Livro Ajuda

CLINICAL MICROBIOLOGY REVIEWS, Apr. 1997, p. 220–241 Vol. 10, No.
2
0893-8512/97/$04.0010
Copyright q 1997, American Society for Microbiology
Enterobacter spp.: Pathogens Poised To Flourish

at the Turn of the Century
W. EUGENE SANDERS, JR., AND CHRISTINE C. SANDERS*
Department of Medical Microbiology and Immunology, Creighton University
School of Medicine, Omaha, Nebraska 68178
INTRODUCTION .......................................................................................................................................................220
MICROBIOLOGY ......................................................................................................................................................221
The Organism..........................................................................................................................................................221
General Epidemiology ............................................................................................................................................221
Pathogenesis ............................................................................................................................................................222
ANTIMICROBIAL SUSCEPTIBILITY....................................................................................................................223
RESISTANCE..............................................................................................................................................................224
Prevalence ................................................................................................................................................................224
Factors Associated with Resistance......................................................................................................................224
Mechanisms of Resistance.....................................................................................................................................224
Emergence of Resistance During Therapy ..........................................................................................................225
CLINICAL MANIFESTATIONS ..............................................................................................................................225
Bacteremia ...............................................................................................................................................................225
Demographics ......................................................................................................................................................225
Signs, symptoms, and laboratory findings ......................................................................................................226
Portals of entry ...................................................................................................................................................227
Risk factors for development of bacteremia ...................................................................................................227
Determinants of the outcome of bacteremia ...................................................................................................228
Comparisons with bacteremias due to other enteric bacilli .........................................................................229
Lower Respiratory Tract Infections .....................................................................................................................230
Infections of Skin and Soft Tissues......................................................................................................................232
Institutionally acquired infections of surgical wounds and burns ..............................................................232
Soft tissue infections in healthy individuals ...................................................................................................232
Endocarditis.............................................................................................................................................................233
Intra-abdominal Infections....................................................................................................................................233
Urinary Tract Infections ........................................................................................................................................233
Central Nervous System Infections ......................................................................................................................233
Ophthalmic Infections............................................................................................................................................234
Septic Arthritis and Osteomyelitis .......................................................................................................................235
Cotton Fever ............................................................................................................................................................235
Downloaded from https://journals.asm.org/journal/cmr on 23 January 2024 by 200.201.21.10.

Mimicry of Syndromes Commonly Attributed to Other Organisms ...............................................................235
PERSPECTIVE ON THE FUTURE.........................................................................................................................235
ACKNOWLEDGMENTS ...........................................................................................................................................236
REFERENCES ............................................................................................................................................................236
INTRODUCTION more easily treatable infectious agents, such as group A strep-

tococci or Staphylococcus aureus. Other recent developments
Enterobacter spp. have been recognized as increasingly im- include recognition of relatively high rates of coinfection with
portant pathogens in recent years. Most of these organisms are other pathogens, predominance in liver and lung transplant
innately resistant to older antimicrobial agents and have the infections, etiologic role in cotton fever, and increasing inci-
ability to rapidly develop resistance to newer agents. They have dence in a variety of clinical syndromes.
increased in incidence as causes of nosocomial infections in Because of dramatic changes and expansion of the knowl-
general, while multiply resistant strains have emerged in areas edge of Enterobacter spp., we initiated a review of the recent
of high cephalosporin use within the hospital. More recently, it literature. The following databases were searched for the pe-
appears that Enterobacter spp., including multiply resistant riod 1990 to 1995: Medline, Excerpta Medica, Biosis, and Zen-
strains, have spilled over into the community, occasionally in- eca internal database. Approximately 1,300 citations were
fecting otherwise well individuals. These organisms have been identified. Abstracts and summaries were obtained for each
implicated in an increasing number of clinical syndromes, oc- whenever possible. From this compilation, complete publica-
casionally mimicking those traditionally associated with other, tions were selected for review on the basis of their relative
contribution of new knowledge to the field or ability to provide
* Corresponding author. Mailing address: Department of Medical access to the voluminous older literature. Herein, we have
Microbiology and Immunology, Creighton University School of Med- preferentially cited these publications. In addition, we have
icine, 2500 California Plaza, Omaha, NE 68178. Phone: (402) 280- selectively cited older publications that provided necessary
1881. Fax: (402) 280-1225. background to document recent trends, represented major
220
VOL. 10, 1997 ENTEROBACTER SPP. 221
TABLE 1. Differentiation between species of Enterobacter most 43, 77, 80, 91, 125, 126, 137, 140, 167, 204, 208, 229, 237, 238).
commonly recovered from clinical materiala Due to the metabolic diversity within certain species, biotyping
Reaction of:
has been a useful approach for strain identification in certain
settings (125, 126). However, biotyping may not distinguish
Test E. E. E. E. true strain differences in some instances (18, 80, 91, 137, 167,
aerogenes cloacae sakazakii agglomerans
237). The antimicrobial susceptibility pattern is generally un-
Lysine decarboxylase 1 2 2 2 reliable for strain differentiation (18, 80, 91, 167). Different
Arginine dihydrolase 2 1 1 2 patterns can arise from the same strain before and after mu-
Ornithine decarboxylase 1 1 1 2 tation of chromosomal genes affecting the expression of b-lac-
Growth in KCN 1 1 1 Variable tamase (see below). Conversely, similar antimicrobial suscep-
Fermentation of D-sorbitol 1 1 2 Variable tibility patterns can be seen among strains shown to be distinct
a
Data from references 58 to 60 and 136. by a variety of other methods. Typing by bacteriocin or bacte-
riophage pattern or serotyping based upon O or H antigens has
also been developed (43, 77, 126, 137, 144, 238). However, all
original contributions, or complemented the presentation of of these approaches require the use of highly specific reagents
recent material. We review microbiology, epidemiology, anti- that may not be available outside a limited number of refer-
microbial susceptibility and resistance, clinical manifestations, ence laboratories. Furthermore, the susceptibility to bacterio-
and outcomes of therapy, and we conclude with a perspective phages may change with the age of the culture, and some
on the future. strains are not typeable by these methods. Therefore, a num-
ber of molecular approaches to strain identification have been
developed. These include the determination of plasmid pro-
MICROBIOLOGY files with or without analysis of restriction endonuclease pat-
terns, restriction endonuclease analysis of chromosomal DNA,
The Organism pulsed-field gel electrophoresis of genomic DNA restriction
The genus Enterobacter belongs to the family Enterobacteri- fragments, random amplification of polymorphic DNA, ampli-
aceae and can be readily distinguished from the genus Kleb- fication of short interspersed repetitive sequences, and ribotyp-
siella in that the former is motile, usually ornithine decarbox- ing (18, 38, 80, 91, 107, 146, 167, 204, 208, 229, 237). Plasmid
ylase positive, and urease negative (58). Additionally, most profiles, although the easiest to determine, may be of limited
Enterobacter spp. are resistant to cephalothin and cefoxitin value, since many strains of Enterobacter may possess few, if
whereas Klebsiella spp. are often susceptible to these agents. any, plasmids. The utility of other molecular approaches ap-
Although rare strains of Enterobacter may appear nonmotile pears to be maximal when used in concert with biotyping,
and may decarboxylate ornithine slowly, care must be taken serotyping, bacteriocin typing, or another molecular typing
not to confuse these with strains of Klebsiella (55). The antibi- method (18, 80, 91, 167, 237). For epidemiological purposes,
otic susceptibility pattern of such strains can be most useful in the most reliable approach to strain identification appears to
heightening the suspicion that they belong to the genus Enter- be the use of multiple methods coupled with inclusion of con-
obacter (55). trol strains that consist of known related and unrelated strains.
There are 14 species or biogroups of Enterobacter listed in
the most recent edition of Manual of Clinical Microbiology (58). General Epidemiology
Not all of these have been implicated as causes of diseases in
humans. Among those that have, the most commonly encoun- Species of Enterobacter are becoming increasingly important
tered species include Enterobacter aerogenes, Enterobacter clo- nosocomial pathogens (20, 57, 78, 105, 107, 174, 194, 236). In

acae, Enterobacter agglomerans, and Enterobacter sakazakii (7, the preantibiotic era, they were not encountered in surveys of
30, 37, 58, 60, 73, 77, 90, 94, 107, 186, 197, 207). Enterobacter nosocomial bacteremia (153). By the 1970s, it was established
taylorae, Enterobacter gergoviae, Enterobacter asburiae, and En- that Enterobacter spp. could be nosocomial pathogens, al-
terobacter amnigenus are only rarely isolated from clinical spec- though they were much less commonly encountered than Esch-
imens (30, 37, 60, 90). Several tests that can be used to differ- erichia coli and Klebsiella strains (153). Data gathered in the
entiate the various species of Enterobacter that are more National Nosocomial Infections Surveillance System (NNIS)
commonly recovered from clinical specimens are shown in have shown that Enterobacter spp. accounted for 5 to 7% of all
Table 1. nosocomial bacteremias in the United States from 1976 to
E. aerogenes and E. cloacae are by far the most frequently 1989 (105, 106, 153, 194). However, the importance of Enter-
encountered human pathogens among the genus Enterobacter obacter spp. as nosocomial pathogens was highlighted in the
(7, 30, 38, 90, 117, 236). These two species can be readily most recent NNIS data published (105). These data showed
differentiated by tests for lysine decarboxylase and arginine that the increasing importance of Enterobacter spp. as nosoco-
dihydrolase (Table 1). E. sakazakii can be differentiated from mial pathogens was most apparent when isolates from inten-
E. cloacae by its inability to ferment D-sorbitol and its produc- sive care units (ICUs) were considered separately from the
tion of a yellow pigment (58–60, 94). E. agglomerans represents hospital at large. In hospital-wide data, Enterobacter spp. were
a heterogeneous group of diverse organisms that are often not among the five most commonly isolated nosocomial patho-
yellow pigmented, grow at 48C, and are usually negative in gens from any body site except the respiratory tract, where they
decarboxylase/dihydrolase tests (58, 60, 136, 207). Although E. were the third most commonly isolated pathogens and ac-
agglomerans has recently been renamed Pantoea agglomerans counted for 10.5% of all isolates (105). However, data from
to reflect its genetic distance from the genus Enterobacter (27, isolates recovered from the ICU revealed that Enterobacter
136), this organism will be referred to in this review as E. spp. were not only the third most common pathogen recovered
agglomerans since it has been included heretofore in the clin- from the respiratory tract (11.1% of all isolates) but also the
ical literature on the genus Enterobacter. fourth most common pathogens recovered from surgical
Numerous approaches have been developed for identifica- wounds (10.3%), the fifth most common pathogens recovered
tion of specific strains within each species of Enterobacter (18, from the urinary tract (6.1%), and the fifth most common
222 SANDERS AND SANDERS CLIN. MICROBIOL. REV.
pathogens recovered from blood (5.3%) (105). Since patients patients with foreign devices implanted (1, 7, 38, 236), it has
in special care units of the hospital appear to be at increased been speculated that Enterobacter spp. have a greater affinity
risk of acquisition of Enterobacter infections (see below), it is for such devices than do other organisms (236). However, a
now obvious that data from these units must be analyzed sep- recent study of E. cloacae failed to show any specific serotype
arately from hospital-wide data to appreciate the increasing or biotype associated with infections involving foreign devices
importance of this genus as a nosocomial pathogen. (237). The same study found that certain types were more
Although community-acquired infections with Enterobacter frequently associated with bacteremia or urinary tract infection
spp. do occur, the majority of infections with this organism are (237). Nevertheless, the authors concluded that these trends
nosocomial (107, 117). Patients at increased risk of acquiring may have been more of a reflection of the type of patient
an Enterobacter infection include those with a prolonged hos- involved (ICU versus non-ICU) than any intrinsic virulence of
pital stay, especially if a portion of it is spent in an ICU (1, 30,
the organism itself.
65, 73, 80, 126, 151, 174). The presence of a serious underlying
Most epidemiologic aspects of Enterobacter infections reflect
illness, especially malignancy, burns, and diabetes, also in-
creases the risk of infection (6, 30, 37, 40, 71, 73, 78, 90, 107, the opportunity for infection rather than the intrinsic virulence
149, 227, 236). Immunosuppression from any cause, prematu- of the organism involved. For example, infections due to E.
rity and low birth weight in neonates, and the presence of a sakazakii and E. agglomerans are much less common than those
foreign device (central venous catheters, endotracheal tubes, caused by E. cloacae and E. aerogenes (1, 7, 30, 37, 65, 73, 77,
urinary catheters) are also associated with increased risk of 90, 107, 117). This difference probably reflects the special cir-
acquisition of an Enterobacter infection (1, 7, 21, 38, 148, 151, cumstances in which infections by the first two species but not
174, 236). The single most frequently cited risk factor for the last two are usually seen. Infections by E. sakazakii are
acquisition of an Enterobacter infection is the prior use of usually seen in neonates, and this organism has been recovered
antimicrobial agents in the patient involved (1, 6, 7, 20, 30, 37, from powdered milk and infant formula (74, 94, 161, 169, 242).
38, 73, 80, 108, 151, 174, 236). Whether this predilection for neonates reflects intrinsic viru-
Enterobacter infections can be acquired from either endog- lence or the fact that the organism has the opportunity to be an
enous or exogenous sources. This is not surprising, given the early colonizer of the infants is unknown. Infections by E.
ubiquitous nature of the organism. Various species can be agglomerans are usually associated with an identifiable exoge-
found in the feces of humans and animals and in water, plants nous source (17, 61, 148, 207, 228). This organism grows well at
and plant materials, insects, and dairy products (38, 57, 61, 77, 48C, is often associated with plants, and can be readily recov-
94, 107, 136, 137, 140, 151, 169, 200, 205). Single-source out- ered from cotton (61, 136). Therefore, it is not surprising that
breaks have been traced to contaminated intravenous solu- it is often associated with outbreaks due to contaminated in-
tions, blood products, distilled water, endoscopes, hands of travenous solutions and stored blood products as well as “cot-
personnel, hydrotherapy water, stethoscopes, cotton swabs,
ton fever” in intravenous drug abusers (17, 61, 148, 207, 228).
cryopreserved pancreatic islet infusions, lipoidal solutions, and
Although ubiquitous in nature, E. agglomerans is not as fre-
devices used for monitoring intraarterial pressure (17, 29, 38,
quent a cause of endogenous nosocomial infections as E. clo-
77, 94, 148, 149, 155, 157, 207–210, 228, 229). However, most
nosocomial infections cannot be traced to a single common acae or E. aerogenes (7, 30, 37, 73, 90, 117). This probably
exogenous source or to any of a number of modes of nosoco- reflects the greater intrinsic susceptibility of E. agglomerans
mial transmission (6, 57, 65, 77, 107, 126, 151). Most nosoco- than other Enterobacter spp. to b-lactam antibiotics (see be-
mial Enterobacter infections appear to arise endogenously from low).
a previously colonized site in the involved patient (57, 65, 77, Although E. cloacae and E. aerogenes are the two most
125, 126, 151). Colonization of the gastrointestinal tract and common Enterobacter species causing nosocomial infections,

other body sites with Enterobacter spp. occurs frequently in the little is known about their pathogenetic potential. A greater
seriously ill patient, especially one who has received prior an- resistance to disinfectants and antimicrobial agents than that of
tibiotic therapy (24, 43, 62, 65, 67, 72, 96, 107, 116, 180). In fact, other members of the Enterobacteriaceae is likely to play a role
patients may be colonized with more than one strain at any in their increasing prevalence as nosocomial pathogens (120,
given time (43, 65, 77). Thus, it appears that severe debility, 226) (see also below). E. cloacae has also been shown to be
coupled with the suppressive effects of antibiotics on the nor- capable of growth in 5% dextrose solution, which explains the
mal flora, provides an excellent opportunity for colonization by early outbreaks reported with this organism (77, 148). A study
Enterobacter spp. This colonization most often precedes infec- of patients undergoing cardiac surgery suggested that E. cloa-
tion by the organism. Infection with Enterobacter spp. is more cae may be more virulent than E. aerogenes (65). Of patients
likely to ensue with longer hospital stays, more debilitating colonized with one or the other species, 26% of those colo-
underlying illnesses, and more persistent and heavy coloniza- nized by E. cloacae went on to develop an infection while only
tion. 7% of those colonized by E. aerogenes subsequently developed
infection (65). Another report suggesting greater virulence of
Pathogenesis Enterobacter spp. over other gram-negative nosocomial patho-
Species of Enterobacter are clearly opportunistic pathogens gens involved postoperative wound infections (218). In that
and rarely cause disease in the otherwise healthy individual. As study, specimens of the site were obtained intraoperatively for
opportunistic pathogens that have only recently become im- culture and patients were monitored for subsequent wound
portant causes of nosocomial infections, very little is known infection. Data showed that among patients from whom an
about the factors impacting their pathogenicity and virulence. Enterobacter sp. was recovered intraoperatively, 100% subse-
As gram-negative pathogens, they possess endotoxin and thus quently developed a wound infection with the organism (218).
have all of the pathogenetic properties imparted to an organ- Intraoperative recovery of no other organism carried a 100%
ism by this virulence factor (22). Beyond endotoxin, however, prediction of subsequent infection. Clearly, much more needs
very little is known about the pathogenetic potential of Enter- to be learned about the genus Enterobacter and its pathoge-
obacter strains. Since Enterobacter infections often occur in netic potential for the seriously ill patient.
TABLE 2. Antibiotic susceptibility of the four species of The in vitro activity of a variety of antimicrobial agents
Enterobacter most commonly recovered from clinical materiala against E. cloacae and E. aerogenes has been examined by a
MIC50/MIC90 for following species (no. of strains tested)b: number of investigators. Unfortunately, some investigators did
Antibiotic
not separate the results by species (3, 25, 84, 141, 215, 224, 233)
E. sakazakii E. agglomerans E. aerogenes E. cloacae and some examined E. cloacae only (34, 66, 71, 86, 99, 199).
(195) (27) (25) (29)
Nevertheless, the overall activity of a variety of agents becomes
Ampicillin 2/4 32/.128 .128/.128 .128/.128 apparent from a composite of results from studies that exam-
Piperacillin 2/2 4/32 4/.128 4/.128 ined each of these species specifically (Table 3) (15, 34, 66,
Cephalothin 64/128 16/.128 .128/.128 .128/.128 68–71, 92, 112–115, 118, 119, 135, 160, 162, 165, 166, 185, 196,
Cefamandole 2/4 2/.128 4/.128 8/.128 198, 199, 203, 206, 213, 225, 241, 244). Both E. aerogenes and E.
Cefoxitin 8/16 8/.128 .128/.128 128/.128
cloacae are predictably resistant to ampicillin, cephalothin and
Cefotaxime 0.12/0.12 0.25/32 0.12/0.5 0.25/8
Imipenem 0.12/0.25 0.5/0.5 1.0/2.0 0.5/1.0 other older cephalosporins, and cefoxitin (3, 34, 66, 71, 132,
Gentamicin 0.25/0.5 0.5/1.0 0.5/32 0.5/8.0 160, 162, 214, 215, 232). Any laboratories showing 5% or more
Ciprofloxacin #0.06/#0.06 #0.06/1.0 #0.06/#0.06 #0.06/0.12 of strains of these species to be susceptible to these agents
a
should examine their testing methods for possible sources of
Modified from reference 162 with permission of the publisher.
b
The MICs are given in micrograms per milliliter.
error (231). A low inoculum or short incubation period can
lead to results falsely indicating susceptibility of strains of E.
aerogenes or E. cloacae to these agents. Among the remaining
b-lactam antibiotics, the in vitro activity varies widely (Table
ANTIMICROBIAL SUSCEPTIBILITY
3). In general, ureidopenicillins and carboxypenicillins are ac-
Due to the diverse species within the genus Enterobacter, the tive against one-half or more of strains tested, and addition of
antimicrobial susceptibility varies widely within the genus. One a b-lactamase inhibitor does not improve the activity of these
of the most complete analyses of differences in antimicrobial agents against E. aerogenes or E. cloacae (Table 3) (34, 68, 115,
susceptibility between the various Enterobacter spp. was re- 160, 206, 213, 215). In fact, addition of clavulanate to ticarcillin
ported by Muytjens and van der Ros-van de Repe (162). These may actually decrease the activity of the drug due to the ability
authors examined the activity of 29 antimicrobial agents of this inhibitor to induce the chromosomal b-lactamase that is
against eight species of Enterobacter. As shown in Table 2, characteristically present in these species (223) (see below).
there are important differences in the antimicrobial suscepti- Cephalosporins like cefamandole and cefuroxime are not
bility of the four species most often recovered from clinical highly active against E. aerogenes or E. cloacae (Table 3) (34,
specimens. Some strains of E. sakazakii and E. agglomerans 66, 71, 135, 141, 160, 162). The MICs at which 50% of isolates
may be susceptible to ampicillin, cephalothin, and cefoxitin, are inhibited (MIC50s) are often at or above the susceptible
three b-lactam drugs to which E. cloacae and E. aerogenes are breakpoint for these agents. The activity of the expanded-
uniformly resistant (59, 61, 94, 135, 162, 214). This is due to the spectrum cephalosporins and aztreonam exceeds that of the
absence of the characteristic inducible Bush group 1 chromo- older cephalosporins (Table 3). However, MIC90s are often
somal b-lactamase in these strains (see below). Strains of E. above the susceptible breakpoint for these agents. In recent
sakazakii and E. agglomerans also tend to be susceptible to the studies, the new expanded-spectrum cephalosporins like cefpi-
aminoglycosides (Table 2). This reflects the fact that these rome and cefepime have been the most potent agents among
species usually cause nosocomial infections from identifiable the cephalosporin family, with MIC50s and MIC90s usually
exogenous sources and are probably not part of the “stable” within the susceptible breakpoint for these drugs (Table 3).
hospital flora. Thus, they have less opportunity than E. cloacae Among the b-lactam antibiotics, the carbapenems like imi-

or E. aerogenes to acquire plasmids encoding for aminoglyco- penem and meropenem are most active against E. aerogenes
side-inactivating enzymes. and E. cloacae (Table 3). The MIC50s and MIC90s of these
TABLE 3. In vitro activity of various antibiotics against E. aerogenes and E. cloacaea

Enterobacter aerogenes Enterobacter cloacae
Antibiotic (breakpoint)b
No. of strains MIC50 (mg/ml) MIC90 (mg/ml) No. of strains MIC50 (mg/ml) MIC90 (mg/ml)
Ticarcillin (16) 259 2 64 550 2–8 .64

Piperacillin (16) 2,398 4–16 8–.64 3,361 2–32 64–.64
Ticarcillin-clavulanate (16) 1,401 2–8 4–.64 3,247 4–64 64–.64
Cefamandole (8) 66 2–4 .64 195 4–32 .64
Cefotaxime (8) 1,353 0.06–4 0.12–.64 3,423 0.25–32 2–.64
Ceftazidime (8) 1,575 0.1–4 0.25–.64 3,887 0.25–16 0.8–.64
Cefpirome (8) 316 0.06–1 0.12–4 796 0.12–0.25 0.12–16
Cefepime (8) 219 0.03–0.5 0.06–8 896 0.03–0.5 0.5–4
Aztreonam (8) 1,117 0.06–1 0.25–.64 2,181 0.12–1 1–.64
Imipenem (4) 1,482 0.25–2 0.5–4 3,747 0.12–1 0.25–4
Meropenem (4) 113 0.03–0.06 0.06–0.25 267 0.03–0.12 0.03–0.5
Gentamicin (4) 182 0.25–2.0 0.5–32 1,150 0.25–4 0.5–.64
Amikacin (16) 60 2–4 4–16 425 1–4 2–16
Ciprofloxacin (1) 1,188 0.01–0.25 0.03–.16 3,085 0.01–0.12 0.03–4
Trimethoprim-sulfamethoxazole (2) 25 4 32 713 0.5–8 2.0–32
a
Data for MICs from references 15, 34, 66, 68–71, 92, 112–115, 118, 119, 135, 160, 162, 165, 166, 185, 196, 198, 199, 203, 206, 213, 225, 241, and 244.
b
The breakpoint is the concentration (in micrograms per milliliter) at and below which strains are considered susceptible to the antibiotic. Data from references 52,
163, and 190.
agents are usually below the susceptible breakpoint, especially microbial agents has declined (8, 10, 26, 31, 47, 76, 77, 107, 111,
in tests with meropenem (15, 113, 119, 196, 241). Aminogly- 121, 122, 230). In general, the prevalence of resistance to the
cosides and ciprofloxacin are active against the majority of b-lactam antibiotics, aminoglycosides, trimethoprim-sulfame-
strains of E. aerogenes and E. cloacae, while trimethoprim- thoxazole, and quinolones has increased with time, and this is
sulfamethoxazole shows variable activity (Table 3). associated with increased use of the respective drugs in a given
environment (1, 2, 6, 42, 81, 82, 109, 143). Increases in the
RESISTANCE prevalence of resistance to b-lactam antibiotics have been as-
sociated with increased use of the newer cephalosporins (11,
12, 37, 42, 48, 73, 109, 110, 158, 159, 164, 193, 234, 239).
Prevalence However, it should be noted that in some institutions, once the
Resistance of strains of Enterobacter to each of the major prevalence of resistance to older extended-spectrum cephalo-
groups of antimicrobial agents varies widely among published sporins reaches 25 to 35%, it tends to plateau at that level
reports. For the b-lactam antibiotics, the percentage of strains despite continued high use of these cephalosporins. This prob-
resistant to specific agents ranges from 9 to 50% for ticarcillin, ably reflects the fact, noted above, that most Enterobacter in-
8 to 53% for mezlocillin, 6 to 54% for piperacillin, 5 to 63% for fections arise from a patient’s own endogenous flora rather
cefotaxime, 6 to 59% for ceftazidime, 6 to 44% for aztreonam, than from the environment or a single nosocomial source.
0.2 to 9% for cefepime, and 0 to 4% for imipenem (25, 34, 71, Therefore, the susceptibility or resistance of a particular En-
84, 85, 99, 127, 132, 141, 160, 176, 198, 206, 212, 215, 223–225, terobacter strain will be more dependent upon antibiotic use in
232, 244). These percentages reflect, once again, the greater an individual than in the environment as a whole. This is
activity of the newer expanded-spectrum cephalosporins and reflected in the observation made by several investigators that
carbapenems against Enterobacter spp. in general. For the ami- multiple-b-lactam-resistant Enterobacter infections are en-
noglycosides, the percentage of strains resistant to gentamicin countered significantly more often in patients who have re-
ranges from 0 to 51%, the percentage resistant to tobramycin ceived prior extended-spectrum cephalosporin therapy for any
ranges from 0 to 43%, and the percentage resistant to amikacin reason (37, 104, 234, 238). Moreover, a shift back to suscepti-
ranges from 0 to 34% (25, 34, 71, 84, 85, 99, 127, 132, 141, 160, ble strains occurs when no cephalosporin is given (234). A
176, 198, 206, 212, 215, 223–225, 232, 244). For ciprofloxacin, recent study examined several different extended-spectrum
resistance varies from 0 to 36% of strains tested, and for cephalosporins and their association with the recovery of a
trimethoprim-sufamethoxazole, resistance varies from 0 to resistant strain (104). Interestingly, the risk of recovery of a
60% of strains (34, 71, 85, 99, 127, 132, 141, 160, 198, 212, 213, resistant strain increased linearly over approximately 1 week
215, 216, 223, 224, 232, 244). These wide ranges suggest that during therapy with ceftizoxime or cefotaxime, while with
numerous factors impact the occurrence of antimicrobial re- ceftazidime, even 1 day of therapy maximally increased risk of
sistance among strains of Enterobacter. recovery of a resistant isolate.
Other factors that influence the prevalence of resistance of
Factors Associated with Resistance strains of Enterobacter to antimicrobial agents include the size
and complexity of the hospital and the unit in the hospital (31,
The prevalence of resistance varies greatly among diverse 54, 127, 201, 244). In general, the larger the hospital, the
geographic locations. Although not all geographic regions are greater the prevalence of resistance to b-lactam antibiotics,
equally represented in the published literature, certain trends trimethoprim-sulfamethoxazole, and quinolones (31, 127, 244).
can be seen. In general, resistance to b-lactam antibiotics, Interestingly, the size of the hospital did not affect the suscep-
aminoglycosides, trimethoprim-sufamethoxazole, and quino- tibility of Enterobacter spp. to aminoglycosides in several stud-
lones is most prevalent among Enterobacter strains recovered ies (127, 244). Resistant Enterobacter spp. are also more likely

from patients in hospitals in southern Europe, Belgium, and to be recovered from patients in the ICU of the hospital than
Israel (8, 51, 54, 82, 85, 130, 132, 213, 216, 219, 223, 224). In other areas (31, 54, 201). A recent NNIS survey involving 144
various reports from Greece, resistance to cefotaxime, ceftazi- hospitals across the United States showed that ceftazidime
dime, ceftriaxone, and/or aminoglycosides has been found in as resistance among Enterobacter spp. was associated more often
many as 60 to 70% of strains while resistance to fluoroquino- with isolates recovered from (i) 1990 to 1991 than from those
lones has been found in over 10% in some surveys (82, 85, 130, recovered from 1987 to 1989, (ii) patients in teaching hospitals
219). Although the prevalence of resistance to b-lactam anti- or ICUs, and (iii) blood or urinary tract infections (31). In
biotics is highly variable elsewhere, the resistance of strains of another study, multiple-b-lactam resistant Enterobacter spp.
Enterobacter to aminoglycosides and fluoroquinolones tends to were more frequently recovered from blood than from other
be low in northern Europe, Scandinavia, the United States, sites (104).
and Canada (14, 34, 79, 97, 123, 127, 132, 141, 160, 198, 206,
212, 215, 225, 232, 244). A single report from a hospital in Mechanisms of Resistance
Taipei suggests that resistance to b-lactams, aminoglycosides,
and trimethoprim-sufamethoxazole is prevalent among Enter- There are three major mechanisms whereby organisms can
obacter spp. recovered from blood cultures (71). become resistant to an antimicrobial agent. These include the
One of the earliest studies that examined the antimicrobial production of an inactivating enzyme, alteration of the target
susceptibility of a large number of Enterobacter spp. recovered of the drug, and alteration of the ability of the drug to enter
from a single U.S. hospital was performed in 1969 to 1970, and/or accumulate in the cell. The first mechanism is most
prior to the introduction of extended-spectrum cephalosporins often involved in the resistance of Enterobacter spp. to b-lac-
(214). In that study, all 199 strains of E. cloacae and E. aero- tam antibiotics and aminoglycosides, while the last two are
genes studied were found to be uniformly resistant to ampicillin most often involved in resistance to quinolones and tri-
and cephalothin while one-half were susceptible to carbenicil- methoprim-sulfamethoxazole (32, 41, 45, 46, 84, 100, 101, 107,
lin. Two-thirds of the strains were susceptible to nalidixic acid, 129, 130, 138, 141, 143, 175, 178, 183, 184, 187, 190, 192, 216).
while 98% were susceptible to gentamicin (214). Since that All species of Enterobacter examined to date possess a chro-
early report, susceptibility to all of the major groups of anti- mosomally encoded Bush group 1 b-lactamase (32, 178, 191,
192). In strains of E. agglomerans and E. gergoviae and some Emergence of Resistance During Therapy
isolates of E. sakazakii, the enzyme is produced at very low,
noninducible levels (178). This explains the greater suscepti- It is now well established that strains of Enterobacter may
bility of these species to ampicillin, older cephalosporins, and rapidly develop resistance to multiple b-lactam antibiotics dur-
cefoxitin (Table 2). The uniform resistance to these agents ing therapy with one of a number of b-lactam drugs (reviewed
found among wild-type strains of E. taylorae, E. cloacae, E. in references 37 and 193). The rate at which this occurs varies
aerogenes, and E. asburiae and most strains of E. sakazakii in from less than 20% to over 70% depending upon the site of
infection, the drug used in therapy, and the underlying condi-
general is due to the presence of an inducible Bush group 1
tion of the patient (37, 104, 193, 201, 234). In a prospective
b-lactamase (178). In wild-type strains of these species, this
study of Enterobacter bacteremia by Chow et al. (37), the emer-
resistance arises either from the great lability of the drug to
gence of resistance during therapy occurred significantly more
this particular enzyme or from the drug acting as an inducer of
often when an extended-spectrum cephalosporin was used
the enzyme, which hydrolyzes the drug more efficiently follow-
than when an aminoglycoside or other b-lactam antibiotic was
ing induction. Resistance to extended-spectrum cephalospo-
used. Furthermore, the use of an aminoglycoside in combina-
rins, broad-spectrum penicillins, and aztreonam emerges in tion with the cephalosporin did not prevent the emergence of
these species of Enterobacter following mutation in a chromo- resistance (37). Emergence of resistance can be detected as
somal gene, ampD, that normally prevents high-level expres- early as 24 h after initiation of therapy or can require 2 to 3
sion of the enzyme (192). Once this mutation occurs, high weeks (37).
levels of the chromosomal b-lactamase are expressed. Such Emergence of resistance results from the selective pressure
ampD mutants have been referred to as stably derepressed exerted by the drug used in therapy, which provides a survival
mutants. Since the Bush group 1 b-lactamase is intrinsically advantage for the stably derepressed mutant over the wild type.
resistant to currently available b-lactamase inhibitors like cla- Over the course of therapy, the wild-type cells, expressing their
vulanic acid, these stably derepressed mutants are also resis- chromosomal b-lactamase inducibly, are killed by the drug
tant to b-lactamase inhibitor–b-lactam drug combinations while the mutant cells, producing high levels of chromosomal
(192, 193). Among b-lactam agents, the only drugs maintaining b-lactamase, are able to replicate. Unless the patient’s normal
activity include the carbapenems and newer expanded-spec- defense mechanisms are sufficient to eliminate the mutant
trum cephalosporins like cefepime (23, 54, 193, 241). However, cells, which are present in very small numbers at the onset of
secondary mutations involving permeability through the outer infection (i.e. 1 in 106 to 107 wild-type cells), the multidrug-
envelope can lead to resistance to these agents as well among resistant mutant cells will become predominant. This scenario
mutants already producing high levels of the chromosomal explains why the emergence of resistance is not seen in all
b-lactamase (55, 100, 128, 129, 134, 173, 177, 220). patients infected with a wild-type Enterobacter strain who are
Although the chromosomal b-lactamase of Enterobacter spp. treated with an extended-spectrum cephalosporin. In these
is most commonly involved in b-lactam resistance encountered patients, intrinsic defense mechanisms are capable of eliminat-
in this genus, other b-lactamases can also be found. Wild-type ing the mutant cells. It also explains why the emergence of
Enterobacter strains may become resistant to broad-spectrum resistance occurs more often in severely debilitated patients
penicillins like piperacillin via the acquisition of plasmids en- who are immunocompromised and why resistance can be de-
coding the Bush group 2b TEM-1, TEM-2, or SHV-1 b-lacta- tected in as little as 1 day or may require several weeks.
mase or the Bush group 2d OXA-1 b-lactamase (16, 138, 183,
187). These strains differ from mutants expressing high levels CLINICAL MANIFESTATIONS
of their chromosomal b-lactamases in that they are susceptible
to extended-spectrum cephalosporins and b-lactamase inhibi- Enterobacter spp. have been implicated in a broad range of

tor-b–lactam drug combinations. On occasion, wild-type clinical syndromes. The literature is replete with descriptions
strains of Enterobacter may become resistant to extended-spec- of bacteremia and infections of skin and soft tissues, respira-
trum cephalosporins via the acquisition of plasmids encoding tory tract, urinary tract, bone and joints, central nervous sys-
the Bush group 2be b-lactamases, the extended-spectrum tem, gastrointestinal tract, and other organs. In general, the
b-lactamases (ESBLs) (45, 46, 84, 98, 184). Although it may characteristics of infection due to Enterobacter spp. resemble
seem surprising that an organism with an inducible b-lacta- those due to other facultative gram-negative bacilli. However,
mase would ever acquire an ESBL, the resistance to other there are some distinctive features that may serve as guide-
agents such as the aminoglycosides encoded on the same plas- posts to selection of therapy or to planning of institutional
mid as the ESBL may often be the major factor driving the control measures.
acquisition of these plasmids by Enterobacter spp. Most re-
cently, there has been a report of carbapenem resistance in a Bacteremia
clinical isolate of E. cloacae due to the presence of a chromo- Of all clinical syndromes, bacteremia has been studied most
somally encoded carbapenemase (168). This enzyme, like the often and in greatest depth. Fortunately, there has been gen-
usual Bush group 1 b-lactamase which was also present in the eral agreement among investigators upon the criteria for the
strain, was inducible by cefoxitin and carbapenems. diagnosis. As a result, data in individual reports tend to be
Mechanisms responsible for aminoglycoside resistance reliable and comparisons between studies are facilitated.
among clinical isolates of Enterobacter have been the subject of Demographics. The demographics of Enterobacter bactere-
numerous investigations (101, 107, 130, 141, 143, 175). As with mia are shown in Tables 4 through 6. The incidence of bacte-
other members of the Enterobacteriaceae, resistance of strains remia parallels that of the total of Enterobacter infections re-
of Enterobacter to aminoglycosides is due to the production of ported over the past three decades (see above). Most
one or more aminoglycoside-inactivating enzymes. Acetylating institutions and services have experienced significant increases
enzymes, including AAC (3)-II, AAC (69), AAC (3)-III, AAC extending up to or into the present decade. The rates of bac-
(3)-I, and AAC (3)-V, appear to be the most commonly en- teremia tend to cluster around 1 per 1,000 admissions for
countered. Nucleotidylating enzymes, ANT (20), have also university hospitals or tertiary-care centers. These rates tend to
been encountered. be two- to threefold higher in specialized units, such as cancer
TABLE 4. Characteristics of bacteremia due to Enterobacter spp. encountered in general hospitals
Reference Yr studied Patient population Total no. of Rate/1,000 Male/female Ages

episodes admissions ratio (yr)
Johnson and Ramphal (108) 1985–1989 Univ. teaching 51 NDa ND Adults

Chow et al. (37) 1.5 yr in late 1980s Six teaching centers 129 ND 2.8b 17–95
Haddy et al. (90) 1985–1987 Five community 75 0.3 1.4 10–98
Weischer (236) 1984–1989 Univ. teaching 53 ND 1.4 30–76
Al Ansari et al. (1) 1990–1992 Teaching hospital 22 ND ND ND
Peña et al. (174) 1984–1990 Univ. teaching 226 0.9–1.8 2.4 57e
Vázquez et al. (224) 1981–1990 Univ. teaching 195 2.3–6.7 2.3 All
Bouza et al. (25) 1977–1983 General referral 50f 1.3 1.3 All
Fung et al. (71) 1985 Veterans hospital 41 1.1 3.0 17–82
Watanakunakorn and Weber (232) 1980–1986 Community teaching 58 0.3 1.9 All
Andersen et al. (5) 1987–1988 Univ. teaching 10 ND ND ND
a
ND, not determined.
b
Two of the six hospitals were Veterans Administration Medical Centers with predominantly male populations.
c
Patients had two Enterobacter spp. isolated.
d
Rate at 14 days (the rate at 28 days was 24%).
e
Mean age.
f
Fifty cases randomly selected from a larger total for detailed analysis.
g
Review restricted to E. cloacae.
h
Attributable mortality.
centers, and two- to threefold lower in community hospitals. Several investigators have detected seasonal variations in the
Although rates are lower in the community, the problem is occurrence of bacteremia due to Enterobacter spp. Clustering
significant and growing (64, 182). of cases in summer months has been recognized in children’s
In data gathered from institutions other than veterans’ med- hospitals in Michigan (7) and Texas (6) and in a survey of 18
ical centers, Enterobacter bacteremia tends to occur more com- hospitals in the United States (107). In none of these was the
monly in males in a ratio of 1.3 to 2.5:1.0. Males predominate seasonal increase traced to a common source or mode of
among both infected adults and children. Bacteremia is more spread. Interestingly, a seasonal clustering in winter has been
commonly encountered at the extremes of age, i.e., in neonates reported in a veterans’ hospital in Taipei, China (71).
and the elderly. The majority of bacteremias are acquired Signs, symptoms, and laboratory findings. The incubation
institutionally (range, 56 to 100%). E. cloacae predominates in period of Enterobacter bacteremia has been estimated from
most series (range, 46 to 91% of isolates) followed in order by common-source outbreaks in which the organisms were in-
E. aerogenes (range, 9 to 43%), E. agglomerans, E. sakazakii, fused directly into the bloodstream (148). The time for appear-
and others. From 14 to 53% of bacteremias that involve En- ance of signs and symptoms has varied from as short as 2 h to
terobacter spp. are polymicrobial. The companion organisms in as long as 20 days, with most occurring in a few hours to 2 days.
the polymicrobial bacteremias appear to be randomly distrib- In a pediatric outbreak, the incubation period was a mean of 6

uted between gram-positive and gram-negative isolates. days (148). Signs and symptoms are generally similar to those
Anaerobes have been encountered in the presence of coinci- noted during bacteremia with other enteric bacilli in both
dent gastrointestinal foci. Fungi and additional species of En- adults and children. Two exceptions have been noted. First, E.
terobacter have been recognized occasionally. In comparative sakazakii, unlike other enteric organisms, may cause a highly
studies, the frequency of polymicrobial bacteremia has been lethal syndrome of bacteremia with central nervous system
significantly higher for Enterobacter spp. than for Klebsiella spp. involvement in neonates and young children (73). Second, bac-
(30 and 12%, respectively) (25) or Escherichia coli (53 and 6%, teremia due to Enterobacter spp. has been notable for the
respectively) (236). The very high rate of polymicrobial bacte- relative infrequency of establishment of secondary metastatic
remia has profound implications for the selection of therapy foci (25, 71).
when Enterobacter spp. are suspected or implicated. Fever is the hallmark of bacteremia in both adults and chil-
TABLE 5. Characteristics of bacteremia due to Enterobacter spp. encountered in pediatric hospitals
Reference Yr studied Patient population Total no. Rate/1,000 Male/female Ages %

of episodes admissions ratio Nosocomial
Gallagher (73) 1984–1988 Children’s hospital 33 0.44 1.2 1 day–24 yr 67

Andresen et al. (7) 1989–1992 Children’s hospital 32 0.3–1.1 2.3 6 mo–11 yr 56
Bonadio et al. (21) 1978–1990 Children’s hospital 30 0.27 1.3 6 mo–,1 yr 57
Matsaniotis et al. (148) 1981 Children’s hospital 63 ND ND 10 days–17 yr 100d
a
b
ND, not determined.
c
d
Common-source outbreak within the hospital.
TABLE 4—Continued
% % of species % Crude mortality

Special features
Nosocomial E. cloacae E. aerogenes E. agglomerans E. sakazakii Other Polymicrobial rate (%)
ND ND ND ND ND ND ND 25 One-third of the patients were neutropenic

84 72 27 1 1 2c ND 20d Analysis of emergence of resistance
80 57 36 4 0 1 ND 29 Growing importance in community
83 91 9 0 0 0 53 30 Contrasts to E. coli bacteremia
ND 68 14 0 9 9 ND 15 Most isolates multiply resistant de novo
81 46 27 9 ND 19 14 23 Increasing incidence over decade
ND ND ND ND ND ND 16 ND Slight decrease in incidence over decade
76 ND ND ND ND ND 30 42 Demographics compared to Klebsiella spp.
68 100g ND ND ND ND ND 46, 44h Sporadic cases, no clusters
72 50 43 7 0 0 34 69 High mortality, poor response to
antimicrobial agents
70 100g ND ND ND ND ND 40 Multiple resistance curbed by restriction of
cephalosporin use
dren. Reported rates have ranged from 83 to 87% in children possible in establishing the portal of entry. Weischer and Kol-
(7, 21, 148) and from 92 to 98% in adults or mixed populations mos (236) demanded microbiological confirmation to defini-
(20, 25, 37, 71). Lower rates have been observed in neonates tively establish an entry point. Despite the differing criteria,
(40%) (21) and among adults (61%), a high proportion of their results were near the median of those of all investigators
whom have normal or low leukocyte counts (90). The height of for most portals. The extremes in percentages of portals of
fever is usually substantial (20, 30, 148), and rigors occur in up entry usually reflect the unique nature of the hospital or service
to 75% of patients (148). Temperatures of 1048F or greater in which the study was performed. For example, the highest
were observed in 28% of patients with cancer in one large percentage of “unknown” portals was found in a study per-
series (148). No pattern of fever is predictive; intermittent, formed in a cancer center, while the highest percentage of
remittent, hectic, and sustained fevers have all been observed portals of gastrointestinal origin was reported from a study
(148). weighted with patients with hepatic transplantation. With a few
Hypotension or shock has been reported in 9 to 34% of adult such exceptions, there was a remarkable consistency of results
or mixed populations (20, 25, 37, 71, 90). The frequency is regarding portals of entry in the series of bacteremias.
similar in children (8 to 28%) (7, 21, 148). Altered mentation Risk factors for development of bacteremia. Nearly all stud-
is often (32 to 38%) noted concurrently in both adults and ies of Enterobacter bacteremia have included an evaluation of
children (37, 71, 148). Leukocytosis occurs in approximately potential risk factors. Many simply presented the percentage of
two-thirds of patients with bacteremia (25, 71, 90). Leukopenia bacteremic patients with a long list of putative risk factors. A
has also been reported in 9 to 17% of individuals of a broad few were controlled and subjected to a simple statistical anal-
range of ages (71, 90). Thrombocytopenia (25), hemorrhage ysis, such as a chi-square determination. A minority of inves-
(20), and jaundice (71) have each been noted in a few series. tigators performed univariate or multivariate analyses. How-
The syndrome of disseminated intravascular coagulopathy has ever, despite vast differences in methodology, the conclusions

been recognized in 0 to 6% of bacteremic episodes (20, 25, 71, of the various studies have been remarkably consistent.
90). Most of the usual cutaneous manifestations associated The sine qua non for development of bacteremia due to
with bacteremia have been noted occasionally. These include Enterobacter spp. is severe underlying illness. The few excep-
purpura fulminans (89), hemorrhagic bullae (140), and ec- tions to this statement have generally occurred during out-
thyma gangrenosum (182). Cyanosis and mottling has been breaks when the organism was directly inoculated into rela-
encountered in two-thirds of bacteremic children (148). tively healthy individuals. The most commonly cited factors
Portals of entry. The most commonly implicated portals of associated with the acquisition of bacteremia due to Enter-
entry of Enterobacter spp. into the bloodstream are tabulated in obacter spp. are listed in Table 8. In the absence of multivariate
Table 7. Most investigators relied upon a combination of pre- analyses, many of these factors, such as the various procedures
sumptive evidence, clinical judgment, and cultures whenever and devices, may be mere surrogate markers for the severity
TABLE 5—Continued
% of species % Crude mortality
Special features
E. cloacae E. aerogenes E. agglomerans E. sakazakii Other Polymicrobial rate (%)
70 15 12 3 0 18 24, 18a Prototypical for pediatrics

72 12 16 0 0 34 ND,b 6a Increasing incidence
100c ND ND ND ND 20 10 Restricted to E. cloacae
65 35 0 0 0 ND 6 Common-source outbreak with spread
to hands of personnel
TABLE 6. Characteristics of bacteremia due to Enterobacter spp. encountered in specialized units or populations
Reference Yr studied Patient population Total no. Rate/1,000 Male/female %

of episodes admissions ratio Ages (yr) Nosocomial
Burchard et al. (30) 1980–1984 Surgical service 63 NDa 2.9 Adults Most
Wagener and Yu (227) 1987 Transplant recipients 19 ND ND 16–67 95
John et al. (107) 1977–1980 Primarily burns 18 ND ND ND Most

Mayhall et al. (149) 1976 Burn center 15 ND ND ND Most
Bodey et al. (20) 1972–1986 Cancer hospital 296 1.8 1.3 1–83 74
a
ND, not determined.
b
c
d
Polymicrobial infections excluded from analysis.
and extent of the underlying disease(s). The diseases most on a surgical service. They then noted that the mean duration
commonly identified as risk factors during the last three de- of administration prior to bacteremia was 23.4 6 4.6 days for
cades include those that impair systemic immunity, such as all antimicrobial agents but only 9.3 6 1.6 days for cephalo-
hematological malignancies, or alter natural barriers to inva- sporins (primarily first- and second-generation agents). Two
sion, such as gastrointestinal tract diseases and thermal injury. groups of investigators have demonstrated that restriction of
Procedures or devices that disrupt the integument also appear the use of cephalosporins (especially the newer drugs) reduces
to favor access of the organism to the vasculature. The use of or eliminates the risk of bacteremia due to Enterobacter spp. (5,
antibiotics has consistently been cited for providing a selective 28).
advantage for survival, colonization, and ultimately invasion by Bacteremia due to multiply b-lactam-resistant Enterobacter
more naturally resistant organisms, such as Enterobacter spp. strains has been linked to prior use of ceftazidime versus use of
Recognition of the importance of prior infection or coloniza- penicillins and older cephalosporins (108), as well as use of
tion as risk factors simply documents the second step in this cefotaxime and cefuroxime (73), cefotaxime (28), and newer
selective process. cephalosporins in general (5, 37). The emergence of multiple
Several groups of investigators attempted to more fully char- resistance during therapy of bacteremia with newer cephalo-
acterize putative risk factors that were prominent in their in- sporins has been documented (see above [37]). Multiple b-lac-
stitutions. Bodey et al. (20) calculated the relative risk posed by tam resistance itself has been implicated as a risk factor for
various types of malignancies at the M. D. Anderson Cancer sepsis. Andersen et al. studied 69 patients with infections due
Center for a 10-year interval. Rates of episodes of Enterobacter to E. cloacae and found that 15 (22%) were infected by mul-
bacteremia per 1,000 new registrations were 17 for acute leu- tiply resistant strains whereas 7 of 10 septic patients (70%)
kemias, 8 for hematological malignancies, and 1 for solid tu- were infected by the resistant organisms (5).
mors. One may speculate that the observed differences in rate Determinants of the outcome of bacteremia. The mortality
correlate with the degree of compromise of host defense as- rates for bacteremia due to Enterobacter spp. are shown in
sociated with each class of malignancy. Tables 4 to 6. Crude mortality rates ranged from 15 to 87%,
Wagener and Yu attempted to dissect the risks associated with two of the three highest rates noted in a burn center and

with transplantation of various organs (227). They observed a transplantation unit. Most rates clustered between 20 and
that kidney recipients had the lowest risk of bacteremia or 46%, with a median of 30%. Attributable mortality, when
fungemia (6%). The risk of bloodstream invasion was nearly specified, ranged from 6 to 40%. The disparate rates in the
twofold greater in heart recipients (11%) and fourfold greater various studies may have resulted from differences in (i) the
in liver recipients (24%). Enterobacter spp. predominated as population of patients studied (e.g., burn and cancer centers
causes of nosocomial bacteremia acquired within 2 weeks of versus general hospitals), (ii) the prevalence of multiple resis-
hepatic transplantation (10 of 32 episodes). They were encoun- tance, and (iii) the time following diagnosis (days to months) at
tered infrequently after 2 weeks or at any time in heart and which mortality was assessed. In general, the mortality associ-
kidney transplant recipients. Overall, Enterobacter spp. and ated with bacteremia due to Enterobacter spp. was comparable
Pseudomonas spp. were implicated with equal frequency (19 of to that for bacteremia due to other enteric bacilli, with mean
125 episodes of bacteremia/fungemia each) in the authors’ and median crude rates most often 20 to 35% (20, 22, 53, 131,
experience (227). 222). Mortality rates for Pseudomonas species have been com-
Nearly all investigators have implicated previous antimicro- parable (53, 228) or up to twofold greater (22, 53, 222) in
bial therapy as a factor predisposing to bacteremia (Table 8). various studies.
Among the various agents, the b-lactams and aminoglycosides Factors associated with mortality in the series devoted to
have been cited most often but not exclusively (1, 37). In a Enterobacter bacteremia are listed in Table 9. Most of these
study of bacteremia due to Enterobacter spp., Chow et al. (37) factors have been implicated as determinants of outcome in
demonstrated significant associations of any antimicrobial bacteremias due to other gram-negative bacilli (22, 53, 93, 222,
agent (36 [35%] of 103) versus none (1 [4%] of 26; P 5 0.002) 245). The single most important factor in determining the
and third-generation cephalosporins (22 [69%] of 32) versus outcome of gram-negative bacteremia is the severity of the
other agents (14 [20%] of 71; P 5 0.001) with the detection of underlying disease—rapidly fatal versus ultimately fatal or
multiple resistance in initial isolates. The importance of anti- nonfatal (22, 53, 93, 150, 222, 245). Most of the investigators
biotics in general and cephalosporins in particular was under- who studied Enterobacter bacteremia acknowledged the impor-
scored by Burchard et al. (30). They identified previous anti- tance of severity, but few stratified their analyses of risk factors
microbial agents as risk factors in two-thirds of their patients accordingly. Those who did so reconfirmed the critical impor-
TABLE 6—Continued
% of species % Crude mortality
Special features
E. cloacae E. aerogenes E. agglomerans E. sakazakii Other Polymicrobial rate (%)
60 35 2 2 2 ND 35 Importance of antecedent colonization

ND ND ND ND ND 21 63 Predominance in liver recipients, early
onset postoperatively
100b ND ND ND ND ND ND Reviews of early literature
100b ND ND ND ND ND 87–40c Cross-contamination implicated
75 17 7 1 1 NDd 21 Increasing incidence and survival
during the last 5 years
tance of this factor (Table 9). Many of the factors identified in therapeutic outcomes (37, 193). Survivors with emergence of
Table 9, such as the need for intensive care, parenteral nutri- resistance (although tabulated with “favorable” outcomes)
tion, prolonged hospital stay, or various devices and proce- may continue to shed the organism, posing a potential threat to
dures, may have been indicative of the severity of the under- themselves subsequently or to the environment (30, 37, 234).
lying disease rather than direct contributors to mortality Finally, superinfection may occur during even appropriate and
themselves. Multivariate regression analyses will be required to effective therapy of Enterobacter bacteremia. Bodey et al. doc-
definitively assign a role to these factors. The extent of patho- umented superinfection in 57 (19%) of 296 episodes of Enter-
physiologic changes (shock and associated complications) at obacter bacteremia (20). The propensity for the development
diagnosis of bacteremia has been identified as an important of resistance among Enterobacter spp. has had a profound
determinant of outcome in series of patients with bacteremia impact upon survival and poses increasing challenges for se-
due to Enterobacter spp. (Table 9) and other gram-negative lection of appropriate therapy.
bacilli (22, 53, 222, 245). At present, the weight of evidence suggests that currently
Some determinants related to antimicrobial therapy may set available cephalosporins, with the possible exception of
Enterobacter spp. apart from most other enteric bacilli. The cefepime should be avoided in infections known or presumed
results of analyses of the effect of the appropriateness of an- to be due to Enterobacter spp. Serious infections due to rela-
timicrobial therapy on the outcome of Enterobacter bacteremia tively susceptible “wild-type” strains often respond to the com-
are shown in Table 10. There was wide variation in methods of bination of an expanded-spectrum penicillin and an aminogly-
analysis. For example, outcome was assessed after only 3 days coside. Multiply resistant strains require the use of a
in one study and up to 2 to 4 weeks in others. Most investiga- carbapenem or a fluoroquinolone. Some physicians recom-
tors based outcomes on crude mortality without stratification mend combination with an aminoglycoside, at least initially.
for severity, while one group used attributable mortality only. Some investigators prefer a carbapenem because of their
Most defined appropriate therapy as the use of any agent with greater experience with this class of agent and the relatively
activity demonstrable in vitro, while one group demanded the greater coverage of possible coinfecting gram-positive cocci
use of a bactericidal agent(s) to meet the criteria for appro- and anaerobes.
priateness. Despite these variations in methodology, the weight Comparisons with bacteremias due to other enteric bacilli.
of evidence indicates that appropriate therapy (defined as at Two groups of investigators performed a controlled compari-
least one active agent) may favorably influence the outcome. son of bacteremias due to Enterobacter spp. and another en-

With stratification for severity, beneficial effects were observed teric bacillus. Weischer and Kolmos (236) compared Enter-
in patients who did not have rapidly lethal underlying diseases. obacter spp. to Escherichia coli. During the period 1984 to
An additional factor that impinged upon outcome was de novo 1989, Enterobacter spp. accounted for 1/10 as many bactere-
infection with a multiply resistant strain of Enterobacter or mias as E. coli (53 and 530, respectively). Enterobacter spp.
emergence of resistance during therapy. Johnson and Ramphal were acquired significantly more often in the hospital (83%
(108) noted a disproportionate percentage of deaths in pa- versus 44%; P , 0.0001), and were more likely to be a com-
tients infected with ceftazidime-resistant strains. Chow et al. ponent of a polymicrobial bacteremia (53% versus 6%; P ,
(37) identified multiple resistance as a risk factor for mortality 0.0001). The mean age of patients was lower with Enterobacter
by univariate analysis and confirmed its role by multivariate spp. (53 versus 67 years; P , 0.05). Sources of the bacteremia
regression analysis. Emergence of multiple resistance during differed markedly between these organisms. Microbiologically
therapy has often, but not invariably, resulted in unfavorable documented foci in burns (P 5 0.006), central venous catheters
TABLE 7. Portals of entry among patients with bacteremia due to Enterobacter spp.
Site % of patients Reference(s)
Unknown 12, 17, 19, 21, 21, 26, 30, 40, 47, 51, 72 20, 25, 30, 37, 71, 73, 90, 179, 224, 232, 236
Respiratory tract 8, 8, 9, 10, 11, 12, 18, 19, 34, 40, 50 20, 25, 37, 71, 73, 90, 179, 224, 232, 236
Genitourinary tract 7, 7, 11, 12, 13, 14, 14, 19, 26, 27 20, 25, 37, 71, 73, 90, 179, 224, 232, 236
Intravascular catheter 6, 10, 11, 11, 11, 15, 19 37, 71, 73, 90, 179, 224, 236
Wounds/surgery 7, 7, 11, 20, 20, 25 25, 37, 71, 90, 179, 224
Gastrointestinal tract/abdominal 5, 7, 9, 9, 12, 39 20, 37, 73, 90, 224, 232
Skin/soft tissue 5, 8, 12 20, 73, 90
Biliary tract 18, 19, 20 71, 73, 90
Burns 17 224
TABLE 8. Factors associated with the development of bacteremia due to Enterobacter spp.
Antecedent % of patients Reference(s)
Diagnoses
Diabetes mellitus 8, 8, 10, 12, 40 25, 37, 71, 90, 232
Malignancy 16, 21, 22, 23, 32, 36 25, 37, 71, 90, 232, 236
Cardiovascular disease 18, 20, 29, 44 25, 30, 37, 232
Burns 3, 4, 9, 19 30, 37, 90, 236
Respiratory disease 5, 10, 14 25, 71, 232
Gastrointestinal diseases
Any 16, 20, 37, 59 21, 25, 30, 232
Cirrhosis 10, 10 25, 71
Hepatic 14 232
Alcoholism 9 232
Biliary 4 90
Surgery 9, 24 90, 174
Renal disease 7, 10, 17 25, 71, 232
Genitourinary disease 16 232
Previous infection
Non-Enterobacter bacteremia 15 236
Enterobacter spp. at any site 30, 40 1, 149
Surface colonization, Enterobacter spp. 16 90
Immunosuppressive states 5–26, 15, 57 21, 37, 236
Drugs
Antimicrobial agents
Any 36, 50, 54, 66, 67, 79, 80 7, 25, 30, 37, 73, 174, 236
b-Lactams 68 236
Penicillins 60 236
Cephalosporins 19, 33, 69 37, 73, 236
H2-receptor antagonist 70 1
Immunosuppressants 15, 23, 26 7, 37, 236
Total parenteral nutrition 23, 33 7, 30
Devices, procedures, and locations

Hospitalized recently 28 37
Intensive care 30, 41 1, 174
Intravascular catheter 11, 50, 60, 73 1, 7, 30, 236
Surgery or trauma 13, 16, 20, 24, 36, 42, 50, 54 1, 7, 25, 30, 37, 90, 174, 236
Mechanical ventilation 20, 40 1, 37
Urinary catheter or procedure 46, 65, 66 1, 25, 37
Endotracheal tube 14 25
Nasogastric tube 35 1

(P 5 0.009), and the respiratory tract (P 5 0.08) were more versus 11%). The mortality rate was 42% for Enterobacter spp.
frequently infected with Enterobacter spp., while a urinary fo- and 25% for Klebsiella spp.
cus was most common for E. coli (P 5 0.003). Medical devices
were more frequently associated with Enterobacter bacteremia: Lower Respiratory Tract Infections
urinary catheter with a urinary focus (P 5 0.003), endotracheal
tube (P 5 0.0002), central venous catheter (P 5 0.02), and There is relatively little in the available literature concerning
peripheral venous catheter when no other focus was apparent the clinical manifestations of lower respiratory tract infections
(P 5 0.02). b-Lactam antibiotics, in particular the penicillins, due to Enterobacter spp. The few published series on Enter-
were identified as a risk factor more often with Enterobacter obacter spp. have been limited to less than 12 patients, while
spp. (P 5 0.003), while E. coli bacteremia was more likely to reviews of larger numbers of gram-negative bacillary pneumo-
have occurred without prior antimicrobial exposure (P 5 nias have seldom provided clinical details for Enterobacter spp.
0.006). The mortality associated with Enterobacter bacteremia specifically. The following is thus a composite of largely frag-
(30%) was not significantly different from that associated with mentary data from these sources.
E. coli (24%). Most of the species of Enterobacter have been implicated in
Bouza et al. compared bacteremias due to Enterobacter spp. a wide spectrum of lower respiratory infections, including
and Klebsiella spp. (25). Several potentially important differ- asymptomatic colonization of respiratory secretions, purulent
ences were detected, but unfortunately statistical analyses were bronchitis, lung abscess, pneumonia, and empyema (40, 63,
not performed. Enterobacter spp. were components of polymi- 107, 117, 133, 171). As with other gram-negative bacilli, there
crobial bacteremia (30%) more often than all gram-negative is still divergence of opinion regarding the validity of cultures
bacilli collectively (17%), Klebsiella spp. (12%), or Serratia spp. of expectorated sputum and the optimal criteria for diagnosis
(9%). The two most common portals of entry were “unknown” of each of these clinical entities. As a consequence, data, es-
surgical sites for Enterobacter spp. and urinary tract or “un- pecially regarding incidence, may vary widely from one study to
known” for Klebsiella spp. More patients developed bactere- another. Despite these variations, the incidence of lower re-
mia with Enterobacter spp. than Klebsiella spp. in an ICU (30% spiratory tract infections due to Enterobacter spp. appears to
TABLE 9. Factors associated with unfavorable outcome of approximately one-half of patients (117). Patients with chronic
bacteremia due to Enterobacter spp. obstructive bronchopulmonary disease also appear to be at a
Factor Reference(s) relatively greater risk of concomitant bacteremia, and this risk
may be further enhanced by corticosteroid therapy (117).
Severity of underlying disease..........................20, 25, 37, 90, 232
Other frequently cited risk factors include alcohol abuse, dia-
Inappropriate antimicrobial therapya ..............7, 20, 25, 37, 71, 90, 108
Shock ...................................................................20, 25, 71, 174, 222, 232 betes mellitus, malignancy, mechanical bronchial obstruction,
Thrombocytopenia, hemorrhage......................20, 73 and severe neurological diseases (40, 107, 117). Prior antimi-
Nosocomial acquisitionb....................................222, 232 crobial therapy appeared to be strongly associated with Enter-
Concurrent pulmonary focus of infection ......20, 30, 232 obacter pneumonia in one study (40) and insignificantly so in
Intensive care .....................................................25, 37 another (117).
Renal insufficiency .............................................30, 37 The recent recognition of an important role of Enterobacter
Intravascular catheter, urinary catheter, spp. in community-acquired pneumonia in Spain is disquieting
prior surgery, hepatic disease, coma,
prior cardiac arrest, hemodialysis,
(171). By using relatively strict diagnostic criteria (acute illness,
multiple b-lactam resistance ........................37 pulmonary infiltrates, positive blood cultures or pure cultures
Prolonged hospital stay, prior focus of of respiratory secretions judged to be “adequate” microscopi-
Enterobacter infection, prior bacteremia, cally or repeatedly positive cultures of respiratory secretions)
total parenteral nutrition, and extensive bacteriologic and serologic evaluations, Enter-
respiratory failure ..........................................30 obacter spp. were found to be the fourth most commonly en-
Entry site other than intravenous catheter, countered bacterial pathogens, comprising in excess of 10% of
immunosuppressive therapy .........................174
isolates (171). Although this trend may be confined to areas
Delay in diagnosis of bacteremia, delayed
neutrophil response, low initial with high antimicrobial agent usage, it should be monitored
neutrophil count ............................................20 rigorously.
Failure to remove intravascular catheters Enterobacter spp. have recently been recognized as major
and other foreign bodies...............................7 pathogens in lung transplant recipients (49, 142). Approxi-
a mately 40% of recipients will develop acute bacterial pneumo-
Two studies (30, 232) suggested that antimicrobial agents had little or no
effect on the outcome. nia in the 2 weeks immediately following transplantation. Mor-
b
Two studies (25, 71) indicated that mortality was equivalent in community- tality associated with pneumonia may be as high as 50%.
and hospital-acquired bacteremia. Enterobacter spp. have been the second and fourth most com-
mon causes of pneumonia in two recent series (49, 142). In
many instances, it appears that the etiologic agents in pneu-
have increased steadily over the last four decades. These or- monia in lung transplant recipients were present in the donor
ganisms were seldom linked to respiratory infections prior to lungs at the time of transplantation. Two studies indicate that
1970. Estimates of the incidence of Enterobacter spp. in noso- “donor” organisms vary in their ability to proliferate and in-
comial respiratory infections in the 1970s ranged from less duce pneumonia following their transplantation (49, 142). For
than 2 to 9% (107). The rates increased from 9.5% in the early example, Staphylococcus aureus is the pathogen most com-
1980s (117, 194) to 11% in 1986 to 1990 (105, 194). Enter- monly encountered in donor lungs but pneumonia appears to
obacter spp. have recently surpassed Klebsiella spp. to become result relatively infrequently in recipients (12 to 27% of trans-
the third most common cause of nosocomial respiratory tract fers). On the other hand, Enterobacter spp. are highly efficient
infections in the United States (105, 194). in producing disease following their transplantation; 60 to 67%
Pneumonia is perhaps the most important and well studied of transfers resulted in pneumonia (49, 142). There is no ob-

of lower respiratory infections due to Enterobacter spp. Until vious explanation for these apparent differences in “transfer
recently, it occurred almost exclusively in patients with severe efficiency.”
underlying diseases and demonstrated a predilection for the The clinical and laboratory manifestations of Enterobacter
elderly who were institutionalized. Chronic obstructive bron- pneumonia differ little from those observed for pneumonia due
chopulmonary disease has been identified as a risk factor in to other gram-negative bacilli. Symptoms may be subtle or
TABLE 10. Outcome of antimicrobial therapy in bacteremia due to Enterobacter spp.

Outcome of therapy
Appropriate Inappropriate P Reference Comment

favorable/total (%) favorable/total (%)
45/54 (83) 4/11 (36) 0.001 37 Monotherapy

54/64 (84) 4/11 (36) 0.001 37 Combination therapy
46/55 (84) 9/20 (45) 0.0008 90 Only bactericidal agents appropriate; effect demonstrable only in
nonfatal or ultimately fatal underlying diseases
26/40 (65) 9/18 (50) NSa 30 Only “active agent” administered for 3 days considered
appropriate
195/250 (78) 6/14 (43) NDb 20 Outcome compared to inappropriate therapy
195/250 (78) 6/20 (30) ND 20 Compared to no therapy
22/31 (71) 3/15 (20) #0.05 25
14/16 (88) 8/25 (36) ,0.01 71 Outcome based on attributable mortality
15/33 (46) 4/9 (44) NS 232 Outcome measured at 3 days of therapy
a
NS, not significant.
b
ND, not determined.
muted, especially in the elderly. For example, in a series of 11 The importance of Enterobacter spp. as pathogens in this set-
predominantly elderly patients, Karnad et al. noted fever in 6 ting was first noted in thermal injury units in the late 1960s and
(55%) and cough in only 2 (18%) (117). However, these pa- early 1970s. The ascendency of these organisms as agents of
tients met relatively stringent criteria for the diagnosis of pneu- burn wound sepsis has been reviewed by John et al. (107).
monia (new infiltrates and positive cultures of transtracheal Although Enterobacter spp. have been implicated in surgical
aspirates or sputum plus blood). Most patients demonstrate wound infection in almost every body site, two areas have been
tachypnea and tachycardia. Hemoptysis appears rarely. Leu- recently recognized as especially prone to involvement: ster-
kocytosis with a shift to the left in differential cell count is usual num-mediastinum and posterior spinal tissues.
(82 to 100%) (117). Extrapulmonary sites of infection, such as Infections of the sternal wound and mediastinum have been
the urinary tract, skin, or other tissues, are rarely detected. In reported in 1 to 6% of cases following sternotomy for cardiac
the absence of extrapulmonary foci for possible hematogenous surgery. Historically, staphylococci have predominated, with
seeding of the lungs, it has been presumed that the infecting cases occurring sporadically or in clusters (170). Enterobacter
Enterobacter spp. arise from the normal flora and colonize the spp. were recognized as important pathogens subsequently.
oropharyngeal secretions (117). Although bacteremia is rela- The experience of Palmer et al. has been typical (170). Distin-
tively common in patients with Enterobacter pneumonia, shock guishing features in their hospital were (i) apparent clustering
is infrequent and metastatic foci of infection are seldom de- of cases with no demonstrable common source; (ii) involve-
tected. ment of E. cloacae or E. aerogenes or both; (iii) coinfection
Roentgenographic features of Enterobacter pneumonia may with staphylococci in 25% of patients; (iv) colonization of the
vary widely (20, 40, 117). Chung et al. described 10 patients sternum, groin, and wounds both before and after surgery; and
with nosocomial pneumonia over a 1-year period (40). Diag- (v) correlation of colonization with cephalosporin use. Dimi-
nostic criteria were relatively stringent (isolation from cultures nution of the problem was achieved by (i) enforced barrier
of respiratory secretions as well as blood or pleural fluid). isolation, (ii) decreasing contacts in the immediate postopera-
Infiltrates on chest roentgenograph were lobar (20%), bron- tive period, and (iii) reducing the duration of cephalosporin
chopneumonic (30%), interstitial (20%), and mixed (30%). prophylaxis. Massie et al. have reviewed the literature and
Bodey et al. noted single-lobe involvement in 46% of 54 pa- their experience with postoperative posterior spinal wound
tients and multilobar or diffuse bilateral disease in 54% (20). infections (147). Once again, Enterobacter spp. were noted to
Effusion, empyema, and cavitation have been reported, but have emerged in an area previously dominated almost exclu-
they appear to be relatively infrequent in comparison with sively by S. aureus. E. cloacae accounted for 4 (18%) of 22 of
their occurrence in other gram-negative bacillary pneumonias their cases and was second only to species of staphylococci in
(40, 63, 107, 117). frequency. The authors noted that over half of the infections
Pneumonias due to Enterobacter spp. are often lethal. Re- were polymicrobial and that Enterobacter infection was closely
ported mortality rates range from 14 to 71% and tend to be associated with inferiorly placed drains left in place for greater
higher than those for pneumonias due to many other gram- than 48 h.
negative bacilli (20, 40, 117, 133, 142). The single most impor- Soft tissue infections in healthy individuals. Enterobacter
tant determinant of outcome has been the severity of the spp. have been increasingly recognized as causes of infection
underlying disease (20, 40, 117, 133). Additional risk factors for acquired in the community. More recent evidence indicates
unfavorable outcome include implication of multiple patho- that these infections may occur in previously healthy individ-
gens (40, 117), antecedent corticosteroid therapy (117), and uals and occasionally involve multiply resistant strains. Four
extent of disease on the chest roentgenograph (20, 117). Kar- reports provide cases in point. Ganelin and Ellis described a
nad et al. observed a trend toward a more favorable outcome 58-year-old physician who developed a subungual hematoma
with the use of two or more drugs, rather than one, to which of his great toe while playing tennis in ill-fitting shoes (75).

the infecting Enterobacter spp. was susceptible (117). Unfortu- Within hours, the area developed signs and symptoms of in-
nately, the numbers of patients were too few to permit a mean- fection. Culture of purulent exudate yielded E. cloacae that
ingful statistical analysis. was resistant to all antibiotics tested except imipenem. The
patient recovered uneventfully after a course of parenteral
Infections of Skin and Soft Tissues therapy. McCown described a deep infection of the hand in a
previously well 11-year-old boy who had fallen at the edge of a
Enterobacter spp. have been implicated as causes of an array pond, sustaining a laceration of his hand (152). Cultures of
of clinical syndromes involving the skin and soft tissues: cellu- debrided material grew E. cloacae and a few colonies of
litis, fasciitis, abscesses, emphysema, myositis, and wound in- Citrobacter freundii. The E. cloacae strain was susceptible only
fections (38, 56, 75, 95, 107, 124, 152, 170). The clinical and to extended-spectrum b-lactams and aminoglycosides, while
laboratory features of most of these syndromes differ little the C. freundii strain was susceptible to all agents tested except
from those caused by other enteric bacilli, and approaches to cefazolin. The patient was treated with cefazolin and clinda-
management are comparable. However, two recent trends dis- mycin. He responded definitively only after repeated debride-
tinguish Enterobacter spp.: (i) an increasing role in institution- ments and removal of small pieces of wood from the palmar
ally acquired wound infections and (ii) the occurrence of skin space on several occasions. Kronish and McLeish described the
and soft tissue infections in previously healthy individuals in development of periorbital necrotizing fasciitis in a 26-year-old
the community, occasionally as a result of multiply resistant woman following trauma to her temple. E. aerogenes and
strains. Citrobacter diversus were recovered from debrided necrotic
Institutionally acquired infections of surgical wounds and tissues (124). No gram-positive organisms were seen or cul-
burns. The proportion of nosocomial wound infections due to tured. Although the patient was originally given empirical
Enterobacter spp. has increased throughout recent decades (57, treatment with penicillin and methicillin, she ultimately re-
105, 107, 194). Results of the NNIS program for 1986 to 1990 sponded to debridement and gentamicin followed by oral cip-
indicated that Enterobacter spp. were the fourth most common rofloxacin. The authors noted that each of 15 previously re-
cause (10.3% of total) of surgical wound infections in ICU and ported cases of periorbital necrotizing fasciitis had been caused
the most common gram-negative organisms implicated (105). by a streptococcus, most often belonging to Lancefield’s sero-
TABLE 11. Characteristics of endocarditis due to or emergence of resistance during therapy, the authors con-
Enterobacter spp. in 18 patientsa sider a carbapenem the “antimicrobial agent of choice,” with
Characteristic No. (%) fluoroquinolones as possible alternatives. Clinical experience
has shown the likelihood of medical cure is greater for right-
Antecedent cardiac disease ......................................................12 (67) sided than left-sided endocarditis. Valvular surgery is appro-
Prosthetic valves..................................................................... 5 (28)
priate for those failing medical management.
Rheumatic heart disease....................................................... 4 (22)
Congenital............................................................................... 2 (11)
Trauma .................................................................................... 1 (6) Intra-abdominal Infections
Intravenous drug abuse............................................................. 6 (33)

Enterobacter spp. have often been implicated in intra-ab-
dominal infections. This is consistent with their residence in
Valve involved the colonic flora of many humans. Traditionally, they have
Mitral....................................................................................... 6 (33) gained access to the peritoneum and other viscera by translo-
Mitral and aortic.................................................................... 4 (22) cation or perforation to initiate a broad array of infectious
Tricuspid ................................................................................. 4 (22) syndromes. Their role in biliary sepsis was recognized prior to
1980 and continues prominently into this decade (4, 87, 107).
Polymicrobial etiology ............................................................... 2 (11) More recent literature emphasizes the importance of Enter-
obacter spp. in bacteremia of gastrointestinal origin, especially
Surgical therapy performed ...................................................... 3 (17)
in association with hepatic transplantation (see above). Newly
Mortality recognized or better-defined syndromes include hepatic gas
Overall..................................................................................... 8 (44) gangrene (172), fulminant emphysematous cholecystitis and
Left-sided disease .................................................................. 7/14 (50) bacteremias following endoscopic retrograde cholangiopancre-
Right-sided disease ................................................................ 1/4 (25) atography (4, 208), acute suppurative cholangitis with intermit-
a
tent obstruction due to biliary sludge (87), and secondary peri-
Modified from reference 217 with permission of the publisher.
tonitis following small bowel obstruction in the absence of
perforation or known causes of ascites (195).
group A. Finally, Helovuo et al. described oral infections due
to “multiply resistant bacteria” including Enterobacter spp. and Urinary Tract Infections
other gram-negative bacilli (95). Previous courses of antimi- The clinical manifestations of urinary tract infections due to
crobial agents for periodontal infections may have selected for Enterobacter spp. differ little from those of infections due to
these resistant strains (95). other gram-negative bacilli. The spectrum of illness ranges
from asymptomatic bacteriuria to pyelonephritis and urosepsis
Endocarditis (107). Prior to 1980, Enterobacter spp. accounted for 0 to 14%
of infections reviewed by John et al. (107). The highest rate was
Endocarditis due to gram-negative bacilli appears to be in- in North American women with bacteriuria detected on rou-
creasing in incidence. The risk appears highest in intravenous tine health examination. More recently, Enterobacter spp. have
drug abusers and individuals with prosthetic valves (217). En- accounted for 2.4% of childhood urinary tract infections in
terobacter spp. have been implicated relatively infrequently. Saudi Arabia (3) and 6 to 7% of nosocomial infections in the
Prior to 1980, there were anecdotal reports of Enterobacter United States (105, 194). There is reason to believe that the
endocarditis associated with penetrating foreign bodies, me- incidence of Enterobacter spp. among nosocomial urinary
chanical and porcine prosthetic valves, intravenous drug abuse, pathogens is slowly increasing over the years (105, 194).

and cardiac surgery (107). Multiple drug resistance has been observed in nosocomial
Case reports in English from 1949 to 1990 have recently Enterobacter urinary isolates (3, 88). The role of antecedent
been reviewed by Tunkel et al. (217). The salient features of 18 antimicrobial administration in selecting for resistance has
cases are summarized in Table 11. Underlying heart disease been emphasized (88, 186). Unfortunately, the problem ap-
and intravenous drug abuse were prominent risk factors. Left- pears to have escaped the confines of the hospital setting. Mani
sided cardiac involvement was most common except in intra- and colleagues have described an instance of community-ac-
venous drug abusers. Two (11%) of the cases were polymicro- quired urosepsis due to a multiply resistant Enterobacter sp. in
bial in etiology; additional organisms were S. aureus, Candida a woman who had not received antimicrobial agents known to
albicans, and Paracolobactrum aerogenes in one and E. faecalis predispose to emergence of resistance (144). Continued sur-
and a viridans streptococcus in another. Surgical therapy was veillance of the susceptibility of community-acquired isolates
performed in three patients (17%), two of whom survived. The now appears imperative.
overall mortality was 44%; the rate was twofold higher in
patients with left-sided than in right-sided disease.
Central Nervous System Infections
Tunkel et al. concluded that optimal treatment for Enter-
obacter endocarditis “remains unclear,” but they have provided Enterobacter spp. have been implicated as etiologic agents in
tentative guidelines for management (217). They suggest that a variety of central nervous system infections. Meningitis, ven-
antimicrobial therapy be selected on the basis of in vitro sus- triculitis, brain abscess, and infections proximate to foreign
ceptibility test results plus “bactericidal synergy studies” with a bodies have been reported episodically over the years (107).
b-lactam plus an aminoglycoside. They also recommend main- With few exceptions, the clinical manifestations of these infec-
tenance of trough bactericidal titers in serum of at least 1:8 tions did not differ from those of infections with other mem-
with the combination. Although the appropriate duration of bers of the Enterobacteriaceae. More recent reports have fo-
therapy remains controversial, the authors usually continue cused upon an overall increase in the incidence of meningitis
treatment for 4 to 6 weeks. Repeated culturing of blood is due to enteric bacilli, emergence of resistance among strains of
necessary to detect suboptimal responses or possible emer- Enterobacter, use of novel regimens for treatment, and the
gence of resistance. In instances of de novo multiple resistance special problems posed by E. sakazakii.
Unhanand et al. reviewed 21 years of experience with central fected with a multiply resistant strain or had failed to respond
nervous system infections due to gram-negative bacilli in neo- to cephalosporin-containing regimens.
nates and infants (221). They found that the overall incidence E. sakazakii has been recognized for over three decades as
was low (3.6%) but increasing, and they identified neural tube the cause of a distinctive syndrome of meningitis in neonates.
defects and urinary tract anomalies as major risk factors for all Willis and Robinson described 2 cases of their own and re-
enteric bacilli. Antecedent surgery was also an important risk viewed an additional 15 cases from the literature in 1988 (242).
factor for E. coli, Klebsiella spp., and Enterobacter spp. specif- Although the presenting symptoms were no different from
ically. Wolff et al. reviewed the literature and their experience those due to other gram-negative bacilli, complications were
with Enterobacter meningitis in adults between 1983 and 1992 more common and the ultimate outcome was dismal. Cysts or
(243). They found an increase in incidence over the period of abscesses or both were described in 7 (41%) of 17 patients,
observation and noted that Enterobacter spp. were the second although they were not specifically sought in several instances.
most common cause of meningitis due to gram-negative bacilli Willis and Robinson reported a case/fatality rate of 50% (242),
(17% of the total). which contrasts sharply to the 17% rate noted for meningitis
Almost all recent reports concerning central nervous system due to all enteric bacilli (221). Similarly, the rate of severe
infections highlight the problem of emerging resistance of En- sequelae among survivors (94%) was higher with E. sakazakii
terobacter spp. to multiple drugs. Several anecdotal reports (44, (53) than that (61%) for other enteric bacilli (221).
83, 97) and one systematic retrospective study (243) have been Recent evidence has shed some light on the pathogenesis of
published. The overwhelming majority of instances of emer- the cerebral damage initiated by E. sakazakii. Initially, many of
gence of multiple b-lactam resistance have followed the use of the lesions were interpreted as abscesses. Subsequently, it was
extended-spectrum cephalosporins. Emergence of resistance recognized that others were noninfected cysts (242), and it was
to carbapenems and fluoroquinolones has been described suggested that these were in fact liquefied infarcts (74, 242).
rarely. Wolff et al. identified the emergence of multiple b-lac- Using enhanced computed tomography, Gallagher and Ball
tam resistance in 4 (40%) of 10 patients with Enterobacter have confirmed that the initial event is infarction that, because
meningitis who were given cephalosporins in their institution of ring enhancement, may mimic abscess formation (74). The
and in 8 (27%) of 30 similar patients described in the literature subsequent course of events appears to be liquefaction and
(243). The combined rate of emergence of resistance was 30% usually sterile cyst formation. However, only aspiration and
(12 of 40 patients). This exceeded the rate (19%) of emergence culture may definitively exclude an infectious process. This
of resistance observed by Quinn et al. in patients with bacte- distinctive clinical syndrome has also been observed during the
remia (181). course of meningitis due to C. diversus, an organism that shares
a 50% relationship to E. sakazakii by DNA-DNA hybridization
There is no general agreement on the appropriate regi-
techniques (74).
men(s) for treatment of central nervous system infections due
to gram-negative bacilli in general and Enterobacter spp. in
specific. This was underscored by Unhanand et al., who ob- Ophthalmic Infections
served that 51 different antimicrobial regimens were adminis-
Enterobacter spp. have been implicated in a variety of infec-
tered to the 98 patients seen at their institution between 1969
tious processes involving the eyes and periorbital tissues (39,
and 1989 (221). The problem has been further compounded by 124, 156). Most reports, which span the last three decades,
emergence of multiple drug resistance, especially in the last have been anecdotal. The most important recent development
decade. The early literature described occasional patients who is recognition of the etiologic role of gram-negative bacilli in
were treated successfully with intrathecal or intracisternal plus endophthalmitis, especially that occurring postoperatively or
parenteral aminoglycosides, most often gentamicin (107). following trauma (103). Cataract extraction with placement of

More recent data suggest that in neonates at least, addition of intraocular lenses is the ophthalmic surgical procedure most
local instillations of an aminoglycoside to nonaminoglycoside commonly performed today (156). Postoperative endoph-
parenteral agents has little or no effect on the therapeutic thalmitis is a devastating consequence that often results in loss
outcome. Wolff et al. retrospectively compared outcomes of of vision or of the eye itself. Historically, the overwhelming
regimens containing extended-spectrum cephalosporins or tri- majority of these infections have been due to gram-positive
methoprim-sulfamethoxazole (243). Cure was achieved with organisms. Recent series indicate that up to 30% of cases may
cephalosporin monotherapy in only 4 (50%) of 8 patients in be due to gram-negative bacilli (103, 156). The prognosis is
their institution and 17 (71%) of 24 described in the literature. best for infection due to coagulase-negative staphylococci and
Although the numbers of patients were small (6), the addition worst for infection due to gram-negative bacilli, especially
of an aminoglycoside to the cephalosporin increased the cure Pseudomonas spp. and Enterobacter spp. (103, 156, 157). Al-
rate to 83% overall. In contrast to the experience with cepha- though Enterobacter spp. account for only a small fraction of
losporins, trimethoprim-sulfamethoxazole was successful as cases of endophthalmitis, they are among the most aggressive
monotherapy in seven (100%) of seven patients and as part of pathogens, may be multiply resistant de novo or become resis-
a combination (two with a cephalosporin and one with an tant during therapy, and may cause outbreaks arising from
aminoglycoside) in three (100%) of three additional patients. environmental contamination (103, 156, 157).
Emergence of resistance was not observed during or after the Milewski and Klevjer-Anderson recently described a patient
use of trimethoprim-sulfamethoxazole. Recent anecdotal re- who was prototypical for Enterobacter ophthalmitis (156). An
ports have described cures with fluoroquinolones in two (67%) 81-year-old woman with polymyalgia rheumatica receiving cor-
of three adults with meningitis (243), high-dose imipenem (8 ticosteroid therapy underwent cataract extraction and intraoc-
g/24 h) plus parenteral and intrathecal amikacin in an adult ular lens placement. Three days postoperatively, she developed
with meningitis (44), ciprofloxacin plus amikacin in an infant a relentlessly progressive infection due to E. cloacae. Despite
with ventriculitis (83), chloramphenicol plus trimethoprim-sul- in vitro susceptibility of the E. cloacae, administration of ticar-
famethoxazole in a neonate with meningitis and infected sub- cillin-clavulanate and then ceftazidime, both supplemented by
dural effusion, and meropenem monotherapy in a child with a parenteral and intraocular aminoglycosides, failed to alter the
brain abscess (154). Many of the foregoing patients were in- course of the infection. Current recommendations for therapy
TABLE 12. Mimicry by Enterobacter spp. of syndromes commonly attributed to other organisms
Syndrome (reference[s]) Usual pathogen(s) Traditional empiric antimicrobial therapy
Acute purpura fulminans (89) Meningococci, viruses A penicillin

Ecthyma gangrenosum (182) Pseudomonas aeruginosa Antipseudomonal b-lactam and aminoglycoside
Necrotizing fasciitis, especially periorbital (124) Group A streptococci A penicillin
Posterior spinal wound infection (147) Staphylococcus aureus Penicillinase-resistant b-lactam
Postoperative mediastinitis (170) Staphylococci Penicillinase-resistant b-lactam or vancomycin
Emphysematous cholecystitis (4) Clostridium spp., other enteric A penicillin or other b-lactam
bacteria
Lobar pneumonia in the elderly (20, 40, 117) Streptococcus pneumoniae A penicillin or vancomycin
Neonatal bacteremia, meningitis, cerebral Citrobacter diversus Older penicillins or cephalosporins, aminoglycosides
infarction, and cyst formation (74, 242)
Postoperative endophthalmitis (103, 156) Staphylococci, rare enteric bacteria Penicillinase-resistant b-lactam, aminoglycoside
and prophylaxis of endophthalmitis include ceftriaxone (157) methoprim-sulfamethoxazole. Two strains of E. agglomerans
or ceftazidime (103), especially if the presence of a gram- were isolated from the cotton used for filtration; one had an
negative bacillus is known or suspected. Given the relatively antimicrobial susceptibility pattern that was identical to that of
high rates of de novo resistance and emergence of resistance the bloodstream isolate. Two other observations support the
during therapy, consideration of alternative agents such as proposed role of E. agglomerans. First, cotton and cotton
carbapenems or fluoroquinolones may be prudent. plants are commonly heavily colonized by gram-negative ba-
cilli, especially E. agglomerans (189). Second, E. agglomerans
Septic Arthritis and Osteomyelitis endotoxin has been shown to recruit neutrophils and activate
pulmonary macrophages, resulting in fever, chest tightness,
Enterobacter spp. have been implicated in a variety of syn- and bronchoconstriction in workers exposed to cotton dust
dromes that involve the bones and joints. Although relatively (188). As a result of these observations, it may be prudent to
infrequent, severe septic arthritis (19, 102, 107, 240), osteomy- assume that patients with cotton fever are infected with E.
elitis (102, 107, 240), infections of multiple bones and joints in agglomerans until proven otherwise.
infants and children (107), vertebral osteomyelitis (107, 145,
202), bilateral hip infections (107), and prosthetic hip infec-
Mimicry of Syndromes Commonly Attributed
tions (107) have been reported over the past three decades.
to Other Organisms
Recent literature concerning these entities is scant. However,
two developments are noteworthy. The first is the implication As Enterobacter spp. have been implicated in the causation
of Enterobacter spp. as a cause of septic arthritis following of an increasing number of clinical entities, it has become
arthroscopy, although these organisms are a distant third in apparent that in many instances they may closely mimic patho-
frequency after S. aureus and coagulase-negative staphylococci gens that cause syndromes heretofore commonly or even ex-
(9). The second is a spate of recent case reports of vertebral clusively associated with other organisms. Since the antimicro-
spondylodiscitis due to E. cloacae (35, 145, 202). This syn- bial susceptibilities of the Enterobacter spp. may differ
drome has been seen in elderly individuals and in an intrave- markedly from those of the pathogen mimicked, traditional
nous drug abuser. The diagnosis has been made by culture of regimens for empiric therapy of these syndromes may need to
be modified accordingly. Some of the more common syn-

blood, puncture biopsy, or both. Successful treatment has been
observed with pefloxacin plus amikacin parenterally followed dromes that may be mimicked and their usual etiologies are
by pefloxacin plus cefixime orally (145), trimethoprim-sulfame- shown in Table 12. The literature reviewed gives the impres-
thoxazole parenterally for 10 days followed by 6 months orally sion that mimicry in most of the entities listed is distinctly more
(202), and cefixime orally (35). common with Enterobacter spp. than with other opportunistic
gram-negative bacilli. The need for reevaluation of traditional
Cotton Fever empiric regimens is apparent.
Cotton fever is a “street term” for an acute febrile reaction
experienced after intravenous injection of heroin that has been PERSPECTIVE ON THE FUTURE
filtered through cotton (61). Thompson introduced the term Enterobacter spp. appear well adapted for survival and pro-
into medical jargon in 1975 to describe a syndrome in intrave- liferation as the turn of the century approaches. Options for
nous drug abusers of fever and leukocytosis in the apparent control of these organisms are quite limited. Rigid infection
absence of bacterial infection (211). Since that time, cotton control procedures and meticulous attention to principles of
fever has been thought to be a usually benign, self-limiting antisepsis may reduce the occurrence of the relatively infre-
syndrome that mimics sepsis. A variety of theories have been quent outbreaks that are traceable to human vectors or envi-
advanced to explain the pathogenesis of cotton fever. These ronmental contamination. However, the usual infection con-
include the presence of pyrogenic chemicals in cotton, hyper- trol procedures are unlikely to affect the overall incidence of
sensitivity to components of cotton extracts, and endotoxin nosocomial Enterobacter infections, because the overwhelming
reactivity (61, 188, 189). Ferguson et al. have recently impli- majority arise endogenously from the flora of the patient who
cated E. agglomerans as the most probable cause of cotton has become chronically colonized. Studies to determine fun-
fever (61). They described a 28-year-old patient who experi- damental biological factors that favor colonization are clearly
enced typical signs and symptoms 10 min after intravenous warranted. Selective decontamination of the gastrointestinal
injection of a heroin-tap water mixture that he had filtered tract and avoidance of the use of agents that lower the gastric
through cotton. Cultures of his blood contained E. agglomer- pH to reduce oropharyngeal colonization are rational, but un-
ans. The patient ultimately responded to a course of tri- proven, approaches that should be subject to controlled clinical
trials (50, 116, 235). Evidence, summarized above, is mounting 3. Almugeiren, M. M., and S. M. H. Qadri. 1991. Etiology of childhood
that extended-spectrum cephalosporins play an important, if urinary tract infections and antimicrobial susceptibility of uropathogens at
a teaching hospital in Saudi Arabia. Curr. Ther. Res. 50:454–459.
not major, role in favoring colonization and subsequent infec- 4. Alvarez, C., K. Hunt, S. Ashley, and H. A. Reber. 1994. Emphysematous
tion by Enterobacter spp. In fact, these agents may be equally cholecystitis after ERCP. Dig. Dis. Sci. 39:1719–1723.
important in selecting multiply resistant strains of enterococci 5. Andersen, B. M., S. M. Almdahl, D. Sorlie, R. Hotvedt, J. Backer-Chris-
in the hospital (36, 246) and pneumococci in the community tensen, R. B. Nicolaysen, and O. I. Solem. 1990. Enterobacter cloacae-
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could reduce or eliminate the selective advantages afforded to 6. Anderson, E. L., and J. P. Hieber. 1983. An outbreak of gentamicin-resis-
Enterobacter spp. in general and several other multiply resistant Enterobacter cloacae infections in a pediatric intensive care unit. Infect.
tant organisms as well. Control 4:148–152.
7. Andresen, J., B. I. Asmar, and A. S. Dajani. 1994. Increasing Enterobacter
The evidence that Enterobacter spp., including multiply re- bacteremia in pediatric patients. Pediatr. Infect. Dis. J. 13:787–792.
sistant strains, are increasingly important etiologic agents in 8. Arángiz, A. F., R. Alonso, K. Colom, A. Morla, E. Suinaga, and R. Cisterna.
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risk factors for the acquisition of Enterobacter spp. in the com- Dorche. 1992. Changes in the sensitivity of urinary pathogens to quinolones
between 1987 and 1990 in France. Eur. J. Clin. Microbiol. Infect. Dis.
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the survival and transmissibility of the organisms in solutions 15. Bauernfeind, A., R. Jungwirth, and S. Schweighart. 1989. In-vitro activity of
meropenem imipenem, the penem HRE 664 and ceftazidime against clin-
and on surfaces of catheters or medical devices? What ac- ical isolates from West Germany. J. Antimicrob. Chemother. 24(Suppl.
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17. Bennett, S. N., M. M. McNeil, L. A. Bland, M. J. Arduino, M. E. Villarino,
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ACKNOWLEDGMENTS 21. Bonadio, W. A., D. Margolis, and M. Tovar. 1991. Enterobacter cloacae
bacteremia in children: a review of 30 cases in 12 years. Clin. Pediatr.
Our laboratory has received support for studies involving Enter- 30:310–313.
obacter spp. from the National Institutes of Health, DHEW, Bethesda, 22. Bone, R. C. 1993. Gram-negative sepsis: a dilemma of modern medicine.
Md.; Lederle Laboratories, Pearl River, N.Y.; Bayer Pharmaceuticals, Clin. Microbiol. Rev. 6:57–68.
West Haven, Conn.; Ortho-McNeill Pharmaceuticals, Rahway, N.J.; 23. Bonfiglio, G., S. Stefani, and G. Nicoletti. 1994. In vitro activity of cefpi-
Bristol-Myers Squibb, Princeton, N.J.; bioMérieux Vitek, St. Louis, rome against beta-lactamase-inducible and stably derepressed Enterobac-
Mo.; and Pfizer-Roerig, Inc., New York, N.Y. Zeneca Pharmaceuti- teriaceae. Chemotherapy 40:311–316.
cals, Macclesfield, England, provided assistance for the literature 24. Bonten, M. J. M., C. A. Gaillard, F. H. van Tiel, H. G. W. Smeets, S. van der
Geest, and E. E. Stobberingh. 1994. The stomach is not a source for
search and manuscript preparation. colonization of the upper respiratory tract and pneumonia in ICU patients.
We acknowledge the assistance of Bryn E. Bardsley, John Bell, Chest 105:878–883.
Joseph L. Barry, Andrea Prevan, Shailesh Patel, and Edward Kam- 25. Bouza, E., M. G. de la Torre, E. L. A. Erice, J. M. Diaz-Borrego, and L.
merer with literature searches. We are also grateful to Ernestine Buzón. 1985. Enterobacter bacteremia—an analysis of 50 episodes. Arch.
Fraser and Karen Wise for secretarial assistance. Intern. Med. 145:1024–1027.
26. Breyer, S., S. M. Feistauer, H. Burgmann, M. Georgopoulos, and A. Geor-
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CLINICAL MICROBIOLOGY REVIEWS, Apr. 1997, p. 220–241 Vol. 10, No.

Enterobacter spp.: Pathogens Poised To Flourish

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INTRODUCTION more easily treatable infectious agents, such as group A strep-

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TABLE 3. In vitro activity of various antibiotics against E. aerogenes and E. cloacaea

Ticarcillin (16) 259 2 64 550 2–8 .64

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TABLE 4. Characteristics of bacteremia due to Enterobacter spp. encountered in general hospitals

Reference Yr studied Patient population Total no. of Rate/1,000 Male/female Ages

Johnson and Ramphal (108) 1985–1989 Univ. teaching 51 NDa ND Adults

Andersen et al. (5) 1987–1988 Univ. teaching 10 ND ND ND

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TABLE 5. Characteristics of bacteremia due to Enterobacter spp. encountered in pediatric hospitals

Reference Yr studied Patient population Total no. Rate/1,000 Male/female Ages %

Gallagher (73) 1984–1988 Children’s hospital 33 0.44 1.2 1 day–24 yr 67

% % of species % Crude mortality

ND ND ND ND ND ND ND 25 One-third of the patients were neutropenic

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70 15 12 3 0 18 24, 18a Prototypical for pediatrics

Reference Yr studied Patient population Total no. Rate/1,000 Male/female %

John et al. (107) 1977–1980 Primarily burns 18 ND ND ND Most

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60 35 2 2 2 ND 35 Importance of antecedent colonization

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Devices, procedures, and locations

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TABLE 10. Outcome of antimicrobial therapy in bacteremia due to Enterobacter spp.

Appropriate Inappropriate P Reference Comment

45/54 (83) 4/11 (36) 0.001 37 Monotherapy

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Intravenous drug abuse............................................................. 6 (33)

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Acute purpura fulminans (89) Meningococci, viruses A penicillin

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