Enterobacterales Revisión 2021.en - Es

Traducido del inglés al español - www.onlinedoctranslator.
com
REVISIÓN
El rostro cambiante de la familiaenterobacterias (Pedido:

“Enterobacterales”):Nuevos miembros, problemas taxonómicos,
expansión geográfica y nuevas enfermedades y síndromes de
enfermedades
J. Michael Janda,aSharon L. AbbottB
a Laboratorio de Salud Pública, Departamento de Servicios de Salud Pública, Bakersfield, California, EE. UU.
BReno, Nevada, Estados Unidos
RESUMEN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
INTRODUCCIÓN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Aspectos Históricos. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Marcadores Fenotípicos y Moleculares Tradicionales de la Familia. . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Principales Aspectos Clínicos y de Salud Pública de la Familia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Enfermedades transmitidas por alimentos y brotes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
HAI. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . LA 5
FAMILIAENTEROBACTERIACEAE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Era posterior a 1980: la familia que no fue. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Expansión de géneros y especies (1980 a 2020) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Ampliación de la familia debido a la nueva tecnología. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Temas de taxonomía moderna y expansión familiar. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11
NOMENCLATURA Y TAXONOMÍA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Taxonomía. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11
Nomenclatura y la CIPE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11
Validación. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12 Anomalías de nomenclatura en la familia.enterobacterias. . . . . . . . . . . . . . . . . . . . . . . . . . .12
Clasificación. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12 La familiaenterobacterias—Estado actual . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13
Definición actual de familia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13 Elementos
centrales y periféricos. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14 Estudios
Downloaded from https://journals.asm.org/journal/cmr on 17 March 2022 by 179.56.245.80.

filogenéticos. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14 Especies o
taxones de estatus incierto. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14
(I)Salmonelaespecies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14
(ii)EnterobacteryEnterobacter hormaechei. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15
(iii)Yersinia ruckeri . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
(iv) Edwardsiella tarda biogroup 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
(v) Enteric groups, HGs, and related taxa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Cladistic Analysis, and Phylogenetic Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
A polyphyletic family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16 Proposal to reclassify members of the order “Enterobacterales” . . . . . . . . . . . . . . . . . . . . . 16
Clinical and public health implications of proposed taxonomic changes . . . . . . . . . . . 18
ENTEROBACTERIACEAE—ENVIRONMENTAL DISTRIBUTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Extension in Ecohabitats of Enterobacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Selected
Ecosystems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Vegetation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
CitaciónJanda JM, Abbot SL. 2021. El
Insects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
cambiando la cara de la familiaenterobacterias
(i) Los insectos como vectores mecánicos. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21
(pedido: "enterobacterias”):nuevos miembros,
(ii) Insectos comestibles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22
taxonomic issues, geographic expansion, and
animales . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22 Suelo y
new diseases and disease syndromes. Clin
agua. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23 ENTEROBACTERIACEAE—
Microbiol Rev 34:e00174-20. https://doi.org/10
ANTIGUOS Y NUEVOS AGENTES EN NUEVOS ENTORNOS DE ENFERMEDADES. . . . . . . . . 23
. 1128/CMR.00174-20.
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Copyright © 2021 American Society for
Recently Identified Gastrointestinal Pathogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Microbiology. All Rights Reserved.
Providencia alcalifaciens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Escherichia albertii . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Address correspondence to J. Michael Janda,
Klebsiella oxytoca and colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 jandam@kerncounty.com.
Potential enteropathogens with inconclusive data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Published 24 February 2021
(Continued)
April 2021 Volume 34 Issue 2 e00174-20 Clinical Microbiology Reviews cmr.asm.org 1

Janda and Abbott Clinical Microbiology Reviews
Extraintestinal Diseases and Infectious Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Klebsiella pneumoniae and PLA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Cronobacter sakazakii and neonatal meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Chronic
conditions and potential long-term sequelae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Colorectal cancer and
related malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 THE
FUTURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Issue: The Family Enterobacteriaceae—Expansion or Contraction? . . . . . . . . . . . . . . . . . . . . . 33
Possible classification models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
(i) Proposal 1. Classification of genera into tribes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
(ii) Proposal 2. Classification of genera into subfamilies . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
(iii) Proposal 3. Classification of Enterobacteriaceae into “groups” . . . . . . . . . . . . . . . . . 34
(iv) Proposal 4. Nonclassification system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Issue: Species Identification in the Modern Era for Clinical Laboratories . . . . . . . . . . . . . . . 35
From conventional to commercial to molecular approaches . . . . . . . . . . . . . . . . . . . . . . . . 35
Techniques versus a plethora of taxa: problematic issues . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
ACKNOWLEDGMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
AUTHOR BIOS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
SUMMARY The family Enterobacteriaceae ha sufrido cambios morfogenéticos significativos en

sus más de 85 años de historia, particularmente durante las últimas 2 décadas (2000 a 2020).
El desarrollo y la introducción de métodos moleculares nuevos y novedosos junto con
técnicas de laboratorio innovadoras han dado lugar a muchos avances. Ahora sabemos que
la gama global de enterobacterias es mucho más amplia de lo que se reconocía
anteriormente, ya que desempeñan funciones importantes en el medio ambiente en los
procesos vegetativos y mediante una distribución ambiental generalizada a través de insectos
vectores. En humanos, se han descrito muchas especies nuevas, algunas asociadas con
procesos de enfermedades específicas. Algunas especies establecidas ahora se observan en
nuevos entornos y síndromes de enfermedades infecciosas. Los resultados de estudios
taxonómicos y filogenéticos moleculares sugieren que la familia actualenterobacteriasshould
possibly be divided into seven or more separate families. The logarithmic explosion in the
number of enterobacterial species described brings into question the relevancy, need, and
mechanisms to potentially identify these taxa. This review covers the progression,
transformation, and morphogenesis of the family from the seminal Centers for Disease
Control and Prevention publication (J. J. Farmer III, B. R. Davis, F. W. Hickman-Brenner, A.
McWhorter, et al., J Clin Microbiol 21:46–76, 1985, https://doi . org/10.1128/
JCM.21.1.46-76.1985) to the present.

KEYWORDS Enterobacteriaceae, enterobacteria, insect vectors, liver abscess, meninigitis,
phylogeny, plant diseases, taxonomy, transmissible gastroenteritis virus
INTRODUCTION
Historical Aspects
N o El grupo colectivo de bacterias procarióticas definidas actualmente ha tenido un mayor

impacto médico, de salud pública y veterinario en la comunidad global que la familia.
enterobacterias (1–3). Las enterobacterias no solo están asociadas con una amplia gama de
síndromes clínicos, sino que la familia también es un importante agente causante de enteritis
transmitida por alimentos e infecciones zoonóticas, que incluyen brotes esporádicos o pandémicos
de peste humana (1).
El impacto de la familia no se detiene ahí. Ampliamente dispersos en la naturaleza en muchos
ecosistemas naturales, los miembros de la familia están cada vez más implicados como patógenos
de especies de peces (naturales, acuícolas) (4), así como el agente etiológico de una variedad de
enfermedades de las plantas (5). Finalmente, la familia ha sido reconocida por su impacto en la
biología molecular y celular, la estructura y función de los genes y la patogenicidad microbiana. Una
excelente lista de notables descubrimientos asociados con laenterobacteriasse puede encontrar en
el capítulo de Farmer et al. (1) en la décima edición deMicrobiología e infecciones microbianas de
Topley & Wilson.
Si bien los miembros actuales de esta familia han sido reconocidos por más de
Abril 2021 Volumen 34 Edición 2 e00174-20 cmr.asm.org2

La familiaenterobacterias—2020 Reseñas de microbiología clínica
100 years, the formalized origins of this family can be traced back to the 1937 publication of
Rahn (6). The family Enterobacteriaceae was subsequently created with a single type genus (
Enterobacter) to house a collection of 112 species previously referred to as the “colon-typhoid
group” (2, 7). This group was originally defined by a set of unifying phenotypic traits, including
Gram stain reaction (negative), good growth on artificial media, acid formation from D
-glucose (often with gas), and production of nitrites from nitrate. Many genera with current
taxonomic standing were represented within the genus “Enterobacter” when the family was
first proposed, including Escherichia, Klebsiella, Shigella, and Proteus (2).
Over the next 201 years, considerable controversy occurred regarding the exact number
and names for delineated taxa that existed within the family Enterobacteriaceae
(8). Multiple issues caused these nomenclature problems, including taxonomic proposals
based upon minimal phenotypic data, a limited array of biochemical features available, the
use of nonstandardized test methodologies, and no Bacteriological Code to govern the
legitimacy or correctness of proposed taxa. By 1944, considerable difficulty was reported on
defining criteria for inclusion of members in this family, since the fifth edition of Bergey’s
Manual of Determinative Bacteriology already contained such names as Paracolobactrum,
Colobactrum, Proshigella, and Shigella ambigua (8). Excellent historical perspectives on this
topic can be found elsewhere (1, 2).
During the early and mid-1960s, a more formalized system was developed by the
U.S. Centers for Disease Control and Prevention (CDC), which included a standardized
set of 50 or more biochemical and phenotypic properties and computer-based software
programs employing numerical taxonomy that compared phenotypes of two groups by
matching similarities (Ssm) (9). By the mid-1970s, Don Brenner and his colleagues (10) at
the CDC were defining existing and previously unrecognized taxa of enteric bacteria by
using a polyphasic approach. This approach coupled 50 to 200 morphologic, cultural,
and biochemical features to genetic studies of DNA relatedness by DNA-DNA
hybridization (DDH) as well as mol% G1C content (10). Such pioneering efforts led to
classification changes, such as Enterobacter sakazakii (cloacae), Hafnia alvei
(Enterobacter hafniae), and Morganella (Proteus) morganii as examples. By 1985, the
CDC published a 30-page landmark study in the Journal of Clinical Microbiology
describing new species and biogroups within the family Enterobacteriaceae isolated
from clinical specimens (11).
Both the family name (Enterobacteriaceae versus Enterobacteraceae) and type
genus (Escherichia versus Enterobacter) have been unsuccessfully challenged over the

past several decades (7). For the purposes of this review, the family name
Enterobacteriaceae is used in the traditional or classic sense (pre-2016). Proposed
classification changes for members of the family are discussed below (see
Nomenclature and Taxonomy).
Traditional Phenotypic and Molecular Markers of the Family

Desde la infancia de la familia a fines de la década de 1930 hasta fines de la década de 1980, el medio
principal para identificar inicialmente taxones potenciales (géneros, especies) que residen en las
enterobacterias fue una serie de propiedades colectivas asociadas casi exclusivamente con esta familia.
Estos marcadores taxonómicos fueron elementos clave en el reconocimiento de cepas inusuales, nuevos
biotipos o genomoespecies potencialmente sin nombre antes de determinar la relación genética usando
DDH. Los rasgos utilizados para este propósito se ampliaron y refinaron gradualmente con el tiempo y
ayudaron a definir a la familia desde un punto de vista taxonómico.
Las reacciones generales definitorias que se han utilizado para identificar a los verdaderos
miembros de la enterobacteriasfor decades are listed in Table 1. These biochemical markers
have provided the phenotypic definition for the family and have been used by many
commercial companies in developing semiautomated and automated biochemical platforms
for their recognition. DDH, which came into vogue in the 1970s, further helped to refine this
family on a genetic basis prior to modern-day phylogenetic studies and full genome
sequencing.
Several of the properties listed in Table 1 bear special mention. A key marker almost
April 2021 Volume 34 Issue 2 e00174-20 cmr.asm.org 3

TABLE 1 Traditional markers associated with inclusion in the family Enterobacteriaceae
Characteristic Trait Typical reaction or value Exceptions

Gram stain Structural Negative
Flagella (polar) Structural Negative Plesiomonas, Tatumella
ECAa Structural Positive Dickeya chrysanthemi
Spore formation Structural Negative Serratia marcescens subsp. sakuensisb
Oxidase Biochemical Negative Alterococcusc, Franconibacterd, Plesiomonas Chania, Shigella
Catalase Biochemical Positive dysenteriae 1, Xenorhabdus Photorhabdus, Erwinia, Lonsdalea,
Nitrate reductase Biochemical Positive Rosenbergiella, Yersiniae
O/129 susceptibility Biochemical Positive Plesiomonas
D-Glucose Biochemical Positivef
D-Mannitol Biochemical Positive Edwardsiella tarda, Providencia rustigianii, Rosenbergiella,
Shigella dysenteriae type 1, among others
D-Xylose Biochemical Positive Cedeceae, Cosenzea, Edwardsiella, Izhakiella, Lonsdalea, Morganella,
Plesiomonas shigelloides, Yersinia ruckeri, among others
G1C (mol%) Genetic 38–60%
DNA relatednessg
Core Genetic 40–50% Salmonella, Klebsiella, Citrobacter, Enterobacter
Periphery Genetic 5–20% Edwardsiella, Morganella, Proteus, Providencia, Yersinia
aECA, enterobacterial common antigen.
bThe legitimacy of this subspecies and its ability to produce spores have been questioned (275).
cThis genus and species is listed in the family enterobacteriaspor el Consejo Editorial en la 2ª edición deManual de Bacteriología Sistemática de Bergey (276).
DReacción débil.
miAlgunos aislados.
FRaras excepciones de cepas.

gramoRelación del ADN con la especie tipoEscherichia coli.Los miembros del núcleo y la periferia se basan en el análisis filogenético.
asociado exclusivamente a esta familia se encuentra el antígeno común enterobacteriano o

ECA (12). ECA es un resto de carbohidrato cuya función exacta se desconoce actualmente
pero que se cree que desempeña un papel en el mantenimiento de la barrera de
permeabilidad de la membrana externa (12, 13). ECA se asocia casi exclusivamente con
miembros de laenterobacteriasy es un criterio taxonómico para la transferencia de
Plesiomonas shigelloides,que es ECA positivo, a esta familia en 2005 (14). Sólo dos especies
no entéricas,Actinobacillus equuliy Actinobacillus suis,have been found to possess this
antigen (15). Another point of demarcation used from the 1960s onward is G1C content. G1C
content for bacteria varies from 25 to 75mol% (16). In the case of the enterobacteria, the G1C
content has a wide range (38 to 60 mol%), which is not typically found for phylogenetically
“tight” families (Table 1). The family Moraxellaceae, as an example, has a much narrower G1C

content range of 38 to 50mol% (17). However, most genera in the family Enterobacteriaceae
have a G1C content of 49 to 59mol%, which is more in line with other families containing
phylogenetically related genera (1).
When the characteristics listed in Table 1 were first established, few exceptions to the
metrics were noted. However, with the expansion in the family in both the number of genera
and species and the transfer of other taxa to this family (e.g., P. shigelloides), more
exceptions have been observed. Most of these exceptions have been detected in more
recently described taxa since 2010 which are rarely associated with clinical infections or public
health issues (Table 1, exceptions).
Major Clinical and Public Health Aspects of the Family

Foodborne disease and outbreaks. Infectious diarrhea is a leading cause of
morbidity and mortality on a worldwide basis. The most recent figures released by the
Global Disease Burden (GBD) Diarrheal Diseases Collaborators (18) estimate that there
were 2.39 billion episodes of diarrheal disease in 2015, almost 1 billion of which
occurred in children under 5 years of age. The World Health Organization (WHO) further
estimates that from 550 to 600 million of these cases of diarrhea are foodborne
infections (19, 20). Projections that 70% of all diarrheal disease are food related (21)
translates to between 350 to 420 million episodes of gastroenteritis being of bacterial
etiology (19, 20). The figures are staggering.
Among major foodborne bacterial pathogens, the family Enterobacteriaceae is well

The Family Enterobacteriaceae—2020 Clinical Microbiology Reviews
represented by several groups, including Salmonella, Escherichia coli (O157, non-O157),

Shigella, and Yersinia enterocolitica (19, 21–23). The CDC Foodborne Diseases Active
Surveillance Network (FoodNet) provides active surveillance and epidemiologic studies
in conjunction with 10 state health departments regarding the above-listed agents (21).
FoodNet covers approximately 15% of the U.S. population. Not included in this list are
other members of the family Enterobacteriaceae such as Cronobacter sakazakii
(23). In addition to its association with neonatal meningitis and powdered infant
formula (24, 25), C. sakazakii has been implicated in a large-scale foodborne outbreak of
gastroenteritis in high school students and school employees (26).
Los datos más recientes de FoodNet para los años 2016 a 2019 informaron más de 25 000 casos de
infecciones diagnosticadas en laboratorio para 9 patógenos bacterianos y parasitarios principales
encuestados por 10 departamentos de salud estatales. Estas infecciones acumuladas resultaron en más de
6000 hospitalizaciones y 122 muertes (27). Se registraron altas tasas de incidencia (por 100.000 habitantes)
paraSalmonella (17.1 casos), productoras de toxina ShigaE. coli (STEC) (6,3 casos), yShigela (4,8 casos), que
clasificó a estos tres patógenos, despuésCampylobacter,como el segundo, tercer y cuarto patógeno
transmitido por los alimentos más común en incidencia. Para todos los miembros de esta familia
(incluyendoYersinia),las cifras de incidencia se mantuvieron sin cambios o aumentaron en comparación con
las cifras de 2006-2017, lo que sugiere que el progreso en el control de tales infecciones se ha estancado
(27, 28). Investigaciones previas de los CDC han encontrado Salmonelaser la principal causa de
hospitalizaciones y muertes por infecciones transmitidas por los alimentos (29). Cifras comparables para 26
estados miembros de la Unión Europea (UE) para 2015 incluyeron más de 4000 brotes transmitidos por los
alimentos y el agua y 45 874 casos de enfermedad (23). El patógeno bacteriano más común responsable de
los brotes de origen alimentario en la UE fueSalmonella (;34% de todos los brotes bacterianos).
Varias tendencias alarmantes parecen estar ocurriendo con los patógenos transmitidos
por los alimentos en la familiaEnterobacteriaceae.En primer lugar, además de las fuentes
tradicionales de brotes transmitidos por los alimentos asociados con las enterobacterias
(lácteos, aves, carne de res, cerdo, melones, brotes), un número cada vez mayor de otros
productos consumibles o condimentos se vinculan con los brotes. Estos incluyen albahaca (
Shigela),ensalada en bolsa (Y. enterocolítica),masa para galletas y semillas germinadas (E.
coli),and peanut butter and jalapeno and serrano peppers (Salmonella) (22). C. sakazakii has
also been isolated from various retail foods, including legumes, nuts, dried flour, and spices
(23). A second issue is the recent appearance of enterobacterial strains with “hybrid” virulence
characteristics causing foodborne outbreaks. In 2011, a major outbreak of food-related illness

associated with E. coli O104:H4 occurred in Germany (22). This outbreak was linked to the
consumption of sprouts (30). Of the more than 3,186 infections, approximately 22% of
patients developed hemolytic-uremic syndrome and 54 persons (1.7%) died (22). Subsequent
molecular analysis of the infecting strain revealed that it contained properties of
enteroaggregative E. coli and also had the capacity to produce Shiga toxin 2 (22). Two more
recent California outbreaks involving 56 patients were found to be caused by a Shiga toxin 1-
producing strain of Shigella sonnei (31). This genotype is rarely found in shigellae other than
Shigella dysenteriae type 1. Finally, in addition to CDC data, in Europe (GBD collaborators)
Shigella has become the most common bacterial foodborne pathogen associated with
mortality in children under the age of 5, with an estimated 54,900 deaths annually (18). The
wide distribution of enterobacteria in foods coupled with hygiene and sanitation issues poses
serious problems for developing nations (19).
HAI. The WHO estimates that there are over 4.5 million episodes of health careassociated
infections (HAI) in Europe each year, with a projected 37,000 deaths annually (https://
www.who.int/gpsc/country_work/gpsc_ccisc_fact_sheet_en.pdf). Las cifras comparables
reportadas por última vez para los Estados Unidos incluyen 99,000 muertes y $6,500 millones
en costos asociados con días adicionales de estadía en el hospital.
Géneros en la familiaenterobacteriasson patógenos importantes para tres de las cuatro
categorías principales de HAI según los CDC, a saber, infecciones del torrente sanguíneo asociadas a
la vía central (CLABSI), infecciones del tracto urinario asociadas al catéter (CAUTI) e infecciones del
sitio quirúrgico (SSI) (https://www.cdc.gov/hai/index.html). una investigacion

Janda y Abbot Reseñas de microbiología clínica
estudió la frecuencia relativa de los patógenos HAI dentro de la base de datos de atención
médica de la Universidad de Carolina del Norte durante un período de 28 años (1980 a 2008)
(32). Basado en la frecuencia general,E. coli, Klebsiella,yEnterobacter ranked 2nd, 7th, and
8th, respectively, in number of infections reported, with the genera Proteus, Serratia, and
Citrobacter ranking between 11th and 16th (32). A recent CDC study summarizing data
collected from 2011 to 2017 on CLABSI found the Enterobacteriaceae to be causing 23% to
31% of HAI in adult, pediatric, and oncology wards (33).
To further complicate the health care setting with enterobacterial infections is the
fact that over the last 10 to 15 years, antimicrobial resistance to carbapenem
compounds has emerged, dramatically restricting treatment options for serious
lifethreatening infections (34). A variety of Ambler class A, D, and B enzymes inactivate
carbapenems, including Klebsiella pneumoniae carbapenemase (KPC), New Delhi
metallo-b-lactamase (NDM), and Verona integron-encoded metallo-b-lactamase (VIM),
among others (34). Enteric species most commonly associated with these drug
resistance patterns are the most common HAI-associated species, such as E. coli, K.
pneumoniae, and Enterobacter cloacae complex. Increasing numbers of
carbapenemase-resistant Enterobacteriaceae (CRE) have been thought to be due to
expansion of clonal groups and horizontal gene transfer. However, a phylogenetic
analysis of many CRE strains at three hospitals in the Boston area suggest not only
remarkable genetic diversity but also limited clonal expansion (35). This suggests that
CRE transmission is occurring at multiple unsampled transmission points throughout
the health care process. This rapid rise has been recently documented in a National
Healthcare Safety Network (NHSN) summary report of 5,626 acute care facilities from
2015 to 2017 (36). In that epidemiologic survey of antimicrobial-resistant bacteria, E. coli
and K. pneumoniae were the most common and the third most frequently reported HAI
pathogens, respectively (36).
THE FAMILY ENTEROBACTERIACEAE

Post-1980 Era: The Family That Wasn’t
Modern bacterial nomenclature and taxonomy was born on 1 January 1980 with the
publication of the Approved Lists of Bacterial Names (AL) in the International Journal of
Systematic Bacteriology (IJSB) (37). The AL was created based upon currently valid names of
bacteria that were cultivatable and those published in the International Journal of Systematic
Bacteriology prior to 1 January 1978 (37). What many microbiologists and scientists do not
recognize is the fact that with the publication of the AL, the family name Enterobacteriaceae

automatically became invalid and technically could not be used in subsequent publications
because the name had been omitted under the rank of “family.” Subsequently, the matter was
considered sub judice (under judicial review) because of a challenge to the legitimacy of the
name by Lapage (38, 39), who recommended changing the name to Enterobacteraceae.
However, it was immediately recognized that the AL had serious exclusions to it and that
validly published legitimate names had been arbitrarily omitted (40). In companion articles,
the CDC opposed rejection of the family name (7) and Ewing and coauthors (40) validly
published and proposed reviving the name Enterobacteriaceae under rules defined by the
Bacteriological Code. The Judicial Commission subsequently determined that the family name
Enterobacteriaceae Rahn 1937 with Escherichia Castellani and Chalmers 1919 as the type
genus did have standing and belonged on the AL (39). While other proposals such as
changing the family name to Escherichiaceae have appeared, they have almost always been
uniformly opposed by subcommittees on the enterobacteria (41).
Genus and Species Expansion (1980 to 2020)

The original AL contained 2,366 valid prokaryotic names, of which 2,213 were at the
rank of genus (n = 290), species (n = 1,792), and subspecies (n = 131) (42). While these
numbers are sizable, they pale in comparison to the computational prokaryotic diversity
in the global biosphere, estimated to range between 2 and 4 million species (43). This
figure may actually be much higher (43). Thus, like other families in the

prokaryotes, given the above projected numbers, it is not surprising that membership in the
family Enterobacteriaceae has also increased dramatically over the past 40 years.
The history of taxon expansion in the family Enterobacteriaceae post-1980 has for
the most part mirrored that of other large prokaryotic families. Those increases again
paralleled technical developments in the characterization of prokaryotes which enabled
taxonomists to more easily assess both the uniqueness (new species) and relatedness
(phylogeny) of sets of strains to other named groups. From the early 1980s to the
mid-1990s, the main systematic approach involved the use of polyphasic taxonomy, that
is, a combination of phenotypic (culture, biochemical, serology, cellular fatty acids) and
genetic (DDH, G1C mol%) characteristics. Polyphasic taxonomy is still used today but is
less in vogue. Groups spearheading the description of new species in the family
Enterobacteriaceae during this period included the CDC in Atlanta, the Institute of
Pasteur (IOP) in France, and the National Institutes of Health in Japan (NIH Japan) (44–
47). Virtually all of the named species during this period were accompanied by extensive
biochemical profiles, which allowed laboratories to differentiate on a phenotypic basis a
new taxon from previously named species. When a significant number of strains were
not available to clearly define an unnamed taxon, they were typically given a generic
name, such as CDC enteric group 58 (11).
The “gold standard” for defining these new species during this period was DDH (48,
49). However, DDH has a number of limitations. The traditional technique was
expensive, labor-intensive, time-consuming, and subject to technical errors
(temperature, ionic strength) (48–50). Only a few large international laboratories (CDC,
IOP, NIH Japan) had the personnel and resources to employ such technologies on a
routine basis. Additionally, DNA studies indicated that many existing species in the
family Enterobacteriaceae were polyphyletic, that is, composed of genetically distinct
species that could not easily be resolved by simple biochemical tests, the principal
mechanism most clinical microbiology laboratories used for final species identification.
Thus, such organisms as Enterobacter cloacae, Pantoea (Enterobacter) agglomerans,
and Hafnia alvei (Enterobacter hafniae) were known by DDH to be composed of multiple
hybridization groups (HGs), each representing a unique genomospecies although they
all exhibited common characteristics and could not be separated phenotypically from
each other (51). Such species in actuality were at that time “phenospecies” or a
“complex” of species rather than, for instance, E. cloacae sensu stricto.
Family expansion due to newer technology. In the 1990s, sequencing of

housekeeping genes, such as the 16S rRNA gene, was thought at that time to be a
major breakthrough in bacterial systematics (48, 50, 52). The 16S gene could be
sequenced with relative ease on different platforms and could provide informatics more
quickly than DDH (53). Threshold values were determined for comparing a proposed
new taxon to closely related neighbors, with ,98.7% sequence similarity strongly
suggesting that the unnamed group represented a new species (50, 54). Full-length 16S
rRNA gene sequences (;1,500 bp) quickly became a standard requirement for the
publication of new species proposals, while16S similarity values above 98.7% still
required DDH to determine relatedness. While 16S gene sequencing clearly provided
quicker resolution of taxonomic issues, problems still remained (49, 55). This was
especially true for the Enterobacteriaceae, where in a number of instances 16S gene
sequencing did not have particularly good resolving power at the species level (48). This
was partially due to the highly conserved nature of the ribosomal gene (55). Species in
genera clearly resolvable by DDH (Edwardsiella, Enterobacter) yielded 16S rRNA gene
sequence results that were either identical or showed very little variation (48).
El advenimiento de la secuenciación del gen 16S rRNA como una herramienta taxonómica y una
plataforma de rutina para la identificación bacteriana en el laboratorio clínico fue seguido rápidamente por
la introducción de una amplia gama de técnicas moleculares con las que evaluar la diversidad genética y las
similitudes de las especies nombradas o propuestas. Estas técnicas incluyeron ionización por desorción
láser asistida por matriz: espectrometría de masas de tiempo de vuelo (MALDI-TOF), análisis de secuencia
multilocus (MLSA), identidad de nucleótido promedio (ANI), porcentaje de

TABLA 2Expansión de géneros y especies en la familia.enterobacterias,1974-2020

Fuente año No. de géneros Nº de especies % Aumentoa Referencia
Manual de Bergey de Bacteriología Determinativa (8ª ed.) 1974 12 36 232B 1
Lista aprobada 1980 18 80 122 37
Manual de Bergey de Bacteriología Sistemática Manual de Bergey de 1984 20 76 25 1
Bacteriología Determinativa (9ª ed.) Microbiología e infecciones 1994 30 107 29 1
microbianas de Topley & Wilson (10ª ed.) LPSNC 2005 40 150 41 1
2020 68 355 136
aBasado en el número de especies de la fuente o edición anterior.
BDe Rahn, 1937 (6).
CLPSN, Lista de nombres procarióticos con posición en la nomenclatura (https://www.bacterio.net/).
proteínas conservadas (POCP), DDH digital (dDDH), calculadora de distancia genoma a genoma
(GGDC) y secuenciación del genoma completo (WGS), entre otros (49, 54, 56). Esta avalancha de
nuevas tecnologías y técnicas moleculares era menos costosa y laboriosa y estaba disponible tanto
para los laboratorios clínicos como para los de investigación, lo que resultó en una explosión en el
número de descripciones de nuevos géneros y especies.
While the number of described species was relatively steady through 1994 (50), the
numbers have dramatically risen since then. By 2007, over 8,000 species had been
described, and this was more than a 400% increase since the AL in 1980 (42, 48). The
family Enterobacteriaceae experienced a similar increase in the numbers of genera and
species, with the greatest increase in percentages after 2005, which is a reflection of
technologic developments related to the description and phylogenetic classifications of
new taxa (Table 2). The single technology with the greatest impact has been WGS.
Debido al panorama en rápida evolución de la taxonomía microbiana, la familia ha cambiado
radicalmente en las últimas 4 décadas (1980 a 2020). La Tabla 3 muestra una instantánea de ese
cambio, comparando algunos géneros seleccionados que Farmer et al. (11) descritos en su
publicación histórica de 1985 con su estado actual en 2020. El punto de referencia de 2020 es el sitio
web de la Lista de nombres procarióticos con posición en la nomenclatura (LPSN) (https://
www.bacterio.net/) comisariada por Aidan C. Parte, Leibniz Institute DSMZ.
Los datos de los CDC de 1985 revelaron 23 especies nuevas (40% de las cuales estaban
asociadas con uno de los seis géneros nuevos, a saber,Buttiauxella. Cedecea, Ewingella,
Kluyvera, Moellerella, yTatumella).Most of these species were recovered from clinical sources
or infections (80%) and could be biochemically separated from all other named taxa in the
family at that time. Furthermore, phenotypic properties for these species were based on the

characterization of multiple strains of each taxon. The 49 total species listed in Table 3 for
1985 mushroomed to a total of 152 species in 2020 (one species, aerogenes, remained the
same but was changed to a different genus). By 2020, 16 of the 49 species (33%) listed in 1985
have undergone taxonomic/classification revisions. Two genera, one that has always
presented taxonomic issues (Enterobacter) and another thought to be a relatively
uncomplicated genus (Klebsiella), had 87.5% and 67% of their respective species reclassified
post-1985. In the case of Enterobacter, all but two species listed in 1985 now phylogenetically
reside in other genera, including E. agglomerans (Pantoea), E. amnigenus (Lelliottia), E.
intermedius (Kluyvera), E. gergoviae (Pluralibacter), E. aerogenes (Klebsiella), and E. sakazakii
(Cronobacter) (57–61).
As of 2020, of the 14 genera listed, all but three (Cedecea, Ewingella, Moellerella) have had new
members added to each genus, with the greatest number involving Enterobacter (n = 33). Una
diferencia notable en las especies propuestas para 2020 es el porcentaje creciente de taxones
(51/103, 49,5 %) descritos a partir de fuentes estrictamente ambientales. Esto es un reflejo no solo
de la disponibilidad general de WGS y métodos sistemáticos más nuevos, sino también del hecho de
que los ecosistemas naturales (agua, suelo, plantas) no han sido explotados o explorados
extensamente en busca de posibles especies de enterobacterias. Además, muchas de estas
nomenespecies descritas más recientemente ya no pueden identificarse por características
fenotípicas simples. Los cambios de clasificación adicionales (23,5%) entre 1985 y 2020 se debieron a
investigaciones filogenéticas que dieron como resultado la transferencia de taxones establecidos a
nuevos géneros (sinónimos homotípicos). Los principales ejemplos incluyen

La familiaenterobacterias—2020 Reseñas de microbiología clínica
TABLE 3 Comparison of new genera and species proposed by the CDC in 1985 and present status in 2020a
1985 2020
Human Disease Classification Human Disease Classification

Genusb Species sources associated change Species sources associated change Comments
Buttiauxella (1)/(6) agrestis 2 2 No brennerae 2 2 No
ferragutiae 2 2 No
gaviniae 2 2 No
izardii 2 2 No
noackiae 1 2 No
warmboldiae 2 2 No
Cedecea (3)/(0) davisae 1 2 No Unnamed HGs

lapagei 2 2 No
neteri 1 1 No
Citrobacter (3)/(12) amalonaticus 1 1 No braakii 1 1 No

diversusc 1 1 Yes cronae 1 2 No
freundiid 1 1 No europaeus 1 2 No
farmeri 1 1 No C. amalonaticus
biogroup 1
gillenii 1 1 No
murliniae 1 1 No
pasteurii 1 2 No
portucalensis 2 2 No
rodentium 2 2 No Mouse
pathogen
sedlakii 1 1 No
werkmanii 1 1 No
youngae 1 1 No
Edwardsiella (3)/(2) hoshinae 2 2 No anguillarum 2 2 No Fish/eel

pathogen
ictaluri 2 2 No piscidia 2 2 No Fish pathogen
tarda 1 1 No
Enterobacter (8)/(34) aerogenes 1 1 Yes asburiae 1 1 No

agglomerans 1 1 Yes arachidis 2 2 sí
amnigenus 1 2 Yes bugandensis 1 1 No
cloacaed 1 2 No chengduensise 1 1 No
gergoviae 1 1 Yes chuandensise 1 1 No
intermedium 2 2 Yes cowanii 1 1 sí
sakazakii 1 1 Yes dissolvens 1 1 sí
tayloraef 1 1 Yes helveticus 2 2 sí
hormaechei 1 1 No
huaxensise 1 1 No
kobei 1 1 No

ludwigii 1 1 No
massiliensis 1 2 sí
mori 2 2 No
muelleri 1 1 sí
nimipressuralis 1 2 sí
oligotrophicus 2 2 sí
oryzae 2 2 sí
orizendophyticus 2 2 sí
orizífilo 2 2 sí
pulverizar 2 2 sí
pirinus 2 2 sí
cuasihormaechei 1 2 No
radicincitanos 1 1 sí
roggenkampii 1 2 No
sacchari 2 2 sí
siamensis 2 2 No
sichuanensis 1 2 No
sola 2 2 No
tabachi 2 2 sí
taylorae 1 1 sí
turicensis 2 2 sí
wuhouensis 1 2 No
xiangfangensis 2 2 sí
Escherichia (5)/(2) coli 1 1 sí albertii 1 1 No

fergusonii 1 1 sí marmotas 2 2 No
(Continúa en la siguiente página)

TABLA 3 (Continuado)
1985 2020
Humano Enfermedad Clasificación Humano Enfermedad Clasificación

GéneroB Especies fuentes asociado cambiar Especies fuentes asociado cambiar Comentarios
hermanii 1 1 sí
Vulneris 1 1 No
Blattae 2 2 No
Ewingella (1)/(0) americana 1 1 No
Klebsiella (6)/(13) neumonía 1 1 No aerogenes 1 1 No E. aerogenes

oxitoca 1 No africana 1 2 No
planticola 1 sí Alba 2 2 sí
ozaenaegramo 1 sí grimontii 1 1 No
rinoescleromatisgramo 1 sí huaxiensis 1 2 No
terrígena sí indica 2 2 No
michiganensis 1 1 No
ornithinolytica 1 1 sí
pasteurii 1 2 No
cuasipneumonía 1 1 No
singapurense 2 2 sí K. varicola
spallanzanii 1 2 No
varicola 1 1 No
Kluyvera (2)/(2) ascorbata 1 1 No “cóclea” 2 2 sí k intermedia

criocrescens 1 1 No georgiana 1 2 No
intermedio 1 1 No
Moellerella (1)/(0) Wisconsin No
Proteo (4)/(7) mirabilis 1 1 No alimentorum 2 2 No

vulgaris 1 1 No cibarius 2 2 No
penneri 1 No cibi 2 2 No
myxofaciens Yes columbae 2 2 No
faecis 1 2 No
hauseri 2 2 No
terrae 2 2 No
Providencia (4)/(6) alcalifaciens 1 No burhodogranariea 2 2 No

rettgeri 1 No heimbachae 1 2 No
rustigianii 1 No huaxiensis 1 2 No
stuartii 1 No sneebia 2 2 No
thailandensis 2 2 No
vermicola 2 2 No
Serratia (7)/(12) ficaria 1 No aquatilis 2 2 No

fonticola 1 No entomophila 2 2 No

liquefaciens 1 No “glossinae” 1 1 Yes S. fonticola
marcescens 1 No grimesii 2 2 No
oderifera 1 No inhibens 2 2 No
plymuthica 1 No microhaemolytica 2 2 No
rubidaea 1 No myotis 2 2 No
nematodiphila 2 2 No
oryzae 2 2 No
“quinivora” 1 1 Yes S. quinovorans
quinivorans 1 1 No
symbiotica 2 2 No
ureilytica 2 2 No
vespertilionis 2 2 No
Tatumella (1)/(5) ptyseos 1 No citrea 2 2 No

morbirosei 2 2 No
punctata 2 2 No
saanichensis 1 2 No
terrea 2 2 No
a1985 data are from Table 1 (11) regarding genera with addition of new species (post-1980); 2020 data are from the LPSN website (https://www.bacterio.net/) and include all new
species validly published since the data of Farmer et al. (11). 1, found in clinical samples and/or infections; 2, found in nonclinical samples.
bNumbers in parentheses are number of species in 1985/number of new species (2020).
cRejected name; identical to C. koseri.
dExisted as a phenospecies (genetically heterogeneous).
eRecovered from blood.
fCorrect name, Enterobacter cancerogenus.
gSubspecies of K. pneumoniae.

Kosakonia (Enterobacter spp.), Raoultella (Klebsiella spp.), and Tatumella (Pantoea spp.) (58,
62, 63).
Modern taxonomy and family expansion issues. The changing panorama of the
family Enterobacteriaceae in the modern molecular taxonomy era has resulted in a
number of advantages along with some limitations as well as issues (55, 56, 64). A
central issue for clinical microbiologists is the way new species are described. Already
an observable trend dating back to the late 1990s, the vast majority of new species are
described analyzing only a single strain (type). Today, .90% of new taxa are described on
this basis (50, 65). Although some taxonomists have questioned whether or not a single
strain should be sufficient to propose a new species (66) and ad hoc committees have
encouraged microbiologists to describe new species on the basis of more than one
strain (67), this has not happened. Already many of the recently described new genera
and species in the family Enterobacteriaceae have been proposed with only a type
strain. Recent examples in the enterobacteria include Mangrovibacter (68), Chania
(69), Limnobaculum (70), and Scandinavium (71). While such reports are of general
academic interest, the limited amount of information that can be provided, including
genetic data, is troubling and whether the type strain is actually a centrist isolate
(center of properties for the species) is unknown.
Un segundo problema involucra las propiedades fenotípicas. Dado que el fenotipo se ha considerado
durante mucho tiempo una de las características cardinales en la descripción de nuevas especies, su
importancia con respecto a la clasificación está disminuyendo (55). Muchas propuestas taxonómicas, ya sea
que involucren un solo aislado o una pequeña cantidad de cepas, utilizan principalmente sistemas
miniaturizados API (20E, 32E, 50CH, ZYM) o paneles de utilización de fuentes de carbono como Biolog Gen
III MicroPlate para caracterizaciones bioquímicas integrales de grupos recién propuestos. (68–72). Si bien
estos sistemas son generalmente precisos en las identificaciones bacterianas, los sistemas miniaturizados
no siempre tienen propiedades fenotípicas paralelas generadas por los métodos tradicionales (11) y algunas
pruebas están sujetas a variaciones considerables. Un dilema adicional es el hecho de que cuando se
proponen nuevas especies y se comparan con los vecinos más cercanos, no se prueban internamente; en
cambio, los datos se extraen de publicaciones anteriores que pueden no haber utilizado la misma
metodología de prueba. Dichos factores cuestionan cuán confiables pueden ser los datos bioquímicos, un
tema importante para los laboratorios de diagnóstico.
The general availability of WGS has led to a significant increase in laboratories attempting
to become systematists overnight without understanding the fundamental rules of
nomenclature and taxonomy. This has led to species proposal submissions without any

recognition of technical requirements to formally propose a new taxon (67). A considerable
number of recently proposed species have also been found to represent heterotypic
synonyms, that is, different names and types that in the opinion of taxonomists represent the
same taxon. Table 3 has a number of such examples, including the publication of
Enterobacter muelleri in 2015 (73) that by computational analysis of sequenced Enterobacter
genomes (74) is identical to Enterobacter asburiae, which was described in 1986 (75).
Furthermore, many proposed genera for the family Enterobacteriaceae although effectively
published (in a public journal easily accessible) have not been validly published (see
Nomenclature and Taxonomy). Without validation, these genera and species have no
standing in the medical and scientific literature. A prime example of this situation is the 2005
publication of the taxon Averyella dalhousiensis (76). This report details over 20 isolates,
including one from a case of septicemia, but as of 2020 has no standing in the literature
according to the LPSN website for one or more reasons. Many such genera proposed for the
family are in the same situation and, if validated, would considerably increase the size of the
family listed in Table 2.
NOMENCLATURE AND TAXONOMY

Taxonomy
Nomenclature and the ICNP. The correct name and publication of new taxa within an
ordered system of prokaryotes, including the family enterobacterias,se rigen por el
Código Internacional de Nomenclatura de Procariotas (ICNP), con los rangos

of genus and species being the cornerstone for such a categorical classification system. In
2019, an update of the ICNP (2008 revision) was published for the first time in more than 25
years (77). General Consideration 2 essentially defines the purpose of the ICNP, which is “To
achieve order in nomenclature, it is essential that scientific names be regulated by
internationally accepted Rules” (77). The ICNP covers not only the correct naming of a genus
and/or species but also the requirements to publish and validate a taxon, which constitutes
an official form of registering or indexing a name through a centralized system (55). This
includes such things as Enterobacter oligotrophicus (correct name) rather than Enterobacter
oligotrophica (misspelling) and various homotypic (more than one name associated with the
same types that belong to the same taxon) or heterotypic synonyms of previously published
genera and species (Table 3).
Validation. Rule 27 of the ICNP requires the publication of a new taxon either in the
International Journal of Systematic and Evolutionary Microbiology (IJSEM) or effective
publication in another journal with subsequent publication on a Validation List in IJSEM (78).
Along with this are additional requirements concerning the deposition of type strains,
derivation (etymology) of a new name, and others. A problematic issue related to this
concerns the fact that almost 50% of all taxa between the ranks of subspecies and class that
are effectively published in journals other than IJSEM are never validated (78). Reasons for this
trend are not clear. For the family Enterobacteriaceae, in addition to Averyella (76), this
includes the genera Atlantibacter, Edaphovirga, Jejubacter, Nissabacter, and Oceanomonas
[sic] (https://lpsn.dsmz.de/family/enterobacteriaceae). Failure to validate creates confusion in
the scientific and medical literature. As an example, the genus Atlantibacter was created in
2016 to reclassify two species (Escherichia hermannii and Salmonella subterranean, the latter
of which is not a salmonella but an organism closely related to E. hermannii) to the new
genus (79). Because of lack of validation, it is unclear whether the authors simply failed to
submit the publication for validation to IJSEM or lacked the required components for
validation in their publication or whether there were technical flaws in their analyses. Since E.
hermannii is a known although uncommon human pathogen, this has clinical significance.
Nomenclature anomalies in the family Enterobacteriaceae. With the emergence of

modern-day metrics, including DDH and ANI, with which to assess or reassess
relatedness among taxa in the family Enterobacteriaceae, a number of nomenclature
issues which are of great importance to the medical community have arisen. As early as
1968, Brenner et al. (80) determined that E. coli and Shigella flexneri were more than

75% related by DDH when tested at 75°C, which is well above the threshold level of
species identity of 70% reassociation with #5°C change in melting temperature (DTm)
(81). These studies were subsequently confirmed for all Shigella species, which were
80% to 89% related to E. coli strains (51). Shigella spp. have evolved over time through a
number of gene deletion or plasmid acquisition events but are still, on a genetic basis,
the same species (82, 83). In a similar fashion, Yersinia pestis and Yersinia
pseudotuberculosis are highly related by DDH and whole genome-to-genome sequence
analysis (84, 85). Together they constitute a single species on a genetic basis. According
to the rules of the ICPN (Principle 6), the earliest published name has priority over
synonyms (77). In the case of Yersinia, Y. pseudotuberculosis (1889) has priority over Y.
pestis (1896). Similarly, for Shigella, E. coli (1895) has precedence over Shigella
dysenteriae (1897). However, while genetically a single species, the disease
manifestations of shigellosis (versus E. coli) and plague (versus Y. pseudotuberculosis)
have immense clinical, medical, and epidemiologic ramifications that would result from
the merging of each group. However, Principle 1 of the ICPN requires the maintenance
of the stability of names, particularly when the use of a name could cause error or
confusion. So, these species remain as originally published because of their medical
importance, although both constitute “artificial species” at the DNA level.
Classification. Bacterial classification is the orderly arrangement of taxonomically
defined entities (species) on a genetic basis (55). The present system is data driven and
theoretically attempts to order such groupings on an evolutionary or phylogenetic

basis mimicking nature (86). Like bacterial nomenclature, prokaryotic classification has relied
on similar traits or characteristics to produce the present organizational structure consisting
of a series of artificial hierarchical ranks above species (class, order, family, genus) (55). These
traits or characteristics have, as in the case of bacterial nomenclature, evolved over time from
phenotypic (morphology, physiology, chemotaxonomy) to genetic (DDH, MLSA, ANI) markers.
An excellent minireview on the subject is by Schleifer (86). Unlike nomenclature, however, the
16S ribosomal gene provides the cornerstone to such a classification system and is viewed as
the gold standard for bacterial phylogeny (55, 86). The 16S ribosomal gene and a limited
number of other housekeeping genes found in essentially all prokaryotic species (recA, rpoB,
EF-Tu, gyrA) together form the foundation for modern-day bacterial phylogeny (55, 86).
Unlike bacterial nomenclature, there is no formal body or international organization that

is universally approved to oversee classification changes (1, 55, 86). Rather, the acceptance or
rejection of classification changes is dependent upon the formal data presented and whether
or not the classification proposal is widely accepted or rejected by the scientific community.
This latter point means that it is basically decided by usage in the scientific and medical
literature, which usually takes at least 2 or 3 years from date of publication (1). These
collective facts mean that unlike the proposed name for a new taxon, a classification change
never becomes “official” (1). A second relevant point is the fact that because there are no
governing rules, any researcher may propose a classification change without any focus on
taxonomy or without having been trained in the classification or identification of bacteria (87).
This can lead to additional taxonomic confusion in an already confusing field. Finally, by its
very nature, bacterial classification is always in a state of flux and never relatively stable.
Classification changes can occur rapidly and can be based on the use of new or different
technology, bacterial populations analyzed, and analytical or computational methods chosen.
The family Enterobacteriaceae is an excellent example of this. The genus Metakosakonia was
proposed by Alnajar and Gupta (88) in 2017 to house the taxon Enterobacter massiliensis
based upon comparative genomic studies. Recently, a proposal has been made to unify the
genus Metakosakonia with the genus Phytobacter, since Phytobacter is based upon digital
DDH, average amino acid sequence identity, and conserved signature insertions/deletions
(indels) (89). Other proposed taxonomic classification changes involve the genus Izhakiella (
90), two subspecies of Klebsiella pneumoniae (91), and reassignment of Proteus cibarius as a
later heterotypic synonym of Proteus terrae (92).

The Family Enterobacteriaceae—Current Status
Present definition for the family. The vast majority of established genera and species
presently included in the family Enterobacteriaceae, order “Enterobacterales,” have
been recognized for over 50 years (15). Early taxonomic classifications at the rank of
family relied on a number of common traits in addition to phenotypes and genetic
characteristics. A perfect example of the use of this classification system was the family
Vibrionaceae proposed by Véron in 1965 (93). This family was initially composed of
three genera (Vibrio, Aeromonas, Plesiomonas) that had several features in common,
including ecologic habitats (freshwater, marine), similar disease syndromes
(gastroenteritis, wound infections), and phenotypic features (oxidase positivity,
facultatively anaerobic). It was not until years later that phylogenetic investigations
clearly demonstrated that aeromonads belonged in their own family (94) while
Plesiomonas should be transferred to the family Enterobacteriaceae (14). Despite these
technologic advances, clinical microbiologists continue to think of these genera as a
single cohort because of clinical histories (water exposure) and common cultural and
biochemical properties.
The family Enterobacteriaceae can be thought of in a similar fashion. Members added to
this group over the years share a number of common features, including phenotypes
(oxidase negative, ECA positive, nitrate reductase), habitats (gastrointestinal tract of
vertebrates, including humans), and disease patterns (diarrhea, sepsis, urinary tract
infections) (1–3, 15). They are also recovered from clinical samples on a variety of

common selective and differential agars used in the laboratory for decades. Some of
these groupings within the family have stood the test of time. For instance, the tribe
Proteeae, which was named by Castellani and Chalmers in 1918 and subsequently
contained the genera Proteus, Providencia, and Morganella (https://lpsn.dsmz.de/tribe/
proteeae), still group together today on a phylogenetic level. By 2005, the inclusion of
Plesiomonas (oxidase positive) in the family along with endosymbionts of insects and
other fastidious species has made a literal description of the Enterobacteriaceae
difficult (15). Furthermore, while many new enteric genera with more unusual
properties have been described over the past 20 years, microbiologists again still think
of the main members of this family in a fashion similar to those originally included in
the Vibrionaceae (95).
Core and peripheral members. The present definition for the family became more
uncertain with the introduction of DDH (51). Using DDH as the criterion, DNA from
members of the family exhibited at least 20% relatedness to the type species, E. coli
(15). However, in the 2005 edition of Bergey’s Manual of Systematic Bacteriology, noted
exceptions to this rule included the Proteeae, Hafnia, and Edwardsiella, which were only
5% to 20% related (15). Core members were defined as enterobacteria that were 40% to
50% related to E. coli. This included such genera as Enterobacter, Klebsiella, Citrobacter,
and Salmonella (96). Some other genera were intermediate in their DNA relatedness
values (25% to 30%) compared to core and peripheral groups. Taxa including Cedecea,
Kluyvera, and Serratia showed this intermediate level of relatedness (96).
Phylogenetic studies. There have been surprisingly few phylogenetic investigations
in which a large collection of enterobacterial genera and species have been analyzed in
any great detail. Most of these studies have involved the analysis of one or more
housekeeping genes such as the 16S gene. Unfortunately, in regard to the
Enterobacteriaceae, 16S rRNA gene sequencing has low discriminatory power,
particularly in reference to closely related species (48, 55, 97, 98). Housekeeping genes
used to assess phylogenetic relatedness within the family with higher resolving power
than the 16S gene include elongation factor Tu (tuf), the F-ATPase b-subunit gene (
atpD), the DNase gyrase subunit B gene (gyrB), and the chromosomal replication origin
(oriC), among others (97, 99–102).
Notwithstanding the fact that different genes and taxa have been analyzed and
assessed in various publications, several basic conclusions can be drawn from these
collective phylogenetic studies of the family. First, in general, neighbor-joining

phylogenetic trees constructed from housekeeping gene sequence analysis support
previous DDH studies on the position of genera relative to the deep-rooted core
members of the family, including E. coli. The genera least related to core members and
those located at the periphery of dendritic trees include Plesiomonas, Xenorhabdus/
Photorhabdus, the Proteeae, Yersinia, and Serratia (97, 99, 102). Second, the family
displays polyphyletic branching (98). While some of the cladistic discrepancies
previously noted in the family can be resolved by recent classification changes
proposed for certain species, others cannot. Thus, the present family appears to contain
a number of taxa whose lineage is distinct from core members.
Species or taxa of uncertain status. There are a number of nomenspecies or
taxonomic groups at the genus and/or species rank that have nomenclature or
classification issues at present.
(i) Salmonella species. The genus Salmonella is extremely complex on an evolution-
ary basis (103). Currently, three Salmonella spp. are validly published as correct names (
https://lpsn.dsmz.de/genus/salmonella). One of these species, Salmonella subterranea, was
proposed in 2004 for an acid-resistant bacterium recovered from subsurface sediment (104).
A recent study including 16S rRNA gene sequencing, MLSA of four housekeeping genes, and
concatenated hypervariable sequences of 10 housekeeping proteins indicate that this species
aligns with Escherichia hermannii into a separate clade distinct from both Salmonella and
Escherichia (79). The authors have proposed to transfer both species to a new genus, “
Atlantibacter” (79). However, at the time of writing,

this genus still has not been validated, so both species remain in their originally
assigned genera. Other phylogenetic investigations suggest that two subspecies of
Salmonella enterica (salamae, houtenae) are polyphyletic in nature, being composed of
at least two distinct phylogroups (103). This suggests that more taxa are yet to be
described.
(ii) Enterobacter and Enterobacter hormaechei. Enterobacter hormaechei, previously
referred to as enteric group 75, was originally part of the E. cloacae complex (105). Population
studies suggest that E. hormaechei may be the predominant species within the E. cloacae
complex causing HAI (74). The LPSN website presently lists five validated subspecies (https://
lpsn.dsmz.de/species/enterobacter-hormaechei). E. hormaechei is presently in “taxonomic
chaos” and disarray. Using WGS, Sutton and others (74) have proposed that two subspecies of
E. hormaechei (subsp. hoffmannii and subsp. xiangfangensis) are heterotypic synonyms of a
separate species, E. asburiae. An entirely different conclusion using similar techniques has
just been drawn by Wu et al. (106). In their investigations, the authors propose the following:
(i) that E. hormaechei subsp. hoffmannii should be elevated to species status and not
assigned to E. asburiae (74); (ii) that all present subspecies assignments in the genus
Enterobacter are incorrect; (iii) that many Enterobacter genome sequences in GenBank need
to be corrected and curated; and (iv) at least 14 tentative novel species have been detected in
the genus (106). Other investigators have also identified new lineages representing novel
species within
E. hormaechei (107). If the majority of findings from Wu et al. (106) are confirmed, it throws
the genus Enterobacter into total confusion from a clinical and medical perspective in regard
to terminology, nomenclature, epidemiology, and disease pathogenesis.
(iii) Yersinia ruckeri. Yersinia ruckeri has a very checkered taxonomic history. This
bacterium is one infectious cause of redmouth disease in rainbow trout (108) and has
also been recovered from a human wound infection (109). The taxon was initially placed
in the genus Yersinia based upon mol% G1C content and biochemical similarities;
however, considerable data suggest that it is not a true yersinia. DNA relatedness
investigations indicate that it is 30% related to both Yersinia and Serratia, while early
studies suggest that it biochemically resembles Serratia and Salmonella (“Arizona”) (108,
110). Phylogenetic studies constructing a multilocus enzyme electrophoresis
dendrogram (110) and a 16S RNA maximum-likelihood tree (111) place this taxon at the
extreme periphery (distantly related) of Yersinia, with the cumulative data implying that
Y. ruckeri should not be classified within the genus.
(iv) Edwardsiella tarda biogroup 1. The vernacular name Edwardsiella tarda bio-

group 1 was coined by the CDC in 1985 for a biochemically atypical group of E. tarda
isolates (11). In contrast to classic strains, the atypical isolates were sucrose positive and
H2S negative. All of the original isolates identified by the Japanese were from snakes
(112). Since this report, a biogroup 1 strain has been associated with human cases of
cholelithiasis (113) and sepsis (114). DDH indicates that the biogroup 1 strains are 69%
to 74% related to the type strain of E. tarda (112). Phylogenetic investigations have not
been conducted to date. It may be that these unusual isolates are simply a biotype of E.
tarda or that they may represent a new subspecies unless phylogenetic investigations
indicate otherwise.
(v) Enteric groups, HGs, and related taxa. There are many apparently distinct taxa
residing in the family Enterobacteriaceae that have yet to be named but have been
identified on the basis of both phenotypic and genotypic properties. The CDC has given
a number of these groups the general designation of “enteric group,” followed by a
corresponding number, such as enteric group 17 (1, 11). Table 4 lists some of these
groups that have been described in the literature with their present standing.
In addition to numbered enteric groups, other nomenspecies are known to contain HGs
that have not been characterized to date. This includes Cedecea (genomospecies 3 and 5),
Ewingella (strain 0679-79), and Kluyvera (genomospecies 3), among others (11, 115).

TABLE 4 Present status of CDC enteric groupsa

Enteric group Phenotype Human source(s)b Current designation Reference(s)
17 Atypical Citrobacter or Enterobacter bld, wd, rt, urn Enterobacter asburiae 75
45 Atypical “Hafnia-like” bld, wd, stl Yokenella regensburgei 45, 277
(“Koserella trabulsii”)
57 H2S1 bacteria stl Leminorella 278
58 wd Averyella dalhouensis 77
59 ADH1 “E. agglomerans-like” rt Buttiauxella noackiae 279
60 Inactive group urn, rt Unnamed 1, 11
63 Buttiauxella None Unnamed 1, 11
64 Buttiauxella None Unnamed 1, 11
68 DNase1 urn Unnamed 1, 11
69 “Enterobacter sakazakii-like” bld Unnamed 1, 11, 280
137 “Citrobacter farmeri” or rt, wd, urn Unnamed 1, 281
“Citrobacter amalonaticus-like)
aData from references 1 and 11. Abbreviations: ADH, arginine dihydrolase; bld, blood; H2S, hydrogen sulfide production; rt, respiratory tract; stl, stool; wd, wound; urn, urine.
bClinical sources.
Cladistic Analysis, and Phylogenetic Investigations

A polyphyletic family. Bacterial taxonomy involves three important components,
including identification, nomenclature, and classification (97). Classification involves the
orderly arrangement of genetically similar organisms into a related evolutionary group
or clade (cladistic analysis). Past classification of members of the family
Enterobacteriaceae were primarily restricted to phenotypic properties, DNA relatedness
studies, and 16S rRNA gene sequence studies.
Past phylogenetic findings have augmented earlier DNA relatedness reports,
indicating that there is extensive evolutionary divergence within the family as presently
constructed and defined (see “Phylogenetic studies” above). These phylogenetic
investigations, however, were limited by the number of housekeeping genes
investigated and the number of taxa (genera and species) analyzed. In a landmark 2016
publication by Adeolu and associates (98), the authors constructed three phylogenetic
trees based upon 1,548 core proteins, 53 ribosomal proteins, and 4 MLSAs, respectively,
for 179 whole genomes of members representing 49 validated taxa of the order
“Enterobacterales.” These collective trees indicated that the order could be broken
down into seven monophyletic groups at the rank of family. Only 3 of the 49 genera
evaluated gave atypical results (Buchnera, Plesiomonas, Wigglesworthia). Furthermore,

a series of indel signatures were detected such that five conserved signature indels
(CSIs) were order specific, while an additional 66 CSIs were family or clade specific. A
follow-up investigation by Alnajar and Gupta (88) investigating only members of a
potentially redefined family Enterobacteriaceae found that 78 genome-sequenced
species could be subdivided into six well-circumscribed subfamilies, with a seventh
termed “Enterobacteriaceae incertae sedis clade” containing Mangrovibacter and
Shimwellia (88). Again, in this study, a number of CSIs that were specific to one or more
groups were identified.
Proposal to reclassify members of the order “Enterobacterales.” Based upon a significant
amount of phylogenetic information in the literature, Adeolu et al. (98) have made a number
of classification proposals for members previously assigned to the family Enterobacteriaceae.
In addition to proposing the name “Enterobacterales” to replace the previous order name “
Enterobacteriales,” which has never been validated, the authors propose placing some
current family members into six newly created families while leaving other genera in the
family Enterobacteriaceae. These six new families include the Erwiniaceae, Pectobacteriaceae,
Yersiniaceae, Hafniaceae, Morganellaceae, and Budiviciaceae, which exhibit .60% genome-to-
genome relatedness (98). Figure 1 illustrates how genera would be assigned and reclassified
within the order “Enterobacterales” if formally accepted and approved. The LPSN website has
already adopted these classification changes (Aidan C. Parte, Curator, Leibniz Institute DSMZ).
Figure 1A illustrates what genera would still remain within the family Enterobacteriaceae,


FIG 1 Proposed classification of current members of the family Enterobacteriaceae according to Adeolu et al. (98). (A) Revised
family Enterobacteriaceae; (B) six newly proposed families for inclusion in the order Enterobacterales.
excluding nonvalidated genera. The family Enterobacteriaceae with 33 genera would

still be the largest family within the order “Enterobacterales,” although many genera
with long-standing associations with this family, such as Edwardsiella, Hafnia,
Morganella, Proteus, Providencia, Serratia, and Yersinia, would be transferred into one
of six new families (Fig. 1B). Plesiomonas, located in the top right of Fig. 1A, appears
there because it belongs to the order but has not been assigned to a specific family as
of this date.
Figure 1B depicts the remaining six proposed families, all of which are much smaller
in size than the Enterobacteriaceae. A number of new terms are used in addressing the
phylogenetic relationships of members of this order at the LPSN website. “Children”
refers to a taxon belonging to a hierarchical classification above it, such as the genus
Salmonella being one of a number of “children” of the family Enterobacteriaceae.
“Siblings” refers to other genera in the same family (Fig. 1B), such as Proteus and
Providencia being siblings (along with others) in the proposed family Morganellaceae
(Aidan C. Parte, personal communication). The family Thorselliaceae, which currently

contains two genera, has been listed as a member of the “

Enterobacterales” (Enterobacteriales). However, although a member of the
Gammaproteobacteria, it has not as of this date been assigned to an order (95, 116).
Clinical and public health implications of proposed taxonomic changes. The combined
phylogenetic studies of both Adeolu et al. (98) and Alnajar and Gupta (88) clearly highlight
numerous taxonomic and classification flaws within the Enterobacteriaceae on an
evolutionary basis. Whether these proposed classification changes will be generally accepted
by the medical and scientific communities remains to be seen. The same group has previously
proposed sweeping changes to the genus Mycobacterium (117) and creation of a new order,
families, and genera currently containing Ureaplasma and other genera (118). Both of these
proposals have met with considerable resistance from both august subcommittees of the
ICSP and an international group of medical and scientific professionals and researchers (119,
120). Reasons for the proposed rejections include violation of one or more rules of the ICNP
and confusion for health care and harm for patients.
In a similar fashion, there is concern regarding how such proposals might affect the
family Enterobacteriaceae, in particular in regard to the medical community and clinical
microbiologists. If accepted, archival data accumulated for decades on the family would
not be directly comparable to future research studies of the Enterobacteriaceae as
redefined. This could conceivably impact reports on virulence factors, pathogenicity,
and clinical studies involving isolation, identification, and susceptibility profiles of
organisms such as carbapenem-resistant Enterobacteriaceae (34). Epidemiologic
investigations might also be impacted. As an example, FoodNet foodborne disease
surveillance data currently include four species within the family (Salmonella, Shigella,
Shiga toxin-producing E. coli, Yersinia). If the proposal is subsequently approved,
Yersinia would be removed from the Enterobacteriaceae, even though the four
foodborne disease agents exhibit many properties in common. A similar impact could
be seen for HAI that currently include Proteus and Serratia as enterobacteria (https://
www.cdc.gov/ nhsn/datastat/index.html). While most of the changes proposed above
do not involve genus or species designations, classic references and texts would need
to be revised. More importantly, continued upheaval in nomenclature and taxonomy
involving the fields of medicine and clinical microbiology leads to suggestions to
completely disregard new taxonomy (118), a viewpoint that is counterproductive to
both the medical and scientific communities.
ENTEROBACTERIACEAE—ENVIRONMENTAL DISTRIBUTION

Extension in Ecohabitats of Enterobacteria
One of the less well appreciated aspects of the family is the increasing detection of
members in an expanding panorama of environmental niches and ecosystems. The
majority of these ecohabitats can be broken down into several major categories, with
the predominant genera depicted in Fig. 2. These include the gastrointestinal tracts of
vertebrates (humans, animals), vegetation (plants, trees, fruit, flowering ornamentals,
grains), insects (including endosymbionts), and aquatic habitats such as freshwater,
thermal springs, and marine or saline sources (1, 2, 15). A catch-all category for lack of a
better term has been coined “miscellaneous,” which include such reservoirs as soil
(landfill), shellfish, nematodes, and the International Space Station (69, 121). None of
these categories occur as “silos”; rather, these ecohabitats coexist together in various
symbiotic relationships, such as the rhizosphere and submerged aquatic vegetation as
two examples (122, 123).
Selected Ecosystems
Vegetation. Depending upon the genus and species, plant-associated members can exist
in a number of different states associated with various vegetations (fig. 2). These include
intimate relationships with plant species (epiphyte), within the internal structures of a plant
(endophyte), or as a symbiont, a saprophyte, or a pathogen (124). Of these states, the one of
cardinal importance and concern is the role of enterobacterial species as pathogens of
agricultural produce, ornamental flowers, and trees. There are basically four

FIG 2 Categorical representation of key enterobacterial genera associated with various ecosystems. (Adapted from reference 2.)
types of plant diseases or infections associated with enterobacteria. These include (i) rapid
necrosis, (ii) progressive tissue maceration (soft rot), (iii) occlusion of vascular vessels (wilt),
and (iv) hypertrophy leading to gall, tumor, or canker formation (125).
By far, the plant disease that has received the greatest attention due to its impact is soft
rot, which is most frequently associated with species of two genera, Pectobacterium and
Dickeya (5, 126–128). Both genera secrete a number of extracellular enzymes, including
pectinases, which degrade pectin-containing structures in plant cell walls, leading to wet rot
of storage organs such as tubers and bulbs (128). Data from the early 1980s indicate that at
that time, the economic loss from soft rot ranges from $50 to $100 million per annum (5, 15).
The disease can be sporadic in nature or devastating, attacking either growing fields or
storage units containing beets, corn, and lettuce. Soft rot affects only vegetables and
ornamental plant production.

Another important soft rot infection is blackleg disease of potatoes. This infection,
caused by both Dickeya and Pectobacterium species, but in particular P. atrosepticum,
occurs worldwide, including New York and the northeastern United States. (129).
Blackleg primarily manifests itself by attacking the stems of potatoes after initial growth
in seed tubers. In its more severe form, the stems become darkened and decay, causing
the “blackleg” appearance (128, 130). One study suggests that Dickeya alone can be
responsible for a 20% to 25% reduction in potato yields (5).
Fire blight is a devastating necrogenic disease of pome fruit trees, particularly pears
and apples (126, 130, 131). The etiologic agent is Erwinia amylovora. Fire blight occurs
worldwide but is more associated with young trees (,2 years) growing in temperate
climates (126). In 2003 alone, fire blight was estimated to cause more than $100 million
annual loss to the fruit industry in the United States (131), and massive national
pandemics involving pear trees have occurred multiple times in Israel (132). The disease
progresses from the epiphytic state associated with cankers, where it can subsequently
be released, multiply, and attack various parts of the tree, including flowers, leaves,
branches, and roots (131, 132). Fire blight most often manifests itself in a burnt-like
appearance on infected tissues along with wilting and watermark (132). Currently there
is no cure for this as well as other enterobacterial plant-associated diseases.
Several other enterobacterial plant-associated diseases bear special mention (133).
Acute oak decline (AOD) is a relatively new disease affecting oaks in southeast England
and the midlands bordering Wales. AOD is characterized by weeping lesions on oak

TABLE 5 Key enterobacterial species associated with plant diseases
Pathogen Disease Type of infectionb Hostc Reference(s)

Brenneria alni Canker 1 Alder (Alnus spp.) Walnut (Juglans regia) 125, 136
Brenneria nigrifluens Canker 1 Poplar (Populus euramericana) Oak ( 125
Brenneria populi Canker 1 Quercus robur, Quercus petraea) 282
Brenneria roseae Acute oak disease 1 Walnut (Juglans regia) Willows (Salix 283
Brenneria rubrifaciens Canker 1 spp.) 125
Brenneria salicis Wilt, watermark 3 125, 284, 285
Dickeya chrysanthemi Wilt, soft rot 2, 3 Bananas (Musa spp.), maize (Zea mays), 128, 136, 286, 287
chrysanthemum (Chrysanthemum spp.),
orchids (Vanda spp.)
Dickeya dadantiia Blackleg 2 Potato (Solanum tuberosum), African violets 126
(Saintpaulia ionantha)
Dickeya dianthicola Blackleg 2 Potato (Solanum tuberosum) 129
Dickeya paradisciaca Root rot 1 Bananas (Musa spp.) Potato ( 125, 136, 288
Dickeya solania Blackleg 2 Solanum tuberosum) 126, 128
Dickeya zeae Bacterial stalk rot, rice 2 Bananas (Musa spp.), maize (Zea mays), rice 128, 289, 290
foot rot, soft rot (Oryza sativa)
Erwinia amylovoraa Fire blight, wilt 1 Apples (Malus domestica), pears (Pyrus 125, 126, 131
communis), other fruit
Erwinia mallotivora Dieback disease, black 1 Papaya (Carica papaya) 125, 291, 292
leaf spot
Erwinia tracheiphila Cucumber wilt 3 Cucumber (Cucumis sativus), squash 125, 293
(Cucurbita spp.), pumpkins (Cucurbita
spp.), gourds (Cucurbita pepo)
Lonsdalea quercina Drippy blight 2 Coast live oak (Quercus agrifolia) 125, 155
Pantoea agglomerans Blight, boll rot, center 1, 2, 3, 4 Beet (Beta vulgans), cotton (Gossypium 135, 137
rot, gall formation, wilt hirsutum), maize (Zea mays), onion (Allium
cepa), wisteria (Wisteria) Cantaloupe (Cucumis
Pantoea ananatis Brown spot, brown stalk 1, 2 melo), honeydew 124, 135, 137
rot, center rot melons (Cucumis melo), maize (Zea mays),
onion (Allium cepa), rice (Oryza sativa) Cotton
Pantoea stewartii Leaf blight, Stewart’s wilt 3 (Gossypium hirsutum), eucalyptus, 135
maize (Zea mays)
Pectobacterium atrosepticuma Blackleg 2 Potato (Solanum tuberosum) African 125, 128, 129
Pectobacterium carotovoruma Soft rot 2 violets (Saintpaulia ionantha), 125, 126, 128

cucumber (Cucumis sativus), lettuce (Lactuca
sativa), okra (Abelmoschus esculentus),
potato (Solanum tuberosum), sugar beets (
Beta vulgans), watermelon (Citrellus lanatus)
aOne of the top 10 plant pathogens according to Mansfield et al. (126).

bTypes: 1, necrosis; 2, maceration; 3, vascular wilt; 4, gall or tumor formation.
cSelected hosts.
trees, dark fluid seeping from cracks in the outer bark, and irregularly shaped lesions in the
inner bark (133, 134). While the microbial flora of AOD is complex, two predominant bacteria
are thought to play important roles in the disease process, namely, Brenneria goodwinii and
Gibbsiella quercinecans (134). Severely affected trees can die within 4 to 5 years. Both
Pantoea agglomerans and Pantoea ananatis cause a variety of diseases in fruit, vegetables,
and grains (124, 135). P. agglomerans, which causes boll rot in cotton, has been reported to
be responsible for 10% to 15% of annual crop losses.
Table 5 lists some of the key plant diseases linked to enterobacterial species. There are a
number of excellent reviews that cover various aspects of plant diseases concerning the
etiologic agents, taxonomy, susceptible hosts, disease manifestations, pathogenesis, and
control and remediation processes (128, 130, 135–138).
Insects. Insects collectively comprise the largest number of genera and species on
planet Earth and therefore exhibit the greatest diversity phylogenetically as well as in

total biomass and environmental distribution (139). While insects provide a number of
beneficial effects globally, including pollination, pest control, bioremediation, and saprophytic
“recycling,” they can also have deleterious effects, such as the destruction of agricultural
crops and deforestation (see “Vegetation” above). Very few studies to date have looked at
other roles insects may play in the biosphere.
Enterobacteria are carried by a wide range of insects, including flies, moths, and
cockroaches. The two most extensively investigated species are the house fly (Musca
domestica) and blow flies (Chrysomya megacephala, Protophormia terraenovae) (140–
142). Studies of insects collected from various sites (farms, dairies, kennels, fresh food
markets, restaurants, garbage piles) all show a number of common findings. These
include the following: (i) regardless of the geographic region (Indian subcontinent,
Southeast Asia, Africa), all studies exhibit high enterobacterial positivity rates from
samples analyzed, typically ranging between 20% and 70% (142); (ii) the predominant
species identified in most studies are Escherichia coli and Klebsiella pneumoniae (140,
142); (iii) isolates from a variety of genera have been recovered, including Citrobacter,
Enterobacter, and the Proteeae, among others (140, 142); and (iv) many recognized
human pathogens have been identified, including Shiga toxin-producing E. coli,
Salmonella species including Salmonella enterica serovar Typhi, Shigella, and Y.
enterocolitica (140, 142–144). Members of the family Enterobacteriaceae have also been
found to be predominant flora in flying insects of the order Diptera recovered from
British hospitals (145). Together, these data suggest that these insects might be
important vectors for foodborne or health care-associated infections.
Cockroaches are an omnipresent insect group that inhabit many different niches,
including the hospital environment (146, 147). Some historical data suggest a role for
cockroaches in both human and health care-associated infections. However, much of
these data predate modern taxonomy, laboratory techniques, and epidemiologic
methods (147). Cockroaches have also been implicated as potential pathogens of
consumable products due to the recovery of many foodborne pathogens from this
potential vector, including Salmonella, Shigella, and E. coli O157:H7 (148, 149). The
German cockroach (Blattella germanica) has been studied by several investigators, and
results are surprisingly similar to those from studies on house and blow flies (146, 149).
These cumulative results show that enterobacterial genera and species are commonly
found in B. germanica, including food-associated pathogens, and as with flies, the
principal species isolated are E. coli and K. pneumoniae.

(i) Insects as mechanical vectors. Insects play an important role in the perpetuation
of vegetative diseases by transmission of many viral agents from infected to uninfected
plants (150). It is likely that insects serve as vectors of bacterium-associated plant
diseases in a fashion similar to that of viruses, although to what extent is not
completely understood. Phytopathogens and their associations with insects can have
narrow or broad host specificity, may exist in one of several symbiotic states, and can
vary geographically based upon environmental factors like climate, moisture, and
vegetation (151). The pea aphid (Acyrthosiphon pisum) can serve as host to several
phytopathogens, including Dickeya dadantii, Pantoea stewartii, and Erwinia aphidicola,
which cause disease in potatoes, maize, peas, and beans (151). P. atrosepticum has
been isolated from trapped insects and symptomatic potato plants exhibiting soft rot,
as have turnip root flies, cabbage moths, and green lacewing larvae (152). In contrast, P.
stewartii has a very restricted association with the corn flea beetle (Chaetocnema
pulicaria) in causing Stewart’s wilt (leaf blight) of maize (151, 152).
Many other insect vectors have been involved in the transmission of plant diseases. The
green stink bug (Nezara viridula) can transmit P. agglomerans to cotton, precipitating boll rot
(135, 153). Center rot of sweet onions, which produces bacterial stalk and leaf necrosis, is
caused by P. agglomerans (135). The probable vector of this disease is onion thrips (Thrips
tabaci) (135, 154). Drippy blight disease of red oaks caused by Lonsdalea quercina is
associated with a kermes scale insect, Allokermes galliformis (155).
An excellent article on a variety of alternative and direct insect hosts of bacterial

phytopathogens including the Enterobacteriaceae is the review by Nadarasah and

Stavrinides (151).
(ii) Edible insects. Since 2013, when the Food and Agricultural Organization of the
United Nations issued an edible insects document, a concerted international effort has been
under way to investigate the usefulness of insects as a potential edible and nutritional food
source (156, 157). The impetus for this directive concerns the increasing global population
(estimated at 9 billion), the decreasing acreage of agricultural lands due to climate change,
limited availability of water resources, and the projected need to double food production by
2050 (157). Edible insects are being strongly looked at as a “novel food” potentially rich in
protein, lipids, fiber, and micronutrients to help fill the expected void (158). Of the myriad of
insect species on the planet, those eliciting the most general interest include the mealworn (
Tenebrio molitor), grasshoppers (Locusta migrans), cockroaches (Blattodea), and house
crickets (Acheta domesticus) (158, 159).
Entomophagy, or the practice of consuming insects, has been practiced by many nations
throughout Africa, Asia, Latin America, and Oceania for countless years. It is estimated that
113 countries consume 2,000 distinct species of insects as food sources (157). The
consumption of edible insects in the future, if expanded, raises a number of questions and
issues, including acceptability of such food sources by western cultures, technical production,
and regulations that include food safety. Part of the food safety risk assessment concerns
potential human illnesses related to biologic and chemical agents (158). Many different
microbial species, including bacteria and parasites, have been isolated from most insect
species studied (158–160). These include the family Enterobacteriaceae and many common
genera, such as Escherichia, Klebsiella, Enterobacter, Salmonella, Proteus, and Pantoea (158,
160). Concentrations of enterobacteria vary by family or genus but range from ,1 to .7 log
CFU/g (158). Some studies have focused on the detection of specific human pathogens, such
as Cronobacter
(161), in ready-to-eat edible insects, although C. sakazakii species identification is
questionable.
An outstanding and comprehensive publication by Garofalo et al. (158) reviews
studies conducted between 2000 and 2019 on the isolation of microbial pathogens from
different insect species. Data tabulated include their relative load (microbial burden),
sources (market, wild), and the insect form analyzed (fresh, processed).
Animals. Comparable to plants and insects, animals have an intimate association
with genera in the family Enterobacteriaceae. These associations can be as commensals

or occasionally as pathogens for a number of vertebrate species (2). Salmonella as an
example is a natural commensal of reptiles and amphibians but can also be introduced
into poultry stock, where it can live asymptomatically or on occasion cause disease.
Likewise, E. coli (pathogenic and nonpathogenic types) is another example, living
symbiotically in cattle, deer, and other animals but can be introduced through fecal
contamination into consumable products such as ground beef, fruit, melons, and
sprouts (2). Surprisingly, there have been few comprehensive studies looking at the
distribution of Enterobacteriaceae in mammals, for example, with the exception of the
study by Gordon and FitzGibbon in 1999 (162). In that investigation, the authors isolated
enterobacteria from 642 mammalian hosts in Australia and calculated the relative
abundance and diversity of genera and species.
An increasing but less-well-documented aspect of the enterobacterial group is the
potentially increasing importance of family members in causing animal diseases. Many
traditional taxa within the family produce sporadic or episodic intestinal or extraintestinal
infections in numerous different hosts (1, 2, 15). However, new agent-disease associations are
consistently being described, such as Morganella morganii causing fatal infections in chickens
(163) and hypermucoid K. pneumoniae producing sepsis and meningitis in sea lion pups
(164). What is less well appreciated is the increasing association of various taxa with specific
infectious disease syndromes, as shown in Table 6. While some disease syndromes have a
very specific host range (C. rodentium and murine colonic hyperplasia), others like bovine
mastitis are caused by many different

TABLE 6 Selected examples of enterobacteria-associated disease syndromes in animals
Pathogen Host Disease Symptoms Reference(s)

Citrobacter rodentium Mouse Transmissible murine Thickened colon, rectal prolapse, diarrhea 294
colonic hyperplasia
Edwardsiella ictaluria Channel catfish Enteric septicemia Petechial hemorrhages (mouth), pale gills, 295
(farmed, tilapia) exophthalmia, multiple epithelial lesions Loss
Edwardsiella piscicida Fish (farmed, Edwardsiellosis of pigmentation, external hemorrhage, 4, 296
aquaculture) septicemia
Escherichia coli Cow Bovine mastitis Inflammation of mammary gland; abnormal 297
milk from a mammary quarter Respiratory
Escherichia colia Broiler chicken Colibacillosis tract syndrome; swollen head 298
syndrome
Escherichia colib Pigs Porcine diarrhea, Profuse diarrhea, dehydration, death 299, 300
postweaning diarrhea
Klebsiella pneumoniae Cow Bovine mastitis Inflammation of mammary gland; abnormal 297, 301
milk from a mammary quarter Darkening of
Yersinia ruckeri Fish (salmonid) Enteric redmouth disease skin, subcutaneous hemorrhages 302
(mouth, throat), internal petechial
hemorrhages
aAvian-pathogenic E. coli strains.
bEnterotoxigenic and enteropathogenic E. coli.
microbes in addition to E. coli and K. pneumoniae. Collectively, the group listed in Table 6 can
cause large outbreaks of disease, the listed syndromes are recognized worldwide, and
infections result in huge financial losses, particularly in the food industry such as aquaculture
systems.
Soil and water. The microbial ecology of soil and water is extremely complex.
Sewage, sewage sludges, animal excreta, manure, contaminated agricultural products,
and runoff can result in the contamination of soil and freshwater sources with enteric
bacilli (165). Direct studies linking contaminated soil such as farm soil to human or
animal infections is lacking (165). Compounding this problem is the fact that pathogenic
enterobacteria released into soil may not simply colonize resident plants transiently but
may develop a longer-term relationship with them as alternative hosts (166). Plants
could then act as hosts for enteric species when existing as aquatic vegetation in
freshwater habitats, including lakes (123).
ENTEROBACTERIACEAE—OLD AND NEW AGENTS IN NEW DISEASE SETTINGS

Overview
Advances in molecular techniques and phylogenetic methods over the past 30 years
have resulted in a dramatic transformation in the size and scope of the family
Enterobacteriaceae in terms of the number and type of taxa identified, environmental
distribution, and disease associations. These two events, modernization of bacterial
taxonomy and phylogenetic classification, coupled with better laboratory methods to
achieve a final bacterial identification (16S gene sequencing, MALDI-TOF, WGS) have
revolutionized the field of clinical microbiology.
The ability to generate a more exacting and definitive identification of pathogenic
bacteria, in particular regarding less common or rare species, has led to a better
understanding of their occurrence, pathogenicity, and disease associations in the clinical
environment. This, in turn, has led to significant advances in our knowledge of these
microbial agents with respect to clinical microbiology. Klebsiella variicola is an emerging
human pathogen (167). In the past, this species has constantly been misidentified in the
microbiology laboratory as K. pneumoniae by conventional methods prior to the introduction
of molecular techniques (168–170). K. variicola is now known to cause serious bloodstream
infections, produce hypervirulent strains, and exhibit multidrug resistance (167). The
misidentification of many isolates for years prior to 16S gene sequencing, MALDI-TOF, and
WGS leaves a number of unanswered questions regarding this taxon, including clinical
frequency, environmental distribution, relative pathogenicity, and composite disease
associations. Other taxa with recently identified and

TABLE 7 Reported outbreaks of gastroenteritis caused by P. alcalifaciens
Cohort No. of cases % Attack rate Location Food Clonala Reference

Father and son 2 Unknown Mexico Unknown 1 185
Elementary and high schools 270 27.6–54.7 Japan Teriyaki chicken burger (warm bread) 1 182
Army hospital personnel 27 41.5 Turkey Potato salad ND 181
Church social event 11 Unknown Kenya Mashed potatoes (mukimo) 1 186
aND, not determined.
expanded syndromic presentations include Raoultella ornithinolytica with osteoarticular and

intrathoracic respiratory infections (171), Leclercia adecarboxylata disease in pediatric
patients (172), and the epidemiology, clinical presentation, and antimicrobial resistance of
Escherichia (“Atlantibacter”) hermannii illnesses (173).
Additional changes witnessed within the family Enterobacteriaceae that have been
precipitated by the “molecular revolution” also extend to traditional infectious disease
syndromes and etiologic agents. The family’s natural habitat is the gastrointestinal tract
of vertebrates, and members have long been recognized as a major cause of various
gastrointestinal infections, including enteritis, colitis (including hemorrhagic), and
dysentery. As late as 1985, only three enteric groups, Escherichia coli-Shigella,
Salmonella, and Yersinia enterocolitica, were universally recognized as gastrointestinal
pathogens from a limited list of documented prokaryotic species. However, this list has
continued to expand over time, with more than 40 different agents or pathotypes now
recognized as definitive, probable, or possible etiologic agents of gastrointestinal
disturbances based upon reported outbreaks, case histories, other clinical features
(serologic responses, histopathology), and identification of enteropathogenic virulence-
associated factors (174, 175). For the enterobacteria, over 50% of these 40 agents
currently reside within the family Enterobacteriaceae (175) and several presumptive
pathogens are now recognized as emerging agents of diarrheal infections (176, 177).
Recently Identified Gastrointestinal Pathogens

Providencia alcalifaciens. In 1989, Haynes and Hawkey (178) found a significant
association between the presence of P. alcalifaciens and travelers’ diarrhea in persons
between the ages of 15 and 64 who were primarily returning from travel to
Mediterranean countries. Shortly thereafter, Albert and coinvestigators (179) studied
three cases of diarrhea, one in a deceased Bangladeshi child and two in adults. P.

alcalifaciens was present in all three stools in either pure culture (child) or as
predominant enteric flora, and these strains were later shown to produce potential in
vitro and in vivo enteropathogenic mechanisms, including invasion of HEp-2 cells and
diarrhea in the removable intestinal tie adult rabbit model (179). Together, these two
studies formed the cornerstone for interest in P. alcalifaciens as a possible
gastrointestinal pathogen. Further evidence supporting a causal role for P. alcalifaciens
in diarrheal disease stems from studies showing a statistically significant association of
this species with symptomatic persons versus controls (178, 180, 181), elevated immune
responses in infected persons (182), and identification of multiple virulence-associated
factors potentially operative in the gut. Virulence-associated characteristics included
invasion of cell monolayers (178, 182), production of a cytolethal distending toxin (183),
and barrier dysfunction and apoptosis in tissue culture cells (184).
However, the most compelling evidence to date supporting a role for P. alcalifaciens
in bacterial gastroenteritis comes from several reports on outbreaks of diarrheal
disease attributed to this bacterium (Table 7). These outbreaks ranged in size from 2
(father and son) to 270 involving three schools in Fukui City, Japan, in 1996. In that later
outbreak, 7 of 18 patients were culture positive for a clonal strain of P. alcalifaciens and
7 of 8 symptomatic persons displayed elevated serologic titers against the outbreak
strain (182). Furthermore, the outbreak strains were demonstrated to be invasive in
Caco-2 cells and to illicit moderate fluid accumulation in rabbit ileal loops (RIL) (182). In
three of the four outbreaks listed in Table 7, the outbreak strains were found to be

clonal in nature by a combination of techniques including serogrouping, plasmid analysis,

pulsed-field gel electrophoresis (PFGE), and randomly amplified polymorphic DNA (RAPD)
(182, 185, 186). A food source was implicated in three instances, two associated with potato
dishes, one of which appeared contaminated by a culture-positive cook (181). The largest
outbreak in Japan appeared to originate from a catering company
(182). Travel-related infections are suspected in two outbreaks (181, 185).
Shah et al. (187) recently reviewed the literature on P. alcalifaciens infections; however,
many questions remain unanswered in regard to the role of P. alcalifaciens in diarrheal
disease. Since most laboratories do not look for this organism routinely, its relative frequency
as an enteropathogen in select patient populations is presently unknown, although a
selective medium, polymyxin-mannitol-xylitol medium-Providencia or PMXMP, has been
developed to aid in its recovery and identification (188). While several studies have found an
association between providenciae and gastroenteritis, P. alcalifaciens has also been found to
be present with other copathogens (188) and in very high percentages in one study (180). In
an outbreak in Turkey, at least 44% of infected military personnel who were now healthy were
still culture positive for P. alcalifaciens 10days later (181). Finally, we currently do not know
which of several reported pathogenic mechanisms may be operative in all or select strains
involved in gastroenteritis.
Escherichia albertii. In 2003, a new Escherichia species, E. albertii, was proposed for
five fecal isolates recovered from diarrheal stools of children ,5 years old residing in
Bangladesh (189). These strains had been isolated more than a decade earlier and had
been thought to belong to the genus Hafnia or to be “Hafnia-like” in phenotypic
characteristics. However, they differed markedly in a number of ways from true Hafnia
strains by being Voges-Proskauer negative, acetate positive, and susceptible to
cephalothin, by their failure to be lysed by the Hafnia-specific phage 1672, and by
possessing the E. coli/Shigella outer membrane protein gene phoE (190). DNA
relatedness studies by Huys et al. (189) indicated that these isolates represent a new
species residing in the genus Escherichia.
E. albertii appears to be fairly widely dispersed in the animal kingdom, although its
exact range, distribution, and prevalence in vertebrate hosts still remain to be determined.
Two major animal reservoirs of E. albertii have been identified. Wild and domestic avian
species in both healthy and diseased states have yielded E. albertii (191, 192). Birds found
positive for this taxon include ducks, finches, magpies, wrens, woodpeckers, and chickens
(191–193). This list even extends to the isolation of this species from a penguin in Patagonia

(194). A second major reservoir that has just been discovered is raccoons. A study of over 400
wild raccoons in Osaka, Japan, found that 57.7% of rectal swabs obtained were positive for E.
albertii by PCR; in this study, 143 viable E. albertii isolates were isolated from 62 PCR-positive
samples (195). In addition to these two sources, E. albertii has been recovered from a cat,
seals, and processed meats, including pork and mutton (193, 194, 196).
E. albertii causes diarrheal syndromes in humans, although the actual prevalence of

the disease worldwide is presently unknown. Essentially all E. albertii strains carry two
virulence determinants, the intimin gene (eae) and a cytolethal distending toxin gene (cdt) (
193, 197). The intimin gene appears to be important in disease pathogenesis, while much less
is known regarding what role the cytolethal distending toxin might play (193). Sporadically,
strains of E. albertii also carry variants of Shiga toxin 2 (stx2) (193), but again, there are less
than a handful of case reports describing such infections in the literature (196, 198, 199). Most
of our knowledge regarding E. albertii-associated diarrhea comes from epidemiologic data on
Japanese outbreaks of gastroenteritis associated with this organism. Six of these outbreaks
between 2003 and 2015 were recently summarized by Masuda et al. (200). The chief
symptoms of E. albertii-associated diarrhea compiled from these outbreaks are watery
diarrhea (80% to 100%), abdominal pain (50% to 84%), and fever (26% to 100%) (200). Less
common complications include headaches, nausea, and vomiting. The overall recorded attack
rate was 457/741 or 61.2% (200). The largest of these outbreaks involved 409 students and

TABLE 8 Distinguishing features of Escherichia albertii biogroupsa
% Positive
E. albertii
Test Biogroup 1 Biogroup 2 Biogroup 3 E. colib

Motility 0 0 0 95
Indole 0 100 100 98
LDC 100 0 100 90
Lactose, acid 0 0 0 95
L-Rhamnose, acid 0 0 0 80
D-Sorbitol, acid 0 100 0 94
D-Xylose 0 0 0 95
aData from Strockbine et al. (202) and from Table S2 of Murakami et al. (203).
bDoes not include inactive groups.
teachers from a high school staying at a campground. The suspected cause of the
outbreak was sump water that was unchlorinated and used as a potable water source
(200). In most of these outbreaks, the vehicle of transmission was not definitively
identified, but consumables including restaurant items (salad, other foods, water used)
and purchased lunch box meals were suspected. Two cases of gastroenteritis linked to
Shiga toxin-producing E. albertii have been published (198, 199). In one instance, bloody
diarrhea resulted (198), while in the other case, the child experienced only watery
diarrhea (199). There has been one reported case of extraintestinal infection caused by
E. albertii, that occurring in a 76-year-old woman with multiple comorbid conditions
who developed bacteremia (201). She recovered uneventfully after appropriate
chemotherapy.
The present lack of both laboratory and epidemiologic data concerning E. albertii
stems from general difficulties in the recognition of this Escherichia species. E. albertii
has been dubbed “the evasive enemy,” no doubt in large part due to the difficulty in
isolation and identification of this pathogen in the clinical laboratory (193). This taxon
was originally proposed and described as an indole-negative, lysine decarboxylase
(LDC)-positive species that could be separated from other members of this genus on the
basis of these properties and several others, such as D-xylose (189). However, it quickly
became apparent that variability in phenotypic expression among E. albertii strains was
significantly greater than originally thought. Sequence analysis of multiple

housekeeping genes coupled to eae and cdt gene sequencing by Hyma and colleagues
(197) indicated that strains previously classified as Shigella boydii serotype 13 (known
not to be a true shigella) were actually E. albertii on a genetic basis. These strains
differed biochemically from those described by Huys and others (189) in being indole
positive and LDC negative. Two biogroups were subsequently proposed for these
strains (202). Biogroup 1 represented the former group described by Huys et al. (2018),
while biogroup 2 strains were identical to those previously referred to as Shigella boydii
13. Ongoing research studies have identified many field isolates of E. albertii that do not
fit into either of the two previously recognized biogroups, so a biogroup 3 has been
proposed (203). Table 8 lists distinctive phenotypic features of all E. albertii biogroups
and their differentiation from normal reactive E. coli.
E. albertii has been misidentified frequently. Biochemical methods have often
reported E. albertii isolates as “Hafnia-like” or Hafnia alvei, while molecular methods
assessing both the eae and cdt genes have reported strains as belonging to either the
enteropathogenic E. coli (EPEC) or enterohemorrhagic E. coli (EHEC) groups. Ooka and
others (196) retrospectively analyzed 278 eae-positive E. coli strains and found that 26
(9.3%) were in fact E. albertii. In 2019, a similar study found 17 (4.5%) E. albertii isolates
from a collection of 373 strains to be misclassified as either EPEC or EHEC (204).
Conventional biochemical tests can help to distinguish E. albertii from phenotypically
similar bacteria (Table 8); however, inactive E. coli bacteria, although uncommon, still
present problems (202). Other tests not mentioned in Table 8 can also be helpful (193,

196). Bhatt and coinvestigators (193) have published a composite table on the main
biochemical or phenotypic properties of E. albertii, E. coli, and H. alvei that is also quite
useful.
Two recent developments may significantly help in the accurate identification of E.
albertii in the diagnostic laboratory. A recent report found that enhancing the Bruker
MALDI-TOF database with additional E. albertii spectra not present from the
manufacturer was extremely productive (205). Of 58 E. albertii stains originally tested
on the Bruker MALDI-TOF with a database library of 7,311, only 4 (6.8%) were correctly
identified. However, when enhanced with additional spectra, MALDI-TOF correctly
identified all 58 strains (205). This same group has also developed a selective agar for
the recovery of E. albertii. Named XRM-MacConkey (xylose-rhamnose-melibiose), this
medium was found superior to several other selective media for Enterobacteriaceae,
producing colorless colonies that invariably were identified as E. albertii (206). The
detection limit of XRM-MacConkey was 105 CFU/g of stool. These two innovations
together should significantly improve the ability of laboratories to detect and identify
this enteric pathogen (205, 206).
Klebsiella oxytoca and colitis. Acute colitis is typically a transient inflammation of the
colon accompanied by one or more symptoms such as bloody diarrhea and abdominal
pain or distension. The syndrome can be precipitated by a number of different drugs,
including antibiotics or other irritants. For over half a century, the genus Klebsiella has
been recognized as a possible cause of acute enterocolitis (207). In the late 1980s,
Japanese researchers identified a unique cytotoxin produced by Klebsiella oxytoca
strains associated with cases of hemorrhagic enterocolitis (208). The toxin had a
molecular mass of approximately 271 Da, was protease resistant, and produced
rounding and/or cell death in HEp-2, HeLa, CHO, and Vero cell lines (208, 209).
Subsequent investigations by the same group found that the cytotoxin elicited fluid
accumulation in RIL (210). Histologic examination of these infected tissues revealed
intense mucosal hemorrhaging with erosion of the ileum (210).
Following these discoveries, a series of prospective studies and case reports
provided further documentation linking certain strains of K. oxytoca to antibiotic-
associated hemorrhagic colitis (AAHC) (209). All of these studies had a number of
common features, which included patients on penicillin derivative therapy of short
durations, some persons additionally on nonsteroidal anti-inflammatory drugs (NSAID),
and stools that were negative for Clostridium difficile with no other enteric pathogens

detected. A French study of 20 suspected cases of antibiotic-associated diarrhea found
11 patients with AAHC (right-sided hemorrhagic to diffuse ulcerative colitis) primarily
consisting of bloody and mucousy diarrhea (211). Of 11 such persons, 8 were positive
for K. oxytoca. In contrast, none of 36 colonic biopsy specimens of control patients
contained K. oxytoca (211). The definitive study on K. oxytoca AAHC was published by
Högenauer et al. (212) in 2006. In that investigation, 5 of 6 persons with AAHC as
determined by colonoscopy were positive for cytotoxigenic K. oxytoca on HEp-2 cells, as
opposed to only 1.6% of healthy subjects. The age range of persons with K. oxytoca-
associated AAHC was 28 to 65 years, younger than the typical age range for Clostridium
difficile-associated colitis. In all five positive patients with K. oxytoca, amoxicillin-
clavulanate appeared to be the triggering antimicrobial, and two persons were also
noted to be on an NSAID (212). Furthermore, the authors fulfilled Koch’s postulates by
inducing rightsided hemorrhagic colitis in Sprague-Dawley rats given cytotoxigenic K.
oxytoca and amoxicillin-clavulanate but not in either of two control groups that did not
contain this combination (212). Patient’s conditions resolved completely after
discontinuation of antimicrobial therapy.
The exact frequency of K. oxytoca in gastrointestinal contents is unknown and has
varied in studies from different geographical locales from 1.6% to .4.0% (212–214).
Cytotoxigenic strains are found in higher percentages in patients with C. difficile-
negative AAHC than in those with acute colitis or in healthy carriers (215). The disease
can develop rapidly, with AAHC manifesting itself within 2 to 4 days of the initiation of

antimicrobial chemotherapy (215). A limited study of four patients with AAHC found that
K. oxytoca could be recovered in relatively high concentrations (.106 CFU/ml) from
patient stools (209, 213). A selective medium, Simmons citrate-inositol-tryptophan-bile
salts (SCITB), has been used in a Hong Kong survey to appreciably increase the recovery
rate of K. oxytoca from diarrheal stools (214).
Whether cytotoxigenic K. oxytoca plays a role in other gastrointestinal syndromes is not
known. One large study of 371 patients broken down into four different groups based upon
the presence of diarrhea and whether or not individuals received antibiotics found no
association between the presence of K. oxytoca and nonhemorrhagic antibiotic-associated
gastroenteritis (213). However, Paveglio and colleagues (216) recovered cytotoxigenic K.
oxytoca from 6 of 10 infants with necrotizing enterocolitis characterized by bloody diarrhea,
pneumatosis, and abdominal distension. K. oxytoca has also been linked to a fatal case of
antibiotic-associated pseudomembranous colitis, but the pathogenic characteristics of the
infecting strain were not investigated (217).
Potential enteropathogens with inconclusive data. A number of enterobacterial
species or biotypes have been occasionally implicated in gastroenteritis based upon
clinical disease associations, case reports, and possession of virulence-associated
factors (2, 174, 175). While the data in many instances are very limited, several bear
mentioning, as many recognized enteric pathogens (see above) started under similar
circumstances.
A recent review has suggested that Proteus species might be putative
gastrointestinal pathogens, as has already been demonstrated conclusively for other
Proteeae such as P. alcalifaciens (218). The primary evidence supporting a possible role
for protei in gastroenteritis involves their possession of some potential pathogenic
characteristics (hemolysin, intracellular invasion) and a “guilt by association” recovery of
P. mirabilis from one foodborne outbreak of gastroenteritis in Beijing, China (218). A
more recent publication has characterized potential pathogenic mechanisms in one
food poisoning-associated strain when it was compared to two reference cultures (219).
However, there are presently no clinical or epidemiologic data linking isolations of
Proteus to case-controlled studies of gastroenteritis, detection of common virulence-
associated factors in outbreak-related isolates, animal models of infection, or
demonstration of clonality among isolates associated with instances of food poisoning
(219). Furthermore, there are only a couple of studies with contradictory conclusions on
whether or not the frequencies of Proteus spp. in diarrheal versus healthy stools are
different (218, 220).

Over the last 4 decades, there have been sporadic reports describing the association
of Citrobacter freundii with episodes and outbreaks of gastroenteritis (2). In 1995,
Tschäpe and others (221) described a nursery school outbreak of diarrhea associated
with hemolytic-uremic syndrome (HUS) and thrombocytopenic purpura with anemia. At
least 14 children between the ages of 2 and 6 years were infected, 9 of which required
hospitalization due to renal failure. All C. freundii strains recovered from these children
produced a Shiga toxin (stx2) (221). Sandwiches prepared with green butter containing
contaminated parsley appeared to the likely vehicle of infection. A C. freundii strain
producing an aggregative adherence pattern on HeLa cells has also been isolated from
a child with severe diarrhea (222). Cytotoxigenic and adherent C. freundii isolates have
been identified in the stools of persons with diarrhea (223). One strain, recovered from
a goat, was not only cytotoxic but produced an aggregative adherence pattern on
Hep-2 cells. These publications may be a reflection of the horizontal transmission of
virulence factors from a traditional pathogen (E. coli) to citrobacteria as an isolated
event, or they could signal that C. freundii has been overlooked as a potential
enteropathogen.
Extraintestinal Diseases and Infectious Syndromes

Extraintestinal community-associated infections linked to current members of the
family Enterobacteriaceae appear to be on the rise. Some of these infections are the
result of the translocation of pathogenic strains from the gastrointestinal lumen into

the circulatory system or lymph nodes, producing systemic disease, including bloodstream
infections (BSI). Conditions in the community that exacerbate such situations include an
increasingly elderly population and more residents with underlying diseases or
immunocompromised conditions. Community-acquired extraintestinal infections can also
result from the consumption of contaminated foods, contact with infected animals, or
penetrating traumas (2). Some examples are listed below.
Klebsiella pneumoniae and PLA. A pyogenic liver abscess (PLA) is a solitary mass or
collection of pus-filled masses due to bacterial infection, often located within the right
lobe of the liver. PLAs are typically polymicrobic in nature, with Gram-negative
pathogens predominating, including certain enterobacterial species such as E. coli and
Klebsiella spp. (224). PLA can develop from a number of sources, including trauma, the
circulatory system, due to biliary tract infections, or peritonitis subsequent to bacterial
translocation from the gastrointestinal tract (225). The incidence of PLA has been found
to be higher in Southeast Asia (11.99 to 17.59/100,000) than in various western
countries, including the United States (2.7 to 4.1/100,000), although reasons for these
geographic differences are not well appreciated (226).
Beginning in the mid-1980s, a new variant of K. pneumoniae associated with PLA
and metastatic disease first appeared in Taiwan (227). The seven infections reported in
this clinical series differed from classical K. pneumoniae (cKp) illnesses in that they were
associated with septic endophthalmitis and other metastatic complications, including
meningitis and pulmonary embolism; all seven patients recovered but completely lost
their vision (n = 6) or visual acuity (n = 1). By 1998, a Taiwanese review of 182 cases of
liver abscesses caused by K. pneumoniae occurring between 1990 and 1996 found 160
(88%) to be monomicrobic (228). Differences noted between monomicrobic and
polymicrobic abscess infections included a higher frequency of diabetes or glucose
intolerance and metastatic disease in the former group (228). Today, while this disease
is still centered in Southeast Asia, and in particular in Taiwan and South Korea, it has
now been reported worldwide from India, Europe, Australia, and the United States (229,
230).
This new variant of K. pneumoniae is referred to as hypervirulent K. pneumoniae, or
hvKp (230). Another term used less frequently for this group is hypermucoviscous. It
can be distinguished from cKp strains clinically because illnesses associated with the
variant pathotype are normally community acquired and PLA occurs in the absence of
biliary disease, often presents as metastatic infections at multiple anatomic sites, and is

typically monomicrobic in composition (230). Genetically, these strains harbor a number
of virulence factors that are either chromosomally encoded or on virulence plasmids
such as pK2044 and pLVPK (229, 230). These virulence factors include genes encoding
capsule formation (cps), mucoid regulators (rmpA, rmpA2), K1 and K2 antigenic capsule
types, and several siderophores, including yersiniabactin (229, 230). The predominant
phenotype in all of these strains is hypermucoviscocity (HMV), which is easily detectable
on common media such a blood agar by a “string test” (231). For K1 strains, this
hyperviscous phenotype is linked to the gene magA (mucoviscocity-associated gene A).
Other pathogenicity factors have been described but are less well characterized (230).
Most cases of PLA are preceded by gastrointestinal tract colonization by hvKp prior to
invasion, although initial sources of environmental acquisition are poorly defined. Risk factors
associated with developing hvKp disease include Asian ancestry and diabetes mellitus (225,
229, 230). In its infancy as a recognized emerging pathogen, hvKp infections were initially
defined by their association with cryptogenic PLA. Symptoms associated with hvKp PLA are
not variant specific but rather typical for the syndrome and include fever, chills, abdominal
pain, and leukocytosis (225, 230). Common metastatic sites of hvKp PLA infection identified
early in their history included the eye, central nervous system (CNS), and pulmonary tree in
addition to bacteremia (229, 230); in one large study of over 800 persons, 12% of patients with
hepatic abscesses developed metastatic disease (229). Approximately 5% of patients
presenting with hvKp

bacteremia develop endogenous endophthalmitis, which carries with it a devastating

prognosis of loss of visual acuity for 89% of patients (230). The mortality rate associated
with PLA is roughly 5% but increases to 10% to 16% for metastatic disease (225). Some
studies report an even higher range (3% to 31%) with mortality rates as high as 35%
(229).
Unfortunately, over the last few years, a number of new and emergent trends
concerning hvKp disease have been detected. Various studies have described
extrahepatic illnesses associated with hvKp, including bacteremia, pneumonia, and
musculoskeletal and soft tissue infections along with a variety of less frequently
encountered complications like Bartholin’s abscess (229, 230). Another alarming trend is
the increasing incidence of hvKp causing health care problems, including ventilator-
associated infections (229). A 2020 study from China found that a retrospective analysis
of 79 hvKp strains determined that 53 (67.1%) of these isolates were health care
associated and 19 (24.1%) of these caused true HAI. Only 8.8% of the hvKp isolates in
this survey were community acquired (232). Probably the most disturbing and evolving
tendency of this variant is increasing acquisition of resistance to antibiotics. Historically,
the frequency of drug resistance in this variant was low, with ,2% of isolates resistant to
cephalosporins (229). However, detection of extended-spectrum b-lactamases (ESBLs) in
this group has risen from ,5% to 35% or more in some studies (232). An outbreak of
pneumonia in surgical patients who were subsequently placed on mechanical
ventilation was caused by hvKp (233). The infecting strain belonged to sequence type 11
(ST11) and was carbapenem resistant (233). All five patients in that study died. This
increasing trend in drug resistance in hvKp will clearly impact disease frequency and
associated mortality rates in hospitalized persons in the future if this trend continues to
increase and disseminate globally.
PLA requires a clinical diagnosis via abdominal imaging (225). Suspicion of hvKp
playing a role in PLA is presently challenging, requiring an astute review of clinical and
demographic information that might suggest the presence of K. pneumoniae (230). The
clinical laboratory, however, can play a key role in the diagnosis of such infections by
the identification of hvKp from suspected (blood) or occult (eye) clinical samples. The
defining phenotype for hvKp strains is HMV. The HMV phenotype is detected by a
“string test” test, which is defined as the extension of a mucous string by an inoculating
loop .5mm from a bacterial colony grown overnight on a blood agar plate (231). In the
initial studies, the string test had a 98% sensitivity in recognizing the HMV phenotype

(231). More recent studies suggest that this value is somewhat lower, with an accuracy
of 0.90 (234). Regardless of this difference, it is a simple test than can be performed in
any microbiology laboratory. A number of genotypes have been found to have a
diagnostic accuracy of .0.95. These include rmpA, rmpA2, peg-344 (putative
transporter), and iroB (salmochelin siderophore) (234). In addition to the HMV
phenotype, capsule typing using commercial-grade antisera can be useful, as the
majority of hvKp strains are either K1 or K2 (229, 230). However, other capsular types
can be hvKp with K1 . K2 . K5 . K57 in decreasing order of frequency (229).
One of several problematic issues regarding the laboratory diagnosis of this group is
that no single test encompasses or detects all hvKp isolates. The current gold standard
for identifying these strains is rmpA1 rmpA21 magA1 HMV1 (229). However, again variants
that deviate from the ideal phenotype but are still hvKp have been detected. Due to
their increasing significance worldwide, there has been a call for a consensus definition
for hvKp (235). This will no doubt be a challenging task, as the extent of genetic and
phenotypic variation in the group continues to grow.
A number of excellent reviews on various topical issues of hvKp are available (225,
229, 230).
Cronobacter sakazakii and neonatal meningitis. In 1980, the CDC proposed a new
species for inclusion in the genus Enterobacter, now Cronobacter (“Enterobacter”)
sakazakii (24, 236). This collection of 57 strains came from diverse clinical sources. The
authors commented that strains isolated from sputum, wounds, and species were

probably not clinically significant, although rare cases of neonatal meningitis were
identified. Just 3 years later, the CDC in partnership with international collaborators in
The Netherlands reported 8 additional cases of C. (Enterobacter) sakazakii neonatal
meningitis and septicemia (237). For two of these neonates, their episodes of meningitis
were accompanied by necrotizing enterocolitis. Six of these eight infants subsequently
died (75% fatality). Over the last 15 years, the incidence and breadth of C. sakazakii
invasive disease in neonates and infants have mushroomed on a global basis. An
excellent historical timeline of the progression of C. sakazakii infections and associated
diseases from their initial retrospective recognition (1950, prior to naming) to 2015 can
be found in the review by Farmer (24).
While C. sakazakii can cause illnesses on a sporadic basis in adults and older
persons, its paramount clinical and public health importance is as a causative agent of
two types of invasive neonatal disease, bacteremia and meningitis (238). In up to 40% of
cases of neonatal or infantile meningitis, such infections are accompanied by brain
lesions, typically abscess formation. This makes C. sakazakii one of only three
enterobacterial species (E. coli K1, Citrobacter koseri) intimately linked to causing brain
abscesses in young infants and children (2). The major risk factors in this population
setting for developing invasive C. sakazakii include neonatality (,28 days), low birth
weights (,2,500 g), and consumption of powdered infant formula (PIF) (238–240). Case
fatality rates have been reported as high as 40% to 80% in those presenting with
bacteremia, meningitis, and necrotizing enterocolitis (238). Henry and Fouladkhah (25)
have recently summarized a number of sporadic cases and outbreaks of invasive C.
sakazakii disease in infants. The vast majority of these cases were associated with infant
formula, including PIF.
As in the case of K. pneumoniae and hvKp, infections involving C. sakazakii appear to
be on the rise and changing with respect to demographics in the United States. A report
reviewing the published literature (1961 to 2018) plus all systemic isolates of C.
sakazakii referred to the CDC identified 183 cases of infant infections (240). Of these
illnesses, 63% involved episodes of meningitis, while the remainder were bloodborne
infections. Neonates were the predominant age group impacted, accounting for 67% of
all infections. A review of published studies and information accompanying isolates
forwarded to the CDC indicated that 79% of infants were reported as having consumed
PIF (240). The observed mortality rate was 38%. One of the interesting findings of this
CDC epidemiologic investigation was the changing demographics of disease

presentation. Prior to 2004, only 44% of infections were found in nonhospitalized
children. Between 2004 and 2018, this figure had risen to 78%. Similarly, the percentage
of fullterm neonates infected with C. sakazakii rose from 22% before 2004 to 50%
during the last quarter of the study (240). The incidence in cases also rose from 1.2
cases/year before 2004 to 8.7 cases/year between 2004 and 2018. The reasons behind
these changing demographics in the United States are not apparent. Cronobacter
invasive disease also appears to be emerging outside the United States. An Egyptian
study of 100 cases of neonatal sepsis found that 12% of cases were due to C. sakazakii (
241). Of these 12 cases, two infants died and two others suffered marked physical and
mental impairment. The authors report these dozen infections as the first cases of this
emergent disease in Egypt (241).
Presently, C. sakazakii, like the other above-mentioned agents, is not a reportable disease
in the United States or elsewhere (240). This severely limits our understanding of the
magnitude of neonatal infections caused by this pathogen worldwide. Two other confounding
problems involve their environmental distribution and laboratory identification. Cronobacter
spp., and C. sakazakii in particular, are ubiquitous in the environment, being found in a
variety of consumable products and water. While PIF is clearly the primary implicated vehicle
for most infant infections (242), C. sakazakii illnesses have also been connected to expressed
breast milk on several occasions (240). A key to decreasing the incidence of infections is to
find substitutes for PIF, and the WHO has established recommendations for hospitals and
home use of PIF and its preparation for

the first 2 months of life (25, 242). In addition to PIF, C. sakazakii has been recovered from
flour-based products, flour, cereal kernels, herbs and spices, insects, meats, and other
commodities (25, 161, 238, 241, 243, 244). Their extensive environmental distribution is in no
doubt partially related to the fact that they are resistant to desiccation and dry and acid
growth conditions in comparison to other enterobacteria (238).
For many years, C. (Enterobacter) sakazakii was considered to be a fairly tight
genetic species composed of 15 biotypes (25). However, that opinion changed with the
creation and publication of a new genus, Cronobacter, in 2007 (25). Today the genus
has seven validated species, including C. sakazakii (https://lpsn.dsmz.de/species ?
page=C#Crabtreella). For the clinical laboratory, this presents problems, because
although most cronobacters have been associated with human disease, definitive
identification of C. sakazakii is of immense importance because of its paramount role as
the preeminent pathogen of the genus. The Vitek GN identification system lists most
species under the phenospecies designation “Cronobacter sakazakii group” (245).
Identification matches based on various commercial products (Vitek GN, API 20E, ID32E)
ranged from 82.3% to 90% (245). A multicenter European study involving 11 countries
found that only 59 of 77 (76.7%) isolates submitted as C. sakazakii were, in fact, this
genetic species, as determined by MALDI-TOF and WGS (245). Some misidentified
isolates did not even belong to the genus Cronobacter but rather belonged to a variety
of genera, including Enterobacter, Klebsiella, Kluyvera, Kosakonia, and Siccibacter
(246). These results suggest that better methods for identifying this important clinical and
public health pathogen need to be developed.
Chronic conditions and potential long-term sequelae. The vast majority of medical
personnel and allied scientists associate the family Enterobacteriaceae with foodborne
disease, health care-associated illnesses, and a variety of syndromic diseases, including
gastroenteritis, urinary tract infections, and soft tissue infections subsequent to
traumatic events. However, less well appreciated is the fact that many of these species
as resident commensal gastrointestinal flora may be associated in some aspect with
much longer-term chronic or persistent conditions.
Inflammatory bowel diseases, which include Crohn’s disease and ulcerative colitis,
are thought to be due to host genetic factors, environmental triggers, and endogenous
microbial communities. E. coli is one of the leading candidates to play some role in
these two disease processes. Studies of the microbiome have demonstrated that the
relative abundance of E. coli increases in Crohn’s patients (as does Serratia marcescens)

when compared to healthy individuals and familial controls while beneficial bacteria
decrease (247, 248). The particular pathotype implicated in these inflammatory
processes is adherent-invasive E. coli (AIEC) (249, 250). The data seem clear that
adherentinvasive E. coli bacteria are associated with both conditions, but whether they
are opportunistic bystanders or are intimately involved in the entire immune-mediated
process remains to be determined. Proteus spp. have also been proposed to have a
possible role in Crohn’s disease (218). This proposal is based on two pediatric studies
where there was an overabundance of protei in Crohn’s patients compared to
individuals with other gastrointestinal conditions.
E. coli strains have also been linked to irritable bowel syndrome, a condition affect-
ing 10% to 20% of the population (251). The two pathotypes associated with this
condition are AIEC and enteroaggregative E. coli (251, 252). Increased numbers of E. coli
correlate with disease symptomatology, and patients respond to antimicrobial therapy
directed against this microbe (251).
Enterobacteria are increasingly being implicated as potential infectious agents
associated with immune and nonimmune inflammatory processes of bones, joints, and
associated tissues. Rheumatoid arthritis (RA) is a chronic inflammatory arthritic
condition most often involving symmetrical joints. It primarily affects middle-aged
women. RA is thought to involve genetic, environmental, and microbial factors (253).
Among enterobacteria, several different species have been implicated in RA, but by far
the greatest amount of data linking a group to the etiology of RA is that concerning the

genus Proteus, and in particular P. mirabilis (2, 254). A number of studies have found
significantly elevated antibodies (IgM, IgG, IgA) against P. mirabilis antigens (hemolysin,
urease) in RA patients in comparison to controls (255). These antigens share common
motifs with HLA subtypes found in RA patients. The six-amino-acid sequence ESRRAL
(glutamic acid-serine-arginine-arginine-alanine-leucine) in P. mirabilis hemolysins
shares homology with the EQRRAA (glutamic acid-glutamine-arginine-arginine-alanine-
alanine) motif found in RA-associated HLA-DR (subtypes HALA-DR1 and HLA-DR4) (2,
254). The prevailing theory is that P. mirabilis urinary tract infections elicit significant
immune responses against this uropathogen such that, through molecular mimicry,
cross-reacting antibodies that target self-antigens in the joints are elicited.
A variety of other secondary complications have been associated with
gastrointestinal enterobacterial infections. Reactive arthritis, a sterile nonpurulent
inflammation of limbs, can be triggered by the acquisition of or infection with various
enterobacteria, including diarrheagenic E. coli (DEC) and Yersinia enterocolitica (256,
257). Some cases of reactive arthritis are associated with human leukocyte antigens,
part of the inflammatory process, such as HLA-B27 (257). In one investigation, 17% of
persons developed musculoskeletal symptoms posttravel (256). Multivariate analysis
found a significant association between this illness only with the exclusive isolation of
DEC. Other less frequently encountered infection-associated chronic conditions include
Reiter’s syndrome, ankylosing spondylitis, and prostatitis (2).
Colorectal cancer and related malignancies. An area of potential research that has
received little attention to date concerns the possible association of members of the
Enterobacteriaceae with malignancies. Dysbiosis is a clinical condition where there is an
imbalance in the normal microflora of a person related to ill health. For enterobacteria, this
mainly involves their natural habitat, the gastrointestinal tract. The handful of published
studies to date have primarily shown an abnormal rate or abundance of various
enterobacteria in disease states associated with cancer. Higher rates of colorectal cancer have
been detected in patients with pyogenic liver abscesses (230, 258). In one 11-year study, the
rate of colon cancer was 2.68 times greater for those with PLA due to K. pneumoniae than for
those patients without this enteric pathogen. A 2019 study has found both Escherichia-
Shigella and Enterobacter in higher numbers in patients with primary liver cancer (PLC) than
in healthy controls or those with liver cirrhosis (259). The relative abundance of Enterobacter
ludwigii was 100 times greater in the PLC group than in controls. E. coli has also been
implicated as possibly associated with colorectal cancer (259, 260).

What role some or any enterobacteria play in cancer is unknown. It could be that the
amplification of these species in dysbiotic states is a simple reflection of them as possible
indicators of occult malignancies in a fashion similar to that recorded for Streptococcus bovis
and Clostridium septicum (230). Another possibility is that these bacteria are the direct
causative agents of certain cancers. However, this hypothesis seems unlikely in that host
factors (immunologic, physiologic) as well as environmental triggers are thought to play
important key roles. Finally, enterobacteria might act as important cofactors in dysplasia
formation by one of several mechanisms, including activation or enhancement of
inflammatory processes or release of virulence factors causing DNA damage or genetic
instability (260). Further research in this area seems important.
THE FUTURE
Issue: The Family Enterobacteriaceae—Expansion or Contraction?
The landscape of clinical and diagnostic microbiology has forever been changed by the
introduction of the molecular taxonomic revolution brought about by WGS and related
phylogenetic techniques. These “technologic wonders” have generated a number of
important and positive changes in the field of bacterial taxonomy, including (i) the ability to
detect and identify new genetic species of potential medical, public health, or veterinary
importance (261), (ii) more precise identifications in the laboratory, especially for difficult-to-
identify pathogens, (iii) less reliance on federal, state, or reference laboratories for definitive
identifications, which could take days to weeks, and (iv)

advances in tracing, fingerprinting, and identifying the origins, transmission, and spread of
infectious disease outbreaks associated with the family Enterobacteriaceae (262).
Intimately linked to these novel and constructive taxonomic achievements are
classification issues which have no rules or boundaries regarding their acceptance or
rejection. The work of Gupta and colleagues (98, 117, 118) on various groups of medical
importance is impressive, but the bottom line of whether these changes should be accepted
into practice in medicine and related allied disciplines is questionable. There has already been
negative feedback on proposed classification (division) changes by this group of researchers
for long-standing taxa, including Borrelia (263), Mycobacterium
(119), and Mycoplasma (120), as well as the Enterobacteriaceae. The reasons for rejecting
such changes include inadequate data or evidence, avoidance of unnecessary changes,
importance of the stability in nomenclature, and potential impact on adverse medical
outcomes. Many of these reasons are listed in the rules of the ICNP. Classification changes
can also be a double-edged sword. As an example, Enterobacter aerogenes has been recently
transferred to the genus Klebsiella as K. aerogenes (60). Wesevich et al. (264) have found that
the presence of K. aerogenes in the bloodstream of patients is associated with a poor clinical
outcome (death before discharge, recurrent BSI) in comparison to other Enterobacter species.
In contrast to these findings, there is a concern that the transfer of this species from the
genus Enterobacter to Klebsiella may influence suboptimal therapy (265). Munson (265) in a
recent newsletter has done an outstanding job of providing a detailed and comprehensive
overview summarizing clinical issues concerning proposed taxonomic revisions.
Possible classification models. One of the important aspects of bacterial taxonomy

for clinical microbiologists, physicians, epidemiologists, and related groups is that
nomenclature and taxonomy need to be practical, useful, and workable with the
abovementioned groups in regard to daily communications concerning diagnosis,
prognosis, treatment, and the frequency and distribution of infectious diseases on a
global basis. While the ICNP establishes the rules for nomenclature, many exceptions
have been granted so that certain species that are genetically identical on the DNA level
can remain separate and distinct because of their enormous medical importance.
Several have previously been mentioned, including E. coli/Shigella and Yersinia pestis/
Yersinia pseudotuberculosis. While taxonomic progress is important, it needs to be
balanced by a needs assessment and general utility. Two obvious options are that the
Enterobacteriaceae could remain “status quo” or the proposals of Adeolu et al. (98)

could be adopted as published. Some other possible proposals are listed below.
(i) Proposal 1. Classification of genera into tribes. The classification of genera into
tribes would leave the family Enterobacteriaceae intact at the family level but create 7 to 9
tribes based upon the evolutionary work of Adeolu et al. (98). These tribes could include the
following: tribe 1, Escherichieae (revised definition); tribe 2, Erwinieae (revised definition);
tribe 3, Pectobacterieae (tribe nov.); tribe 4, Yersinieae (tribe nov.); tribe 5, Hafneae (tribe
nov.); tribe 6, Proteeae (revised definition); tribe 7, Budviceae (tribe nov.); tribe 8,
Plesiomonadeae (tribe nov.); and tribe 9, Thorselleae (tribe nov.).
(ii) Proposal 2. Classification of genera into subfamilies. The classification of gen-
era into subfamilies is similar to that of proposal 1 but uses the taxonomic rank of subfamily
instead of tribes to group all genera.
(iii) Proposal 3. Classification of Enterobacteriaceae into “groups.” The classification
of Enterobacteriaceae into “groups” would use nonscientific names to group genera that are
close together in an evolutionary sense. Such a system could include the following: group 1,
core genera (Escherichia-Shigella-Salmonella-Citrobacter-Enterobacter-Klebsiella-Cronobacter
and others; group 2, Erwinia-Pantoea group; group 3, Pectobacterium group; group 4,
Yersinia-Serratia group; group 5, Hafnia-Edwardsiella group; group 6, Proteus-Providencia-
Morganella group; group 7, Budvicia-Leminorella-Pragia group; group 8, Plesiomonas group;
group 9, Thorsellia-Coetzeea group.
(iv) Proposal 4. Nonclassification system. The nonclassification system would sim-
ply be an alphabetical listing of genera in the family but with the type genus listed

first, similar to what was published in Bergey’s Manual of Systematic Bacteriology, 2nd
edition.
Issue: Species Identification in the Modern Era for Clinical Laboratories

From conventional to commercial to molecular approaches. Despite all the
technological advances over the past 20 years, phenotypic identification currently
remains the gold standard for identification of microorganisms (266). Both
semiautomated and automated commercial testing platforms that provide both an
identification and a susceptibility test result still carry the major workload in volume in
the United States and elsewhere in diagnostic settings. Many molecular approaches are
available to aid microbiologists in achieving final identifications when initial test results
provide correct identification with low probabilities or no identification at all (267, 268).
Advances continue to be made in this arena. One investigation has proposed that
broad-range dnaJ PCR and sequencing can produce a higher resolution of species
identification within the family than 16S rRNA gene sequencing (269). The only major
impediment is the Escherichia-Shigella group, which is one species at the genomic level.
Techniques versus a plethora of taxa: problematic issues. The relative explosion in the
number of new enterobacterial species isolated from human samples or clinical infections
over the past decade brings with it a number of clinical decisions for microbiologists
regarding how far and to what extent an isolate should be characterized prior to generating a
final identification. The relevancy of modern taxonomy for clinical laboratories has also been
the subject of some questions and controversy (270). One of the difficulties microbiologists
face with the molecular taxonomic revolution in the current era is that newly described
species are typically “phenotypically light” in regard to biochemical characteristics which are
based upon gene expression and not gene structure (271). Phenotypic methods remain the
mainstay for most laboratories in regard to bacterial identifications as of 2020 (266). Thus, as
modern taxonomy drives us forward, how do laboratories deal with the onslaught of new
genera and species whether phenotypic or molecular methods are used?
The first issue microbiologists face is keeping abreast of all the new enterobacterial
species, including classification changes. A few years ago, one had several options in
this area. Three journals, International Journal of Systematic and Evolutionary
Microbiology, Systematic and Applied Microbiology, and Antonie van Leeuwenhoek,
published the vast majority of new species. Today, while these journals still publish the
majority of new proposals, many other journals now routinely publish articles on new

taxa. This makes the time and effort needed to review all of these periodicals more
demanding. Microbiologists can also search PubMed (https://pubmed.ncbi.nlm.nih .
gov/) for new groups using key words or terms, but this can also be fairly complicated
and articles can be missed. The website LPSN—List of Prokaryotic Names with Standing
in Nomenclature (https://www.bacterio.net/) is useful, but there are no easy methods to
search for new taxa of clinical relevancy for specific ranks such as families. A second
issue with the LPSN is that only validated species are published, and currently up to 40%
of recently published species have not been validated according to ICNP rules. Finally,
two journals routinely publish updates on newly proposed species, Diagnostic
Microbiology and Infectious Diseases (since 2014) and Journal of Clinical Microbiology (
since 2017). While the articles published in both journals differ slightly in scope, length,
and structure, these are excellent sources for microbiologists to review for important
updates (65, 272).
A second issue is identification, phenotypic versus molecular. For the vast majority of
common infections such as those originating from the urinary tract (E. coli, P. mirabilis),
simple and inexpensive phenotypic tests should provide a definitive identification. In
some instances, even rapid spot tests may be applicable. For more-difficult-to-identify
or unusual microorganisms not often seen in the laboratory, such approaches will not
be sufficient. In these cases, molecular approaches are needed, such as 16S ribosomal
gene sequencing, MALDI-TOF, and WGS. Use of molecular approaches for a final
identification must be counterbalanced with need, as these techniques are more

expensive and require skilled personnel and sophisticated instrumentation with

maintenance contracts that are more costly (262). For newly published groups or
species, the majority of publications are generated on the basis of a single type strain
(65). This has several ramifications. Commercial panels or platforms will typically not
include new taxa without a data matrix of 25 or more strains. For MALDI-TOF users, this
will require laboratories to obtain the type strain from an international type culture
collection (not inexpensive) and then add the spectral analysis to the manufacturer’s
database. However, single species strains may not be enough to recognize all isolates
or variants of a recently described taxon. For the present, it seems unwise to
immediately attempt to identify new infectious agents without recognizable
biochemical markers adaptable to multiple formats for phenotypic identifications (270).
Molecular identifications should be restricted to situations where the data generated
are both relevant and required. Examples of situations where such analyses are needed
include the following: (i) where specific species identification is important in a patient
prognosis, diagnosis, or treatment, (ii) in outbreak disease investigations, (iii) for
description of new species, infectious agents, or pathotypes (such as STEC or
PLAassociated K. pneumonia), (iv) in epidemiologic or environmental surveillance
surveys, and (v) in publications defining unique infectious disease syndromes,
pathogenic characteristics, or unusual biochemical or metabolic properties.
CONCLUSIONS
Despite the voluminous number of publications, periodicals, and textbooks on
members of the family Enterobacteriaceae, we are just in our infancy in understanding
the scope, magnitude, and impact of this group on the world around us. Molecular
technology, taxonomy, and phylogenetic analysis have ushered in a new era such that
28 new validated genera and more than 200 new species have been described since
2005 (Table 2). This trend will continue to increase and evolve for the foreseeable
future, as witnessed by the recent description of Intestinirhabdus alba isolated from the
gut of plastic-eating larvae (273). Some species such as E. albertii (189) have already
been found to be important gastrointestinal pathogens in the Far East, while
reclassified taxa such as K. aerogenes are being redefined by new epidemiologic criteria
as important pathogens (264). Determination of the taxon frequency, clinical
significance, and defining markers of these recently described species seems daunting,
and our success in these endeavors remains to be determined.
What might eventually be of greater consequence is increasing our understanding

of how enterobacteria affect the biosphere outside of human hosts. Climate changes
will bring on a specter of new infectious diseases (274). Global warming will extend the
geographic range of many insects carrying enterobacterial species with them. As
vectors, insects could promote new and devastating diseases to trees, shrubs, flowers,
and consumable fruits and vegetables (Table 5). Whether we will be able to detect and
treat such an onslaught of vegetative pathogens remains to be seen.
The family or divisional constructs will continue to challenge a variety of scientific
professionals for both their positive benefits and their negative impact for decades to
come. The hope is that technologic developments and scientific advances will occur at
speeds able to adapt to our changing and evolving world.
ACKNOWLEDGMENT
This review is dedicated to the memory of John James Farmer III (Jim), a dedicated public
health professional who worked at the Centers for Disease Control and Prevention (CDC) for
28 years. Jim served as Chief of the Enterics Reference Laboratory for most of this time. Along
with Don Brenner and many other researchers at the CDC, he isolated, identified, and named
many of the genera and species listed in the present review, including Cronobacter
(Enterobacter) sakazakii, Proteus penneri, Ewingella americana, Moellerella wisconsensis,
Escherichia fergusonii, Enterobacter asburiae, Enterobacter hormaechei, and many others. In
1985, along with numerous CDC colleagues, Jim published a 30-page article describing the
biochemical characteristics, clinical features, and

diagnostic characteristics of new members of the family Enterobacteriaceae that became a

cornerstone reference for many microbiologists over many years.
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J. Michael Janda received his undergraduate Sharon L. Abbott received her Bachelor of
degree from Loyola University (Westchester), Arts degree from California State University
his M.S. in Microbiology from California State at Chico. For over 35 years she worked in the
University-Los Angeles, and his Ph.D. in Microbial Diseases Laboratory Branch (MDL)
Microbiology and Immunology from UCLA. of the California Department of Public
From 1979 to 1986, he was first a Health, primarily in enteric bacteriology. In
postdoctoral fellow (ABMM) at The Mount 1990, she became Supervisor of the Enterics
Sinai Medical Center and then Assistant/ Unit and served in that position for almost
Associate Professor of Clinical Microbiology 15 years. After retiring from the State, she
there, where he was Assistant Director of the was employed by the University of California
Microbiology Laboratory and Coordinator of at Berkeley as a Training Coordinator for a
the ABMM program. From 1986 to 2011, he was Section Chief and then Chief of Postdoctoral Fellowship program at MDL. Her research focus has centered on

the Microbial Diseases Laboratory Branch, California Department of Public the identification of enteric bacteria, particularly Aeromonas species, and the
Health. Since 2015, he has been the Laboratory Director for Kern County. He is development of in vitro pathogenicity assays.
an Associate Editor of Diagnostic Microbiology and Infectious Diseases and is
on the editorial board of Clinical Microbiology Reviews. Past activities include
membership in Bergey’s Trust and on two subcommittees of the International
Committee on the Systematics of Prokaryotes (ICSP). Over his career of more
than 35 years, Dr. Janda has focused on the study of bacterial gastroenteritis,
enteric bacteriology, aquatic pathogens, and microbial taxonomy, with
particular emphasis on the genera Aeromonas, Plesiomonas, and Vibrio and
the family Enterobacteriaceae.

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Traducido del inglés al español - www.onlinedoctranslator.

El rostro cambiante de la familiaenterobacterias (Pedido:

J. Michael Janda,aSharon L. AbbottB

BReno, Nevada, Estados Unidos

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Extraintestinal Diseases and Infectious Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

SUMMARY The family Enterobacteriaceae ha sufrido cambios morfogenéticos significativos en

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N o El grupo colectivo de bacterias procarióticas definidas actualmente ha tenido un mayor

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Traditional Phenotypic and Molecular Markers of the Family

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TABLE 1 Traditional markers associated with inclusion in the family Enterobacteriaceae

Characteristic Trait Typical reaction or value Exceptions

FRaras excepciones de cepas.

asociado exclusivamente a esta familia se encuentra el antígeno común enterobacteriano o

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Major Clinical and Public Health Aspects of the Family

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represented by several groups, including Salmonella, Escherichia coli (O157, non-O157),

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Abril 2021 Volumen 34 Edición 2 e00174-20 cmr.asm.org5

THE FAMILY ENTEROBACTERIACEAE

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Genus and Species Expansion (1980 to 2020)

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TABLA 2Expansión de géneros y especies en la familia.enterobacterias,1974-2020

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Human Disease Classification Human Disease Classification

Cedecea (3)/(0) davisae 1 2 No Unnamed HGs

Citrobacter (3)/(12) amalonaticus 1 1 No braakii 1 1 No

Edwardsiella (3)/(2) hoshinae 2 2 No anguillarum 2 2 No Fish/eel

Enterobacter (8)/(34) aerogenes 1 1 Yes asburiae 1 1 No

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Escherichia (5)/(2) coli 1 1 sí albertii 1 1 No

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Humano Enfermedad Clasificación Humano Enfermedad Clasificación

Ewingella (1)/(0) americana 1 1 No

Klebsiella (6)/(13) neumonía 1 1 No aerogenes 1 1 No E. aerogenes

Kluyvera (2)/(2) ascorbata 1 1 No “cóclea” 2 2 sí k intermedia

Moellerella (1)/(0) Wisconsin No

Proteo (4)/(7) mirabilis 1 1 No alimentorum 2 2 No

Providencia (4)/(6) alcalifaciens 1 No burhodogranariea 2 2 No

Serratia (7)/(12) ficaria 1 No aquatilis 2 2 No

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Tatumella (1)/(5) ptyseos 1 No citrea 2 2 No

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NOMENCLATURE AND TAXONOMY

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Nomenclature anomalies in the family Enterobacteriaceae. With the emergence of

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Unlike bacterial nomenclature, there is no formal body or international organization that