1266 PART 5 Infectious Diseases

intestinal pathogenic E. coli strains to cause disease outside and within

the gastrointestinal tract, respectively. However, even commensal E.

coli strains can be involved in extraintestinal infections in the presence

of an aggravating factor, such as a foreign body (e.g., a urinary catheter), host compromise (e.g., local anatomic or functional abnormalities

[including urinary or biliary tract obstruction] or systemic immunocompromise), or an inoculum that is large or contains a mixture of

bacterial species (e.g., fecal contamination of the peritoneal cavity).

■ EXTRAINTESTINAL PATHOGENIC STRAINS

ExPEC strains are the most common enteric GNB to cause communityacquired and health care–associated bacterial infections. The emerging

propensity of these strains to acquire new mechanisms of antimicrobial

resistance (e.g., FQ resistance mutations, ESBLs, carbapenemases) poses

novel challenges in managing ExPEC infection. Several ExPEC clonal

groups (e.g., sequence types [STs] ST131, ST95, ST69, ST73) are recognized to have undergone global dissemination. The mechanisms underlying the epidemiologic success of such disseminated lineages remain

an area of active investigation. In the case of ST131, efficient human-tohuman transmission followed by colonization and long-term persistence

within the intestinal microbiota appears to be a critical factor. Although

acquisition of ESBL-producing E. coli from the food chain has been

described, this appears to occur relatively uncommonly.

Like commensal E. coli (but unlike intestinal pathogenic E. coli),

ExPEC strains are often found in the intestinal microbiota of healthy

individuals and, except for rare chimeric ExPEC/intestinal pathogenic

E. coli strains, do not cause gastroenteritis in humans. Entry from

their site of colonization (e.g., the colon, vagina, or oropharynx) into

a normally sterile extraintestinal site (e.g., the urinary tract, peritoneal

cavity, or lungs) is the rate-limiting step for infection. ExPEC strains

have acquired accessory genes encoding diverse virulence factors that

enable the bacteria to cause infections outside the gastrointestinal tract

in both normal and compromised hosts (Table 161-1). These virulence

genes define ExPEC and, for the most part, are distinct from the virulence genes that enable intestinal pathogenic strains to cause diarrheal

disease (Table 161-3). All age groups, all types of hosts, and nearly all

organs and anatomic sites are susceptible to infection by ExPEC. Even

previously healthy hosts can become severely ill or die when infected

with ExPEC; however, adverse outcomes are more common among

hosts with comorbid illnesses and host defense abnormalities. The

diversity and the medical and economic impact of ExPEC infections

are evident from consideration of the following specific syndromes.

Extraintestinal Infectious Syndromes • URINARY TRACT

INFECTION The urinary tract is the site most frequently infected by

ExPEC. UTI is an exceedingly common infection among ambulatory

patients, accounting for 1% of ambulatory care visits in the United

States and second only to lower respiratory tract infection among

infections responsible for hospitalization. UTIs are best considered

by clinical syndrome (e.g., cystitis, pyelonephritis, catheter-associated

UTI) and within the context of specific hosts (e.g., premenopausal

women, compromised hosts; Chap. 135). E. coli is the single most common pathogen for all UTI syndrome/host group combinations. Each

year in the United States, E. coli causes 80–90% of the estimated 6–8

million episodes of cystitis that occur in ambulatory, premenopausal

women with an anatomically and functionally normal urinary tract

(i.e., uncomplicated cystitis). Furthermore, 20% of women with an

initial cystitis episode develop frequent recurrences.

Uncomplicated cystitis, the most common acute UTI syndrome, is

characterized by dysuria, urinary frequency and urgency, and suprapubic pain. Progression to more severe infection is rare; the natural

history is slow spontaneous symptom resolution, which antimicrobial

therapy hastens. Fever and/or back pain suggest progression to pyelonephritis. Even when pyelonephritis is treated effectively, fever may

take 5–7 days to resolve completely. Persistently elevated or increasing

fever, flank pain, and neutrophil counts should prompt evaluation for

intrarenal or perinephric abscess and/or obstruction. Pyelonephritis

uncommonly causes renal parenchymal damage and loss of renal function, primarily in association with urinary obstruction, which can be

preexisting or, rarely, occurs de novo in diabetic patients who develop

renal papillary necrosis as a result of kidney infection. Pregnant women

are at unusually high risk for developing pyelonephritis, which can

adversely affect the outcome of pregnancy. As a result, prenatal screening for and treatment of asymptomatic bacteriuria during pregnancy

are standard. Prostatic infection (prostatitis), a potential complication

of UTI in men, can present either acutely (severe), which is rare, or in

a chronic manner (recurrent cystitis), which is much more common.

Acute pyelonephritis, acute prostatitis, and other systemic illnesses

due to UTI can be designated collectively as urosepsis, febrile UTI, or

systemic UTI, and may or may not be accompanied by bacteremia.

The diagnosis and treatment of UTI, as detailed in Chap. 135, should

be tailored to the individual host, the nature and site of infection, and

local patterns of antimicrobial susceptibility.

ABDOMINAL AND PELVIC INFECTION The abdomen/pelvis is the second most common site of extraintestinal infection due to E. coli. A wide

variety of clinical syndromes occur in this location, including acute

peritonitis secondary to fecal contamination, spontaneous bacterial

peritonitis, dialysis-associated peritonitis, diverticulitis, appendicitis,

intraperitoneal or visceral abscesses (hepatic, pancreatic, splenic),

infected pancreatic pseudocysts, and septic cholangitis and/or cholecystitis. In intraabdominal infections, E. coli can be isolated either

alone or, as occurs more often, in combination with other facultative

and/or anaerobic members of the intestinal microbiota (Chap. 132).

PNEUMONIA E. coli is not usually considered an important cause of

pneumonia (Chap. 126). Indeed, enteric GNB account for only 1–3%

TABLE 161-3 Intestinal Pathogenic Escherichia coli

PATHOTYPE EPIDEMIOLOGY CLINICAL SYNDROMEa DEFINING MOLECULAR TRAIT RESPONSIBLE GENETIC ELEMENTb

STEC/EHEC/

ST-EAEC

Food, water, person-to-person; all

ages, industrialized countries

Hemorrhagic colitis,

hemolytic-uremic

syndrome

Shiga toxin Lambda-like Stx1- or Stx2-encoding

bacteriophage

ETEC Food, water; young children in and

travelers to developing countries

Traveler’s diarrhea Heat-stable and labile enterotoxins,

colonization factors

Virulence plasmid(s)

EPEC Person-to-person; young children and

neonates in developing countries

Watery diarrhea,

persistent diarrhea

Localized adherence, attaching and

effacing lesion on intestinal epithelium

EPEC adherence factor plasmid

pathogenicity island (locus for

enterocyte effacement [LEE])

EIEC Food, water; children in and travelers

to developing countries

Watery diarrhea,

occasionally dysentery

Invasion of colonic epithelial cells,

intracellular multiplication, cell-to-cell

spread

Multiple genes contained primarily in

a large virulence plasmid

EAEC ?Food, water; children in and travelers

to developing countries; all ages,

industrialized countries

Traveler’s diarrhea, acute

diarrhea, persistent

diarrhea

Aggregative/diffuse adherence, virulence

factors regulated by AggR

Chromosomal or plasmid-associated

adherence and toxin genes

a

Classic syndromes; see text for details on disease spectrum. b

Pathogenesis involves multiple genes, including genes in addition to those listed.

Abbreviations: EAEC, enteroaggregative E. coli; EHEC, enterohemorrhagic E. coli; EIEC, enteroinvasive E. coli; EPEC, enteropathogenic E. coli; ETEC, enterotoxigenic E. coli;

ST-EAEC, Shiga toxin–producing enteroaggregative E. coli; STEC, Shiga toxin–producing E. coli.

1267CHAPTER 161 Diseases Caused by Gram-Negative Enteric Bacilli

of cases of community-acquired pneumonia, in part because these

organisms colonize the oropharynx only transiently in a minority of

healthy individuals. However, rates of oral colonization with E. coli

and other GNB increase with severity of illness and antibiotic use.

Consequently, GNB are a more common cause of pneumonia among

residents of LTCFs and are the most common cause (60–70% of cases)

of hospital-acquired pneumonia (Chap. 142), particularly among postoperative and ICU patients (e.g., ventilator-associated pneumonia).

Pulmonary infection is usually acquired by small-volume aspiration

but occasionally occurs via hematogenous spread, in which case multifocal nodular infiltrates can be seen. Tissue necrosis, probably due

in part to bacterial cytotoxins, is common. Despite significant institutional variation, E. coli is generally the third or fourth most commonly

isolated type of GNB in hospital-acquired pneumonia, accounting

for 5–8% of episodes in both U.S.-based and Europe-based studies.

Regardless of the host, pneumonia due to ExPEC is a serious disease,

with high crude and attributable mortality rates (20–60% and 10–20%,

respectively).

MENINGITIS (See also Chap. 138) E. coli is one of the leading causes

of neonatal meningitis, together with group B Streptococcus. Most

E. coli strains that cause neonatal meningitis possess the K1 capsular antigen and derive from a limited number of meningitis-associated clonal

groups. Ventriculomegaly occurs commonly. After the first month of

life, E. coli meningitis is uncommon, and usually accompanies surgical

or traumatic disruption of the meninges or hepatic cirrhosis. In patients

with cirrhosis who develop meningitis, the meninges are presumably

seeded due to poor hepatic clearance of portal vein bacteremia.

CELLULITIS/MUSCULOSKELETAL INFECTION E. coli contributes frequently to infections of decubitus ulcers and occasionally to infections

of lower-extremity ulcers and wounds in diabetic patients and other

hosts with neurovascular compromise. Osteomyelitis secondary to

contiguous spread can occur in these settings. E. coli also causes cellulitis or infections of burn sites and surgical wounds (accounting for

~10% of surgical site infections), particularly when the infection originates close to the perineum. E. coli causes hematogenously acquired

osteomyelitis, especially of vertebral discs and bodies, accounting for

up to 10% of cases in some series (Chap. 131). E. coli occasionally

causes orthopedic device–associated infection or septic arthritis and

rarely causes hematogenous myositis. Myositis or fasciitis of the thigh

due to E. coli should prompt an evaluation for an abdominal source

with contiguous spread.

ENDOVASCULAR INFECTION Despite being one of the most common

causes of bacteremia, E. coli rarely seeds native heart valves. When the

organism does infect native valves, it usually does so in the setting of

prior valvular disease. E. coli infections of aneurysms, the portal vein

(pylephlebitis), and vascular grafts are quite uncommon.

MISCELLANEOUS INFECTIONS E. coli can cause infection in nearly

every organ and anatomic site. It occasionally causes postoperative mediastinitis or complicated sinusitis and uncommonly causes

endophthalmitis, ecthyma gangrenosum, or brain abscess.

BACTEREMIA E. coli bacteremia can arise from infection at any

extraintestinal site. In addition, E. coli bacteremia can arise from

percutaneous intravascular devices, transrectal prostate biopsy, and

the increased intestinal mucosal permeability seen in neonates and

patients with advanced cirrhosis, neutropenia, chemotherapy-induced

mucositis, trauma, and extensive burns. E. coli bacteremia due to an

ESBL-producing strain also has been reported after fecal microbiota

transplant in patients with increased mucosal permeability. Roughly

equal proportions of E. coli bacteremia cases originate in the community and in health care settings. Isolation of E. coli from the blood is

almost always clinically significant and may be accompanied by the

sepsis syndrome (dysfunction of at least one organ or system) or septic

shock (Chap. 304).

The urinary tract is the most common source for E. coli bacteremia,

accounting for one-half to two-thirds of episodes. Bacteremia from

a urinary tract source is particularly common among patients with

pyelonephritis, urinary tract obstruction, or urinary instrumentation

in the presence of infected urine. The abdomen is the second most

common source, accounting for ~25% of episodes. Although many

of these episodes result from biliary obstruction (stones, tumor) and

overt bowel disruption, which typically are readily apparent, some

abdominal sources (e.g., abscesses) are remarkably silent clinically and

require identification via imaging studies (e.g., computed tomography). Therefore, especially given the high prevalence of asymptomatic

bacteriuria among elderly and functionally compromised individuals,

the physician should be cautious in attributing E. coli bacteremia to a

urinary source in the absence of characteristic signs and symptoms of

UTI. Soft tissue, bone, pulmonary infections, and intravascular catheter infections are other sources of E. coli bacteremia.

Diagnosis Strains of E. coli that cause extraintestinal infections usually grow both aerobically and anaerobically within 24 h on standard

diagnostic media and are identified readily by the clinical microbiology

laboratory according to routine biochemical criteria. More than 90%

of ExPEC strains are rapid lactose fermenters and are indole-positive.

TREATMENT

Extraintestinal E. coli Infections

E. coli does not possess clinically significant intrinsic resistance to

antimicrobials; however, increasing acquired resistance is making

treatment problematic. Although geographic differences exist, in

general, the prevalence of resistance is >20% for ampicillin,

amoxicillin-clavulanate, ampicillin-sulbactam, cefazolin, TMPSMX, and fluoroquinolones, even in community-acquired infections. This resistance precludes empirical use of these agents for

serious infections. Travel outside of the United States, prior exposure to an antimicrobial agent, or exposure to a health care setting

further increases the likelihood of resistance. Fortunately, >90%

of isolates that cause uncomplicated cystitis remain susceptible to

nitrofurantoin and fosfomycin.

From 2015 to 2017, the U.S. National Healthcare Safety Network (USNHSN) identified 24% of E. coli clinical isolates

as ESBL-producers. Higher prevalences are reported from Asia,

Eastern Europe, South America, and Africa; prevalence is also

greater in isolates from health care settings, especially LTCFs.

However, community-acquired UTIs caused by E. coli strains that

produce CTX-M ESBLs are increasingly common. Oral treatment

options for such strains are limited; however, in vitro and limited clinical data indicate that fosfomycin, pivmecillinam, and nitrofurantoin

are highly active and can be used for cystitis, and omadacycline

is predicted to be active based on in vitro data. For parenteral

therapy of carbapenem-sensitive strains, the most predictably

active agents (>90%) include carbapenems, amikacin, plazomicin, ceftazidime-avibactam, ceftolozane-tazobactam, meropenemvaborbactam, imipenem/cilastatin-relebactam, piperacillintazobactam, polymyxins, cefiderocol, tigecycline, eravacycline, and

omadacycline. Treatment of carbapenemase-producing strains is

dependent of the class of enzyme produced (see “Carbapenemase”

above). Uncertainty exists on the optimal treatment for non-CP-CR

E. coli.

Empirical treatment decisions for critically ill patients should be

dictated by local susceptibility patterns and patient-specific risk factors (1.2% prevalence from the USNHSN 2015−2017 data). Equally

important as prompt institution of effective empirical therapy for

seriously ill patients is use of appropriate narrower-spectrum agents

for definitive therapy whenever possible and avoidance of treatment

for patients who are colonized but not infected.

■ INTESTINAL PATHOGENIC STRAINS

Pathotypes Certain strains of E. coli are capable of causing diarrheal disease. (Other important intestinal pathogens are discussed

in Chaps. 133, 134, and 165–168.) At least in the industrialized world,

intestinal pathogenic E. coli strains are rarely encountered in the fecal

flora of healthy persons, and instead appear to be essentially obligate

1268 PART 5 Infectious Diseases

pathogens. These strains have evolved a special ability to cause enteritis, enterocolitis, and colitis when ingested in sufficient quantities by

a naive host. At least five distinct pathotypes of intestinal pathogenic

E. coli exist: (1) Shiga toxin–producing E. coli (STEC), which includes

the subsets enterohemorrhagic E. coli (EHEC) and the recently evolved

Shiga toxin–producing enteroaggregative E. coli (ST-EAEC); (2)

enterotoxigenic E. coli (ETEC); (3) enteropathogenic E. coli (EPEC); (4)

enteroinvasive E. coli (EIEC); and (5) enteroaggregative E. coli (EAEC).

Diffusely adherent E. coli (DAEC) and cytodetaching E. coli are additional putative pathotypes. Lastly, a variant termed adherent invasive E.

coli (AIEC) has been associated with Crohn’s disease (although a causal

role remains unproven) but does not cause acute diarrheal disease.

Contaminated food and water are the primary transmission vehicles

for ETEC, STEC/EHEC/ST-EAEC, EIEC, and EAEC, whereas personto-person spread (direct or indirect) is the primary transmission

route for EPEC and a secondary transmission route for STEC/EHEC/

ST-EAEC. Gastric acidity confers some protection against infection;

therefore, persons with decreased stomach acid levels are especially

susceptible. Humans are the major reservoir for such strains (except

for STEC/EHEC, for which bovines are the main carriers); host range

appears to be dictated by species-specific attachment factors. Although

some overlap exists, each pathotype possesses a distinctive combination of virulence traits that results in a pathotype-specific pathogenic mechanism (Table 161-3). With rare exceptions, these strains

are largely incapable of causing disease outside the intestinal tract.

Whereas disease due to STEC/EHEC/ST-EAEC occurs primarily in

high-income countries, disease due to ETEC, EPEC, and EIEC occurs

primarily in low- and middle-income countries in Asia, Africa, and

Latin America, and disease due to EAEC occurs globally.

SHIGA TOXIN–PRODUCING E. COLI STEC/EHEC/ST-EAEC strains are

pathogens that can cause hemorrhagic colitis and the hemolytic-uremic

syndrome (HUS). In contrast to other intestinal pathotypes, STEC/

EHEC/ST-EAEC causes infections more frequently in industrialized

countries than in developing regions. Several large outbreaks resulting

from the consumption of fresh produce (e.g., lettuce, spinach, sprouts)

and of undercooked ground beef have received significant media attention. In addition, a dramatic 2011 outbreak—mainly in Germany—

involved an EAEC strain that acquired a Shiga toxin–encoding phage,

resulting in a novel genotype, ST-EAEC (O104:H4). This strain was

transmitted to the primary cases by sprouted fenugreek seeds, with

subsequent human-to-human transmission, and resulted in >4000 cases

and 54 deaths.

STEC strains are the fourth most commonly reported cause of bacterial diarrhea in the United States (after Campylobacter, Salmonella,

and Shigella). O157:H7 is the most prominent serotype among STEC

strains, but many other serogroups have been described, including O6,

O26, O45, O55, O91, O103, O111, O113, O121, and O145. Domesticated ruminant animals, particularly cattle and young calves, serve as

the major reservoir for STEC/EHEC. Ground or mechanically tenderized beef—the most common food source of STEC/EHEC strains—is

often contaminated with intestinal bacteria from the source animals

during processing. Furthermore, manure from cattle or other animals

(including in the form of fertilizer) can contaminate produce (potatoes,

lettuce, spinach, sprouts, fallen fruits, nuts, strawberries), and fecal

runoff from manure can contaminate water systems. Dairy products

and petting zoos are additional sources of infection.

It is estimated that <102

 colony-forming units (CFU) of STEC/

EHEC/ST-EAEC can cause disease. Therefore, not only can low levels

of food or environmental contamination (e.g., in water swallowed

while swimming) result in disease, but person-to-person transmission

(e.g., at day-care centers and in institutions) is an important route for

secondary spread. Laboratory-associated infections also occur. Illness

due to this group of pathogens peaks in the summer months and

occurs both as outbreaks and as sporadic cases.

For STEC/EHEC/ST-EAEC, production of Shiga toxin (Stx2a-g

and/or Stx1a,c,d) is a critical factor for occurrence of clinical

disease, as demonstrated by the 2011 ST-EAEC outbreak. The

stx gene is present on chromosomally integrated prophages, and

various combinations of stx types and subtypes can occur in a given

strain. Shigella dysenteriae strains that produce the closely related Shiga

toxin Stx also can cause hemorrhagic colitis and HUS. Stx2 (especially Stx2a,c,d) appears to be more important than Stx1 in the development of HUS. All Shiga toxins studied to date are multimers; they

comprise one A subunit that is enzymatically active and five identical

B subunits that mediate binding to globosyl ceramides, which are

membrane-associated glycolipids expressed on certain host cells. As in

ricin, the Stx A subunit cleaves an adenine from the host cell’s 28S

rRNA, thereby irreversibly inhibiting ribosomal function (i.e., protein

synthesis) and potentially leading to apoptosis.

For full pathogenicity, STEC strains require additional properties

such as acid tolerance and epithelial cell adherence. Most disease-causing

isolates possess the chromosomal locus for enterocyte effacement

(LEE). This pathogenicity island was first described in EPEC strains; it

contains genes that mediate adherence to intestinal epithelial cells and

a system that subverts host cells by the translocation of bacterial proteins (type III secretion system). EHEC strains make up the subgroup

of STEC strains that possess stx1

 and/or stx2

, as well as LEE. In contrast,

the 2011 ST-EAEC outbreak strain lacked LEE, yet was associated

with a higher proportion of patients developing HUS (22%) than the

historical average for STEC/EHEC outbreaks (2–8%). Data support the

essential role of the 2011 outbreak strain’s EAEC-associated virulence

factors (e.g., AAF/I fimbriae, serine proteases SigA, SepA) in adherence, increased inflammation, and disruption of the intestinal epithelial barrier, which in turn increased the systemic translocation of Stx2a.

After exposure to STEC/EHEC/ST-EAEC and a 3- to 4-day incubation period, colonization of the colon and perhaps the ileum results in

symptoms. Colonic edema and an initial nonbloody secretory diarrhea

may progress to the hallmark syndrome of grossly bloody diarrhea

(identified by history or examination). Significant abdominal pain

and fecal leukocytes are common (70% of cases), whereas fever is not;

absence of fever can incorrectly lead to consideration of noninfectious

conditions (e.g., intussusception and inflammatory or ischemic bowel

disease). Occasionally, infections caused by C. difficile, K. oxytoca (see

“Klebsiella Infections,” below), Campylobacter, and Salmonella present

in a similar fashion. STEC/EHEC disease is usually self-limited, lasting

5–10 days.

A feared complication of infection with STEC/EHEC strains is HUS,

which occurs 2–14 days after diarrhea, most often in young children

(estimated to occur in 15% of infected children <10 years of age) or

elderly patients. It is estimated that in the United States >50% of all

HUS cases—and 90% of HUS cases in children, which is a leading

cause of acute renal failure in this latter population—are caused by

STEC/EHEC. In contrast, with ST-EAEC infection, HUS occurs more

commonly among nonelderly adults, especially young women. HUS is

mediated by the systemic translocation of Shiga toxins. Erythrocytes

may serve as carriers of Stx to endothelial cells located in the small

vessels of the kidney and brain. The subsequent development of thrombotic microangiopathy (perhaps with direct toxin-mediated effects on

various nonendothelial cells) commonly produces some combination

of fever, hemolytic anemia, thrombocytopenia, renal failure, and

encephalopathy. Stx-mediated complement activation may also play

a role in the development of HUS. Although with dialysis support the

mortality rate of HUS is <10%, survivors often have persisting renal

and neurologic dysfunction.

ENTEROTOXIGENIC E. COLI ETEC is a major cause of endemic diarrhea in low- and middle-income countries and is responsible for an

estimated 800 million cases annually. After weaning, children in these

locales commonly experience several episodes of ETEC infection during the first 3 years of life. The incidence of disease diminishes with

age, a pattern that correlates with the development of mucosal immunity to colonization factors (i.e., adhesins).

In industrialized countries, ETEC is the most common agent of

traveler’s diarrhea, causing 25–75% of cases. The incidence of infection

may be decreased by prudent avoidance of potentially contaminated

fluids and foods, particularly items that are raw, insufficiently cooked,

peeled, or unrefrigerated (Chap. 124). ETEC infection is uncommon

1269CHAPTER 161 Diseases Caused by Gram-Negative Enteric Bacilli

in the United States, but outbreaks secondary to consumption of

food products imported from endemic areas have occurred. A large

inoculum (106

–108

 CFU) is needed to produce disease, which usually

develops after an incubation period of 12–72 h.

After adherence of ETEC to enterocytes via colonization factors

(e.g., CFA/I, CS), disease is mediated, primarily by a heat-labile

toxin (LT) and/or a heat-stable toxin (STa), leading to diarrheal

disease. Disease is less severe with strains that produce only LT. Both

LT and STa cause net fluid secretion via activation of adenylate cyclase

and/or guanylate cyclase C (STa) in the jejunum and ileum. The result

is watery diarrhea accompanied by cramps.

LT consists of an A and a pentameric B subunit and is structurally

and functionally similar to cholera toxin. Strong binding of the B

subunit to the GM1

 ganglioside on intestinal epithelial cells leads to

the intracellular translocation of the A subunit, which functions as

an ADP-ribosyltransferase. Mature STa is an 18- or 19-amino-acid

secreted peptide that leads to increased intracellular concentrations

of cGMP. Characteristically absent in ETEC-mediated disease are

histopathologic changes within the small bowel; mucus, blood, and

inflammatory cells in stool; and fever.

The disease spectrum of ETEC infection ranges from mild illness

to a life-threatening, cholera-like syndrome. Although symptoms are

usually self-limited (typically lasting for 3–5 days), infection may result

in significant morbidity and mortality (>250,000 deaths annually,

mostly from profound volume depletion) when access to health care

or suitable rehydration fluids is limited and when small and/or undernourished children are affected.

ENTEROPATHOGENIC E. COLI EPEC causes disease primarily in young

children, including neonates. The first E. coli pathotype recognized

as an agent of diarrheal disease, EPEC was responsible for outbreaks

of infantile diarrhea (including in hospital nurseries) in industrialized countries in the 1940s and 1950s. At present, EPEC infection is

uncommon in high-income countries, but among infants in low- and

middle-income countries, it is an important cause of diarrhea (both

sporadic and epidemic), often accompanied by vomiting and fever.

Breast-feeding diminishes the incidence of EPEC infection. Rapid person-to-person spread may occur.

Symptoms develop after colonization of the small bowel and a

brief incubation period (1 or 2 days). Initial localized adherence

to enterocytes via type IV bundle-forming pili leads to a characteristic effacement of microvilli, with the formation of cuplike,

actin-rich pedestals mediated by factors in the LEE. Diarrhea production is a complex and regulated process in which host cell modulation

by a type III secretion system plays an important role. Strains lacking

bundle-forming pili have been categorized as atypical EPEC (aEPEC);

increasing data support a role for these strains as intestinal pathogens

in all age groups and among HIV-infected individuals. Diarrheal stool

often contain mucus but not blood. Although EPEC diarrhea is usually

self-limited (lasting 5–15 days), it may persist for weeks.

ENTEROINVASIVE E. COLI EIEC, a relatively uncommon (or perhaps

underrecognized) cause of diarrhea, is rarely identified in the United

States, although a few food-related outbreaks have been described.

In low- and middle-income countries, sporadic disease is recognized

infrequently in children and travelers.

EIEC shares many genetic and clinical features, as well as a common

ancestor, with Shigella. Both are intracellular pathogens for which virulence is mediated by the presence of specific factors and by the loss or

inactivation of other factors (antivirulence genes), which presumably

occurred during these organisms’ transition from an extracellular to

an intracellular lifestyle.

Colonization and invasion of the colonic mucosa, followed by

replication therein and cell-to-cell spread (in part via a type III

secretion system), result in the development of inflammatory colitis.

However, unlike Shigella, EIEC produces disease only with a large

inoculum (108

–1010 CFU) and is less virulent, typically causing only

mild, self-limited (7–10 days), watery diarrhea. Onset generally

follows an incubation period of 1–3 days. Occasionally, EIEC can

cause a shigellosis-like (dysentery) syndrome characterized by fever,

abdominal pain, tenesmus, and scant stool containing mucus, blood,

and inflammatory cells.

ENTEROAGGREGATIVE AND DIFFUSELY ADHERENT E. COLI EAEC has

been described primarily in low- and middle-income countries and in

young children. However, recent studies indicate that it also may be a

relatively common cause of diarrhea in all age groups in industrialized

countries. EAEC has been recognized increasingly as an important

cause of traveler’s diarrhea. It is highly adapted to humans—the probable reservoir. A large inoculum is required for infection, which usually

manifests as watery and sometimes persistent diarrhea in healthy but

also malnourished or HIV-infected hosts.

In vitro, EAEC cells exhibit a diffuse or “stacked-brick” pattern of

adherence to small-intestine epithelial cells. Virulence factors that

probably are necessary for disease are regulated in large part by the

transcriptional activator AggR. The pathogenesis of EAEC disease begins

with intestinal adherence, which results from stimulation of epithelial

mucus production and bacterial biofilm formation, the latter mediated

by fimbriae and possibly the mucinase Pic and dispersin. Inflammation

ensues, resulting in epithelial cell exfoliation and intestinal secretion,

which is mediated by the enterotoxins Pet, EAST-1, ShET1, and HlyE.

An additional enteric pathotype, DAEC, is associated with diarrheal

disease, primarily in children 2–6 years of age in some developing

countries, and may cause traveler’s diarrhea. The Afa/Dr adhesins may

contribute to the pathogenesis of such infections.

Diagnosis Acute infectious diarrhea can be classified as noninflammatory (most commonly viral) or inflammatory (usually bacterial); the

latter is suggested by grossly bloody or mucoid stools or a positive test

for fecal leukocytes, lactoferrin, or calprotectin (Chap. 133). ETEC,

EPEC, DAEC, and EAEC cause noninflammatory diarrhea. Identification of these agents can be achieved with a commercial platform (e.g.,

BioFire® Film Array® Gastrointestinal Panel can detect STEC, ETEC,

EPEC, EAEC, and EIEC). However, organism identification is rarely

needed because the associated diseases are self-limited. ETEC causes the

majority and EAEC a minority of cases of noninflammatory traveler’s

diarrhea; here again, however, definitive diagnosis generally is not necessary for management (as discussed below). If diarrhea persists for >10

days despite treatment, Giardia or Cryptosporidium (or, in immunocompromised hosts, certain opportunistic pathogens) should be sought.

Because of the considerable public-health importance of STEC/

EHEC/ST-EAEC infections, including the threat of HUS, the CDC

now recommends that all patients with community-acquired diarrhea,

whether inflammatory or not, be evaluated for these pathogens by

simultaneous culture (to provide an isolate for strain typing and for

outbreak detection and control) and detection of Shiga toxin or the

corresponding genes. The rationale for testing all cases of communityacquired diarrhea, regardless of clinical features, is that bloody stool

and fecal white blood cells (or lactoferrin) are not reliably present with

STEC/EHEC/ST-EAEC infection. In addition, the use of both tests

increases diagnostic sensitivity over that with either test alone.

O157 STEC/EHEC may be identified via culture by screening for

E. coli strains that do not ferment sorbitol, with subsequent serotyping and testing for Shiga toxin. Selective or screening media are

not available for culture-based detection of non-O157 STEC/EHEC/

ST-EAEC strains. Detection of Shiga toxins or toxin genes via DNAbased, enzyme-linked immunosorbent, and cytotoxicity assays offers

the advantages of rapidity and detection of non-O157 STEC/EHEC/

ST-EAEC strains. Specimens positive for toxin but culture-negative for

O157 should be forwarded to the local or state public-health laboratory

for specialized testing.

TREATMENT

Intestinal E. coli Infections

The mainstay of treatment for all diarrheal syndromes is replacement of water and electrolytes. This measure is especially important

for STEC/EHEC/ST-EAEC infection because appropriate volume

expansion may protect against renal injury and improve outcome.

1270 PART 5 Infectious Diseases

FIGURE 161-1 Hypervirulent pathotype of K. pneumoniae (hvKp). Top: Abdominal

CT scan of a previously healthy 24-year-old Vietnamese man shows a primary liver

abscess (red arrow) with metastatic spread to the spleen (black arrow). (Courtesy

of Drs. Chiu-Bin Hsaio and Diana Pomakova.) Middle: A previously healthy 33-yearold Chinese man presented with endophthalmitis. (AS Shon, RP Bajwa, TA Russo:

Hypervirulent (hypermucoviscous) Klebsiella pneumoniae: A new and dangerous

breed. Virulence 4:107, 2013.) Bottom: A hypermucoviscous phenotype (which does

not necessarily equate with a mucoid phenotype) has been associated with hvKp

strains. A positive string test is shown. However, this test is not optimally sensitive

or specific. Identification of the combination of the biomarkers iucA, iroB, peg-344,

rmpA, and rmpA2 is presently the most accurate means to identify hvKp.

The use of prophylactic antibiotics to prevent traveler’s diarrhea

generally should be discouraged, especially in light of high rates of

antimicrobial resistance. However, in selected patients (e.g., those

who cannot afford a brief illness or are predisposed to infection),

the use of rifaximin, which is nonabsorbable and is well tolerated,

is reasonable.

When stools are free of mucus and blood, early patient-initiated

treatment of traveler’s diarrhea with a fluoroquinolone or azithromycin decreases the duration of illness, and the use of loperamide

may halt symptoms within a few hours. Although dysentery caused

by EIEC is self-limited, antimicrobial therapy hastens the resolution

of symptoms, particularly in severe cases. In contrast, antimicrobial therapy for STEC/EHEC/ST-EAEC infection (the presence of

which is suggested by grossly bloody diarrhea without fever) should

be avoided because antibiotics may increase the incidence of HUS

(possibly via increased production/release of Stx). In the treatment

of HUS, plasmapheresis has no benefit and the value of inhibition

of C5 (via eculizumab) is unresolved.

KLEBSIELLA INFECTIONS

K. pneumoniae is the most important Klebsiella species from a medical

standpoint, causing community-acquired, LTCF-acquired, and nosocomial infections. K. oxytoca and K. (formerly Enterobacter) aerogenes

are primarily pathogens in LTCFs and hospitals. Klebsiella species are

broadly prevalent in the environment and colonize the mucosal surfaces of mammals. In healthy humans, the prevalence of K. pneumoniae

colonization is 5–35% in the colon and 1–5% in the oropharynx; skin is

usually colonized only transiently.

Most Klebsiella infections in Western countries are caused by “classical” K. pneumoniae (cKp) and occur in hospitals and LTCFs. The

most common clinical syndromes due to cKp are pneumonia, UTI,

abdominal infection, intravascular device infection, surgical site infection, soft tissue infection, and secondary bacteremia. cKp strains have

gained notoriety because of their propensity for acquiring treatmentconfounding antimicrobial resistance determinants and causing both

localized and widespread outbreaks, such as with the global spread

of NDM-1-producing cKp strains from India associated with medical

tourism. Clonal groups STs 11, 15, 101, 307, and 258/512, many members of which produce carbapenemases, are undergoing international

dissemination. Transmission within or between institutions is common. K. pneumoniae is nearly four-fold more transmissible than E. coli,

and, disconcertingly, carbapenemase-producing strains are associated

with increased spread compared to carbapenem-susceptible strains.

In addition, hypervirulent K. pneumoniae (hvKp) strains that are

phenotypically and clinically distinct from cKp have emerged recently,

after their initial recognition in Taiwan in 1986. Although hvKp infections have occurred globally in all ethnic groups, most cases have been

reported in individuals of Asian ethnicity residing in countries from

the Asian Pacific Rim, but also in Asians living in other countries.

Affected individuals often have diabetes mellitus. These demographics

raise the possibility of a locale-specific distribution of the organism

or an increased susceptibility of Asian hosts, especially those who are

diabetic. In contrast to the usual health care–associated context for

cKp infections in the West, hvKp is capable of causing serious life- and

organ-threatening infections in younger, healthy individuals from

the community and can spread metastatically from the primary site

of infection or present with multiple sites of infection. Of concern,

recent reports from Asian countries have demonstrated that hvKp is

responsible for an increasing number of health care–associated or

hospital-acquired infections.

hvKp infection initially was characterized and distinguished from

traditional infections caused by cKp strains by its (1) presentation as

community-acquired monomicrobial pyogenic liver abscess (Fig. 161-1,

top), (2) occurrence in patients lacking a history of hepatobiliary

disease, and (3) propensity for metastatic spread to distant sites.

Subsequently, the hvKp pathotype has been recognized as the cause

of extrahepatic abscesses and infections with or without liver involvement, including pneumonia; meningitis (in the absence of trauma or

1271CHAPTER 161 Diseases Caused by Gram-Negative Enteric Bacilli

Bacteremia Klebsiella infection at any site can produce bacteremia. Infections of the urinary tract, respiratory tract, and abdomen

(especially hepatic abscess) each account for 15–30% of episodes of

Klebsiella bacteremia. Intravascular device–related infections account

for another 5–15% of episodes, and surgical site and miscellaneous

infections account for the rest. Klebsiella is an occasional cause of sepsis

in neonates and of bacteremia in neutropenic patients. However, like

enteric GNB in general, Klebsiella rarely causes endocarditis or other

endovascular infections, although the endocarditis can involve extensive valvular destruction.

■ DIAGNOSIS

Klebsiellae are readily isolated and identified in the laboratory. These

organisms usually ferment lactose, although the subspecies rhinoscleromatis and ozaenae are nonfermenters and are indole-negative. hvKp

usually possesses a hypermucoviscous phenotype (Fig. 161-1, bottom),

although the sensitivity and specificity of the string test are less than

optimal. Identification of the combination of the biomarkers iucA,

iroB, peg-344, rmpA, and rmpA2 is presently the most accurate means

to identify hvKp, although currently, this test is not routinely available.

TREATMENT

Klebsiella Infections

K. (formerly Enterobacter) aerogenes has a similar resistance profile

to E. cloacae, the treatment of which is discussed below. K. pneumoniae and K. oxytoca have similar antibiotic resistance profiles; both

are intrinsically resistant to ampicillin. The prevalence of acquired

resistance in K. pneumoniae and K. oxytoca is generally >30%

for amoxicillin-clavulanate, ampicillin-sulbactam, nitrofurantoin,

and TMP-SMX and ~10−20% for fluoroquinolones, piperacillintazobactam, fosfomycin, and omadacycline.

USNHSN data from 2015−2017 identified 25% of K. pneumoniae

as ESBL-producing strains; higher rates are reported from Asia,

South America, and Africa. Although prevalent ESBL-producing

strains are greatest in LTCF, isolates of cKp that produce CTX-M

ESBLs are increasingly described from the community. Oral treatment for infection due to ESBL-producing strains is more challenging with Klebsiella than with E. coli because of the comparatively

poor activity of nitrofurantoin, the lesser activity of fosfomycin

(~80%), and limited available data regarding pivmecillinam (>80%)

and omadacycline (75–100% susceptible for ESBL-producing isolates, but 60% if resistant to tetracycline).

Predictably, the ESBL-driven use of carbapenems has selected for

strains of cKp and K. oxytoca that express carbapenemases (8–18%

based on the study and locale, 8.6% prevalence from 2015−2017

USNHSN data). Treatment can be problematic for such organisms,

especially those with a metallo-β-lactamase (e.g., NDM), for which

the highest prevalences are in cKp and K. oxytoca isolates from

Eastern Europe and Asia and among health care–associated isolates.

Likewise, hvKp strains from Asia are also increasingly reported to

produce ESBLs and carbapenemases.

Treatment options for carbapenem-resistant Klebsiella are similar to those described for E. coli and depend on the class of carbapenemase produced (see “Carbapenemase” above); consultation

with relevant experts is advised. For carbapenem-sensitive strains,

the most predictably active agents include carbapenems, amikacin, plazomicin, ceftazidime-avibactam, ceftolozane-tazobactam,

meropenem-vaborbactam, imipenem/cilastatin-relebactam, polymyxins, cefiderocol, tigecycline, eravacycline, and omadacycline. Empirical

treatment decisions for the critically ill patient should be dictated by

local susceptibility patterns and patient-specific risk factors.

PROTEUS INFECTIONS

Proteus species are part of the colonic flora of a wide variety of mammals, birds, fish, and reptiles. The ability of these GNB to generate

histamine from contaminated fish has implicated them in the pathogenesis of scombroid (fish) poisoning (Chap. 460).

neurosurgery); endophthalmitis (Fig. 161-1, middle); splenic, psoas,

prostatic, epidural, and brain abscesses; and necrotizing fasciitis.

Survivors often suffer catastrophic morbidity, such as vision loss and

major neurologic sequelae. Most recently, clinicians are faced with

an even greater challenge—the confluence of antimicrobial resistance

determinants possessed by cKp and the virulence factors possessed by

hvKp on the same or coexisting plasmids. The result is the evolution of

MDR and XDR hvKp.

K. pneumoniae subspecies rhinoscleromatis is the causative agent of

rhinoscleroma, a granulomatous mucosal upper-respiratory infection

that progresses slowly (over months or years) and causes necrosis

and occasionally obstruction of the nasal passages. K. pneumoniae

subspecies ozaenae has been implicated as a cause of chronic atrophic rhinitis and rarely of invasive disease in compromised hosts. K.

(Calymmatobacterium) granulomatis, a sexually transmitted pathogen,

is the causative agent of granuloma inguinale (donovanosis) that results

in chronic genital ulcers (Chap. 173). These Klebsiella pathotypes are

usually isolated from patients in tropical climates and are genomically

distinct from both cKp and hvKp.

■ INFECTIOUS SYNDROMES

Pneumonia Although cKp accounts for only a small proportion of

cases of community-acquired pneumonia in Western countries (Chap.

126), cKP and K. oxytoca are common causes of pneumonia among

LTCF residents and hospitalized patients because of increased rates of

oropharyngeal colonization with these organisms in such individuals.

Mechanical ventilation is an important risk factor. In Asia and South

Africa, community-acquired pneumonia due to hvKp is becoming

increasingly common, rivaling Streptococcus pneumoniae, and may

occur in younger patients with no underlying disease. Klebsiella is also

a common cause of pneumonia in severely malnourished children in

developing countries.

As in all pneumonias due to enteric GNB, typical manifestations

include production of purulent sputum and evidence of airspace disease.

Presentation with earlier, less extensive infection is now more common

than is the classically described lobar infiltrate, bulging fissure, and currant-jelly sputum. Pulmonary infection due to hvKp that has spread metastatically (e.g., from a hepatic abscess) usually includes nodular bilateral

densities, more commonly in the lower lobes. Pulmonary necrosis, pleural effusion, and empyema can occur with disease progression.

UTI cKP accounts for only 1–2% of UTI episodes among otherwise healthy adults but for 5–17% of episodes of UTI in patients with

anatomic and functional abnormalities of the urinary tract, including

indwelling urinary catheter use (complicated UTI). UTI due to hvKp

presents more commonly as renal or prostatic abscess due to bacteremic spread than as ascending infection from the urethra and bladder.

Abdominal Infection cKp causes a spectrum of abdominal infections similar to that caused by E. coli but is less frequently isolated from

such infections than is E. coli. hvKp is a common cause of monomicrobial community-acquired pyogenic liver abscess; in the Asian Pacific

Rim, it has been recovered with steadily increasing frequency over

the past two decades, replacing E. coli as the most common pathogen

causing this syndrome. hvKp also is increasingly described as a cause

of spontaneous bacterial peritonitis and splenic abscess.

Other Infections When cKp and K. oxytoca cause cellulitis or soft

tissue infection, the process most frequently involves devitalized tissue

(e.g., decubitus and diabetic ulcers, burn wounds) and immunocompromised hosts. cKp and K. oxytoca cause some cases of surgical site

infection and nosocomial sinusitis as well as occasional cases of osteomyelitis contiguous to soft tissue infection, nontropical myositis, and

meningitis (during the neonatal period and after neurosurgery). By

contrast, hvKp has become an important cause of community-acquired

monomicrobial necrotizing fasciitis, meningitis, endophthalmitis

(Fig. 161-1, middle), and abscesses within the brain, subdural space,

and epidural space, particularly in the Asian Pacific Rim but also globally. Cytotoxin-producing strains of K. oxytoca have been implicated

as a cause of non–C. difficile antibiotic-associated hemorrhagic colitis.