CHAPTER 58: DISEASES CAUSED BY GRAM-NEGATIVE ENTERIC BACILLI

Escherichia coli, Klebsiella, Proteus, Enterobacter, Serratia, Citrobacter, Morganella, Providencia, Cronobacter, and Edwardsiella are gram-negative enteric bacilli that are members of the family Enterobacteriaceae. Salmonella, Shigella, and Yersinia, also in the family Enterobacteriaceae, are discussed in Chaps. 62, 63, and 68, respectively. These pathogens cause a wide variety of infections involving diverse anatomic sites in both healthy and compromised hosts. Increasing antimicrobial resistance in this group has put them at the forefront of an evolving public health crisis. In addition, new infectious syndromes have emerged. Therefore, a thorough knowledge of clinical presentations and appropriate therapeutic choices is necessary for optimal outcomes.

EPIDEMIOLOGY

E. coli, Klebsiella, Proteus, Enterobacter, Serratia, Citrobacter, Morganella, Providencia, Cronobacter, and Edwardsiella are components of the normal animal and human colonic microbiota and/or the microbiota of a variety of environmental habitats, including long-term-care facilities (LTCFs) and hospitals. As a result, except for certain pathotypes of intestinal pathogenic E. coli, these genera are global pathogens. The incidence of infection due to these agents is increasing because of the combination of an aging population and increasing antimicrobial resistance. In healthy humans, E. coli is the predominant species of gram-negative bacilli (GNB) in the colonic flora; Klebsiella and Proteus are less prevalent. GNB (primarily E. coli, Klebsiella, and Proteus) only transiently colonize the oropharynx and skin of healthy individuals. In contrast, in LTCFs and hospital settings, a variety of GNB emerge as the dominant microbiota of both mucosal and skin surfaces, particularly in association with antimicrobial use, severe illness, and extended length of stay. LTCFs are emerging as an important reservoir for resistant GNB. This colonization may lead to subsequent infection; for example, oropharyngeal colonization may lead to pneumonia. Interestingly, the use of ampicillin or amoxicillin was associated with an increased risk of subsequent infection due to the hypervirulent variant of Klebsiella pneumoniae in Taiwan; this association suggests that changes in the quantity or prevalence of ­colonizing bacteria may be important. Serratia and Enterobacter infection may be acquired through a variety of infusates (e.g., medications, blood products). Edwardsiella infections are acquired through freshwater and marine environment exposures and are most common in Southeast Asia.

STRUCTURE AND FUNCTION

Enteric GNB possess an extracytoplasmic outer membrane, which consists of a lipid bilayer with associated proteins, lipoproteins, and polysaccharides (capsule, lipopolysaccharide). The outer membrane interfaces with the external environment, including the human host. A variety of components of the outer membrane are critical determinants in pathogenesis (e.g., capsule) and antimicrobial resistance (e.g., permeability barrier, efflux pumps).

PATHOGENESIS

Multiple bacterial virulence factors are required for the pathogenesis of infections caused by GNB. Possession of specialized virulence genes defines pathogens and enables them to infect the host efficiently. Hosts and their cognate pathogens have been co-adapting throughout evolutionary history. During the host-pathogen “chess match” over time, various and redundant strategies have emerged in both the pathogens and their hosts (Table 58-1).

Intestinal pathogenic mechanisms are discussed below. The members of the Enterobacteriaceae family that cause extraintestinal infections are primarily extracellular pathogens and therefore share certain pathogenic features. Innate immunity (including the activities of complement, antimicrobial peptides, and professional phagocytes) and humoral immunity are the principal host defense components. Both susceptibility to and severity of infection are increased with dysfunction or deficiencies of these components. By contrast, the virulence traits of intestinal pathogenic E. coli—i.e., the distinctive strains that can cause diarrheal disease—are for the most part different from those of extraintestinal pathogenic E. coli (ExPEC) and other GNB that cause extraintestinal infections. This distinction reflects site-specific differences in host environments and defense mechanisms.

A given strain usually possesses multiple adhesins for binding to a variety of host cells (e.g., in E. coli: type 1, S, and F1C fimbriae; P pili). Nutrient acquisition (e.g., of iron via siderophores) requires many genes that are necessary but not sufficient for pathogenesis. The ability to resist the bactericidal activity of complement and phagocytes in the absence of antibody (e.g., as conferred by capsule or O antigen of lipopolysaccharide) is one of the defining traits of an extracellular pathogen. Tissue damage (e.g., as mediated by hemolysin in the case of E. coli) may facilitate spread within the host. Without doubt, many important virulence genes await identification (Chap. 2).

The ability to induce septic shock is another defining feature of these genera. GNB are the most common causes of this potentially lethal syndrome. Pathogen-associated molecular pattern molecules (PAMPs; e.g., the lipid A moiety of lipopolysaccharide) stimulate a proinflammatory host response via pattern recognition receptors (e.g., Toll-like or C-type lectin receptors) that activate host defense signaling pathways; if overly exuberant, this response results in shock (Chap. 19). Direct bacterial damage of host tissue (e.g., by toxins) or collateral damage from the host response can result in the release of damage-associated molecular pattern molecules (DAMPs; e.g., HMGB1) that can propagate a detrimental proinflammatory host response.

Many antigenic variants (serotypes) exist in most genera of GNB. For example, E. coli has more than 150 O-specific antigens and more than 80 capsular antigens. This antigenic variability, which permits immune evasion and allows recurrent infection by different strains of the same species, has impeded vaccine development (Chap. 5).

INFECTIOUS SYNDROMES

E. coli can cause either intestinal or extraintestinal infection, depending on the particular pathotype, and Edwardsiella tarda can cause both intestinal and extraintestinal infection. Klebsiella primarily causes extraintestinal infection, but hemorrhagic colitis has been associated with a toxin-producing variant of Klebsiella oxytoca. Depending on both the host and the pathogen, nearly every organ or body cavity can be infected with GNB. E. coli and—to a lesser degree—Klebsiella account for most extraintestinal infections due to GNB and are the most virulent pathogens within this group; this virulence is demonstrated by the ability of E. coli and Klebsiella pneumoniae (primarily the hypervirulent variant) to cause severe infections in healthy, ambulatory hosts from the community. However, the other genera are also important, especially among LTCF residents and hospitalized patients, in large part because of the intrinsic or acquired antimicrobial resistance of these organisms and the increasing number of individuals with compromised host defenses. The mortality rate is substantial in many GNB infections and correlates with the severity of illness. Especially problematic are pneumonia and bacteremia (arising from any source), particularly when complicated by organ failure (severe sepsis) and/or shock, for which the associated mortality rates are 20–50%.

DIAGNOSIS

Isolation of GNB from sterile sites almost always implies infection, whereas their isolation from nonsterile sites, particularly from open soft-tissue wounds and the respiratory tract, requires clinical correlation to differentiate colonization from infection. Tentative laboratory identification based on lactose fermentation and indole production (described for each genus below), which usually is possible before final identification of the organism and determination of its antimicrobial susceptibilities, may help to guide empirical antimicrobial therapy.

TREATMENT

PREVENTION

(See also Chap. 17) Avoidance of inappropriate antimicrobial use is a key measure in preventing infections due to antimicrobial-resistant strains and the further development of antimicrobial resistance. Antimicrobial stewardship programs should be adopted to facilitate achievement of this goal. Diligent adherence to hand-hygiene protocols by health care personnel, cleaning/disinfection of objects that come into contact with patients (e.g., stethoscopes and blood pressure cuffs), and contact precautions should be implemented for patients colonized or infected with carbapenem-resistant (and perhaps other XDR) GNB. Avoidance of the use of indwelling devices (e.g., urinary and intravascular catheters, endotracheal tubes) and, when such devices are necessary, placement according to an appropriate protocol decrease infection risk. Likewise, protocols for daily use evaluation and removal as soon as possible should be implemented. Patient positioning (e.g., head of bed at ≥30°) and good oral hygiene decrease the incidence of pneumonia among ventilated patients. Increasing data support the implementation of universal decolonization to prevent infection in ICU patients.

Strains of E. coli are united by a core genome of ~2000 genes. A strain’s ability to cause infections and the nature of such infections are defined by ancillary genes that encode various virulence factors. This experiment of nature is fluid and ongoing, as demonstrated by the recent evolution of Shiga toxin–producing enteroaggregative E. coli.

COMMENSAL STRAINS

For the most part, commensal E. coli variants, which constitute the bulk of the normal facultative intestinal flora in most humans, confer benefits to the host (e.g., resistance to colonization with pathogenic organisms). These strains generally lack the specialized virulence traits that enable extraintestinal and 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, such as 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 community-acquired and health care–associated bacterial infections. The emerging propensity of these strains to acquire new antimicrobial resistance mechanisms (e.g., ESBL and carbapenemase production) has posed challenges in managing ExPEC infection. One clonal group—ST131, the members of which are usually resistant to fluoroquinolones and increasingly express an ESBL (CTX-M)—has undergone global dissemination.

Like commensal E. coli (but in contrast to intestinal pathogenic E. coli), ExPEC strains are often found in the intestinal flora of healthy individuals and 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 genes encoding diverse extrain-testinal virulence factors that enable the bacteria to cause infections outside the gastrointestinal tract in both normal and compromised hosts (Table 58-1). These virulence genes define ExPEC and, for the most part, are distinct from those that enable intestinal pathogenic strains to cause diarrheal disease (Table 58-2). 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. An exceedingly common infection among ambulatory patients, UTI accounts for 1% of ambulatory care visits in the United States and is second only to lower respiratory tract infection among infections responsible for hospitalization. UTIs are best considered by clinical syndrome (e.g., uncomplicated cystitis, pyelonephritis, and catheter-associated UTIs) and within the context of specific hosts (e.g., premenopausal women, compromised hosts; Chap. 33). 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 an estimated 6–8 million episodes of uncomplicated cystitis in premenopausal women. 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 suprapubic pain. Fever and/or back pain suggests progression to pyelonephritis. Even with appropriate treatment of pyelonephritis, fever may take 5–7 days to resolve completely. Persistently elevated or increasing fever and neutrophil counts should prompt evaluation for intrarenal or perinephric abscess and/or obstruction. Renal parenchymal damage and loss of renal function during pyelonephritis occur primarily 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 are standard. Prostatic infection is a potential complication of UTI in men. The diagnosis and treatment of UTI, as detailed in Chap. 33, 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 often occurs) in combination with other facultative and/or anaerobic members of the intestinal flora (Chap. 29).

Pneumonia

E. coli is not usually considered a cause of pneumonia (Chap. 21). Indeed, enteric GNB account for only 1–3% of cases of community-acquired pneumonia, in part because these organisms only transiently colonize the oropharynx 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. 17), 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 to bacterial cytotoxins, is common. Despite significant institutional variation, E. coli is generally the third or fourth most commonly isolated 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. 36) E. coli is one of the two leading causes of neonatal meningitis, the other being 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 commonly occurs. After the first month of life, E. coli meningitis is uncommon, occurring predominantly in the setting of surgical or traumatic disruption of the meninges or in the presence of cirrhosis. In patients with cirrhosis who develop meningitis, the meninges are presumably seeded as a result of poor hepatic clearance of portal vein bacteremia.

Cellulitis/musculoskeletal infection

E. coli contributes frequently to infections of decubitus ulcers and occasionally to infections of ulcers and wounds of the lower extremity 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. Hematogenously acquired osteomyelitis, especially of vertebral bodies, is more commonly caused by E. coli than is generally appreciated; this organism accounts for up to 10% of cases in some series (Chap. 28). E. coli occasionally causes orthopedic device–associated infection or septic arthritis and rarely causes hematogenous myositis. Upper-leg myositis or fasciitis 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 seed 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 primary infection at any extraintestinal site. In addition, primary E. coli bacteremia can arise from percutaneous intravascular devices or transrectal prostate biopsy or from the increased intestinal mucosal permeability seen in neonates and in the settings of neutropenia and chemotherapy-induced mucositis, trauma, and burns. Roughly equal proportions of E. coli bacteremia cases originate in the community and in health care settings. In most studies, E. coli and Staphylococcus aureus are the two most common blood isolates of clinical significance. Isolation of E. coli from the blood is almost always clinically significant and is typically accompanied by the sepsis syndrome, severe sepsis (sepsis-induced dysfunction of at least one organ or system), or septic shock (Chap. 19).

The urinary tract is the most common source of 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 biliary obstruction (stones, tumor) and overt bowel disruption, which typically are readily apparent, are responsible for many of these cases, some abdominal sources (e.g., abscesses) are remarkably silent clinically and require identification via imaging studies (e.g., CT). Therefore, the physician should be cautious in designating the urinary tract as the source of E. coli bacteremia in the absence of characteristic signs and symptoms of UTI. Soft tissue, bone, pulmonary, 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 easily identified 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

Pathotypes

Certain strains of E. coli are capable of causing diarrheal disease. Other important intestinal pathogens are discussed in Chaps. 30, 31, and 62, 63, 64, 65. At least in the industrialized world, intestinal pathogenic strains of E. coli are rarely encountered in the fecal flora of healthy persons and instead appear to be essentially obligate 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 of enterohemorrhagic E. coli (EHEC) and the recently evolved Shiga toxin–producing enteroaggregative E. coli (STEAEC); (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. Transmission occurs predominantly via contaminated food and water for ETEC, STEC/EHEC/STEAEC, EIEC, and EAEC and by person-to-person spread for EPEC (and occasionally STEC/EHEC/STEAEC). Gastric acidity confers some protection against infection; therefore, persons with decreased stomach acid levels are especially susceptible. Humans are the major reservoir (except for STEC/EHEC, with regard to which bovines are the main concern); host range appears to be dictated by species-specific attachment factors. Although there is some overlap, each pathotype possesses a largely unique combination of virulence traits that results in a distinctive intestinal pathogenic mechanism (Table 58-2). These strains are largely incapable of causing disease outside the intestinal tract. Except in the cases of STEC/EHEC/STEAEC and EAEC, disease due to this group of pathogens occurs primarily in developing countries.

Enterohemorrhagic E. Coli/Shiga Toxin–Producing Enteroaggregative E. Coli

STEC/EHEC/STEAEC strains constitute an emerging group of pathogens that can cause hemorrhagic colitis and the hemolytic-uremic syndrome (HUS). Several large outbreaks resulting from the consumption of fresh produce (e.g., lettuce, spinach, sprouts) and of undercooked ground beef have received significant attention in the media. An outbreak in central Europe in 2011 due to STEAEC (O104:H4) that was probably transmitted by sprouts, with some subsequent human-to-human transmission, resulted in more than 800 cases of HUS and 54 deaths. Within this group of organisms, O157:H7 is the most prominent serotype, but many other serotypes have also been associated with these syndromes, including O6, O26, O45, O55, O91, O103, O111, O113, O121, O145, and OX3.

The ability of STEC/EHEC/STEAEC to produce Shiga toxin (Stx2 and/or Stx1) or related toxins is a critical factor in the occurrence of clinical disease. Shigella dysenteriae strains that produce the closely related Shiga toxin Stx can cause the same syndrome. Stx2 and its Stx2C variant (which may be variably present in combination with Stx2 and/or Stx1) appear to be more important than Stx1 in the development of HUS. All Shiga toxins studied to date are multi-mers comprising one enzymatically active A subunit 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 A subunit cleaves an adenine from the host cell’s 28S rRNA, thereby irreversibly inhibiting ribosomal function and potentially leading to apoptosis. Stx2-mediated activation of complement may also play a role in the development of HUS.

Additional properties, such as acid tolerance and epithelial cell adherence, are necessary for full pathogenicity among STEC strains. Most disease-causing isolates possess the chromosomal locus for enterocyte effacement (LEE). This pathogenicity island was first described in EPEC strains and 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. STEAEC (LEE-negative) evolved from EAEC via the acquisition of a number of genes, including those that encode Stx2, the Iha adhesin, tellurite resistance, a type VI secretion system, and the CTX-M-15 ESBL.

Domesticated ruminant animals, particularly cattle and young calves, serve as the major reservoir for STEC/EHEC. Ground beef—the most common food source of STEC/EHEC strains—is often contaminated during processing. Furthermore, manure from cattle or other animals (including that in the form of fertilizer) can contaminate produce (potatoes, lettuce, spinach, sprouts, fallen fruits, nuts, strawberries), and fecal runoff from this source can contaminate water systems. Dairy products and petting zoos are additional sources of infection. By contrast, humans appear to be the reservoir for STEAEC. It is estimated that <10² colony-forming units (CFU) of STEC/EHEC/STEAEC 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 occurs both as outbreaks and as sporadic cases, with a peak incidence in the summer months.

In contrast to other intestinal pathotypes, STEC/EHEC/STEAEC causes infections more frequently in industrialized countries than in developing regions. O157:H7 strains are the fourth most commonly reported cause of bacterial diarrhea in the United States (after Campylobacter, Salmonella, and Shigella). Colonization of the colon and perhaps the ileum results in symptoms after an incubation period of 3 or 4 days. Colonic edema and an initial nonbloody secretory diarrhea may develop into the STEC/EHEC/STEAEC hallmark syndrome of grossly bloody diarrhea (identified by history or examination) in >90% of cases. 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. An uncommon but feared complication of this infection is HUS, which occurs 2–14 days after diarrhea in 2–8% of cases, most often affecting very young or elderly patients. Distinctive features of STEAEC infection, as compared with classical STEC/EHEC disease, include a higher incidence among adults, especially young women, and a higher rate of HUS (~20%). It is estimated that >50% of all cases of HUS in the United States and 90% of HUS cases in children are caused by STEC/EHEC. This complication 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, thrombocytopenia, renal failure, and encephalopathy. Although the mortality rate with dialysis support is <10%, residual renal and neurologic dysfunction may persist.

Enterotoxigenic E. coli

In tropical or developing countries, ETEC is a major cause of endemic diarrhea. 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, infection usually follows travel to endemic areas, although occasional food-borne outbreaks occur. 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 poorly cooked, unpeeled, or unrefrigerated (Chap. 6). ETEC infection is uncommon in the United States, but outbreaks secondary to consumption of food products imported from endemic areas have occurred. A large inoculum (10⁶–10¹⁰ CFU) is needed to produce disease, which usually develops after an incubation period of 12–72 h.

After adherence of ETEC via colonization factors (e.g., CFA/I, CS1-6), disease is mediated primarily by a heat-labile toxin (LT-1) and/or a heat-stable toxin (STa) that causes net fluid secretion via activation of adenylate cyclase (LT-1) and/or guanylate cyclase (STa) in the jejunum and ileum. The result is watery diarrhea accompanied by cramps. LT-1 consists of an A and a 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 whose biologic activity is mediated by binding to the guanylate cyclase C found in the brush-border membrane of enterocytes and results in increased intracellular concentrations of cyclic GMP. 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 ranges from a mild illness to a life-threatening cholera-like syndrome. Although symptoms are usually self-limited (typically lasting for 3 days), infection may result in significant morbidity and mortality (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 some outbreaks in hospital nurseries) in industrialized countries in the 1940s and 1950s. At present, EPEC infection is an uncommon cause of diarrhea in developed countries but is an important cause of diarrhea (both sporadic and epidemic) among infants in developing countries. Breast-feeding diminishes the incidence of EPEC infection. Rapid person-to-person spread may occur. Upon colonization of the small bowel, symptoms develop after a brief incubation period (1 or 2 days). Initial localized adherence via 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. Diarrheal stool often contains 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 cause of diarrhea, is rarely identified in the United States, although a few food-related outbreaks have been described. In developing countries, sporadic disease is infrequently recognized in children and travelers. EIEC shares many genetic and clinical features with Shigella, both of which evolved from a common ancestor. However, unlike Shigella, EIEC produces disease only with a large inoculum (10⁸–10¹⁰ CFU), with onset generally following an incubation period of 1–3 days. Initially, enterotoxins are believed to induce secretory small-bowel diarrhea. Subsequently, colonization and invasion of the colonic mucosa, followed by replication therein and cell-to-cell spread, result in the development of inflammatory colitis characterized by fever, abdominal pain, tenesmus, and scant stool containing mucus, blood, and inflammatory cells. Symptoms are usually self-limited (7–10 days).

Enteroaggregative and diffusely adherent E. coli

EAEC has been described primarily in developing countries and in young children. However, recent studies indicate that it may be a relatively common cause of diarrhea in all age groups in industrialized countries. EAEC has also 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, malnourished, and HIV-infected hosts. In vitro, the organisms 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 part by the transcriptional activator AggR and include the aggregative adherence fimbriae (AAF/I-III); the Hda adhesin; the mucinase Pic; the enterotoxins Pet, EAST-1, ShET1, and HlyE; and dispersin, an antiaggregation protein that promotes mucosal spread. Some strains of DAEC are capable of causing diarrheal disease, primarily in children 2–6 years of age in some developing ­countries, and may perhaps cause traveler’s diarrhea. The Afa/Dr adhesins may contribute to the pathogenesis of such infections.

Diagnosis

A practical approach to the evaluation of diarrhea is to distinguish noninflammatory from inflammatory cases; the latter is suggested by grossly bloody or mucoid stool or a positive test for fecal leukocytes (Chap. 30). ETEC, EPEC, and DAEC cause noninflammatory diarrhea and are uncommon in the United States; in this country, the incidence of EAEC infection, which also causes noninflammatory diarrhea, may be underrecognized. The diagnosis of these infections requires specialized assays (e.g., polymerase chain reaction–based tests for pathotype-specific genes) that are not routinely available and are rarely needed because the diseases are self-limited. ETEC causes the majority and EAEC a minority of cases of noninflammatory traveler’s diarrhea. Definitive diagnosis generally is not necessary. Empirical antimicrobial (or symptom-based) treatment, along with rehydration therapy, is a reasonable approach. If diarrhea persists for >10 days despite treatment, Giardia or Cryptosporidium (or, in immunocompromised hosts, certain other microbial agents) should be sought. The diagnosis of infection with EIEC, a rare cause of inflammatory diarrhea in the United States, also requires specialized assays. The CDC now recommends that all patients with community-acquired diarrhea, whether inflammatory or not, be evaluated for STEC/EHEC/STEAEC infection by simultaneous culture (which is important for outbreak detection and control) and assay for the detection of Shiga toxin or its associated genes. The reasons for this recommendation are that bloody stool is not always present and detection of fecal white blood cells is not optimally sensitive for the diagnosis of STEC/EHEC/STEAEC infection. The use of both tests increases the rate of identification of infection over rates obtained 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 the culture of non-O157 strains. Detection of Shiga toxins or toxin genes via DNA-based, enzyme-linked immunosorbent, and cytotoxicity assays offers the advantages of rapidity plus detection of non-O157 STEC/EHEC/STEAEC strains. Specimens positive for toxin but culture-negative for O157 should be forwarded to the local or state public health laboratory.

K. pneumoniae is the most important Klebsiella species from a medical standpoint, causing community-acquired, LTCF-acquired, and nosocomial infections. K. oxytoca is primarily a pathogen in LTCF and hospital settings. Klebsiella species are broadly prevalent in the environment and colonize 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; the skin is usually colonized only transiently. Person-to-person spread is the predominant mode of acquisition. Most Klebsiella infections in Western countries are caused by “classic” 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 subsequent bacteremia. cKP strains have gained notoriety because their propensity for acquiring antimicrobial resistance determinants makes treatment challenging. Clonal group ST258, many members of which produce the KPC carbapenemase, is undergoing international dissemination. The spread of NDM-1 carbapenemase-producing strains from India in association with medical tourism has captured the attention of physicians and the lay press.

cKP strains appear to be phenotypically and clinically distinct from hypervirulent K. pneumoniae (hvKP), an emerging variant that was first recognized in Taiwan in 1986. Although hvKP infections have occurred globally in all ethnic groups, the majority have been reported in the Asian Pacific Rim. This concentration of cases raises the question of whether a geo-specific distribution of the organism or increased susceptibility of Asian hosts is responsible. In contrast to the usual health care–associated venue for cKP infections in the West, hvKP causes serious life- and organ-threatening infections in younger, healthy individuals from the community and can spread metastatically from primary sites of infection. hvKP infection initially was characterized and distinguished from traditional infections due to cKP by (1) presentation as community-acquired pyogenic liver abscess (Fig. 58-1, top), (2) occurrence in patients lacking a history of hepatobiliary disease, and (3) a propensity for metastatic spread to distant sites (e.g., eyes, central nervous system, lungs), which occurred in 11–80% of cases. More recently, this variant has been recognized as the cause of a variety of serious community-acquired extrahepatic abscesses/infections in the absence of liver involvement, including pneumonia, meningitis, endophthalmitis (Fig. 58-1, middle), splenic abscess, and necrotizing fasciitis. The affected individuals often have diabetes mellitus and are of Asian ethnicity; however, nondiabetics and all ethnic groups can be affected. Survivors often suffer catastrophic morbidity, such as loss of vision and neurologic sequelae.

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. These two K. pneumoniae subspecies 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. 21), cKP and K. oxytoca are common causes of pneumonia among LTCF residents and hospitalized patients because of increased rates of oropharyngeal colonization. Mechanical ventilation is an important risk factor. In Asia and South Africa, community-acquired pneumonia due to hvKP is becoming increasingly common and often occurs 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, production of purulent sputum and evidence of airspace disease are typical. Presentation with earlier, less extensive infection is now more common than that with the classically described lobar infiltrate and bulging fissure. 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 complicated UTI, including infections associated with indwelling urinary catheters. UTI due to hvKP presents more commonly as renal or prostatic abscess due to bacteremic spread than as ascending infection.

Abdominal infection

cKP causes a spectrum of abdominal infections similar to that caused by E. coli but is less frequently isolated from these infections. hvKP is a common cause of monomicrobial community-acquired pyogenic liver abscess and in the Asian Pacific Rim has been recovered with steadily increasing frequency over the past two decades, replacing E. coli as the most common pathogen causing this syndrome. hvKP is increasingly described as a cause of spontaneous bacterial peritonitis and splenic abscess.

Other infections

cKP- and K. oxytoca–mediated cellulitis or soft tissue infection most frequently affects devitalized tissue (e.g., decubitus and diabetic ulcers, burn sites) and immunocompromised hosts. cKP and K. oxytoca cause some cases of surgical site infection and nosocomial sinusitis in addition to occasional cases of osteomyelitis contiguous to soft tissue infection, nontropical myositis, and meningitis (both during the neonatal period and after neurosurgery). By contrast, hvKP has become an important cause of community-acquired monomicrobial necrotizing fasciitis; meningitis; brain, subdural, and epidural abscess; and endophthalmitis (Fig. 58-1, middle), particularly in the Asian Pacific Rim but also globally. Cytotoxin-producing strains of K. oxytoca have been implicated as a cause of hemorrhagic antibiotic-associated non–C. difficile colitis.

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 a cause of sepsis in neonates and of bacteremia in neutropenic patients. Like enteric GNB in general, Klebsiella rarely causes endocarditis or endovascular infection.

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. 58-1, bottom), although the sensitivity and specificity of this test are undefined and probably less than optimal. A better diagnostic test for hvKP is desirable.

TREATMENT

Proteus mirabilis causes 90% of Proteus infections, which occur in the community, LTCFs, and hospitals. Proteus vulgaris and Proteus penneri are associated primarily with infections acquired in LTCFs or hospitals. 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. 136). P. mirabilis colonizes healthy humans (prevalence, 50%), whereas P. vulgaris and P. penneri are isolated primarily from individuals with underlying disease. The urinary tract is by far the most common site of Proteus infection, with adhesins, flagella, IgA-IgG protease, iron acquisition systems, and urease representing the principal known urovirulence factors. Proteus less commonly causes infection at a variety of other extraintestinal sites.

INFECTIOUS SYNDROMES

UTI

Most Proteus infections arise from the urinary tract. P. mirabilis causes only 1–2% of UTIs in healthy women, and Proteus species ­collectively cause only 5% of hospital-acquired UTIs. However, Proteus is responsible for 10–15% of cases of complicated UTI, ­primarily those associated with catheterization; indeed, among UTI isolates from chronically catheterized patients, the prevalence of Proteus is 20–45%. This high prevalence is due in part to bacterial production of urease, which hydrolyzes urea to ammonia and results in alkalization of the urine. Alkalization of urine, in turn, leads to precipitation of organic and inorganic compounds, which contributes to formation of struvite and carbonate-apatite crystals, formation of biofilms on catheters, and/or development of frank calculi. Proteus becomes associated with the stones and biofilms; thereafter, it usually can be eradicated only by removal of the stones or the catheter. Over time, staghorn calculi may form within the renal pelvis and lead to obstruction and renal failure. Thus, urine samples with unexplained alkalinity should be cultured for Proteus, and identification of a Proteus species in urine should prompt consideration of an evaluation for urolithiasis.

Other infections

Proteus occasionally causes pneumonia (primarily in LTCF residents or hospitalized patients), nosocomial sinusitis, intraabdominal abscesses, biliary tract infection, surgical site infection, soft tissue infection (especially decubitus and diabetic ulcers), and osteomyelitis (primarily contiguous); in rare cases, it causes nontropical myositis. In addition, Proteus uncommonly causes neonatal meningitis, with the umbilicus frequently implicated as the source; this disease is often complicated by development of a cerebral abscess. Otogenic brain abscess also occurs.

Bacteremia

The majority of Proteus bacteremia episodes originate from the urinary tract; however, any of the less common sites of infection as well as intravascular devices are also potential sources. Endovascular infection is rare. Proteus species are occasional agents of sepsis in neonates and of bacteremia in neutropenic patients.

DIAGNOSIS

Proteus is readily isolated and identified in the laboratory. Most strains are lactose negative, produce H₂S, and demonstrate characteristic swarming motility on agar plates. P. mirabilis and P. penneri are indole negative, whereas P. vulgaris is indole positive. The inability to produce ornithine decarboxylase differentiates P. penneri from P. mirabilis.

TREATMENT

E. cloacae and E. aerogenes are responsible for most Enterobacter infections (65–75% and 15–25%, respectively); Cronobacter sakazakii (formerly Enterobacter sakazakii) and Enterobacter gergoviae are less commonly isolated (1% for each). Enterobacter species cause primarily health care–related infections. The organisms are widely prevalent in foods, environmental sources (including equipment at health care facilities), and a variety of animals. Few healthy humans are colonized, but the percentage increases significantly with LTCF residence or hospitalization. Although colonization is an important prelude to infection, direct introduction via IV lines (e.g., contaminated IV fluids or pressure monitors) also occurs. Extensive antibiotic resistance has developed in Enterobacter species and probably has contributed to the emergence of the organisms as prominent nosocomial pathogens. Individuals who have previously received antibiotic treatment, have comorbid disease, and are ICU residents are at greatest risk for infection. Enterobacter causes a spectrum of extraintestinal infections similar to that described for other GNB.

INFECTIOUS SYNDROMES

Pneumonia, UTI (particularly catheter-related), intravascular device–related infection, surgical site infection, and abdominal infection (primarily postoperative or related to devices such as biliary stents) are the most common syndromes encountered. Nosocomial sinusitis, meningitis related to neurosurgical procedures (including use of intracranial pressure monitors), osteomyelitis, and endophthalmitis after eye surgery are less frequent. C. sakazakii is associated with neonatal bacteremia, necrotizing enterocolitis, and meningitis (which is often complicated by brain abscess or ventriculitis); contaminated formula has been implicated as a source for such infections. Enterobacter bacteremia can result from infection at any anatomic site. In bacteremia of unclear origin, the contamination of IV fluids or medications, blood components or plasma derivatives, catheter-flushing fluids, pressure monitors, and dialysis equipment should be considered, particularly in an outbreak setting. Enterobacter can also cause bacteremia in neutropenic patients. Enterobacter endocarditis is rare, occurring primarily in association with illicit IV drug use or prosthetic valves.

DIAGNOSIS

Enterobacter is readily isolated and identified in the laboratory. Most strains are lactose positive and indole negative.

TREATMENT

S. marcescens causes the majority (>90%) of Serratia infections; Serratia liquefaciens, Serratia rubidaea, Serratia fonticola, Serratia grimesii, Serratia plymuthica, and Serratia odorifera are isolated occasionally. Serratiae are found primarily in the environment (including in health care institutions), particularly in moist settings. Serratiae have been isolated from a variety of animals, insects, and plants, but healthy humans are rarely colonized. In LTCFs or hospitals, reservoirs for the organisms include the hands and fingernails of health care personnel, food, milk (on neonatal units), sinks, respiratory and other medical equipment or devices, pressure monitors, IV solutions or parenteral medications (particularly those generated by compounding pharmacies), prefilled syringes and multiple-access medication vials (e.g., heparin, saline), blood products (e.g., platelets), hand soaps and lotions, irrigation solutions, and even disinfectants. Infection results from either direct inoculation (e.g., via IV fluid) or colonization (primarily of the respiratory tract). Sporadic infection is most common, but epidemics (often involving MDR strains in adult and neonatal ICUs) and common-source outbreaks also occur. The spectrum of extraintestinal infections caused by Serratia is similar to that for other GNB. Serratia species are usually considered causative agents of health care–associated infection and account for 1–3% of hospital-acquired infections. However, population-based laboratory surveillance studies in Canada and Australia demonstrated that community-acquired infections occur more commonly than was previously appreciated.

INFECTIOUS SYNDROMES

The respiratory tract, the genitourinary tract, intravascular devices, the eye (contact lens–associated keratitis and other ocular infections), surgical wounds, and the bloodstream (from contaminated infusions) are the most common sites of Serratia infection; the former five sites are the most common sources of Serratia bacteremia. Soft tissue infections (including myositis, fasciitis, mastitis), osteomyelitis, abdominal and biliary tract infection (postprocedural), and septic arthritis (primarily from intraarticular injections) occur less commonly. Serratiae are uncommon causes of neonatal or postsurgical meningitis and of bacteremia in neutropenic patients. Endocarditis is rare.

DIAGNOSIS

Serratiae are readily cultured and identified by the laboratory and are usually lactose and indole negative. Some S. marcescens strains and S. rubidaea are red pigmented.

TREATMENT

C. freundii and Citrobacter koseri cause most human Citrobacter infections, which are epidemiologically and clinically similar to Enterobacter infections. Citrobacter species are commonly present in water, food, soil, and certain animals. Citrobacter is part of the normal fecal flora in a minority of healthy humans, but colonization rates are higher in LTCFs and hospitals—the settings in which nearly all Citrobacter infections occur. Citrobacter species account for 1–2% of nosocomial infections. The affected hosts are usually immunocompromised or have comorbid disease. Citrobacter causes extraintestinal infections similar to those described for other GNB.

INFECTIOUS SYNDROMES

The urinary tract accounts for 40–50% of Citrobacter infections. Less commonly involved sites include the biliary tree (particularly with stones or obstruction), the respiratory tract, surgical sites, soft tissue (e.g., decubitus ulcers), the peritoneum, and intravascular devices. Osteomyelitis (usually from a contiguous focus), adult central nervous system infection (from neurosurgical or other types of meningeal disruption), and myositis occur rarely. Citrobacter (primarily C. koseri) also causes 1–2% of neonatal meningitis cases, of which 50–80% are complicated by brain abscess. Further, case reports in adults suggest that C. koseri infection has a predilection for abscess formation. Bacteremia is most often due to UTI, biliary/abdominal infection, or intravascular device infection. Citrobacter occasionally causes bacteremia in neutropenic patients. Endocarditis and endovascular infections are rare.

DIAGNOSIS

Citrobacter species are readily isolated and identified; 35–50% of isolates are lactose positive, and 100% are oxidase negative. C. freundii is indole negative, whereas C. koseri is indole positive.

TREATMENT

M. morganii, Providencia stuartii, and (less frequently) Providencia rettgeri are the members of their respective genera that cause human infections. The epidemiologic associations, pathogenic properties, and clinical manifestations of these organisms resemble those of Proteus species. However, Morganella and Providencia occur more commonly among LTCF residents; to a lesser degree, they affect hospitalized patients. In settings with extensive use of polymyxins and tigecycline, these organisms may become increasingly common because of their intrinsic resistance to these agents.

INFECTIOUS SYNDROMES

These species are primarily urinary tract pathogens, causing UTIs that are most often associated with long-term (>30-day) catheterization. Such infections commonly lead to biofilm formation and catheter encrustation (sometimes causing catheter obstruction) or to the development of struvite bladder or renal stones (sometimes causing renal obstruction and serving as foci for relapse). Morganella is also commonly isolated from snakebite infection. Other, less common infectious syndromes include surgical site infection, soft tissue infection (primarily involving decubitus and diabetic ulcers), burn site infection, pneumonia (particularly ventilator-associated), intravascular device infection, and intraabdominal infection. Rarely, the other extraintestinal infections described for GNB also occur. Bacteremia is uncommon; any infected site can serve as the source, but the urinary tract accounts for most cases, with the next most common sources being surgical site, soft tissue, and hepatobiliary infections.

DIAGNOSIS

M. morganii and Providencia are readily isolated and identified. Nearly all isolates are lactose negative and indole positive.

TREATMENT

E. tarda is the only member of the genus Edwardsiella that is associated with human disease. This organism is found predominantly in freshwater and marine environments and in the associated aquatic animal species. Human acquisition occurs primarily during interaction with these reservoirs and ingestion of inadequately cooked aquatic animals. E. tarda infection is rare in the United States; recently reported cases are mostly from Southeast Asia. This pathogen shares clinical features with Salmonella species (as an intestinal pathogen; Chap. 62), Vibrio vulnificus (as an extraintestinal pathogen; Chap. 65) and Aeromonas hydrophila (as both an intestinal and extraintestinal pathogen; Chap. 55).

INFECTIOUS SYNDROMES

Gastroenteritis is the predominant infectious syndrome (50–80% of infections). Self-limiting watery diarrhea is most common, but severe colitis also occurs. The most common extraintestinal infection is wound infection due to direct inoculation, which is often associated with freshwater, marine, or snake-related injuries. Other infectious syndromes result from invasion of the gastrointestinal tract and subsequent bacteremia. Most afflicted hosts have comorbidities (e.g., hepatobiliary disease, iron overload, cancer, or diabetes mellitus). A primary bacteremic syndrome, sometimes complicated by meningitis, has a 40% case-fatality rate. Visceral (primarily hepatic) and intraperitoneal abscesses also occur. Endocarditis and empyema have been described.

DIAGNOSIS

Although E. tarda can readily be isolated and identified, most laboratories do not routinely seek to identify it in stool samples. Production of hydrogen sulfide is a characteristic biochemical property.

TREATMENT

Species of Hafnia, Kluyvera, Cedecea, Pantoea, Ewingella, Leclercia, and Photorhabdus are occasionally isolated from diverse clinical specimens, including blood, sputum, urine, cerebrospinal fluid, joint fluid, bile, and wounds. These organisms are rare and usually cause infection in a compromised host or in the setting of an invasive procedure or a foreign body. Cephalosporinases from Kluyvera have been implicated as the progenitors of CTX-M ESBLs.