieu of β-lactams.

Subsequent antibiotic therapy must be tailored once the

infecting organism and its drug susceptibility pattern are

known.

Baddour LM et al: Infective endocarditis: Diagnosis, antimicrobial

therapy, and management of complications. A Statement for

Healthcare Professionals from the Committee on Rheumatic Fever,

Endocarditis, and Kawasaki Disease, Council on Cardiovascular

Disease in the Young, and the Councils on Clinical Cardiology,

Stroke, and Cardiovascular Surgery and Anesthesia, and the

American Heart Association. Circulation 2005;111:e394–434.

[PMID: 15956145]

Beynon RP, Bahl VK, Prendergast BD: Infective endocarditis. Br

Med J 2006;333:334–9. [PMID: 16902214]

Definite infective endocarditis 1. Two major criteria, or

2. One major criterion and three minor criteria, or

3. Five minor criteria

Possible infective endocarditis 1. One major criterion and one minor criterion, or

2. Three minor criteria

Endocarditis rejected 1. Firm alternate diagnosis explaining evidence of infective endocarditis, or

2. Resolution of infective endocarditis syndrome with antibiotic therapy for less than 4 days, or

3. No pathologic evidence of infective endocarditis at surgery or autopsy, with antibiotic therapy for less than

4 days, or

4. Does not meet criteria for possible infective endocarditis, as above

Definitions for modified Duke clinical criteria

Major criteria

1. Blood culture positive for IE

a. Typical microorganisms consistent with IE from two separate blood cultures:

Viridans

streptococci,

Streptococcus bovis

, HACEK group,

S. aureus,

ii. Community-acquired enterococci, in the absence of a primary focus, or

b. Microorganisms consistent with IE from persistently positive blood cultures, defined as follows:

i. At least two positive cultures of blood samples drawn 12 hours apart, or

ii. All of three or a majority of more than four separate cultures of blood (with first and last samples drawn at

least 1 hour apart)

iii. Single positive blood culture for

C. burnetii

or IgG antibody to phase I antigen ≥ 1:800 by IFA

2. Evidence of endocardial

involvement

a. Echocardiogram

positive for IE, defined as follows:

i. Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on

implanted material in the absence of an alternative anatomic explanation, or

ii. Abscess, or

iii. New partial dehiscence of prosthetic valve

b. New valvular regurgitation (worsening or changing of preexisting murmur not sufficient)

Minor criteria 1. Predisposition, predisposing heart condition or injection drug use

2. Fever, temperature >38ºC

3. Vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial

hemorrhage, conjunctival hemorrhages, or Janeway’s lesions

4. Immunologic phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots, and rheumatoid factor

5. Microbiological evidence: positive blood culture but does not meet a major criterion as noted above

or sero-

logic evidence of active infection with organism consistent with IE

Transesophageal echocardiogram recommended in patients with prosthetic valves, rated at least “possible IE” by clinical criteria, or compli-

cated IE (paravalvular abscess); otherwise, use transthoracic echocardiogram.

Excludes single positive cultures for coagulase-negative staphylococci and organisms that do not cause endocarditis.

Table 15–4. Modified Duke clinical criteria for infective endocarditis.

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CHAPTER 15

370

Karth G et al: Complicated infective endocarditis necessitating

ICU admission: Clinical course and prognosis. Crit Care 2002;6:

149–54. [PMID: 11983041]

Mourvillier B et al: Infective endocarditis in the intensive care unit:

Clinical spectrum and prognostic factors in 228 consecutive

patients. Intensive Care Med 2004;30:2046–52. [PMID:

15372147]

Mylonakis E, Calderwood SB: Infective endocarditis in adults.

N Engl J Med 2001;345:1318–30. [PMID: 11794152]

Sachdev M, Peterson GE, Jollis JG: Imaging techniques for diagno-

sis of infective endocarditis. Cardiol Clin 2003;21:185–95.

[PMID: 12874892]

Sexton DJ, Spelman D: Current best practices and guidelines:

Assessment and management of complications in infective

endocarditis. Cardiol Clin 2003;21:273–82. [PMID: 12874898]



Necrotizing Soft Tissue Infections

ESSENTIALS OF DIAGNOSIS



Patients complain of pain out of proportion to physical

findings.



Essential to differentiate a necrotizing soft tissue infection

from a simple cellulitis.



Metabolic acidosis, renal insufficiency, and other signs

of organ dysfunction may be present.

General Considerations

Necrotizing fasciitis is an uncommon soft tissue infection

caused by a variety of toxin-producing bacteria. There is fas-

cial necrosis, often with less marked involvement of overly-

ing skin and underlying muscle, and signs of systemic

toxicity. The true incidence of necrotizing soft tissue infec-

tions is difficult to quantify because they are not reportable.

Necrotizing fasciitis can result from a large number of asso-

ciated conditions, including trauma, surgical procedures,

and relatively benign local infections of the skin or soft tis-

sues. The mortality rate ranges between 15% and 52% in

most series. Risk factors for necrotizing soft tissue infections

include diabetes mellitus (the most common preexisting

condition), peripheral vascular disease, alcoholism, injection

drug use, obesity, malnutrition, and immunosuppression,

including HIV infection.

The multitude of terms used to describe soft tissue

infections may be confusing to the reader: hemolytic strep-

tococcal gangrene, progressive synergistic bacterial gangrene,

necrotizing erysipelas, suppurative fasciitis, acute dermal

gangrene, Fournier’s gangrene, and progressive postoperative

bacterial synergistic gangrene all have appeared in the liter-

ature. Distinguishing between the various categories of

necrotizing soft tissue infections is not always necessary

because prognosis and treatment of these conditions are

quite similar.

Pathophysiology

In the pathogenesis of necrotizing soft tissue infections, bac-

teria typically are introduced into the skin or soft tissues by

trauma, either inadvertently or iatrogenically. Inciting events

that have been reported to lead to soft tissue infections

include surgery, blunt or penetrating trauma, insect bites,

varicella infection, injection drug use, perforated viscus, per-

ineal abscess, diverticulitis, percutaneous drainage of

intraabdominal abscess, renal calculi, dental infection or

procedure, pharyngitis, and exposure to sea water.

Hematogenous introduction of the bacteria into soft tissue

has been documented with S. pyogenes and S. aureus (includ-

ing methicillin-resistant S. aureus).

Once bacteria gain entry into the host tissues, bacterial

toxins and endogenous cytokines act synergistically to pro-

duce tissue damage. Both exotoxin A and exotoxin B have

been identified in invasive group A streptococcal infections.

Histopathologic examination of involved tissue typically

reveals widespread necrosis of the fascia and subcutaneous

fat and thrombosis and endarteritis of small vessels.

Occasionally, myonecrosis of underlying skeletal muscle will

be observed.

Microbiologic Etiology

There are three predominant types of necrotizing fasciitis,

with distinctions based on microbiologic etiology. Type 1 is

polymicrobial infection, with a combination of non–group A

streptococci, anaerobes, and facultative anaerobes, usually

Enterobacteriaceae. Among persons developing type 1

necrotizing fasciitis, certain host factors are associated with

infection by specific bacteria. For example, diabetics tend to

become infected with Bacteroides species, S. aureus, and the

Enterobacteriaceae. Immunosuppressed patients may become

infected with P. aeruginosa and other Enterobacteriaceae. Of

note, recent reports describe necrotizing fasciitis owing to

MRSA in patients with underlying HIV infection. Clostridium

species are seen more commonly following trauma. On aver-

age, four different species of bacteria are identified by culture

in patients with type 1 necrotizing fasciitis.

Type 2 necrotizing fasciitis is defined by infection with

group A β-hemolytic streptococci, occurring either alone or

in combination with staphylococci. Type 3 necrotizing fasci-

itis is characterized by infection with marine vibrios follow-

ing exposure to sea water. This group of gram-negative rods

consists of Vibrio vulnificus, V. parahaemolyticus, V. damsela,

and V. alginolyticus; V. vulnificus is considered to be the most

virulent.

Clinical Features

A. Symptoms and Signs—The typical patient presents with

a history of 5–7 days or fewer of localized pain, redness, and

swelling. On physical examination, the patient may be tachy-

cardiac or tachypneic (in compensation for metabolic acido-

sis). Fever is not uniformly present, with up to 50% of

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INFECTIONS IN THE CRITICALLY ILL

371

patients being afebrile. An area of what initially appears to be

simple cellulitis may be noted, with localized warmth, ery-

thema, and tenderness of the skin and soft tissues. An impor-

tant clue to the diagnosis of necrotizing fasciitis is the

presence of pain disproportionate to physical findings. Rapid

progression of soft tissue involvement is typical, with the

evolution of a smooth, tense, and edematous lesion to blister

and bulla formation with an underlying dusky blue hue to

skin surfaces. With progression of soft tissue involvement,

the subcutaneous nerves are destroyed, resulting in anesthe-

sia of overlying skin. However, physical findings may be non-

specific: About 75% of patients present only with pain,

swelling, and cutaneous erythema. Specific findings sugges-

tive of invasive soft tissue involvement, such as crepitus and

blistering, are present in less than 40% of patients.

B. Laboratory Findings—Complete blood count, a chem-

istry panel, and liver enzymes should be obtained on all

patients. Leukocytosis with left shift is typically present;

blood chemistries may reveal metabolic acidosis, renal insuf-

ficiency, and other evidence of organ dysfunction. Creatine

kinase may be elevated, reflecting myonecrosis. One retro-

spective study identified a white blood cell count of greater

than 14,000/μL, a serum sodium of less than 135 mmol/L,

and a serum urea nitrogen of greater than 15 mg/dL as use-

ful in distinguishing patients with necrotizing fasciitis from

patients with cellulitis. Plain films occasionally reveal gas in

the soft tissue, a finding that is specific for necrotizing fasci-

itis. MRI may be a more sensitive tool in differentiating a

necrotizing soft tissue infection from simple cellulitis; how-

ever, this diagnostic modality is not readily available at all

centers. Diagnosis requires surgical exploration of the

involved soft tissue—the hallmark of necrotizing fasciitis is

nonadherence of fascia to underlying muscles on blunt dis-

section. In some cases, a full-thickness biopsy with immedi-

ate frozen section will reveal fascial necrosis. Surgically

debrided tissue should be submitted for aerobic and anaero-

bic bacterial cultures to allow appropriate tailoring of antibi-

otic therapy. Gram stain of an aspirate from the necrotic

center of the lesion has been shown to correlate well with

culture results.

Differential Diagnosis

The differential diagnosis of necrotizing fasciitis includes cel-

lulitis, erysipelas, thrombophlebitis, myositis, and compart-

ment syndrome. In many cases, the differentiation of these

entities from necrotizing fasciitis can be made on clinical

grounds.

Treatment

A. Empirical Antibiotic Therapy—Empirical antimicrobial

treatment of necrotizing fasciitis should include coverage of

aerobic gram-positive cocci, aerobic gram-negative rods, and

anaerobes. Initial antimicrobial choices could include a peni-

cillin or a first-generation cephalosporin along with an

aminoglycoside and either clindamycin or metronidazole.

Given the dramatic increase in rates of community-acquired

MRSA infections, empirical therapy should include clin-

damycin, trimethoprim-sulfamethoxazole, or in some cases,

vancomycin. If S. pyogenes is suspected, the treatment of

choice is high-dose penicillin. In this setting, animal data

support the addition of clindamycin; in the presence of a

high inoculum of organisms in a stationary phase of growth,

penicillin-binding proteins are not fully expressed, reducing

the efficacy of penicillin. Furthermore, clindamycin acts as a

protein synthesis inhibitor at the ribosome, which may sup-

press streptococcal toxin production. If Vibrio infection is

suspected, tetracycline should be added to the regimen.

When clostridial myonecrosis is a consideration, high-dose

penicillin with or without clindamycin should be initiated.

B. Surgery—Because of tissue hypoxia, necrosis, and blood

vessel thrombosis, antibiotics alone never should be consid-

ered definitive therapy for necrotizing fasciitis. Early

debridement of all necrotic tissue is imperative for control of

infection. The goal of surgery is twofold: to render a prompt

diagnosis and to perform definitive debridement. Patients

require frequent reevaluation of the surgical site—at least

every 12 hours. Repeat debridement is often necessary.

C. Adjunctive Therapies—Supportive care is critical, with

appropriate fluid resuscitation and nutritional support to

promote wound healing. The issue of adjunctive hyperbaric

oxygen therapy is controversial; however, the data to support

its use consist of retrospective studies, case reports, and ani-

mal studies. If hyperbaric oxygen is readily available, its use

can be considered. However, it never should be considered an

alternative to adequate surgical debridement.

Prognosis

The mortality rate associated with necrotizing fasciitis is high.

Risk factors for mortality have been identified as age over

60 years, female sex, extent of infection on presentation, delay

in surgical debridement, elevated creatinine, elevated blood

lactate, white blood cell count greater than 30,000/μL, presence

of bacteremia, and degree of organ dysfunction on admission.

The physician should maintain a high level of suspicion when

evaluating patients with soft tissue infections because early

diagnosis with prompt surgical debridement remains the

most important modifiable determinant of prognosis.

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by methicillin-resistant Staphylococcus aureus. N Engl J Med

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tions and surgical site infections. Clin Infect Dis

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Stevens DL et al: Practice guidelines for the diagnosis and manage-

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North Am 2001;39:277–303. [PMID: 11316360]



Intraabdominal Infections

ESSENTIALS OF DIAGNOSIS



Symptoms may be nonspecific, with patients reporting

vague abdominal pain, anorexia, and fever.



Abdominal examination may reveal absent or dimin-

ished bowel sounds, with peritoneal signs.



Laboratory findings are nonspecific in patients with

intraabdominal sepsis.

General Considerations

Intraabdominal infections are a significant cause of mortal-

ity and morbidity in the ICU. The actual incidence of

intraabdominal infections is difficult to quantify because this

category includes a wide range of diagnoses.

Pathophysiology

See Table 15–5.

Microbiologic Etiology

See Table 15–5. The majority of intraabdominal infections

are polymicrobial in nature, caused by Enterobacteriaceae,

anaerobes, or streptococci. The organisms isolated from a

given intraabdominal infection reflect the flora native to the

involved region of the GI tract. The normal flora of the stom-

ach, duodenum, and proximal small bowel consist of small

numbers of viridans streptococci and other microaerophilic

streptococci. The distal small bowel is populated with larger

numbers of Enterobacteriaceae, enterococci, and anaerobes.

The colon is estimated to contain up to 10

organisms per

Intraabdominal

Infection

Pathophysiology Microbiologic Etiology Diagnostic Tests

Empirical Antimicrobial

Therapy

Peritonitis (spontaneous) Translocation of bacteria

across gut lumen in

cirrhosis

E. coli

(most frequent),

K. pneumoniae, S. pneumo-

niae,

streptococci, enterococci

Paracentesis (neu-

trophils >250/μL,

positive Gram stain

or culture)

Third-generation cephalosporin

(preferably cefotaxime or

ceftriaxone)

Peritonitis (secondary) Perforation of viscus Enterobacteriaceae, anaer-

obes, streptococci, entero-

cocci,

Candida

species

Paracentesis (polymi-

crobial Gram stain or

culture), plain films

or CT showing free

peritoneal air

β-lactam/β-lactamase inhibitor

Third-generation cephalosporin (or

cefepime) + metronidazole

Quinolone + metronidazole

Carbapenem

Monobactam + metronidazole

Intraperitoneal abscess Complication of

spontaneous or

secondary

peritonitis

Enterobacteriaceae, anaer-

obes, streptococci,

Candida

species

CT scan, ultrasound,

perhaps radionuclide

scan

Pancreatic abscess Complication of pancre-

atitis (biliary, ethanol,

postoperative, or post-

traumatic)

Enterobacteriaceae, anaer-

obes, streptococci, entero-

cocci,

Candida

species

CT scan or ultrasound

Hepatic abscess Local spread from con-

tiguous infection or

hematogenous seeding

of liver

Mixed facultative and anaero-

bic species (most common),

unless biliary tract source

(enteric gram-negative bacilli

and enterococci); consider

E. histolytica

CT scan or ultrasound

Table 15–5. Intraabdominal infections: Pathophysiology, microbiology, and treatment.

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INFECTIONS IN THE CRITICALLY ILL

373

gram of feces. The predominant flora consists of anaerobes,

Enterobacteriaceae, and enterococci. Candida species colo-

nize the GI tract in approximately 50% of individuals, which

may be an important pathogen in patients with bowel perfo-

ration. The normal microbiologic flora of the GI tract are

altered dramatically by antibiotic therapy, selecting for

increased colonization with Candida species, enterococci,

and other relatively resistant gram-negative bacilli such as

Pseudomonas and Enterobacter species.

Intraabdominal infections may be caused by pathogens

not typically associated with GI flora. In patients with spe-

cific risks (ie, suspected exposure or immunocompromised),

the following organisms should be considered: M. tuberculo-

sis, N. gonorrhoeae, C. trachomatis, C. immitis, Yersinia ente-

rocolitica, and Actinomyces.

Clinical Features

A. Symptoms and Signs—The symptoms and signs of

intraabdominal sepsis not only vary among patients but also

depend on the underlying etiology of the infection.

Symptoms may be nonspecific, with patients reporting vague

abdominal pain, anorexia, or subjective fever. Patients may

be febrile or hypothermic; tachycardia is common, and

tachypnea may be present in compensation for an underly-

ing metabolic acidosis. Abdominal examination may reveal

absent or diminished bowel sounds, with peritoneal signs.

Patients who are morbidly obese, elderly, neutropenic, or

receiving steroids or other immunosuppressive agents are

more likely to have nonspecific complaints, along with rela-

tively benign abdominal findings on physical examination,

even in the presence of severe intraabdominal pathology.

Thus the physician must maintain a high level of suspicion

when evaluating these patient populations.

B. Laboratory Findings—Laboratory findings are nonspe-

cific in patients with intraabdominal sepsis. Peripheral leuko-

cytosis is common, although leukopenia may be seen in some

patients, perhaps owing to intraabdominal sequestration of

white blood cells. Metabolic acidosis may be present and

should prompt consideration of bowel ischemia. Elevation of

liver aminotransferases, although relatively common, is a

nonspecific finding in intraabdominal infection and only

rarely heralds a focal intrahepatic infection. Elevation of

serum alkaline phosphatase and total bilirubin mandates

prompt investigation of the biliary tree to rule out cholecysti-

tis, cholangitis, or an obstructing mass. An elevated serum

amylase or lipase may point to pancreatitis, although an

abnormal serum amylase also may be seen with bowel infarc-

tion or perforation. If ascites is present, a diagnostic paracen-

tesis should be performed, with assessment of cell count,

protein, albumin, Gram stain, and culture of ascitic fluid.

C. Imaging Studies—Supine and upright films of the

abdomen may reveal free air if viscus perforation is present.

Other diagnostic clues may be present on plain radiographs,

such as an elevated hemidiaphragm that may herald an

intraabdominal abscess. Abdominal ultrasound is another

radiographic diagnostic tool that is often readily available

and relatively inexpensive to perform. Abdominal ultra-

sonography is particularly useful in detecting pathology of

the right upper quadrant, retroperitoneum, and pelvis,

where its sensitivity is about 90%. However, ultrasound is less

sensitive in the interloop areas, and the presence of large

amounts of bowel gas may limit the utility of ultrasonography.

CT scan of the abdomen is more sensitive than ultrasound in

the diagnosis of intraabdominal pathology; however, it is more

expensive and requires administration of intravenous and oral

contrast agents. MRI may be a useful diagnostic tool because

it avoids the need for intravenous contrast agent administra-

tion; however, it is costly, not readily available in all centers, and

is not usable in unstable or mechanically ventilated patients.

Treatment

Most intraabdominal infections are caused by polymicrobial

enteric flora; thus empirical therapy should be targeted toward

facultative gram-negative bacilli and anaerobes. In the past,

aminoglycosides were used as first-line therapy against gram-

negative bacilli but are no longer used widely because newer

agents have demonstrated improved penetration and reduced

toxicity. β-lactam/β-lactamase-inhibitor combinations, a car-

bapenem, a third- or fourth-generation cephalosporin, a

quinolone, and a monobactam in conjunction with metron-

idazole are all recommended regimens. None of these regi-

mens has demonstrated consistent superiority over the others.

While metronidazole resistance among B. fragilis is rare,

increasing prevalence of clindamycin-resistant B. fragilis has

rendered this agent less useful for anaerobic coverage. The

combination of metronidazole and aztreonam is not used

widely because of the lack of gram-positive coverage. The

decision to add an antifungal agent should be individualized.

Immediate empirical antifungal therapy is rarely indicated

unless a primary fungal process is suspected. If, during the

course of therapy, Candida is isolated from blood or peritoneal

cultures, or if histopathologic evidence of fungal tissue inva-

sion is obtained, initiation of antifungal therapy with flucona-

zole or other agent is appropriate. In addition to empirical

antimicrobial therapy, surgical consultation should be

obtained for all patients with suspected intraabdominal sepsis.

Cheadle WG, Spain DA: The continuing challenge of intraabdom-

inal infection. Am J Surg 2003;186:15S–22S. [PMID: 14684221]

Marshall JC, Innes M: Intensive care unit management of intraab-

dominal infection. Crit Care Med 2003;31:2228–37. [PMID:

12973184]

Solomkin JS et al: Guidelines for the selection of anti-infective

agents for complicated intraabdominal infections. Clin Infect

Dis 2003;37:997–1005. [PMID: 14523762]



Infections in Special Hosts

Many patients have underlying diseases that render them

susceptible to specific pathogens. Included among these are



CHAPTER 15

374

patients with neutropenia, organ transplant recipients, dia-

betics, asplenic individuals, patients on chronic corticos-

teroid therapy, and HIV-infected patients. Knowledge of an

underlying condition may lead a physician to modify or

broaden empirical antibiotic therapy when such a patient is

admitted to the ICU with infection or suspected infection.

The physician also should keep in mind that relative

immunosuppression may alter or minimize presenting

symptoms and physical findings. Patients with HIV infection

represent a population with specific management issues (see

Chapter 27). In general, immunocompromised patients who

require intensive care for an infectious process should have

an infectious disease consultant involved in their care.

The Neutropenic Patient

Advances in the fields of oncology and hematology have led to

increasing numbers of patients undergoing intensive

chemotherapy for hematologic or solid-organ malignancies,

with significant resulting immunosuppression. One of the

major complications of such therapy—and an important cause

of morbidity and mortality—is supervening infection. At least

50% of febrile neutropenic patients have either established or

occult infection; only 30–50% of these episodes can be docu-

mented microbiologically. Because these patients have a dimin-

ished immune response to infection owing to their

neutropenia, it often happens that no obvious signs of infection

such as purulent drainage, erythema, or edema are present.

Fever is frequently the only sign. Empirical antimicrobial ther-

apy of the febrile neutropenic patient is the standard of care.

Using the Infectious Disease Society of America (IDSA) guide-

lines, neutropenia is defined as fewer than 500 neutrophils/μL

or fewer than 1000 neutrophils/μL with an anticipated decline

to fewer than 500 neutrophils/μL. Fever is defined as a single

oral measurement of 38.3°C or greater or 38°C or greater over

a period of 1 hour. A thorough history and physical examina-

tion should be performed in patients with neutropenia and

fever, with scrutiny of the skin, oropharynx, and perirectal areas

to localize a source of infection. Blood cultures for bacteria and

fungi, a chest x-ray, liver enzymes, a complete blood count, and

a chemistry panel should be obtained. Once such tests have

been performed, empirical antimicrobial therapy should be

initiated without delay. In previous decades, the most common

pathogens identified in febrile neutropenic patients were aero-

bic gram-negative bacilli of enteric origin, including E. coli,

Klebsiella species, and P. aeruginosa. However, an increasing

incidence of bacteremia owing to gram-positive organisms

such as S. epidermidis, S. aureus, β-hemolytic streptococci, and

enterococci has been documented in recent years, thought to be

the result of increased use of indwelling intravenous catheters,

administration of chemotherapeutic regimens that induce

mucositis, induction of profound and prolonged neutropenia,

unrecognized herpetic mucositis, routine use of H

antagonists,

and use of prophylactic antimicrobial agents with broad gram-

negative coverage (such as trimethoprim-sulfamethoxazole or

ciprofloxacin).

Initial empirical therapy should be targeted against gram-

negative bacilli using an antipseudomonal antibiotic (eg,

piperacillin, ceftazidime, cefepime, meropenem, or

imipenem-cilastin) in conjunction with an aminoglycoside.

Monotherapy with ceftazidime, cefepime, meropenem, or

imipenem-cilastin can be considered. The decision to add

vancomycin to initial empirical therapy should be individu-

alized; if an indwelling catheter is considered a likely source

of infection, if resistant gram-positive infection is considered

likely because of prophylactic administration of antibiotics,

or if significant mucositis, hypotension, or other hemody-

namic instability is present, then vancomycin may be added

to the initial regimen. However, it has been demonstrated

that patients do not suffer increased morbidity or mortality

if vancomycin is withheld until clinical or microbiologic

evidence for such an infection exists.

Once results of blood and other body fluid cultures

become available, antimicrobial therapy may be directed at

specific organisms identified. If, however, the patient remains

febrile after 5–7 days of broad-spectrum antimicrobial ther-

apy and no source of infection has been found, empirical

antifungal therapy should be considered. Amphotericin B

traditionally has been the antifungal agent of choice in this

setting. Acceptable alternatives include lipid formulations of

amphotericin B or echinocandins. Approximately one-third

of neutropenic patients who remain febrile for 1 week or

more on broad-spectrum antimicrobial therapy will be found

to have a systemic fungal infection, usually with Candida or

Aspergillus species. Importantly, isolation of C. glabrata and

C. krusei is more common than C. albicans in some centers,

and affects the choice of empirical antifungal agent.

Organ Transplant Recipients

Organ transplant recipients, because of the nature of their

immunosuppressive therapy, are particularly vulnerable to

infectious complications. Susceptibility to specific infectious

complications in the transplant host varies over time in the

posttransplant setting. A patient’s risk of acquiring a partic-

ular infection is determined by his or her state of immuno-

suppression, as well as individual epidemiologic exposures,

both in the community and in the hospital (eg,M.tubercu-

losis or Legionella). In the first month after transplantation,

90% of infectious complications are typical hospital-

acquired infections, such as transplant wound infection,

pneumonia, urinary tract infection, or catheter-related infec-

tion. Rarely, a systemic infection may be transmitted with

the allograft, or more commonly, an underlying latent infec-

tion in the transplant recipient may recrudesce with

immunosuppression. One to six months following trans-

plantation, organ transplant recipients experience maximal

T-cell immune dysfunction and therefore are particularly

vulnerable to intracellular pathogens (eg, cytomegalovirus,

human herpes virus 7, P. jiroveci, L. monocytogenes, cryptococci,

Toxoplasma, and M. tuberculosis) and endemic mycoses that

may reactivate during this period. In the absence of an



INFECTIONS IN THE CRITICALLY ILL

375

environmental exposure to a specific pathogen, other oppor-

tunistic infections are rare during this time period. Six

months after transplantation, an individual’s risk of infec-

tion depends on the clinical course and health care status. In

the 80% of patients who have experienced an uneventful

posttransplant course, infectious complications are typically

the same as those of the community at large (eg, influenza

and pneumococcal infection). Another approximately 10%

of patients will develop chronic or progressive viral infec-

tions such as cytomegalovirus, hepatitis B virus, hepatitis C

virus, or Epstein-Barr virus. In the remaining 10% of

patients, chronic or recurrent rejection requires repeated

courses of high-dose immunosuppressive therapy. This pop-

ulation remains at risk for infection with the intracellular

pathogens mentioned earlier, as well as with Aspergillus

species.

Asplenic Patients

The spleen serves a critical function in antibody synthesis,

microbial filtration, and opsonin production. Patients with

asplenia therefore are uniquely susceptible to overwhelming

infection with encapsulated organisms such as S. pneumo-

niae, N. meningitidis, and H. influenzae. Other less common

pathogens seen in the asplenic host include K. pneumoniae,

S. agalactiae, E. coli, Capnocytophaga canimorsus, and S. aureus.

They are also prone to severe infection with intracellular par-

asites such as Babesia and Plasmodium. When attempting to

identify at-risk patients, a history of surgical splenectomy

should be elicited from the patient. When the patient can-

not provide an accurate history, physical examination may

reveal the presence of a surgical splenectomy scar. However,

a functional asplenic state may be overlooked. Conditions

that can lead to functional asplenia include congenital

hyposplenism, sickle cell disease, graft-versus-host disease,

rheumatoid arthritis, systemic lupus erythematosus, amyloi-

dosis, ulcerative colitis, celiac disease, and chronic alcoholism.

A clue to asplenia is the presence of Howell-Jolly bodies on

peripheral blood smear because these inclusions typically are

removed by a functioning spleen. In an asplenic patient with

overwhelming sepsis, high-grade bacteremia is often present;

thus Gram stain of the buffy coat may reveal the infecting

organism. Empirical antimicrobial therapy should include

coverage for the encapsulated organisms, with a third-

generation cephalosporin being a reasonable choice.

Patient on Chronic Corticosteroid Therapy

In one meta-analysis, the rate of infection in patients taking

steroids was 12.7% compared with 8% in patients not on

chronic steroids. The rate of infection was not increased in

patients taking less than 10 mg/day or a cumulative dose of

less than 700 mg prednisone. In addition to increased suscep-

tibility to community-acquired pathogens, patients on

chronic steroid therapy are particularly vulnerable to intra-

cellular pathogens. Examples include Salmonella species,

Legionella species, L. monocytogenes, M. tuberculosis, and

various viruses (eg, herpesviruses). Other organisms that

must be considered when evaluating a steroid-treated patient

with clinical evidence of severe infection include Candida

species, Aspergillus species, C. neoformans, Nocardia species,

Toxoplasma gondii, and P. jiroveci.

Patients with Diabetes Mellitus

Patients with diabetes mellitus often have more severe man-

ifestations of infectious disease than other hosts. In addition,

there are specific disease entities that occur more commonly

in diabetics than in other hosts. For example, rhinocerebral

mucormycosis should be considered in any patient with dia-

betic ketoacidosis and facial pain, ocular complaints, or neuro-

logic symptoms. Physical examination may be unremarkable

or may reveal a black eschar on the hard palate or nasal

mucosa, facial swelling, and/or proptosis late in the course of

the infection. Definitive diagnosis of this life-threatening

infection is made by tissue biopsy to demonstrate fungal

elements invading tissues. Therapy consists of surgical

debridement with adjunctive high doses of liposomal

intravenous amphotericin B. Diabetics are also uniquely

susceptible to urinary tract infections. Serious complications

of urinary tract infections are not uncommon, such as

emphysematous pyelonephritis, which requires surgical ther-

apy along with antimicrobial therapy. Emphysematous chole-

cystitis may develop in the diabetic host, usually the result of

an anaerobic infection with clostridia. Emphysematous

cholecystitis should be suspected when gas is seen on abdom-

inal plain film or CT scan; emergent cholecystectomy is indi-

cated for this condition. Because of impaired vascular

perfusion, patients with diabetes mellitus are prone to more

severe necrotizing soft tissue infections, necessitating a high

degree of vigilance for these life-threatening infections, with

rapid diagnosis and immediate surgical debridement.

Mora-Duarte J et al: Comparison of caspofungin and ampho-

tericin B for invasive candidiasis. N Engl J Med

2002;347:2020–9. [PMID: 12490683]

Calvet HM, Yoshikawa TT: Infections in diabetes. Infect Dis Clin

North Am 2001;15:407–22. [PMID: 11447703]

Hughes WT et al: 2002 Guidelines for the use of antimicrobial

agents in neutropenic patients with cancer. Clin Infect Dis

2002;34:730–51. [PMID: 11850858]

Kang I, Park SH: Infectious complications in SLE after immuno-

suppressive therapies. Curr Opin Rheumatol 2003;15:528–34.

[PMID: 12960476]

Klastersky J: Management of fever in neutropenic patients with

different risks of complications. Clin Infect Dis 2004;39:S32–7.

[PMID: 15250018]

Klein NC, Go CH, Cunha BA: Infections associated with steroid

use. Infect Dis Clin North Am 2001;15:423–32. [PMID:

11447704]

Martino R, Viscoli C: Empirical antifungal therapy in patients

with neutropenia and persistent or recurrent fever of

unknown origin. Br J Haematol 2006;132:138–54. [PMID:

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

CHAPTER 15

376

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Immunocompromised Host Society consensus conference on

epidemiology, prevention, diagnosis, and management of infec-

tions in solid-organ transplant patients. Clin Infect Dis

2001;33:S1–4. [PMID: 11389514]

Sumaraju V, Smith LG, Smith SM: Infectious complications in

asplenic hosts. Infect Dis Clin North Am 2001:15;551–66.

[PMID: 11447709]



Principles of Antibiotic Use in the ICU

The choice of antimicrobial agents to be used in established or

strongly suspected bacterial or other infections must be based

on an assessment of what organisms are most likely to be

involved. Initial empirical therapy should be dictated, when

possible, by results of Gram-stained smears of properly col-

lected specimens such as sputum, urine, aspirated purulent

material, or body fluids (eg, blood, cerebrospinal fluid, peri-

toneal fluid, synovial fluid, pleural fluid, or pericardial fluid).

Epidemiologic factors, site of infection, and the clinical

status of the patient also must be considered in selecting

antibiotics. The results of pretreatment cultures can provide

a definitive microbiologic diagnosis, and in vitro antibiotic

susceptibility testing, if appropriate, can be performed.

Interpretation of microbiologic cultures obtained after initi-

ation of antimicrobial therapy is difficult; in this setting, the

presence of sterile cultures may be misleading.

Some general guidelines may be helpful in selecting therapy.

Certain pathogens have a predilection for causing infection at

specific sites, for example, S. pneumoniae (ie, pneumonia or

meningitis) and E. coli (ie, urinary tract infections or bac-

teremia). Certain antimicrobial agents have predictable activity

against specific organisms, for example, penicillins for strepto-

cocci and vancomycin for staphylococci and streptococci,

including methicillin-resistant strains. However, an increasing

number of microorganisms are manifesting resistance to stan-

dard antimicrobials (Table 15–6). Therefore, obtaining cultures

in conjunction with susceptibility testing is imperative.

Despite the availability of numerous antimicrobial

agents, most pathogens are optimally treated with only a few

drugs. Antimicrobial therapy should be as specific, nontoxic,

and inexpensive as confirmatory cultures and susceptibility

tests allow. Used wisely, antimicrobials rarely fail; regimens

should not be changed haphazardly. Any changes should be

based on a complete database, which includes results of stan-

dardized susceptibility testing performed in a reliable labora-

tory. In the ICU patient, the choice of antibiotics may be

dictated by the presence of hepatic or renal dysfunction. In

addition, the doses of some agents must be modified in

patients with impaired excretion of the drugs because of

decreased kidney or liver function.

This section describes some of the newer antimicrobial

agents with the goal of establishing general guidelines for

their use. It is important to keep in mind that the choice of a

specific agent should be based on the nature of the infection

as well as patient factors; the newest antimicrobial drug is

often not the best choice.

Since the development and use of the sulfonamides in the

1930s and penicillin in the 1940s, numerous effective anti-

bacterial and antifungal agents—and, more recently, antivi-

ral agents—have become available. However, there exists a

paucity of new antimicrobial agents under development tar-

geting the increasingly resistant bacteria responsible for

infection, threatening our ability to provide optimal treat-

ment. The similarities of many of existing antibiotics are

more striking than their differences. Nonetheless, many

antibiotics occupy specific niches in the treatment of the

infected patient.

Cephalosporins

Cefepime has been referred to as a fourth-generation

cephalosporin. It has excellent activity against the

Enterobacteriaceae, Enterobacter species, P. aeruginosa, and S.

pneumoniae; moderate activity against S. aureus; and limited

antianaerobe activity.

Carbapenems

Imipenem, meropenem, and ertapenem are the three car-

bapenems currently available for use. The presence of the

carbapenem ring increases the potency and antibacterial

spectrum of these agents. In place of an acylamino side

Organisms With Emerging

Resistance

Antibiotics

Streptococcus pneumoniae

Beta-lactams, macrolides, quinolones

Staphylococcus aureus

Beta-lactams, aminoglycosides,

vancomycin, linezolid quinolones

Enterococcus Aminoglycosides, penicillin,

vancomycin, linezolid, quinupristin-

dalfopristin

Haemophillus influenzae

Ampicillin (beta-lactamase-negative),

chloramphenicol

Pseudomonas aeruginosa

(including other group 1 beta-

lactamase-producing gram-

negative bacilli)

Aminoglycosides, beta-lactams,

carbapenems, quinolones

Enterobacteriaceae Beta-lactams

Acinetobacter baumanii

Beta-lactams, carbapenems,

quinolones, aminoglycosides

Bacteroides fragilis

Clindamycin

Table 15–6. Emerging resistance to antibiotics.