Bongard Frederic , Darryl Sue. Diagnosis and Treatment Critical Care

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INFECTIONS IN THE CRITICALLY ILL

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with this disorder ranges from simple diarrhea to pseudomem-

branous colitis, rarely complicated by toxic megacolon, which

can result in colonic perforation and death.

The most common antibiotics implicated in the develop-

ment of C. difficile–associated diarrhea are ampicillin, clin-

damycin, and the cephalosporins. Antibiotics less commonly

associated include trimethoprim-sulfamethoxazole, the

quinolones, aztreonam, the carbapenems, and metronidazole.

Vancomycin, erythromycin, tetracycline, and the aminoglyco-

sides rarely cause C. difficile–associated diarrhea. Although the

disorder is often self-limited, resolving when antibiotics are

stopped and treatment is initiated, severe complications may

occur. Recently, C. difficile strains associated with quinolone

and cephalosporin use have been responsible for several ICU

outbreaks. The presence of this particularly virulent C. difficile

led to increased attributable mortality in these patients.

Clinical Features

A. Symptoms and Signs—C. difficile typically produces

watery diarrhea and low-grade fever with or without abdom-

inal pain. Diarrhea may develop after a single dose of an

antibiotic or may be delayed as long as 6 weeks following the

last dose of the antimicrobial agent. If the patient develops

pseudomembranous colitis, sigmoidoscopy may reveal char-

acteristic white or yellow plaques or pseudomembranes.

Patients may become seriously ill, with fluid and electrolyte

imbalance, toxic megacolon, and colonic perforation.

B. Laboratory Findings—It is recommended that diarrheal

stools of patients who have been hospitalized for more than

72 hours with a history of prior antibiotic use be evaluated

for C. difficile–associated diarrhea. The diagnosis rests on the

identification of C. difficile toxin in the stool. The most sen-

sitive and specific test for this disorder is a tissue culture

assay for toxin B cytotoxicity, with a sensitivity of 94–100%

and a specificity of 99%. However, this test is cumbersome to

perform and takes 1–3 days to complete. Enzyme-linked

immunoassays for identification of toxins A and B have a

sensitivity of 63–99% and a specificity of 75–100%. In 20%

of patients, toxin assays on multiple stool samples may be

required to demonstrate the presence of the toxin.

Identification of fecal leukocytes is neither sensitive nor

specific for C. difficile–associated diarrhea. Nosocomial acqui-

sition of enteric pathogens such as Salmonella, Shigella, and C.

jejuni is extremely rare; thus, performing routine stool cultures

is not cost-effective in hospitalized patients with diarrhea.

Differential Diagnosis

Noninfectious causes of nosocomial diarrhea include various

medications, enteral feeding, inflammatory bowel disease,

ischemic colitis, GI bleeding from a variety of lesions, and

systemic illness. Antimicrobial administration can cause

diarrhea by altering normal bowel flora (eg, ceftriaxone,

tetracycline, and amoxicillin-clavulanic acid) or by bowel

irritation (eg, erythromycin). Infectious causes of nosocomial

diarrhea are rare and include enteric pathogens and

cytomegalovirus colitis in the immunocompromised host.

Treatment

If antibiotic-associated colitis develops in patients receiving

antibiotic therapy, improvement often occurs with discontin-

uation of antibiotics. Specific antimicrobial therapy should be

administered to those with persistent diarrhea or in patients

with severe illness. Asymptomatic carriers of C. difficile

should not be treated because doing so may prolong the car-

rier state. Oral vancomycin and metronidazole are equally

effective for most patients. Metronidazole is less expensive and

does not exert selective pressure for vancomycin-resistant ente-

rococci; for these reasons, it is thus the agent of choice. It should

be given at a dose of 500 mg orally three times a day for 10–14

days. In patients unable to tolerate oral medications, intra-

venous metronidazole at a dose of 500 mg every 8 hours can be

used as initial therapy. Vancomycin is recommended at a dosage

of 125–250 mg orally every 6 hours for 10–14 days in the event

of treatment failure, for persistent symptoms, or probably for

severe cases. As many as 20% of patients will relapse within the

first 2 weeks of completing a course of treatment, although most

will respond to a second course of metronidazole. Risk factors

for relapse include chronic renal failure, multiple previous

episodes of C. difficile–associated diarrhea, continuation of

other antimicrobial therapy, community-acquired C. difficile–

associated diarrhea, and high white blood cell counts.

Patients diagnosed with or suspected of having C. difficile–

associated diarrhea should be managed with enteric precau-

tions. The organism is particularly well suited to survive for

prolonged periods on a variety of surfaces and has been cul-

tured from hospital carpeting, beds, and walls. It is easily trans-

mitted by the hands of hospital personnel from patient to

patient. Therefore, appropriate isolation precautions are essen-

tial when caring for these patients. Note that conventional

handwashing is necessary for hospital personnel because alcohol-

based hand cleansers do not kill C. difficile spores.

It has become clear that C. difficile is a significant nosoco-

mial pathogen; thus prevention and control in the hospital

setting are crucial. C. difficile–associated diarrhea has been

strongly associated with the use of certain antimicrobial

agents, so alteration of patterns of antimicrobial use may be

helpful in reducing its incidence.

Given the high recurrence rate of C. difficile–associated

diarrhea, various non-antimicrobial approaches have been

employed to allow the bowel to reestablish its normal flora,

such as oral administration of Saccharomyces boulardii, lacto-

bacilli, or normal fecal flora. However, these strategies have not

been adequately studied to support formal recommendations.

Bartlett JG, Gerding DN: Clinical recognition and diagnosis of

Clostridium difficile infection. Clin Infect Dis 2008;46 Suppl

1:S12–8. [PMID: 18177217]

Bouza E, Burillo A, Munoz P: Antimicrobial therapy of Clostridium

difficile–associated diarrhea. Med Clin North Am 2006;90:

1141–63. [PMID: 17116441]

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CHAPTER 15

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Loo VG et al: A predominantly clonal multi-institutional outbreak of

Clostridium difficile–associated diarrhea with high morbidity and

mortality. N Engl J Med 2005;353:2442–9. [PMID: 16322602]

Nelson R: Antibiotic treatment for Clostridium difficile–associated

diarrhea in adults. Cochrane Database Syst Rev 2007;3:

CD004610. [PMID: 17636768]

Riley TV: Nosocomial diarrhoea due to Clostridium difficile.Curr

Opin Infect Dis 2004;17:323–27. [PMID: 15241076]

Zar FA, Bakkanagari SR, Moorthi KM, et al. A comparison of van-

comycin and metronidazole for the treatment of Clostridium

difficile-associated diarrhea, stratified by disease severity. Clin

Infect Dis 2007;45:302–7. [PMID: 17599306]



Hematogenously Disseminated Candidiasis

ESSENTIALS OF DIAGNOSIS



Fever despite broad-spectrum antibacterial therapy and

negative bacterial blood cultures.



Possible skin manifestations.



Consider in neutropenic hosts and patients with long-

term vascular access.

General Considerations

Candida species are an increasing cause of nosocomial

bloodstream infections and are associated with high rates of

mortality and morbidity. Patients at increased risk for

hematogenously disseminated candidiasis include those with

extensive burns, indwelling venous catheters, broad-

spectrum antibiotic exposure, immunosuppression (espe-

cially neutropenia), severe mucositis, previous surgical

procedures (particularly GI surgery), total parenteral nutri-

tion, concomitant bacteria or other infections, and mucosal

colonization by Candida species. Mortality from candidemia

is highest among those patients with high APACHE II scores,

severe underlying disease, and persistent candidemia despite

appropriate antifungal therapy.

Microbiologic Etiology

C. albicans is the species most commonly isolated from blood

cultures; however, recent emergence of non-albicans species

has been noted, most notably an increase in the incidence of

C. glabrata. Why non-albicans species are increasingly isolated

is not entirely clear. However, the widespread use of empirical

fluconazole may exert selective pressure leading to the emer-

gence of Candida species that are less sensitive to the triazoles.

Fungemia caused by C. tropicalis usually occurs as a result

of endogenous infection, although cases of nosocomial

transmission also have been documented. Most isolates of

C. tropicalis are sensitive to amphotericin B, flucytosine, and

the triazoles. C. glabrata, a pathogen with decreased suscep-

tibility to fluconazole, is the second most common Candida

species isolated in nosocomial bloodstream infections.

C. parapsilosis infection occurs almost exclusively in the

presence of indwelling venous catheters, prosthetic devices,

or invasive devices and is not usually a member of the

patient’s endogenous flora. This organism is usually suscep-

tible to both amphotericin B and fluconazole. C. krusei is

considered to be resistant to fluconazole and is seen most

commonly in neutropenic patients, especially those receiving

fluconazole for antifungal prophylaxis or empirical therapy.

Clinical Features

A. Symptoms and Signs—Most patients with hematoge-

nously disseminated candidiasis have no systemic symptoms

or signs of infection other than persistent fever in the setting

of broad-spectrum antibiotics. Careful physical examination

should be performed to assess the presence of skin lesions

characteristic of candidemia. Three types of lesions have

been described with hematogenously disseminated candidia-

sis: The classic lesion is macronodular, erythematous, and

0.5–1 cm in diameter. Lesions resembling ecthyma gan-

grenosum and purpura fulminans also have been described.

In all three types of lesions, the organisms are seen readily on

histopathologic examination of punch biopsy specimens.

Any new neurologic symptom should prompt a CT scan or

MRI of the brain because candidal micro- and macroab-

scesses of the CNS have been described in patients with can-

didemia. Patients should undergo daily physical examination

looking for new cardiac murmurs, bone or joint findings,

and hepatosplenomegaly. Endocarditis, osteomyelitis, arthri-

tis, and hepatosplenic candidiasis are all documented com-

plications of candidemia. All patients should have a

thorough ophthalmoscopic examination to rule out candidal

endophthalmitis, typically appearing as white “cotton ball”

lesions that may extend into the vitreous.

B. Laboratory Findings—Laboratory findings in hematoge-

nously disseminated candidiasis are nonspecific. The rate of

premortem diagnosis of disseminated candidemia is typi-

cally low. With the development of new blood culturing tech-

niques such as the BACTEC system, the yield of positive

blood cultures for Candida has increased, although it is still

less than 50%. Thus the diagnosis is made mainly on clinical

grounds. Appropriate imaging studies should be obtained

when there is suspicion of end-organ dissemination; biopsy

of suspicious lesions should be pursued to look for

histopathologic evidence of invasive candidal infection.

Treatment

A. Empirical Antifungal Therapy—The diagnosis of

hematogenously disseminated candidemia typically is

made on clinical grounds, and patients are often treated

empirically based on the presence of multiple risk factors

or evidence for mucosal colonization with Candida

species. A critical intervention in the treatment of can-

didemia is the removal of all potentially infected venous

catheters, especially in neutropenic patients.

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INFECTIONS IN THE CRITICALLY ILL

389

The antifungal agent of choice depends on the clinical

status of the patient and the physician’s knowledge of the

possible infecting Candida species. In the pretriazole era,

amphotericin B was used exclusively in all patients with sus-

pected or documented fungal infection. However, data now

suggest that in a nonneutropenic patient who is hemodynami-

cally stable, fluconazole will provide response rates of 60–100%.

Factors that may prompt the physician to use amphotericin B as

empirical therapy include hemodynamic instability or known

colonization of the patient with non-albicans species, such as

C. glabrata or C. krusei. Caspofungin or micafungin are other

alternatives. There is general agreement that a neutropenic

patient with suspected invasive fungal infection should receive

amphotericin B, micafungin or caspofungin. Flucytosine may

be used in combination with either amphotericin B, micafungin

or fluconazole in severe infections. Itraconazole is available in an

intravenous formulation, but formal studies to support recom-

mendations for its use have not been completed.

Betts R et al: Efficacy of caspofungin against invasive Candida or

invasive Aspergillus infections in neutropenic patients. Cancer

2006;106:466–73. [PMID: 16353208]

Ostrosky-Zeichner L, Pappas PG: Invasive candidiasis in the inten-

sive care unit. Crit Care Med 2006;34:857–63. [PMID: 16505666]

Pappas PG et al: Guidelines for treatment of candidiasis. Clin

Infect Dis 2004;38:161–89. [PMID: 14699449]

Spellberg BJ, Filler SG, Edwards JE Jr: Current treatment strategies

for disseminated candidiasis. Clin Infect Dis 2006;42:244–51.

[PMID: 16355336]



Antimicrobial Resistance in the ICU

Critically ill patients often receive broad-spectrum antimi-

crobial therapy during their hospitalization; thus the ICU is

fertile ground for the emergence of antimicrobial resistance.

In this section, specific resistance problems encountered in

the ICU will be reviewed, including vancomycin-resistant

enterococci, methicillin-resistant S. aureus, glycopeptide-

insensitive S. aureus, gram-negative bacilli with extended-

spectrum β-lactamases, gram-negative bacilli that produce

group 1 β-lactamases, and Acinetobacter baumanii.

Vancomycin-Resistant Enterococci

A. Incidence—Enterococci are normal inhabitants of the GI

tract and generally are considered to be organisms of low vir-

ulence. Patients with serious nosocomial infections caused

by enterococci have high morbidity and mortality rates owing

to their underlying disease. In the past, most enterococcal

infections were caused by E. faecalis, and only about 5–10% of

infections owing to enterococci were due to E. faecium.

However, the emergence of glycopeptide-resistant E. faecium

has led to a shift in the relative frequency of infection with

this species. The most common site of origin of enterococcal

infection is the urinary tract, followed by intraabdominal

or pelvic infection as part of a polymicrobial process.

Bacteremia usually occurs as a complication of one of the

preceding or may result from infection of an indwelling

venous catheter or prosthetic device.

National nosocomial surveys have demonstrated an

increase in the prevalence of vancomycin-resistant entero-

cocci among enterococcal isolates to levels of 25% or greater.

Case-control studies have identified several risk factors for

acquisition of vancomycin-resistant enterococci. Host factors

include advanced age, severity of underlying disease, hema-

tologic malignancy, neutropenia, cirrhosis, hemodialysis,

recent intraabdominal surgery, prior nosocomial infection,

the presence of pressure sores, prolonged hospitalization,

invasive procedures, contact with another person colonized

or infected with vancomycin-resistant enterococci, and previ-

ous antimicrobial therapy (especially with a third-generation

cephalosporin and vancomycin). Patients in certain health

care settings, including long-term care facilities, outpatient

dialysis units, ICUs, and oncology or transplant wards, have

the highest prevalence of vancomycin-resistant enterococci

carriage.

B. Mechanism of Resistance—Enterococci develop resist-

ance to vancomycin through acquisition of genes conferring

resistance; these genes are specified as vanA or vanB. The

most common phenotype, vanA, is transmitted by a transpo-

son and confers high-level resistance to vancomycin and

teicoplanin. The vanB phenotype is chromosomally based

and confers variable resistance to vancomycin while main-

taining susceptibility to teicoplanin. Both phenotypes are

easily transferable among different enterococci via conjuga-

tion. The mechanism of resistance involves a change in the

cell wall building block,

-alanine-

-alanine, the target site

for vancomycin, to

-alanine-

-lactate.

C. Therapy—Treatment of serious vancomycin-resistant ente-

rococcal infections is difficult. Many strains are resistant to

ampicillin and aminoglycosides, so the remaining options

are few in number, and antienterococcal activity is limited.

Carbapenems, fluoroquinolones, tetracyclines, chlorampheni-

col, rifampin, novobiocin, and nitrofurantoin all have been

used in various combinations in an attempt to treat infection

with vancomycin-resistant enterococci. Quinupristin-

dalfopristin, linezolid, and daptomycin are drugs recently

licensed in the United States that include vancomycin-

resistant enterococci in their spectrum of activity. Urinary

tract infections may be treated successfully with nitrofuran-

toin and removal of the urinary catheter. Mixed infections,

such as intraabdominal abscesses or skin and soft tissue infec-

tions, should undergo aggressive debridement. Indwelling

venous catheters and prosthetic devices should be removed

whenever possible. Treatment of serious vancomycin-

resistant enterococcal infection should include at least two

antimicrobial agents to which the organism is susceptible,

and one of these should be an aminoglycoside unless the

class is contraindicated or resistance is present.

D. Prevention—In the United States, most carriage of van-

comycin-resistant enterococci and outbreaks of infection are

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390

due to patient-to-patient spread. Thus strict infection con-

trol measures are necessary to prevent spread and persistence

of the organisms. Strict contact isolation should be observed

for any patient infected or colonized with the organism. In

addition, the use of empirical vancomycin for the treatment

of hospitalized patients should be limited to those with clear

indications.

Methicillin-Resistant

S. aureus

(MRSA)

A. Incidence—The National Nosocomial Infection Surveillance

surveys have demonstrated an increase in the percentage of

MRSA from about 2–3% of all S. aureus isolates in 1975 to

over 50% in the current era. The incidence of community-

acquired MRSA is also increasing. The major route of spread

of MRSA is direct patient-to-patient contact or via the hands

of medical personnel. Common sites of MRSA colonization

include the anterior nares, wounds, burns or other areas of

decreased skin integrity, the perineal area, the upper respira-

tory tract, and the skin adjacent to invasive devices, gastros-

tomy tubes, and tracheostomies. Risk factors for both

colonization and infection with MRSA include previous hos-

pitalization, prolonged hospital stay, hospitalization in a burn

unit or ICU, chronic prior antimicrobial therapy, exposure to

a colonized health care worker or patient, the presence of sur-

gical wounds or burns, and the use of invasive devices.

B. Mechanism of Resistance—Resistance of S. aureus to

methicillin is transmitted chromosomally via the mecA gene.

Acquisition of this gene results in altered penicillin-binding

protein 2A. Presence of the mecA gene is also associated with

resistance to other antibiotics, including all β-lactams,

aminoglycosides, macrolides, tetracycline, rifampin, and flu-

oroquinolones.

C. Therapy—Most strains of MRSA are sensitive to the gly-

copeptide vancomycin. In the United States, vancomycin is

the drug of choice for serious infections with MRSA. There

may be a role for quinupristin-dalfopristin, linezolid, and

daptomycin in the treatment of infections with this organ-

ism. Eradication of MRSA carriage may be attempted with

either topical or systemic antimicrobials or by bathing with

antiseptic soaps. The efficacy of any of these approaches in

eradication is inconsistent and often incomplete. Many

community-acquired strains of MRSA are susceptible to

trimethoprim-sulfamethoxazole, clindamycin, rifampin, and

in some cases macrolides.

Vancomycin-Insensitive

S. aureus

(VISA) and

Vancomycin-Resistant

S. aureus

(VRSA)

A. Incidence—The emergence of VISA is probably the most

disturbing development to occur in the antibiotic era.

Vancomycin insensitivity among S. aureus is defined as an

MIC to vancomycin of 8–16 μg/mL. The first reported case

of infection with this organism occurred in Japan in May of

1996. Most patients with VISA were on hemodialysis, and

most had had recurrent MRSA bacteremias that were treated

with prolonged courses of vancomycin. The first case of

vancomycin-resistant S. aureus (MIC to vanomycin of 32

μg/dL or more) was reported in 2002, with only a few addi-

tional cases reported subsequently.

B. Mechanism of Resistance—The mechanism of van-

comycin insensitivity is not clear. Scanning and transmission

electron microscopy of the insensitive organisms show a

thickened bacterial cell wall. A fully vancomycin-resistant

S. aureus strain has been created in vitro, demonstrating a

similarly thickened bacterial cell wall. It is hypothesized that

decreased vancomycin access to the target sites may occur as

a result of sequestration of the drug in the cell wall. Full van-

comycin resistance is mediated via the vanA gene, which con-

fers vancomycin resistance to enterococci.

C. Therapy—Therapy of VISA and VRSA infection is not

standardized; thus antimicrobial therapy should be based on

the organism’s susceptibility profile. Preliminary in vitro data

suggest that as the bacteria become more resistant to van-

comycin, they become more susceptible to oxacillin. Thus

there may be a role for combination therapy with van-

comycin and oxacillin in infections with VISA. A role for

quinupristin-dalfopristin, linezolid, and daptomycin in the

treatment of these infections is a possibility as well.

Gram-Negative Bacilli Producing

Extended-Spectrum β-Lactamases (ESBLs)

A. Incidence—Bacterial strains with ESBLs were first identi-

fied in the mid-1980s. Most are strains of K. pneumoniae or

E. coli. ESBL production has been noted in other species of

Enterobacteriaceae as well but with much lower frequency.

The actual incidence of ESBL-producing strains is difficult to

quantify because surveillance and reporting are incomplete.

Most strains are isolated from hospitalized patients. Risk fac-

tors for acquisition include prolonged hospital stay; severity

of illness; admission to an ICU, oncology unit, or nursing

home; emergency surgical or invasive procedures; central

venous, arterial, or urinary catheterization; and prior

extended-spectrum cephalosporin use. Notably, outbreaks

with ESBL-producing strains have been linked to heavy cef-

tazidime use within a hospital.

B. Mechanism of Resistance—The ESBLs are descendants

of the β-lactamases responsible for ampicillin resistance in

E. coli and penicillin resistance in K. pneumoniae. This plasmid-

mediated gene confers resistance not only to the extended-

spectrum cephalosporins but also to aztreonam. The gene

also may encode resistance to aminoglycosides, tetracyclines,

trimethoprim-sulfamethoxazole, and chloramphenicol. The

plasmids bearing these genes are stable and are easily trans-

missible from bacteria to bacteria.

C. Therapy—On routine susceptibility testing, ESBL-

producing strains may appear to be sensitive to the

extended-spectrum cephalosporins and aztreonam. Clues to

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INFECTIONS IN THE CRITICALLY ILL

391

the presence of an ESBL-producing strain are (1) clinical

failure in the setting of “appropriate” antimicrobial therapy,

(2) presence of resistance to certain antibiotics, such as amino-

glycosides, tetracyclines, trimethoprim-sulfamethoxazole, and

chloramphenicol, which are often transmitted on the same

plasmid as the ESBL, and (3) diminished susceptibility to cef-

triaxone, ceftazidime, or aztreonam (if this pattern is seen,

resistance to all extended-spectrum cephalosporins and aztre-

onam should be presumed). ESBL-producing organisms usu-

ally display susceptibility to cephamycins (eg, cefotetan and

cefoxitin) and the carbapenems, with variable susceptibility

to the β-lactam/β-lactamase inhibitor combinations.

Carbapenems are the mainstay of therapy in the seriously ill

patient infected with an ESBL-producing organism because

cases of cephamycin resistance have been reported to emerge

during the course of cephamycin therapy.

Gram-Negative Bacilli Producing Group 1

β-Lactamases

A. Incidence—Group 1 β-lactamases are chromosomally

based β-lactamases. The most commonly encountered organ-

isms with group 1 β-lactamase production are Enterobacter

species, P. aeruginosa, Citrobacter species, S. marcescens, and

some Proteus species. According to the National Nosocomial

Infection Surveillance System, infections owing to these

organisms have been increasing in incidence. This recent

trend is of concern given the resistance of these pathogens to

extended-spectrum cephalosporins, with documented

cephalosporin resistance developing even while on appropri-

ate therapy. Risk factors for acquisition of these pathogens

include prior therapy with ceftizoxime, cefotaxime, or cef-

tazidime and perhaps with extended-spectrum penicillins—

as well as length of previous antimicrobial therapy.

B. Mechanism of Resistance—The mechanism of resist-

ance of group 1 β-lactamase-producing organisms is induc-

tion of a chromosomally based gene that encodes for

production of a group 1 β-lactamase (a cephalosporinase)

that inactivates all cephalosporins.

C. Therapy—Therapy should be based on antimicrobial sus-

ceptibility data for a given strain. These organisms usually

retain their sensitivity to the carbapenems and the fluoro-

quinolones. Emergence of resistance in the setting of ongoing

antimicrobial therapy occurs in approximately 5% of patients

and is more likely to occur with use of a third-generation

cephalosporin rather than an aminoglycoside or an extended-

spectrum penicillin. Whether combination therapy will

decrease the risk of emerging resistance is not yet known. At

this time, it appears that monotherapy with an extended-

spectrum cephalosporin should be avoided when treating

infection caused by group 1 β-lactamase-producing organisms.

Acinetobacter baumanii

A. Incidence—A. baumanii is a gram-negative coccobacillus

that may occur as a normal skin colonizer. It is considered to

be relatively nonvirulent; however, the worldwide emergence

of this organism has been noted increasingly in the nosocomial

setting, sometimes in persistent outbreaks in ICUs. The

treatment challenge with this organism results from its

inherent resistance to a wide array of antimicrobial agents.

Risk factors for infection include underlying illness, prior

broad-spectrum antimicrobial therapy use, length of ICU

stay with use of invasive devices, and prior colonization with

the organism.

B. Mechanism of Resistance—The mechanism of resistance

to the β-lactam drugs is the production of a plasmid-mediated

penicillinase. Resistance to cephalosporins occurs as a result of

overproduction of a chromosomal cephalosporinase.

C. Therapy—As with most multidrug-resistant pathogens,

therapy should be based on available susceptibility data.

However, pending such information, one of the carbapen-

ems can be considered for empirical therapy because these

agents tend to retain their activity against A. baumanii. There

is, however, increasing resistance owing to bacterial produc-

tion of carbapenemases. Other considerations include tige-

cycline and colistin.

Infection Control Concepts

The specter of antimicrobial resistance increasingly threatens

physicians’ ability to treat bacterial infections. To complicate

matters, there is limited development of new antimicrobial

agents targeting resistant bacteria. Numerous studies have

demonstrated a stepwise increase in incidence of drug resist-

ance from the community to the general inpatient ward to the

ICU. Control of antimicrobial resistance is the responsibility

of every critical care physician. This can be broken down into

two critical components: (1) prevention of emergence of new

resistance mechanisms or resistant species and (2) prevention

of spread of organisms from patient to patient.

A. Prevention of Emergence of Resistance—The central

component of prevention is reducing selection pressure for

resistance by judicious use of antimicrobials. Several studies

have demonstrated that while overuse of antibiotics can fos-

ter antimicrobial resistance, changes in antibiotic use can

result in recovery of susceptibility. Judicious antimicrobial

use includes careful consideration of which patients are

appropriate candidates for antimicrobial therapy, when

antimicrobial therapy should be initiated, which antimicro-

bial agents should be administered, and for what duration.

The goal of antimicrobial therapy in the ICU is to expedi-

tiously treat a seriously ill patient with suspected or con-

firmed infection with the appropriate agent(s). The

physician should make every attempt to differentiate

between true bacterial infection and simple colonization.

Moreover, it should be kept in mind that not all fever is the

result of infection; when no source of infection can be iden-

tified, noninfectious causes of fever should be considered

(Table 15–7). Prophylactic use of antimicrobial agents

should be avoided in the absence of a clear indication.

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Much controversy surrounds the empirical use of combi-

nation therapy (eg, a β-lactam plus an aminoglycoside) in

a patient suspected of being infected with an aerobic

gram-negative bacillus. Some in vitro data suggest that com-

bination therapy may decrease the emergence of chromoso-

mally mediated resistance, although it actually may worsen

plasmid-mediated resistance. While it is acceptable to use

broad-spectrum empirical antimicrobial therapy initially,

antibiotics should be tailored once culture data become

available. In addition, focal collections of purulent material

should be drained whenever possible to decrease inoculum

size, thereby improving the outcome of antimicrobial ther-

apy. Prolonged courses or inappropriately broad-spectrum

antibiotics should be avoided.

B. Prevention of Spread of Infection—Prevention of

nosocomial spread of infection involves prompt identifica-

tion of patients colonized or infected with multidrug-resistant

organisms plus rapid institution of appropriate isolation pro-

cedures. Even in wards or ICUs not known to have patients

colonized or infected with multidrug-resistant organisms,

routine hand washing with antiseptic soaps or use of alcohol-

based cleansers by all health care personnel is critical.

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2007;45:594–8. [PMID: 17682994]

Lockhart SR et al: Antimicrobial resistance among gram-negative

bacilli as causes of infections in intensive care unit patients in

the United States between 1993 and 2004. J Clin Microbiol

2007; 45:3352–9. [PMID: 17715376]

Paterson DL, Bonomo RA: Extended-spectrum beta-lactamases: A

clinical update. Clin Microbiol Rev 2005;18:657–86. [PMID:

16223952]

BOTULISM & TETANUS

Patients with botulism and tetanus have primarily neuro-

logic complications that almost always require management

in an ICU. Both disorders are caused by toxins produced by

clostridia. In tetanus, patients have traumatic or surgical

wounds contaminated by C. tetani. Most cases of botulism

are due to ingestion of preformed food-borne toxin; how-

ever, botulism may result from toxin produced by cutaneous

infection with C. botulinum.



Botulism

ESSENTIALS OF DIAGNOSIS



Nausea, vomiting, dysphagia, diplopia, dilated and

fixed pupils.



Sudden weakness in a previously healthy person.



Cranial nerves affected first (except I and II), followed

by descending symmetric paralysis or weakness.



Autonomic nervous system involvement: paralytic ileus,

gastric dilation, urinary retention, and orthostatic

hypotension.



Absence of sensory or mental status changes.



Botulism toxin isolated from serum, stool, or other body

fluids.

General Considerations

Botulism is an acute neurologic disorder caused by the pro-

duction of a neurotoxin produced by C. botulinum.

Improperly canned or home-prepared foods are common

sources of the toxin. There are three clinical forms of botu-

lism: food-borne botulism, wound botulism, and infant bot-

ulism. Infant botulism results from the ingestion of botulism

spores, which germinate in the intestine and produce toxin.

Most infants recover with supportive care only. Food-borne

and wound botulism are generally more serious illnesses.

C botulinum

and Botulism Toxins—C. botulinum is an

anaerobic gram-positive rod that survives in soil and marine

Common causes

Drug fever

Malignancy

Deep venous thrombosis

Posttransfusion

Postoperative (atelectasis)

Thrombophlebitis

Chemical aspiration pneumonitis

Less common causes

Hyperthyroidism

Adrenal insufficiency

Transplant rejection

Alcohol withdrawal, drug withdrawal

Pancreatitis

Pulmonary embolism

Hematoma

Table 15–7. Some noninfectious causes of fever

in the ICU.

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INFECTIONS IN THE CRITICALLY ILL

393

sediment by spore formation. Under anaerobic conditions

that permit germination, toxin production occurs. Although

boiling for 10 minutes will kill bacteria and destroy toxins,

spores are heat-resistant and can survive boiling for 3–5 hours.

Food contaminated by botulism toxin may have no detectable

change in appearance or taste.

Botulism toxin is the most potent toxin known on a per-

weight basis. Eight immunologically distinct toxins have

been described: A, B, Cα and Cβ, D, E, F, and G. Each strain

of C. botulinum can produce only a single toxin type. Toxins

A, B, and E have been the most common causes of human

disease. Toxins A and B are the most potent; even small tastes

of food contaminated with these toxins have resulted in full-

blown disease.

Specific C. botulinum toxins appear to be geographically

distributed throughout the world. In the United States, toxin

A is found predominantly west of the Mississippi, whereas

toxin B is found in the eastern states. Toxin E is found in the

Great Lakes region and in Alaska, where one of the highest

rates of botulism worldwide is seen.

Toxins produced by C. botulinum block acetylcholine

release at peripheral neuromuscular and autonomic nerve

junctions, resulting in weakness, flaccid paralysis, and some-

times respiratory failure. Toxin binding is irreversible.

B. Food-Borne Botulism—Botulism toxins are large pro-

teins. In food-borne botulism, ingested preformed toxin is

absorbed in the stomach and upper small intestine. Toxins

are reduced in size by proteolytic enzymes, but their activity

remains unchanged. Pancreatic trypsin actually may

enhance the toxicity of some toxin strains. In addition to

improperly home-canned foods, outbreaks of botulism have

been traced to noncanned foods such as eviscerated dried

fish, yogurt flavored with hazelnut conserve, a garlic-in-oil

product, homemade salsa, cheese sauce, baked potatoes

sealed in aluminum foil, and sautéed onions stored under a

layer of butter.

Botulism toxin has potential as a weapon of bioterrorism,

both from ingestion and by inhalation. Clinical findings

would be identical, but possible features would include a

large outbreak with common environmental exposure, an

unusual toxin type, or multiple simultaneous outbreaks.

C. Wound Botulism—Wound botulism results when C.

botulinum grows and produces toxin in traumatized, devitalized

tissue. The wound may appear insignificant. Toxin produc-

tion is followed by onset of symptoms after an incubation

period of 4–14 days. Many cases of wound botulism have

occurred in teenagers, children, and injection drug users.

Sinus infection with C. botulinum has been reported after

intranasal cocaine use; evidence suggests that botulism toxin

can be inhaled or inoculated through the eye. In recent years,

there has been a dramatic increase in the number of cases of

wound botulism linked to the subcutaneous injection of

impure “black tar” heroin imported from Mexico, perhaps

the result of contamination of the drug during the “cutting”

process with adulterants such as dirt.

D. Adult Infectious Botulism—While most cases of adult

botulism are the result of ingested preformed toxin, there

have been cases of botulism in patients with documented

C. botulinum colonization of the intestinal tract. Risk factors

include abdominal surgery, GI tract abnormalities, and

recent antibiotic administration, all of which presumably

alter the normal GI flora.

Clinical Features

The diagnosis of food-borne botulism should be considered

when an acute illness with GI or neurologic manifestations

affects two or more persons who have shared a meal during

the preceding 72 hours. Wound botulism presents with sim-

ilar neurologic symptoms but without GI complaints.

A. Symptoms and Signs—An initial pentad of signs and

symptoms has been described in botulism, consisting of nau-

sea and vomiting, dysphagia, diplopia, dilated and fixed

pupils, and an extremely dry mouth unrelieved by drinking

fluids. Over 90% of patients have at least three of these signs

or symptoms. Symptoms can occur as early as 2 hours or as

late as 8 days after toxin ingestion but usually occur within

18–36 hours. Onset of symptoms can be abrupt or may

evolve over several days. Abnormalities of cranial nerve

motor functions are followed by descending symmetric

paralysis or weakness. Respiratory muscle weakness may be

subtle or may progress rapidly to respiratory failure. Somatic

musculature is affected last. Patients may develop autonomic

nervous system manifestations, including constipation from

paralytic ileus, gastric dilation, urinary retention, and ortho-

static hypotension.

Notably absent in patients with botulism are sensory dis-

turbances, changes in sensorium, and fever. Cranial nerves I

and II are spared. Deep tendon reflexes may be intact, dimin-

ished, or absent, but pathologic reflexes cannot be demon-

strated. In addition, the heart rate may be normal or slow

unless secondary infection is present.

B. Laboratory Findings—The diagnosis of botulism is con-

firmed by isolating botulism toxin through a mouse neutral-

ization bioassay. Toxin may be identified in samples of

serum, stool, vomitus, gastric aspirate, and suspected foods.

C. botulinum may be grown on selective media from samples

of stool or foods. Specimens for toxin analysis should be

refrigerated, but culture samples for C. botulinum should

not. Because the toxin may enter the bloodstream through

the eye or a small break in the skin, only experienced person-

nel, preferably immunized with botulinum toxoid, should

handle specimens.

Electromyography may be useful in establishing a diagno-

sis of botulism but can be nonspecific and nondiagnostic

even in severe cases. Low-amplitude and short-duration

motor unit action potentials, small M-wave amplitudes, and

posttetanic fasciculation may be seen. A modest increment in

M-wave amplitude with rapid repetitive nerve stimulation

may help to localize the disorder to the neuromuscular



CHAPTER 15

394

junction. Single-fiber electromyography may be a more use-

ful and sensitive method for the rapid diagnosis of botulism

intoxication, particularly when signs of general muscular

weakness are absent. Cerebrospinal fluid is normal.

Differential Diagnosis

Differentiating botulism from other diseases is critical to

early implementation of appropriate therapy. Table 15–8 lists

diseases that must be differentiated from botulism.

Treatment

A. Supportive Care—Meticulous supportive care is essential

for patients with all forms of botulism. If respiratory failure

has not already occurred at the time of diagnosis, the patient

should be hospitalized in a monitored setting with serial

measurements of vital capacity. Respiratory failure can occur

with unexpected rapidity. Pulmonary infections are a com-

mon complication of botulism, often the result of aspiration

of oropharyngeal secretions or a complication of atelectasis.

The development of fever should prompt an evaluation of

possible pneumonia. Improvement in ventilatory and upper

airway muscle strength in patients who develop respiratory

failure is most significant over the first 12 weeks, but recov-

ery may not be complete for up to a year.

Wound botulism requires thorough debridement of the

infected wound and administration of penicillin in addition

to antitoxin therapy.

B. Botulism Antitoxin—Botulism antitoxin should be

administered to all patients with food-borne or wound bot-

ulism. Because only equine antitoxin is available, all patients

first must undergo testing for hypersensitivity to equine

serum. Twenty percent of patients will experience some

degree of hypersensitivity, and anaphylaxis also can occur.

Trivalent antitoxin for toxins A, B, and E is distributed

through the Centers for Disease Control and Prevention.

Polyvalent antitoxin for toxins A, B, C, D, E, and F is also

available for specific outbreaks.

Antitoxin should be given as soon as available, but it may

be beneficial even when given several weeks after toxin inges-

tion because circulating toxin can be detected in serum up to

30 days after intoxication. Antitoxin will not neutralize toxin

already bound to neuromuscular junctions, and although it

can slow disease progression, it has no effect on established

neurologic impairment. Two vials of the appropriate anti-

toxin should be given, one intramuscularly and one intra-

venously. This regimen may be repeated after 2–4 hours.

Because of the risk of adverse reactions, prophylactic

antitoxin is not recommended for those who have been

exposed to botulism toxin but have no symptoms. If inges-

tion is recognized early, patients may undergo gastric lavage

or induced vomiting in an attempt to eliminate the toxin

prior to absorption.

Current Controversies and Unresolved Issues

Administration of antibiotics to patients with food-borne

botulism is controversial, although some physicians give

penicillin to eradicate potential bowel carriage of the organ-

ism. The benefit of this approach is uncertain.

Guanidine hydrochloride is thought to increase acetyl-

choline release from terminal nerve endings and is advocated

by some in the treatment of botulism. Reports of its efficacy

are conflicting.

Arnon SS et al: Botulinum toxin as a biological weapon: Medical

and public health management. JAMA 2001;285:1059–70.

[PMID: 11209178]

Cherington M: Botulism: Update and review. Semin Neurol

2004;24:155–63. [PMID: 15257512]



Tetanus

ESSENTIALS OF DIAGNOSIS



Generalized weakness or stiffness, with trismus (“lock-

jaw”) and severe generalized spasms.



Opisthotonos and abdominal rigidity.



Respiratory failure, tachycardia, hypertension, fever,

and diaphoresis may be present.

General Considerations

Although entirely preventable by appropriate vaccination,

tetanus still occurs in developing countries and infrequently

in developed countries. It remains endemic in developing

countries. In the United States, 50–70 cases are reported

annually, typically in patients who have never received a pri-

mary immunization series with tetanus toxoid. Many elderly

patients and patients born or raised in developing countries

have not been vaccinated and are at risk. Elderly women may

be at higher risk than elderly men because many men were

vaccinated during military service. Male gender and black

race are risk factors for tetanus in the United States, perhaps

because of the higher incidence of trauma in these groups.

Myasthenia gravis

Tick paralysis

Poliomyelitis

Guillain-Barré syndrome (Miller-Fisher variant)

Psychiatric disorder

Stroke (brain stem)

Rabies

Diphtheria

Eaton-Lambert syndrome

Table 15–8. Differential diagnosis of botulism.

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INFECTIONS IN THE CRITICALLY ILL

395

Injection drug users, particularly “skin poppers,” are predis-

posed to tetanus. Tetanus is more frequent in warmer cli-

mates and months in part because of the greater frequency of

contaminated wounds. Tetanus is not transmitted from per-

son to person.

C. tetani

and Tetanospasmin—The clinical syndrome

of tetanus is caused by a potent neurotoxin, tetanospasmin,

released from C. tetani. A slender, motile, gram-positive

nonencapsulated anaerobic rod, C. tetani is a spore-forming

organism that is found commonly in nature. Spores may be

found in soil and dust but are particularly common in areas

contaminated with human or animal excreta. Spores may

remain viable for years and then germinate when they are

introduced into an appropriate anaerobic environment such

as devitalized tissue. The presence of other bacterial organ-

isms appears to enhance the reversion of spores to vegetative

forms and the release of tetanospasmin.

B. Pathophysiology—Tetanospasmin migrates into the

CNS either transsynaptically along peripheral motor nerves

or by hematogenous or lymphatic routes. It binds to the

presynaptic inhibitory neurons and prevents the release of

acetylcholine from nerve terminals in muscle. The functional

loss of inhibitory neurons allows lower motor neurons to

increase muscle tone, producing rigidity and spasm of both

agonist and antagonist muscles. Once tetanospasmin is fixed

to nervous tissue, it cannot be neutralized by antitoxin.

Tetanospasmin also binds to cerebral gangliosides, which

may be the cause of seizures seen in tetanus. Disturbances of

the autonomic nervous system are common, manifested by

sweating, fluctuating blood pressure, tachycardia and cardiac

arrhythmias, and increased production of catecholamines.

Clinical Features

Tetanus may occur in the neonate in the first month of life or

as one of three patterns in adult patients. Generalized tetanus

is the most common adult presentation. Local tetanus and,

even more rarely, cephalic tetanus are manifested by local

muscle spasms in areas contiguous with an infected wound.

Both local and cephalic tetanus may progress to generalized

tetanus. Tetanus is a diagnosis of exclusion. If the diagnosis is

not considered, the opportunity for early treatment will be

lost.

A. Introduction of

C. tetani

—The wound into which C.

tetani has been introduced may appear insignificant.

However, particularly high-risk wounds include those con-

taminated with dirt, feces, soil, or saliva, as well as any punc-

ture wound, crush wound, burn, decubitus ulcer, or frostbite

injury. Tetanus also has been reported following elective and

emergency surgical procedures, particularly those involving

the GI tract. The postpartum uterus is also susceptible to

C. tetani infection. Thus tetanus should be considered in the

postoperative patient who develops crampy abdominal pain

and abdominal wall rigidity with no history of tetanus vacci-

nation. C. tetani may be harbored in the middle ear (chronic

otitis media) and in wounds of the head, predisposing a

patient to cephalic tetanus.

B. Symptoms and Signs—Tetanus can present 1–54 days

following a puncture or other wound, but an incubation

period shorter than 14 days is most common. Longer incuba-

tion periods generally are related to injury sites farther away

from the CNS. Generalized weakness or stiffness is a frequent

initial symptom, with trismus (“lockjaw”) being the most

common complaint. As symptoms progress over 1–7 days,

severe generalized reflex spasms develop. Opisthotonos, abdom-

inal rigidity, and a grotesque facial expression called risus sar-

donicus are classic signs. Spasms may be precipitated by

minor disturbances such as a draft or noise or by jarring the

bed. In the absence of seizures, the patient’s sensorium is

usually clear. Involvement of the respiratory muscles may

lead to hypoventilation. Autonomic dysfunction may occur,

causing tachycardia, hypotension, fever, and diaphoresis, and

can be difficult to manage.

Tetanus severity scores provide prognostic information.

Extremes of heart rate, high blood pressure, advanced age,

short duration of symptoms, and presence of underlying dis-

eases are associated with worse outcome.

Complications of tetanus include pneumonia, venous

thrombosis, pulmonary embolism, and long bone and spine

fractures from severe sustained muscle contractures. The

mortality rate from tetanus ranges from 21–31% in the

United States and may be as high as 52% in patients over

60 years of age. Poor outcome is associated with autonomic

disturbances such as blood pressure lability, with cardiac

arrhythmias and rate disturbances, and with hyperglycemia,

hyperthermia, and anticoagulation therapy.

Some studies have suggested a poor prognosis when

patients present with short incubation periods and heavily

contaminated wounds. A better prognosis is suggested if

there is no demonstrable focus of infection.

C. Laboratory Findings—The wound in a patient suspected

of having tetanus should be cultured anaerobically for C. tetani.

However, the etiologic confirmation is infrequently made in

this manner, and the diagnosis usually is based on the absence

of detectable tetanus toxoid antibody and the exclusion of

other diseases.

Differential Diagnosis

The differential diagnosis of tetanus includes a list of rather

unusual diseases not commonly encountered in the ICU

(Table 15–9).

Treatment

A. Tetanus Immune Globulin—Patients who present with

tetanus should receive tetanus immune globulin as early as

possible to neutralize unbound toxin. Delay in treatment

may result in a poorer prognosis. The optimal dose of

tetanus immune globulin has not been established, but a

single dose of 3000–6000 units intramuscularly can be given.



CHAPTER 15

396

It is advised that some of the dose be injected into the area of

the presumed injury.

B. Supportive Care—Metronidazole is accepted as the drug

of choice. Far more important, wounds should be debrided

properly. In patients with wounds that continue to be

infected, it may be necessary to repeat passive immunization

with tetanus immune globulin after 3–4 weeks because toxin

production may continue, and antibiotic therapy will not

eradicate the spores.

Tracheostomy should be performed in all but very mild

cases to allow for prolonged respiratory assistance with a

ventilator. Problems arising from cardiovascular instability

should be treated appropriately.

Analgesics should be used to relieve pain from muscle

contractions. Benzodiazepines—particularly diazepam—

may be effective in reducing muscle spasms. Inadequate

muscle relaxation or inadequate control of seizure activity

can lead to complications such as long bone and vertebral

fractures. Benzodiazepines may not prevent reflex spasms,

however, and effective respiration may require neuromuscu-

lar blockade.

Patients require nutritional support and meticulous

attention to the prevention of decubiti and flexion contrac-

tures. Consideration should be given to subcutaneous

heparin therapy, particularly in illicit injection drug users

and elderly patients, who appear to be at highest risk for pul-

monary embolism. Constipation is common, and an initial

cleansing enema is helpful. A rectal tube helps to control

abdominal distention. Nosocomial infections may develop

and should be considered if a patient with tetanus develops

more than a moderate elevation in temperature.

C. Immunization—Patients who develop tetanus are not

subsequently immune to the infection. Tetanospasmin is

toxic in such minute quantities that it appears to escape reac-

tion by the immune system, and protective antibody is not

produced. Therefore, active immunization with a primary

immunization series with tetanus toxoid should be adminis-

tered to all patients during the convalescent phase of illness—

usually a period of several weeks.

Current Controversies and Unresolved Issues

Many controversies remain in the management of patients

with tetanus, particularly with respect to cardiovascular

complications. Suggested therapeutic modalities occasionally

are based on single case reports.

Clonidine has been reported to control sympathetic over-

activity in severe tetanus. More recently, the beta-blocker

esmolol was reported to be effective in controlling auto-

nomic instability. Patients with severe tetanus who failed to

respond to beta blockade and low doses of ganglionic block-

ing agents had dramatic suppression of cardiovascular insta-

bility when given continuous spinal anesthesia with

bupivacaine, which provided complete blockade of sympa-

thetic and parasympathetic portions of the autonomic nerv-

ous system.

Another area of interest in the treatment of tetanus is the

control of the severe spasms without sedation and artificial

ventilation. Intrathecal baclofen and intravenous magnesium

sulfate have both been used for control of spasms owing to

tetanus. In patients treated with these modalities, it appears

that less autonomic instability is encountered, and spasms

are controlled while preserving spontaneous ventilation.

Propofol has been used similarly.

Bunch TJ et al: Respiratory failure in tetanus: Case report and

review of a 25-year experience. Chest 2002;122:1488–92.

[PMID: 12377887]

Cook TM, Protheroe RT, Handel JM: Tetanus: A review of the liter-

ature. Br J Anaesth 2001;87:477–87. [PMID: 11517134]

Thwaites CL et al: Predicting the clinical outcome of tetanus: The

tetanus severity score. Trop Med Int Health 2006;11:279–87.

[PMID: 16553907]

Meningoencephalitis (viral, bacterial)

Phenothiazine overdose

Peritonsillar abscess

Hypercalcemic tetany

Retropharyngeal abscess

Retroperitoneal hemorrhage

Dental abscess

Epilepsy

Mandibular fracture

Opioid withdrawal

Tonsillitis

Strychnine poisoning

Diphtheria

Rabies

Mumps

Neuroleptic–malignant syndrome

Trichinosis

Septicemic spondylitis

Mandibular osteomyelitis

Table 15–9. Differential diagnosis of tetanus.